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The clinical and cost-effectiveness of neurostimulation for relief of chronic/neuropathic pain: an evidence based review
A WEST MIDLANDS COMMISSIONING SUPPORT UNIT REPORT
Report commissioned by: West Midlands Specialised Commissioning Team
Produced by: West Midlands Commissioning Support Unit (WMCSU)
Unit of Public Health, Epidemiology & Biostatistics
The University of Birmingham
Authors: Janine Dretzke
Angela Meadows
Anne Fry-Smith
David Moore
Correspondence to: Janine Dretzke
Unit of Public Health, Epidemiology & Biostatistics
University of Birmingham
Edgbaston
Birmingham
B15 2TT
Tel +44 (0)121 414 7850
Date completed: 26 May 2011
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West Midlands Commissioning Support Unit The West Midlands Commissioning Support Unit (WMCSU) reviews evidence and
analyses data to produce up-to-date intelligence for health practitioners, policy-
makers and researchers involved in healthcare commissioning and policy
development. This report is from our series of rapid evidence reviews examining the
clinical effectiveness and cost-effectiveness of health care interventions.
ACKNOWLEDGEMENTS We thank Ellen Sainsbury and Ann Massey for administrative support, and Zulian Liu
for data extraction and translation of a Chinese paper. We also thank Kristina Routh
for help with defining the question and Wendy Greenheld for preliminary input into
the section on back pain.
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Abbreviations AD Anaesthesia dolorosa
AE Adverse event
BDI Beck Depression Inventory
BPI Brief Pain Inventory
CES Cranial electrotherapy stimulation
CI Confidence interval
CMM Conventional medical management
CRPS Complex regional pain syndrome
DBS Deep brain stimulation
ELF-PEMF Extreme low-frequency pulsed electromagnetic field stimulation
EQ-5D EuroQol -5D (generic preference-based instrument of measuring health in five different dimensions)
FBSS Failed back surgery syndrome
HRQoL Health-related quality of life
HTA Health Technology Assessment
IASP International Association for the Study of Pain
ICER Incremental cost-effectiveness ratio
IHS International headache society
IMMPACT The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus group
ITT Intention-to-treat
LBP Lower back pain
MCS Motor cortex stimulation
MIDAS Migraine Disability Assessment Scale
MS Multiple sclerosis
MPQ McGill Pain Questionnaire
MSQoL-54 Multiple Sclerosis Quality of Life-54 scale
NRS Nerve root stimulation
NS Neurostimulation
ODI Oswestry Disability Index
ON Occipital neuralgia
ONB Occipital nerve block
ONS Occipital nerve stimulation
PEMF Pulsed electromagnetic field stimulation
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Abbreviations PENS Percutaneous electrical nerve stimulation
PNS Peripheral nerve stimulation
PRI Pain Rating Index
PT Physical therapy
QALY Quality-adjusted life year
RCT Randomised controlled trial
rTMS Repetitive transcranial magnetic stimulation
SAE Serious adverse event
SCI Spinal cord injury
SCS Spinal cord stimulation
SF-36 Short Form Health Survey 36
SF-MPQ Short Form McGill Pain Questionnaire
sTMS Single-pulse transcranial magnetic stimulation
TENS Transcutaneous electrical nerve stimulation
TN Trigeminal neuralgia
TDP Trigeminal deaffentiation pain
TNP Trigeminal neuropathic pain
tDCS Transcranial direct current stimulation
TMS Transcranial magnetic stimulation
VAS Visual Analogue Scale
WMSCT West Midlands Specialised Commissioning Team
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Glossary of Terms Acute pain Pain related to injury which resolves during an
appropriate healing period.
Allodynia Pain due to a stimulus which does not normally provoke pain.
Anaesthesia dolorosa
Pain in an area or region which is anaesthetic.
Analgesia
Absence of pain in response to stimulation which would normally be painful.
Chronic pain Pain that persists for more than 3 months or that outlasts the healing process.
Central pain
Pain initiated or caused by a primary lesion or dysfunction in the central nervous system.
Dysaesthesia An unpleasant abnormal sensation, whether spontaneous or evoked .
Hyperalgesia
Increased pain from a stimulus that normally provokes pain.
Hyperaesthesia
Increased sensitivity to stimulation.
Hypoesthesia
Decreased sensitivity to stimulation.
Neuralgia
Pain in the distribution of a nerve or nerves.
Neuropathic pain
Pain initiated or caused by a primary lesion or dysfunction in the nervous system.
Nociceptive Pain
Pain arising from activation of nociceptors.
Nociceptor
A high-threshold sensory receptor of the peripheral somatosensory nervous system that is capable of transducing and encoding noxious stimuli.
Noxious stimulus A stimulus that is damaging or threatens damage to normal tissues.
Pain
An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.
Paraesthesia
An abnormal sensation, whether spontaneous or evoked.
Terms according to the International Association for the Study of Pain (IASP) classifications
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EXECUTIVE SUMMARY Background Chronic pain is defined as persisting beyond normal tissue healing time, which is
around three months. It can be associated with varying degrees of disability and can
impact negatively on quality of life. Neuropathic pain is defined as pain initiated or
caused by a primary lesion or dysfunction in the nervous system. A substantial
number of patients with chronic and/or neuropathic pain do not respond to
conventional medication or physical and psychological therapies, or find that these
do not give sufficient relief from pain. Previous alternative management included
surgical lesions (neurotomies), however this has been largely abandoned in favour of
neurostimulation therapies, which are being increasingly used across a variety of
pain indications.
Aim The aim of this report was to assess the clinical effectiveness, safety and cost-
effectiveness of neurostimulation for the treatment of chronic/neuropathic pain,
specifically failed back surgery syndrome (FBSS), chronic non-specific low back pain,
back pain after spinal cord injury (SCI), trigeminal pain, complex regional pain
syndrome (CRPS), headache disorders and neuropathic pain associated with
multiple sclerosis (MS).
Methods Systematic literature searches were undertaken in the major bibliographic databases
(including Cochrane Library (CDR, DARE, HTA Database, EED and CENTRAL),
MEDLINE and EMBASE) to identify systematic reviews and cost-effectiveness
studies assessing the clinical and cost-effectiveness of different types of
neurostimulation in the treatment of neuropathic/chronic pain. These searches were
supplemented by searches for randomised controlled trials (RCTs) in order to identify
RCTs not included in relevant systematic reviews or published after the completion
date of relevant reviews. Safety information was sought from within identified reviews
and RCTs.
Results Thirty-nine systematic reviews and/or economic evaluations and 47 RCTs were
identified. These reported on a total of 10 types of neurostimulation, variously applied
in the different indications. The evidence was of variable quality; methodologically
well-conducted systematic reviews often included only case-series evidence, whilst
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many RCTs had methodological flaws or lack of methodological detail associated
with them, with blinding a particular issue. Many studies suggested that there was a
benefit of neurostimulation over sham-stimulation or other alternatives, but the
evidence was not always convincing. Statistically significant results in favour of
neurostimulation were found for spinal cord stimulation (SCS) in FBSS and CRPS,
percutaneous electrical nerve stimulation (PENS) in chronic low back pain, and non-
invasive brain stimulation in pain after SCI, trigeminal pain, headache and
neuropathic pain in MS. It should be noted that significant differences were not
necessarily consistent across all outcomes or time-points reported, and that follow-up
was often insufficient. Many studies found no significant differences. Quality of life
was generally not reported.
Adverse event data were reported inconsistently across studies and it was not
possible to give an overall estimate of frequency of different adverse events. More
serious side effects are likely to be associated with more invasive techniques. Deaths
have been reported as a (rare) adverse event with deep brain stimulation (DBS).
Adverse events for transcutaneous electrical nerve stimulation (TENS), PENS and
non-invasive brain stimulation were generally minor.
Economic evaluations were identified only for SCS in FBSS and CRPS. Those on
FBSS consistently found that SCS is likely to be cost-effective over a 15 year time
horizon. The findings for CRPS are less convincing and there is a large discrepancy
between results from different evaluations. It is possible that CRPS may be cost-
effective in the long-term.
Conclusions
The evidence suggests that some types of neurostimulation are likely to be effective
in some pain indications, notably SCS in FBSS and CRPS, and TENS, PENS and/or
non-invasive forms of neurostimulation in chronic low back pain, pain after SCI and
some types of headache. SCS in FBSS, and possible CRPS, appears to be cost-
effective. The evidence is very limited for trigeminal pain and neuropathic pain in MS.
Ideally, large well-designed RCTs would be needed to confirm some of these results
and to fill any current gaps in the evidence.
This is only a very brief synopsis of the findings of this report. Readers are strongly
encouraged to read the whole report, or the whole of relevant chapters, and to
consult the relevant literature cited.
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Contents 1 AIM OF THE REVIEW .................................................................................................... 11 2 BACKGROUND .............................................................................................................. 11
2.1 Chronic and/or neuropathic pain ............................................................................. 11 2.2 Neurostimulation for pain relief ................................................................................ 13 2.3 Overview of different types of neurostimulation ...................................................... 14
3 OBJECTIVES OF THE REVIEW .................................................................................... 17 4 METHODS ...................................................................................................................... 19
4.1 Search strategy ........................................................................................................ 19 4.2 Making inclusion/exclusion decisions ...................................................................... 20 4.3 Quality assessment and data extraction strategy .................................................... 21 4.4 Data handling and synthesis ................................................................................... 21
5 Chronic Low Back pain ................................................................................................... 22 5.1 Description of the underlying health problem .......................................................... 22 5.2 Epidemiology ........................................................................................................... 23 5.3 Treatment ................................................................................................................ 24 5.4 Quantity and quality of evidence ............................................................................. 25 5.5 Failed back surgery syndrome ................................................................................ 28
5.5.1 Spinal cord stimulation for failed back surgery syndrome ............................... 28 5.5.2 Deep brain stimulation for failed back surgery syndrome ............................... 30 5.5.3 Conclusion failed back surgery syndrome ....................................................... 31
5.6 Non-specific chronic low back pain ......................................................................... 32 5.6.1 Deep brain stimulation for non-specific chronic low back pain ........................ 32 5.6.2 Transcutaneous electrical nerve stimulation for non-specific chronic low back
pain .................................................................................................................. 32 5.6.3 Percutaneous electrical nerve stimulation for non-specific chronic low back
pain .................................................................................................................. 35 5.6.4 Cranial electrotherapy stimulation for non-specific chronic low back pain ...... 36 5.6.5 Conclusion non-specific chronic low back pain ............................................... 39
5.7 Back pain resulting from spinal cord injury .............................................................. 40 5.7.1 Spinal cord stimulation for back pain resulting from spinal cord injury ............ 40 5.7.2 Deep brain stimulation for back pain resulting from spinal cord injury ............ 40 5.7.3 Motor cortex stimulation for back pain resulting from spinal cord injury .......... 41 5.7.4 Transcutaneous electrical nerve stimulation for back pain resulting from spinal
cord injury ........................................................................................................ 42 5.7.5 Non-invasive brain stimulation (rTMS, tDCS, CES) for back pain resulting from
spinal cord injury .............................................................................................. 42 5.7.6 Conclusion back pain resulting from spinal cord injury ................................... 45
5.8 Safety ....................................................................................................................... 46 5.9 Cost-effectiveness ................................................................................................... 51 5.10 Discussion ............................................................................................................... 54
6 Trigeminal neuropathic and deafferentation pain ........................................................... 58 6.1 Description of the underlying health problem .......................................................... 58 6.2 Epidemiology ........................................................................................................... 60 6.3 Treatment ................................................................................................................ 61 6.4 Quantity and quality of evidence ............................................................................. 64 6.5 Deep brain stimulation for trigeminal neuropathic/deafferentation pain .................. 65 6.6 Motor cortex stimulation for trigeminal neuropathic/deafferentation pain ................ 65 6.7 Repetitive transcranial magnetic stimulation for trigeminal
neuropathic/deafferentation pain ............................................................................. 67 6.8 Conclusion trigeminal neuropathic/deafferentation pain ......................................... 68 6.9 Safety ....................................................................................................................... 68 6.10 Cost-effectiveness ................................................................................................... 70 6.11 Discussion ............................................................................................................... 70
7 Complex regional pain syndrome ................................................................................... 71 7.1 Description of the underlying health problem .......................................................... 71 7.2 Epidemiology ........................................................................................................... 71
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7.3 Treatment ................................................................................................................ 72 7.4 Quantity and quality of evidence ............................................................................. 73 7.5 Spinal cord stimulation for complex regional pain syndrome .................................. 74 7.6 Motor cortex stimulation for complex regional pain syndrome ................................ 76 7.7 Repetitive transcranial magnetic stimulation for complex regional pain syndrome . 77 7.8 Transcutaneous electrical nerve stimulation for complex regional pain syndrome . 77 7.9 Conclusion complex regional pain syndrome .......................................................... 78 7.10 Safety ....................................................................................................................... 79 7.11 Cost-effectiveness ................................................................................................... 80 7.12 Discussion ............................................................................................................... 84
8 Headache ........................................................................................................................ 86 8.1 Description of the underlying health problem .......................................................... 86 8.2 Epidemiology ........................................................................................................... 87 8.3 Treatment ................................................................................................................ 88 8.4 Quantity and quality of evidence ............................................................................. 89 8.5 Migraine ................................................................................................................... 92
8.5.1 Occipital nerve stimulation for migraine ........................................................... 92 8.5.2 Transcutaneous electrical nerve stimulation for migraine ............................... 94 8.5.3 Pulsed electromagnetic field stimulation for migraine ..................................... 96 8.5.4 Transcranial magnetic stimulation for migraine ............................................... 99 8.5.5 Cranial electrotherapy stimulation for migraine ............................................. 100 8.5.6 Percutaneous electrical nerve stimulation for migraine ................................. 101 8.5.7 Conclusion migraine ...................................................................................... 103
8.6 Tension-type headache ......................................................................................... 104 8.6.1 Transcutaneous electrical nerve stimulation for tension-type headache ...... 104 8.6.2 Pulsed electromagnetic field stimulation EMF for tension-type headache .... 105 8.6.3 Cranial electrotherapy stimulation for tension-type headache ...................... 105 8.6.4 Percutaneous electrical nerve stimulation for tension-type headache .......... 105 8.6.5 Conclusion tension-type headache ............................................................... 106
8.7 Cluster headache ................................................................................................... 107 8.7.1 Deep brain stimulation for cluster headache ................................................. 107 8.7.2 Occipital nerve stimulation for cluster headache ........................................... 108 8.7.3 Pulsed electromagnetic field stimulation for cluster headache ...................... 109 8.7.4 Conclusions cluster headache ....................................................................... 110
8.8 Occipital neuralgia ................................................................................................. 111 8.8.1 Occipital nerve stimulation for occipital neuralgia.......................................... 111 8.8.2 Conclusion occipital neuralgia ....................................................................... 111
8.9 Other headache disorders ..................................................................................... 112 8.9.1 Transcutaneous electrical nerve stimulation for other headache disorders .. 112 8.9.2 Occipital nerve stimulation for other headache disorders ............................. 112 8.9.3 Conclusion other headache disorders ........................................................... 113
8.10 Safety ..................................................................................................................... 114 8.11 Cost-effectiveness ................................................................................................. 119 8.12 Discussion ............................................................................................................. 119
9 Neuropathic pain associated with MS ........................................................................... 122 9.1 Description of the underlying health problem ........................................................ 122 9.2 Epidemiology ......................................................................................................... 122 9.3 Treatment .............................................................................................................. 123 9.4 Quantity and quality of evidence ........................................................................... 123 9.5 Spinal cord stimulation for neuropathic pain associated with MS ......................... 124 9.6 Transcranial direct current stimulation for neuropathic pain associated with MS . 124 9.7 Transcutaneous electrical nerve stimulation for neuropathic pain associated with
MS .......................................................................................................................... 125 9.8 Conclusion neuropathic pain in MS ....................................................................... 125 9.9 Safety ..................................................................................................................... 126 9.10 Cost-effectiveness ................................................................................................. 126 9.11 Discussion ............................................................................................................. 126
10 Any type of neuropathic pain ........................................................................................ 127 11 Discussion ..................................................................................................................... 132 12 CONCLUSIONS ............................................................................................................ 139
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13 Appendices ................................................................................................................... 140 14 References .................................................................................................................... 236 Tables Table 1 Types of neurostimulation .......................................................................................... 14Table 2 Inclusion and exclusion criteria................................................................................... 20Table 3 Epidemiological data back pain .................................................................................. 24Table 4 Evidence identified for neurostimulation in back pain ................................................ 27Table 5 Trigeminal neuralgia classification ............................................................................. 60Table 6 Epidemiological data TNP and TDP ........................................................................... 61Table 7 Evidence on neurostimulation for TNP or TDP .......................................................... 64Table 8 Epidemiological data CRPS ....................................................................................... 72Table 9 Evidence on neurostimulation for CRPS .................................................................... 73Table 10 Epidemiological data headache ............................................................................... 88Table 11 Overview of evidence identified for headache.......................................................... 91Table 12 Epidemiological data pain in MS ............................................................................ 123Table 13 Evidence on neurostimulation for neuropathic pain associated with MS ............... 124Table 14 Systematic reviews of neurostimulation for any type of chronic/neuropathic pain . 128Table 15 Characteristics of included systematic reviews on back pain ................................ 178Table 16 Quality of included systematic reviews: back pain ................................................. 180Table 17 Primary evidence covered in systematic reviews of SCS for FBSS ....................... 188Table 18 Characteristics of RCTs for back pain .................................................................... 189Table 19 Quality RCTs: back pain ......................................................................................... 191Table 20 Critical appraisal of cost-effectiveness models: FBSS ........................................... 194Table 21 Characteristics of included systematic reviews: TNP and TDP ............................. 197Table 22 Quality of included systematic reviews: TNP and TDP .......................................... 197Table 23 Characteristics of included RCTs: TNP and TDP................................................... 198Table 24 Quality of included RCTs: TNP and TDP ............................................................... 199Table 25 Characteristics of included systematic reviews: CRPS .......................................... 201Table 26 Quality of included systematic reviews: CRPS....................................................... 202Table 27 Characteristics of included RCTs: CRPS ............................................................... 205Table 28 Quality of included RCTs: CRPS ............................................................................ 206Table 29 Quality of cost-effectiveness studies: CRPS .......................................................... 209Table 30 Characteristics of included systematic reviews: headache .................................... 214Table 31 Quality of included systematic reviews: headache ................................................. 215Table 32 Characteristics of included RCTs: headache ......................................................... 219Table 33 Quality of included RCTs: headache ...................................................................... 222Table 34 Characteristics of included systematic reviews: neuropathic pain in MS ............... 232Table 35 Quality of included systematic reviews: neuropathic pain in MS............................ 233Table 36 Characteristics of included RCTs: neuropathic pain in MS .................................... 234Table 37 Quality of included RCTs: neuropathic pain in MS ................................................. 235
Figures Figure 1 Treatment algorithm for TNP and TDP ..................................................................... 63
Appendices Appendix 1 Search strategies ................................................................................................ 140 Appendix 2 Critical appraisal checklists ................................................................................ 174 Appendix 3 Back Pain............................................................................................................ 178 Appendix 4 Trigeminal neuropathic and deafferentation pain ............................................... 197 Appendix 5 Complex regional pain syndrome ....................................................................... 201 Appendix 6 Headache ........................................................................................................... 214 Appendix 7 Neuropathic pain in MS ...................................................................................... 232
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1 AIM OF THE REVIEW The aim of this report was to (i) review the evidence for the clinical and cost-
effectiveness of neurostimulation techniques for selected pain indications (chronic
low back pain, including failed back surgery syndrome and pain after spinal cord
injury, trigeminal pain, complex regional pain syndrome, headache disorders and
neuropathic pain associated with MS); this was based on a review of existing
systematic reviews and cost-effectiveness studies, supplemented by RCT evidence
where appropriate, and (ii) to map the available evidence on neurostimulation for any
type of chronic/neuropathic pain in order to highlight any evidence for pain indications
not covered by (i). This report was commissioned by the West Midlands Specialised
Commissioning Team (WMSCT) and built on a previous report, which mapped out
the evidence relating to neurostimulation in all health-related areas (not restricted to
pain).1
2 BACKGROUND It is pertinent to begin the report by giving a brief overview of chronic and neuropathic
pain, the use of neurostimulators for pain relief and an overview of the different types
of neurostimulation.
2.1 Chronic and/or neuropathic pain Pain is defined by the International Association for the Study of Pain (IASP) as “an
unpleasant sensory and emotional experience associated with actual or potential
tissue damage, or described in terms of such damage”.2 Chronic pain is further
defined as pain persisting beyond normal tissue healing time, which is assumed to be
three months.2,3 Chronic pain is accompanied by physiological and psychological
changes such as sleep disturbances, irritability, medication dependence and frequent
absence from work.3,4 People with chronic pain may continue to experience pain
despite conventional medical management (CMM) and complete relief is rare.5
Estimates of the prevalence of chronic pain range from 2% to 50%.3 Likely
explanations for this substantial variation include the use of poor measurement tools,
inadequate study sizes and heterogeneity in the types of pain-related diagnoses
assessed.6
In addition to classification according to length of time (acute or chronic pain), pain
can be classified as nociceptive or neuropathic.7 In practice, both types of pain can
coexist.7 Nociceptive pain, or tissue damage pain, results from mechanical, chemical
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or thermal stimulation of nociceptors, for example after surgery or trauma, or is
associated with degenerative processes such as arthritis.7
Neuropathic pain, or nerve damage pain, is defined by the IASP as pain initiated or
caused by a primary lesion or dysfunction in the peripheral or central nervous
system.2 Symptoms are very different to those associated with nociceptive pain and
include spontaneous pain (in the absence of stimulus) and abnormal responses to
non-painful or painful stimuli. The pain is sometimes described as shooting or
burning, and can include sensations such as tingling, pins and needles or abnormal
thermal sensations.8 Four broad classes of neuropathic pain are recognised: (i)
peripheral nervous system focal and multifocal lesions (e.g. trigeminal neuralgia,
post-herpetic neuralgia), (ii) peripheral nervous system generalised polyneuropathies
(e.g. diabetes mellitus, acute inflammatory polyneuropathy), (iii) central nervous
system lesions (spinal cord injuries, multiple sclerosis) and (iv) complex neuropathic
disorders (complex regional pain syndrome types I and II).8
Neuropathic pain is usually a chronic condition that can be difficult to treat, as
conventional analgesics do not typically provide effective relief; it is usually
associated with greater impairment of quality of life compared with other types of
chronic pain.8 Previously, alternative management included surgical lesions
(neurotomies), however this has been largely abandoned in favour of
neurostimulation therapies, which are being increasingly used across a variety of
chronic pain indications.9
The following chronic pain indications of both neuropathic and/or nociceptive origin
are included in this report (see section 3 for rationale for selecting pain indications):
• Chronic low back pain
o Failed back surgery syndrome (FBSS): neuropathic pain (may include
elements of nociceptive pain)
o Chronic low back pain (non-specific): nociceptive and/or neuropathic
o Back pain resulting from spinal cord injury: neuropathic pain
• Trigeminal neuropathic and deafferentation pain: neuropathic pain
• Complex regional pain syndrome (CRPS): neuropathic pain
• Neuropathic pain associated with MS
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Headache is pain anywhere in the region of the head or neck. It can be a symptom of
a number of different conditions of the head and neck. It has its own classification,
which includes types of nociceptive pain, neuropathic pain, mixed
nociceptive/neuropathic pain and those which are neither. There is for example
currently ongoing debate regarding the pathophysiology of migraine pain (see for
example Chakravarty & Sen 201010). So headache is best classified as a separate
entity, even though there is clear overlap with some categories of nociceptive and
neuropathic pain. The main headache disorders included in this report are: migraine,
tension-type headache, cluster headache and occipital neuralgia.
A more detailed description of the above pain conditions will be provided in
subsequent chapters.
2.2 Neurostimulation for pain relief Neurostimulation involves the alteration of neural activity via the application of
electrical or magnetic impulses. In the crudest form, the practice dates back
thousands of years with current from electric fish being used to treat pain and other
conditions.11,12 An increasing range of devices and techniques are now available,
including both implantable and non-invasive procedures, and both the range of
technologies and the market are expanding rapidly.13 The mechanisms of pain relief
achieved with neurostimulation are not well understood, but are likely to involve a
number of different pathways including modulation of endogenous opioid production,
inhibition of the transmission of pain signals and/or alterations in pain perception.9,14
There is some evidence that optimal stimulation parameters may vary for pain of
different aetiologies,15 and it is likely that some conditions may respond better to
some kinds of neurostimulation than to others.
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2.3 Overview of different types of neurostimulation Types of neurostimulation can be broadly classified as cranial, spinal or peripheral,
and as invasive or non-invasive. Table 1 lists the different types, whilst brief
descriptions are given below. Table 1 Types of neurostimulation Cranial Spinal Peripheral Invasive Motor cortex
stimulation (MCS) Deep brain stimulation (DBS)
Spinal cord stimulation (SCS)
Peripheral nerve stimulation (PNS, for example occipital nerve stimulation (ONS), trigeminal nerve stimulation) Percutaneous electrical nerve stimulation (PENS) Nerve root stimulation (NRS)
Non-invasive Transcranial magnetic stimulation (TMS) Transcranial direct current stimulation (tDCS) Cranial electrotherapy stimulation (CES)
N/A Pulsed electromagnetic field stimulation (PEMF) Extreme low-frequency pulsed electromagnetic field stimulation (ELF-PEMF) Transcutaneous electrical nerve stimulation (TENS)
Spinal cord stimulation (SCS) In SCS, a number of electrode contacts are inserted near the spinal cord (in the
dorsal epidural space) under local or general anaesthetic. The electrode contacts are
connected via leads to an electrical pulse generator. The ascending and descending
dorsal column fibres and/root fibres are stimulated using different stimulation patterns
to achieve paraesthesia covering the area of pain. If trial stimulation over a 5-7 day
period is successful, the pulse generator is surgically implanted under the skin in the
abdomen, in the buttock are or in the lateral chest wall. In an alternative system, a
radio-frequency receiver is implanted and the power source worn externally with an
antenna over the receiver.3,16
Motor cortex stimulation (MCS) Following a craniotomy, an electrode strip is placed epidurally over the precentral
gyrus. The position is adjusted intra-operatively until test stimulation produces
minimal muscle contractions in the painful area. After closure of the craniotomy, the
electrode cable is externalised for a period of trial stimulation (approximately 3–
7 days). If pain relief is successful, a battery-powered stimulator is then implanted in
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the subclavian subcutaneous tissue and sends impulses to the epidural
electrode.17,18
Deep brain stimulation (DBS) Electrodes are implanted using stereotactic guidance. A parasagittal frontal burr hole
is created through a small incision; this is performed under local anaesthesia with
intravenous sedation as needed. To define the exact target for stimulation, intra-
operative physiological stimulation is required. Once the targets have been identified
with stimulation, permanent electrodes are introduced and the leads externalised
through a stab wound in the scalp for trial stimulation (lasting approximately 5–9
days). If pain relief is successful, the electrodes are connected to an implantable
pulse generator.18
Peripheral nerve stimulation (PNS) Patients initially undergo diagnostic nerve blocks to establish which nerves (e.g.
trigeminal, occipital) participate in the generation of pain. Electrodes are then
inserted under local anaesthetic with fluoroscopic guidance and positioned adjacent
to the nerve chosen as a stimulation target. The electrode is attached to an external
stimulation system for trial stimulation and adjustment. After completion of the trial,
the temporary system is replaced with a permanent implanted generator under
general anaesthetic.19
Percutaneous electrical nerve stimulation (PENS) In percutaneous electrical nerve stimulation (PENS; also called percutaneous
neuromodulation therapy) electrical current is delivered via needles inserted around
or adjacent to the nerves supplying the painful area. PENS is different to
electroacupuncture in that needle placement is based on location of pain, rather than
on Traditional Chinese Medicine theories of energy meridians.20
Transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and cranial electrotherapy stimulation (CES) TMS consists of high-intensity magnetic fields emanating from a wire coil applied to
the scalp, which in turn activate neuronal elements in the underlying regions of the
brain. This can induce changes in brain activity both locally and in more remote
regions. These changes may be long-lasting, particularly with repetitive TMS (rTMS)
as opposed to single-pulse TMS (sTMS). In tDCS, weak direct currents (commonly <
2 mA) are delivered to the brain via scalp electrodes, increasing or decreasing the
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level of cortical excitability.21 CES similarly involves the passage of weak currents
across the head; the current is commonly pulsed and is applied via electrodes
attached to the earlobes or near the ear.22
Pulsed electromagnetic field stimulation (PEMF) A device emitting electromagnetic energy in pulsed bursts is held above the area to
be treated and turned on for a set amount of time. Such devices have been in clinical
use for over 40 years. They have been used for example in the US for the treatment
of slow-healing fractures.23
Transcutaneous electrical nerve stimulation (TENS) Transcutaneous electrical nerve stimulation (TENS) is a non-invasive electrical
therapy that stimulates peripheral nerves via electrodes placed on the surface of the
skin near the area of most intense pain. The technology is simple to use and a wide
variety of units are available for home use. Stimulation parameters can be easily
manipulated to produce different stimulation effects. The two most common
application modes are high- and low-frequency TENS, although other stimulation
modes are also available and in use in clinical practice.24
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3 OBJECTIVES OF THE REVIEW The objectives of this review were to address the clinical effectiveness, cost-
effectiveness and safety of neurostimulation in the following specific pain indications:
• chronic low back pain, including failed back surgery syndrome (FBSS), non-
specific chronic low back pain and back pain after spinal cord injury (SCI)
• trigeminal neuropathic pain (TNP) or trigeminal deafferentation pain (TDP)
• complex regional pain syndrome (CRPS)
• headache (migraine, tension-type headache, cluster headache, occipital
neuralgia and others)
• neuropathic pain associated with multiple sclerosis (MS)
Rationale for choice of pain indications Scoping searches indicated that neurostimulators are used across many pain
indications. A decision to focus on these specific pain indications was determined by
the West Midlands SCT and driven by an attempt to cover those areas in which
commissioners may most likely have to make commissioning decisions. As such, the
pain indications include chronic pain of both neuropathic and nociceptive origin and
different broad areas such as low back pain and headache. We have not
systematically covered all chronic and/or neuropathic pain indications, for which
neurostimulators could be used. It should be noted that for headache, we did not
restrict searches or inclusion by type of headache and we have included all available
evidence. The different types of headache listed above are thus those for which
evidence was available, but it should be noted that this is not an exhaustive list of
headache disorders.
In order to highlight any other areas of pain (not included in the above list) where
neurostimulation may be of importance, a further objective of the review was to
provide a broad overview of the available evidence associated with different types of
neurostimulation treatment for any type of chronic/neuropathic pain.
Rationale for methodological approach Scoping searches indicated that the volume and nature of evidence was likely to vary
significantly for different indications and/or types of neurostimulation. In discussion
with WMSCT, it was decided that the preferred approach was to be consistent and
limit searches to systematic reviews, RCTs and economic evaluations across all
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indications and types of stimulation. We therefore did not attempt to search for all
primary studies (including case-series) for each indication/neurostimulator
combination. Given the breadth of the topic, this would require extensive additional
research. By focussing on systematic reviews (and recent RCTs) we aimed to give
an overview of the volume and nature of available evidence for each
indication/neurostimulator combination and to report on the broad overall direction of
effect.
19
4 METHODS
4.1 Search strategy Separate searches were conducted for (i) systematic reviews, (ii) RCTs published
subsequent to existing systematic reviews, or RCTs published at any time that were
not included in the scope of previous systematic reviews and (iii) economic
evaluations.
Searches for systematic reviews were conducted in the following sources:
• Cochrane Library (CDR, DARE and HTA Database) 2010 Issue 3
• MEDLINE (Ovid) 2009 – 2010
• EMBASE (Ovid) 2009 – 2010
• ARIF database of reviews
• TRIP database
• HTAi Vortal
Text and index terms representing the type of neurostimulation were used and where
possible a methodological filter for reviews was included. The results were scanned
for references that included the various pain relief indications. References within
relevant papers were also scanned. Searches were in the main restricted to 2009 to
August 2010, as searches of earlier literature were conducted as part of a previous
report relating to neurostimulators.1 No language limits were applied.
Searches for randomised controlled trials were conducted in the following databasesi
• Cochrane Library (CENTRAL) 2010 Issue 3
:
• MEDLINE (Ovid) 1950 – July/Aug 2010
• EMBASE (Ovid) 1980 – July/Aug 2010
Text and index terms were used representing the type of neurostimulator and the
pain indications – failed back surgery, low back pain, spinal cord injury, trigeminal
neuralgia, complex regional pain syndrome, headache and neuropathic pain in
multiple sclerosis. A methodological filter for randomised controlled trials was
included in MEDLINE and EMBASE. No date or language restrictions were applied.
i The searches were conducted over a period of two weeks spanning the end of July to beginning August 2010.
20
Specific searches for economic evaluations to supplement those already undertaken
were conducted in Cochrane Library (NHS EED) 2010 Issue 4 and MEDLINE (Ovid)
1950 – Dec 2010. Text and index terms representing the type of neurostimulator and
terms for costs and economic evaluations were used. No date or language
restrictions were applied.
Detailed search strategies for MEDLINE are presented in Appendix 1.
4.2 Making inclusion/exclusion decisions
Studies were included if they met the following criteria:
Table 2 Inclusion and exclusion criteria Inclusion criteria Exclusion criteria
Population For systematic reviews: adults (aged ≥ 18 years) with chronic and/or neuropathic pain. For RCTs: adults (aged ≥ 18 years) with chronic low back pain, FBSS, back pain after spinal cord injury (SCI), CRPS, trigeminal pain, headache or neuropathic pain associated with MS.
For RCTs: adults with any other type of chronic/neuropathic pain; mixed populations where results could not be disaggregated for the specific pain indications.
Intervention Any type of neurostimulation. N/A Comparators Any type of comparator as
specified by the authors, or none. N/A
Outcomes Any, including: Pain relief (immediate and long-term) and time to pain relief; pain recurrence rates and time to pain recurrence; adverse events/ complications/technical failures/ complications of procedure; quality of life; cost-effectiveness.
N/A
Study design
Systematic reviews, cost-effectiveness studies. For the specific pain indications also RCTs.
Narrative reviews, case-series (unless included in a systematic review), studies reporting on aspects of cost that were not full economic evaluations.
N/A=not applicable
For each pain indication, one reviewer assessed papers eligible for
inclusion/exclusion by examining the titles and, where available, abstracts. Full
21
copies of relevant, or potentially relevant, references were obtained for detailed
examination. Final inclusion/exclusion decisions for each indication were made by
one reviewer.
Given that inclusion of studies was limited to systematic reviews, RCTs and
economic evaluations, evidence in the form of narrative reviews was not considered;
as such there are some indication/neurostimulator combinations for which no
evidence is included. Furthermore, whilst studies beyond RCTs in the hierarchy of
evidence were not selected for inclusion, such study designs were considered in this
report where they were included in systematic reviews that met the above inclusion
criteria.
4.3 Quality assessment and data extraction strategy The included reviews were assessed using a modified version of the ARIF Critical
Appraisal Checklist.25 Quality assessment was undertaken for selected RCTs using
an in-house checklist which evaluates the main risks of bias associated with RCTs
based broadly on the criteria outlined by the Cochrane Collaboration.26 Quality
assessment of cost-effectiveness studies was undertaken using the Drummond
checklist (see Appendix 2 for all checklists).27
4.4 Data handling and synthesis Data pertinent to the specific report questions were summarised narratively, using
tables where appropriate. The following chapters are organised according to pain
indication. A brief background is followed by a description of the quantity and quality
of evidence identified and the main clinical effectiveness results for each type of
neurostimulator where evidence was identified. This is followed by safety results and
cost-effectiveness data where applicable. Each pain indication chapter can be read
as a stand-alone chapter, together with the background, methods and discussion
sections.
22
5 CHRONIC LOW BACK PAIN
5.1 Description of the underlying health problem
Chronic low back pain is defined as pain and discomfort, localised below the coastal
margin and above the inferior gluteal folds, with or without referred leg pain, and
persisting for at least 12 weeks.28 Chronic low back pain can be further categorised
into (i) specific spinal pathology, (ii) nerve root pain/radicular pain or (iii) non-specific
low back pain; this latter category is the most common with around 85% of low back
pain not attributable to a specific cause.28
Chronic low back pain represents a major long-term health problem and is
associated with high healthcare utilisation. Consultations for back pain account for
approximately 5% of GP workloads, and approximately one in three patients consult
again within three months of initial presentation; most patients with chronic back pain
continue to suffer some degree of pain or disability one year after initial consultation,
and patients off work with chronic back pain for over a year are unlikely to return to
work in the foreseeable future.29 The condition is also associated with high socio-
economic costs. In addition to its duration and absence of associated pathology,
chronic back pain often has an unpredictable prognosis and may include varying
amounts of disability. It is also often accompanied by psychological problems,
particularly anxiety and depression.3,4
Chronic neuropathic low back pain has been described as pain that is severe, sharp,
stabbing, burning or cold. It is associated with feelings of ongoing numbness, tingling
and weakness, and may be felt travelling along the nerve path from the spine down
to the arms/hands or legs/feet. The aetiology of chronic neuropathic low back pain,
beyond its association with a primary lesion or dysfunction in the peripheral or central
nervous system,2 is poorly understood. A common example of chronic neuropathic
low back pain is failed back surgery syndrome (FBSS), although FBSS also involves
elements of nociceptive pain.3 FBSS is clinically defined as persistent or recurrent
pain, mainly in the lower back and legs, after technically and anatomically successful
lumbosacral spine surgery.3 Spinal cord injury can result in the development of
chronic neuropathic pain below the level of the lesion; this chronic pain in partially or
completely paralysed body regions is also termed ‘central pain’, is considered very
severe and has considerable impact on daily activities and quality of life.30 It is also
often resistant to pharmacologic treatment.30
23
Chronic low back pain has been sub-categorised in this report according to the those
back pain indications specified by the West Midlands Specialised Commissioning
Team and according to those back pain indications identified in the literature where
neurostimulation is frequently used (see previous report, which mapped out the
evidence relating to neurostimulation1). This includes FBSS, chronic low back pain
after spinal cord injury and non-specific chronic low back pain; this latter category is
generally described in the literature as ‘low back pain’ or ‘chronic low back pain’, and
it has been assumed for this report that this refers to the non-specific type. Duration
of low back pain is also variable across studies, but appears generally to have
persisted for >3 months. There were no descriptions regarding the nociceptive and/or
neuropathic nature of the chronic non-specific low back pain.
There are other types of chronic low back pain associated with a specific cause (e.g.
compression fractures, spinal deformities28), for which we have not specifically
sought studies. It is uncertain whether neurostimulation has been investigated in
these areas.
5.2 Epidemiology A study conducted in the Grampian region of the UK and published in 1999, reported
prevalence rates amongst adults (aged ≥ 25 years) of 50.4% for chronic pain in
general and 16% for chronic back pain specifically.6 Similarly an Office for National
Statistics survey undertaken in 1998 indicated prevalence rates of chronic back pain
(defined as pain suffered for at least a year) amongst adults (aged ≥ 16 years) were
16% and 15% amongst men and women, respectively.31 Using a prevalence rate of
16%, we would expect approximately 864,000 cases annually in the West Midlands,
given a West Midlands population of 5.4 million (Office for National Statistics 2007
estimate).32
Epidemiological research on the prevalence of chronic pain with neuropathic features
appears somewhat sparse. A study, published in 2006, conducted in three UK cities
(Aberdeen, Leeds and London) suggested the prevalence of chronic pain of
predominantly neuropathic origin to be 8.2%, of which 70.7% (or 5.8% of the total
population) was back pain.33
With regard to back pain of the specific aetiologies covered in this report, there are
estimated to be approximately 2000 new cases of FBSS each year in the UK,34 a
24
figure that would translate into approximately 176 new cases annually in the West
Midlands. Between 75 and 115 new cases of spinal cord injury (SCI) can be
expected in the West Midlands annually,35,36 over 80% due to traumatic events such
as falls, motor vehicle accidents or sporting injuries.36 Demographically, young
people between the ages of 21 and 30 are the most likely to suffer SCIs, and as
improvements in care have reduced mortality from such injuries,37 many can be
expected to live normal lifespans. It is estimated that 40,000 people in Britain are
living with paralysis due to SCI,35 a figure that would translate to approximately 3,500
individuals in the West Midlands. Survey data from several countries suggest that
over 60% of people with SCI experience chronic pain and/or dysaesthaesias, and the
majority describe their pain as ‘severe’.38,39;40
Table 3 below summarises the epidemiological data. Please note that systematic
searches for this type of data were not performed and the validity of the results has
not been assessed (e.g. by looking at the sample size, methods of obtaining data
and case definitions).
Table 3 Epidemiological data back pain Indication
Measure Source
Chronic back pain Prevalence: 16% 1999 Study in Grampian region of UK6
Chronic back pain Prevalence: 16% (men), 15% (women)
1998 Office of National Statistics survey31
Chronic neuropathic back pain
Prevalence: 5.8% 2006 survey conducted in three UK cities (Aberdeen, Leeds and London)33
FBSS New cases per year (UK): 2000
Talbot L. Failed back surgery syndrome. BMJ 2003; 327:985.34
SCI New cases per year (UK): 75-115
Grundy D, Swain A. ABC of spinal cord injury. 4th ed. London: BMJ Books; 200235 and a 1997 audit of a British centre for spinal injury36
SCI Total cases: 40,000 Prevalence (based on total population of 61.8 million): 0.06%
Grundy D, Swain A. ABC of spinal cord injury. 4th ed. London: BMJ Books; 200235
5.3 Treatment
Given its pervasive nature, effective treatment of chronic back pain often requires a
multi-disciplinary approach. Treatment goals are to make pain tolerable, and improve
25
functionality and quality of life. Pharmacological options include tricyclic
antidepressants, anticonvulsants and analgesics; patients with neuropathic pain
appear not to respond well to non-steroidal anti-inflammatory drugs and resistance or
insensitivity to opioids is common.41
Non-pharmacological interventions include physiotherapy, acupuncture,
transcutaneous electrical nerve stimulation (TENS) and psychological therapies.5 For
conditions such as FBSS a repeat operation may be performed.5 Neurostimulation
appears to form one part of this multimodal treatment strategy and is used only when
more conservative treatments have failed. The major types of neurostimulation used
in the treatment of chronic back pain are SCS, DBS, MCS, PENS, TENS and non-
invasive brain stimulation techniques, such as rTMS, CES and tDCS.
5.4 Quantity and quality of evidence Thirty systematic reviews and/or health economic evaluations were identified for pain
indications that included chronic and/or neuropathic back pain. These were of varying
methodological quality. Interventions covered by these reviews were SCS, DBS,
MCS, TENS, PENS and non-invasive brain stimulation (rTMS, CES and tDCS). See
Table 4, p27 for an overview of the evidence.
The majority of the secondary evidence related to FBSS, which was covered in 14
systematic reviews3,5,42-53 published between 1995 and 2009. Of these, 13
reviews3,5,42-52 reviewed the use of SCS for FBSS, and one, Bittar 200553, reviewed
the use of DBS. Another area of focus within the literature was the use of TENS for
lower back pain, which was addressed in seven24,54-59 of the 10 systematic reviews
found for that indication published between 1997 and 2010. The other three covered
PENS20, DBS53 and SCS44 for lower back pain. Seven systematic reviews published
between 2001 and 2010 reviewed the evidence for neurostimulation for the treatment
of pain following SCI, covering a range of techniques including SCS48,60, DBS53,60,61,
MCS60-63, non-invasive brain stimulation22,62 and TENS.60
One review62 on MCS for chronic pain included back pain. However, results were not
presented in a disaggregated way for different indications, and there were no useable
results for back pain. This review will therefore not be discussed further.
26
In addition to RCTs identified in the included systematic reviews, two additional RCTs
were identified, one on TENS for low back pain (Itoh 200964) and one on PENS for
low back pain (Pérez-Palomares 201065).
We found five reports evaluating the cost-effectiveness of SCS for various indications
including back pain. Two were systematic reviews of cost-effectiveness (Bala 200845,
Taylor 200448), one included both a systematic review and a new economic model
(Simpson 20093), and two further studies were of primary economic models (Taylor
2005b66, Taylor 201067). Taylor 200448 identified no full economic evaluations on
back pain; one identified for CRPS is included in section 7.11. Bala 200845 included
the Taylor 2005b66 economic evaluation, and one by North 200768. We therefore
identified four primary economic evaluations in total for SCS in FBSS (Simpson
20093, Taylor 2005b66, Taylor 201067 and North 200768). No cost-effectiveness
studies were found for other types of back pain or neurostimulation.
Given the overall number of reviews identified for some indication/neurostimulator
combinations, only the most relevant, comprehensive and/or recent reviews were
selected for this report. Table 15 and Table 16 (Appendix 3, p178 and p180) detail
the characteristics and quality assessment of the included reviews for all types of
back pain. Subsequent sections describe the quantity, quality and findings of the
most relevant studies by indication/neurostimulator combination. Back pain
indications are FBSS, low back pain and pain after spinal cord injury.
27
Table 4 Evidence identified for neurostimulation in back pain Indication Type of neurostimulation Failed back surgery syndrome Back pain after spinal
cord injury Chronic low back pain (non-specific)
Spinal cord stimulation Taylor 201067-EE Simpson 20093- SR & EE British Pain Society 200942- SR Frey 200943- SR NICE guidance 20085- SR Chou 200944- SR Bala 200845- SR & EE Taylor 2006b46- SR Taylor 2005b66- model & EE Taylor 2005a47- SR Taylor 200448- SR of EE Turner 200449- SR Mailis-Gagnon 200450- SR ASERNIP 200351-SR Turner 199552- SR
Taylor 200448- SR of EE Jadad 200160- SR
Chou 200944- SR Taylor 2005a47-SR
Deep brain stimulation Bittar 200553- SR Bittar 200553- SR Jadad 200160-SR Previnaire 200961- SR
Bittar 200553- SR
Motor cortex stimulation Lima 200862- SR Fontaine 200963-SR Previnaire 200961- SR
Non-invasive brain stimulation (rTMS, tDCS, CES)
O'Connell 201022- SR
Transcutaneous electrical nerve stimulation (TENS)
Jadad 200160-SR
Dubinsky 201054-SR Walsh 200955-SR Khadilkar 200824- SR Khadilkar 200556- SR Brosseau 200257- SR Carroll 200058- SR Flowerdew 199759- SR Itoh 200964-RCT
Percutaneous electrical nerve stimulation (PENS)
Blue Cross of Idaho Report 201020-SR Pérez-Palomares 201065-RCT
SR=systematic review; EE=economic evaluation; RCT=randomised controlled trial; rTMS=repetitive transcranial magnetic stimulation; tDCS=transcranial direct current stimulation; CES=cranial electrotherapy stimulation
28
5.5 Failed back surgery syndrome
5.5.1 Spinal cord stimulation for failed back surgery syndrome Thirteen reviews3,5,42-52 included the use of SCS for FBSS (see Table 4, p27). Despite
the large volume of reviews, there was considerable overlap in terms of primary
evidence assessed (see Appendix 3, p188, Table 17), all of which relates to a series
of publications from two RCTs: the PROCESS trial69-73 and the trial conducted by
North and colleagues.74-77
The most thorough, and relatively up-to-date, examination of these two RCTs
appeared to be that undertaken by Simpson 2009 (see Appendix 3, p178 and p180,
Table 15 for review characteristics and Table 16 for quality assessment).3 It was
therefore used as the main source of evidence for this report, supplemented with
results of the PROCESS trial, at 24 months follow-up, published after completion of
the review.71,72
The PROCESS trial (n=100)69-73, which compared SCS to conventional medical
management (CMM), appeared overall to be of good quality. Methods of
randomisation and concealment of allocation were appropriate. There was however
an imbalance at baseline in the two treatment groups with the SCS having
significantly higher scores for back pain. Due to the nature of the intervention,
patients and treatment administrators were not blinded. Analyses were not all on an
intention-to-treat basis. The North trial (n=50)74,75,77 also seemed overall to be of good
quality. Methods of randomisation and concealment of allocation were appropriate.
Again, due to the nature of the intervention patients and treatment administrators
were not blinded, but outcome assessors were. Analyses included those patients
who were lost to follow-up, but not those who received no treatment. Further trial
details and quality assessments are given in Table 18 and Table 19 (Appendix 3,
p189 and 191).
In addition, a systematic review by Taylor 2005a47 with searches to January 2002,
identified 72 case-series of SCS encompassing a total of 3427 patients, 3313 of
whom received treatment for FBSS or chronic back and leg pain. The authors
deemed the quality of these case-series to be poor in both design and reporting
(median quality score 1 out of possible 7) and the results are aggregated for the two
conditions, reducing the usefulness of the findings for clinical decision making.
29
However, these case-series cumulatively represent 3427 implanted patients and may
be of use in assessing safety outcomes.
In the PROCESS trial,69-73 48% (24/50) patients reported at least 50% pain reduction
at six months, compared with only 9% (4/44) of patients receiving CMM (p<0.001).
This effect was sustained at 12 months (34% vs 7%; p=0.005) and 24 months follow-
up (37% vs 2%; p=0.003).71,72 It should be noted that patients who withdrew consent
or were lost to follow-up were not included in this analysis, and therefore these
results may overestimate the treatment effect size. Although similar numbers of
patients were excluded in both groups (6/52 in the SCS group versus 7/48 in the
control group), reasons for withdrawal may differ.
The trial by North and colleagues74,75,77 had a mean follow-up of 2.9 years and also
reported significantly higher positive outcomes in the SCS group, with 39% (9/23)
reporting the composite primary outcome of at least 50% improvement in pain scores
and being prepared to undergo the procedure again, as compared with 12% (3/26) in
the group undergoing re-operation (p=0.04). Results are not reported for pain scores
alone. It has been reported that patient satisfaction in neurostimulation studies does
not always correlate well with clinical outcomes such as pain relief; as patient
satisfaction can be influenced by a number of factors, it has been proposed that
aggregate measures should not be used as primary efficacy endpoints or in
establishing the efficacy of highly experimental techniques such as
neurostimulation.78
In the PROCESS trial, functional ability at six months (measured by the Oswestry
Disability Index (ODI)) improved significantly from baseline for the SCS group (ODI
reduced from mean of 57.4 to 44.9 at six months; p<0.001), and this was sustained
at 24 months.71 No improvements in ODI were reported in the CMM group (ODI 55.2
at baseline versus 56.1 at six months) and the between-group differences were
significant.70 In the North trial, patient self-report of neurological function (lower
extremity strength and co-ordination, sensation, bladder/bowel function) were
generally worse at long-term follow-up in the re-operation group than the SCS group,
although the differences were not statistically significant.3 Employment status did not
differ significantly between the groups in either trial.3,71
The North trial reported increased opiate use in 42% (11/26) of the re-operation
group compared with 13% (3/23) in the group receiving SCS (p=0.025) at a mean
30
follow-up of 2.9 years. In contrast, the PROCESS trial reported no difference in
opiate, other analgesic, or antidepressant use between the SCS and CMM groups at
six months,70 and there was no clear pattern of change in medication or non-drug
therapy from baseline values in the 42/52 patients randomised to SCS and followed
for at least 24 months.71 Despite this, patients receiving SCS in the PROCESS trial
reported significant improvements over baseline on the EQ-5D and in seven of eight
HRQoL measures rated by the Short-Form Health Survey-36 (SF-36) at 6-month
follow-up.70 Patients receiving CMM reported significant improvement in the General
Health category only.70
5.5.2 Deep brain stimulation for failed back surgery syndrome
A systematic review by Bittar 200553 (see Table 4, p27) covered all types of pain and
included six case-series, totalling 424 patients, of whom approximately 200 suffered
with various types of back pain.53 This review had a documented search strategy
(searches up to Jan 2003) and study selection criteria, and was considered to be of
reasonably good quality (see Appendix 3, p178and p180, Table 15 for review
characteristics and Table 16 for quality assessment). Results for 59 patients with
FBSS drawn from different case-series were available. Given that patients from
different case-series are not necessarily comparable, any results need to be treated
very cautiously. This is in addition to the usual caveats around interpreting results
from case-series.
The six case-series79-84 were deemed by the authors to be of high quality, with clear
definition of patient group, treatment protocol and follow-up, which ranged from one
month to 15 years. Due to wide variations in outcome measures used, treatment
success was defined in the review as per the original studies. Given the
heterogeneity of outcome measures utilised – from “complete or partial relief”83 to
“cumulative score from four criteria: completeness of pain relief, duration of analgesia
following stimulation, absence of adverse effects, and long-term effectiveness”79 –
the validity of the meta-analysis conducted by aggregating these case-series data
may be debatable. Despite conducting searches of the literature up to 2003, these
reports were all published between 1977 and 1997. The cases included 59 patients
with FBSS. Results of the meta-analysis indicate that the success rate in this patient
population was relatively high.53 Nearly all patients (54/59, 92%) responded well to
initial stimulation and had the device internalised. Of these, 85% (46/54), or 78%
(46/59) for all cases, reported long-term treatment success.
31
5.5.3 Conclusion failed back surgery syndrome Clinical effectiveness of neurostimulation for failed back surgery syndrome
• Spinal cord stimulation (SCS): Evidence from two RCTs (n=73 receiving SCS)
suggests SCS is more effective than conventional medical management
(CMM) or re-operation in terms of pain relief. The composite outcome
measure used for the comparison between SCS and re-operation may not
have been the most appropriate. Opiate use is reduced more with SCS than
with re-operation, but medication use is similar between SCS and CMM. SCS
may be more effective at improving function and health-related quality of life.
Neither SCS, CMM nor re-operation significantly improves employment status.
• Deep brain stimulation: Evidence from six case-series including 59 patients
with failed back surgery syndrome suggests that the technique is effective in
providing long-term improvements in this condition. However, the absence of
control groups in these reports means that the effect size may be inflated;
further, the validity of pooling patients (who may not be comparable) from
different case-series is debatable, as is the aggregation of different outcome
measures. It should be noted that 8% (5/59) did not have the stimulation
device internalised due to poor response, but still experienced the risk from
the electrode implantation procedure.
32
5.6 Non-specific chronic low back pain
5.6.1 Deep brain stimulation for non-specific chronic low back pain A systematic review by Bittar 200553(see Table 4, p27) covered all types of pain and
included six case-series, totalling 424 patients, of whom approximately 200 suffered
with various types of back pain (see section 5.5.2 for further details on this review
and Appendix 3, p178 and p180, Table 15 for review characteristics and Table 16 for
quality assessment). Pooled results are available for 103 ‘low back and skeletal pain’
patients drawn from across case-series. Given that patients from different case-
series are not necessarily comparable, any results need to be treated cautiously.
This is in addition to the usual caveats around interpreting results from case-series.
Approximately two-thirds (70/103, 68%) of patients had positive responses to initial
stimulation and had the devices internalised. Of these, 80% (56/70), or 54% (56/103)
for all cases, benefited from long-term stimulation. This success rate appears to be
lower than that for FBSS.
5.6.2 Transcutaneous electrical nerve stimulation for non-specific chronic low back pain
Seven systematic reviews24,54-59 of TENS in back pain were identified and these were
published between 1997 and 2010 (see Table 4, p27). One of these, Walsh (2009)55
limited study design to RCTs in their inclusion criteria; no RCTs were identified for
(acute) back pain and this review will not be discussed further. The remaining six
reviews between them included a total of 16 RCTs. There were considerable
differences in the RCTs included in the individual reviews, largely explained by study
inclusion criteria and search dates. For example, Dubinsky 201054 focussed on
patients with neurological disorders whereas Khadilkar 200824 excluded them. Some
of the 16 RCTs were identified but excluded by most of the reviews due to small size
or methodological issues. In others, results for patients with back pain were not
disaggregable from other patient populations.
As such, the discussion of TENS in the treatment of chronic low back pain in this
report is based on the three most recent systematic reviews,24,54,57 which between
them include over 1000 patients across 11 RCTs, including all those published in the
last 15 years and all those with larger sample sizes (>50). All three systematic
reviews were assessed as being of generally good quality (see Appendix 3, p178 and
p180, Table 15 for review characteristics and Table 16 for quality assessment). Due
33
the volume of RCTs and time constraints, these have not been individually quality
assessed for this report.
Two of the systematic reviews24,54 reported their findings narratively, having deemed
the included trials too heterogeneous for meta-analysis to be conducted. However, in
the third systematic review (Brosseau 200157) a meta-analysis was conducted based
on five included trials. These RCTs displayed considerable heterogeneity in trial
protocols. Treatments in the various studies included a range of TENS modalities
including conventional and acupuncture-like TENS, high- and low-frequency TENS,
Nu-Waveform TENS, and TENS plus exercise. Treatment duration also ranged from
5 hours per day for two days to twice per week for 10 weeks. Concurrent therapies
were banned in some studies, whereas others allowed free use of heat therapy or
normal pain medication.
One additional RCT (Itoh 200964) was identified by own searches for this report. This
trial compared TENS to acupuncture, TENS + acupuncture and no treatment (topical
poultice).
In general, results of the 11 RCTs do not support the use of TENS in the treatment of
chronic low back pain. Although there was a tendency to lower pain intensity and
improved function in active treatment groups versus controls, few of these
differences were statistically significant. Nine trials (n=370) reported on changes in
pain intensity using a VAS, with six reporting no significant difference in pain
reduction between TENS and sham-TENS control groups.64,85-89 One study90 reported
a significant improvement following treatment in 13/33 patients; however, this study
compared three different modes of TENS, and there was no sham-TENS or other
placebo control group. It should also be noted that in the conventional TENS arm of
this study, the success rate was only 1/11. Two trials (n=75) reported a significant
improvement following treatment with conventional (Cheing91,92) or both conventional
and acupuncture-like TENS (Topuz 200493). Due to the difficulty of blinding patients
to treatment allocation in interventions that produce sensory stimuli, Topuz and
colleagues93 included only TENS-naïve patients; however, treatment providers were
not blinded to treatment allocation. It is not clear whether Cheing and colleagues
excluded patients with prior experience of TENS. It should also be noted that there
was a high drop-out rate in the study by Cheing – with four patients withdrawing from
each group (26.6% of initial sample), six due to adverse events relating to pain.
Three patients withdrew from the placebo-TENS group in the study by Topaz, none
34
from the active TENS intervention arms. Neither trial provided ITT analysis; thus the
positive effect of treatment may be inflated in these reports.
Five trials reported on functional status using a range of instruments including the
well-validated Roland-Morris Disability Questionnaire and the Oswestry Disability
Index (ODI). The study by Topuz and colleagues found a statistically significant
difference in ODI scores for acupuncture-like TENS (n=15), but not conventional
TENS (n=15), compared with sham TENS (n=12); the improvement was not deemed
to be clinically significant.93 The remaining trials found no difference between active
and sham treatments (Deyo 199085; Jarzem 199794; Jarzem 200595; Itoh 200964).
In terms of general health, conflicting results have been reported. Deyo and
colleagues (n=145) found no significant effect on Sickness Impact Profile scores,85
whereas Topuz and colleagues reported improvements in a number of the
subsections of the SF-36. Specifically, both conventional and acupuncture-like TENS
resulted in improved emotional and mental health scores, but only conventional
TENS resulted in improved physical health and vitality scores.93 In contrast, Jarzem
and colleagues (n=350) found no improvement in mental health scores using the
Zung depression scale.95 Two trials (n= 475) reported on activity levels using self-
rated activity85 and the McGill Activity Scale95 and neither reported statistically
significant benefits. Work status was assessed in one study (n=350) and was not
significantly better with TENS treatment than with placebo,95 One study (n=145)
evaluated use of medical services and found no difference between active and sham
treatment.85 In the two trials that assessed both conventional and acupuncture-like
TENS,93,95 results were similar for the two modalities on the majority of outcomes,
consistent with previous reports.59
Taken as a whole, only two trials (Topuz 200493; Cheing 199691 and 199992) reported
any significant benefit for TENS treatment compared with placebo. Although these
studies were generally well-conducted, due to the relatively small sample sizes (in
total, these studies represent 41 patients who received conventional or acupuncture-
like TENS), the relatively high drop-out rate, absence of ITT analysis, and lack of
blinding of treatment providers, these data may overestimate the efficacy of TENS in
treating chronic low back pain and are not sufficient to outweigh the balance of the
evidence suggesting no benefit for TENS beyond that observed with placebo.
35
5.6.3 Percutaneous electrical nerve stimulation for non-specific chronic low back pain
One systematic review of PENS20 that updated two previous reports with literature
searches up to February 2010 was identified (see Table 4, p27). Details of the
databases searched were not provided in the report of this study and thus the
possibility of selection bias cannot be ruled out. Generally, there were few
methodological details reported for this review (see Appendix 3, p178 and p180,
Table 15 for review details and Table 16 for quality assessment). The review
included eight RCTs investigating PENS in chronic low back pain. One more recent
RCT (Perez-Palomares 201096) that compared PENS with dry-needling of myofascial
trigger points, also for the treatment of chronic low back pain, was identified by
searches for this report.
The systematic review included a series of four sham-controlled crossover RCTs
encompassing 267 patients with chronic low back pain conducted by one research
group (Ghoname 199997; Ghoname 199998; Hamza 199999; Ghoname 1999100).
Except where otherwise noted, treatments were delivered for 30 minutes, three times
per week, for two or three weeks, with a one-week washout period between
interventions. Active PENS performed better than sham PENS across the trials with
reductions in pain intensity, daily analgesic medication use, physical impairment and
impact on quality of sleep. In addition, one trial99 (n=75) found that sessions of 30 or
45 minutes were more effective than those of 15 minutes, and another trial100 (n=68)
that an alternating frequency of 15 and 30 Hz was more effective than fixed 4 Hz or
100 Hz treatments. Two of the trials97,98 (n=124) also compared active and sham
PENS with TENS treatment and found that both PENS and TENS outperformed
placebo, but PENS rated more highly on functionality and quality of life measures. It
should be noted that the report is not clear on whether the differences noted above
are statistically significant.
A further study (White 2001101) by the same group compared four different patterns of
needle placement for stimulation, without a sham control. All four resulted in
significant improvements in pain, physical activity, quality of sleep and use of oral
analgesia compared with baseline, but the pattern of needle insertion did have an
effect on treatment efficacy and may have implications for future research and clinical
implementation. Across the five trials a series of PENS treatment sessions of at least
30 minutes duration resulted in reductions in VAS scores of between 42% and 82%.
TENS produced between 10% and 23% pain relief. Sham PENS had between 4%
36
and 10% effect on pain scores, lower than is generally seen in such studies. While
these results appear impressive, a number of methodological concerns limit the
usefulness of these data. In particular, adequacy of blinding is not certain, the
treatment of any withdrawals is not dealt with and it is unclear if ITT analyses have
been performed.20 Thus, the treatment effect may be overstated. In addition, the one-
week washout period between treatment crossover may not be sufficient and a carry-
over effect cannot be ruled out. Further, these studies did not assess long-term
effects of treatment on this chronic condition.
A recent RCT of 122 participants with chronic low back pain randomised patients to
receive either three 30-minute sessions of PENS per week for three weeks or dry-
needling once per week for three weeks (Pérez-Palomares 201065). Both groups
reported similar reductions in pain and improved quality of life, although 54% of the
PENS group were considered to have a clinically significant response (>40%
reduction in pain VAS) compared with 46% in the dry-needling group. However, the
lack of a sham control makes it difficult to draw conclusions about these results.
Three additional RCTs considered medium-term outcomes but produced conflicting
results (Weiner 2003102; Yokoyama 2004103; Weiner 2008104). In one study102 (n=34)
of older adults randomised to physical therapy plus active or sham PENS twice
weekly for six weeks, significant reductions in pain intensity and pain-related
disability were reported after treatment and were sustained at three-month follow-up
in the active treatment arm only. However, a larger study104 (n=200) by the same
group randomised patients into four groups of active or sham PENS with or without
exercise therapy, twice a week for six weeks. All four groups reported similar
improvements in pain, disability and gait velocity at one week, sustained at six
months. No significant between-group differences were observed. A third trial103
comparing eight weeks of PENS with four weeks of PENS followed by four of TENS
or eight weeks of TENS also found pain reduction occurred earlier and to a greater
extent with PENS treatment, with the effects being sustained at one, but not two
months.
5.6.4 Cranial electrotherapy stimulation for non-specific chronic low back pain
A recent Cochrane review (O’Connell 201022, see Table 4, p27) assessed the
literature on the use of non-invasive brain stimulation techniques – rTMS, CES and
tDCS – in the treatment of chronic pain (see Table 4, p27). This was a well-
37
conducted review, which is unlikely to have missed any relevant studies (see
Appendix 3, p178 and p180, Table 15 for review details and Table 16 for quality
assessment). This review included 33 studies of non-invasive brain stimulation: 19
investigated rTMS and randomised a total of 422 patients; eight CES studies
included a total of 391 patients; and six tDCS studies included 83 participants. The
studies covered a variety of chronic pain conditions but included at least 95 patients
with chronic neck/back pain and 110 with chronic neuropathic pain subsequent to
SCI. A number of the RCTs had mixed populations from which the back pain patients
could not be disaggregated. However, there were two RCTs (Gabis 2009105,106 and
Gabis 2003105) on CES in back pain patients (note: one of these RCTs106 is also
discussed in detail in the context of headache, see section 8).
Both studies were carried out by the same research group. It should be noted that in
both trials, the stimulation parameters of the ‘placebo’ differed in frequency and
intensity to the CES intervention, but were not inert (CES: frequency 77 Hz, intensity
≤ 4 mA; placebo: frequency 50 Hz, intensity ≤ 0.75 mA). These parameters were
intended to provide sensory input to patients to assist in maintaining blinding.
However, an intensity of 0.75 mA is higher than the ‘active’ treatment in some other
CES studies, and may have influenced the outcome variables and reduced any
between-group differences.
In the first study, 20 patients were randomised to receive either CES or the active
placebo treatment.105 Stimulation was delivered for 30 minutes per day on eight
consecutive days. Pain levels were measured on a VAS before and after each
treatment session and were found to be significantly reduced in both treatment
groups. Serum beta-endorphin levels were also measured and were increased in the
‘active’ but not the ‘placebo’ group (p=0.057). The authors concluded that CES
produces immediate short-term benefits in pain response associated with increases
in serum beta-endorphins. They suggested that the lack of endorphin release in the
control group might limit the duration of the immediate powerful placebo response.
The second study105,106 investigated the same treatment parameters but with follow-
up at three weeks and three months. This study randomised a total of 119 patients
with chronic pain, including 33 with chronic low back pain (17 CES, 16 ‘active
placebo’), and results were reported by pain aetiology. Four treatment outcomes
were assessed namely level of pain, frequency of pain, frequency of analgesic
medication use, and frequency that pain interfered with sleep. Pain levels were
38
significantly reduced in both groups at 3-week follow-up, and were still significantly
improved over baseline at three months, despite some rebound in mean pain
intensity. A similar trend was seen for the other outcome measures, although
reductions in pain frequency did not reach statistical significance in the CES group.
No significant differences were observed between the groups on any measure at any
time point. Thus despite the lack of an endorphin response reported in the first study,
the treatment effect in the ‘active placebo’ group was sustained over time. While the
use of such a control for the purpose of helping to maintain blinding is admirable,
further trials using an inert placebo treatment would be required to definitively
demonstrate any group differences and prevent the discounting of what may be a
successful treatment. Nevertheless, it is perhaps worth noting that significant
differences between treatment groups were observed in all four outcome measures
at 3-month follow-up for the other indications (i.e. non-back pain).
39
5.6.5 Conclusion non-specific chronic low back pain Clinical effectiveness of neurostimulation for non-specific chronic low back pain
• Deep brain stimulation (DBS): Evidence from six case-series including 103
patients with low back/skeletal pain suggests that the technique is moderately
effective in this condition, although long-term efficacy is achieved in four of five
patients responding to trial stimulation. However, the absence of control
groups in these reports means that the effect size may be inflated; further, the
validity of pooling patients (who may not be comparable) from different case-
series is debatable, as is the aggregation of different outcome measures. It
should be noted that 32% (33/103) did not have the stimulation device
internalised due to poor response, but still experienced the risk from the
electrode implantation procedure.
• Transcutaneous electrical nerve stimulation (TENS): The majority of evidence
finds no statistically significant differences between TENS and comparator
groups (mainly sham-TENS) for most outcome measures of pain, functional
status and general health. There is no significant difference in efficacy
between conventional (high-frequency) and acupuncture-like (low-frequency)
TENS for most outcome measures.
• Percutaneous nerve stimulation (PENS): A number of RCTs from a single
group suggest that PENS may be beneficial in the short-term treatment of
chronic low back pain; however, methodological flaws limit the usefulness of
these data. Studies from other groups provide conflicting results but suggest
that any immediate benefit from treatment is not sustained over the medium to
long-term.
• Non-invasive brain stimulation (Cranial electrotherapy stimulation, CES):
Evidence from two small but well-conducted RCTs (total n=53) does not find a
significant difference between active and sham CES for pain relief or
medication use; it should be noted that the level of stimulation used in the
sham group was lower than in the active group, but higher than active
treatment in other CES studies.
40
5.7 Back pain resulting from spinal cord injury 5.7.1 Spinal cord stimulation for back pain resulting from spinal cord
injury Two systematic reviews (Taylor 200448 and Jadad 200160) were identified, which
included patients with pain after SCI (see Table 4, p27). Both included evidence in
the form of case-series only. As the focus of the Taylor 200448 review was on studies
reporting cost/cost-effectiveness, we have considered the Jadad 200160 systematic
review only. This was considered to be of good methodological quality and is unlikely
to have missed any studies (see Appendix 3, p178 and p180, Table 15 for review
characteristics and Table 16 for quality assessment).
The review included two prospective107,108 and three retrospective109-111 series of
cases of 12 or more subjects, totalling 84 patients in all, and a further 12 smaller
studies with sample sizes of seven or fewer patients. Based on the evidence from the
larger case-series, the authors concluded that SCS resulted in an initial improvement
in terms of pain relief in 50–70% of patients selected for device implantation. Only
two of the studies provided long-term follow-up and sustained pain relief was
experienced in 19–41% of patients (NB follow-up times not stated for initial or long-
term pain relief). Similar results were observed in the 12 smaller studies. Given that
patients from different case-series are not necessarily comparable, any pooled
results need to be treated cautiously. This is in addition to the usual caveats around
interpreting results from case-series.
5.7.2 Deep brain stimulation for back pain resulting from spinal cord injury
Three relevant systematic reviews were identified (see Table 4, p27).53,61 The
systematic review by Jadad 200160 contained little useful information for this
indication (two case reports) and will not be further considered. The systematic
review by Prévinaire 200961 was the most recent review and appeared to include all
relevant data from the third review (Bittar 200553). It was difficult to assess the quality
of the Prévinaire 200961 review, as the published report referred to a methodology
described in another paper, which addressed a different topic area. However, it is
likely that a degree of methodological rigour was applied in the review by Prévinaire61
(see Appendix 3, p178 and p180, Table 15 for review characteristics and Table 16 for
quality assessment). Evidence was in the form of mixed population case-series only.
41
The review by Prévinaire 200961 identified 36 patients with neuropathic pain following
SCI from across different case-series. Of these, 18 benefited from test stimulation of
thalamic sensory nuclei (some studies also stimulated additional regions). Test
stimulation periods ranged from between five and 14 days. Permanent implants of
stimulation devices were performed in 19 patients with follow-up from six months to
five years. The success rate was low, with only three (15.8%) reporting long-term
improvement (8.3% of whole cohort). However, outcome measures differed
somewhat between studies and included a variety of pain assessment instruments,
improvements in daily living, reduction in medication use, and the presence or
absence of adverse events, and it is unclear whether the systematic review utilised
the success criteria as defined in the original studies or some other measure. The
report by Bittar and colleagues53 that included the same pre-2000 case-series
suggested that seven of 10 test patients were implanted and five reported long-term
success. The discrepancy cannot be easily explained, but it is clear that the overall
benefit for DBS in SCI neuropathic pain appears moderate at best.
5.7.3 Motor cortex stimulation for back pain resulting from spinal cord injury
There is limited evidence on this intervention (see Table 4, p27). The systematic
review by Fontaine 200963 identified 14 case-series of MCS for chronic neuropathic
pain (including the two series reported by Prévinaire 200961). These case-series
included a total of 210 patients, of whom 11 were treated for pain subsequent to SCI.
Although it is not clear which series provided the data for the SCI patients, results for
pain relief are presented by pain aetiology. The review had a limited search strategy,
so it is possible that some studies may have been missed (see Appendix 3, p178 and
p180, Table 15 for review characteristics and Table 16 for quality assessment).
Given that patients from different case-series are not necessarily likely to be
comparable, any results need to be treated cautiously. This is in addition to the usual
caveats around interpreting results from case-series. This was the most
comprehensive review and no additional relevant evidence was identified in the other
two relevant reviews (Prévinaire 200961 and Lima 200862).
Based on these data, almost all (10/11) patients experienced at least a 40%
reduction in pain intensity, and over one-third (4/11) experienced over 70% relief.
Long-term follow-up (>1 year) was available in six patients. At this time, half (3/6)
reported moderate pain relief (40–50%). These results are based on very small
42
numbers from patients drawn from across 14 case-series, and are thus associated
with substantial uncertainty.
5.7.4 Transcutaneous electrical nerve stimulation for back pain resulting from spinal cord injury
The systematic review by Jadad 200160 (see Table 4, p27) identified two studies (one
RCT (n=40) and one case-series (n=31), which included patients with pain post-SCI
(n=20 and n=11 respectively). The review was considered to be of good
methodological quality and is unlikely to have missed any studies (see Appendix 3,
p178 and p180, Table 15 for review characteristics and Table 16 for quality
assessment).
The double-blind placebo-controlled RCT with 40 subjects included 20 patients with
central pain post-SCI and 20 with musculoskeletal pain (Doctor 1996112). Results
suggested that TENS was ineffective for pain relief in either patient population. In the
case-series113, TENS appeared to be not effective in patients with pain post-SCI, with
9/11 (72%) reporting no benefit from treatment.
5.7.5 Non-invasive brain stimulation (rTMS, tDCS, CES) for back pain resulting from spinal cord injury
Only one systematic review was identified, the Cochrane review by O’Connell 201022
on chronic pain (see Table 4, p27). This included 5 RCTs in patients with SCI: two of
rTMS (Kang 2009114; Defrin 200730), two of CES (Capel 2003115; Tan 2006116) and
one of tDCS (Fregni 2006117). This was a well-conducted review, which is unlikely to
have missed any relevant studies, however, the review does not present results
disaggregated by pain aetiology (see Appendix 3, p178 and p180, Table 15 for
review characteristics and Table 16 for quality assessment). In order to provide
information relevant to this report, presented below is the specific RCT evidence for
the various sub-types of non-invasive brain stimulation in the treatment of SCI related
pain.
rTMS Two small RCTs of high-frequency rTMS were identified, representing a total of 25
patients (n=12 and n=13 respectively).30,114 Both studies blinded patients and
outcome assessors to treatment allocation, although the investigators delivering the
treatment were not blinded.
43
The RCT by Defrin 200730 had a parallel design, with patients receiving 10 sessions
of either active or sham treatment. Outcomes were measured post-treatment (at two
weeks) and after a follow-up period of between two and six weeks (mean not stated).
Whilst there were significant improvements over time in both groups, there were no
significant differences between groups in VAS rating of chronic pain, the Pain Rating
Index (PRI) of the McGill pain questionnaire or the Beck Depression Inventory (BDI),
either at post-treatment or follow-up. The authors state that a decrease in PRI
scores continued post-treatment and during the follow-up period in the active
treatment group, whilst the PRI scores increased in the sham treatment group;
however at follow-up there was little difference between the absolute scores in the
two groups. A significant difference between groups was apparent only for magnitude
of change in pain threshold.
The RCT by Kang 2009114 had a crossover design, with patients receiving both an
active and sham session; the sessions were separated by 12 weeks and performed
in random order. Outcomes were measured at day 3, day 5, week 1, week 3, week 5
and week 7. There were no significant differences between groups in numerical
rating scale (NRS) scores for average pain or scores on the Brief Pain Inventory
(BPI) at any follow-up times. There was a significant difference in worst pain intensity
between groups at three weeks, but not at any other time points. The authors note
that the maximum reductions in NRS score for average and worst pain were 1.09 and
1.64 respectively, which fall short of the 2.0 points (or 30%) recommended as
representing clinically meaningful reductions in pain by The Initiative on Methods,
Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus
group.118
CES Two RCTs of CES representing a total of 68 SCI patients were identified from the
O’Connell review (Capel 2003115; Tan 2006116). In Capel 2003115, randomisation
appeared to involve subjects themselves choosing a device, which was set up to
deliver either active or sham treatment; it is unclear how successful this method of
randomisation is likely to be, but bias cannot be ruled out. The trial was designed to
have a crossover design, but after the first treatment period, it was decided to offer
the active treatment to all patients. Both studies made good attempts to ensure
blinding.
44
The first study115 involved 30 participants who received two active or sham treatment
sessions per day administered on four consecutive days, with each treatment lasting
for 53 minutes. There was a significant difference between groups in average daily
pain rating on days 2, 3 and 4. Medication usage was monitored before, during and
for seven days after treatment, but was not reported for the randomised phase of the
study.
The second study116 involved 38 subjects who received one hour of active or sham
treatment daily for 21 days. Whilst the average change in daily pain intensity from
pre-to post-session was significantly larger in the active group, daily pain ratings did
not differ significantly between treatment groups. There were also no significant
differences between groups in scores on four Pain Intensity sub-scales and 10 Pain
Interference sub-scales of the Brief Pain Inventory (BPI). Exploratory analyses
indicate that treatment effect may differ by type of SCI (traumatic versus non-
traumatic, level and completeness of injury), type of pain (muscular versus
neuropathic) and baseline pain intensity, however this requires further investigation.
tDCS In a well-designed but small study (Fregni 2006117) of tDCS for central pain due to
traumatic SCI, 17 subjects were randomised 2:1 to receive either active or sham
treatment for 20 minutes daily on five consecutive days. Mean pain scores (VAS)
dropped continuously over the five days of treatment in the active but not in the sham
treatment arm (p<0.0001). Unusually, the placebo response in this study was low and
the difference between the groups became statistically significant after the second
treatment session. In the active group, mean pain reduction was 58% with 7/11
(63%) classified as responders (>50% improvement). In the sham tDCS group, 1/6
(16%) patients reported over 50% improvement in pain intensity. Pain was evaluated
before and after each daily session and it was found that the analgesic effect of
treatment was maintained over at least 24 hours. The effect diminished over 16 days
of follow-up with only four subjects in the active tDCS group still considered
responders versus none in the sham group. Scores on the Clinical Global
Assessment and Patient Global Assessment were also significantly different between
active and sham groups at some time-points up to day 5 but not beyond.
45
5.7.6 Conclusion back pain resulting from spinal cord injury Clinical effectiveness of neurostimulation for back pain resulting from spinal cord injury
• Spinal cord stimulation (SCS): Based on systematic review evidence from
case-series (total n=101), SCS may provide initial pain relief in 50−70% of
patients selected for device implantation; there is little evidence on longer-term
pain relief. Results from case-series need to be interpreted cautiously,
particularly where data has been pooled from across several case-series.
• Deep brain stimulation (DBS): Based on systematic review evidence on 36
patients (of which 19 had permanent DBS implants) from across five case-
series, both initial and long-term response rate to DBS appears to be poor to
moderate in patients with pain subsequent to spinal cord injury (SCI). Results
from case-series need to be interpreted cautiously, particularly where data has
been pooled from across several case-series.
• Motor cortex stimulation (MCS): Based on systematic review evidence on 11
patients from case-series, MCS appears, at best, moderately effective in the
long-term treatment of neuropathic pain subsequent to SCI. Results from
case-series need to be interpreted cautiously, particularly where data has
been pooled from across several case-series.
• Transcutaneous electrical nerve stimulation (TENS): One small RCT (20
relevant patients) found no difference between TENS and placebo.
• Repetitive transcranial magnetic stimulation (rTMS): Results from two small
RCTs (total n=25) suggest little difference between rTMS and sham rTMS.
• Cranial electrotherapy stimulation (CES): Results from one RCT (n=30)
suggest that CES may be effective at reducing pain intensity during, and
immediately after treatment, compared to sham CES; the other RCT (n=38)
found no significant differences.
• Transcranial direct current stimulation (tDCS): There is evidence from one
RCT of tDCS (n=17) that this treatment may have positive short-term effects
(up to 5 days) on chronic central pain following traumatic SCI.
Note: all the above RCTs are small and may not have been powered to show
significant differences.
46
5.8 Safety Spinal cord stimulation Both trials reviewed by Simpson 20093 (PROCESS and North trials) assessed SCS
device-related complications. Commonly reported complications included electrode
migration (16%), pain at implant incision site (9%), device lead fracture (5%), loss of
paraesthesia (9%) and infection or wound breakdown (9%).69,77 The North trial
reported adverse events at 6-month follow-up. Four of 15 patients (27%) experienced
a device-related adverse event, all of which required surgical correction.77 This
included the removal of the stimulation device in one patient due to infection. The
device was later re-implanted with no further complications. The other three cases
involved electrode migration or malposition. Similar rates of device-related
complications were reported in the PROCESS trial. At 12 months’ follow-up,
84 patients had received SCS. This figure included some patients originally
randomised to CMM who had opted to crossover to neurostimulation treatment after
six months. Forty device-related events were reported in 27/84 patients (32%), of
whom 20 (24%) required surgical revision.70 Long-term follow-up data were reported
only for patients originally randomised to SCS. Of the 52 patients originally treated
with SCS, 24-month results were available in 42. Nearly half of patients (19/42, 45%)
experienced 34 device-related events between them, 13 of whom (31%) required
correctional surgery.71 The majority (79%) of complications occurred in the first year
after implantation of the device. The PROCESS trial authors asserted the
complications were “benign, reversible and not incapacitating” and stated the
frequency of device-related revisions showed a marked reduction after the first
year.71
Additional safety data can be gleaned from the systematic review by Taylor 2005a47,
which included case-series evidence encompassing over 3000 patients implanted
with SCS devices, with the majority (97%) suffering specifically from FBSS or chronic
low back or leg pain. Data specifically for back pain indications could be extracted
from 18 of the case-series representing 112 back pain patients, of whom 48 (43%)
experienced one or more complication with SCS. Overall, the type and rate of
adverse events reported in these case-series was similar to that seen in the RCTs
above, with the majority due to hardware issues: electrode or lead problems occurred
in just over a quarter of cases (195/722, 27%), extension cable problems in 10% and
generator problems in 6%. Infections were reported in 6% of implanted patients and
cerebrospinal fluid leaks in 7%. No neurological complications were reported. These
47
data are consistent with non-disaggregated data from other RCTs3 and case-series60
of SCS.
Deep brain stimulation The five case-series80,82,84,119,120 of DBS identified in the review by Prévinaire 200961
encompassed a total of 334 patients, 36 of whom had pain resulting from SCI, with a
further 72 experiencing pain due to FBSS80,84,120 and 51 with low back pain82. Only
four80,82,84,119 of these case-series reported adverse events. The systematic review by
Bittar 200553 did not report on safety outcomes. The original reports of the three
studies79,81,83 not included in Prévinaire 2009 were consulted. These case-series
comprised a further 148 patients, 61 with FBSS and two with SCI. Follow-up times
ranged from 2 months to 15 years; mean follow-up times (stated for three case-
series) ranged from 20 months to 6.8 years.
Based on these reports, approximately one-quarter of patients experienced major
adverse events. A total of 100 major adverse events occurred in 409 implanted
patients, the most common being infection (9%, n=37), followed by intracranial
haemorrhage (3%, n=12, with two deaths), scalp erosion (3%, n=13), and seizures
(1%, n=4). The intracranial haemorrhages were thought to be caused by the insertion
tool – a risk likely to be decreased by technological developments.81 Complications
required surgical intervention in 74 cases (18%), and explant of the device in 19
cases (5%). The most commonly reported minor complications were migraine (in
51% of 141 patients in the study by Levy and colleagues82), headache (in 22% of 68
patients in the study by Kumar and colleagues84), and device-related issues,
although these have decreased with technical improvements in electrodes,
stimulation devices and surgical technique over the last 20 years. Compared with 32
instances (9%) in 337 reported cases79,80,82,83 in the 1980s, only six device-related
complications (4%) were reported among the 145 patients in the three case-series
since then.84,119,120 With the development of rechargeable units, battery depletion no
longer requires surgical replacement. Visual disturbances were reported in five
patients (3%), although improvements in surgical knowledge relating to electrode
placement has resolved this issue in recent years.81
Motor cortex stimulation Only one of the three relevant studies identified by Prévinaire 200961 reported on
adverse events. This study121 comprised a total of 32 patients who received MCS for
the treatment of central neuropathic pain (three with pain aetiology subsequent to
48
SCI), with a mean follow-up of 27.3 months. Five patients experienced minor adverse
events. The most common was headache in the region of the electrode (n=3). Two of
these cases resolved after reducing stimulation intensity without loss of analgesia.
The other complications were a spinal haematoma and an infection in the stimulator
pocket and along the lead that required device explant. One instance of dehiscence
(splitting open) of the stimulator pocket scar was also reported and this required
surgical intervention to re-close the suture site. Explant was also necessary in a case
following an implant site infection at six months.122
Transcutaneous electrical nerve stimulation Only one24 of the three included systematic reviews reported on safety aspects of
TENS in the treatment of back pain and the other systematic reviews identified by the
literature searches for this report and original RCT reports were consulted where
possible. There was a paucity of information regarding adverse events in the
included RCTs, with only one85 of the four85,92,93,95 reporting on complications. In the
trial by Deyo and colleagues85, minor skin irritation at the site of electrode placement
was reported in one-third of participants (exact number not reported), with the rate of
events being similar in the active and sham arms. One participant randomised to the
sham group developed severe dermatitis four days after treatment commenced and
was forced to withdraw from the trial. None of the other RCTs covered in this report
reported specifically on adverse events; however, six patients dropped out of the
study by Cheing and colleagues due to pain-related adverse events (two due to
experimental pain, four due to increased low-back pain or lack of treatment effect,
reported in Khadilkar 2008).24 Similarly, one patient receiving TENS plus acupuncture
withdrew from the study by Itoh and colleagues due to worsening of pain and a
further five patients, spread across all four treatment arms, withdrew due to lack of
analgesic effect of treatment.64 Overall, the rate of adverse events from TENS
treatment appears to be low, with minor skin irritation being the most commonly
reported. This is consistent with other reports in the literature.58,59 None of the RCTs
reported adverse events. In the study of PENS versus TENS, three participants of 60
(5%) withdrew due to poor treatment acceptability.103
Non-invasive brain stimulation Based on 19 studies (n= 416) of non-invasive brain stimulation techniques reported
in Connell 201022 that reported adverse events, complications appear relatively
infrequent, minor and short-lived, the most common being headache (13 active, 7
sham), followed by nausea and skin irritation. Fregni and colleagues also tested
49
effects of tDCS on cognitive and motor function and found no significant change in
either treatment group.117
50
Conclusions
Safety of neurostimulation for chronic/neuropathic back pain
• Spinal cord stimulation (SCS): Two RCTs (N=101) reported device-related
complication rates in between 23% and 45% of patients, but these were usually
minor. The incidence of adverse events necessitating removal of the SCS device
was low (1%). The number of device-related complications falls significantly after
the first year. Similarly, 43% of subjects in 18 case-series (N=112) experienced
complications, with hardware problems being the most common. Other
complications included infections and cerebrospinal fluid leakage.
• Deep brain stimulation (DBS): Major adverse events occurred in 100 of 409
implanted patients across seven case-series. Three-quarters of these required
surgical revision. Infections were the most common complication (9%) followed by
scalp erosion (3%) and intracranial haemorrhage (3%). Two deaths occurred
following intracranial bleeds. Other complications included seizures (1%) and
involuntary eye movements (1%). Hardware issues appear to have significantly
reduced in number with improvements in surgical expertise and in the hardware
itself.
• Motor cortex stimulation (MCS): Based on reports from 33 patients, adverse
events occur in approximately one in five cases, although the majority are minor
and resolve spontaneously. Infections requiring device removal occurred in 6%
(2/33) patients.
• Transcutaneous electrical nerve stimulation (TENS): Based on evidence from four
RCTs, treatment-related adverse events are relatively frequent but generally
minor, with skin irritation at electrode placement site being the most commonly
reported complication, occurring in up to one-third of cases.
• Non-invasive brain stimulation: Based on evidence from 19 RCTs (N=416),
adverse events are relatively infrequent, and generally minor and short-lived. Skin
irritation and itching at electrode site, mild headache and nausea are the most
commonly reported.
• Percutaneous electrical nerve stimulation (PENS): Insufficient information is
available from the sources used in this report to comment on the safety of this
intervention for the treatment of chronic low back pain.
51
5.9 Cost-effectiveness Spinal cord stimulation Four full economic evaluations (Simpson 20093, Taylor 2005b66, Taylor 201067 and
North 200768) were identified. The economic evaluation by Taylor 2005b66 compared
SCS with CMM, however at the time of writing the report, results of the PROCESS
trial69-73 had not yet been published and effectiveness data were estimated based on
an indirect comparison using the North trial74,75,77 (comparing SCS with re-operation)
and an RCT of CMM versus re-operation in patients with chronic leg and back pain.
As this is likely to introduce uncertainty, this economic evaluation is not discussed
further, as there are more recent evaluations available that do use effectiveness data
from the PROCESS trial to inform their model.
Simpson 20093 evaluated the cost-effectiveness of SCS in comparison with both
conventional medical management and re-operation, using a UK NHS perspective.
A Markov model with five health states was used and input parameters were based
where possible on a systematic review of RCTs. Probabilities for trial stimulation
success and numbers of patients achieving pain relief of at least 50% were based on
RCT evidence. Cost data from one of the RCTs could not be used due to
confidentiality issues and were thus taken from a number of other sources. Utility
values were based on those from the PROCESS trial.69 The evaluation was
assessed as being of good quality overall (see Appendix 5 on CRPS, p209, Table
29).
The base-case results found costs per QALY of £7996 (with conventional medical
management as comparator) and £7043 (with re-operation as comparator). The
base-case assumes a 15-year time horizon, device longevity of four years and device
cost of £7,745. ICERs (incremental cost-effectiveness ratios) at one and two years
are £71,010 and £29,855 (SCS versus CMM) and £63,201 and £26,114 (SCS versus
re-operation).
The base-case results were found to be sensitive to variations in device longevity
and cost. When SCS device costs varied from £5,000 to £15,000 the ICERs ranged
from £2,563 per QALY to £22,356 per QALY for FBSS in comparison with CMM, and
from £2,283 per QALY to £19,624 per QALY for FBSS in comparison with re-
operation. If device longevity (one to 14 years) and average device price (£5,000 to
£15,000) were varied simultaneously, ICERs were below or very close to £30,000 per
52
QALY when device longevity was three years and below, or very close to £20,000
per QALY when device longevity was four years. Probabilistic sensitivity analyses
found a high likelihood of SCS being cost-effective for FBBS at a threshold of
£20,000/QALY (99.02% where the comparator is CMM and 100% where the
comparator is re-operation).
North 200768 evaluated the cost-effectiveness of SCS compared to re-operation only
using a US hospital health services perspective. This was conducted alongside an
RCT, which provided effectiveness data. Cost data were collected directly from the
patients in the trial. Based on previous studies, utility values were ‘imputed’. This
evaluation was assessed as being of reasonably good quality, though there was less
methodological detail than in the other two evaluations and sensitivity analyses were
lacking (see Appendix 3, p194, Table 20 for quality assessment).
The ICER was dominant (SCS more effective and cheaper) at a trial follow-up period
of 3.1 years. This was the case for both analyses conducted (intention-to-treat, and
‘treated-as-intended’ where crossovers were counted as failures). No sensitivity
analyses were performed, despite the authors stating that the confidence intervals for
costs and outcomes were wide. The study was supported in part by the
manufacturer.
Taylor 201067 evaluated the cost-effectiveness of SCS compared to both CMM and
re-operation from a UK perspective. A Markov model with six health states was
constructed. Clinical data (pain relief, complications) were based on the PROCESS
and North trials. Utility values were based on EQ-5D measurements taken during the
PROCESS trial. Costs were taken from standard UK sources and from the
PROCESS trial. This evaluation was assessed as being of good quality (see
Appendix 3, p194, Table 20).
Over a 15-year time period (base-case) the ICERs were £5624 and £6392 for SCS
versus CMM and re-operation respectively. Further, there was a probability of 89%
that SCS would be cost-effective at a willingness to pay threshold of £20,000 and a
probability of 98% of cost-effectiveness at a willingness to pay threshold of £30,000
(82% and 93% respectively for SCS versus re-operation). Sensitivity analyses found
that the factors having the greatest impact on increasing cost-effectiveness were (i)
decreasing cost of adjunct pain therapy for SCS, (ii) time before a replacement pulse
generator is needed decreases, (iii) cost of alternative therapy increases and (iv)
53
annual probability of no pain relief with SCS decreases. Overall sensitivity analyses
found that ICERs ranged from >£20,000 to dominant depending on the parameters
varied. However, SCS was found only to be no longer cost-effective (at a willingness
to pay threshold of £20,000) when pulse generator longevity decreased substantially
(for SCS versus CMM and versus re-operation) or when adjunct drug therapy costs
for SCS patients increased (for SCS versus re-operation).
Based on the two economic evaluations with the most robust methodology (Taylor
201067 and Simpson 20093), SCS appeared to be cost-effective compared to both
CMM or re-operation (ICERs between £6000 and £8000) over a time-horizon of 15
years and assuming a willingness to pay threshold of £20,000. These base-case
ICERs varied across sensitivity analyses. For example, a decrease in pain relief over
time and increase in medication use would decrease the cost-effectiveness, whilst
increased device longevity and decreased device cost would increase cost-
effectiveness. Probabilistic sensitivity analyses in both analyses found high
probabilities of achieving cost-effectiveness at willingness to pay thresholds of
£20,000 and £30,000. The evaluation by North found a much greater cost-
effectiveness with SCS dominant compared to re-operation at 3.1 years.
It should be noted that there are a number of assumptions underpinning these
results, and that effectiveness data has been extrapolated beyond the length of the
trials. Effectiveness data is based on fairly small patient numbers from the North trial,
which will introduce some uncertainty. Further in-depth analysis of model structures,
assumptions made and range of input variables would need to be undertaken in
order to fully assess the validity of these results.
Conclusion
Cost-effectiveness of neurostimulation for chronic/neuropathic back pain
Spinal cord stimulation (SCS): Based on two good economic evaluations, SCS
appears to be cost-effective at recognised willingness to pay thresholds over a time
horizon of 15 years; there are a number of assumptions underpinning these results
that need to be taken into account when interpreting results; not all of these have
been fully explored herein.
54
5.10 Discussion
Failed back surgery syndrome The bulk of evidence indentified was for SCS for FBSS in the form of numerous
systematic reviews. These all referred mainly to two RCTs, comparing SCS to CMM
(PROCESS trial) or re-operation (North trial). The RCTs were of reasonably good
quality.
The PROCESS trial suggested that SCS was significantly more effective than CMM
in relieving pain and functional status. There was little difference in medication use
but HRQoL was overall significantly better in the SCS group at six months. The
North trial used a composite outcome measure (50% improvement in pain scores
and being prepared to undergo procedure again). Results for this outcome were also
significantly better in the SCS group compared to re-operation, however, it has been
suggested that this may not be the most appropriate outcome measure to use; pain
scores alone were not reported. Opiate use in the re-operation group was
significantly increased compared to the SCS group.
There are no long-term quality of life data. Overall the evidence appears to be slightly
stronger for the benefits of SCS versus CMM compared with SCS versus re-
operation. Due to the number of reviews identified, and through searches for RCTs
for this report, it appears that these are the only two relevant RCTs. Based on two
good economic evaluations, SCS was also found likely to be cost-effective compared
to CMM or re-operation at willingness to pay thresholds of £20,000 and £30,000. This
is based on a number of assumptions, which have not all been fully explored in this
report.
Evidence for DBS in FBSS is in the form of 59 patients drawn from across six case-
series. These patients appeared to benefit from DBS, though the usual concerns
regarding case-series evidence apply. There is an additional concern around the
validity of pooling results from different case-series. Furthermore, not all patients
(92%) went on to have the stimulator implanted, suggesting that some patients (8%)
went through the procedure and associated risks of having electrodes implanted, but
were not able to benefit. The case-series were published over a decade or more ago,
and procedural improvements may have increased the conversion rate.
55
Low back pain Most of the evidence for this indication lies with RCTs of non-invasive (or less
invasive) neurostimulation techniques (TENS, PENS, CES). For TENS, only more
recent evidence from three good quality systematic reviews has been included in this
report; we know that there are at least five RCTs in addition to the ones within the
three systematic reviews, however, these are likely to have been small and/or of poor
quality or with non-disaggregated results for back pain. It is therefore unlikely that
they would have added useful information. The evidence for PENS stems from the
only relevant systematic review identified; there is little reporting on the review
methodology and thus the quality of the review. Searches for this report, however,
only identified one further (recent) RCT. For DBS, the relevant review identified,
indicates that the evidence is limited to that from case-series.
There were 11 RCTs of TENS versus sham-TENS (or other comparators) included in
the reviews. Overall, there is no evidence that TENS is significantly better than any
comparator, though a small number of trials found significant differences for some
outcomes. Trials showed considerable heterogeneity in their protocols (e.g. type of
TENS, treatment frequency and duration). There were methodological issues with
many of the trials, including small sample size, uncertainty around analyses (e.g.
intention-to-treat or not) and issues around blinding; it may not always have been
possible to successfully blind patients.
There is some evidence (from four RCTs conducted by one research group) to
suggest that PENS might be effective in reducing pain intensity, medication use and
physical impairment in the short term. There is some uncertainly associated with
these results due to methodological concerns (e.g. inadequacy of blinding, lack of
clarity over how missing data was dealt with). Three further RCTs considering
medium-term outcomes produced somewhat conflicting results. PENS performed
significantly better than sham-PENS in one trial (up to three months), another found
significant differences in favour of PENS at one but not at two months, and a third
large RCT (n=200) found no significant differences at any time-point up to six
months. There was some heterogeneity in trial protocols (e.g. comparators or
concomitant therapy).
For CES, there was evidence from two small but well-conducted RCTs (total n=53).
These did not find a significant difference between active and sham CES for pain
relief or medication use; it should be noted that the level of stimulation used in the
56
sham group was lower than in the active group, but higher than active treatment in
other CES studies.
Evidence for DBS for chronic low back pain is in the form of 103 patients drawn from
across six case-series. These patients appeared to benefit moderately from DBS,
though the usual concerns regarding case-series evidence apply. There is an
additional concern around the validity of pooling results from different case-series.
The previous caveats around conversion from electrode implantation to having the
stimulator internalised also apply here (see previous page), only more so as only
68% of patients had the stimulator implanted.
Spinal cord injury Evidence for SCS, DBS and MCS is in the form of case-series evidence, with SCI
patients drawn from mixed populations. There were 101, 36 and 11 patients for the
three types of neurostimulation respectively. SCS appears to be effective in the short
term, but there is little evidence on longer term effects. The results for MCS appear
modest particularly over the longer term and are based on very few patients. The
results for DBS appear to show only minor benefit, though there are some
discrepancies depending on the review informing the results; patient numbers are
also very low. Not all patients will respond successfully to test stimulation and not all
will go on to have a device implanted; these patients would still be exposed to the
risks associated with electrode implantation.
There is some evidence from (mainly small) RCTs for TENS, rTMS, CES and tDCS;
only 1 or 2 RCTs were identified for each of the techniques. For TENS, one small
RCT (20 relevant patients) found no difference between TENS and placebo. For the
other techniques, there was some evidence of benefit from the active compared to
the sham treatment for some outcome measures, at some time-points; there was,
however, some uncertainty over long-term benefits and whether differences were
always clinically meaningful.
Safety As expected, the more serious adverse events occur with the more invasive
technologies. These are mainly hardware related, in some cases requiring surgical
revision or re-implantation. Other adverse events include infections, cerebrospinal
fluid leakage (with SCS) and intracranial haemorrhage (with DBS). Deaths have been
reported for DBS. Adverse events associated with the less invasive techniques are
57
generally minor and include mainly skin irritation. It is not possible to draw
conclusions regarding the frequency of the events, as a systematic review of adverse
events across indications for each technology has not been undertaken for this
report. The information provided here is designed to give the reader an indication of
the possible adverse events that are likely to occur.
58
6 TRIGEMINAL NEUROPATHIC AND DEAFFERENTATION PAIN
6.1 Description of the underlying health problem The International Classification of Headache Disorders (ICHD-II 2005) classifies
trigeminal neuralgia as a secondary headache disorder in the category of ‘cranial
neuralgias and central causes of facial pain’.123 This is further categorised as
classical or symptomatic trigeminal neuralgia. Classical trigeminal neuralgia is
characterised by severe unilateral paroxysmal facial pain, which is described as
stabbing, shooting, excruciating, burning and extremely strong.124 Onset of pain is
sudden and usually lasts from a few seconds to around two minutes affecting one or
more branches of the trigeminal nerve.125 Attacks can be triggered by routine daily
activities such as brushing teeth, encountering a breeze, speaking, eating or smiling;
they can be repetitive and can persist in total for several minutes or even hours, and
the intensity of the pain can be physically and mentally incapacitating.17,124 The
diagnostic criteria for classical trigeminal neuralgia (ICHD-II) are:123
A. Paroxysmal attacks of pain lasting from a fraction of a second to 2 minutes, affecting one or more divisions of the trigeminal nerve and fulfilling criteria B and C B. Pain has at least one of the following characteristics: 1. Intense, sharp, superficial or stabbing 2. Precipitated from trigger areas or by trigger factors C. Attacks are stereotyped in the individual patient D. There is no clinically evident neurological deficit E. Not attributed to another disorder In symptomatic trigeminal neuralgia, the pain is indistinguishable from classical
trigeminal neuralgia but caused by a demonstrable structural lesion other than
vascular compression. The diagnostic criteria for symptomatic trigeminal neuralgia
are: 123
A. Paroxysmal attacks of pain lasting from a fraction of a second to 2 minutes, with or without persistence of aching between paroxysms, affecting one or more divisions of the trigeminal nerve and fulfilling criteria B and C B. Pain has at least one of the following characteristics: 1. Intense, sharp, superficial or stabbing 2. Precipitated from trigger areas or by trigger factors C. Attacks are stereotyped in the individual patient D. A causative lesion, other than vascular compression, has been demonstrated by special investigations and/or posterior fossa exploration Anaesthesia dolorosa is defined by the ICHD-II as persistent and painful anaesthesia
or hypaesthesia in the distribution of the trigeminal nerve or one of its divisions or of
the occipital nerves. Diagnostic criteria are:123
59
A. Persistent pain and dysaesthesia within the area of distribution of one or more divisions of the trigeminal nerve or of the occipital nerves B. Diminished sensation to pin-prick and sometimes other sensory loss over the affected area C. There is a lesion of the relevant nerve or its central connections Anaesthesia dolorosa (AD) is frequently related to surgical trauma of the occipital
nerves or trigeminal ganglion, occurring most frequently after rhizotomy or
thermocoagulation has been performed for treatment of classical trigeminal
neuralgia.123
A classification system was also proposed by Eller 2005126, which has been adopted
by the National Pain Foundation127 and the Facial Pain Association (see Table 5
below).128 In this system, idiopathic trigeminal neuralgia 1 corresponds to the
classical trigeminal neuralgia described above. There is a further category of
idiopathic trigeminal neuralgia 2, which is categorised by a more constant, aching
pain. The definitions for symptomatic trigeminal neuralgia and anaesthesia dolorosa
appears to broadly correspond to the ICHD-II classification, however, Eller 2005126
also defines the terms trigeminal neuropathic pain (TNP) and trigeminal
deafferentation pain (TDP), with AD a sub-category of TDP. In the literature, terms
for trigeminal neuralgia are not always used consistently and the pain may be
described generally as ‘trigeminal pain’ or ‘pain in the trigeminal area’.
TNP occurs after an injury to one or more branches of the trigeminal nerve, for
example, following dental procedures, sinus surgery or facial fractures. As surgery
can be used to treat TN, patients in whom the surgery for TN has failed may also
suffer from TNP, in which case it is referred to as TDP, or, in severe cases, AD.129
There are currently few effective treatment options for these conditions and it is for
this patient group, TNP and TDP, rather than those with classical trigeminal
neuralgia, that neurostimulation techniques are being investigated. For the purposes
of this report, we will include any populations described as having TNP, TDP or AD.
There is a paucity of evidence on the natural history of TN and limited information on
the natural history of the TNP or TDP sub-groups was identified for this report.
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Table 5 Trigeminal neuralgia classification Types of trigeminal neuralgia (TN):126,127,128
• Idiopathic TN1 (typical TN, classic TN), characterised by sharp, shooting, electrical
shock-like, episodic pain (with greater than 50% of pain limited to the duration of a
temporary episode of pain).
• Idiopathic TN2: aching, throbbing, burning pain, >50% constant pain.
• Trigeminal neuropathic pain (TNP): resulting from unintentional injury to the
trigeminal system from: facial trauma; oral surgery; ear, nose and throat surgery; root
injury from posterior fossa or skull base surgery; or stroke. This is described as
unremitting throbbing or burning pain.
• Trigeminal deafferentation pain (TDP): resulting from intentional injury to the
trigeminal system from procedures performed for the treatment of trigeminal neuralgia
(neurectomy, rhizotomy, nucleotomy, radiosurgery or other). This pain is described as
burning, crawling, itching or tearing. A severe form of this pain is anaesthesia dolorosa (AD), described as excruciating pain in a numb region of the face.
• Symptomatic TN (MS): TN associated with MS thought to be due to demyelination
in the trigeminal nerve or within the descending tract of the trigeminal system in the
brainstem.
• Symptomatic TN (other causes):TN associated with posterior fossa mass lesions,
Chiari malformation
• Post-herpetic TN: trigeminal pain resulting from an outbreak of facial herpes
zoster.
• Atypical facial pain: pain with a predominantly psychological rather than
physiological origin.
6.2 Epidemiology In the UK, a diagnosis of TN is made in 27/100,000 people each year, however
previous population based studies using a strict case definition estimated the rate at
4–13/100,000 per year.125 A prospective UK study estimated an incidence of
8/100,000.130 The incidence increases with age and is rare below 40; average age of
pain onset is typically in the sixth decade, but it can occur at any age.125,131
Symptomatic or TN secondary to a structural lesion is more likely to occur in younger
patients, whilst TN caused by compression of the artery is more likely in older
patients.131 More women than men are affected (3:2).131
61
Based on the strict case definition estimate of new diagnoses above, between 216
and 702 newly diagnosed cases can be expected in the West Midlands each year,
given a West Midlands population of 5.4 million (Office for National Statistics 2007
estimate).32 One estimate (based on a report from 1996132) suggests that around
25% of patients do not respond to medication. This does not take into account newer
(combinations of) medications or the fact that some initially responding patients will
become intolerant. No epidemiological data relating to the TNP and TDP sub-groups
specifically were identified for this report, however, there are likely to be fewer
patients than in the overall TN population.
Table 6 below summarises the epidemiological data. Please note that systematic
searches for this type of data were not performed and the validity of the results has
not been assessed (e.g. by looking at the sample size, methods of obtaining data
and case definitions).
Table 6 Epidemiological data TNP and TDP Indication
Measure Source
Trigeminal neuralgia Incidence: 27/100,000 per year Incidence: 4–13/100,000 per year (stricter case definition)
UK survey UK and US survey All cited in: Bennetto 2007125
Trigeminal neuralgia Incidence: 8/100,000 Prospective UK study130 TNP, TDP, AD No data identified No data identified
6.3 Treatment There are few, if any, effective treatment options for patients with TNP or TDP.
Medication is unlikely to be effective, although anticonvulsant and antidepressant
drugs may be used.129 Other procedures such as microvascular decompression and
radiosurgery that are effective for TN may worsen TNP are also likely to be of limited
value, and in fact many treatments that are effective for may worsen TNP.129,133
The limited treatment choices include peripheral (trigeminal) nerve stimulation (PNS),
motor cortex stimulation (MCS) and trigeminal tractotomy/nucleotomy; due to a high
risk of complications, this latter intervention is reserved for patients with cancer-
62
related pain and those with a short life expectancy.133 Deep brain stimulation (DBS)
has been investigated for this patient group (TNP/TDP).
No general consensus guidelines (UK or other) were identified on the treatment of
TNP or TDP, but a treatment algorithm developed by neurosurgeons at one US
centre was found,133 part of which is shown below (Figure 1). In these guidelines,
patients with a diagnosis of TNP or TDP would be considered for either PNS or MCS,
depending on presence/absence of numbness and distribution of pain.
63
Figure 1 Treatment algorithm for TNP and TDP CP=cerebellopontine, MCS=motor cortex stimulation , MRI=magnetic resonance imaging, MS=multiple sclerosis, MVD=microvascular decompression, PNS=peripheral nerve stimulation, RF=radiofrequency, SRS=stereotactic radiosurgery, TDP=trigeminal deafferentation pain, TN=trigeminal neuralgia, TNP=trigeminal neuropathic pain Adapted from Slavin et al., 2007133
Distribution of pain (branches):
Distribution of pain:
Complete numbness:
Treatment:
Prefers to avoid surgery:
General health/young age:
Diagnosis:
Previous surgery:
Presence of numbness:
Pain nature:
MRI findings:
Trigeminal pain
Normal CP angle mass lesion
MS Skull base cancer
Constant Sharp shooting
No Yes
No Yes
TN Type 1 TN Type 2 TNP TDP Symptomatic TN Cancer facial pain
Yes No
No Yes No Yes
No Yes
Mandibular
MVD RF gangliolysis Balloon compression
SRS PNS Neurectomy MCS Tractotomy
2, 3, 2+3
1, 1+2, 1+2+3
Supraorbital/ infraorbital
64
6.4 Quantity and quality of evidence The evidence in this area is very sparse (see Table 7 below). We identified no
systematic reviews specifically on neurostimulation for TNP or TDP pain, although
two systematic reviews53,62 on general pain conditions that included TNP/TDP
patients were found. Two narrative reviews only were identified for trigeminal
(peripheral) nerve stimulation in the treatment of TNP/TDP134,19. In order to be
consistent with our inclusion criteria (systematic review evidence and RCTs only),
narrative reviews have been excluded. Four RCTs, two on MCS, and two on rTMS,
all in mixed neuropathic pain populations, were identified. No cost-effectiveness
studies were found.
Table 7 Evidence on neurostimulation for TNP or TDP Indication Neurostimulator type Neuropathic/chronic pain (including
trigeminal/facial pain) Deep brain stimulation
Bittar 200553-SR
Motor cortex stimulation
Lima 200862-SR Lefaucheur 2009135-RCT Nguyen 2008136-RCT
Repetitive transcranial magnetic stimulation (rTMS)
Lefaucheur 2001137-RCT Lefaucheur 2004138-RCT
SR=systematic review; RCT=randomised controlled trial
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6.5 Deep brain stimulation for trigeminal neuropathic/deafferentation pain One systematic review (Bittar 2005)53 on deep brain stimulation (DBS) for any type of
neuropathic pain, which included results for four patients with trigeminal neuropathy,
was identified (see Table 7, p64). Twenty-eight patients defined as having
anaesthesia dolorosa (AD) were also included, and we have assumed that this refers
to pain in the trigeminal area. This review had a documented search strategy
(searches up to Jan 2003) and study selection criteria, and was considered to be of
reasonably good quality (see Appendix 4, p197, Table 21 for review characteristics
and Table 22 for quality assessment). The review found only case-series evidence.
No relevant RCTs were identified.
Of the four patients with TNP identified, all four were described as having “success
on both initial and chronic stimulation”. Electrodes were subsequently internalised in
all four patients (“100% success rate”). Regarding the AD patients, 17/28 (61%) were
described as having success on initial stimulation, and 8/28 (29%) as having success
on chronic stimulation. It is unclear if these patients were drawn from one or more
case-series; follow-up times and definitions of pain relief may be variable. Included
studies were published between 1977 and 1997, and it is possible that the treatment
of interest and alternative treatments have changed over time. Thus, results from
different years may not be directly comparable. There is no information on the patient
characteristics (e.g. age, duration of pain, cause of pain etc.), but it states in the
selection criteria for the systematic review that “all reasonable conventional methods
had failed or were poorly tolerated.” It is not possible to draw any conclusions from
this review regarding the overall effectiveness and applicability of this technique to a
general UK population with TNP, TDP or AD. It is notable that no evidence was
identified post 1997 and it is unclear if this technique is still being investigated in this
patient group.
6.6 Motor cortex stimulation for trigeminal neuropathic/deafferentation pain One systematic review62 on MCS for chronic pain generally was identified (see Table
7, p64). The systematic review appeared to be of good quality; however results were
not presented in a disaggregated way for different indications, and this report will not
be discussed further.
Two crossover RCTs of MCS, one for the treatment of refractory peripheral
neuropathic pain with 16 patients in total135 and one for chronic neuropathic pain with
10 patients,136 were identified. Both of these trials had mixed populations, and
66
included only six135 and three136 patients, respectively, with trigeminal pain. Results
were not available separately for the trigeminal pain patients for the randomised
phase of either trial, and as such the results are of limited value. In both trials, the
authors acknowledge that there may be potential carry-over effects.
A potentially relevant RCT was the planned CONCEPT trial of MCS for intractable
neuropathic pain, in particular for central post-stroke pain (CPSP) and TNP/facial
pain. However, this trial was terminated early due to a “consistently low enrolment
rate and procedural challenges that were unknown at the study start. It was not
based on safety or efficacy concerns.”139
A crossover RCT (Lefaucher 2009) included 16 eligible patients with various types of
neuropathic pain, 13 of whom were randomised to have the neurostimulator switched
on or off for a month.135 Six patients were described as having trigeminal pain. Trial
results based on several pain scores for all patients (not disaggregated for trigeminal
pain) showed little difference between the ‘on’ and ‘off’ conditions. An open phase
was continued up to 12 months, during which time all patients had the
neurotransmitter on. At 12 months the mean rate of pain relief for the trigeminal pain
patients was “good or satisfactory” for three of the six patients. Given the absence of
a control group at 12 months, this result is difficult to interpret, in particular due to the
lack of information on the natural history of the condition.
A crossover RCT by Nguyen included ten patients, of whom three suffered with
trigeminal pain and one with post-stroke facial pain.136 The 10 patients were
randomised to have the stimulator switched ‘on’ or ‘off’ for a 2-week period. There
was a significant improvement in four pain rating scales in the ‘on’ compared with the
‘off’ condition for the total patient group (not disaggregated for the trigeminal pain
patients); there was no significant difference in three further outcome measures
(quality of life, analgesic drug consumption and affective and sensory-discriminative
aspects of pain). All scores showed a significant decrease between pre-operative
evaluation and any time after one month and up to one year. Three of four patients
with facial pain were found to benefit from MCS at one year. Again, the lack of a
control group at this time-point hampers interpretation of this result.
67
6.7 Repetitive transcranial magnetic stimulation for trigeminal neuropathic/deafferentation pain
Two crossover RCTs (Lefaucheur 2001137 and 2004138) of rTMS versus ‘sham’ rTMS
were identified (see Table 7, p64). These were in mixed populations but both
included patients with trigeminal neuropathic pain, and some results were available
separately for these patients (n=7 and n=10, respectively). The 2001 trial included
seven TNP patients (of 14 patients in total).137 Efforts were made to ensure patient
blinding, but there were few details on other quality criteria. The trial appeared to
have a crossover design but this was not clearly described and there was no
discussion of wash out periods or potential carry over effects (see Appendix 4, p198
and p199, Table 23 for study characteristics and Table 24 for quality assessment).
The 2004 trial included 12/60 patients with facial pain (10 of which had TNP).138 This
appeared to be of better methodological quality. The authors tried to ensure a good
level of patient blinding and also had a 3-week wash out period between (active or
sham) treatment sessions. Pain assessments were performed only before and
immediately after treatment sessions, so no long-term results are available (see
Appendix 4, p198 and p199, Table 23 for study characteristics and Table 24 for
quality assessment).
In the 2001 trial137, 14 patients (7 with TNP) received one session of active or sham
rTMS treatment, after which they rated their daily pain every evening for 12 days
using a pain VAS.137 For the TNP patients, lower VAS scores (reduced pain) were
observed with active treatment on all follow-up days. Pain scores in the active group
decreased to day 4, then increased to day 12, though they remained lower than in
the sham group. Statistical tests for significance were not performed, and the authors
state that due to the small sample size it was not possible to obtain significant
results. Other relevant outcomes, such as quality of life, were not measured.
In the 2004 trial138, 60 patients (10 with trigeminal neuropathic pain) received one
session of either active or sham rTMS treatment.138 After a gap of at least three
weeks, patients then received the alternative treatment. Pain was measured on a
VAS, once before and once immediately after the treatment session. There were no
longer-term assessments and no other outcomes such as quality of life were
measured. Results show that for the 10 TNP patients, mean pain reduction on the
VAS was 36% greater with active compared to sham rTMS. Good individual results
(>30% reduction in pain VAS) were achieved in 58% of TNP patients. Statistical
significance was not calculated for these results. Origin of pain appeared to affect the
extent of benefit and patients with facial pain benefited more than those with limb
68
pain. The authors stated that the optimal effect of rTMS was delayed by 2–4 days but
this was not assessed in this study. They also state that repeated daily sessions may
be more effective as shown for other clinical indications, however, this was also not
assessed in this study.
6.8 Conclusion trigeminal neuropathic/deafferentation pain Clinical effectiveness of neurostimulation for trigeminal neuropathic/deafferentation pain
• Deep brain stimulation (DBS): there is insufficient evidence to draw any
conclusions; no recent reports (post-1997) on the use of this technique were
identified.
• Motor cortex stimulation (MCS): Results from two small RCTs on MCS do not
report results for the sub-group of trigeminal pain patients separately; results
for these few patients are available only for later time-points (open phase)
when there is no control group; they are therefore difficult to interpret
• Repetitive transcranial magnetic stimulation (rTMS): Evidence from two RCTs
(n=17) suggests a short-term reduction in pain. Long-term effects of repeated
treatment and the effect on quality of life are not known.
6.9 Safety
Deep brain stimulation The systematic review on DBS did not report safety outcomes/adverse events for the
four TNP/TDP patients. Generally, complications of DBS can include intracranial
haemorrhage (reported incidence of between 1.9% and 4.1%), mortality (0–1.6%),
infections (e.g. meningitis, encephalitis, incidence of between 3.3% and 13.3%);
more minor complications include transient headache, nausea and blurred vision.18
Motor cortex stimulation In the trial by Lefaucheur135 (n=16), there were no cases of haemorrhage, infection or
neurological complications. Nguyen 2008136 (n=10) also reported that no adverse
events occurred (no seizures and no infection). The systematic review by Lima
200862 did not report adverse events. The wider literature suggests that although the
rate of adverse events is low, serious complications have been reported in some
cases, including epidural haematomas and cerebral haemorrhage.18,129 Infection
69
requiring hardware removal or antibiotic treatment is slightly more common. Other
adverse events that have been reported include wound dehiscence, breakage of
hardware and transient or permanent neurological deficits. Adverse events
associated with programming/stimulation include the risk of seizures. Whilst seizures
do not necessarily lead to the development of epilepsy, there is at least one patient
who developed severe epilepsy after long-term MCS. In a case-series of 100 patients
(33 of whom had trigeminal pain, see Nguyen 2009140), the following complications
were reported: three with infection necessitating removal and re-implantation, one
with epidural haematoma, two with skin ulceration, one with an ischaemic event
(subsequently resolved), one with a cranial scar breakdown and two had the implant
removed due to lack of efficacy.
Repetitive transcranial magnetic stimulation There were no details on adverse events in the Lefaucheur 2001 trial.137 The
Lefaucheur 2004 trial reported that no adverse events were observed and in
particular that no seizures were induced.138
Conclusion
Safety of neurostimulation for trigeminal neuropathic/deafferentation pain
• Deep brain stimulation (DBS): Serious complications have been reported with
DBS, including mortality, haemorrhage, haematoma and infection. No details
on adverse events in TNP/TDP patients specifically were identified for this
report.
• Motor cortex stimulation (MCS): No adverse events occurred in the two small
RCTs (total n=26); the wider literature suggests that rates of complications are
low but can include haemorrhage, haematoma and infection, as well as wound
breakdown, breakage of hardware or neurological deficits.
• Repetitive transcranial magnetic stimulation (rTMS): One RCT reported no
adverse events in 60 patients after one 20-minute treatment session.
70
6.10 Cost-effectiveness No cost-effectiveness studies were identified.
Conclusion
Cost-effectiveness of neurostimulation for trigeminal neuropathic/deafferentation pain
• No cost-effectiveness data were identified.
6.11 Discussion
There is little evidence for the effectiveness of neurostimulation in TNP/TDP,
particularly for DBS. Two small RCTs of MCS (MCS ‘on’ versus MCS ‘off’), which
included six and three relevant (trigeminal pain) patients, respectively, presented
separate results for these patients at 12 months only, at which point the trial was
open label and there was no longer a control group.
Two RCTs on rTMS with small numbers of TNP patients show some evidence of pain
reduction after a single treatment session, although the small study size precludes
definitive conclusions. Longer-term studies would be necessary to determine whether
repeat treatments are beneficial, and which treatment protocols are most effective.
There are major and minor side effects associated with all techniques except rTMS,
where no adverse events were reported. Given the fact that adverse events are not
reported consistently, and the report only considers few studies, no definitive
conclusions can be drawn on the frequency of specific adverse events.
It was apparent that patients with TNP or TDP were often included in a trial or a
review as part of a wider patient group with neuropathic pain. With regard to literature
identification, it is possible that some reports or trials with mixed populations may not
have been identified, as this particular patient group may not have been mentioned in
the abstract or the terms used to index the study.
Primary research in the form of sufficiently powered RCTs would be necessary to
ascertain the effectiveness of neurostimulation in this patient population; however,
given the small numbers of patients with this condition, this may not be feasible, as
indicated by the premature termination of the planned CONCEPT trial.
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7 COMPLEX REGIONAL PAIN SYNDROME
7.1 Description of the underlying health problem Complex regional pain syndrome (CRPS) is an uncommon condition that causes
chronic severe burning pain in a limb (arms, legs, hands or feet). It often starts in an
arm or a leg and is characterised by a combination of autonomic, sensory or
vasomotor symptoms, including: pain, temperature asymmetry, impaired movement,
change in skin colour, hyperaesthesia (increased sensitivity to stimulation),
hyperalgesia (increased response to a stimulus that is normally painful), involuntary
movement, paresis (partial or mild paralysis), skin, muscle and bone atrophy,
hyperhydrosis (abnormally increased perspiration) and changes in hair and nail
growth. The condition usually requires long-term intensive therapy and has a major
impact on quality of life.96
The pathophysiology of CRPS is unclear, but it is usually triggered by a previous
injury or trauma. There are two types: type I is triggered by an apparently trivial injury
where no nerve damage has occurred (such as a sprained or fractured ankle); type II
is a result of a more serious injury such as a fracture, surgery or serious infection
with associated nerve damage, but the signs and symptoms are the same for
type I.141
The natural history of CRPS is poorly understood, partly due to the diversity of
patients, difficulty in diagnosis and retrospective data collection. It is common for
patients to have multiple failed or partially successful treatments. Some individuals
experience repeated episodes of CRPS throughout their life, whilst some achieve
remission from symptoms after a few months.141 Pain relief, functional capacity and
disease remission often remain suboptimal.142
7.2 Epidemiology CRPS appears more common in individuals aged between 40 and 60, but can affect
any age group including children; more women than men may be affected.141 Most
incidence estimates identified in the literature appear to rely on two population-based
studies, one from the Netherlands (2007)143 and one from the US (2003).144 The
Netherlands study found incidence rates of between 16.8 per 100,000 person years
(95% CI 14.7–19.2) and 26.2 per 100,000 person years (95% CI 23.0–29.7)
depending on whether more or less stringent case definition criteria were used. The
72
incidence estimate from the US study was lower, at 5.5 per 100,000 person years at
risk, and a prevalence of 20.6 per 100,000.
Using the US figure, this would suggest a prevalence of 1112 patients in the West
Midlands, given a West Midlands population of 5.4 million (Office for National
Statistics 2007 estimate).32
Table 8 below summarises the epidemiological data. Please note that systematic
searches for this type of data were not performed and the validity of the results has
not been assessed (e.g. by looking at the sample size, methods of obtaining data
and case definitions).
Table 8 Epidemiological data CRPS Indication
Measure Source
CRPS (no distinction between type I and II)
Incidence: 16.8 per 100,000 person years (95% CI 14.7–19.2) and 26.2 per 100,000 person years (95% CI 23.0–29.7) depending on case definition criteria
2007 population-based study from the Netherlands143
CRPS (no distinction between type I and II)
Incidence: 5.5 per 100,000 person years at risk Prevalence: of 20.6 per 100,000
2003 population-based study from the US144
7.3 Treatment Initial treatment options are pain medication such as anticonvulsants and tricyclic
antidepressants, and physical and/or occupational therapy to increase functionality.
Vasodilatory medication or percutaneous sympathetic blockades can be used to
promote peripheral blood flow. Psychological treatments such as cognitive-
behavioural psychotherapy or hypnosis may be offered, particularly where there is
continued extensive pain.96 A treatment algorithm from 201096 for CRPS type I states
that spinal cord stimulation (SCS) in a specialised clinic should be considered when
other therapies have had insufficient effect.
NICE guidelines from 2008 state that SCS is recommended as a treatment option for
adults with chronic pain of neuropathic origin who (i) continue to experience chronic
pain (measuring at least 50 mm on a 0–100mm VAS) for at least six months despite
73
appropriate conventional medical management, and (ii) who have had a successful
trial stimulation.5
7.4 Quantity and quality of evidence Most of the available evidence was for spinal cord stimulation (see Table 9 below) for
overview of evidence). The best systematic reviews were selected for evaluation.
There was very limited evidence for other types of neurostimulation.
Table 9 Evidence on neurostimulation for CRPS Type of NS Various indications including
CRPS CRPS only
Spinal cord stimulation British Pain Society Guidelines 200935-SR Simpson HTA 20093-SR Cruccu 20079 guidelines-SR Taylor 2006b46-SR Turner 200449-SR Mailis-Gagnon 200450-SR Cameron 2004145-SR Kemler 2000146, 2001147, 2004148, 2008149-RCT (reports of 6-month, 12-month, 2-year and 5-year follow-up) Kemler 2002150-EE
Kemler 2010151-EE* Perez 201096 guidelines-SR Tran 2010152-SR Taylor 2006a16-SR & EE Grabow 2003153-SR
Motor cortex stimulation
Velasco 2009154-RCT
Transcutaneous electrical nerve stimulation (TENS)
Perez 201096 Guidelines-SR
Repetitive transcranial magnetic stimulation (rTMS)
Cruccu 20079-SR (NB 10 patients with CRPS, no disaggregated results) Pleger 2004155-RCT
SR=systematic review; RCT-randomised controlled trial; EE=economic evaluation *identified after cut-off date for searches
74
7.5 Spinal cord stimulation for complex regional pain syndrome Seventeen reviews were identified, 11 of which 3,9,16,42,46,49,50,96,145,152,153 were
systematic (see Table 9 above). The most recent of these was published in 2010 by
Tran and colleagues and reviewed all treatments for CRPS. However, the 2009 HTA
report by Simpson3 utilised a more comprehensive search strategy and was more
specific in its remit, looking particularly at the use of neurostimulation for this
condition. As this review was of good methodological quality and fairly recent, it
forms the basis of our report in this section (see Appendix 5, p201 and p202, Table
25 for review characteristics and Table 26 for quality assessment).
The only evidence identified in this HTA was one small RCT in patients with CRPS
type I (Kemler 2000146 n=54, see Appendix 5, p205 and p206, Table 27 for study
characteristics and Table 28 for quality assessment of RCTs). Searches for this
report and inspection of the systematic reviews by Tran 2010152 and the Cochrane
review by Mailis-Gagnon 200450 failed to identify any further RCTs.
The overall quality of the Kemler trial was found to be generally good. The trial
appeared to have appropriate randomisation and concealment. Blinding of patients
was not feasible, as SCS treatment is associated with experiencing paraesthesias.
There were no details on blinding of outcome assessment where this was by study
investigators and not self-assessed. The trial was small (n=54). A power calculation
was performed but it was unclear if this took into account estimated early drop-out;
12/36 in the SCS group did not have an implant as trial stimulation was not
successful.
As there was only one RCT, the systematic review by Taylor 2006a16 was also
utilised as it had broader inclusion criteria for study design and included 25 case-
series (patients with CRPS type I and II). This review was also considered to have a
robust methodology (see Appendix 5, p201 and p202, Table 25 for review
characteristics and Table 26 for quality assessment). More recent systematic reviews
(Perez 201096 and Cruccu 20079 guidelines) were checked for additional case-series
evidence; only four case-series in total were included (one of them included in Taylor
2006a16). Little useful information was reported and these reviews are not considered
further. We identified one economic evaluation of SCS for CRPS (Kemler 2002,150
the results of which are also reported in Taylor 2006a.16)
75
The RCT randomised patients to SCS plus physical therapy (PT) or PT only. Results
were reported in four publications: Kemler 2000 (follow-up at six months),146 Kemler
2001 (follow-up at 12 months),147 Kemler 2004 (follow-up at two years)148 and
Kemler 2008 (follow-up at five years).149 Patients had to meet the diagnostic criteria
for reflex sympathetic dystrophy (now known as CRPS I) established by the
International Association for the Study of Pain (1994156). Additionally the condition
had to be restricted to one hand or foot, affect the entire hand or foot, to have lasted
for at least six months with no sustained response to standard therapy and be
associated with a mean pain intensity of 5 cm (pain VAS).
Results were presented as ITT analyses at six months, two years and five years,
which is the method least likely to overestimate treatment effects. Three patients
were excluded at year two, which should not be the case in an ITT analysis, but the
analysis did include 12 (33%) patients in the SCS group who did not have an implant
after the test period. It is unclear how many results were carried forward from
previous assessments and how this would influence results. Ideally a sensitivity
analysis would also have been undertaken rather than relying on the last observed
results. There was some crossover of patients over time: by five years, four patients
in the PT-only group had received implants.
Implanted patients reported a significant reduction in pain as measured by a VAS at
both six months (–2.4±2.5 compared with +0.2±1.6 in controls, p<0.001) and two
years (–2.1±2.8 versus 0±1.5 in controls, p=0.001). Similar results were reported for
changes in global perceived effect. The effect appeared to diminish somewhat at the
three year time-point, and at five years, there were no longer any significant
differences between the groups for either measure.149 This finding appeared to be
partly due to reduced effects of treatment and partly to improvements in the PT-only
control group; the fact 4/18 patients in this group had received an implant may also
have had an effect. SCS did not appear to influence health-related quality of life or
functional status. Nevertheless, patient satisfaction was high in those who received a
permanent implant. At 12-month follow-up, sensory test parameters were evaluated
in patients with and without implants (not per randomisation), with little or no long-
term effect of treatment being observed on detection of pain thresholds for pressure,
warmth and cold, or the extent of mechanical hyperalgesia.
In addition to the RCT evidence, the systematic review by Taylor (2006a)16 identified
25 case-series with a total of 500 patients with CRPS type I or II. Overall the case-
76
series were assessed as being at high risk of bias. The authors found there were few
details on patient selection, co-interventions, methods of outcome assessment or
loss to follow-up. Outcomes were not reported consistently across the 25 case-series
and only selected studies contributed to individual pooled results. Median follow-up
time was 33 months. Based on evidence from seven case-series, SCS resulted in a
significant pooled mean reduction in VAS score of 4.7 (95% CI 3.4, 6.0), although
length of follow-up across the case-series was not clear. Further, an average of 67%
of patients (95% CI 51%, 84%) achieved pain relief of at least 50%. It was not clear
how many, or which, case-series informed this finding. Functional capacity was also
improved across all subscales following implantation in the three case-series that
reported on this outcome. There was no evidence on potential differences in
effectiveness for CRPS type I or type II. There were also no details on the success
rate of trial stimulation and percentage of patients receiving permanent implants.
Given the nature of the evidence and inherent biases associated with it, no firm
conclusions can be drawn from this data.
7.6 Motor cortex stimulation for complex regional pain syndrome One small study (Velasco 2009, n=5)154 was identified (see Table 5, p60), which had
a double-blind, randomised phase during which MCS was ‘on’ or ‘off’. The biggest
methodological problem with this trial was the sample size and the fact that the
authors do not discuss potential carry-over effects (see Appendix 5, p205 and p206,
Table 27 for study characteristics and Table 28 for quality assessment).
Randomisation was by ‘lottery number’ which may not have been an adequate
method.
Results were available in four of five patients in whom the system was implanted.
There were two patients with CRPS type I and two with CRPS type II. MCS was
switched off randomly after either 60 or 90 days, for a period of 30 days. It was found
that pain measured on three different scales decreased during the ‘on’ period (with
the exception of one measure in one patient), and increased during the ‘off’ period
(also with the exception of one measure in one patient). It is unclear at which time-
points during the ‘on’ and ‘off’ periods pain was measured and whether this was the
same for all patients. At the end of the follow-up period (36–72 months), pain scores
were reduced in all four patients compared with baseline and ‘off’ period (no details
on statistical significance); however, it should be noted that there was no control
group at this time.
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7.7 Repetitive transcranial magnetic stimulation for complex regional pain syndrome
One small RCT (Pleger 2004)155 was found where rTMS was tested against 'sham'
rTMS in 10 patients with CRPS type I (see Table 5, p60). This appears to be a
reasonably well-conducted crossover trial, which is limited by (i) the small sample
size and (ii) the short treatment period and follow-up time (90 minutes). Patients were
blinded as far as possible, but it is not known how successful this was (see Appendix
5, p205 and p206, Table 27 for study characteristics and Table 28 for quality
assessment).
Patients were randomised to treatment or placebo for a 90-minute period, and the
treatments were reversed the following day. Pain was measured on a VAS (0–10).
There was a significant difference in pain levels between groups after 30 seconds, 15
minutes, 45 minutes and 90 minutes, favouring active rTMS treatment. Pain intensity
increased again 45 minutes after treatment had ceased. It is unclear whether there is
likely to be a carry-over effect from the treatment period to the placebo period. Other
outcome measures, such as quality of life, could not be considered given the short
treatment period.
7.8 Transcutaneous electrical nerve stimulation for complex regional pain syndrome
The evidence for the use of TENS was very limited (see Table 5, p60). The
systematic review by Perez 201096 (see Appendix 5, p201and p202, Table 25 for
review characteristics and Table 26 for quality assessment) identified two small (total
n=21) case-series described as being of limited quality and concluded that there was
insufficient evidence to demonstrate effectiveness.
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7.9 Conclusion complex regional pain syndrome
Clinical effectiveness of neurostimulation for CRPS
• Spinal cord stimulation (SCS): Evidence from one small but well-conducted
RCT (n=54) suggests a significant reduction in pain and a significant
improvement in global perceived effect at six months and two years. After
three years the effect appears to diminish, although patient satisfaction
remained high. At five years, there were no longer significant differences
between groups on any measure. The effect on quality of life at any time-point
is uncertain.
• Motor cortex stimulation (MCS): Pain decreased during the ‘on’ phase of one
small RCT (n=4). No long-term results are available. Quality of life did not
differ between stimulation ‘on’ and ‘off’ periods.
• Repetitive transcranial magnetic stimulation (rTMS): Evidence from one small
trial (n=10) suggests that pain levels can be significantly reduced with active
treatment versus sham treatment over a 90-minute treatment period. Pain
recurred once the treatment ceased and the longer-term effects of extended or
repeated treatment periods are unknown.
• Transcutaneous electrical nerve stimulation (TENS): There is insufficient
evidence to draw any conclusions.
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7.10 Safety Spinal cord stimulation The Kemler RCT reported 29 complications requiring re-operation in 10/24 patients
during a five year period.148,149 These included repositioning of the lead, pulse-
generator pocket revision and re-implantation of system. Most of these (21/29)
occurred during the first two years. In total, 17 pulse-generator replacements were
required, most in years three to five. Side effects were reported by all patients with an
implant (e.g. pain/irritation from subcutaneous system parts; amplitude changes from
electrode relocation during spinal movement). More serious complications were dural
puncture during implantation of system (n=2) and infection (n=1).
Only eight of the 25 case-series included in the systematic review by Taylor (2006a)
reported on adverse events.16 Based on these studies, 33% (22/66) patients had at
least one complication, the majority of which (20%) were related to electrode issues.
Other complications included infections, generator issues and haematomas. None of
the complications were considered to be serious.
Motor cortex stimulation No immediate complications were reported. Over a five year period, complications
were reported in three of five patients (one with electrode fracture at three years, one
with epidural fibrosis at 14 months and one with electrode migration at five years).154
Repetitive transcranial magnetic stimulation Of the 10 patients in the trial,155 three experienced no side effects, whilst the other
seven experienced the following during the 90-minute treatment period: right or left
hemihyperthermaesthesy (n=2), prickling paraesthesia in the CRPS limb (n=2),
tiredness (n=1), light dizziness (n=1) and light headache (n=1). This small sample
and short duration does not allow estimation of what overall rates and types of side
effects may be.
Transcutaneous electrical nerve stimulation Reports of adverse events were not identified for this report.
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Conclusion
Safety of neurostimulation for complex regional pain syndrome
• Spinal cord stimulation (SCS): Side effects are common and mainly relate to
electrode problems or pain/irritation from the implant; other complications are
infections, generator issues and haematomas. There were 29 instances of re-
operation (24 patients over five years) in the Kemler RCT.
• Motor cortex stimulation (MCS): Complications were reported in 3/5 patients
over a five year period (electrode fracture, epidural fibrosis and electrode
migration.
• Repetitive transcranial magnetic stimulation (rTMS): Side effects were
experienced in 7/10 patients over a short follow-up period, some consistent
with the symptoms of CRPS. None appeared to be serious. Longer-term
adverse events have not been reported.
• Transcutaneous electrical nerve stimulation (TENS): No reports of adverse
events were identified.
7.11 Cost-effectiveness Spinal cord stimulation Two economic evaluations (Simpson 20093 and Kemler 2002150) of SCS for CRPS
were identified through our searches, and a further one was identified after the
search cut-off date (Kemler 2010151).
The economic evaluation by Kemler 2010151 was assessed as being of generally
good quality (see Appendix 5, p209, Table 29).The analysis was conducted from an
NHS perspective and compared SCS to conventional medical management (CMM).
A two stage model was developed. The first was a decision tree to reflect treatment
response at six months, the second was a Markov model, which simulated costs and
QALYs over a 15-year time horizon. Where possible data were taken from the trial by
Kemler 2000146 (see section 7.5 for results).
Costs were taken from a trial on SCS in FBSS patients (the PROCESS trial69) as
there was a lack of detailed cost data available from the Kemler trial.150 Utility values
based on the EQ-5D and measured at six months were taken from the Kemler trial;
disutility associated with complications was estimated by the authors, and it was
(conservatively) assumed that no complications occurred in patients in the control
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arm. Effectiveness data was taken from the Kemler trial where the primary outcome
was a reduction of at least 50% in pain VAS. VAS scores at six months were used to
determine initial success rates of the treatment. After that it was assumed, based on
individual patient data, that patients’ annual probability of losing pain relief was
approximately 3%. It should be noted that the comparator in the economic evaluation
was conventional medical management whilst the comparator in the Kemler trial was
physical therapy; it is unclear to what extent differences exist and whether this would
affect effectiveness estimates. The base-case cost per QALY was calculated as
£3562 (over a 15 year time horizon). Sensitivity analyses found four variables that
had the most impact on cost per QALY. SCS became more cost-effective with: a
decrease in adjunct pain therapy for SCS patients; an increase in time before a
replacement implanted pulse generator was required; an increase in the cost of drug
therapy associated with CMM; and a decrease in the annual probability of no pain
relief with SCS. Where cost-effectiveness was found to decrease, the cost/QALY was
still below a £15,000 threshold for all sensitivity analyses. Probabilistic sensitivity
analyses found a 74% (87%) probability that SCS is cost-effective at willingness-to-
pay thresholds of £20,000 (£30,000).
There are a number of assumptions underpinning these results. Effectiveness data
have been extrapolated beyond the length of the trial and are based on longer-term
observational data. Further, effectiveness and utility data are based on fairly small
patient numbers from the Kemler trial, which will introduce some uncertainty. It was
not possible to assess whether model effectiveness estimates at later time-points (up
to five years) were consistent with effectiveness estimates from the trial, and thus
whether the decrease in probability of pain relief assumed in the model was
appropriate. In particular it was unclear whether the model reflects the fact that in the
trial there were no significant differences between groups in outcome measures at
five years. Optimal pain relief was defined as ≥50% reduction in pain; it is unclear
whether this is a validated measure of pain and whether it translates into quality of
life improvements for the patient. A different patient group (with FBSS) were used for
assessment of costs and resource use; it is unclear whether resource use would
differ significantly from that of CRPS patients, though the authors state that the
pattern of care is likely to be broadly similar. It was noted that the model structure did
not allow patients in either group to progress from sub-optimal pain relief to optimal
pain relief; it is unclear whether this accurately reflects the course of the disease for
all patients.
82
Further in-depth analysis of model structures, assumptions made and range of input
variables would need to be undertaken in order to fully assess the validity of these
results.
A previous economic evaluation (Kemler 2002150), also based on the Kemler RCT
was also assessed as being of generally good quality (see Appendix 5, p209, Table
29 for quality assessment). This compared SCS with physical therapy to physical
therapy alone. Here, a societal perspective was taken and costs included costs of the
generator, costs of complications, routine CRPS costs (e.g. hospital visits, physical
therapy, aids such as crutches) and patient expenses. Loss of productivity was
excluded as the vast majority of patients in both groups were unfit for work both
before and after treatment. The EQ-5D was measured during the trial, which allowed
the calculation of utilities and cost per QALY. Cost per QALY was calculated at one
year and over a lifetime horizon.
The base case cost per QALY at one year was €22,582 (1998 currency value,
£19,631.40 based on November 2010 exchange rate of £1=€1.1503), which might be
considered to be cost-effective at certain willingness-to-pay thresholds. This was
based on a 3% discount rate, life expectancy of 40 years, an annual complication
rate of 30%, pulse-generator longevity of five years, implantation rate of 67% and a
reduction of routine CRPS costs of 100%. Over a lifetime horizon (40 years), the cost
per QALY was ‘dominant’ (both reduced costs and better quality of life). Sensitivity
analyses were performed by varying the following parameters: discount rate,
complication rate, longevity of pulse generator, life expectancy, implantation rate and
reduction of routine CRPS costs. All cost per QALY estimates resulting from the
sensitivity analyses were found to be dominant or ≤€9352 per QALY.
Some of the assumptions of the evaluation raise concerns. The reduction of routine
CRPS costs by 100% in the SCS arm appears generous; this assumption was tested
in sensitivity analyses, but only for the lifetime estimate (not at one year). No
sensitivity analyses were performed around utilities. Given that the trial was small, it
is likely that there is some uncertainty associated with the measured utilities, and this
should have been explored. It is also unclear how benefit was estimated over a 40-
year time-horizon as trial results were available for only one year at the time of the
economic evaluation. More recent results from the trial (not available at the time)
show that effectiveness diminishes after three years, and this will not have been
taken into account. Therefore, any results after one year need to be treated
83
cautiously. The results would also only be applicable to the specific type of patient
included in the trial (see earlier section on clinical effectiveness), and only when SCS
+ PT is compared with PT alone, which may not always constitute standard care.
An independent economic evaluation was also performed as part of the Simpson
HTA.3 This was also assessed as being of overall good quality (see Appendix 5,
p209, Table 29, for quality assessment). An NHS perspective was taken, and SCS
was compared to conventional medical management. Costs included trial stimulation
(to assess eligibility), costs of the device and implantation and costs of complications
(including device explantation). In contrast to the Kemler evaluation described above,
the conventional management costs were assumed to be reduced by 50% (rather
than 100%) in the SCS group in year one and by 40% in subsequent years. Utilities
were taken from a cross-sectional survey that investigated the burden of (general)
neuropathic pain. It is unclear why utilities were not taken directly from the Kemler
trial. A Markov model with five health states was used. Cost per QALY was
calculated at 15 years based on a four-year device longevity (base case). Costs per
QALY were also calculated at six months, one year and every year up to 15 years.
Device cost and longevity were varied in sensitivity analyses.
The base case cost per QALY at 15 years was £25,095 (2007 currency value). This
was based on a 0.444 probability of achieving ≥ 50% pain relief, a probability of trial
stimulation success of 0.667, and an annual complication rate of 18%. The
probability estimate of 0.444 was an assumed value and not one reported in the
Kemler trial. The cost per QALY at one year was £219,597, more than 10 times the
one year cost per QALY calculated in the Kemler study. From year seven onwards,
the cost per QALY fluctuates between £24,273 and £36,950, with increases from
year to year based on battery replacement. Where sensitivity analyses were
performed for device cost and longevity, cost per QALY varied between £113,304
and ‘dominant’ (both reduced costs and better quality of life). Results of probabilistic
sensitivity analyses found a 78.36% chance of SCS being cost-effective at a
threshold of £20,000 per QALY, and a 97.38% chance of cost-effectiveness at a
threshold of £30,000 per QALY.
These estimates were based on a number of assumptions. One is the 0.444
probability of achieving ≥ 50% pain relief. It is unclear what follow-up time this
estimate relates to and a potential reduction in effectiveness over time does not
appear to have been considered, although longer-term data from the Kemler trial
84
suggest such diminishing efficacy occurs. The authors themselves stated that
estimating cost-effectiveness of SCS for CRPS was speculative because no primary
cost data were available, and uncertainty around length of benefit and proportion of
patients achieving optimal pain relief.
The reasons for differences in cost/QALY estimates between the economic
evaluations have not been fully explored. Although all have used data from the
Kemler trial, there are likely to be differences in model structure and the range of
input parameters used. Generally, all three evaluations find SCS to be cost-effective
over the longer-term (15 years or more), though less so in the HTA evaluation.
Conclusion
Cost-effectiveness of neurostimulation for complex regional pain syndrome
• Three well-conducted cost-effectiveness analyses based on the same
effectiveness trial produced varying cost/QALY results, most likely due to variations
in model structure, input parameters and underlying assumptions; these variations
have not been explored fully in this report.
• All evaluations found SCS to be cost-effective (or ‘dominant’) at willingness-to-pay
thresholds of £30,000 or less over a time-horizon of 15 years. Initial high costs are
related to the upfront device implantation.
• Given the uncertainty around the estimates of benefit and cost data, these results
must be interpreted cautiously.
7.12 Discussion The bulk of the evidence for the effectiveness of SCS lies with the Kemler RCT
(n=54), which found evidence for a reduction in pain and global perceived benefit at
six months and two years.146 This is likely to be a reasonably unbiased assessment,
although the small sample size does mean the result is associated with some
uncertainty. The comparator in this trial was physical therapy only, which may not be
representative of standard treatment and should be taken into account when
interpreting the results. Similarly the patients in the trial may not be representative of
all patients with CRPS, as the disease can be heterogeneous in its manifestation.
The patients in the trial specifically had an affected hand or foot and may have been
at the more severe end of the disease spectrum.
85
Further assessment of case-series is unlikely to add information given the high risk of
bias associated with these studies. Whilst the case-series broadly confirmed the
result of the RCT on pain relief, they also found more benefit in terms of quality of life
and function. This finding needs to be treated cautiously, as there may be an element
of selection bias, there is no control group and there is limited knowledge on the
natural history of the disease. The RCT found that patients reported improvement
once they were aware of treatment assignment and the results of the test stimulation
but before treatment had commenced. Whilst the trial took this into account in the
analysis, it does demonstrate a possible placebo effect.
For MCS, there is evidence from only four patients who underwent a double-blind
procedure of having the stimulator switched ‘on’ or ‘off’ for a 30-day period. There is
evidence of pain relief, but given the sample size, the results must be viewed with
caution. There are no long-term comparative data as all patients went on to have
active treatment.
For rTMS there is evidence from one small crossover trial only; whilst this does
demonstrate a significant reduction in pain over a short (90-minute) treatment period,
further evidence would be necessary to show whether pain relief (or other benefits)
could be sustained over longer periods with prolonged treatment.
Reporting of adverse events across case-series was inconsistent and RCTs were
very small so no conclusions can be drawn regarding the overall frequency of the
complications identified.
The economic evaluations found base-case cost/QALY results of £3562 (15 year
time horizon), €22,582 (1 year time horizon) and £25,095 (15 year time horizon). The
reasons for differences in cost/QALY estimates between the economic evaluations
have not been fully explored. Although all have used data from the same trial, there
are likely to be differences in model structure, underlying assumptions, and the range
of input parameters used. Generally, all three evaluations find SCS to be cost-
effective over the longer-term (15 years or more), though less so in the (independent)
HTA evaluation.
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8 HEADACHE
8.1 Description of the underlying health problem Headache comprises a physiologically diverse group of conditions and accurate
diagnosis is necessary both for clinical and research purposes. The International
Classification of Headache Disorders, 2nd edition (ICHD-II) subdivides headache
disorders into primary headaches, secondary headaches, and cranial neuralgias,
facial pain, and other pain.123 However, some patients suffer with more than one type
of headache, and diagnosis is often a matter of clinical judgment; difficulty in
reaching a clear diagnosis may result not only in suboptimal clinical management of
primary headache disorders but also have implications for headache research.123
The main primary headache types include (1) migraine, (2) tension-type headache,
(3) cluster headache (and other trigeminal autonomic cephalagias) and (4) other
primary headaches (e.g. exertional headache, hemicrania continua). Secondary
headaches are defined as a de novo headache occurring with another disorder
recognised to be capable of causing it. These include cranial neuralgias and central
causes of facial pain, which in turn include trigeminal neuralgia and occipital
neuralgia (please note that trigeminal pain is dealt with separately in section 6 of this
report.)
In pain terminology generally, chronic denotes persistence over a period of more
than 3 months, whilst in headache terminology, it retains this meaning for secondary
headache disorders, but for primary headache disorders that are more usually
episodic (e.g. migraine), chronic is used whenever headache occurs on more days
than not over more than 3 months (with the exception of the trigeminal autonomic
cephalalgias).123
We did not limit inclusion of evidence in this report to specific headache disorders.
Most evidence was identified for the following types of headache: migraine, tension-
type headache, cluster headache (primary headache disorders) and occipital
neuralgia (secondary headache disorder). Limited evidence was also found for the
following headache disorders: hemicrania continua (primary), post-traumatic
headache (secondary), cervicogenic headache (secondary) and C2-mediated
occipital headache (this term is not used by the ICHD-II; C2 is one of the occipital
sensory nerves that can be involved in headache).
87
The headings in this report therefore reflect the amount of evidence found rather than
being consistent with the ICHD-II heading structure.
It should be noted that not all of the included studies used the ICHD-II classification,
and that some diagnoses may therefore not meet the current criteria. We did also not
restrict inclusion to reviews/studies meeting the criteria of ‘chronic’ headache as
outlined above, but have included any evidence where neurostimulators were used
for headache. Often, the condition was described as ‘chronic’ or ‘recurrent’ or
‘treatment resistant’.
8.2 Epidemiology Headache affects all ages and both sexes, with a lifetime prevalence of over 90%,
although it is most common in adults aged 20 to 50 years.157 Globally, 46% of adults
are estimated to suffer from an active headache disorder, with tension-type
headaches being the most common, followed by migraine, and chronic daily
headache.158 It is thought that 18% of women and 6% of men in the USA and
Western Europe are affected by migraine.159 Tension-type headaches have a lifetime
prevalence of almost 80%, and hence account for possibly the greatest overall
socioeconomic burden of all the primary headaches.160 Although tension-type
headaches are the most prevalent, migrainous headaches are the most
debilitating.161 A recent meta-analysis of population-based epidemiological studies
suggests that approximately 1/1000 individuals suffer from cluster headache, with
more cases in males than females (4.3:1 overall, 15:1 for chronic cluster
headache).162
The socioeconomic impact of headache renders these conditions a major public
health issue. In the UK, migraine alone is responsible for the loss of approximately 25
million days of work and school each year.163 In addition, headache disorders are
associated with enormous personal cost in terms of pain and disability, and are
among the ten most disabling conditions worldwide across the genders in terms of
Years Lived with Disability, and in the top five for women.158 Despite the enormous
human and economic burden associated with headache disorders, it is suggested
that these conditions remain under-recognised and under-treated worldwide.164
Table 10 below summarises the epidemiological data. Please note that systematic
searches for this type of data were not performed and the validity of the results has
not been assessed (e.g. by looking at the sample size, methods of obtaining data
and case definitions).
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Table 10 Epidemiological data headache Indication
Measure Source
Headache generally Lifetime prevalence: over 90%
WHO Headache disorders. Fact Sheet No 277. 2004. 6-10-2010.157
Any active headache disorder (with tension-type headaches being the most common, followed by migraine, and chronic daily headache)
Prevalence: 46% of adults Global estimate, Stovner 2007158
Migraine Prevalence: 18% of women and 6% of men
USA and Western Europe estimate, Lipton 2010159
Tension-type headaches Lifetime prevalence: almost 80%
Global estimate, Crystal 2010160
Cluster headache Prevalence: 1/1000 (0.001%)
A 2008 meta-analysis of population-based epidemiological studies162
8.3 Treatment Many patients suffering from headache disorders do not present for treatment as the
condition is often considered self-limiting and non-serious. Wide availability of over-
the-counter analgesics also encourages self-management and may lead to overuse
of headache medication. Medication overuse headache is the most prevalent of the
secondary headaches, affecting up to 5% of individuals in population studies.157
Medical management may be hampered by trivialisation of the condition in primary
care or by misdiagnosis of headache type.
A variety of acute treatment options are available, including analgesic drugs,165 ergot
derivatives, triptans,166 corticosteroid injection,167 and botulinum toxin injections.168
Non-pharmacological options include relaxation and biofeedback techniques,169 and
physical therapies such as manipulation and acupuncture.170 Non-drug therapies and
lifestyle modification may also be effective in headache prophylaxis.
However, a proportion of headache sufferers cannot tolerate, or do not respond to
medication, or such treatments may be contraindicated. Due to the lack of defined
criteria for diagnosing refractory headache disorders, it is not possible to quantify the
89
number of afflicted patients. However, these patients are likely to require an
enhanced level of medical care.171 Typically, symptoms are refractory to a number of
different drug classes and patients may also have experimented with one or more
non-pharmaceutical treatments. In cases where the condition continues to be highly
debilitating, surgical interventions such as ablation or sectioning of the trigeminal
nerve can be considered.172 Destructive surgical procedures are irreversible and
carry with them the risk of serious adverse events and neurostimulation may
therefore offer a less destructive option.173
The lack of efficacy of analgesic medications in chronic tension-type headache has
led to the recommendation that non-pharmacological management be given serious
consideration for the prevention and treatment of this condition. 174 However, as
tension-type (or muscle contraction) headaches are generally less debilitating than
migraine or cluster headache, it is unlikely that invasive procedures would be suitable
for this indication.
A number of neurostimulation methods have been assessed to treat specific types of
headache. As the most disabling of the primary headaches, migraine is one of the
most studied, and a number of different neurostimulation techniques have been
tested in migraine, including occipital nerve stimulation (ONS), transcutaneous
electrical nerve stimulation (TENS), transcranial magnetic stimulation (TMS) and
pulsed electromagnetic fields (PEMF).
8.4 Quantity and quality of evidence Thirty-three reviews were identified, of which five were systematic20,22,55,175,176. One of
these, Walsh 200955, reviewed the use of transcutaneous electrical nerve stimulation
(TENS) to treat acute pain. This was a Cochrane Review and considered only
evidence from randomised controlled trials. Although headache was one of the acute
pain conditions included in the searches, no RCTs were found for this indication, and
this review will not be discussed further. Of the other four reviews, two focussed
specifically on headache: Brønfort 2004175 reviewed the use of non-invasive physical
techniques for the treatment of chronic headache and Jasper 2008176 reviewed the
evidence on implanted occipital nerve stimulators. The systematic review by
O’Connell 201022 reviewed non-invasive brain stimulation techniques for chronic
pain. Many of the included RCTs reported mixed pain populations; however, the
review identified one RCT of cranial electrostimulation (CES) that included 44
patients suffering with migraine, tension-type or other headache diagnoses.106
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Combined results were presented for all headache patients. The Blue Cross of Idaho
systematic review discussed the evidence for percutaneous electrical nerve
stimulation (PENS) across a range of pain indications, including headache.20 The
authors identified one cross-over RCT (Ahmed 2000177) of 30 patients with chronic
migraine, tension or post-traumatic headache based on International Headache
Society (IHS) criteria, with results presented separately for each pain aetiology.
Further details and quality assessment of these systematic reviews are presented in
Appendix 6, p214 and p215, Table 30 and Table 31.
In addition to RCTs identified within the included systematic reviews, six additional
RCTs were identified: Fontaine 2010: DBS for chronic headache178; Lipton 2009
(PRISM trial): TMS for migraine159; Saper 2010 (ONSTIM trial): ONS for migraine179;
Lipton 2010: ONS for migraine180; Chen 2007: TENS for cervicogenic headache181
and Pelka 2001: PEMF for headache.182 Brief descriptive details of these RCTs, and
those referred to in the secondary evidence, are shown in Appendix 6, p219 Table 32
and brief critical appraisals are presented in Appendix 6, p222 Table 33.
No relevant cost-effectiveness studies were identified; one study (Leone 2009183) of
hypothalamic stimulation in drug-resistant cluster headache measuring costs only of
different treatment pathways was identified, but will not be further discussed.
Table 11 below gives an overview of the identified evidence. In the following
sections, evidence will be presented by the following indications: migraine, tension-
type headache, cluster headache, occipital neuralgia and other headache disorders.
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Table 11 Overview of evidence identified for headache Indication Type of NS Migraine Tension-type
headache Cluster headache Occipital
neuralgia Other headache disorders
Occipital nerve stimulation
Jasper 2008176-SR Saper 2010179-RCT Lipton 2009180-RCT
Jasper 2008176-SR Jasper 2008176-SR Jasper 2008176-SR
Deep brain stimulation Fontaine 2010178-RCT
Pulsed electromagnetic field stimulation (PEMF)
Brønfort 2004175-SR Pelka 2001182-RCT
Pelka 2001182-RCT
Transcranial magnetic stimulation (TMS)
Lipton 2010159-RCT
Transcutaneous electrical nerve stimulation (TENS)
Brønfort 2004175-SR
Chen 2007181-RCT
Percutaneous electrical nerve stimulation (PENS)
Blue Cross of Idaho 201020-SR
Blue Cross of Idaho 201020
Cranial electrotherapy stimulation (CES)
O’Connell 201022-SR O’Connell 201022-SR
SR=systematic review; RCT=randomised controlled trial
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8.5 Migraine
8.5.1 Occipital nerve stimulation for migraine Two RCTs looking at ONS were identified (see Table 11, p91). The PRISM trial
(Lipton 2009180, n=140) compared active with sham stimulation of the implanted
device, and the ONSTIM trial (Saper 2010179, n=75) compared active stimulation,
pre-set (ineffective /placebo) stimulation or medical management. The PRISM trial
was reported as an abstract only, and it is therefore not possible to accurately gauge
the quality of this trial. It was reported to be double-blind (for the first 12 weeks; open
phase up to 52 weeks). The ONSTIM trial appeared to be well-conducted in terms of
randomisation and allocation concealment. Blinding was undertaken where possible,
but patients were necessarily aware of whether they had received an implant or not.
Missing data (11%) was not accounted for in the analysis; all withdrawals were from
the devices groups. After three months, follow-up of the trial was open label.
The remaining evidence is of relatively poor quality, consisting of small prospective or
retrospective case-series. The systematic review by Jasper 2008176 included four
case-series on ONS for patients with migraine.
The PRISM trial180 was a multi-centre, double-blind, randomised controlled trial in
patients with migraine with aura, migraine without aura, or chronic migraine. 140
subjects were randomised 1:1 to receive either bilateral active or sham stimulation for
12-weeks post-implantation of an ONS device. Of 132 subjects implanted, 125
completed the 12-week follow-up. At 12 weeks there was no significant difference
between groups in change from baseline in the number of migraine days per month
(5.5±8.7 fewer days in the active group, compared with 3.9±8.2 fewer days in the
sham group (p=.29)). Sub-group analyses suggest that patients not overusing
medication at baseline were slightly more responsive to the treatment compared with
the medication overuse subgroup (not statistically significant). Further suitably
powered studies are required to ascertain efficacy in this group. Pre-implantation
percutaneous trial stimulation in the active arm was moderately predictive of 12-week
response rate (positive likelihood ratio 2.0, 95% CI 1.4 to 2.9; negative likelihood ratio
0.21, CI 0.06 to 0.78) and thus might be utilised as a tool prior to surgical
implantation to limit unnecessary exposure to invasive interventions if ONS is to be
used in this population. There appeared to be no trial of stimulation treatment.
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The ONSTIM trial179 was a multi-centre, randomised controlled feasibility study of
ONS in 75 patients with chronic migraine, characterised by headache on 15 or more
days per month, who also responded to occipital nerve block (ONB) treatment.
Subjects were randomised 2:1:1 to adjustable stimulation (AS), pre-set (ineffective)
stimulation (PS), or medical management (MM). In addition, eight ONB non-
responders were also implanted with adjustable ONS units and treated in the same
manner as the active experimental group. There was no trial of stimulation treatment;
if, during intraoperative testing, the implanter believed that inadequate paresthesia
occurred, the leads were removed and the patients excluded from the study. It
appears that of 53 patients consenting to implant, 2 (4%) were operative failures.
At three months post-implantation, the AS group experienced greater improvements
from baseline in most outcomes compared to the other groups, but none of the
differences between groups were statistically significant (outcomes included number
of headache days, overall pain intensity, peak pain intensity, headache-free days,
number of days with prolonged and severe headache, and average headache
duration compared with the PS and MM controls, disability and quality of life scores).
The effect size was similar to that seen in the PRISM trial with 6.7±1.0 fewer
headache days at three months in the AS groups, versus 1.5±4.6 and 1.0±4.2 fewer
headache days in the PS and MM groups, respectively.
There was a significant difference in the responder rate, defined as the percentage of
subjects achieving a 50% or greater reduction in number of headache days per
month or a three-point or greater reduction in overall pain intensity compared with
baseline (39% vs. 6% and 0% in the AS, PS and MM groups respectively) suggesting
a physiological difference between actual and sham treatment.
However, this was an exploratory study, and as such it was not powered for a single
primary endpoint. It should also be noted that despite attempts to maintain allocation
concealment (with neurologists responsible for follow-up visits blinded to treatment
arm, and implanted patients not being informed of the significance of adjustable
versus pre-set stimulation), the personnel responsible for implanting the devices,
programming them, patient education and device-related follow-up were necessarily
not blinded as to allocation. As such potential introduction of bias cannot be ruled
out.
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Larger studies of ONS for migraine might be warranted, particularly if a sub-group of
good-responders can be identified. Interestingly, patients in the ancillary group (ONB
non-responders) exhibited similar responses to those in the adjustable stimulation
group, suggesting that ONB response may not be predictive of ONS efficacy in
migraine. This finding is consistent with other recent reports in chronic cluster
headache184, but must be treated with caution due to the small size of the ancillary
sample and the wide variation in treatment response.
Further evidence is available only in the form of case-series. The review by Jasper
(2008)176 identified two prospective185,186 and two retrospective case-series187,188
involving ONS in migraine sufferers. The prospective studies involved a total of 35
patients, with follow-up from eight months to five years. Both studies reported 100%
positive short-term response. In the first, 25/25 patients achieved at least a 50%
reduction in Migraine Disability Assessment (MIDAS) scores following surgery, and
80% experienced over 70% reduction.185 Average MIDAS improvement was 88.7%.
After a mean of 18.3 months, 20/25 maintained 75% improvement in MIDAS scores,
with the remaining 5/25 experiencing at least a 50% improvement. Similarly, the
second study reported 100% short-term relief in 10/10 transformed migraine patients,
90% with sustained intermediate-term response.186 Retrospective review of a further
16 patients also suggested positive short- and intermediate-term results.187 In the
latter study by Schwedt and colleagues, pooled results were reported for a
heterogeneous mix of headache patients but migraine sufferers made up the largest
proportion of the sample (8/15 patients).188 These results are likely to be associated
with more bias compared to those from the RCTs, and the usual caveats regarding
evidence from uncontrolled studies apply.
8.5.2 Transcutaneous electrical nerve stimulation for migraine
The systematic review by Brønfort 2004175 included one relevant RCT (Reich
1989189, see Table 11, p91), which randomised patients to (i) traditional TENS or
electrical neurotransmitter modulation, (ii) receive thermal or EMG biofeedback, (iii)
psychotherapy/hypnosis/relaxation or combination or (iv) multi-modal treatment
(combination of two of the other treatments) . This was a large study (n=1015 with
either vascular/migraine or tension-type headache), but there were concerns over the
methodological quality. There were no details on randomisation, allocation
concealment or blinding. Patient demographics were not given by intervention arm so
it is unclear whether the treatment arms were comparable. It is also unclear whether
treatment arms were balanced by type of headache. Patients who did not complete
95
three or more assessments were excluded from the analysis; missing data was not
accounted for. Overall loss to follow-up was high at approximately 38%. There was
no placebo or sham treatment group.
Of the 1015 patients randomised, 703 were followed up for three years; of these, 392
were migraine patients and follow-up data was presented for 345/392. Total loss to
follow-up for migraine patients specifically was unclear. Eighty-seven migraine
patients received electrical treatment, which consisted of either traditional TENS,
electrical neurotransmitter modulation, or both. Results were pooled for all types of
electrical treatment. The number of migraine patients in the other treatment groups
was not stated. Treatments were generally poorly described and could be variable in
terms of intensity and treatment components received.
All four types of treatment resulted in a reduction in pain intensity and headache
frequency, as well as decreased usage of pain medication in migraine patients. The
biofeedback group displayed the largest improvements, followed by the electrical
group, multi-modal group, and relaxation group. These results were maintained over
three years of follow-up. It was not reported whether there were any significant
differences between groups. There was a significant correlation for migraine patients
between number of sessions (of any treatment) and both short- and long-term
outcomes, with better outcomes observed with more frequent treatment.
In the electrical group the number of mean weekly headache hours for migraine
patients was approximately 23 at intake, reduced to 4 h at discharge, and 6 h at 36-
months post-discharge (estimated from graph). Mean pain intensity for migraine
patients was rated as 3.9 on a five-point scale at intake, reduced to 2.0 at discharge
and 2.3 at 36 months. The absence of a placebo or sham-treatment control group in
this study means that the effect size is likely to be inflated. Placebo effects in both
prophylactic and acute migraine studies are usually in the 20–40% range,190,191 and
physical treatments may result in a higher placebo response than oral
pharmacological agents in the treatment of acute migraine.192 It is now recommended
that all migraine studies include a placebo or sham control.190 This lack of a placebo
group, together with the other methodological concerns detailed above, means that
any results from this trial should be interpreted cautiously.
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8.5.3 Pulsed electromagnetic field stimulation for migraine The systematic review by Brønfort 2004175 (see Table 11, p91) included two small
RCTs in migraine patients (Sherman 1999193 (n=42) and Sherman 199823 (n=12)).
Both randomised to active or sham PEMF. An additional RCT identified was Pelka
2001182 (n=82), which randomised migraine and other headache patients to PEMF or
sham PEMF.
The Sherman 199823 crossover trial was very small (n=12) and there were some
methodological concerns. There were some issues around technical failure of the
machine, which meant not all patients received exposure as planned. Furthermore, it
appears that patients became aware of treatment assignment during the course of
the study. The authors stated that the crossover design of the study was not
appropriate as there was no wash-out period.
The Sherman 1999193 study appeared to be of reasonably good quality. There were
no details on allocation concealment but patients and therapists were blinded; the
placebo machine was identical to the active machine in looks and sounds and
subjects couldn’t sense an active field. Missing data (10%) was not however
accounted for in the analysis and the sample size was relatively small. After a one-
month period, patients from both active and placebo groups were offered further
treatment.
In the study by Pelka 2001182, it appears that a good attempt was made to blind
patients, but there were other methodological concerns. First, patient recruitment
and selection criteria protocols were not transparent, and the reported enrolment of
patients “when good compliance could be expected” requires further explanation. It is
also not clear what symptoms were included in the assessment. There were no
details on randomisation, but it did not appear to be stratified by headache type.
There was some inequality in treatment allocation within the different headache
groups. In their discussion, the authors report an improvement in vitality and
wellbeing among patients that they attribute to increased oxygen supply secondary to
improved circulation. However, there was no suggestion that patient general
wellbeing was assessed during this study, and neither circulation nor oxygenation
levels appear to have been monitored in any way.
In the Sherman 1998 study, 12 subjects were randomised to receive two weeks of
actual or sham PEMF applied to the inner thigh area, with treatment for 1 h daily, five
97
days per week. Subjects were then scheduled to crossover to the other treatment
arm for an additional two weeks, followed by a further three weeks of diary
maintenance. The PEMF device was set to produce 65 µs bursts of electromagnetic
energy at 27.12 MHz at a power of 975 watts with 600 pulses per second.
Prophylactic medications were stopped following the baseline period and prior to
receiving PEMF treatment.
Due to a technical problem, three patients were accidentally exposed to inadequate
magnetic fields during their actual treatment phase, and these patients reported no
change in headache number over the course of the study.
The six patients who received full-dose active treatment first experienced a
significant reduction in the number of headaches following two weeks of treatment,
from 3.32±1.40 to 0.67±0.26 per week (p=0.003). However, of these six patients, five
refused to cross over to the other arm of the trial. Therefore, these patients did not
act as their own control, and a comparison between active and sham treatment in
these patients is not possible. Three patients received placebo treatment first,
followed by active treatment; no statistically significant differences in outcomes were
observed between the two treatment periods, although two of the three experienced
a reduction in the number of headaches per week, sustained over follow-up. There
was a significant difference in headache incidence rates between the active
treatment first (n=6) and placebo first (n=3) patients during the first two weeks of the
study.
In the 1999 study, 42 subjects were randomised to receive two weeks of active or
sham PEMF treatment, followed by a further one month of diary data collection.193
Treatment parameters were as outlined above. Changes in headache frequency,
duration, intensity, medication use, and ratings of associated discomfort were
assessed and a composite score created for each patient.
There were no statistically significant differences between the groups in terms of
headache decrease after 2 weeks (p=0.13), but there were after 4 weeks (p=0.016).
This is based on a composite score, which included a range of variables (frequency,
duration, intensity, medication use, rating of associated discomfort). It should be
noted that composite scores may not always be the most appropriate outcome
measure. A number of cut-off points were chosen to divide the composite scores into
‘excellent’, ‘good’ and ‘minor’ decreases, ‘no change’ or ‘worse’. When only good or
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excellent improvement was considered, there was also a significant difference
between active and placebo group at 4 weeks. Three placebo patients (16%)
reported worsening of symptoms, whereas none in the active group did.
A double-blind, placebo-controlled study of extreme low-frequency (ELF) PEMF was
reported by Pelka and colleagues.182 Eighty-two patients with migraine and other
headache types were randomly assigned to receive either an active treatment or
sham stimulation device. The matchbox-sized device was worn around the neck for a
period of four weeks, with the active devices administering ELF (16 Hz) magnetic
waves at a field strength of 5 µTs. Clinical data were collected before treatment, at
two weeks, and at four weeks. Headache intensity, frequency, and duration of
attacks were assessed, as was any difficulty the patients experienced in
concentrating. Headache symptoms were rated on an 11-point scale, and frequency
of concomitant sleeplessness, photosensitivity, spasm and difficult menstruation
were rated on a 5-point scale.
Of the 82 randomised patients, 22 suffered with migraine, 29 with both migraine and
tension-type headaches, 12 with tension headache only, six with cluster headache
and 23 with other types of headache. The results of this study were not presented by
headache diagnosis but combined for all headache types.
Seventy-seven patients completed the treatment. The active treatment group
experienced significantly better improvement in all primary headache outcomes than
did the placebo group. In the active stimulation group, both headache intensity and
frequency were reduced at two weeks, with further improvement after four weeks of
treatment (all p<.0001). Clear symptomatic improvement was reported in 76%
(29/38) of the active treatment group, with only 8% (3/38) reporting no improvement
in frequency of symptoms at four weeks. This compared with 2% (1/39) with clear
improvement and 90% (35/39) with no improvement in the placebo group (p<.0001).
Concomitant symptoms were also significantly improved in the active treatment
group (data not reported; p<.01 vs placebo).
A highly significant treatment effect appears to apply to the active treatment in this
study. However, the extremely low placebo response seems inconsistent with other
trials of both neurostimulation and pharmacological interventions for headache, and
is clinically unlikely. As this was a double-blinded study, it cannot be ruled out that
these differences may be due to chance, given the relatively small sample sizes
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involved. Alternatively, methods for blinding participants and/or investigators may not
have been effective.
8.5.4 Transcranial magnetic stimulation for migraine One RCT was identified (see Table 11, page 91), Lipton 2010159 (n=267), which
compared single-pulse TMS (sTMS) to sham sTMS for the treatment of acute
migraine with aura. This appeared to be a well-conducted study in terms of
randomisation, allocation concealment and patient blinding. Analysis was on a
modified intention-to-treat basis (all patients who were randomised and treated at
least one migraine episode) and the study appeared sufficiently powered.
Following a one-month lead-in phase to acquire baseline data, patients were
randomised 1:1 to receive either a handheld, portable sTMS device or an identical
sham device. As soon as possible after the onset of aura, patients applied the device
to the back of the head and manually delivered two brief pulses about 30 seconds
apart. The magnetic field pulses had a rise time of 180 µs, with a peak of 0.9 T and a
total pulse length under 1 ms. Outcomes were recorded at baseline, 30 min, 1 h, 2 h,
24 h, and 48 h after treatment. Patients were allowed to continue with their existing
preventive medication, but medication for symptom relief was not permitted until two
hours after TMS treatment.
For the primary endpoint, of the 164 patients who treated at least one aura episode,
39% (32/82) in the active treatment group were pain free at 2 h compared with 22%
(18/82) in the sham stimulation group (p=.0179). The effect was sustained over time,
and the secondary outcome of pain-free at 2 h, with no recurrence and no use of
rescue medication was achieved by 29% (24/82) of the active sTMS group at 24 h
compared with 16% (13/82; p=.0405) in the sham stimulation group, and by 27%
(22/82) of the active sTMS group at 48 h compared with 13% (11/82; p=.0327) in the
control group. The 2 h response was more pronounced in patients who used
migraine prophylaxis (35.5% [12/34] vs. 3.2% [1/31] pain-free at 2 h in the active and
sham groups, respectively, compared with patients who did not use preventative
medication (41.7% [20/48] vs 33.3% [17/51] in the active and sham groups,
respectively), representing an absolute risk difference of 32.1% in the prophylaxis
group compared with 8.3% in the non-prophylaxis group (p=0.0014). One possible
explanation for the generally higher pain-free rates at two hours in both active and
sham treatments arms in the non-prophylaxis group is that these patients may have
less severe headache symptoms at baseline or differences in headache pathology
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that result in their differential use of preventive medication. Although baseline
headache intensity was not reported separately based on use of preventive
medications, patients receiving sham treatment were more likely to report
improvement if their baseline pain was mild or absent at onset of aura symptoms.
Baseline pain intensity was not correlated to likelihood of efficacy in the active
treatment group.
Secondary symptoms of migraine including phonophobia, photophobia, and nausea
were also evaluated. Not all patients would experience all such symptoms with each
attack and the trial was therefore not powered to prove superiority.194 However,
sTMS was non-inferior to sham treatment in resolution of secondary symptoms at 2 h
post-treatment in patients who had moderate or severe pain at onset of aura
(planned sub-group analysis). No difference was observed between the groups for
patients with only mild or no pain at baseline. No significant difference was observed
in the use of rescue medication between the two groups at either 2 h or 48 h. Other
secondary outcomes including consistency of pain relief, global assessment of relief,
MIDAS scores, and total disability time did not differ between active and sham
stimulation groups.
8.5.5 Cranial electrotherapy stimulation for migraine
The systematic review by O’Connell22 (see Table 11, p91) included one RCT (Gabis
2009106), which included some patients with migraine. The study appeared to be well-
conducted in terms of allocation concealment and of blinding of patients and outcome
assessors, however, patient numbers were fairly small and there were no details on
loss to follow-up or how any missing data might have been dealt with. The active
placebo was designed to simulate treatment, however, the intensity used (0.75 mA)
was higher than the ‘active’ treatment in some other CES studies, and may have
influenced results by reducing any between-group differences. The authors state that
follow-up time (three months) may not have been adequate.
Of 119 patients with chronic pain diagnoses, 44 met the IHS criteria for migraine,
tension-type or other headaches. The number of patients with each headache type
was not reported, and aggregated results were presented for all headache patients.
Patients were randomised 1:1 to receive either CES or ‘active placebo’. Stimulation
was delivered for 30 minutes per day on eight consecutive days. Three-weeks post-
treatment, patients receiving CES reported a significant reduction in pain levels
compared with baseline (from a mean VAS score of 6.20±2.81 to 3.55±3.81, p<0.05)
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whereas those receiving ‘active placebo’ did not (significant difference between
groups, p=0.007). Statistically significant improvements were reported in pain
frequency, use of pain medication and interference of pain with sleep in both groups,
with no significant difference between intervention and controls. However,
improvements in all four outcome measures were sustained or further improved at 3-
month follow-up in the CES treatment arm, whereas those in the ‘active placebo’
group were no longer significantly different to baseline (inter-group differences: pain
level, p=0.000; sleep, p=0.011; pain frequency, p=0.000; medication use, p=0.000).
These results need to be viewed cautiously as loss to follow-up was not reported and
it is unclear if there is any missing data. However, of the three pain aetiologies
included in this study – headache, low back pain and cervical pain – headache
appears to be the most responsive to this intervention (statistically significant
decreases on both follow-ups in active treatment group with headache compared to
sham group with headache). It is not clear whether treatment response differed
between headache diagnoses. The study was not powered to investigate
effectiveness in different subtypes of pain, and randomisation did not appear to be
stratified by pain subtype, though there were equal numbers of headache patients in
each group. Regarding length of follow-up, the authors of the study suggest that 6-12
months may be a more adequate follow-up time than 3 months.
8.5.6 Percutaneous electrical nerve stimulation for migraine The Blue Cross of Idaho20 systematic review (see Table 11, p91) identified one
sham-controlled RCT (Ahmed 2000177), which included patients with migraine and
tension-type headache. There were few details on the search strategy of this review,
so it is not possible to assess the likelihood of studies being missed. There were
some concerns over the quality of the RCT. Although a sample size calculation was
performed, the sample size was small for the different headache types (n=12 for
migraine, n=13 for tension type). Patients were not blinded, which may bias the
results in favour of active treatment. Further there were no details on drop-outs or
missing data. This is a crossover trial and the authors state that there is a possibility
of a carry-over effect in those patients who received the active treatment first.
Patients received alternating frequency (15/30 Hz) PENS or sham control for 30
minutes (applied to the neck and upper back), three times per week for two weeks,
with a one-week washout period between treatment arms. Sham PENS involved an
identical machine but without the electrical stimulation. The lack of sensation would
have been noticeable by participants making full blinding difficult, but patients were
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told that the sham treatment was actually an acupuncture-like treatment so they may
have expected some treatment effect. There were significant differences between
active PENS and needles only groups in pain scores, activity levels and quality of
sleep (measured 48 hours after completing treatment). The number of weekly
headaches was reduced by half compared with baseline in the PENS but not the
control group, and oral analgesia was required less frequently in the active treatment
group. Whilst these results suggest that PENS may be effective in the short-term
treatment of chronic migraine, inherent problems with blinding to treatment allocation
may have introduced a degree of performance bias into the effect size, a possibility
strengthened by the low placebo effect size in this study. In addition, studies in PENS
for back pain discussed above would suggest that a one-week washout period
between treatment arms may have been insufficient to rule out a crossover effect. As
long-term follow-up was not performed, the sustainability of the response cannot be
confirmed.
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8.5.7 Conclusion migraine Clinical effectiveness of neurostimulation for migraine
• Occipital nerve stimulation (ONS): based on two RCTs in migraine patients (n=140
and n=75) there is no evidence of significant benefit from ONS for the prevention and
treatment of chronic, refractory migraine. ONS may be useful in a sub-group of
migraine sufferers, particularly those not overusing medication, but further studies are
needed. Occipital nerve block may not be predictive of treatment success with ONS.
• Transcutaneous electrical nerve stimulation (TENS): Based on one large trial in a
mixed headache population of poor methodological quality, electrical modalities may
be effective at reducing pain intensity, headache frequency, and medication usage in
migraine patients, although they appear not to be superior to biofeedback. The trial
did not have a placebo group.
• Pulsed electromagnetic field stimulation (PEMF) and extreme low-frequency (ELF)
PEMF: One trial (n=12) in migraine patients suggests that PEMF may reduce the
frequency of migraine headache. In addition to the small sample size, technical
difficulties were encountered during this trial. A further trial of PEMF (n=42) in
migraine patients found a significant reduction in a composite migraine headache
score after 4 but not after 2 weeks. There are some concerns over the validity of the
composite outcome measure.
One trial (n=82) in a mixed headache population on active versus sham ELF-PEMF
found significant differences between groups in favour of ELF-PEMF for a number of
headache outcomes; there is some uncertainty over whether blinding was successful
as the placebo response in this trial appeared to be unusually low. Results were not
presented for migraine patients only.
• Single-pulse transcranial magnetic stimulation (sTMS): based on one well-conducted
trial (n=267) in migraine patients TMS was found to be significantly better than sham
sTMS for the relief of acute pain in migraine with aura at 2 hours post-treatment.
Absence from pain was sustained at 24 and 48 hours post-treatment. The 2 h
response was more pronounced in patients who used migraine prophylaxis. No
significant difference was observed in the use of rescue medication or other
secondary outcomes (including consistency of pain relief, global assessment of relief,
MIDAS scores, and total disability time).
• Cranial electrotherapy stimulation (CES): Evidence from one RCT (n=44) in a mixed
headache population suggests that a course of CES may be effective in the medium-
term (up to three months) at reducing pain intensity, pain frequency, use of analgesic
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medication and reduce pain interference with sleep. It is not clear how migraine
patients specifically respond to this treatment.
• Percutaneous electrical nerve stimulation (PENS): Based on one RCT (n=25), PENS
was significantly more effective in the short-term than a needle-only sham PENS in
reducing pain, headache frequency, medication requirement, physical impairment and
sleep interruption in patients with migraine and tension-type headache (not presented
separately). However, the small sample size and difficulty in blinding patients to
treatment group introduce some uncertainty.
8.6 Tension-type headache
8.6.1 Transcutaneous electrical nerve stimulation for tension-type headache
The systematic review by Brønfort 2004175 (see Table 11, p91) included one RCT
(Reich 1989189), which included patients with tension-type headache. See section
8.5.2 for further details and methodological limitations of this trial.
Of the 1015 patients randomised, 703 were followed up for three years; of these, 311
had tension/muscle-contraction headaches and follow-up data was presented for
287/311. Total loss to follow-up for tension-type headache patients specifically was
unclear. Seventy-four patients with tension-type headache received electrical
treatment, which consisted of either traditional TENS, electrical neurotransmitter
modulation, or both. Results were pooled for all types of electrical treatment. The
number of tension-type headache patients in the other treatment groups was not
stated. Treatments were generally poorly described and could be variable in terms of
intensity and treatment components received.
The results for electrical treatment in tension-type headaches were very similar to
those observed in migraine patients. All four types of treatment resulted in
improvements. It was not reported whether there were any significant differences
between groups. The order of effectiveness was as for the migraine group, with the
greatest effect seen in the biofeedback group, followed by electrical treatment,
mixed-modality group, and relaxation group. Weekly headache hours in the electrical
group averaged approximately 26 hours at intake, 5 hours at discharge, and 7 hours
after 36-months. Degree of pain dropped from approximately 4.1 at intake to 2.1 at
discharge after an unspecified number of treatments, with the effect maintained at
36 months post-discharge. There was also a significant correlation between a greater
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number of treatment sessions and more favourable outcome. Again, the lack of a
placebo group, the lack of patient blinding and other methodological concerns,
means the treatment effect is likely to be overestimated, and results should be
interpreted cautiously.
8.6.2 Pulsed electromagnetic field stimulation EMF for tension-type headache
One RCT (Pelka 2001182, n=82) was identified (see Table 11, p91), which included
some patients with tension type headache and some with both tension and migraine
headaches. Patients were randomised to active or sham PEMF. Results were not
reported separately for different type of headache. See section 8.5.3 for further
details and results of this trial.
8.6.3 Cranial electrotherapy stimulation for tension-type headache The systematic review by O’Connell22 (see Table 11, p91) included one relevant RCT
(Gabis 2009106), which included some patients with tension type headache (number
not reported, 44 patients with headache in total). See section 8.5.5 for further details
and methodological limitations.
The number of patients with a diagnosis of tension-type headache was not reported
and the results were presented for all headache patients combined. At 3-month
follow-up, all outcome measures, including pain intensity and pain frequency, were
significantly reduced compared with baseline in patients receiving CES but not those
receiving the ‘active placebo’ treatment, as reported above under migraine. It is not
clear whether treatment response differed between headache diagnoses.
8.6.4 Percutaneous electrical nerve stimulation for tension-type
headache The Blue Cross of Idaho20 systematic review (see Table 11, p91) identified one RCT
(Ahmed 2000177), which included patients with migraine and tension-type headache
(n=13). See section 8.5.6 for further details and methodological limitations.
The effect of PENS and the needle-only sham PENS was very similar to that seen in
migraine patients in all outcome variables, including pain, physical activity, quality of
sleep, number of weekly headaches and daily use of oral analgesia. Patients
reported statistically and clinically significant improvements in pain scores following
active but not sham treatment, from a mean baseline VAS of 7.1 ± 1.0 to 3.1 ± 0.7 in
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the PENS group (58%; p<0.05) versus 6.3 ± 0.9 (20%; ns) in the needles-only control
arm.
8.6.5 Conclusion tension-type headache
Clinical effectiveness of neurostimulation for tension-type headache
• Transcutaneous electrical nerve stimulation (TENS): Based on one large trial
in a mixed headache population of poor methodological quality, electrical
modalities may be effective at reducing pain intensity, headache frequency,
and medication usage in tension-type headache patients, although they
appear not to be superior to biofeedback. The trial did not have a placebo
group.
• Extreme low-frequency pulsed electromagnetic field stimulation (ELF-PEMF):
One trial (n=82) in a mixed headache population on active versus sham ELF-
PEMF found significant differences between groups in favour of ELF-PEMF for
a number of headache outcomes; there is some uncertainty over whether
blinding was successful as the placebo response in this trial appeared to be
unusually low. Results were not presented for tension-type headache patients
only.
• Percutaneous electrical nerve stimulation (PENS): Based on one RCT (n=25),
PENS was significantly more effective in the short-term than a needle-only
sham PENS in reducing pain, headache frequency, medication requirement,
physical impairment and sleep interruption in patients with migraine and
tension-type headache (not presented separately). However, the small sample
size and difficulty in blinding patients to treatment group introduce some
uncertainty.
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8.7 Cluster headache
8.7.1 Deep brain stimulation for cluster headache One RCT of DBS versus sham stimulation was identified (Fontaine 2010178, n=11,
see Table 11, p91). This small study appeared to be well-conducted regarding
randomisation, allocation concealment and blinding of patients and outcome
assessors. This was a crossover study, but a wash-out period was included and the
authors found no statistical evidence for a carry-over effect. The small study size
does mean that results are associated with some uncertainty, and the authors state
that a follow-up of one month may have been insufficient to observe relevant
outcome.
Patients with a diagnosis of severe refractory chronic cluster headache were
randomised 1:1 to receive one month of actual or sham stimulation, followed by a
one-week wash-out period, and then one month of the other stimulation condition. All
11 patients had the pulse generator implanted after intra-operative test stimulation.
Active stimulation was given at a frequency of 185 Hz with a pulse duration of 60 ms.
Voltages were adjusted by the neurosurgeon based on individual responses to side
effects, and ranged from 1.0 to 2.8 V. Stimulation parameters were kept constant
during the randomisation phase but could be altered during a ten month open follow-
up period. Prophylactic treatment was to be continued unaltered during the
randomised phase of the trial, but could be changed during follow-up. Primary
outcome was the number of attacks during the final week of each treatment period.
Secondary outcomes were subcutaneous sumatriptan administration, pain intensity,
patient satisfaction, anxiety and depression, and quality of life scores during the
same periods.
None of the measured outcomes differed significantly between actual and sham
treatment periods during the randomised phase of the study. During the ten-month
open phase, attack frequency was reduced by nearly half (48.4%, p=.08) and
emotional impact was significantly improved compared with baseline. Six of the
eleven patients reported at least a 50% reduction in attack frequency and were
considered ‘responders’. There was no difference in pain intensity, sumatriptan
administration, or quality of life.
The authors suggested that flawed assumptions based on the data available at the
time of protocol design may have led to the study being underpowered and of
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insufficient duration to achieve significance in its primary outcome. They also noted
that previously reported stimulation parameters were used as default values during
the randomised phase, and that these often differed from individually optimised
parameters achieved through trial and error during the open phase. A further
randomised study was proposed with the previously identified responders as
subjects, but all six refused, fearing loss of the clinical improvements experienced.
The authors conclude that due to the intractable and debilitating nature of chronic
cluster headache, DBS remains a potential option that warrants further studies, but
suggest that these should be of longer duration, and should optimise patients during
a preliminary open phase prior to randomisation. However, they also note that the
less invasive technique of occipital nerve stimulation has shown promise in the
treatment of chronic cluster headache, and suggest that this option be explored
further, with DBS restricted to cases where ONS has failed.
8.7.2 Occipital nerve stimulation for cluster headache The systematic review by Jasper (2008)176 (see Table 11, p91) reported two case-
series of eight patients each (Burns 2007172, Magis 2007195) who were treated with
ONS for medically intractable chronic cluster headache, and a further case-series of
15 patients (Schwedt 2007188), of which three suffered from cluster headache.188
In the retrospective case-series by Burns 2007172, six of eight patients reported
improvements over a median follow-up of 20 months, with four of eight achieving a
greater than 50% improvement, and two reporting changes of 90% or better in
frequency and severity of attacks.172 Triptan use was reduced in three of the eight
patients, with one no longer requiring rescue medication. It is worth noting that the
first patient in the series had a history of left-sided cluster headaches, but following
unilateral electrode placement and stimulation on this side, a large percentage of
attacks began or were restricted to the right hand side. A right-sided electrode was
added resulting in considerable improvement and subsequent patients received
bilateral stimulation from the outset.
In the prospective case-series by Magis 2007195, unilateral stimulation was employed,
and two of the eight patients reported transient side shifts of attacks, remedied in
both cases by sub-occipital steroid injection.195 One patient discontinued after four
months due to side effects and lack of efficacy. In the remaining seven patients,
attack intensity decreased gradually over the first two months post-implantation, with
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a mean reduction at two months of 44%. Reduction in attack frequency occurred
more slowly, reaching its lowest point between six and ten months post-implantation
for most patients. Analysis of the six patients for whom there was data for at least six
months showed a 93.2% reduction in weekly attack frequency after ONS. At
22 months follow-up, two patients were attack-free, and all but one had reduced their
use of preventive medication. One patient had ceased prophylactic medication
completely.
Although the improvements occurred gradually over a period of time in both studies,
attacks returned within days on failure of the stimulation devices or loss of battery
power. However, loss of stimulation is accompanied by perceptible sensory changes,
and thus an inverse placebo effect cannot be ruled out.
In the retrospective case-series by Schwedt 2007184, all headache measures showed
improvement over a mean of 19 months follow-up. However, as the results were
pooled for all headache diagnoses, and cluster headache represented only 20% of
the total sample (3/15), it is difficult to draw conclusions based on these data.
It appears that all patients from the three case-series had permanent implants, with
some undergoing periods of trial stimulation beforehand. Overall, the procedure
resulted in reductions in the frequency, duration, and intensity of headache and the
use of medication over a period of weeks to months, although the effect was less
pronounced than in migraine patients. The usual caveats regarding evidence from
uncontrolled studies apply.
8.7.3 Pulsed electromagnetic field stimulation for cluster headache One RCT (Pelka 2001182, see Table 11, p91) was identified, which randomised
patients to active or sham PEMF. Only six patients (of 82) had a diagnosis of cluster
headache. See section 8.5.3 for further details of this study.
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8.7.4 Conclusions cluster headache
Clinical effectiveness of neurostimulation for cluster headache
• Deep brain stimulation (DBS): Evidence from one recent RCT finds no
significant benefit for DBS compared to sham DBS. The sample size (n=11)
may have been too small to detect potential benefits and the authors state that
the follow-up time may not have been adequate.
• Occipital nerve stimulation (ONS): Evidence from case-series (n=19) suggest
that the technique merits further investigation but RCTs are needed to confirm
these positive findings.
• Extreme low-frequency pulsed electromagnetic field stimulation (ELF-PEMF):
One trial (n=82) in a mixed headache population on active versus sham ELF-
PEMF found significant differences between groups for a number of headache
outcomes; there is some uncertainty over whether blinding was successful as
the placebo response in this trial appeared to be unusually low. Results were
not presented separately for the six cluster headache patients.
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8.8 Occipital neuralgia
8.8.1 Occipital nerve stimulation for occipital neuralgia The evidence is limited to six case-series (total of 57 patients) reported in the
systematic review by Jasper 2008176 (see Table 11, p91).
A prospective case-series (Oh 2004186) included ten patients suffering from ON, as
well as ten transformed migraine patients (see section 8.5.1). The ON patients, who
had failed at least three modes of conservative treatments including medication,
physical therapy, and neural blockade, were implanted with unilateral paddle
electrodes. At 1 month post-surgery, all patients reported at least 75% pain relief,
and eight of the ten patients reported over 90% pain relief. At 6-month follow-up,
seven of the eight patients with over 90% relief had sustained effects. The other
reported some reduction in pain relief but still rated the efficacy over 75%.
A further five retrospective case-series (Weiner 1999196; Weiner 1999197; Kapural
2005198; Slavin 2006199; Johnstone 2006200) encompassing a further 47 patients
(incorrectly tabulated in the systematic review) were also identified, as well as a
number of case reports and narrative reviews. Approximately 90% of patients
responded favourably during trial stimulation and underwent full implantation of the
devices. Overall, these studies reported good to excellent short- and medium-term
results, with follow-up from three months to six years.176 The usual caveats regarding
the interpretation of results from uncontrolled studies apply.
8.8.2 Conclusion occipital neuralgia
Clinical effectiveness of neurostimulation for occipital neuralgia (ON)
• Occipital nerve stimulation (ONS): Evidence from case-series in mixed
headache populations suggests that the technique merits further investigation,
but RCTs are needed to confirm these positive findings.
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8.9 Other headache disorders
8.9.1 Transcutaneous electrical nerve stimulation for other headache disorders
One RCT (Chen 2007181, see Table 11, p91) was identified, which randomised 70
patients with cervicogenic headache to either TENS or manipulation therapy every
other day for 40 days. There was no placebo group. The randomisation method does
not appear adequate (according to time/date patient arrived at clinic). It was not
possible to blind patients or therapists due to the nature of the therapy, and there are
no details regarding blinding of outcome assessors. All patients were included in the
analysis.
Four weeks after treatment, there was a significant difference between groups for
headache duration (favouring manipulation therapy), but it was not reported if there
were significant differences for headache frequency or intensity. Patients receiving
TENS had significant reductions from baseline in headache intensity (mean 7.86 to
5.26 on a numeric rating scale) and frequency (from 1.92 to 1.13 attacks per week).
Headache duration was also reduced (from 6.22 to 3.52 hours), but this result was
not statistically significant. It is worth noting that manipulation therapy out-performed
TENS on all three measures. Five patients in the TENS group discontinued treatment
early, after between five and eight treatments, due to resolution of symptoms.
Similarly, 10 patients discontinued manipulation therapy after between three and 12
treatments.
8.9.2 Occipital nerve stimulation for other headache disorders The evidence is extremely limited for ONS for other headache disorders. Four case
reports and two case-series were identified in the systematic review by Jasper
2008176 (see Table 11, p91). One case-series188 of 15 patients included two with
hemicrania continua and two with post-traumatic headache, the other included 11
patients with C2-mediated headache.201
In the prospective case-series of ONS for treatment of C2-mediated headache201, 16
patients were screened for the study but three (19%) failed to experience at least a
50% reduction in pain intensity during trial stimulation and did not participate further.
Two patients were excluded for other reasons, and the remaining 11 underwent
permanent device implantation. Patients reported significant improvements across a
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range of pain measures at 4-week and 12-week follow-up. The majority of patients
reported their overall pain relief as excellent (55%) or good (18%), with only 27%
reporting a fair improvement. No patients rated the change in their condition as
‘poor’. A majority of patients reported a decrease in headache number (64%) and use
of headache medication (91%). Patients also reported a reduction in headache
symptoms, symptom severity, and impact of headaches on their daily activities. The
authors of this study noted that responses from pain evaluator measures did not
always correlate well with questionnaire responses. It may be of interest that
although 12-week questionnaire responses showed significant improvement
compared with baseline in all categories, the majority had rebounded slightly from
greater efficacy at 4 weeks. Improvements in data collection methods and/or
extended follow-up periods may be required to confirm the sustainability of the
response to stimulation over the long-term. The usual caveats around interpreting
results from uncontrolled studies apply.
In the case-series by Schwedt 2007188, two patients had a diagnosis of hemicrania
continua and two of post-traumatic headache. This study found ONS to be effective
in improving all measures of headache activity, but results were not reported by
diagnosis. Thus, it is difficult to draw conclusions about the value of this treatment in
these indications.
8.9.3 Conclusion other headache disorders
Clinical efficacy of neurostimulation for other headache disorders
• Cervicogenic headache: There is some evidence from a single RCT (n=70)
that TENS may be effective in reducing the intensity and frequency of
cervicogenic headache, although manipulation appears to be more effective.
The trial had no placebo group. There is limited evidence regarding the
efficacy of occipital nerve stimulation (ONS) for the treatment of cervicogenic
headache.
• C2-mediated headache: There is limited evidence from one case-series that
ONS may be effective in the treatment of C2-mediated headache.
• Hemicrania continua and post-traumatic headache: There is insufficient
evidence to draw any conclusions.
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8.10 Safety Non-invasive brain stimulation In the only RCT of sTMS for headache published to date, the procedure appeared to
be well tolerated over multiple episodes.159 There were no treatment-related serious
adverse events, and similar rates and type of adverse events in the actual (14/102,
14%; 5 treatment-related) and sham (9/99, 9%; 2 treatment-related) intervention
groups. The most common adverse events were headache (active n=2, sham n=1),
migraine (active n=2, sham n=0), sinusitis (active n=2, sham n=1), and paraesthesias
(active n=0, sham n=2). All adverse events were classed as mild to moderate except
for severe nausea (active n=1, sham n=1), severe migraine (active n=1) and severe
headache (active n=1). There were no discontinuations due to adverse events.
This technology is not new, and repetitive TMS (rTMS) has been in use for over
30 years, particularly for the treatment of depression and other psychiatric disorders.
In contrast to the single pulses used for the treatment of headache, rTMS usually
involves stimulation with continuous rhythmic pulses for approximately 30 minutes
per session, administered on a daily basis for several weeks, and potential adverse
events include seizure, local scalp discomfort, headache, nausea, neck stiffness,
hearing loss, and induction of mania.202 However, an extensive review of the TMS
literature, including a number of RCTs, systematic reviews, and meta-analyses,
reported a low overall rate of adverse events.203 Mild, transient discomfort or pain is
the most commonly reported side effect, but the treatment is generally well tolerated.
Nevertheless, sTMS should not be used in patients with epilepsy due to the potential
risk of seizures.194 NICE has not produced guidance on sTMS for migraine as there is
currently no device with a CE marking available in the UK.204
Cranial electrotherapy stimulation The sole RCT identified specifically in headache patients106 did not report adverse
events. However, the systematic review by O’Connell 201022 reported that in general,
complications are relatively infrequent, minor and short-lived. There may be a small
risk of treatment-medication interactions with this therapy.115
Transcutaneous electrical nerve stimulation Neither of the two RCTs of TENS for headache included in this report discussed
adverse events.181,189 Although TENS has been used for pain relief in a number of
indications with generally low rates of mild adverse events,55 further data are required
115
before recommendations can be made regarding the safety of the procedure when
applied to the head.
Percutaneous electrical nerve stimulation One RCT (Ahmed 2000177, n=25) of PENS for the treatment of chronic migraine and
tension-type headache was identified. Adverse events were not reported. Extreme low-frequency pulsed electromagnetic field stimulation In the 2001 study of ELF PEMF, active or sham devices were worn on ribbons
around the neck over a period of weeks.182 It is not clear whether the devices were
worn continuously and hence total exposure cannot be determined. The authors
reported no adverse events or complications in either treatment group, a finding
repeated in all other papers published by this team across a variety of indications.
In the 1998 and 1999 studies by Sherman and colleagues, active or sham PEMF was
applied to the medial thigh area, following anecdotal reports of improved headache
symptoms from a patient receiving this treatment for wound healing.23,193 The authors
did not report adverse events; however, clinical use of PEMF generators was first
approved in the United States in 1979, and 20% of slow-healing fractures – over
100,000 cases – are treated with PEMF each year.205 Whether PEMFs can safely be
applied to the head area is likely to depend on the stimulation parameters, and
further data are required regarding this issue. However, it has been suggested that
waveforms with a frequency over 50 Hz or intensity over 20 µT not be applied directly
to the head.205
Deep brain stimulation Over 50 cases of DBS for intractable trigeminal autonomic cephalalgias have now
been reported in the literature, with chronic refractory cluster headache being the
most common indication.206 In the sole RCT of DBS for the treatment of headache,
three serious adverse events (SAE) were reported in two of 11 patients.178 A post-
surgical infection in one patient was treated by explant of the device and antibiotic
administration. The device was re-implanted six months later. In the second patient,
a pre-surgical loss of consciousness with hemiparesia triggered by trial stimulation
was deemed a SAE. A computerised tomography (CT) scan was normal and the
attack resolved in 2 hours with no repetition. The same patient later experienced
multiple severe micturition syncopes due to reduced blood pressure associated with
upright posture during the 10-month open phase of the trial. Similar cases of
116
orthostatic hypotension have been associated with chronic stimulation in a previous
case-series.207 A further 23 non-serious adverse events were reported. One was
surgery-related and four further test stimulation events were recorded. The most
common was oculomotor disturbances (n=4), but these were mild and transient. This
finding is consistent with the previous literature, which suggests that dizziness and
oculomotor effects may be observed during test stimulation at voltages above 1.5 to
3 V.206 Similar numbers and type of adverse events were reported during the
randomised ‘on’ (n=6) and ‘off’ (n=8) periods of the study. Most involved changes
(increases and decreases) in appetite, thirst, and libido. Again, these effects were
mild and transient. Despite active monitoring during the course of this study, no
changes in baseline electrolytes were reported. One patient experienced a shortened
menstrual cycle during the ‘off’ phase of the study, and another experienced
increased testosterone levels during the ‘off’ phase and open extension.
Intracranial haemorrhage is one of the most serious potential side effects associated
with DBS, and has been reported in previous studies, including one fatality.208,209
There were no occurrences of intracranial haemorrhage in this study. The authors
elected not to utilise microelectrode recording to reduce the risk of bleeding, but
given the small sample size (n=11), no conclusions can be drawn about the success
of this safety precaution.
Occipital nerve stimulation In the four prospective185,186,195,201 and six retrospective case-series172,188,196,198-200 of
ONS for any type of headache identified in the systematic review by Jasper (2008),176
a total of 123 patients were implanted with occipital nerve stimulators. The most
common adverse event appeared to be lead migration, although this complication
appears to be less problematic with paddle-type surgical leads. Only two occurrences
of lead migration were reported in 35 patients (6%) receiving paddle-type
leads186,195,200 compared with 31 instances in 82 patients (38%) receiving cylindrical
percutaneous leads.172,185,187,188,196,201 It is difficult to calculate average rates of lead
migration as the studies varied considerably in length of follow-up, ranging from
12 weeks to 6 years. However, in the study by Popeney and Aló185, nine of 25
patients experienced lead migration after a mean 18.3 months follow-up, often
accompanied by loss of pain relief – a state that the authors claim acts as a form of
control group.185 In the outcome review by Schwedt 2007188 six of 10 patients with 2-
year follow-up needed revision surgery for lead migration by two years post-
implantation, and all eight remaining patients required repeat surgery by three years.
117
Advancements in lead placement and fixation techniques may result in fewer cases
of lead migration in the future,176 and other serious complications appear to be
relatively uncommon. Infection was reported in seven of 117 patients (6%), and four
patients requested device explant due to pain at lead or generator sites.176 Non-
serious adverse events included battery depletion requiring replacement of the
implantable pulse generators (IPGs). However, rechargeable IPGs are now available,
obviating this potential complication.176
The ONSTIM trial179 of ONS for intractable chronic migraine reported safety
outcomes for 51 subjects undergoing successful implantation. Fifty-six adverse
device-related events occurred in 36 patients. This study utilised percutaneous
cylindrical leads and lead migration was the most frequently reported event,
occurring in 12 of 51 subjects (24%). Surgical procedures for minimising lead
migration were improved over the course of the study and recommendations to study
centres altered accordingly. In particular, use of strain-relief loops to allow for neck
movement, appropriate anchors, and implant locations are likely to result in fewer
complications in future procedures. Eleven implant site infections occurred in nine
subjects (18%), and three SAEs requiring hospitalisation were recorded – namely
lead migration, implant site infection, and post-operative nausea. The most common
non-device related adverse event was worsening of migraine symptoms, which
occurred in 9% of the adjustable stimulation group, compared with 41% of the pre-set
(sham) stimulation group and 24% of the medical management group.
Two-year aggregate safety data are available for the PRISM study of ONS for drug-
refractory migraine.210 Of 138 subjects undergoing trial stimulation, 132 received
permanent implants. Two-year follow-up was available for 74 patients. The most
frequent device-related adverse events were non-target sensory symptoms (18.0% of
subjects), including muscle spasms, pressure sensations, jolting, or stimulation of
inappropriate tissue, such as shoulder. Other common adverse events included
implant site pain (17.3%) and infection (15.1% requiring systemic antibiotics, 8.6%
requiring explant). Despite the use of percutaneous leads, only 9 of 132 patients
(6.8%) receiving permanent systems experienced lead migration requiring surgical
revision, suggesting that improvements in surgical techniques may have indeed
resulted in fewer complications.
118
Conclusion
Safety of neurostimulation for headache
• The non-invasive neurostimulation techniques appear to be generally well
tolerated, with only mild, transient symptoms, most commonly pain or
discomfort at the site of stimulation. Although both transcutaneous electrical
nerve stimulation (TENS) and pulsed electromagnetic field stimulation (PEMF)
have been used clinically for many years, there is a paucity of evidence
regarding the safety of these procedures when applied to the head. It is
advisable not to use single-pulse transcranial magnetic stimulation (sTMS) for
patients with epilepsy due to the possible risk of seizure. No data are available
on the safety profile of percutaneous electrical nerve stimulation (PENS) for
the treatment of chronic headache.
• The implanted neurostimulator interventions carry additional risks associated
with surgery, including infection, intracranial haemorrhage and death. Other
adverse events tend to be mild and transient, most commonly paraesthesias.
Technical complications such as lead migration and battery depletion occur
but frequently may be reduced by use of paddle-type electrodes, improved
surgical technique, and product improvements.
119
8.11 Cost-effectiveness No relevant cost-effectiveness studies or economic evaluations were identified.
Conclusion
Cost-effectiveness of neurostimulation for headache
No relevant studies were identified.
8.12 Discussion Migraine Eight RCTs in total were identified - one or two for different types of neurostimulation
respectively. There were a number of methodological issues across these RCTs,
including small sample size (particularly where relevant patients formed a sub-group
of a larger trial population), the absence of an inactive control group (the TENS RCT)
and issues around successful blinding; unusually low placebo rates were noted in
two trials (PENS and PEMF) indicating that blinding may not have been successful,
whilst higher than usual rates were found in the trial of CES versus sham CES. In this
latter trial, the placebo frequencies were higher than the active frequencies of some
other CES studies. A number of different outcome measures were used across trials,
though most related to pain relief. One of the PEMF trials used a composite outcome
only, and there were some concerns around the validity of this. None of the trials
looked at long-term or quality of life outcomes.
Overall there is evidence across studies of statistically significant differences for
some outcome measures; these differences favour neurostimulation over sham
neurostimulation. The evidence is limited by the small number of studies for each
type of neurostimulation and the methodological concerns described above. There is
least convincing evidence for TENS as the study did not include a sham comparator
and for ONS, as there was a significant difference for one outcome measure, in one
of two RCTs, only. For the remaining types of neurostimulation (PEMF/ELF, PENS,
CES, TMS) the extent of benefit will most likely depend on the type of patient, the
exact treatment protocol, the success of blinding and the outcomes measured. For
PEMF/ELF and CES, results were reported in an aggregated way only; it is unclear
whether headaches with different underlying pathologies would respond equally to
any given treatment and so pooling of data could result in masking of true treatment
120
effects for different headache types. Larger, well-conducted studies focussing on the
headache population of interest and with adequate follow-up times would be required
to confirm whether benefits can be consistently achieved and to establish whether
there are any long-term benefits.
Tension-type headache The evidence in tension-type headache is limited to four RCTs, all with mixed
populations. The RCT on TENS (as for migraine) has no placebo controlled group
and it is therefore unclear whether the results show a true benefit. The remaining
three trials (PEMF, CES and PENS, all also included in the migraine section) find
significant differences for some outcomes favouring neurostimulation over sham
neurostimulation. Two of these do not report results for tension-type headache
patients only, and it is therefore unclear to what extent this patient group may benefit.
The remaining study found significant benefits in a sub-group (n=12) of tension-type
headache patients; this is a very small sample size and there were concerns over
success of blinding in this study.
Cluster headache Evidence in this area was very sparse. One well-conducted but small (n=11)
crossover RCT was identified on DBS versus sham-DBS. This found no significant
differences between groups. The authors stated that the follow-up time may have
been inadequate and the small sample size may not have been sufficient to detect
potential differences. Evidence on ONS was limited to three case-series, which
appear to show some benefits; these results must be interpreted cautiously. The
RCT on ELF-PEMF (as discussed under migraine and tension-type headache) found
statistically significant differences favouring active treatment, but results were not
presented separately for the six cluster headache patients.
Occipital neuralgia Evidence from six case series suggests that the treatment is beneficial; again, this
evidence must be interpreted cautiously in the absence of a control group. No RCT
evidence exists for ONS as a treatment for ON. As stimulation is accompanied by
noticeable paraesthesias, blinding is likely to be a problematic issue in any trials
conducted, and active controls may thus be preferable to sham stimulation.
121
Other headache disorders For TENS, there is evidence from one RCT that it may be effective in cervicogenic
headache; however, the active comparator outperformed TENS and there was no
placebo control. Other evidence is very limited and based on small case-series.
Safety Adverse events data was not always reported specifically for headache patients and
we found no information for CES, TENS, PEMF or PENS. Whilst reports on the
safety of these techniques generally find a low rate of mainly minor adverse events, it
is unclear whether this would be the case if neurostimulation is applied to the head
area. No adverse events were found to occur in an RCT of ELF-PEMF, which
included headache patients. Those occurring with sTMS were mainly mild to
moderate, though there were reports of severe headache and nausea. Adverse
events associated with DBS were generally mild and transient, but did include more
serious ones such as infection and intracranial haemorrhage; there was one report of
a death. Serious adverse events were rare with ONS; most common ones were lead
migrations, site infections or pain.
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9 NEUROPATHIC PAIN ASSOCIATED WITH MS
9.1 Description of the underlying health problem Multiple sclerosis (MS) is an inflammatory disease, which results in demyelination in
the central nervous system. This leads to the development of sclerotic plaques in the
brain and spinal cord. Main presenting symptoms include weakness in one or more
limbs, optical neuritis, paraesthesia, diplopia and vertigo. On disease progression
other symptoms become more apparent, including fatigue, bladder and bowel
problems, muscle spasms, spasticity and pain.211
Types of pain experienced in MS can be nociceptive or neuropathic. Nociceptive pain
results from damage to muscles, tendons, ligaments and soft tissue. It is not caused
directly by MS, but can result from some of the symptoms. Examples include pain in
the lower back or hips, which can results from long periods of immobility (e.g. if in a
wheelchair) or a certain way of walking. Spasms and spasticity may also cause pain.
Generally, nociceptive pain can be more successfully managed than neuropathic
pain. Treatment includes common pain-relieving drugs, such as paracetamol or
ibuprofen, and physiotherapy.212
Examples of neuropathic pain in MS are dysaesthesia or paraesthesia (altered
sensation), varyingly described as pins and needles, burning, tightness, numbness,
prickling, itching, aching etc. These symptoms are usually experienced in the
extremities and can be painful and distressing. Another form of altered sensation is
banding ('MS hug'), which is a feeling of constriction or tightness around the chest.
Trigeminal neuralgia associated with MS (symptomatic TN) is thought to be due to
demyelination in the trigeminal nerve or within the descending tract of the trigeminal
system in the brainstem. Another type of neuropathic pain is L'hermitte's
sign/syndrome, which is a sudden sensation resembling an electric shock in the neck
and spinal column – this is rarely treated as it does not last long enough for
treatments to take effect. Optic neuritis is a severe pain behind the eyes caused by
inflammation of the optic nerve.212
9.2 Epidemiology Multiple sclerosis affects around 85,000 people in the UK.213 It is most often
diagnosed in people between the ages of 20 and 40, and women are almost twice as
likely to develop it as men.213 It is estimated that at least a third of all people with MS
123
will feel some level of pain at some time.214 Observational studies found a pain
prevalence of between 29% and 86% in patients attending neurology clinics.211
Table 12 below summarises the epidemiological data. Please note that systematic
searches for this type of data were not performed and the validity of the results has
not been assessed (e.g. by looking at the sample size, methods of obtaining data
and case definitions).
Table 12 Epidemiological data pain in MS Indication
Measure Source
General pain in MS ‘Some level of pain at some time’: 1/3 of all people with MS*
MS Society UK214
Pain in MS patients attending neurology clinics
Prevalence: between 29% and 86%
Based on 13 observational studies (various countries) reported in systematic review211
*not specified whether UK patients
9.3 Treatment NICE guidelines from 2003 recommend that musculoskeletal pain secondary to
reduced or abnormal movement be treated with exercise, manipulation or
ergodynamic improvements in the first instance. Analgesic drugs are only
recommended after non-pharmacological methods have failed. In the case of
continuous unresolved secondary musculoskeletal pain, TENS or antidepressant
medication are recommended.215 Neuropathic pain, characterised by its sharp and
often shooting nature, and any painful hypersensitivity, should be treated using
anticonvulsants such as carbamazepine or gabapentin, or antidepressants such as
amitriptyline. If the neuropathic pain remains uncontrolled after initial treatments have
been tried, the individual should be referred to a specialist pain service.215 For this
report, no recommendations or guidelines for any type of neurostimulation to be used
for neuropathic pain were identified.
9.4 Quantity and quality of evidence There was very little evidence on treatment of neuropathic pain in MS with
neurostimulation (see Table 13 below). There were no systematic reviews and no
cost-effectiveness studies specifically for this patient group. One RCT was identified
for transcranial direct current stimulation (tDCS).21 There are two potentially relevant
registered Cochrane protocols: Claydon 2010,216 which will look at TENS for
124
neuropathic pain in adults (MS patients will be included) and Rog 2001,217 which will
look at treatment of neuropathic pain in MS (including TENS and SCS).
Table 13 Evidence on neurostimulation for neuropathic pain associated with MS Indication Neurostimulator type General neuropathic pain
(including in MS) Neuropathic pain associated with MS
Spinal cord stimulation (SCS)
Mailis-Gagnon 200450-SR Cruccu 20079-SR
Transcutaneous electrical nerve stimulation (TENS)
Nnoaham 2008218-SR Claydon 2010216 (Protocol for a Cochrane SR)
Several treatments including TENS & SCS
Rog 2001217 (Protocol for a Cochrane SR)
Transcranial direct current stimulation (tDCS)
Mori 201021-RCT
SR= Systematic review; RCT=randomised controlled trial
9.5 Spinal cord stimulation for neuropathic pain associated with MS The systematic review by Mailis-Gagnon 200450 (see Table 13 above) included MS
patients in their inclusion criteria, however no evidence was identified. The
systematic review by Cruccu 20079 on general neuropathic pain included one case-
series on SCS in 410 patients with central pain of spinal cord origin, 19 of whom
were patients with MS (see Appendix 7, p232 and p233, Table 34 for review
characteristics and Table 35 for quality assessment). The authors state that long-
term pain relief was achieved on five outcome measures in 15/19 patients with
central pain of spinal cord origin. There are no further details and overall there is
insufficient evidence to draw any conclusions on the effectiveness of SCS in MS
patients with neuropathic pain.
9.6 Transcranial direct current stimulation for neuropathic pain associated with MS
One small RCT was identified (Mori 201021, see Table 13 above), where 19 patients
were randomised to either real or ‘sham’ tDCS. This appeared to be a generally well-
conducted trial, with every effort being made to ensure blinding (see Appendix 7,
p234 and p235, Table 36 for study characteristics and Table 37 for quality
assessment). Blinding may not have been possible to achieve throughout. The
sample size was small, and follow-up was likely to be too short to observe potential
longer-term benefits.
125
Active or sham treatment was applied once a day for 20 minutes over a 5 day period.
The follow-up period was 4 weeks. All patients had relapsing remitting MS in remitting
phase and presented with chronic, drug-resistant, central neuropathic pain. Pain was
measured on a pain VAS and the short form McGill Pain Questionnaire (SF-MPQ). A
minimum baseline score of 40 mm on the VAS (0=no pain, 100=worst possible pain)
was required for inclusion into the trial. Quality of life was assessed with the Multiple
Sclerosis Quality of Life-54 scale (MSQoL-54). Depression and anxiety were also
measured (Beck Depression inventory, BDI, and VAS for anxiety). Results show that
there was a significant difference in pain scores (measured on VAS and SF-MPQ)
and quality of life (MSQoL-54) between the active and sham treatment groups at
weeks 1, 2, 3 and 4, with pain reduced and quality of life being increased in the
active group. The effect of the 5-day treatment therefore appeared to be sustained for
approximately an additional 3 weeks. There was no significant difference between
groups for anxiety or depression.
9.7 Transcutaneous electrical nerve stimulation for neuropathic pain associated with MS
A recent Cochrane review by Nnoaham218 (see Table 13, p124) included 2 RCTs of
TENS in patients with MS and chronic (back) pain. One was a pilot-study (Al-Smadi
2003),88 the other a larger RCT by the same group (Warke 2006).57 It is unclear from
the full publication whether the pain is of musculoskeletal origin or neuropathic.
Section 5 of this report presents the evidence for the effectiveness of TENS for (any
type of) back pain, and the two RCTs are included therein.
9.8 Conclusion neuropathic pain in MS
Clinical effectiveness of neurostimulation for neuropathic pain in MS
• Spinal cord stimulation (SCS): There is insufficient evidence to draw any
conclusions on the effectiveness of SCS in MS patients with neuropathic pain
• Transcranial direct current stimulation (tDCS): There is evidence from one
small trial (n=19) that a 5-day treatment period significantly reduced pain and
improved quality of life for 4 weeks compared with ‘sham’ treatment.
126
9.9 Safety Spinal cord stimulation No data pertaining to the safety of SCS for neuropathic pain specifically in MS
patients were reported in the systematic review.9 In a safety analysis across all
indications, the most common adverse events were lead migration, lead breakage
and other minor hardware problems.
Transcranial direct current stimulation There were no adverse events reported and no discontinuations (19 patients).
Conclusion
Safety of neurostimulation for neuropathic pain in MS
• Spinal cord stimulation (SCS): No safety/adverse event data were identified
specifically for this patient group. Generally, common adverse events relate to
hardware problems.
• Transcranial direct current stimulation (tDCS): No adverse events were
observed in 19 patients over a 5-day study period.
9.10 Cost-effectiveness No studies of the cost-effectiveness of neurostimulation in neuropathic pain
associated with MS were identified.
Conclusion
Cost-effectiveness of neurostimulation for neuropathic pain in MS
• No cost-effectiveness data were identified.
9.11 Discussion Very little evidence on the use of neurostimulation to treat neuropathic pain in MS
was identified. It is possible that this is a fairly new area of investigation and that
studies have not yet been conducted or summarised in reviews. There are two
Cochrane protocols that appear to be relevant, but it is not known when the
completed reviews are likely to be published. TENS does appear to be used for back
pain in MS patients, but it is unclear whether this is for neuropathic and/or
musculoskeletal pain. TENS for back pain is discussed in sections 5.6.2 and 5.7.4 of
this report.
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10 ANY TYPE OF NEUROPATHIC PAIN
In this report, we have focussed on those pain indications for which commissioners
are most likely to have to make commissioning decisions. However, a further aim of
this report was to provide a broad overview of the available evidence associated with
different types of neurostimulation treatment for any type of chronic/neuropathic pain.
In order to achieve this, only broad systematic reviews that did not restrict to specific
indications were included. So, for example, searches for, or inclusion of a systematic
review on neurostimulation for diabetic neuropathy only would not have occurred.
The following is therefore unlikely to be a comprehensive list of systematic reviews
for all indications in which neurostimulation could be a treatment option. However,
the results of this search do provide a broad overview, highlighting the main areas
where neurostimulators are used and the evidence to support them, some of which
may not have been covered in earlier chapters of this report. Where possible, the
most recent and methodologically sound systematic reviews have been chosen. The
reviews identified are shown in Table 14, p128. Formal quality assessment of these
reviews has not been undertaken.
Table 14 shows that there are some indications not covered in this report for which
there is RCT evidence. This includes:
• SCS for ischaemic limb pain, angina pain and diabetic neuropathy
• TENS for patients with acute pain conditions (which may include neuropathic
pain)
• Non-invasive brain stimulation for patients with a range of indications
• PENS for patients with neck pain and diabetic neuropathy.
The less invasive techniques are more likely to be tested in RCTs. For more invasive
techniques such as DBS and MCS, further evidence is available from several case-
series only. These cover patients with a wide range of conditions and the individual
case-series often include mixed populations.
128
Table 14 Systematic reviews of neurostimulation for any type of chronic/neuropathic pain Review Pain indications
covered by inclusion criteria
Pain indications for which evidence identified*
Included in this report Excluded from this report
Spinal cord stimulation Simpson HTA 20083
FBSS CRPS Phantom limb pain Central pain (e.g. post-stroke) Diabetic neuropathy Post-herpetic neuralgia
FBSS CRPS
2 RCTs FBSS (see section 5.5.1) 1 RCT CRPS (see section 7.5)
None.
Kleijnen 2006219
FBSS Phantom pain Postherpetic neuralgia Spinal cord lesion Traumatic brachial plexus lesion
FBSS 2 RCTs FBSS (see section 5.5.1) Evidence from uncontrolled studies on FBSS. (Systematic review of uncontrolled studies mentioned in section 5.4 but not further discussed in this report)
Canadian HTA 2005220
Any neuropathic pain FBSS CRPS Diabetic neuropathy Critical limb ischaemia Angina
2 RCTs FBSS (see section 5.5.1) 1 RCT CRPS (see section 7.5)
Includes 6 HTAs, 2 of which contain some additional RCT information on indications not covered in this report (diabetic neuropathy, critical limb ischemia, angina): Cameron 2004145: Ischaemic limb pain:2 RCTs Angina pain: 3 RCTs (Mixed indications-no RCTs) ASERNIP 200351: Ischaemic limb pain: 2 RCTs Angina pain: 4 RCTs Diabetic neuropathy: 1 RCT
129
Review Pain indications covered by inclusion criteria
Pain indications for which evidence identified*
Included in this report Excluded from this report
Motor cortex stimulation (MCS) Lima 200862
Chronic pain
Mainly trigeminal neuropathic pain, central post-stroke pain, cerebrovascular disease, peripheral nerve lesion, spinal cord injury, brachial plexus lesion, phantom limb pain and dental surgery; individual patients with other pain aetiologies included
No evidence included in this report. .
35 case-series with mainly mixed population; overall (pooled) responder rates given separately for invasive and non-invasive studies. There were methodological concerns over pooling data from case-series with mixed populations. No results presented by individual indication.
Non-invasive brain stimulation (rTMS, CES and tDCS) O’Connell 201022 Any type of pain
(including neuropathic) Neuropathic pain (mixed central, peripheral and facial), fibromyalgia, neuromuscular, musculoskeletal, back and neck pain, chronic pelvic pain, hip and knee osteoarthritis and other indications.
1 RCT in MS patients with neuropathic pain (see section 9.6) 1 RCT in CRPS (see section 7.7) 5 RCTs in spinal cord injury pain(see section 5.7.5) 2 RCTs in TNP patients (see section 6.7) 2 RCTs in low-back pain (see section 5.6.4) 1 RCT in migraine and tension type headache (see section 8.5.5 and 8.6.3)
6 RCTs in patients with fibromyalgia 1 RCT in patients with chronic pelvic pain 1 RCT in patients with chronic pancreatitis pain 1 RCT in patients with phantom limb and central neuropathic pain 1 RCT in patients with hip and knee osteoarthritis 2 RCTs in patients with neuromuscular or musculoskeletal pain 10 RCTs with mixed neuropathic pain
Deep brain stimulation
130
Review Pain indications covered by inclusion criteria
Pain indications for which evidence identified*
Included in this report Excluded from this report
Bittar 200553
All types of pain 24 indications in total, most with low back & skeletal pain, FBSS and central lesion pain. Four patients with TNP.
Case-series results for patients with TNP (see section 6.5), FBSS (see section 5.5.2) and lower back pain (see section 5.6.1) included.
Case-series evidence for other indications including: central lesion pain, peripheral neuropathy, cancer pain, paraplegia/paraparesis/quadriplegia, lumbosacral radiculopathy, cervical root/brachial plexus lesion. Total of six case-series with mixed populations. Short and long-term ‘success’ rates listed by indication, by type of pain (nociceptive or deafferentation/neuropathic) and by site of electrode implantation.
TENS Dubinsky 201054
Neuropathic pain Low back pain and diabetic neuropathy (mixed pain studies excluded).
RCT evidence on TENS for low back pain (see section 5.6.2)
Additional evidence on diabetic neuropathy from three controlled studies. The exact study type is unclear from published paper (and online appendices).
Walsh 200955
Acute pain conditions Procedural pain, haemophiliac pain, pain from sprains or fractures, pain from postpartum uterine contractions, acute orofacial pain, post thoracotomy pain, pain from rib fractures, neuropathic pain
None. 5 RCTs in procedural pain (cervical laser treatment , office hysteroscopy, screening flexible sigmoidoscopy, flexible cystoscopy, venipuncture) 1 RCT in haemophiliac pain 1 RCT in pain from sprains or fractures 1 RCT in pain from postpartum uterine contractions 1 RCT acute orofacial pain 1 RCT in post thoracotomy pain 1 RCT in pain from rib fractures 1 RCT in neuropathic pain (hypersensitive hands due to peripheral nerve injuries-not CRPS)
Claydon 2010216 Protocol for Cochrane review
Neuropathic pain in adults
N/A N/A N/A
PENS
131
Review Pain indications covered by inclusion criteria
Pain indications for which evidence identified*
Included in this report Excluded from this report
Blue Cross of Idaho report updated 201020
Any type of pain. Chronic low back pain, chronic neck pain, diabetic neuropathy, headache, osteoarthritis of the knee.
RCT evidence on low back pain (see 5.6.3). RCT evidence on migraine and tension type headache (see sections 8.5.6 and 8.6.4).
1 RCT chronic neck pain. 1 RCT chronic diabetic neuropathy.
PNS Cruccu 20079
Any type of neuropathic pain.
Various kinds of peripheral neuropathy or mixed pains.
None. Six uncontrolled studies in patients with mixed pains/various kinds of peripheral neuropathy.
NRS Cruccu 20079 Any type of neuropathic
pain. Pelvic pains or interstitial cystitis.
None. Two studies of poor methodological quality (patients with pelvic pains or interstitial cystitis).
ONS Jasper 2008
Any type of chronic headache.
Migraine, cluster headache, occipital neuralgia, cervicogenic headache, C2-mediated headache.
Case-series evidence on migraine, cluster headache, occipital neuralgia, cervicogenic headache and C2-mediated headache.
None.
*May be limited by inclusion criteria relating to specific study designs rTMS=repetitive transcranial magnetic stimulation, CES=cranial electrotherapy stimulation, tDCS=transcranial direct current stimulation TENS=transcutaneous electrical nerve stimulation, PENS=percutaneous electrical nerve stimulation, PNS=peripheral nerve stimulation, NRS-nerve root stimulation, ONS=occipital nerve stimulation
132
11 DISCUSSION Main results A total of 10 types of neurostimulation (SCS, MCS, DBS, ONS, TENS, PENS, CES,
TMS, DCS, PEMF) that were variously used to treat the five main pain conditions
(with three sub-categories for back pain and five sub-categories for headache) were
identified. Thirty-nine systematic reviews and/or economic evaluations (7/39) were
identified, which included at least one of the specified pain indications and at least
one type of neurostimulation. A total of 47 RCTs were identified (from within reviews
and identified in separate searches), as well as numerous case-series (within
included reviews).
The bulk of the systematic review evidence (30 reviews) related to all types of back
pain, with most of the RCT evidence (17 RCTs) relating to chronic low back pain. The
number of reviews identified did not necessarily relate to the volume of primary
evidence; 14 systematic reviews included a series of publications on the same two
trials of SCS for FBSS. There were 12 systematic reviews, which included
information on CRPS, but only three RCTs in total. Only four systematic reviews
were found for headache, but 11 RCTs were identified. There was least information
on neurostimulation for trigeminal pain and neuropathic pain in MS.
The evidence was of variable quality; many systematic reviews were found to be of
good methodological quality, but often the only relevant evidence was in the form of
case series. There were methodological concerns over many of the included RCTs,
which were often small, had issues with adequacy of blinding, insufficient follow-up
and insufficient information on missing data.
The main clinical effectiveness findings were as follows:
FBSS:
• Based on one RCT, SCS compared to CMM appears to be effective and is
likely to be cost-effective
• Based on one RCT, SCS compared to re-operation is also effective and likely
to be cost-effective; a composite outcome measure was used in this trial,
which may not be the most appropriate
• There is case-series evidence only for DBS for FBSS
133
Chronic low back pain:
• Evidence from 11 RCTs found no significant differences overall between
TENS and sham-TENS in LBP
• There is some RCT evidence (from eight trials) that PENS may be better in
the short-term than sham-PENS in LBP; some methodological concerns are
associated with these RCTs. One trial found no significant differences.
Pain after SCI:
• Evidence from one small RCT suggests that TENS is no better than sham-
TENS for SCI
• Evidence from two small RCTs suggests there is little difference between
rTMS and sham-rTMS
• There is some evidence that CES (one RCT) and tDCS (one RCT) may be
effective in the short-term for some (pain-related) outcomes compared to
sham treatments; one RCT in CES versus sham CES found no difference
• There is case-series evidence only for DBS, SCS and MCS in pain after SCI
Trigeminal neuropathic and deafferentation pain:
• No evidence is available from two small RCTs on MCS as they did not report
results for TNP/TNP patients separately
• There is some evidence from two RCTs on rTMS versus sham rTMS of
(short-term) pain reduction after a single treatment session with the active
treatment
• There is case-series evidence only for DBS for TNP/TNP
CRPS:
• Evidence from one small but well-conducted RCT suggests that SCS (plus
physical therapy) is more effective than physical therapy alone; this effect
persists up to two years, but at five years there is no difference between
groups
• One very small RCT (n=4) on MCS found that pain decreased during the ‘on’
phase treatment; quality of life did not differ between stimulation ‘on’ and ‘off’
periods
• One small RCT (n=10) on rTMS versus sham rTMS found that pain levels
were significantly reduced during a 90-minute treatment period with the active
treatment
134
• There is insufficient evidence on TENS to draw any conclusions
Migraine:
• There is no evidence that TENS is more effective than placebo in migraine,
as the only RCT identified had only active comparators and results were not
disaggregated for different headache types
• Evidence from two RCTs did not find significant differences between ONS
and sham-ONS
• There was some evidence (one or two RCTs respectively) that other types of
neurostimulation (PEMF, ELF-PEMF, PENS, CES and TMS) were more
effective than sham treatment for some outcome measures; there were some
methodological uncertainties associated with these trials (NB results for ELF-
PEMF and CES were not disaggregated for migraine)
Tension-type headache:
• There is no evidence that TENS is more effective than placebo in tension-
type headache, as the only RCT identified had only active comparators and
results were not disaggregated for different headache types
• Three RCTs on PEMF, CES and PENS (one for each type of treatment)
found some significant differences in favour of active treatment; results from
two of these could not be disaggregated for tension-type headache
Cluster headache:
• One small RCT (n=11) found no significant differences between DBS and
sham-DBS
• Evidence on ONS was limited to case-series
Occipital neuralgia:
• Evidence on ONS was limited to case-series
Other headache disorders:
• There is evidence from one RCT that TENS may be effective in cervicogenic
headache; however, the active comparator outperformed TENS.
135
Neuropathic pain in MS:
• One small RCT found that tDCS was more effective than sham-tDCS for up to
four weeks in alleviating central neuropathic pain
• Evidence on SCS was limited to one case-series
All neuropathic pain (mapping exercise):
• There is further RCT evidence, not included in this report, for: SCS for
ischaemic limb pain, angina pain and diabetic neuropathy; TENS for patients
with acute pain conditions (which may include neuropathic pain); non-invasive
brain stimulation for patients with a range of indications; and PENS for
patients with neck pain and diabetic neuropathy.
There was a general lack of evidence on quality of life and long-term effectiveness.
Adverse event data were reported inconsistently across studies and it was not
possible to give an overall estimate of frequency of different adverse events. More
serious side effects were likely to be associated with more invasive techniques.
Deaths have been reported as a (rare) adverse event with DBS. Adverse events for
TENS, PENS and non-invasive brain stimulation are generally minor.
Economic evaluations were identified only for SCS in FBSS and CRPS. Those on
FBSS found consistently that SCS is likely to be cost-effective over a 15 year time
horizon. The findings for CRPS are less convincing and there is a large discrepancy
between results from different evaluations. It is possible that CRPS may be cost-
effective in the long-term. Further in-depth analysis of model structures, assumptions
made and range of input variables would be necessary in order to fully assess the
validity of the economic evaluations.
Strengths of the report Validated methods were used for searching for studies. These included search filters
for systematic reviews and RCTs where possible. Included systematic reviews were
not solely relied on for identifying RCTs, but further searches were conducted. It is
thus unlikely that any relevant RCTs have been missed. All systematic reviews that
were used for informing the results and many of the included RCTs were quality
136
assessed using validated criteria. A consistent methodological approach across all
indications in terms of study inclusion and presentation of results was applied.
Limitations of the report Study identification
Studies beyond RCTs in the hierarchy of evidence were not sought for this report.
Such studies are reported where included in identified and utilised systematic
reviews. As such there may be some recent, non-RCT evidence not reported here.
RCTs were often in mixed pain populations and an RCT with a sub-group of relevant
patients may not have been identified where there were no keywords in the abstract
or index terms relating to these patients specifically.
Analysis of evidence
Summarising and presenting the evidence was complicated by the fact that many
general reviews include some studies on relevant patient groups; further, they also
included studies (RCTs and case-series) with mixed populations. Results were not
always presented in a disaggregated way (by indication), or not consistently (e.g.
disaggregated results available from open phase of a trial, but not from randomised
phase). Due to the volume and strength of the evidence, in-depth analysis of all
included RCTs in terms of quality of methodology and its likely impact on results has
not been undertaken.
Limitations in the evidence
Whilst many of the included reviews were of good quality, they identified poor quality
(case-series) evidence only. The lack of RCTs may be partly due to ethical concerns
of randomising patients with a painful condition to placebo, and also to the rare
nature of some of the conditions, which makes it difficult to assemble a patient group
sufficiently large to conduct an RCT. Case-series evidence is difficult to interpret in
the absence of a control group, as changes may be due to a placebo effect. A lack of
detail on patient selection and little knowledge of the natural history of the condition
further hampers interpretation. For example, pain may be of a remitting and relapsing
nature and unless the natural history is known, it is difficult to ascribe changes to a
particular treatment. Further, some studies aggregated individual patient data from
different case-series, which adds further uncertainty; it is not known for example
whether the patients were at the same stage of disease progression, whether pain
137
severity was similar, whether similar outcome measures were used or whether
follow-up was of similar length.
There were also methodological concerns over many of the included RCTs; these
included small sample size, inadequacy of blinding, insufficient wash-out periods and
no test for carry-over effect in crossover trials, inadequate reporting on missing data
and analysis and insufficient follow-up of randomised phase of trial.
Placebo rates in some of the RCTs appeared to be unusually high or low indicating
that the placebo was either too similar to the active treatment (in terms of stimulation
frequency), or that blinding was not successful and patients were aware of treatment
allocation. Perfect blinding is difficult to achieve, as active and sham-treatments may
produce different sensations. Some types of neurostimulation may be easier to blind,
for example in PEMF the active field cannot be sensed.
One of the most frequently used outcome measures was the pain VAS. This may not
be sufficient for capturing all relevant patient related outcomes especially quality of
life. Some studies also used composite measures, which may not be the most
clinically appropriate. It is also likely that not all studies followed patients for a
sufficient period of time to ascertain the duration of a beneficial effect.
Issues beyond the scope of this report
It was beyond the scope of this report to investigate, for one type of neurostimulation,
the effect of different stimulation intensities or sites of stimulation, or length or
frequency of treatment, but it is likely that these would influence effectiveness. The
length of follow-up is also likely to be important, though optimum length of follow-up
may not always be known. An in-depth exploration how studies differ in these
variables and how this may affect results has not been undertaken. The merits of
such analysis are questionable given the nature of the evidence for most indications.
Averse events identified within the included reviews and RCTs on the specified
indications have been reported. Reporting was not consistent and not all studies
reported on adverse events (or a lack of adverse events). Whilst it is likely that the
most common adverse events associated with the different techniques have been
identified, a systematic review of all the relevant literature and searches for studies
reporting specifically on adverse events have not been undertaken; therefore overall
estimates on the frequencies with which these are likely to occur may not be precise.
138
It was beyond the scope of this report to undertake in-depth analyses of the included
economic evaluations, including assessment of underlying assumptions and ranges
of clinical and cost variables, or choice of sensitivity analyses undertaken.
139
12 CONCLUSIONS The evidence suggests that some types of neurostimulation are likely to be effective
in some pain indications, notably SCS in FBSS and CRPS, and some of the non-
invasive forms of neurostimulation in LBP, pain after SCI and some types of
headache. SCS in FBSS, and possible CRPS, appears to be cost-effective. The
evidence is very limited for trigeminal pain and neuropathic pain in MS. Ideally, large
well-designed RCTs would be needed to confirm some of these results and to fill in
any current gaps in the evidence.
140
13 APPENDICES Appendix 1 Search strategies Systematic reviews MEDLINE (Ovid) searches strategies 2009 to August 2010 Cerebral cortex stimulation 1 cerebral cortex stim$.mp. (21) 2 exp cerebral cortex/ (241600) 3 electric stimulation therapy/ (14340) 4 electric stimulation/ (99436) 5 3 or 4 (113067) 6 2 and 5 (19607) 7 1 or 6 (19626) 8 limit 7 to (yr="2009 -Current" and "reviews (specificity)") Cranial nerve stimulation 1 Cranial Nerves/ (2850) 2 electric stimulation/ (99436) 3 electric stimulation therapy/ (14340) 4 2 or 3 (113067) 5 1 and 4 (118) 6 transcranial direct stimulat$.mp. (3) 7 transcranial magnetic field stimulat$.mp. (2) 8 5 or 6 or 7 (123) 9 limit 8 to (yr="2009 -Current" and "reviews (optimized)") (3) Deep brain stimulation 1 pallidotomy.mp. (700) 2 subthalamotomy.mp. (65) 3 subthalamic stimulat$.mp. (172) 4 deep brain stimulat$.mp. (3543) 5 or/1-4 (4192) 6 subthalamic nucleus/ (1685) 7 electric stimulation/ (99436) 8 electric stimulation therapy/ (14340) 9 or/7-8 (113067) 10 6 and 9 (547) 11 5 or 10 (4420) 12 limit 11 to (yr="2009 -Current" and "reviews (specificity)") (14) Functional electric stimulation 1 functional electric$ stimulat$.mp. (1120) 2 limit 1 to (yr="2009 -Current" and "reviews (optimized)") (14)
141
Motor cortex stimulation 1 motor cortex stimulat$.mp. (347) 2 cortical stimulat$.mp. (1376) 3 or/1-2 (1663) 4 motor cortex/ (13423) 5 electric stimulation/ (99436) 6 electric stimulation therapy/ (14340) 7 or/5-6 (113067) 8 4 and 7 (3059) 9 3 or 8 (4313) 10 limit 9 to (yr="2009 -Current" and "reviews (specificity)") (3) Neuromuscular stimulation 1 neuromuscular electric$ stimulat$.mp. (297) 2 limit 1 to (yr="2009 -Current" and "reviews (optimized)") (12) Occipital nerve stimulation 1 occipital nerve$ stimulat$.mp. (43) 2 occipital cortex stim$.mp. (3) 3 Occipital Lobe/ (6696) 4 electric stimulation/ (99436) 5 electric stimulation therapy/ (14340) 6 4 or 5 (113067) 7 3 and 6 (229) 8 1 or 2 or 7 (272) 9 limit 8 to (yr="2009 -Current" and "reviews (optimized)") (16) Percutaneous electrical nerve stimulation 1 pens.tw. (2708) 2 percutaneous electric$ neurostimulat$.mp. (0) 3 percutaneous electric$ nerve$ stimulat$.mp. (28) 4 percutaneous electric$ neuromodulat$.mp. (0) 5 or/1-4 (2723) 6 limit 5 to (yr="2009 -Current" and "reviews (optimized)") (9) Pudendal sympathetic nerve stimulation 1 peripheral nerve stimulat$.mp. (720) 2 pudendal nerve stimulat$.mp. (90) 3 sympathetic nerve stimulat$.mp. (1338) 4 or/1-3 (2147) 5 peripheral nerves/ (20326) 6 sympathetic nervous system/ (32494) 7 or/5-6 (52419) 8 electric stimulation/ (99436) 9 electric stimulation therapy/ (14340) 10 or/8-9 (113067) 11 7 and 10 (6669) 12 4 or 11 (7917) 13 limit 12 to (yr="2009 -Current" and "reviews (specificity)") (5)
142
Pulsed magnetic fields 1 pulsed magnetic field$.mp. (285) 2 limit 1 to (yr="2009 -Current" and "reviews (optimized)") (2) Retinal nerve stimulation 1 retinal stimulat$.mp. (143) 2 retina stimulat$.mp. (39) 3 retinal nerve$ stimulat$.mp. (0) 4 retina nerve$ stimulat$.mp. (0) 5 or/1-4 (178) 6 retina/ (53867) 7 electric stimulation/ (99436) 8 electric stimulation therapy/ (14340) 9 or/7-8 (113067) 10 6 and 9 (805) 11 5 or 10 (950) 12 limit 11 to (yr="2009" and "reviews (specificity)") Sacral nerve stimulation 1 sacral nerve stimulat$.mp. (283) 2 sacrum/ (5735) 3 electric stimulation therapy/ (14340) 4 electric stimulation/ (99436) 5 3 or 4 (113067) 6 2 and 5 (152) 7 1 or 6 (405) 8 limit 7 to (yr="2009 -Current" and "reviews (specificity)") (1) Spinal cord stimulation 1 spinal cord stimulat$.mp. (1294) 2 spinal column stimulat$.mp. (3) 3 dorsal cord stimulat$.mp. (11) 4 dorsal column stimulat$.mp. (177) 5 spinal cord/ (63269) 6 electric stimulation/ (99436) 7 electric stimulation therapy/ (14340) 8 or/6-7 (113067) 9 5 and 8 (6647) 10 1 or 2 or 3 or 4 or 9 (7134) 11 scs.mp. (2351) 12 10 or 11 (9013) 13 limit 12 to (yr="2009 -Current" and "reviews (specificity)") (13) TENS 1 Transcutaneous Electric Nerve Stimulation/ (2766) 2 tens.mp. (5004) 3 transcutaneous electric$ nerve$ stimulat$.mp. (3082) 4 or/1-3 (7236) 5 limit 4 to (yr="2009 -Current" and "reviews (specificity)") (20)
143
Trigeminal nerve stimulation 1 Trigeminal Nerve/ (7535) 2 electric stimulation therapy/ (14447) 3 electric stimulation/ (100853) 4 2 or 3 (114584) 5 trigeminal nerve$ stimulat$.mp. (91) 6 1 and 4 (926) 7 5 or 6 (988) 8 limit 7 to "reviews (optimized)" (29) 9 limit 8 to humans (22) Vagal nerve stimulation 1 vagal nerve stimulat$.mp. (512) 2 vagus nerve stimulat$.mp. (956) 3 or/1-2 (1409) 4 vagus nerve/ (18858) 5 electric stimulation therapy/ (14340) 6 electric stimulation/ (99436) 7 5 or 6 (113067) 8 4 and 7 (4276) 9 3 or 8 (4794) 10 limit 9 to (yr="2009 -Current" and "reviews (specificity)") (3) Primary studies Cerebral cortex stimulation MEDLINE (ovid) searches strategies 1950 to July 2010 Complex regional pain syndrome 1 cerebral cortex stim$.mp. (21) 2 exp cerebral cortex/ (240973) 3 electric stimulation therapy/ (14301) 4 electric stimulation/ (99329) 5 3 or 4 (112921) 6 2 and 5 (19579) 7 1 or 6 (19598) 8 (crps or complex regional pain).mp. (1403) 9 exp complex regional pain syndromes/ (3767) 10 8 or 9 (4184) 11 7 and 10 (18) Failed back surgery syndrome 1 (failed back surgery syndrome or fbss).mp. [mp=title, original title, abstract, name
of substance word, subject heading word, unique identifier] (275) 2 exp back pain/ (23563) 3 1 or 2 (23694) 4 cerebral cortex stim$.mp. (21) 5 exp Cerebral Cortex/ (240444) 6 electric stimulation therapy/ (14275) 7 electric stimulation/ (99202)
144
8 6 or 7 (112770) 9 5 and 8 (19545) 10 4 or 9 (19564) 11 3 and 10 (7) Headache 1 cerebral cortex stim$.mp. (21) 2 exp cerebral cortex/ (240973) 3 electric stimulation therapy/ (14301) 4 electric stimulation/ (99329) 5 3 or 4 (112921) 6 2 and 5 (19579) 7 1 or 6 (19598) 8 (headache$ or migraine$ or trigeminal autonomic cephalalgias).mp. (64126) 9 headache/ (19426) 10 exp headache disorders/ (21759) 11 8 or 9 or 10 (64150) 12 7 and 11 (58) 13 limit 12 to "therapy (optimized)" (4) Neuropathic pain in MS 1 cerebral cortex stim$.mp. (21) 2 exp cerebral cortex/ (240973) 3 electric stimulation therapy/ (14301) 4 electric stimulation/ (99329) 5 3 or 4 (112921) 6 2 and 5 (19579) 7 1 or 6 (19598) 8 neuropathic pain.mp. (6471) 9 neuralgia/ (5535) 10 8 or 9 (10363) 11 7 and 10 (70) 12 limit 11 to "therapy (optimized)" (8) Trigeminal neuralgia 1 cerebral cortex stim$.mp. (21) 2 exp cerebral cortex/ (240973) 3 electric stimulation therapy/ (14301) 4 electric stimulation/ (99329) 5 3 or 4 (112921) 6 2 and 5 (19579) 7 1 or 6 (19598) 8 (trigeminal neuralgia or trigeminal pain).mp. (5534) 9 exp trigeminal nerve diseases/ (5338) 10 8 or 9 (5942) 11 7 and 10 (17)
145
Cranial nerve stimulation MEDLINE (Ovid) searches strategies 1950 to July/Aug 2010 Complex regional pain syndrome Ovid MEDLINE(R) <1950 to August Week 2 2010> 1 Cranial Nerves/ (2847) 2 electric stimulation/ (99403) 3 electric stimulation therapy/ (14321) 4 2 or 3 (113015) 5 1 and 4 (118) 6 transcranial direct stimulat$.mp. (3) 7 transcranial magnetic field stimulat$.mp. (2) 8 5 or 6 or 7 (123) 9 (crps or complex regional pain).mp. (1417) 10 exp complex regional pain syndromes/ (3782) 11 9 or 10 (4200) 12 8 and 11 (0) Failed back surgery syndrome Ovid MEDLINE(R) 1950 to July 2010 1 Cranial Nerves/ (2842) 2 electric stimulation/ (99202) 3 electric stimulation therapy/ (14275) 4 2 or 3 (112770) 5 1 and 4 (118) 6 transcranial direct stimulat$.mp. (3) 7 transcranial magnetic field stimulat$.mp. (2) 8 5 or 6 or 7 (123) 9 FBSS.mp. (73) 10 failed back surgery.mp. (302) 11 exp back pain/ (23563) 12 9 or 10 or 11 (23716) 13 8 and 12 Headache Ovid MEDLINE(R) 1950 to August 2010 Search Strategy: 1 Cranial Nerves/ (2847) 2 electric stimulation/ (99403) 3 electric stimulation therapy/ (14321) 4 2 or 3 (113015) 5 1 and 4 (118) 6 transcranial direct stimulat$.mp. (3) 7 transcranial magnetic field stimulat$.mp. (2) 8 5 or 6 or 7 (123) 9 (headache$ or migraine$ or trigeminal autonomic cephalalgias).mp. (64243) 10 headache/ (19448)
146
11 exp headache disorders/ (21799) 12 9 or 10 or 11 (64267) 13 8 and 12 (6) Neuropathic pain in MS Ovid MEDLINE(R) 1950 to August 2010 1 Cranial Nerves/ (2847) 2 electric stimulation/ (99403) 3 electric stimulation therapy/ (14321) 4 2 or 3 (113015) 5 1 and 4 (118) 6 transcranial direct stimulat$.mp. (3) 7 transcranial magnetic field stimulat$.mp. (2) 8 5 or 6 or 7 (123) 9 neuropathic pain.mp. (6508) 10 neuralgia/ (5547) 11 9 or 10 (10401) 12 8 and 11 (1) Trigeminal neuralgia Ovid MEDLINE(R) 1950 to August Week 2 2010 1 Cranial Nerves/ (2847) 2 electric stimulation/ (99403) 3 electric stimulation therapy/ (14321) 4 2 or 3 (113015) 5 1 and 4 (118) 6 transcranial direct stimulat$.mp. (3) 7 transcranial magnetic field stimulat$.mp. (2) 8 5 or 6 or 7 (123) 9 (trigeminal neuralgia or trigeminal pain).mp. [mp=title, original title, abstract,
name of substance word, subject heading word, unique identifier] (5541) 10 exp trigeminal nerve diseases/ (5346) 11 9 or 10 (5950) 12 8 and 11 (1) Deep brain stimulation MEDLINE (Ovid) searches strategies 1950 to July/Aug 2010 Complex regional pain syndrome 1 Cranial Nerves/ (2847) 2 electric stimulation/ (99403) 3 electric stimulation therapy/ (14321) 4 2 or 3 (113015) 5 1 and 4 (118) 6 transcranial direct stimulat$.mp. (3) 7 transcranial magnetic field stimulat$.mp. (2) 8 5 or 6 or 7 (123)
147
9 (crps or complex regional pain).mp. (1417) 10 exp complex regional pain syndromes/ (3782) 11 9 or 10 (4200) 12 8 and 11 (0) Failed back surgery syndrome 1 Cranial Nerves/ (2842) 2 electric stimulation/ (99202) 3 electric stimulation therapy/ (14275) 4 2 or 3 (112770) 5 1 and 4 (118) 6 transcranial direct stimulat$.mp. (3) 7 transcranial magnetic field stimulat$.mp. (2) 8 5 or 6 or 7 (123) 9 FBSS.mp. (73) 10 failed back surgery.mp. (302) 11 exp back pain/ (23563) 12 9 or 10 or 11 (23716) 13 8 and 12 Headache 1 Cranial Nerves/ (2847) 2 electric stimulation/ (99403) 3 electric stimulation therapy/ (14321) 4 2 or 3 (113015) 5 1 and 4 (118) 6 transcranial direct stimulat$.mp. (3) 7 transcranial magnetic field stimulat$.mp. (2) 8 5 or 6 or 7 (123) 9 (headache$ or migraine$ or trigeminal autonomic cephalalgias).mp. (64243) 10 headache/ (19448) 11 exp headache disorders/ (21799) 12 9 or 10 or 11 (64267) 13 8 and 12 (6) Neuropathic pain in MS 1 Cranial Nerves/ (2847) 2 electric stimulation/ (99403) 3 electric stimulation therapy/ (14321) 4 2 or 3 (113015) 5 1 and 4 (118) 6 transcranial direct stimulat$.mp. (3) 7 transcranial magnetic field stimulat$.mp. (2) 8 5 or 6 or 7 (123) 9 neuropathic pain.mp. (6508) 10 neuralgia/ (5547) 11 9 or 10 (10401) 12 8 and 11 (1)
148
Trigeminal neuralgia 1 Cranial Nerves/ (2847) 2 electric stimulation/ (99403) 3 electric stimulation therapy/ (14321) 4 2 or 3 (113015) 5 1 and 4 (118) 6 transcranial direct stimulat$.mp. (3) 7 transcranial magnetic field stimulat$.mp. (2) 8 5 or 6 or 7 (123) 9 (trigeminal neuralgia or trigeminal pain).mp. [mp=title, original title, abstract,
name of substance word, subject heading word, unique identifier] (5541) 10 exp trigeminal nerve diseases/ (5346) 11 9 or 10 (5950) 12 8 and 11 (1) Functional electrical stimulation MEDLINE (Ovid) searches strategies 1950 to July/Aug 2010 Complex regional pain syndrome 1 functional electric$ stimulat$.mp. (1120) 2 (crps or complex regional pain).mp. (1417) 3 exp complex regional pain syndromes/ (3782) 4 2 or 3 (4200) 5 1 and 4 (0) Failed back surgery syndrome 1 (failed back surgery syndrome or fbss).mp. [mp=title, original title, abstract, name
of substance word, subject heading word, unique identifier] (275) 2 exp back pain/ (23563) 3 1 or 2 (23694) 4 functional electric$ stimulat$.mp. (1113) 5 3 and 4 (1) 6 from 5 keep 1 (1) Headache 1 functional electric$ stimulat$.mp. (1120) 2 (headache$ or migraine$ or trigeminal autonomic cephalalgias).mp. (64243) 3 headache/ (19448) 4 exp headache disorders/ (21799) 5 2 or 3 or 4 (64267) 6 1 and 5 (0) Neuropathic pain in MS 1 functional electric$ stimulat$.mp. (1120) 2 neuropathic pain.mp. (6508) 3 neuralgia/ (5547) 4 2 or 3 (10401) 5 1 and 4 (0)
149
Trigeminal neuralgia 1 functional electric$ stimulat$.mp. (1120) 2 trigeminal neuralgia.mp. (5457) 3 trigeminal pain.mp. (178) 4 exp trigeminal nerve diseases/ (5346) 5 2 or 3 or 4 (5950) 6 1 and 5 (0) Motor cortex stimulation MEDLINE (Ovid) searches strategies 1950 to July/Aug 2010 Complex regional pain syndrome 1 motor cortex stimulat$.mp. (346) 2 cortical stimulat$.mp. (1372) 3 or/1-2 (1658) 4 motor cortex/ (13385) 5 electric stimulation/ (99329) 6 electric stimulation therapy/ (14301) 7 or/5-6 (112921) 8 4 and 7 (3051) 9 3 or 8 (4303) 10 (crps or complex regional pain).mp. (1403) 11 exp complex regional pain syndromes/ (3767) 12 10 or 11 (4184) 13 9 and 12 (19) Failed back surgery syndrome 1 (failed back surgery syndrome or fbss).mp. [mp=title, original title, abstract, name
of substance word, subject heading word, unique identifier] (275) 2 exp back pain/ (23563) 3 1 or 2 (23694) 4 motor cortex stimulat$.mp. (346) 5 cortical stimulat$.mp. (1367) 6 or/4-5 (1653) 7 motor cortex/ (13364) 8 electric stimulation/ (99202) 9 electric stimulation therapy/ (14275) 10 or/8-9 (112770) 11 7 and 10 (3045) 12 6 or 11 (4292) 13 6 and 12 (1653) 14 limit 13 to "therapy (optimized)" (59) Headache 1 motor cortex stimulat$.mp. (346) 2 cortical stimulat$.mp. (1372) 3 or/1-2 (1658) 4 motor cortex/ (13385) 5 electric stimulation/ (99329)
150
6 electric stimulation therapy/ (14301) 7 or/5-6 (112921) 8 4 and 7 (3051) 9 3 or 8 (4303) 10 (headache$ or migraine$ or trigeminal autonomic cephalalgias).mp. (64126) 11 headache/ (19426) 12 exp headache disorders/ (21759) 13 10 or 11 or 12 (64150) 14 9 and 13 (17) Neuropathic pain in MS 1 motor cortex stimulat$.mp. (346) 2 cortical stimulat$.mp. (1372) 3 or/1-2 (1658) 4 motor cortex/ (13385) 5 electric stimulation/ (99329) 6 electric stimulation therapy/ (14301) 7 or/5-6 (112921) 8 4 and 7 (3051) 9 3 or 8 (4303) 10 neuropathic pain.mp. (6471) 11 neuralgia/ (5535) 12 10 or 11 (10363) 13 9 and 12 (84) 14 limit 13 to "therapy (optimized)" (14) Trigeminal neuralgia 1 motor cortex stimulat$.mp. (346) 2 cortical stimulat$.mp. (1372) 3 or/1-2 (1658) 4 motor cortex/ (13385) 5 electric stimulation/ (99329) 6 electric stimulation therapy/ (14301) 7 or/5-6 (112921) 8 4 and 7 (3051) 9 3 or 8 (4303) 10 (trigeminal neuralgia or trigeminal pain).mp. (5534) 11 exp trigeminal nerve diseases/ (5338) 12 10 or 11 (5942) 13 9 and 12 (21) Neuromuscular stimulation MEDLINE (Ovid) searches strategies 1950 to July/Aug 2010 Complex regional pain syndrome 1 neuromuscular electric$ stimulat$.mp. (297) 2 (crps or complex regional pain).mp. (1417) 3 exp complex regional pain syndromes/ (3782) 4 2 or 3 (4200)
151
5 1 and 4 (0) Failed back surgery syndrome 1 (failed back surgery syndrome or fbss).mp. [mp=title, original title, abstract, name
of substance word, subject heading word, unique identifier] (275) 2 exp back pain/ (23563) 3 1 or 2 (23694) 4 neuromuscular electric$ stimulat$.mp. (290) 5 3 and 4 (2) Headache 1 neuromuscular electric$ stimulat$.mp. (297) 2 (headache$ or migraine$ or trigeminal autonomic cephalalgias).mp. (64243) 3 headache/ (19448) 4 exp headache disorders/ (21799) 5 2 or 3 or 4 (64267) 6 1 and 5 (0) Neuropathic pain in MS 1 neuromuscular electric$ stimulat$.mp. (297) 2 neuropathic pain.mp. (6508) 3 neuralgia/ (5547) 4 2 or 3 (10401) 5 1 and 4 (0) Trigeminal neuralgia 1 neuromuscular electric$ stimulat$.mp. (297) 2 (trigeminal neuralgia or trigeminal pain).mp. (5541) 3 exp trigeminal nerve diseases/ (5346) 4 2 or 3 (5950) 5 1 and 4 (0) Occipital nerve stimulation MEDLINE (Ovid) searches strategies 1950 to July 2010 Complex regional pain syndrome 1 occipital nerve$ stimulat$.mp. (40) 2 occipital cortex stim$.mp. (3) 3 Occipital Lobe/ (6677) 4 electric stimulation/ (99329) 5 electric stimulation therapy/ (14301) 6 4 or 5 (112921) 7 3 and 6 (229) 8 1 or 2 or 7 (269) 9 (crps or complex regional pain).mp. (1403) 10 exp complex regional pain syndromes/ (3767) 11 9 or 10 (4184) 12 8 and 11 (0)
152
Failed back surgery syndrome 1 (fbss or failed back surgery).mp. (312) 2 exp back pain/ (23612) 3 (failed back surgery syndrome or fbss).mp. [mp=title, original title, abstract, name
of substance word, subject heading word, unique identifier] (276) 4 exp back pain/ (23612) 5 3 or 4 (23744) 6 occipital nerve$ stimulat$.mp. (40) 7 occipital cortex stim$.mp. (3) 8 Occipital Lobe/ (6677) 9 electric stimulation/ (99329) 10 electric stimulation therapy/ (14301) 11 occipital cortex implant$.mp. (0) 12 6 and 7 and 11 (0) 13 9 or 10 (112921) 14 8 and 13 (229) 15 6 or 7 or 11 or 14 (269) 16 5 and 15 (0) Headache 1 occipital nerve$ stimulat$.mp. (40) 2 occipital cortex stim$.mp. (3) 3 Occipital Lobe/ (6677) 4 electric stimulation/ (99329) 5 electric stimulation therapy/ (14301) 6 4 or 5 (112921) 7 3 and 6 (229) 8 1 or 2 or 7 (269) 9 (headache$ or migraine$ or trigeminal autonomic cephalalgias).mp. (64126) 10 headache/ (19426) 11 exp headache disorders/ (21759) 12 9 or 10 or 11 (64150) 13 8 and 12 (45) 14 limit 13 to "therapy (optimized)" (3) Neuropathic pain in MS 1 occipital nerve$ stimulat$.mp. (40) 2 occipital cortex stim$.mp. (3) 3 Occipital Lobe/ (6677) 4 electric stimulation/ (99329) 5 electric stimulation therapy/ (14301) 6 4 or 5 (112921) 7 3 and 6 (229) 8 1 or 2 or 7 (269) 9 neuropathic pain.mp. (6471) 10 neuralgia/ (5535) 11 9 or 10 (10363) 12 8 and 11 (7)
153
Trigeminal neuralgia 1 occipital nerve$ stimulat$.mp. (40) 2 occipital cortex stim$.mp. (3) 3 Occipital Lobe/ (6677) 4 electric stimulation/ (99329) 5 electric stimulation therapy/ (14301) 6 4 or 5 (112921) 7 3 and 6 (229) 8 1 or 2 or 7 (269) 9 (trigeminal neuralgia or trigeminal pain).mp. (5534) 10 exp trigeminal nerve diseases/ (5338) 11 9 or 10 (5942) 12 8 and 11 (1) PENS MEDLINE (Ovid) searches strategies 1950 to July 2010 Complex regional pain syndrome 1 pens.tw. (2700) 2 percutaneous electric$ neurostimulat$.mp. (0) 3 percutaneous electric$ nerve$ stimulat$.mp. (28) 4 percutaneous electric$ neuromodulat$.mp. (0) 5 or/1-4 (2715) 6 (crps or complex regional pain).mp. (1403) 7 exp complex regional pain syndromes/ (3767) 8 6 or 7 (4184) 9 5 and 8 (1) Failed back surgery syndrome 1 (failed back surgery syndrome or fbss).mp. [mp=title, original title, abstract, name
of substance word, subject heading word, unique identifier] (275) 2 exp back pain/ (23563) 3 1 or 2 (23694) 4 pens.tw. (2696) 5 percutaneous electric$ neurostimulat$.mp. (0) 6 percutaneous electric$ nerve$ stimulat$.mp. (28) 7 percutaneous electric$ neuromodulat$.mp. (0) 8 or/4-7 (2711) 9 3 and 8 (11) 10 from 9 keep 1-11 (11) Headache 1 pens.tw. (2700) 2 percutaneous electric$ neurostimulat$.mp. (0) 3 percutaneous electric$ nerve$ stimulat$.mp. (28) 4 percutaneous electric$ neuromodulat$.mp. (0) 5 or/1-4 (2715) 6 (headache$ or migraine$ or trigeminal autonomic cephalalgias).mp. (64126) 7 headache/ (19426) 8 exp headache disorders/ (21759)
154
9 6 or 7 or 8 (64150) 10 5 and 9 (4) Neuropathic pain in MS 1 pens.tw. (2700) 2 percutaneous electric$ neurostimulat$.mp. (0) 3 percutaneous electric$ nerve$ stimulat$.mp. (28) 4 percutaneous electric$ neuromodulat$.mp. (0) 5 or/1-4 (2715) 6 neuropathic pain.mp. (6471) 7 neuralgia/ (5535) 8 6 or 7 (10363) 9 5 and 8 (4) Trigeminal neuralgia 1 pens.tw. (2700) 2 percutaneous electric$ neurostimulat$.mp. (0) 3 percutaneous electric$ nerve$ stimulat$.mp. (28) 4 percutaneous electric$ neuromodulat$.mp. (0) 5 or/1-4 (2715) 6 (trigeminal neuralgia or trigeminal pain).mp. (5534) 7 exp trigeminal nerve diseases/ (5338) 8 6 or 7 (5942) 9 5 and 8 (0) Pulsed electromagnetic field stimulation. MEDLINE (Ovid) searches strategies 1950 to July / Aug 2010 Complex regional pain syndrome 1 pulsed magnetic field$.mp. (285) 2 (crps or complex regional pain).mp. (1417) 3 exp complex regional pain syndromes/ (3782) 4 2 or 3 (4200) 5 1 and 4 (0) Failed back surgery syndrome 1 (failed back surgery syndrome or fbss).mp. [mp=title, original title, abstract, name
of substance word, subject heading word, unique identifier] (275) 2 exp back pain/ (23563) 3 1 or 2 (23694) 4 pulsed magnetic field$.mp. (285) 5 pulsed electromagnetic field$.mp. (446) 6 or/4-5 (712) 7 3 and 6 (3) Headache 1 pulsed magnetic field$.mp. (285) 2 (headache$ or migraine$ or trigeminal autonomic cephalalgias).mp. (64243) 3 headache/ (19448)
155
4 exp headache disorders/ (21799) 5 2 or 3 or 4 (64267) 6 1 and 5 (1) Neuropathic pain in MS 1 pulsed magnetic field$.mp. (285) 2 neuropathic pain.mp. (6508) 3 neuralgia/ (5547) 4 2 or 3 (10401) 5 1 and 4 (3) Trigeminal neuralgia 1 pulsed magnetic field$.mp. (285) 2 (trigeminal neuralgia or trigeminal pain).mp. (5541) 3 exp trigeminal nerve diseases/ (5346) 4 2 or 3 (5950) 5 1 and 4 (0) Retinal stimulation MEDLINE (Ovid) searches strategies 1950 to July / Aug 2010 Complex regional pain syndrome 1 retinal stimulat$.mp. (143) 2 retina stimulat$.mp. (39) 3 retinal nerve$ stimulat$.mp. (0) 4 retina nerve$ stimulat$.mp. (0) 5 or/1-4 (178) 6 retina/ (53841) 7 electric stimulation/ (99403) 8 electric stimulation therapy/ (14321) 9 or/7-8 (113015) 10 6 and 9 (804) 11 5 or 10 (949) 12 exp complex regional pain syndromes/ (3782) 13 (crps or complex regional pain).mp. (1417) 14 12 or 13 (4200) 15 11 and 14 (0) Failed back surgery syndrome 1 retinal stimulat$.mp. (143) 2 retina stimulat$.mp. (39) 3 retinal nerve$ stimulat$.mp. (0) 4 retina nerve$ stimulat$.mp. (0) 5 or/1-4 (178) 6 retina/ (53792) 7 electric stimulation/ (99329) 8 electric stimulation therapy/ (14301) 9 or/7-8 (112921) 10 6 and 9 (803) 11 5 or 10 (948)
156
12 (fbss or failed back surgery).mp. (312) 13 exp back pain/ (23612) 14 12 or 13 (23766) 15 11 and 14 (0) Headache 1 retinal stimulat$.mp. (143) 2 retina stimulat$.mp. (39) 3 retinal nerve$ stimulat$.mp. (0) 4 retina nerve$ stimulat$.mp. (0) 5 or/1-4 (178) 6 retina/ (53841) 7 electric stimulation/ (99403) 8 electric stimulation therapy/ (14321) 9 or/7-8 (113015) 10 6 and 9 (804) 11 5 or 10 (949) 12 (headache$ or migraine$ or trigeminal autonomic cephalalgias).mp. (64243) 13 headache/ (19448) 14 exp headache disorders/ (21799) 15 12 or 13 or 14 (64267) 16 11 and 15 (0) Neuropathic pain in MS 1 retinal stimulat$.mp. (143) 2 retina stimulat$.mp. (39) 3 retinal nerve$ stimulat$.mp. (0) 4 retina nerve$ stimulat$.mp. (0) 5 or/1-4 (178) 6 retina/ (53841) 7 electric stimulation/ (99403) 8 electric stimulation therapy/ (14321) 9 or/7-8 (113015) 10 6 and 9 (804) 11 5 or 10 (949) 12 neuropathic pain.mp. (6508) 13 neuralgia/ (5547) 14 12 or 13 (10401) 15 11 and 14 (0) Trigeminal neuralgia 1 retinal stimulat$.mp. (143) 2 retina stimulat$.mp. (39) 3 retinal nerve$ stimulat$.mp. (0) 4 retina nerve$ stimulat$.mp. (0) 5 or/1-4 (178) 6 retina/ (53841) 7 electric stimulation/ (99403) 8 electric stimulation therapy/ (14321) 9 or/7-8 (113015) 10 6 and 9 (804) 11 5 or 10 (949)
157
12 (trigeminal neuralgia or trigeminal pain).mp. (5541) 13 exp trigeminal nerve diseases/ (5346) 14 12 or 13 (5950) 15 11 and 14 (0) Sacral nerve stimulation. MEDLINE (Ovid) searches strategies 1950 to July / Aug 2010 Complex regional pain syndrome 1 sacral nerve stimulat$.mp. (279) 2 sacrum/ (5722) 3 electric stimulation therapy/ (14301) 4 electric stimulation/ (99329) 5 3 or 4 (112921) 6 2 and 5 (150) 7 1 or 6 (400) 8 (crps or complex regional pain).mp. (1403) 9 exp complex regional pain syndromes/ (3767) 10 8 or 9 (4184) 11 7 and 10 (0) Failed back surgery syndrome 1 (failed back surgery syndrome or fbss).mp. [mp=title, original title, abstract, name
of substance word, subject heading word, unique identifier] (275) 2 exp back pain/ (23563) 3 1 or 2 (23694) 4 sacral nerve stimulat$.mp. (278) 5 sacrum/ (5710) 6 electric stimulation/ (99202) 7 electric stimulation therapy/ (14275) 8 or/6-7 (112770) 9 5 and 8 (150) 10 4 or 9 (399) 11 3 and 10 (6) Headache 1 sacral nerve stimulat$.mp. (279) 2 sacrum/ (5722) 3 electric stimulation therapy/ (14301) 4 electric stimulation/ (99329) 5 3 or 4 (112921) 6 2 and 5 (150) 7 1 or 6 (400) 8 (headache$ or migraine$ or trigeminal autonomic cephalalgias).mp. (64126) 9 headache/ (19426) 10 exp headache disorders/ (21759) 11 8 or 9 or 10 (64150) 12 7 and 11 (0)
158
Neuropathic pain in MS 1 sacral nerve stimulat$.mp. (279) 2 sacrum/ (5722) 3 electric stimulation therapy/ (14301) 4 electric stimulation/ (99329) 5 3 or 4 (112921) 6 2 and 5 (150) 7 1 or 6 (400) 8 neuropathic pain.mp. (6471) 9 neuralgia/ (5535) 10 8 or 9 (10363) 11 7 and 10 (1) Trigeminal neuralgia 1 sacral nerve stimulat$.mp. (279) 2 sacrum/ (5722) 3 electric stimulation therapy/ (14301) 4 electric stimulation/ (99329) 5 3 or 4 (112921) 6 2 and 5 (150) 7 1 or 6 (400) 8 (trigeminal neuralgia or trigeminal pain).mp. (5534) 9 exp trigeminal nerve diseases/ (5338) 10 8 or 9 (5942) 11 7 and 10 (0) Spinal cord stimulation. MEDLINE (Ovid) searches strategies 1950 to July / Aug 2010 Complex regional pain syndrome 1 spinal cord stimulat$.mp. (1287) 2 spinal column stimulat$.mp. (3) 3 dorsal cord stimulat$.mp. (11) 4 dorsal column stimulat$.mp. (177) 5 spinal cord/ (63176) 6 electric stimulation/ (99329) 7 electric stimulation therapy/ (14301) 8 or/6-7 (112921) 9 5 and 8 (6637) 10 1 or 2 or 3 or 4 or 9 (7123) 11 scs.mp. (2338) 12 10 or 11 (8991) 13 (crps or complex regional pain).mp. (1403) 14 exp complex regional pain syndromes/ (3767) 15 13 or 14 (4184) 16 12 and 15 (122) 17 limit 16 to "therapy (optimized)" (25)
159
Failed back surgery syndrome 1 spinal cord stimulat$.mp. (1284) 2 spinal column stimulat$.mp. (3) 3 dorsal cord stimulat$.mp. (11) 4 dorsal column stimulat$.mp. (177) 5 spinal cord/ (63090) 6 electric stimulation/ (99202) 7 electric stimulation therapy/ (14275) 8 or/6-7 (112770) 9 5 and 8 (6631) 10 1 or 2 or 3 or 4 or 9 (7116) 11 scs.mp. (2334) 12 10 or 11 (8981) 13 (failed back surgery syndrome or fbss).mp. [mp=title, original title, abstract, name
of substance word, subject heading word, unique identifier] (275) 14 exp back pain/ (23563) 15 13 or 14 (23694) 16 12 and 15 (167) 17 limit 16 to "therapy (optimized)" (34) 18 from 17 keep 1-34 (34) Headache 1 spinal cord stimulat$.mp. (1287) 2 spinal column stimulat$.mp. (3) 3 dorsal cord stimulat$.mp. (11) 4 dorsal column stimulat$.mp. (177) 5 spinal cord/ (63176) 6 electric stimulation/ (99329) 7 electric stimulation therapy/ (14301) 8 or/6-7 (112921) 9 5 and 8 (6637) 10 1 or 2 or 3 or 4 or 9 (7123) 11 scs.mp. (2338) 12 10 or 11 (8991) 13 (headache$ or migraine$ or trigeminal autonomic cephalalgias).mp. (64126) 14 exp headache disorders/ (21759) 15 headache/ (19426) 16 13 or 14 or 15 (64150) 17 12 and 16 (39) Neuropathic pain in MS 1 spinal cord stimulat$.mp. (1287) 2 spinal column stimulat$.mp. (3) 3 dorsal cord stimulat$.mp. (11) 4 dorsal column stimulat$.mp. (177) 5 spinal cord/ (63176) 6 electric stimulation/ (99329) 7 electric stimulation therapy/ (14301) 8 or/6-7 (112921) 9 5 and 8 (6637) 10 1 or 2 or 3 or 4 or 9 (7123) 11 scs.mp. (2338)
160
12 10 or 11 (8991) 13 neuropathic pain.mp. (6471) 14 neuralgia/ (5535) 15 13 or 14 (10363) 16 12 and 15 (198) 17 limit 16 to "therapy (optimized)" (20) Trigeminal neuralgia 1 spinal cord stimulat$.mp. (1287) 2 spinal column stimulat$.mp. (3) 3 dorsal cord stimulat$.mp. (11) 4 dorsal column stimulat$.mp. (177) 5 spinal cord/ (63176) 6 electric stimulation/ (99329) 7 electric stimulation therapy/ (14301) 8 or/6-7 (112921) 9 5 and 8 (6637) 10 1 or 2 or 3 or 4 or 9 (7123) 11 scs.mp. (2338) 12 10 or 11 (8991) 13 trigeminal neuralgia.mp. (5450) 14 trigeminal pain.mp. (178) 15 exp trigeminal nerve diseases/ (5338) 16 or/13-15 (5942) 17 12 and 16 (15) TENS MEDLINE (Ovid) searches strategies 1950 to July / Aug 2010 Complex regional pain syndrome 1 Transcutaneous Electric Nerve Stimulation/ (2763) 2 tens.mp. (4996) 3 transcutaneous electric$ nerve$ stimulat$.mp. (3079) 4 or/1-3 (7226) 5 (crps or complex regional pain).mp. (1417) 6 exp complex regional pain syndromes/ (3782) 7 5 or 6 (4200) 8 4 and 7 (56) 9 limit 8 to "therapy (optimized)" (3) Failed back surgery syndrome 1 FBSS.mp. (73) 2 failed back surgery.mp. (302) 3 exp back pain/ (23563) 4 1 or 2 or 3 (23716) 5 Transcutaneous Electric Nerve Stimulation/ (2752) 6 tens.mp. (4964) 7 transcutaneous electric$ nerve$ stimulat$.mp. (3066) 8 or/5-7 (7183) 9 4 and 8 (166) 10 limit 9 to "therapy (optimized)" (71)
161
Headache 1 Transcutaneous Electric Nerve Stimulation/ (2763) 2 tens.mp. (4996) 3 transcutaneous electric$ nerve$ stimulat$.mp. (3079) 4 or/1-3 (7226) 5 (headache$ or migraine$ or trigeminal autonomic cephalalgias).mp. (64243) 6 headache/ (19448) 7 exp headache disorders/ (21799) 8 5 or 6 or 7 (64267) 9 4 and 8 (64) 10 limit 9 to "therapy (optimized)" (19) Neuropathic pain in MS 1 Transcutaneous Electric Nerve Stimulation/ (2763) 2 tens.mp. (4996) 3 transcutaneous electric$ nerve$ stimulat$.mp. (3079) 4 or/1-3 (7226) 5 neuropathic pain.mp. (6508) 6 neuralgia/ (5547) 7 5 or 6 (10401) 8 4 and 7 (112) 9 limit 8 to (humans and "therapy (optimized)") (10) Trigeminal neuralgia 1 Transcutaneous Electric Nerve Stimulation/ (2763) 2 tens.mp. (4996) 3 transcutaneous electric$ nerve$ stimulat$.mp. (3079) 4 or/1-3 (7226) 5 (trigeminal neuralgia or trigeminal pain).mp. [mp=title, original title, abstract,
name of substance word, subject heading word, unique identifier] (5541) 6 exp trigeminal nerve diseases/ (5346) 7 5 or 6 (5950) 8 4 and 7 (37) 9 limit 8 to "therapy (optimized)" (0) Trigeminal nerve stimulation. MEDLINE (Ovid) searches strategies 1950 to July / Aug 2010 Complex regional pain syndrome 1 Trigeminal Nerve/ (7471) 2 electric stimulation therapy/ (14321) 3 electric stimulation/ (99403) 4 2 or 3 (113015) 5 1 and 3 (881) 6 trigeminal nerve$ stimulat$.mp. (90) 7 5 or 6 (947) 8 exp complex regional pain syndromes/ (3782) 9 (crps or complex regional pain).mp. (1417) 10 8 or 9 (4200) 11 7 and 10 (0)
162
Failed back surgery syndrome 1 FBSS.mp. (73) 2 failed back surgery.mp. (302) 3 exp back pain/ (23563) 4 1 or 2 or 3 (23716) 5 Trigeminal Nerve/ (7450) 6 electric stimulation therapy/ (14275) 7 electric stimulation/ (99202) 8 6 or 7 (112770) 9 5 and 7 (881) 10 trigeminal nerve$ stimulat$.mp. (89) 11 9 or 10 (946) 12 4 and 11 (0) Headache 1 Trigeminal Nerve/ (7471) 2 electric stimulation therapy/ (14321) 3 electric stimulation/ (99403) 4 2 or 3 (113015) 5 1 and 3 (881) 6 trigeminal nerve$ stimulat$.mp. (90) 7 5 or 6 (947) 8 headache/ (19448) 9 exp headache disorders/ (21799) 10 (migraine$ or headache$).mp. (64230) 11 trigeminal autonomic cephalalgias.mp. (122) 12 9 or 10 or 11 (64267) 13 8 or 12 (64267) 14 7 and 13 (80) 15 limit 14 to "therapy (optimized)" (2) Neuropathic pain in MS 1 Trigeminal Nerve/ (7471) 2 electric stimulation therapy/ (14321) 3 electric stimulation/ (99403) 4 2 or 3 (113015) 5 1 and 3 (881) 6 trigeminal nerve$ stimulat$.mp. (90) 7 5 or 6 (947) 8 neuropathic pain.mp. (6508) 9 neuralgia/ (5547) 10 8 or 9 (10401) 11 7 and 10 (8) Trigeminal neuralgia 1 Trigeminal Nerve/ (7471) 2 electric stimulation therapy/ (14321) 3 electric stimulation/ (99403) 4 2 or 3 (113015) 5 1 and 3 (881)
163
6 trigeminal nerve$ stimulat$.mp. (90) 7 5 or 6 (947) 8 (trigeminal neuralgia or trigeminal pain).mp. [mp=title, original title, abstract,
name of substance word, subject heading word, unique identifier] (5541) 9 exp trigeminal nerve diseases/ (5346) 10 8 or 9 (5950) 11 7 and 10 (54) 12 limit 11 to (humans and "therapy (optimized)") (1) Vagal nerve stimulation. MEDLINE (Ovid) searches strategies 1950 to July / Aug 2010 Complex regional pain syndrome 1 vagal nerve stimulat$.mp. (509) 2 vagus nerve stimulat$.mp. (951) 3 or/1-2 (1403) 4 vagus nerve/ (18854) 5 electric stimulation therapy/ (14321) 6 electric stimulation/ (99403) 7 5 or 6 (113015) 8 4 and 7 (4275) 9 3 or 8 (4788) 10 complex regional pain.mp. (1200) 11 crps.mp. (808) 12 exp complex regional pain syndromes/ (3782) 13 10 or 11 or 12 (4200) 14 9 and 13 (0) Failed back surgery syndrome 1 (failed back surgery syndrome or fbss).mp. [mp=title, original title, abstract, name
of substance word, subject heading word, unique identifier] (275) 2 exp back pain/ (23563) 3 1 or 2 (23694) 4 vagal nerve stimulat$.mp. (509) 5 vagus nerve stimulat$.mp. (941) 6 or/4-5 (1393) 7 vagus nerve/ (18828) 8 electric stimulation therapy/ (14275) 9 electric stimulation/ (99202) 10 8 or 9 (112770) 11 7 and 10 (4271) 12 6 or 11 (4776) 13 3 and 12 (0) Headache 1 vagal nerve stimulat$.mp. (509) 2 vagus nerve stimulat$.mp. (951) 3 or/1-2 (1403) 4 vagus nerve/ (18854) 5 electric stimulation therapy/ (14321) 6 electric stimulation/ (99403)
164
7 5 or 6 (113015) 8 4 and 7 (4275) 9 3 or 8 (4788) 10 headache/ (19448) 11 exp headache disorders/ (21799) 12 (migraine$ or headache$).mp. (64230) 13 trigeminal autonomic cephalalgias.mp. (122) 14 10 or 11 or 12 or 13 (64267) 15 9 and 14 (23) 16 limit 15 to "therapy (optimized)" (2) Neuropathic pain in MS 1 vagal nerve stimulat$.mp. (509) 2 vagus nerve stimulat$.mp. (951) 3 or/1-2 (1403) 4 vagus nerve/ (18854) 5 electric stimulation therapy/ (14321) 6 electric stimulation/ (99403) 7 5 or 6 (113015) 8 4 and 7 (4275) 9 3 or 8 (4788) 10 neuropathic pain.mp. (6508) 11 neuralgia/ (5547) 12 10 or 11 (10401) 13 9 and 12 (3) Trigeminal neuralgia 1 vagal nerve stimulat$.mp. (509) 2 vagus nerve stimulat$.mp. (951) 3 or/1-2 (1403) 4 vagus nerve/ (18854) 5 electric stimulation therapy/ (14321) 6 electric stimulation/ (99403) 7 5 or 6 (113015) 8 4 and 7 (4275) 9 3 or 8 (4788) 10 trigeminal neuralgia.mp. (5457) 11 trigeminal pain.mp. (178) 12 exp trigeminal nerve diseases/ (5346) 13 10 or 11 or 12 (5950) 14 9 and 13 (3) Peripheral nerve and pudendal nerve stimulation. MEDLINE (Ovid) searches strategies 1950 to July 2010 Complex regional pain syndrome 1 peripheral nerve stimulat$.mp. (718) 2 pudendal nerve stimulat$.mp. (89) 3 sympathetic nerve stimulat$.mp. (1337) 4 or/1-3 (2143) 5 peripheral nerves/ (20295)
165
6 sympathetic nervous system/ (32453) 7 or/5-6 (52347) 8 electric stimulation/ (99329) 9 electric stimulation therapy/ (14301) 10 or/8-9 (112921) 11 7 and 10 (6665) 12 4 or 11 (7909) 13 (crps or complex regional pain).mp. (1403) 14 exp complex regional pain syndromes/ (3767) 15 13 or 14 (4184) 16 12 and 15 (38) Failed back surgery syndrome 1 (failed back surgery syndrome or fbss).mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier] (275) 2 exp back pain/ (23563) 3 1 or 2 (23694) 4 peripheral nerve stimulat$.mp. (717) 5 pudendal nerve stimulat$.mp. (89) 6 sympathetic nerve stimulat$.mp. (1337) 7 or/4-6 (2142) 8 peripheral nerves/ (20276) 9 sympathetic nervous system/ (32419) 10 or/8-9 (52294) 11 electric stimulation/ (99202) 12 electric stimulation therapy/ (14275) 13 or/11-12 (112770) 14 10 and 13 (6663) 15 7 or 14 (7906) 16 3 and 15 (16) Headache 1 peripheral nerve stimulat$.mp. (718) 2 pudendal nerve stimulat$.mp. (89) 3 sympathetic nerve stimulat$.mp. (1337) 4 or/1-3 (2143) 5 peripheral nerves/ (20295) 6 sympathetic nervous system/ (32453) 7 or/5-6 (52347) 8 electric stimulation/ (99329) 9 electric stimulation therapy/ (14301) 10 or/8-9 (112921) 11 7 and 10 (6665) 12 4 or 11 (7909) 13 (headache$ or migraine$ or trigeminal autonomic cephalalgias).mp. (64126) 14 headache/ (19426) 15 exp headache disorders/ (21759) 16 13 or 14 or 15 (64150) 17 12 and 16 (32)
166
Neuropathic pain in MS 1 peripheral nerve stimulat$.mp. (718) 2 pudendal nerve stimulat$.mp. (89) 3 sympathetic nerve stimulat$.mp. (1337) 4 or/1-3 (2143) 5 peripheral nerves/ (20295) 6 sympathetic nervous system/ (32453) 7 or/5-6 (52347) 8 electric stimulation/ (99329) 9 electric stimulation therapy/ (14301) 10 or/8-9 (112921) 11 7 and 10 (6665) 12 4 or 11 (7909) 13 neuropathic pain.mp. (6471) 14 neuralgia/ (5535) 15 13 or 14 (10363) 16 12 and 15 (71) Trigeminal neuralgia 1 peripheral nerve stimulat$.mp. (718) 2 pudendal nerve stimulat$.mp. (89) 3 sympathetic nerve stimulat$.mp. (1337) 4 or/1-3 (2143) 5 peripheral nerves/ (20295) 6 sympathetic nervous system/ (32453) 7 or/5-6 (52347) 8 electric stimulation/ (99329) 9 electric stimulation therapy/ (14301) 10 or/8-9 (112921) 11 7 and 10 (6665) 12 4 or 11 (7909) 13 (trigeminal neuralgia or trigeminal pain).mp. (5534) 14 exp trigeminal nerve diseases/ (5338) 15 13 or 14 (5942) 16 12 and 15 (8) Economic evaluations MEDLINE (Ovid) searches strategies 1950 to Nov week 3 2010 Cerebral cortex stimulation 1 cerebral cortex stim$.mp. (23) 2 exp cerebral cortex/ (249083) 3 electric stimulation therapy/ (14618) 4 electric stimulation/ (101302) 5 3 or 4 (115196) 6 2 and 5 (20034) 7 1 or 6 (20053) 8 economics/ (26024) 9 exp "costs and cost analysis"/ (155035) 10 cost of illness/ (13694) 11 exp health care costs/ (37127)
167
12 economic value of life/ (5176) 13 exp economics medical/ (13094) 14 exp economics hospital/ (17021) 15 economics pharmaceutical/ (2168) 16 exp "fees and charges"/ (25142) 17 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 18 or/8-17 (448331) 19 7 and 18 (32) Cranial nerve stimulation 1 economics/ (26024) 2 exp "costs and cost analysis"/ (155035) 3 cost of illness/ (13694) 4 exp health care costs/ (37127) 5 economic value of life/ (5176) 6 exp economics medical/ (13094) 7 exp economics hospital/ (17021) 8 economics pharmaceutical/ (2168) 9 exp "fees and charges"/ (25142) 10 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 11 or/1-10 (448331) 12 Cranial Nerves/ (2888) 13 electric stimulation/ (101302) 14 electric stimulation therapy/ (14618) 15 13 or 14 (115196) 16 12 and 15 (119) 17 transcranial direct stimulat$.mp. (3) 18 transcranial magnetic field stimulat$.mp. (2) 19 16 or 17 or 18 (124) 20 11 and 19 (1) Deep brain stimulation 1 economics/ (26024) 2 exp "costs and cost analysis"/ (155035) 3 cost of illness/ (13694) 4 exp health care costs/ (37127) 5 economic value of life/ (5176) 6 exp economics medical/ (13094) 7 exp economics hospital/ (17021) 8 economics pharmaceutical/ (2168) 9 exp "fees and charges"/ (25142) 10 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 11 or/1-10 (448331) 12 pallidotomy.mp. (703) 13 subthalamotomy.mp. (65) 14 subthalamic stimulat$.mp. (179) 15 deep brain stimulat$.mp. (3737) 16 or/12-15 (4390) 17 subthalamic nucleus/ (1761) 18 electric stimulation/ (101302)
168
19 electric stimulation therapy/ (14618) 20 or/18-19 (115196) 21 17 and 20 (556) 22 16 or 21 (4619) 23 11 and 22 (77) Functional electrical stimulation 1 economics/ (26024) 2 exp "costs and cost analysis"/ (155035) 3 cost of illness/ (13694) 4 exp health care costs/ (37127) 5 economic value of life/ (5176) 6 exp economics medical/ (13094) 7 exp economics hospital/ (17021) 8 economics pharmaceutical/ (2168) 9 exp "fees and charges"/ (25142) 10 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 11 or/1-10 (448331) 12 functional electric$ stimulat$.mp. (1149) 13 11 and 12 (67) Motor cortex stimulation 1 economics/ (26024) 2 exp "costs and cost analysis"/ (155035) 3 cost of illness/ (13694) 4 exp health care costs/ (37127) 5 economic value of life/ (5176) 6 exp economics medical/ (13094) 7 exp economics hospital/ (17021) 8 economics pharmaceutical/ (2168) 9 exp "fees and charges"/ (25142) 10 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 11 or/1-10 (448331) 12 motor cortex stimulat$.mp. (355) 13 cortical stimulat$.mp. (1415) 14 or/12-13 (1710) 15 motor cortex/ (13766) 16 electric stimulation/ (101302) 17 electric stimulation therapy/ (14618) 18 or/16-17 (115196) 19 15 and 18 (3122) 20 14 or 19 (4412) 21 11 and 20 (12) Neuromuscular stimulation 1 economics/ (26024) 2 exp "costs and cost analysis"/ (155035) 3 cost of illness/ (13694) 4 exp health care costs/ (37127) 5 economic value of life/ (5176)
169
6 exp economics medical/ (13094) 7 exp economics hospital/ (17021) 8 economics pharmaceutical/ (2168) 9 exp "fees and charges"/ (25142) 10 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 11 or/1-10 (448331) 12 neuromuscular electric$ stimulat$.mp. (310) 13 11 and 12 (10) Occipital nerve stimulation 1 economics/ (26024) 2 exp "costs and cost analysis"/ (155035) 3 cost of illness/ (13694) 4 exp health care costs/ (37127) 5 economic value of life/ (5176) 6 exp economics medical/ (13094) 7 exp economics hospital/ (17021) 8 economics pharmaceutical/ (2168) 9 exp "fees and charges"/ (25142) 10 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 11 or/1-10 (448331) 12 occipital nerve$ stimulat$.mp. (46) 13 occipital cortex stim$.mp. (3) 14 Occipital Lobe/ (6835) 15 electric stimulation/ (101302) 16 electric stimulation therapy/ (14618) 17 15 or 16 (115196) 18 14 and 17 (231) 19 12 or 13 or 18 (276) 20 11 and 19 (3) PENS 1 economics/ (26024) 2 exp "costs and cost analysis"/ (155035) 3 cost of illness/ (13694) 4 exp health care costs/ (37127) 5 economic value of life/ (5176) 6 exp economics medical/ (13094) 7 exp economics hospital/ (17021) 8 economics pharmaceutical/ (2168) 9 exp "fees and charges"/ (25142) 10 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 11 or/1-10 (448331) 12 percutaneous electric* neurostimulat*.ti,ab. (0) 13 percutaneous electric* nerve* stimulat*.ti,ab. (28) 14 percutaneous electric* neuromodulat*.ti,ab. (0) 15 or/12-14 (28) 16 11 and 15 (2)
170
Pudendal sympathetic nerve stimulation 1 economics/ (26024) 2 exp "costs and cost analysis"/ (155035) 3 cost of illness/ (13694) 4 exp health care costs/ (37127) 5 economic value of life/ (5176) 6 exp economics medical/ (13094) 7 exp economics hospital/ (17021) 8 economics pharmaceutical/ (2168) 9 exp "fees and charges"/ (25142) 10 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 11 or/1-10 (448331) 12 peripheral nerve stimulat*.ti,ab. (737) 13 pudendal nerve stimulat*.ti,ab. (91) 14 sympathetic nerve stimulat*.ti,ab. (1352) 15 12 or 13 or 14 (2179) 16 peripheral nerves/ (20711) 17 sympathetic nervous system/ (32955) 18 16 or 17 (53262) 19 electric stimulation/ (101302) 20 electric stimulation therapy/ (14618) 21 19 or 20 (115196) 22 18 and 21 (6756) 23 15 or 22 (8025) 24 11 and 23 (22) Pulsed magnetic fields 1 economics/ (26024) 2 exp "costs and cost analysis"/ (155035) 3 cost of illness/ (13694) 4 exp health care costs/ (37127) 5 economic value of life/ (5176) 6 exp economics medical/ (13094) 7 exp economics hospital/ (17021) 8 economics pharmaceutical/ (2168) 9 exp "fees and charges"/ (25142) 10 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 11 or/1-10 (448331) 12 pulsed magnetic field$.mp. (290) 13 11 and 12 (5) Retinal nerve stimulation 1 economics/ (26024) 2 exp "costs and cost analysis"/ (155035) 3 cost of illness/ (13694) 4 exp health care costs/ (37127) 5 economic value of life/ (5176) 6 exp economics medical/ (13094) 7 exp economics hospital/ (17021) 8 economics pharmaceutical/ (2168)
171
9 exp "fees and charges"/ (25142) 10 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 11 or/1-10 (448331) 12 retinal stimulat$.mp. (147) 13 retina stimulat$.mp. (39) 14 retinal nerve$ stimulat$.mp. (0) 15 retina nerve$ stimulat$.mp. (0) 16 or/12-15 (182) 17 retina/ (55037) 18 electric stimulation/ (101302) 19 electric stimulation therapy/ (14618) 20 or/18-19 (115196) 21 17 and 20 (827) 22 16 or 21 (976) 23 11 and 22 (2) Sacral nerve stimulation 1 economics/ (26024) 2 exp "costs and cost analysis"/ (155035) 3 cost of illness/ (13694) 4 exp health care costs/ (37127) 5 economic value of life/ (5176) 6 exp economics medical/ (13094) 7 exp economics hospital/ (17021) 8 economics pharmaceutical/ (2168) 9 exp "fees and charges"/ (25142) 10 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 11 or/1-10 (448331) 12 sacral nerve stimulat$.mp. (296) 13 sacrum/ (5966) 14 electric stimulation therapy/ (14618) 15 electric stimulation/ (101302) 16 14 or 15 (115196) 17 13 and 16 (158) 18 12 or 17 (423) 19 11 and 18 (17) Spinal cord stimulation 1 economics/ (26024) 2 exp "costs and cost analysis"/ (155035) 3 cost of illness/ (13694) 4 exp health care costs/ (37127) 5 economic value of life/ (5176) 6 exp economics medical/ (13094) 7 exp economics hospital/ (17021) 8 economics pharmaceutical/ (2168) 9 exp "fees and charges"/ (25142) 10 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 11 or/1-10 (448331) 12 spinal cord stimulat$.mp. (1318)
172
13 spinal column stimulat$.mp. (3) 14 dorsal cord stimulat$.mp. (11) 15 dorsal column stimulat$.mp. (182) 16 spinal cord/ (64414) 17 electric stimulation/ (101302) 18 electric stimulation therapy/ (14618) 19 or/17-18 (115196) 20 16 and 19 (6749) 21 12 or 13 or 14 or 15 or 20 (7251) 22 11 and 21 (100) 23 exp animals/ not humans/ (3604852) 24 22 not 23 (99) TENS 1 economics/ (26024) 2 exp "costs and cost analysis"/ (155035) 3 cost of illness/ (13694) 4 exp health care costs/ (37127) 5 economic value of life/ (5176) 6 exp economics medical/ (13094) 7 exp economics hospital/ (17021) 8 economics pharmaceutical/ (2168) 9 exp "fees and charges"/ (25142) 10 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 11 or/1-10 (448331) 12 Transcutaneous Electric Nerve Stimulation/ (2856) 13 transcutaneous electric$ nerve$ stimulat$.mp. (3181) 14 12 or 13 (3181) 15 11 and 14 (69) Trigeminal nerve stimulation 1 economics/ (26024) 2 exp "costs and cost analysis"/ (155035) 3 cost of illness/ (13694) 4 exp health care costs/ (37127) 5 economic value of life/ (5176) 6 exp economics medical/ (13094) 7 exp economics hospital/ (17021) 8 economics pharmaceutical/ (2168) 9 exp "fees and charges"/ (25142) 10 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 11 or/1-10 (448331) 12 Trigeminal Nerve/ (7562) 13 electric stimulation therapy/ (14618) 14 electric stimulation/ (101302) 15 13 or 14 (115196) 16 trigeminal nerve$ stimulat$.mp. (91) 17 12 and 15 (926) 18 16 or 17 (988) 19 11 and 18 (0)
173
Vagal nerve stimulation 1 economics/ (26024) 2 exp "costs and cost analysis"/ (155035) 3 cost of illness/ (13694) 4 exp health care costs/ (37127) 5 economic value of life/ (5176) 6 exp economics medical/ (13094) 7 exp economics hospital/ (17021) 8 economics pharmaceutical/ (2168) 9 exp "fees and charges"/ (25142) 10 (econom$ or cost or costs or costly or costing or price or pricing or
pharmacoeconomic$).tw. (335969) 11 or/1-10 (448331) 12 vagal nerve stimulat$.mp. (528) 13 vagus nerve stimulat$.mp. (997) 14 or/12-13 (1457) 15 vagus nerve/ (19116) 16 electric stimulation therapy/ (14618) 17 electric stimulation/ (101302) 18 16 or 17 (115196) 19 15 and 18 (4329) 20 14 or 19 (4881) 21 11 and 20 (45)
174
Appendix 2 Critical appraisal checklists
Critical appraisal checklist for systematic reviews Paper assessed: Was the review up-to-date?
The cut-off dates used for ascertainment of relevant literature should be identified.
Was a clear review question defined?
The review question should be defined in terms of the question type and the population, intervention and outcome(s) to which it refers. Comments should be made as to whether the question is sufficiently well defined to allow the review to be executed systematically (internal validity).
Were inclusion/ exclusion criteria clearly stated?
The inclusion and exclusion criteria should be listed and comments made on whether they are clearly stated and consistent with the review question.
What are the implications for the validity of the review given the type and range of study designs included?
The types of study designs included should be stated and the implications for the overall validity of the review commented on in the context of an appropriate hierarchy of evidence.
Was the search strategy adopted likely to have missed many potentially relevant studies?
The search strategy should be recorded and comments made on its comprehensiveness in terms of databases searched; dates searches undertaken; language restrictions applied; reference lists searched; ongoing trials registers searched; and contact made with authors or relevant manufacturers. Also any elements of the search strategy that might potentially introduce bias should be noted.
Were the methods used to decide on study inclusion/ exclusion stated?
Comments should be made on how potentially relevant papers were identified (i.e. by examination of study titles/abstracts/full papers) and inclusion/exclusion decisions made. It should also be noted whether more than one assessor performed these tasks.
Was the process of data abstraction adequate?
The way in which the relevant data items were abstracted should be recorded. Comments should be made on whether this was consistent with the review question and what the implications were for the validity of the review
Was the validity of included studies assessed?
The way in which the validity of the included studies was assessed and how information on the validity of the included studies was applied should be noted taking into account whether an assessment of quality using a recorded checklist or scoring system was made; whether there was more than one assessor of quality; whether the review authors reported the results of their quality assessment or discussed quality issues; and whether there were any quality issues that might impact on the results of the review.
What were the relevant and justifiable review conclusions?
The summary estimate of effect or key results for each outcome, subgroup or comparison examined by the review should be stated. Comments should be made on whether meta-analysis was used and, if so, whether this was appropriate in relation to the homogeneity or heterogeneity of the study results. Any other conclusions reported which seem reasonable given the data presented, should also be noted.
General comments
Comment should be made on the general quality of the review including the elements it incorporates which might make it systematic.
175
Critical appraisal checklist for randomised controlled trials Criterion Reviewer assessment Was allocation concealed? How was allocation concealed?
Was study randomised? What randomisation technique was used?
Were patients unaware of allocation (blinded)?
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Were the study groups comparable (in terms of patient characteristics)?
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Was follow-up adequate? (to be able to observe relevant outcomes)
Were there any withdrawals and/or discontinuations?
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
Was a justification of the sample size provided?
Comparability to UK setting and population?
176
Critical appraisal checklist for cost-effectiveness models (Drummond 1996)27 Item Yes No Not
clear Not appropriate
Study design 1. The research question is stated. 2. The economic importance of the research question is stated. 3. The viewpoint(s) of the analysis are clearly stated and
justified.
4. The rationale for choosing alternative programmes or interventions compared is stated.
5. The alternatives being compared are clearly described. 6. The form of economic evaluation used is stated. 7. The choice of form of economic evaluation is justified in
relation to the questions addressed.
Data collection 8. The source(s) of effectiveness estimates used are stated. 9. Details of the design and results of effectiveness study are
given (if based on a single study).
10. Details of the methods of synthesis or meta-analysis of estimates are given (if based on a synthesis of a number of effectiveness studies).
11. The primary outcome measure(s) for the economic evaluation are clearly stated.
12. Methods to value benefits are stated. 13. Details of the subjects from whom valuations were obtained
were given.
14. Productivity changes (if included) are reported separately. 15. The relevance of productivity changes to the study question is
discussed.
16. Quantities of resource use are reported separately from their unit costs.
17. Methods for the estimation of quantities and unit costs are described.
18. Currency and price data are recorded. 19. Details of currency of price adjustments for inflation or
currency conversion are given.
20. Details of any model used are given. 21. The choice of model used and the key parameters on which it
is based are justified.
Analysis and interpretation of results 22. Time horizon of costs and benefits is stated. 23. The discount rate(s) is stated. 24. The choice of discount rate(s) is justified. 25. An explanation is given if costs and benefits are not
discounted.
26. Details of statistical tests and confidence intervals are given for stochastic data.
27. The approach to sensitivity analysis is given. 28. The choice of variables for sensitivity analysis is justified. 29. The ranges over which the variables are varied are justified. 30. Relevant alternatives are compared. 31. Incremental analysis is reported.
177
Item Yes No Not clear
Not appropriate
32. Major outcomes are presented in a disaggregated as well as aggregated form.
33. The answer to the study question is given. 34. Conclusions follow from the data reported. 35. Conclusions are accompanied by the appropriate caveats.
178
Appendix 3 Back Pain Table 15 Characteristics of included systematic reviews on back pain Review Population Intervention Comparator Outcomes Blue Cross of Idaho Report 201020
Adults with chronic pain. PENS or percutaneous neuromodulation therapy (a variant of PENS).
Not specified (but RCTs only specified so no studies without a comparator).
Not specified.
Dubinsky 201054 Well-defined neurological disorders.
TENS. Placebo or another therapy.
Not specified: but the review aimed to assess the efficacy of TENS in the treatment of pain.
O’Connell 201022
Adults with chronic pain. NB headache excluded but one RCT with mixed population included with headache patients.
Repetitive transcranial magnetic stimulation (rTMS), cranial electrotherapy stimulation (CES) and transcranial direct current stimulation (tDCS).
Not specified. Included sham interventions for many studies.
Change in self-reported pain using validated measures of pain intensity such as visual analogue scales (VAS), verbal rating scales (VRS) or numerical rating scales (NRS).
Simpson 20093 Patients with chronic pain of neuropathic or ischaemic origin.
SCS. Medical or surgical treatment appropriate to condition that does not include SCS.
Pain, HrQoL, physical and functional abilities, anxiety and depression, medication use, complications and adverse events (NB these are pre-specified criteria, and are not necessarily reported).
Fontaine 200963 Patients with intractable neuropathic pain.
MCS. Not specified. Any quantitative post-operative outcome.
Khadilkar 200824 Chronic LBP: defined as persistent pain (lasting >12 weeks) localised between the inferior gluteal fold and the costal margin in the absence of malignancy, infection, fracture, inflammatory disorder or neurological syndrome.
TENS: all standard modes.
Placebo - sham TENS. Pain, back-specific functional status, generic health status, work disability, patient satisfaction, treatment related side effects, medication use & use of medical services.
Prévinaire 200861 Patients with chronic neuropathic pain following traumatic spinal cord injury.
DBS, MCS. Not specified. Not specified.
179
Review Population Intervention Comparator Outcomes Bittar 200553 Patients with chronic
intractable pain (nociceptive or neuropathic), where ‘all reasonable conventional methods had failed or were poorly tolerated’.
Deep brain stimulation; variety of stimulation sites.
No comparator (case-series).
Large variability in methods used to assess pain, therefore used ‘success or failure as reported in individual studies’.
Brousseau 200257 Patients with low back pain of musculoskeletal origin.
TENS: all standard modes.
Placebo - sham TENS. Not specified. Main outcome measures were pain intensity and patient satisfaction.
Jadad 200160 Patients with chronic central neuropathic pain following traumatic spinal cord injury.
Any conventional management intervention, including pharmacological, SCS, DBS, TENS.
Not specified. Not specified.
180
Table 16 Quality of included systematic reviews: back pain Quality criteria Reviews Was the
review up-to-date?
Was a clear review question defined?
Were inclusion/ exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion/ exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
Blue Cross of Idaho Report 201020
This 1996 report was updated with a literature search in 2004 and 2010, but it is unclear which search results feed into the results.
This is a policy guideline to assess PENS for the treatment of chronic pain.
Yes, studies were included if they: contained original empirical data, the design included a treatment and a control group, they reported on a health outcome relevant to the pain condition treated and they used random assignment, control group design.
RCTs are likely to give the least biased evidence.
Few details on search strategy, so unclear.
No details. No details. No formal methods, but validity discussed in the text.
Dubinsky 201054
Yes: searches to April 2009.
Yes: the review aimed to determine if TENS was efficacious in the treatment of pain in neurologic disorders. This appraisal focuses on the evidence assessing the clinical
Some lack of clarity. Stated inclusion criteria were clinical trials of TENS compared to placebo or another therapy for well-defined painful neurologic disorders with more than 10 subjects. Inclusion criteria regarding study outcomes were not stated. Although pain appeared implicit as an outcome of interest. Exclusion criteria were not reported.
Five studies were identified. The reviewers designated two as Class I* studies and three as Class II** studies. All assessed study population, intervention, comparators and outcomes relevant to this report enhancing the reviews external validity. Meta-analysis was not undertaken and reasons for its omission not given. The two Class I studies (by definition well-conducted RCTs) were reported to appear adequately powered to detect a
Possibly. Only two electronic databases were searched (MEDLINE: from inception to April 2009; and the Cochrane Library: search dates not reported), supplemented by hand searches of the bibliographies of identified trials and review articles. Searches were limited to clinical trials, meta-analyses, practice guidelines and RCTs. A language restriction was not reported.
Yes. The reviewers reported that ‘the titles and abstracts were reviewed, and articles meeting (inclusion) criteria were reviewed in full’. However they did not state whether or not a second independent review of the material was performed.
Difficult to tell. Only pain-related outcomes were reported – presumably the only outcome of interest in this review. The authors stated they adopted the definitions used in each paper for meaningful reduction in
Yes. The included studies were assigned one of the following classes of evidence: Class I,*Class II,** Class III,*** and Class IV.****
181
Quality criteria Reviews Was the
review up-to-date?
Was a clear review question defined?
Were inclusion/ exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion/ exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
effectiveness of TENS in the treatment of chronic low back pain (patients experienced low back pain for at least 3 months).
significant treatment effect enhancing confidence in the validity (internal) of the reported results. Of the three Class II studies, one was a RCT, but was reported to appear inadequately powered to detect a significant treatment effect.
pain. A second independent review of this material would help discount concerns regarding possible selection bias and/or reviewer error but whether or not this was undertaken was not reported.
O’Connell 201022
Yes. Searches were conducted up to end 2009/ beginning 2010.
Yes. The objective was to assess the effectiveness of non-invasive brain stimulation techniques for relief of chronic pain.
Yes. Criteria were defined for population (any chronic pain with a duration > 3months), intervention (CES, rTMS or tDCS), type of study (parallel or crossover RCTs or quasi-randomised studies) and outcomes (self-reported pain using validated outcome measures).
Only RCTs are included and these are most likely to give unbiased evidence.
The search strategy was comprehensive and it is unlikely that many studies were missed.
Yes, the selection of studies was described (two independent reviewers, assessment of full paper where abstract unclear and resolution of disagreements through a third reviewer).
Yes, data was extracted independent-ly by two reviewers using a standardised and piloted data extraction form; discrepan-
Yes, risk of bias was assessed independently by two reviewers using the Cochrane risk of bias assessment tool; additional assessment criteria were
182
Quality criteria Reviews Was the
review up-to-date?
Was a clear review question defined?
Were inclusion/ exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion/ exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
cies were resolved by consensus.
used for crossover trials and for assessment of sham credibility.
Simpson 20093
Relatively up-to-date: searches to August/ September 2007.
Yes: the HTA addressed the following question: ‘What is the clinical and cost-effective-ness of spinal cord stimulation in the manage-ment of chronic neuropathic or ischaemic pain?’ This appraisal focuses on the evidence identified
Yes. Inclusion criteria were, intervention: spinal cord devices; population: adults with chronic neuropathic or ischaemic pain resonding inadequately to medical or surgical treatment other than SCS; comparator: medical and/or surgical treatment not including SCS; outcomes: pain, health-related quality of life, physical and functional abilities, anxiety and depression, medication use, complications and adverse effects; study type: RCTs. Trials were excluded if neurostimulation involved stimulation of other parts of the nervous system, If
Two RCTs (the PROCESS trial and North et al’s trial) were identified. Both assessed study population, intervention, comparators and outcomes relevant to this report enhancing the HTAs external validity. The trials used different comparators preventing meta-analysis (CMM in PROCESS, and re-operation in North). In both trials SCS was provided in addition to CMM. In both participants had neuropathic pain of radicular origin and had undergone back surgery at least once. The trials were generally well-conducted. Both had adequate methods of randomisation and appeared to be adequately powered to detect a significant treatment effect
No. An extremely comprehensive search strategy was employed. Thirteen electronic databases were searched from inception, including MEDLINE (1950-2007), EMBASE (1980-2007), and the Cochrane Library (1991-2007). Relevant journals were hand-searched and appropriate websites for specific conditions causing chronic neuropathic/ischaemic pain were browsed. Also any industry submissions along with relevant systematic reviews were hand-searched to identify any further clinical trials. Searches were not restricted by language, date or publication type.
Yes. Study selection based on pre-defined inclusion/exclusion criteria was made by one reviewer. A second independent review of this material would better help discount concerns regarding possible selection bias and/or reviewer error.
Probably. Data were extracted with no blinding to authors or journal by one reviewer using a standardised form. Pre-specified outcomes were tabulated and discussed within a descriptive synthesis. A second independent review of this material would better help discount
Yes. The quality of the studies was assessed according to criteria based on NHS CRD Report No 4.
183
Quality criteria Reviews Was the
review up-to-date?
Was a clear review question defined?
Were inclusion/ exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion/ exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
assessing the clinical effectiveness of SCS in the management of FBSS.
patients had prior experience of SCS, were pregnant or children, or if the trial was only published in languages other than English
enhancing confidence in the validity (internal) of the reported results.
concerns regarding possible selection bias and/or reviewer error.
Fontaine 200963
Searches were conducted up to December 2006.
Yes. To assess the outcome of MCS for the treatment of intractable neuropathic pain.
Yes. Studies had to (i) clearly describe the clinical characteristics of pain, (ii) provide quantitative postoperative outcome, (iii) clearly state that patients had failed all other conventional treatments (except for DBS).
No study design specified, but all included studies were case-series.
The search strategy was limited to MEDLINE, and it is therefore possible that some studies might have been missed.
No details. No details. Where there were separate reports of case-series, the authors selected only the largest, with the longest follow-up and most detailed evaluation of pain or pain relief.
Khadilkar 200824
Relatively up-to-date: searches to July 2007.
Yes. The review aimed to determine whether TENS was more effective than placebo for the
Yes. Inclusion criteria were, intervention: TENS - all standard modes; population: adults with chronic LBP defined as persistent pain (lasting > 12 weeks) localised between the inferior gluteal fold and the
Four RCTs were identified. All assessed study population, intervention, comparators and outcomes relevant to this report enhancing the reviews external validity. Meta-analysis was considered inappropriate given observed clinical heterogeneity amongst the
No. A comprehensive search strategy was employed. The Cochrane Central Register of Controlled Trials (Issue 3, 2007) was searched, and MEDLINE, EMBASE, PEDRO and CINAHL were searched from
Yes. The methods used helped negate concerns regarding possible selection bias and/or reviewer error. Two review authors independently selected studies by screening the titles, abstracts and
Yes. The methods used helped negate concerns regarding possible selection bias and/or reviewer error.
Yes. Study quality was assessed independently by two reviewers based on a list of 11 methodolo-gical criteria recommended
184
Quality criteria Reviews Was the
review up-to-date?
Was a clear review question defined?
Were inclusion/ exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion/ exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
manage-ment of low back pain.
costal margin in the absence of malignancy, infection, fracture, inflammatory disorder or neurological syndrome; comparator: placebo – sham TENS; outcomes: pain, back-specific functional status, generic health status, work disability, patient satisfaction, treatment related side effects, medication use & use of medical services; study type: RCTs with >5 subjects per treatment group. Trials were excluded where they reported on subjects with a mix of chronic and acute or subacute LBP or a mix of low, middle or upper back pain and data were not disagregable. Also trials were excluded if either the experimental or control groups received electrical stimulation percutaneously using
trials. The trials were all reported to be of high quality enhancing confidence in the validity (internal) of the reported results.
inception to July 2007 without language restriction. Conference proceeding and reference lists from guidelines, literature reviews and retrieved articles were screened and experts for contacted for additional studies. Also the International Clinical Trials Registry was searched for ongoing trials.
keywords of articles identified in the literature search. The full text of potentially relevant studies was retrieved for closer examination and disagreement was resolved by discussion with the review authors.
Information about the study design, study population, treatment characteris-tics, study outcomes and adverse effects was collected from each trial. Differences in data extraction between review authors were resolved by referring back to the original article and establishing consensus.
by the Cochrane Back Review Group. Differences in scoring were resolved by consensus, which was reached for all trials. A third reviewer was consulted for additional guidance.
185
Quality criteria Reviews Was the
review up-to-date?
Was a clear review question defined?
Were inclusion/ exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion/ exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
acupuncture needles. Prévinaire 200861
Unclear when searches were performed, but studies from 2006 were included.
Efficiency of DBS and MCS for neuropathic pain in spinal cord injury patients.
Not clearly specified. Case-series and reports only included, which are likely to be associated with bias.
Unclear. The report refers to a methodology described elsewhere, which does appear to be fairly comprehensive but was used for a different study question.
Unclear. The report refers to a methodology described elsewhere; this does include two experts independently analysing manuscripts and assessing the quality of studies according to a grading scale.
Bittar 200553 Searches were conducted up to Jan/Feb 2003 and may therefore not be up-to date.
Yes, though it was fairly broad (DBS for any pain relief).
Yes, for patients, outcome measure and follow-up.
Study design was not described but all appeared to be case-series, which are unlikely to give unbiased information.
The search strategy was fairly comprehensive, but could have included additional databases or contact with experts. Reference lists were checked and it is unlikely that a substantial number of studies would have been missed.
No details. No details. No, though only studies where the period of follow-up was stated and loss to follow-up was explicit were included.
Brousseau 200257
Searches were completed June 2000.
Yes, the aim was to determine the efficacy of TENS in the treatment of chronic low back pain; a secondary objective
Yes: RCTs with >5 patients, adults with a diagnosis of chronic (>12 weeks) LBP, all modes of TENS. Articles were excluded if the active or placebo treatment group received TENS percutaneously with
RCTs are most likely to give unbiased evidence. Very small RCTs, the results of which are likely to be associated with more uncertainty, have been excluded.
The search strategy was very comprehensive and it is unlikely that many studies were missed.
Two reviewers independently selected articles for review and all articles selected by at least one reviewer were retrieved for closer examination.
Data were extracted independent-ly by two reviewers, with discussion or involvement of a third reviewer where there
Quality was assessed independently by two reviewers regarding the extent that studies avoided or minimised biases. A
186
Quality criteria Reviews Was the
review up-to-date?
Was a clear review question defined?
Were inclusion/ exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion/ exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
was to determine the most effective mode of administe-ring TENS.
acupuncture needles. were discrepan-cies. Additional information was sought from the authors.
validated scale was used.
Jadad 200160
Searches were performed up to May 2000.
This was a large report on the overall management of chronic central neuropathic pain following SCI; several review questions defined, including one of the efficacy and safety of spinal cord and deep brain stimulation techniques for this indication.
These were clearly stated; they were kept deliberately broad (any definition of chronic neuropathic pain as provided by the primary study authors, treatment options confined to conventional medicine)
Any study design included (though case-series with less than 8 patients described in separate supplemental tables only). Validity will therefore depend on what was identified for the various interventions. For SCS, these were case-series only which are associated with bias.
The search strategy was comprehensive and was unlikely to have missed any relevant studies.
Clearly stated. Involved three pairs of two independent individuals for initial screening, with use of proforma for second screening. Discrepancies resolved through discussion.
Yes. Data extracted in duplicate by two independent reviewers using piloted data extraction form. Discrepancies resolved through discussion.
Yes; for RCTs, a three-item validated scale, complemented with assessments of individual components supported by empirical methodolo-gical evidence was used; other assessment tools used as appropriate for other study designs.
187
*Class I = prospective, randomised, controlled clinical trial with masked outcome assessment, in a representative population. The following are required: a) primary outcome(s) is/are clearly defined; b) exclusion/inclusion criteria are clearly defined; c) adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias; d) relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. ** Class II = prospective matched group study in a representative population, with masked outcome assessment that meets a-d above OR a RCT in a representative population that lack one criterion a-d. Class III = all other controlled trials. Class IV = uncontrolled studies, case-series, case reports, or expert opinion.
188
Table 17 Primary evidence covered in systematic reviews of SCS for FBSS
RCTs The PROCESS trial North et al’s trial
Evidence source Publications of the PROCESS and North RCTs
Meg
lio 2
00872
Kum
ar 2
00871
Milb
ouw
200
773
Kum
ar 2
00770
Kum
ar 2
00569
Nor
th 2
00577
Nor
th 2
00276
Nor
th 1
99575
Nor
th 1
99474
Systematic reviews identified for this report
Date searches concluded
Frey 200943 Dec 2008 x x British Pain Society 200942 Sep 2008 x x x x Chou 200944 Jul 2008 x x Bala 200845 Jan 2008 x x Simpson 20093 Aug 2008 x x x x x x NICE guidance 20085 Aug 2008 x x x x x x Mailis-Gagnon 200450 Sep 2003 x x Turner 200449 May 2003 Taylor 2005a47 Jan 2002 x x x Taylor 2006b46 Apr 2003 x x ASERNIP 200351 Apr 2003 x x x Taylor 200448 Jan 2002 x x Turner 199552 Jun 1994 Publications of RCTs identified for this report
Jul/Aug 2010 x x x x x x x
X indicates where an RCT publication was included in a systematic review
189
Table 18 Characteristics of RCTs for back pain Trial Population Intervention Comparator Outcomes The PROCESS trial 69-73
Patients with neuropathic pain of radicular origin predominantly in the legs (exceeding back pain), pain intensity of at least 50mm on VAS 0-100mm, documented history of nerve injury, pain duration of at least six months (after anatomically successful surgery), aged ≥18 years.
SCS plus CMM (as for control group). Could request crossover at six months.
CMM (could request crossover at six months) at the discretion of the study investigator and according to local clinical practice included oral medications (i.e. opioids, non-steroidal anti-inflammatory drugs, antidepressants, anticonvulsants or antiepileptics and other analgesics), nerve blocks, epidural corticosteroids, physical and psychological rehabilitative therapy, and/or chiropractic care. Other invasive therapy (i.e. spinal surgery, intrathecal drug delivery) was excluded.
Priimary: proportion of patients achieving at least 50% reduction in leg pain. Secondary: Pain VAS, medication use, Oswestry Disability Index, employment status, SF-36, patient satisfaction, complications, adverse events.
North et al74,75,77
Patients with surgically remedial nerve root compression, concordant complaints of persistent or radicular pain, with or without low back pain, meeting criteria for surgery,(pain refractory to conservative care, with
SCS plus CMM (analgesics and physical therapy as for control group). If test stimulation failed, patients could immediately cross over to control treatment
Re-operation: laminectomy and/or foraminotomy and/or disectomy in all patients with/without fusion, with/without instrumentation. Patients could cross over to SCS after a six month postoperative period.
Primary: at least 50% pain relief plus patient satisfaction. Secondary: Crossover to alternative treatment group, pain related to daily activities, patient self-reported neurological function, medication use, employment status, complications.
190
Trial Population Intervention Comparator Outcomes neurological tension and/or mechanical signs and imaging findings of neural compression), previous therapy ≥ lumbosacral spine surgeries.
Plus CMM: standard postoperative analgesics, preoperative analgesics (tapered as rapidly as possible), physical therapy in accordance with the post-spinal surgery physical therapy protocol of the institution.
191
Table 19 Quality RCTs: back pain Criterion
Reviewer assessment
The PROCESS trial69-73 Was allocation concealed? How was allocation concealed?
Yes. Randomisation was electronically locked and only accessed after patients entered the trial.
Was study randomised? What randomisation technique was used?
Yes. Random computer-generated blocks (random sequence of either 2 or 4 patients) prepared on a per site basis.
Were patients unaware of allocation (blinded)?
No.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
No.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
No.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Parallel group design.
Were the study groups comparable (in terms of patient characteristics)?
Baseline comparability was achieved for all variables except back pain which was significantly higher amongst the SCS group (p=0.03).
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Yes.
Was follow-up adequate? (to be able to observe relevant outcomes)
Yes. Data available at 6, 12 and 24 months follow-up.
Were there any withdrawals and/or discontinuations?
Yes. Prior to the six months assessment, two SCS patients and four CMM patients withdrew consent. By 24 months, three SCS patients and one CMM patient were lost to follow-up, also an additional SCS patient and two more CMM patients withdrew consent. Between six and 12 months five SCS patients crossed to CMM, and 28 CMM patients crossed to SCS, another four CMM patients requested crossover but failed SCS trial screening. .
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
Although described as ITT, patients who withdrew consent and were lost to follow-up were not included in the six month analyses. Patients who crossed over were included in the analyses. A sensitivity analysis was performed using ‘last observation carried forward’ to explore the impact of missing values.
192
Criterion
Reviewer assessment
Was a justification of the sample size provided?
Yes. The required sample size of 100 assumed an attrition rate of 20%, successful treatment of 42.5% SCS and 14.5% CMM patient, groups of 40 patients each, 80% power and two-tailed alpha of 0.05.
Comparability to UK setting and population?
Study setting and population comparable to the UK. Multicentre RCT conducted in 12 centres in Europe (UK, Belgium, Spain, Italy, Switzerland), Canada, Australia and Israel.
The North trial74,75,77 Was allocation concealed? How was allocation concealed?
Yes. Numbered, sealed opaque envelopes provided by someone independent of the trialists.
Was study randomised? What randomisation technique was used?
Yes. Computer generated list.
Were patients unaware of allocation (blinded)?
No.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
No.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
Yes.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Parallel-group design.
Were the study groups comparable (in terms of patient characteristics)?
Unclear
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Yes.
Was follow-up adequate? (to be able to observe relevant outcomes)
Yes. Data available at six months and mean 2.9 years.
Were there any withdrawals and/or discontinuations?
Yes. 6/30 patients randomised to SCS and 4/30 randomised to re-operation were not treated as their insurance company refused authorisation. Of the 24 patients given SCS, five crossed over to re-operation (one of which was lost to follow-up) and four were lost to follow-up. None of the patients undergoing re-operation were lost to follow-up but 14 crossed over to SCS.
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
Patients randomised but not treated were excluded from the analysis. An ITT analysis was undertaken for the 23 patients randomised to SCS and 26 patients randomised to re-operation – this worst-case analysis included the four SCS patients lost to follow-up and assumed they were treatment failures.
193
Criterion
Reviewer assessment
Was a justification of the sample size provided?
Yes. It was calculated a sample size of 50 was required to detect a significant (alpha =0.05) difference in outcomes, with 80% power.
Comparability to UK setting and population?
Study setting and population comparable to the UK. Single centre RCT conducted in the USA.
194
Table 20 Critical appraisal of cost-effectiveness models: FBSS Item Yes No Not
clear Not appropriate
Taylor 201067 Study design 1. The research question is stated. √ 2. The economic importance of the research question is stated. √ 3. The viewpoint(s) of the analysis are clearly stated and
justified. √ based on NICE
analysis
4. The rationale for choosing alternative programmes or interventions compared is stated.
√
5. The alternatives being compared are clearly described. √ 6. The form of economic evaluation used is stated. √ 7. The choice of form of economic evaluation is justified in
relation to the questions addressed. √
Data collection 8. The source(s) of effectiveness estimates used are stated. √ 9. Details of the design and results of effectiveness study are
given (if based on a single study). √*
10. Details of the methods of synthesis or meta-analysis of estimates are given (if based on a synthesis of a number of effectiveness studies).
√
11. The primary outcome measure(s) for the economic evaluation are clearly stated.
√
12. Methods to value benefits are stated. √ 13. Details of the subjects from whom valuations were obtained
were given. √
14. Productivity changes (if included) are reported separately. √ 15. The relevance of productivity changes to the study question is
discussed. √
16. Quantities of resource use are reported separately from their unit costs.
√ Partly
17. Methods for the estimation of quantities and unit costs are described.
√ Partly
18. Currency and price data are recorded. √ 19. Details of currency of price adjustments for inflation or
currency conversion are given. √
20. Details of any model used are given. √ 21. The choice of model used and the key parameters on which it
is based are justified. √
Analysis and interpretation of results 22. Time horizon of costs and benefits is stated. √ 23. The discount rate(s) is stated. √ 24. The choice of discount rate(s) is justified. 25. An explanation is given if costs and benefits are not
discounted. √
26. Details of statistical tests and confidence intervals are given for stochastic data.
√
27. The approach to sensitivity analysis is given. √ 28. The choice of variables for sensitivity analysis is justified. √ 29. The ranges over which the variables are varied are justified. √ 30. Relevant alternatives are compared. √
195
Item Yes No Not clear
Not appropriate
31. Incremental analysis is reported. √ 32. Major outcomes are presented in a disaggregated as well as
aggregated form. √
33. The answer to the study question is given. √ 34. Conclusions follow from the data reported. √ 35. Conclusions are accompanied by the appropriate caveats. √ *Details of RCTs given, but model covers 15 year time
horizon and thus draws on additional observational data
Item Yes No Not clear
Not appropriate
North 200768 Study design 1. The research question is stated. √ 2. The economic importance of the research question is stated. √ 3. The viewpoint(s) of the analysis are clearly stated and
justified. √
4. The rationale for choosing alternative programmes or interventions compared is stated.
√
5. The alternatives being compared are clearly described. √ 6. The form of economic evaluation used is stated. √ 7. The choice of form of economic evaluation is justified in
relation to the questions addressed. √
Data collection 8. The source(s) of effectiveness estimates used are stated. √ 9. Details of the design and results of effectiveness study are
given (if based on a single study). √
10. Details of the methods of synthesis or meta-analysis of estimates are given (if based on a synthesis of a number of effectiveness studies).
√
11. The primary outcome measure(s) for the economic evaluation are clearly stated.
√
12. Methods to value benefits are stated. √ 13. Details of the subjects from whom valuations were obtained
were given. √
14. Productivity changes (if included) are reported separately. √ 15. The relevance of productivity changes to the study question is
discussed. √
16. Quantities of resource use are reported separately from their unit costs.
√
17. Methods for the estimation of quantities and unit costs are described.
√
18. Currency and price data are recorded. √ 19. Details of currency of price adjustments for inflation or
currency conversion are given. √
20. Details of any model used are given. √ 21. The choice of model used and the key parameters on which it
is based are justified. √
Analysis and interpretation of results 22. Time horizon of costs and benefits is stated. √
196
Item Yes No Not clear
Not appropriate
23. The discount rate(s) is stated. √ 24. The choice of discount rate(s) is justified. √ 25. An explanation is given if costs and benefits are not
discounted. √
26. Details of statistical tests and confidence intervals are given for stochastic data.
√
27. The approach to sensitivity analysis is given. √ 28. The choice of variables for sensitivity analysis is justified. √ 29. The ranges over which the variables are varied are justified. √ 30. Relevant alternatives are compared. √ 31. Incremental analysis is reported. √ 32. Major outcomes are presented in a disaggregated as well as
aggregated form. √
33. The answer to the study question is given. √ 34. Conclusions follow from the data reported. √ 35. Conclusions are accompanied by the appropriate caveats. √
197
Appendix 4 Trigeminal neuropathic and deafferentation pain Table 21 Characteristics of included systematic reviews: TNP and TDP Review Population Intervention Comparator Outcomes Bittar 200553 Patients with chronic
intractable pain (nociceptive or neuropathic), where ‘all reasonable conventional methods had failed or were poorly tolerated’.
Deep brain stimulation; variety of stimulation sites.
No comparator (case-series).
Large variability in methods used to assess pain, therefore used ‘success or failure as reported in individual studies’.
Table 22 Quality of included systematic reviews: TNP and TDP
Review Was the review up-to-date?
Was a clear review question defined?
Were inclusion/exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was the search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion /exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
Bittar 200553
Searches were conducted up to Jan/Feb 2003 and may therefore not be up-to date.
Yes, though it was fairly broad (DBS for any pain relief).
Yes, for patients, outcome measure and follow-up.
Study design was not described but all appeared to be case-series, which are unlikely to give unbiased information.
The search strategy was fairly comprehensive, but could have included additional databases or contact with experts. Reference lists were checked and it is unlikely that a substantial number of studies would have been missed.
No details. No details. No, though only studies where the period of follow-up was stated and loss to follow-up was explicit were included.
198
Table 23 Characteristics of included RCTs: TNP and TDP Trial Population Intervention Comparator Outcomes Lefaucheur 2001137
Patients (n=14) with intractable pain due to thalamic stroke or trigeminal neuropathy.
20 minute session of rTMS at 10Hz
Sham coil Pain level on a 0-10 VAS (day 1-12)
Lefaucheur 2004138
Patients (n=60) with intractable pain due to thalamic stroke, brainstem stroke, spinal cord lesion, brachial plexus region or trigeminal nerve lesion
20 minute session of rTMS at 10Hz
Sham coil Pain level on a 0-10 VAS (before and after treatment session)
199
Table 24 Quality of included RCTs: TNP and TDP Criterion Reviewer assessment Lefaucheur 2001137 Was allocation concealed? How was allocation concealed?
No details.
Was study randomised? What randomisation technique was used?
‘Protocols were randomly applied’. No further details.
Were patients unaware of allocation (blinded)?
A ‘sham’ TMS coil designed not to have a stimulating effect on the cortex was applied and held in position the same way as the ‘real’ TMS coil. This was said by the authors to be a better way of blinding than using a real TMS coil in both instances but angling the coil differently in the ‘sham’ condition.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
No details.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
No details.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Appears to be crossover, but not clearly stated. No discussion of wash out periods or potential carry over effects.
Were the study groups comparable (in terms of patient characteristics)?
Crossover trial, so patients act as their own controls.
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Yes, all patients were treated for the same length of time and recorded their VAS scores in the same way.
Was follow-up adequate? (to be able to observe relevant outcomes)
Follow-up was for 12 days and likely to be too short to look at longer lasting effects of rTMS.
Were there any withdrawals and/or discontinuations?
None.
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
N/A
Was a justification of the sample size provided?
No. The authors state the sample size was too small to yield significant results for the sub-groups.
Comparability to UK setting and population?
Likely to be comparable if same stimulation protocol is used.
Criterion Reviewer assessment Lefaucheur 2004138 Was allocation concealed? How was allocation concealed?
No details.
Was study randomised? What randomisation technique was used?
Active and sham sessions performed in a random order (no further details).
Were patients unaware of allocation (blinded)?
Patients not told that one treatment session was with sham rTMS, instead were told that different stimulation parameters were going to be tested (in case they experienced a difference in the two sessions).
200
Criterion Reviewer assessment Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
No details.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
No details.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Crossover trial, sessions separated by at least 3 weeks. The authors stated that session order did not influence the results.
Were the study groups comparable (in terms of patient characteristics)?
Crossover trial, so patients act as their own controls.
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Yes, patients received same number of treatments and assessments.
Was follow-up adequate? (to be able to observe relevant outcomes)
Pain measured before and after the 20 minute treatment session; this does allow for the assessment of longer term benefits.
Were there any withdrawals and/or discontinuations?
No.
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
N/A
Was a justification of the sample size provided?
No. Sub-groups of patients with different types of pain were small (n=12 for facial pain)
Comparability to UK setting and population?
Likely to be comparable if same stimulation protocol is used.
201
Appendix 5 Complex regional pain syndrome Table 25 Characteristics of included systematic reviews: CRPS Trial Population Intervention Comparator Outcomes Perez 201096 Patients with CRPS type I Any interventions
(drug treatment, invasive interventions including SCS, physiotherapy)
Not specified as inclusion criteria; in the one RCT on SCS comparator was physical therapy
Not specified as inclusion criteria For the RCT on SCS reported outcomes were change on pain VAS and QoL
Simpson 20093 Patients with chronic pain of neuropathic or ischaemic origin
SCS Medical or surgical treatment appropriate to condition that does not include SCS
Pain, HrQoL, physical and functional abilities, anxiety and depression, medication use, complications and adverse events (NB these are pre-specified criteria, and are not necessarily reported)
Taylor 2006a16 Patients with CRPS type I or II
SCS (SCS + physical therapy in the RCT, SCS only in the case-series)
Not specified as inclusion criteria Comparators were: Physical therapy (RCT) None in case-series
None specified as inclusion criteria Actual outcomes were: RCT: Change on pain VAS, HrQoL, utility score, cost Case-series: change on pain VAS, % achieving pain relief
202
Table 26 Quality of included systematic reviews: CRPS
Review Was the review up-to-date?
Was a clear review question defined?
Were inclusion/exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was the search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion/exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
Perez 201096
Searches were completed in June 2005.
The aim was to identify relevant evidence on all types of treatment for CRPS in order to produce guidelines, but no formal review question was stated.
No formal criteria were given. It states that studies were selected on the basis of their methodological strength with systematic reviews and RCTs given precedence. Where these were not available, studies of lesser methodological quality were included. Other criteria were adequate size, follow-up and exclusion of selection bias, but a cut-off was not stated.
SCS: included studies were one RCT (Kemler 2000, see quality assessment) and two ‘retrospective cohort studies’ (n=23-31). The evidence from the RCT is likely to outweigh any additional evidence from the poorer quality studies. TENS: two case-series were identified, which are likely to be subject to bias.
The search strategy was fairly comprehensive and it is unlikely many studies would have been missed (five databases searched, reference list scanning and guideline checking; studies reported in one of five languages were included).
No details. No details. The quality was assessed on the basis of ‘evidence-based guideline development forms’ and studies graded according to quality.
Simpson 20093
Relatively up-to-date: searches to August/ September
Yes: the HTA addressed the following question: ‘What is the
Yes. Inclusion criteria were, intervention: spinal cord devices; population: adults
Only RCTs were included, the results of which are most likely to give unbiased results.
No. An extremely comprehensive search strategy was employed. Thirteen electronic
Yes. Study selection based on pre-defined inclusion and exclusion
Probably. Data were extracted with no blinding to
Yes. The quality of the studies was assessed according to
203
Review Was the review up-to-date?
Was a clear review question defined?
Were inclusion/exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was the search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion/exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
2007.
clinical and cost-effectiveness of spinal cord stimulation in the management of chronic neuropathic or ischaemic pain?’ This appraisal focuses on the evidence identified assessing the clinical effectiveness of SCS in the management of FBSS.
with chronic neuropathic or ischaemic pain resonding inadequately to medical or surgical treatment other than SCS; comparator: medical and/or surgical treatment not including SCS; outcomes: pain, health-related quality of life, physical and functional abilities, anxiety and depression, medication use, complications and adverse effects; study type: RCTs. Trials were excluded if neurostimulation involved stimulation of other parts of the nervous system, If patients had prior
One relevant RCT was identified (Kemler 2000 and following publications; see the separate quality assessment of this trial)
databases were searched from inception, including MEDLINE (1950-2007), EMBASE (1980-2007), and the Cochrane Library (1991-2007). Relevant journals were hand-searched and appropriate websites for specific conditions causing chronic neuropathic/ischaemic pain were browsed. Also any industry submissions along with relevant systematic reviews were hand-searched to identify any further clinical trials. Searches were not restricted by language, date or publication type.
criteria was made by one reviewer. A second independent review of this material would better help discount concerns regarding possible selection bias and/or reviewer error.
authors or journal by one reviewer using a standardised form. Pre-specified outcomes were tabulated and discussed within a descriptive synthesis. A second independent review of this material would better help discount concerns regarding possible selection bias and/or reviewer error.
criteria based on NHS CRD Report No 4.
204
Review Was the review up-to-date?
Was a clear review question defined?
Were inclusion/exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was the search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion/exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
experience of SCS, were pregnant or children, or if the trial was only published in languages other than English
Taylor 2006a16
Searches were conducted up to January 2002 only.
Yes. To evaluate the clinical and cost-effectiveness of SCS in patients with CRPS
Yes. There were clear inclusion and exclusion criteria for population, intervention and outcomes.
One RCT was included; this was fairly small but appeared to be well-conducted and is likely to give unbiased results. The remaining studies were poor quality case-series, which are unlikely to give unbiased information.
The search strategy was extensive and is unlikely to have missed many studies.
Yes. Study selection was performed independently by two reviewers using a standardised inclusion and exclusion form.
Partly-one reviewer extracted data using a standardised data extraction form; there was no double-data extraction.
Yes, different checklists using recognised quality criteria were used for the RCT and the case-series.
205
Table 27 Characteristics of included RCTs: CRPS Trial Population Intervention Comparator Outcomes Kemler 2000146, 2001147, 2004148 and 2008149
Patients (n=54) with CRPS type I; clinically restricted to one hand or foot; for at least six months; with no sustained response to standard therapy
SCS + physical therapy Physical therapy alone Pain VAS, McGill Pain Questionnaire, functional status, various measures of HrQoL, complications
Pleger 2004155
Patients (n=10) with CRPS type I
rTMS Sham rTMS Pain VAS
Velasco 2009154
Patients (n=5) with CRPS MCS (‘on’) MCS (‘off’) Pain VAS, McGill Pain Questionnaire, Bourhis scale for pain
206
Table 28 Quality of included RCTs: CRPS Criterion Reviewer assessment Kemler 2000146, 2001147, 2004148 and 2008149 Was allocation concealed? How was allocation concealed?
The assignments were made by a research assistant and were concealed from the study investigators.
Was study randomised? What randomisation technique was used?
Computer-generated list of random numbers with stratification according to location of CRPS I; 2:1 ratio SCS + physical therapy (PT) versus PT alone. Only 2/3 of the SCS group actually received SCS (after an initial test period).
Were patients unaware of allocation (blinded)?
Not possible-SCS cannot be blinded due to the paraesthesias that accompany stimulation
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
No. Only one groups received SCS, no sham SCS.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
No details. Some self-assessment measures, some measured by study investigators.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Parallel
Were the study groups comparable (in terms of patient characteristics)?
Groups similar on baseline pain and symptom scores; some differences in age, sex and duration of disorder (not statistically significant). These scores relate to the initially randomised patients, however only 24/36 patients actually received SCS in the SCS group; baseline characteristics for this and drop-out group are not presented. Characteristics of patients with and without implants (not randomised groups) are presented (not all the same characteristics). These appear to be largely similar.
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Yes, it appears to be.
Was follow-up adequate? (to be able to observe relevant outcomes)
Yes, a five year trial report is available.
Were there any withdrawals and/or discontinuations?
At six months: 24/36 received SCS + PT (after initial test period), 12/36 in SCS group received PT only and 18/18 received PT as allocated (no loss to follow-up) At 12 months: 4 patients in PT group and 1 patients in SCS + PT group not included; scores from 6 months carried over At 2 years: 3 patients excluded; not clear if this is in addition to those excluded at 12 months At 5 years: a total of 10 patients excluded (of these, 4 patients in the PT group had received implants)
207
Criterion Reviewer assessment How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
At 6 months: results presented for all patients including those in the SCS group that did not receive SCS (ITT) At 12 months: scores from 6 months carried over to 12 months for 5 patients; results not presented for randomised groups, only for those with and without implant-no ITT At 2 years: ITT analysis in 51/54, unclear if there are results that are carried over from previous assessments and why ITT not in 54 At 5 years: results presented for 44/54 patients and also as an ITT analysis (unclear how many results carried over from previous assessments)
Was a justification of the sample size provided?
Yes, however, the number actually receiving SCS was 1/3 less than initially randomised. It is unclear if estimated drop-out was taken into account and the sample size may therefore be inadequate.
Comparability to UK setting and population?
The study is set in the Netherlands and care is likely to be similar to that in the UK. Patients had to meet the diagnostic criteria for reflex sympathetic dystrophy (now known as CRPS I) established by the International Association for the Study of Pain (1994). Additionally the disease had to be restricted to one hand or foot, affect the entire hand or foot, had to have lasted for at least 6 months and have had no sustained response to standard therapy and with a mean pain intensity of 5 cm (pain VAS).
Pleger 2004155 Was allocation concealed? How was allocation concealed?
No details.
Was study randomised? What randomisation technique was used?
Computerised random generator.
Were patients unaware of allocation (blinded)?
Sham rTMS was applied to the same position over the motor cortex using identical stimulation parameters, however the coil was angled differently. The authors state that patients’ impression during sham rTMS was similar to real rTMS.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
No details.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
No details.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Crossover. It is not known whether there may be a carry over effect where patients received active treatment first.
Were the study groups comparable (in terms of patient characteristics)?
No details.
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Yes, patients likely to be treated similarly during the 90 minute study periods.
208
Criterion Reviewer assessment Was follow-up adequate? (to be able to observe relevant outcomes)
No, follow-up was only for 90 minutes.
Were there any withdrawals and/or discontinuations?
None.
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
N/A
Was a justification of the sample size provided?
No. This is small sample size (n=10) and results are likely to be associated with uncertainly.
Comparability to UK setting and population?
This is a German study and population/setting and treatment protocol is likely to be similar to the UK.
Velasco 2009154 Was allocation concealed? How was allocation concealed?
No details.
Was study randomised? What randomisation technique was used?
By ‘lottery number’. There are no further details and it is unclear if this is an appropriate method.
Were patients unaware of allocation (blinded)?
It states that the study was double-blind; there were no further details.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
It states that the study was double-blind; there were no further details.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
It states that the study was double-blind; there were no further details.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Crossover trial. There was the possibility of a crossover effect, first from the implantation process. Then from the ‘on’ period of the trial. There was no statistical test performed for effect of sequence.
Were the study groups comparable (in terms of patient characteristics)?
Crossover trial, so patients act as their own controls.
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
It is likely that patients were treated the same regardless of when they entered the ‘on’ or ‘off’ periods.
Was follow-up adequate? (to be able to observe relevant outcomes)
Patients were followed up for 36-72 months, which appears adequate, however, this was not part of the trial. The randomised phase only lasted for 30 days.
Were there any withdrawals and/or discontinuations?
Only 4/5 patients underwent implantation and entered the trial.
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
Data was available for all 4 patients who underwent implantation. MCS was not found to be appropriate for the 5th patient.
Was a justification of the sample size provided?
No, this is a very small sample size.
Comparability to UK setting and population?
The study was set in Mexico. The included patients (2 with CRPS type I and 2 with CRPS II) may be similar to certain UK patients with CRPS, however, the disease is heterogenous in its manifestation.
209
Table 29 Quality of cost-effectiveness studies: CRPS Item Yes No Not
clear Not appropriate
Kemler 2010151 cost-effectiveness study Study design 1. The research question is stated. √ 2. The economic importance of the research
question is stated. √
3. The viewpoint(s) of the analysis are clearly stated and justified.
√ NHS
4. The rationale for choosing alternative programmes or interventions compared is stated.
√
5. The alternatives being compared are clearly described.
√
6. The form of economic evaluation used is stated.
√
7. The choice of form of economic evaluation is justified in relation to the questions addressed.
√
Data collection 8. The source(s) of effectiveness estimates
used are stated. √ Kemler RCT
9. Details of the design and results of effectiveness study are given (if based on a single study).
√
10. Details of the methods of synthesis or meta-analysis of estimates are given (if based on a synthesis of a number of effectiveness studies).
√
11. The primary outcome measure(s) for the economic evaluation are clearly stated.
√ Cost/QALYs
12. Methods to value benefits are stated. √ EQ5D 13. Details of the subjects from whom
valuations were obtained were given. √
14. Productivity changes (if included) are reported separately.
√
15. The relevance of productivity changes to the study question is discussed.
√
16. Quantities of resource use are reported separately from their unit costs.
√
17. Methods for the estimation of quantities and unit costs are described.
√
18. Currency and price data are recorded. √ 19. Details of currency of price adjustments for
inflation or currency conversion are given. √
20. Details of any model used are given. √ 21. The choice of model used and the key
parameters on which it is based are justified.
√ Decision analytic & Markov
Analysis and interpretation of results 22. Time horizon of costs and benefits is
stated. √
23. The discount rate(s) is stated. √ 24. The choice of discount rate(s) is justified. √
210
Item Yes No Not clear
Not appropriate
25. An explanation is given if costs and benefits are not discounted.
√
26. Details of statistical tests and confidence intervals are given for stochastic data.
√
27. The approach to sensitivity analysis is given.
√
28. The choice of variables for sensitivity analysis is justified.
√
29. The ranges over which the variables are varied are justified.
√
30. Relevant alternatives are compared. √
31. Incremental analysis is reported. √ 32. Major outcomes are presented in a
disaggregated as well as aggregated form. √
33. The answer to the study question is given. √ 34. Conclusions follow from the data reported. √ 35. Conclusions are accompanied by the
appropriate caveats. √
Kemler 2002150 cost-effectiveness study Study design 1. The research question is stated. √ 2. The economic importance of the research
question is stated. √
3. The viewpoint(s) of the analysis are clearly stated and justified.
√ societal
4. The rationale for choosing alternative programmes or interventions compared is stated.
√
5. The alternatives being compared are clearly described.
√
6. The form of economic evaluation used is stated.
√
7. The choice of form of economic evaluation is justified in relation to the questions addressed.
√
Data collection 8. The source(s) of effectiveness estimates
used are stated. √ Kemler RCT
9. Details of the design and results of effectiveness study are given (if based on a single study).
√
10. Details of the methods of synthesis or meta-analysis of estimates are given (if based on a synthesis of a number of effectiveness studies).
√
11. The primary outcome measure(s) for the economic evaluation are clearly stated.
√ Cost/QALYs
12. Methods to value benefits are stated. √ EQ5D 13. Details of the subjects from whom
valuations were obtained were given. √
14. Productivity changes (if included) are reported separately.
√
15. The relevance of productivity changes to the study question is discussed.
√
211
Item Yes No Not clear
Not appropriate
16. Quantities of resource use are reported separately from their unit costs.
√
17. Methods for the estimation of quantities and unit costs are described.
√
18. Currency and price data are recorded. √ 19. Details of currency of price adjustments for
inflation or currency conversion are given. √
20. Details of any model used are given. √ 21. The choice of model used and the key
parameters on which it is based are justified.
√ Decision analytic
Analysis and interpretation of results 22. Time horizon of costs and benefits is
stated. √
23. The discount rate(s) is stated. √ 24. The choice of discount rate(s) is justified. √ 25. An explanation is given if costs and
benefits are not discounted. √
26. Details of statistical tests and confidence intervals are given for stochastic data.
√
27. The approach to sensitivity analysis is given.
√
28. The choice of variables for sensitivity analysis is justified.
√
29. The ranges over which the variables are varied are justified.
√
30. Relevant alternatives are compared. √
31. Incremental analysis is reported. √ 32. Major outcomes are presented in a
disaggregated as well as aggregated form. √
33. The answer to the study question is given. √ 34. Conclusions follow from the data reported. √ 35. Conclusions are accompanied by the
appropriate caveats. √
Simpson 20093 Study design 1. The research question is stated. √ 2. The economic importance of the research
question is stated. √
3. The viewpoint(s) of the analysis are clearly stated and justified.
√ UK NHS perspective
4. The rationale for choosing alternative programmes or interventions compared is stated.
√
5. The alternatives being compared are clearly described.
√
6. The form of economic evaluation used is stated.
√
7. The choice of form of economic evaluation is justified in relation to the questions addressed.
√
Data collection 8. The source(s) of effectiveness estimates
used are stated. √
212
Item Yes No Not clear
Not appropriate
9. Details of the design and results of effectiveness study are given (if based on a single study).
√
10. Details of the methods of synthesis or meta-analysis of estimates are given (if based on a synthesis of a number of effectiveness studies).
√
11. The primary outcome measure(s) for the economic evaluation are clearly stated.
√ Cost/QALYs
12. Methods to value benefits are stated. √ 13. Details of the subjects from whom
valuations were obtained were given. √
14. Productivity changes (if included) are reported separately.
√
15. The relevance of productivity changes to the study question is discussed.
√
16. Quantities of resource use are reported separately from their unit costs.
√
17. Methods for the estimation of quantities and unit costs are described.
√
18. Currency and price data are recorded. √ 19. Details of currency of price adjustments
for inflation or currency conversion are given.
√
20. Details of any model used are given. √ 21. The choice of model used and the key
parameters on which it is based are justified.
√ Markov
Analysis and interpretation of results 22. Time horizon of costs and benefits is
stated. √
23. The discount rate(s) is stated. √ 24. The choice of discount rate(s) is justified. √ 25. An explanation is given if costs and
benefits are not discounted. √
26. Details of statistical tests and confidence intervals are given for stochastic data.
√
27. The approach to sensitivity analysis is given.
√
28. The choice of variables for sensitivity analysis is justified.
√
29. The ranges over which the variables are varied are justified.
√
30. Relevant alternatives are compared. √
31. Incremental analysis is reported. √ 32. Major outcomes are presented in a
disaggregated as well as aggregated form.
√
33. The answer to the study question is given. √ 34. Conclusions follow from the data reported. √ 35. Conclusions are accompanied by the
appropriate caveats. √
Notes 8: Kemler RCT for CRPS; PROCESS trial for FBSS 12/13: EQ-5D measures for CRPS taken from cross-sectional survey of general neuropathic pain; EQ-5D measures from PROCESS trial for FBSS
213
22: 15 years 27: univariate sensitivity analyses for device longevity and device cost; also probabilistic sensitivity analyses, results of which are presented as cost-effectiveness acceptability curves
214
Appendix 6 Headache Table 30 Characteristics of included systematic reviews: headache Publication Population Intervention Comparator Outcomes Blue Cross of Idaho Report 201020
Adults with chronic pain. PENS or percutaneous neuromodulation therapy (a variant of PENS).
Not specified (but RCTs only specified so no studies without a comparator).
Not specified.
O’Connell 201022
Adults with chronic pain. NB headache excluded but one RCT with mixed population included with headache patients.
Repetitive transcranial magnetic stimulation (rTMS), cranial electrotherapy stimulation (CES) and transcranial direct current stimulation (tDCS).
Not specified. Included sham interventions for many studies.
Change in self-reported pain using validated measures of pain intensity such as visual analogue scales (VAS), verbal rating scales (VRS) or numerical rating scales (NRS).
Walsh 200955 Adults with acute pain. TENS. Sham TENS, no treatment control, pharmacological control, or non-pharmacological intervention.
Primary: subjective scales for pain intensity and/or pain relief. Secondary: other measures of pain, AEs, compliance, magnitude and duration of effect also noted.
Jasper 2008176 Adult patients with chronic headache.
Implanted occipital nerve stimulators.
Not specified; no comparative studies.
Primary: pain relief; secondary: other functional measures.
Brønfort 2004175 Patients of any age suffering from chronic/recurrent headache.
Any non-invasive physical treatment, including TENS and electromagnetic therapy.
Placebo, no treatment, or any type of active intervention.
At least one patient-rated outcome. Also considered data on costs and adverse events.
215
Table 31 Quality of included systematic reviews: headache
Review Was the review up-to-date?
Was a clear review question defined?
Were inclusion/exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was the search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion/exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
Blue Cross of Idaho Report 201020
This 1996 report was updated with a literature search in 2004 and 2010, but it is unclear which search results feed into the results.
This is a policy guideline to assess PENS for the treatment of chronic pain.
Yes, studies were included if they: contained original empirical data, the design included a treatment and a control group, they reported on a health outcome relevant to the pain condition treated and they used random assignment, control group design.
RCTs are likely to give the least biased evidence.
Few details on search strategy, so unclear.
No details. No details. No formal methods, but validity discussed in the text.
O’Connell 201022
Yes. Searches were conducted up to end 2009/ beginning 2010.
Yes. The objective was to assess the effectiveness of non-invasive brain stimulation techniques for relief of chronic pain.
Yes. Criteria were defined for population (any chronic pain with a duration > 3months), intervention (CES, rTMS or tDCS), type of study (parallel or crossover RCTs or quasi-randomised studies) and outcomes (self-reported pain using validated outcome measures).
Only RCTs are included and these are most likely to give unbiased evidence.
The search strategy was comprehensive and it is unlikely that many studies were missed.
Yes, the selection of studies was described (two independent reviewers, assessment of full paper where abstract unclear and resolution of disagreements through a third reviewer).
Yes, data was extracted independently by two reviewers using a standardised and piloted data extraction form; discrepancies were resolved by consensus.
Yes, risk of bias was assessed independently by two reviewers using the Cochrane risk of bias assessment tool; additional assessment criteria were used for crossover trials and for assessment of sham credibility.
216
Review Was the review up-to-date?
Was a clear review question defined?
Were inclusion/exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was the search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion/exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
Jasper176 2008
Relatively up-to-date: searches up to October 2007
Yes. The authors reviewed the efficacy of implanted occipital nerve neurostimulators in the treatment of intractable headache.
Inclusion criteria were: 1) study type: randomised controlled trials and observational studies; 2) population: adult patients with frequent and intense headaches of >6 months duration who had not adequately responded to conventional headache therapies such as injections and/or ablative techniques, medication, and psychological intervention; 3) intervention: implanted peripheral nerve stimulation applied as primary treatment modality for headache; 4) comparators: not specified; 5) outcomes: primary outcome was measurement of pain relief; secondary outcomes included headache frequency, intensity, duration, medication use, Morphine Dose Equivalents, number of
No systematic reviews, RCTs, or cohort studies were identified. The review was based on ten case-series, only four of which were prospective, and a number of technical reports, case reports and narrative reviews. Given the lack of controlled trials, selection bias cannot be eliminated and no firm conclusions can be drawn from the data. In addition, only a small number of patients were followed prospectively – 8 with cluster headache, 16 with C2-mediated headache, 10 with occipital neuralgia and 35 with transformed migraine.
Possibly. Medline and Embase were searched, supplemented by reference list searches of the identified papers and reviews on the topic. However, only English-language articles were included, so the possibility of publication bias cannot be discounted.
Yes. Papers were triaged for inclusion by either of the two authors if the methods section stated that peripheral nerve stimulation was applied as the primary treatment modality for headache.
Not stated. Yes. Included articles were scored by both authors independently using published criteria based on the recommenda-tions of the Agency for Healthcare Research and Quality. Scoring discrepancies were reconciled with a third party not involved in the assessment.
217
Review Was the review up-to-date?
Was a clear review question defined?
Were inclusion/exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was the search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion/exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
doctor or ER visits, ratio of trial to permanent implantation, complications, the Neck Pain Disability Questionnaire, the Migraine Disability Assessment scores, return to work, and Quality of Life; 6) publication language: English. Exclusion criteria were: 1) narrative reports lacking study data, case reports, and technical reports with follow-up of less than three months.
Brønfort 2004175
Not really – last assessed as up to date on 14 November 2002. First published 2004. Converted to new review format and republished
Yes. To quantify and compare the magnitude of short- and long-term effects of specific non-invasive physical treatments for chronic/recurrent headaches.
Inclusion criteria were: 1) study type: randomised controlled trials and quasi-randomised studies; 2) population: patients of any age with chronic/recurrent headaches of any type; 3) intervention: non-invasive physical treatments of any kind, excluding acupuncture
RCTs included, which are likely to give the least biased evidence.
No. Extensive reviews of allopathic and complementary medicine databases, supplemented by hand-searching of non-indexed sources.
Yes. Inclusion was decided by two reviewers independently. Disagreements were resolved by discussion, and consultation with a third reviewer if necessary. Blinded inclusion and exclusion decisions were
Yes. Two non-blinded reviewers independently extracted and recorded relevant data from each article using standardised forms. All original data on outcomes
Yes. Structured appraisals were conducted using the short methodological quality checklist developed by Jadad et al, and a further 20-item list modified from a previously published
218
Review Was the review up-to-date?
Was a clear review question defined?
Were inclusion/exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was the search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion/exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
2009, but no new searches conducted and no change to conclusions.
(which was dealt with in a separate Cochrane Review); 4) comparators: placebo, no-treatment, or any other type of active intervention; 5) outcomes: at least one patient-rated outcome measure such as pain intensity, headache index, frequency, duration, improvement, analgesic use, activities of daily living, quality of life, functional health status, or patient satisfaction; 6) publication language: no restrictions. Exclusion criteria were: studies not fulfilling the above inclusion criteria.
not possible due to reviewer knowledge of the relevant RCTs.
were standardised into percentage points and effect size scores whenever possible. Efforts were made to contact authors if important information was unclear from the published reports.
instrument, and detailed in the review. Two reviewers independently scored methodological quality for each paper and differences were resolved by discussion, and consultation with a third reviewer if necessary.
NB No quality assessment of Walsh 2009 undertaken, as no relevant data in results
219
Table 32 Characteristics of included RCTs: headache Publication Population Intervention Comparator Outcomes Fontaine 2010178
Adults with daily refractory chronic cluster headache over 3 years’ duration
Deep brain stimulation; Sham stimulation (cross-over design)
Primary: number of attacks during the last week of each 1-month trial period; Secondary: subcutaneous sumatriptan in last week, oxygen use, attack intensity, patient satisfaction, anxiety and depression levels, and quality of life.
Saper 2010179 Adults with chronic migraine Implanted ONS device with adjustable stimulation – patients instructed to keep device in ‘on’ position as much as possible.
Two control groups: pre-set (ineffective) stimulation group and medical management group; Ancillary group (failed occipital nerve block test) not-randomised, but implanted and allowed to adjust stimulation.
Range of outcomes measured included reduction in headache days/month, decrease in overall pain intensity, and responder rate. Assessed one month and three months post-implantation.
Lipton 2010159 Adults, migraine with aura (ICHD-II classification 1.2.1)
Self-administered single-pulse transcranial magnetic stimulation (sTMS) delivered within one hour of onset of aura symptoms.
Sham sTMS. Primary: proportion of pain-free patients at 2 h post-treatment for first treated attack; proportion with photophobia, phonophobia or nausea 2 h post-treatment for first treated attack. Secondary: Proportion with mild or no pain at 2 hours post-treatment, and sustained pain-free response at 24 and 48 hours post-treatment; proportion needing rescue medication, consistency of response over three attacks, proportion with vomiting, and patient global assessment of pain relief.
Gabis 2009106
Adults with chronic pain, either cervical pain or lower back pain, or headaches (migraine, tension or other).
Eight 30-minute treatments with transcranial electrostimulation on 8 consecutive days
‘Active placebo’. Pain VAS, frequency of sleep disturbance, frequency of pain and frequency of pain medication use.
220
Publication Population Intervention Comparator Outcomes Lipton 2009180 (abstract)
Participants with ICHD-II migraine with or without aura, or chronic migraine, refractory to medical treatment, ≥6 days/month long duration migraine with moderate/severe pain
Implanted ONS device.
Sham stimulation. Change from baseline in migraine days/month evaluated 12 weeks after implantation.
Chen 2007181 Adult patients with cervicogenic headache.
Manipulation (physical therapy) every other day for 40 days.
TENS every other day for 40 days.
Headache degree (numeric rating scale), frequency, duration, and range of motion of cervical spine, assessed two weeks before and four weeks after treatment.
Pelka 2001182 Adult patients suffering from headache/migraine.
Extreme low-frequency PEMF device worn around neck for four weeks
Sham device. Intensity, frequency, and duration of attacks; difficulty concentrating; concomitant sleeplessness, photosensitivity, spasm, and difficult menstruation. Measured at baseline, two weeks into treatment regimen, and at end of four weeks.
Ahmed 2000177
Adults with tension headache, migraine or post-traumatic headache syndrome.
PENS (needles with electricity) for 30 minutes, three times a week for 2 weeks.
Sham device-needles alone. VAS pain score, physical activity and quality of sleep.
Sherman 1999193
Adult patients with multiyear history of migraine.
PEMF delivered to thigh for 1 hour daily, five times per week, for two weeks.
Sham device. Frequency, duration, and intensity of attack; use of medication.
Sherman 199823
Adult patients with multiyear history of migraine.
PEMF delivered to thigh for 1 hour daily, five times per week, for two weeks.
Sham device. Number of attacks per week.
221
Publication Population Intervention Comparator Outcomes Reich 1989189 Adult patients with ICD
diagnosis of vascular/migraine headache or muscle-contraction/tension headache.
TENS and/or electrical neurotransmitter modulation; treatment protocols not reported.
Three other active groups: biofeedback, relaxation, or a combination of any two of the four treatments.
Weekly headache hours, pain intensity, use of prescription and over-the-counter pain medication. Measured by 4-week headache diary at five time points: prior to intake, directly following discharge, at eight months, 24 months, and 36 months post-discharge.
222
Table 33 Quality of included RCTs: headache Criterion Reviewer assessment Fontaine 2010178 Was allocation concealed? How was allocation concealed?
Likely, as central randomisation.
Was study randomised? What randomisation technique was used?
Yes. Block scheme randomisation and central randomisation procedure without stratification. Randomised 1:1 into on-off vs off-on stimulation.
Were patients unaware of allocation (blinded)?
Yes. Hypothalamic stimulation does not induce perceptible sensations. Patients unable to identify allocation at end of study.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
Method of switching between active and sham treatment, and the one-week washout period, not stated.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
Clinical evaluation performed by neurologist blinded to stimulation status. Neurologists unable to identify allocation at end of study.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Crossover trial. Stimulation periods of one month each with one week washout period. Carry-over effect tested for and shown not to be present (p=.855).
Were the study groups comparable (in terms of patient characteristics)?
Yes.
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Yes
Was follow-up adequate? (to be able to observe relevant outcomes)
10 month open phase sufficient for long-term evaluation of side effects. One month treatment phase may have been too short to observe full therapeutic effects of treatment – evidence in literature mixed on this.
Were there any withdrawals and/or discontinuations?
12 patients included, one declined to participate. Eleven operated. One explanted due to infection, but re-implanted later prior to randomisation.
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
All eleven operated completed study. All analyses conducted on ITT basis.
Was a justification of the sample size provided?
Yes – no literature so estimated baseline weekly attack frequency based on patient database of institution, namely 23.9 (SD 3.7). Based on this estimate, study had 90% power to detect 50% drop in attack frequency. However, variability in weekly attack number higher in included patients than in database (SD 13.2), and study may therefore have been underpowered.
Comparability to UK setting and population?
Yes
223
Criterion Reviewer assessment Lipton 2010159 Was allocation concealed? How was allocation concealed?
Likely. Randomisation and allocation undertaken by statistician, who had no involvement with remainder of study.
Was study randomised? What randomisation technique was used?
Yes. Randomisation procedure developed by independent statistician with no involvement in remainder of study. 1:1 allocation to actual/sham devices.
Were patients unaware of allocation (blinded)?
Yes. Machines identical. Patients guessed allocation prior to and post-stimulation with device. No difference between groups.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
Yes. Identical machines operated in same manner.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
Patients entered data into electronic diaries.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Parallel group.
Were the study groups comparable (in terms of patient characteristics)?
Yes, although some differences in nature of aura experienced with typical migraine, with more visual-only symptoms in sham group and more visual-plus-other symptoms in sTMS group.
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Yes.
Was follow-up adequate? (to be able to observe relevant outcomes)
Yes. Three months.
Were there any withdrawals and/or discontinuations?
201/267 enrolled completed phase 1 (29 diary compliance, 37no migraine attack); 164/201 randomised treated at least one aura episode. 3/82 sham group discontinued (1 due to lack of efficacy) and 7/82 active group. No discontinuations due to adverse events.
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
Safety analysis conducted on ITT basis (n=201); Modified ITT (all patients treating at least one episode of aura, n=164) used to test pain outcome hypothesis. Per protocol group used to test non-inferiority of symptoms as more conservative (n=141).
Was a justification of the sample size provided?
Yes. Based on literature, expected positive response in primary outcome of 20% in sham group and 45% in active group. 80 subjects per group needed to detect an effect of this side with 90% power. 200 patients recruited to allow for a 20% drop-out rate.
Comparability to UK setting and population?
Yes.
224
Criterion Reviewer assessment Saper 2010179 (ONSTIM trial) Was allocation concealed? How was allocation concealed?
Yes. Active vs sham stimulation assigned in sealed envelopes and sent to sites. Opened by implanter at activation visit.
Was study randomised? What randomisation technique was used?
Yes. Central randomisation facility provided by device manufacturer allocated implant/medical management.
Were patients unaware of allocation (blinded)?
No – subjects in medical management group aware they did not have surgery. Implanted groups aware of adjustable vs. pre-set stimulation, but not informed of significance of this (pre-set at ineffective levels, i.e. sham surgery group), so effectively blinded.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
Implanters not blinded and responsible for implantation, device-related follow-up, programming and activation of devices. Neurologists assigned with patient care, diagnosis, medical management, and follow-up visits blinded to allocation.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
Patients recorded data in electronic diaries and paper questionnaires (e.g. QoL).
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Parallel group.
Were the study groups comparable (in terms of patient characteristics)?
Yes.
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Mostly. Following a number of cases of lead migration and corrective surgery, use of strain-relief loop and abdominal implant location recommended for later implants.
Was follow-up adequate? (to be able to observe relevant outcomes)
Yes. 3 months blinded for safety and efficacy. Long-term open-label follow-up to 36 months incomplete at time of publication.
Were there any withdrawals and/or discontinuations?
35/110 patients enrolled withdrew before randomisation (didn’t meet criteria after min 9 week lead-in period, withdrew consent, physician-determined withdrawal – no reason given) 8/75 randomised discontinued before end of blinded phase, all in device implantation arms (four withdrew consent pre-surgery, two intraoperative failures, one lost to follow-up pre-surgery, one discontinued due to lack of efficacy). 1/67 completing 3-month blinded phase did not complete electronic daily questionnaire (active group). 66 completed blinded phase plus questionnaire.
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
Per protocol analysis performed. Missing data not accounted for. No ITT analysis performed.
225
Criterion Reviewer assessment Was a justification of the sample size provided?
Exploratory study, not powered for a single primary endpoint.
Comparability to UK setting and population?
Yes.
Gabis 2009106 Was allocation concealed? How was allocation concealed?
Yes. Computer generated randomisation list, to which the investigator did not have access until study completion.
Was study randomised? What randomisation technique was used?
Yes. Computer generated randomisation list.
Were patients unaware of allocation (blinded)?
Likely. Placebo device described as indistinguishable from active device, and was designed to give the patients the feeling of being treated.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
Unclear. Placebo device described as indistinguishable from active device, but settings likely to be different during administration.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
Yes. Evaluating doctor did not administer treatment sessions and research staff were unaware of treatment allocation.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Parallel.
Were the study groups comparable (in terms of patient characteristics)?
Yes, for baseline parameters and demographics.
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Yes (same number of treatments and assessments).
Was follow-up adequate? (to be able to observe relevant outcomes)
Follow-up at 3 weeks and 3 months. The authors state that a longer follow-up period would be necessary to establish the consolidation of the effect (6-12 months).
Were there any withdrawals and/or discontinuations?
No details.
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
No details.
Was a justification of the sample size provided?
No. The headache patients represented a sub-group of the total patients group (44/119), which is fairly small.
Comparability to UK setting and population?
Likely to be similar.
Lipton 2009180 PRISM study – abstract only Was allocation concealed? How was allocation concealed?
No details.
Was study randomised? What randomisation technique was used?
Yes. 1:1 active vs sham stimulation. Randomisation method not stated.
Were patients unaware of allocation (blinded)?
Reported to be double-blind but no further details.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
Reported to be double-blind but no further details.
226
Criterion Reviewer assessment Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
Not known.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Parallel group.
Were the study groups comparable (in terms of patient characteristics)?
Not known.
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Apparently.
Was follow-up adequate? (to be able to observe relevant outcomes)
Yes. 12 weeks randomised phase. Minimum 52-week open-phase follow-up electronic diary maintenance.
Were there any withdrawals and/or discontinuations?
132/140 eligible subjects implanted. 125/132 completed 12-week follow-up. Reason/allocation not stated in abstract.
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
Not known.
Was a justification of the sample size provided?
Not in abstract.
Comparability to UK setting and population?
Yes.
Chen 2007181 Was allocation concealed? How was allocation concealed?
No details.
Was study randomised? What randomisation technique was used?
Inadequate method of randomisation: allocation was ‘random’ according to the time/date they appeared in the clinic
Were patients unaware of allocation (blinded)?
Not possible to blind patients.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
Not possible to blind individuals administering the treatment.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
No details.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Parallel.
Were the study groups comparable (in terms of patient characteristics)?
The authors stated that there were no statistically significant differences between the comparison groups at baseline, in terms of age, gender, length of the condition, CEH symptoms and ROM (p>0.05)
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Patient care: NR Number of assessments: yes
Was follow-up adequate? (to be able to observe relevant outcomes)
Follow-up duration was 4 weeks after the treatment.
227
Criterion Reviewer assessment Were there any withdrawals and/or discontinuations?
Discontinuation (number of patients) due to headache released: Manipulation (N=10) After three times of treatment: n=3 After six times of treatment: n = 2 After eight times of treatment: n=3 After nine times of treatment: n=1 After 12 times of treatment: n=1 TENS (N=5) After five times of treatment: n=2 After six times of treatment: n=1 After seven times of treatment: n=1 After eight times of treatment: n=1
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
Seems that the analysis was based on ITT
Was a justification of the sample size provided?
No
Comparability to UK setting and population?
Unclear
Ahmed 2000177 Was allocation concealed? How was allocation concealed?
No details.
Was study randomised? What randomisation technique was used?
Sequence in which patients received active or sham treatment described as random but no further details.
Were patients unaware of allocation (blinded)?
Patients were not blinded; sham PENS described as ‘acupuncture-like’ therapy.
Were idividuals administering the treatment/involved in patient care unaware of allocation (blinded)?
Study described as single-blind; as patients were not blinded it could be assumed that care-givers were, however, the amplitude was set differently for active/sham treatment and it is unclear who was responsible for this.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
No details. Patient reported outcomes.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Crossover. No test for carry over effect performed. There was a one-week wash-out period, but the authors suggest there may have been a ‘carry-over effect’ in the active group.
Were the study groups comparable (in terms of patient characteristics)?
Crossover trial, so patients act as their own controls. No details on whether groups comparable in first part of crossover (and this data not analysed due to small sample size).
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Yes, appears that all patients treated the same.
Was follow-up adequate? (to be able to observe relevant outcomes)
Outcomes measured 48 hours post treatment, which does not provide information on long term effects.
Were there any withdrawals and/or discontinuations?
No details.
228
Criterion Reviewer assessment How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
No details.
Was a justification of the sample size provided?
Power calculation performed and n=18 deemed to be an adequate sample size, which appears small.
Comparability to UK setting and population?
US setting; unclear how similar this is. Patients likely to be similar.
Pelka 2001182 Was allocation concealed? How was allocation concealed?
No details.
Was study randomised? What randomisation technique was used?
Yes. Method not stated. Inclusion criteria included “when good compliance could be expected”. The meaning of this term is unclear and may have introduced sample bias.
Were patients unaware of allocation (blinded)?
Yes. Identical dev ices used.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
Reported as double-blind but no further details.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
Not stated.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Parallel group.
Were the study groups comparable (in terms of patient characteristics)?
No. Patients with seven different headache diagnoses participated in the study, and were not distributed evenly in the actual and sham treatment groups.
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Yes.
Was follow-up adequate? (to be able to observe relevant outcomes)
Unclear. Patients wore device for four weeks. Final assessment taken at end of four-week period. No further follow-up. In pilot studies, effect often seen in 1 to 3 weeks. Authors report in discussion that main differences between actual and sham groups became apparent during weeks 3 and 4 – it is possible that further follow-up would have affected outcome.
Were there any withdrawals and/or discontinuations?
3 active and 2 placebo patients dropped out for reasons not related to treatment. No information on headache diagnosis of dropouts given.
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
PP analysis only. Patients who dropped out were excluded. No ITT analysis.
Was a justification of the sample size provided?
No
Comparability to UK setting and population?
Unclear – patient recruitment, detailed inclusion/exclusion criteria, and detailed demographics are not reported.
229
Criterion Reviewer assessment Sherman 1999193 Was allocation concealed? How was allocation concealed?
Likely. Machine randomisation and maintenance by senior author who was not involved in treating patients.
Was study randomised? What randomisation technique was used?
Yes. Computer-generated algorithm randomised in 20-patient blocks.
Were patients unaware of allocation (blinded)?
Yes. Yes. Identical machines administering sham stimulation.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
Yes.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
Patient-reported outcomes in headache logs. Mostly numeric data but some description. Unclear if individuals scoring outcomes were blinded to allocation.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Parallel group
Were the study groups comparable (in terms of patient characteristics)?
Yes.
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Treatment comparable. Headache log used changed form during study – final version used with most of patients collected additional data about symptoms, including vomiting, description of pain, and presence/absence of aura.
Was follow-up adequate? (to be able to observe relevant outcomes)
Yes. Minimum of one month following exposure.
Were there any withdrawals and/or discontinuations?
One subject dropped out before completing exposure to PEMF – treatment arm not stated. Excluded from analysis. No ITT. Two actual and one sham group patients dropped out after exposure phase but prior to one-month follow-up diaries.
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
The one subject who dropped out during the intervention period was replaced by a new enrolee. No ITT analysis. Three subjects dropped out before follow-up complete – unclear how missing data dealt with, but appear to have simply been omitted and PP analyses performed.
Was a justification of the sample size provided?
No.
Comparability to UK setting and population?
Patients recruited from large military medical centre in US. However demographics appear similar to UK population for this condition.
Sherman 199823 Was allocation concealed? How was allocation concealed?
Likely. Machine randomisation and maintenance by senior author who was not involved in treating patients.
Was study randomised? What randomisation technique was used?
Yes, but inadequate method of randomisation. Patients picked sealed envelopes from basket containing letter ‘A’ or ‘B’ corresponding to the real or
230
Criterion Reviewer assessment sham machine. First treatment period as allocated before crossover.
Were patients unaware of allocation (blinded)?
Yes. Patients cannot sense EMF so unable to identify whether field delivered or not. However, after two weeks of treatment, most patients were aware which group they had been assigned to, and those in the active group refused to cross over to the other machine.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
Therapists working with subjects blinded to active/sham machine.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
Patients provided written logs of outcome variables. Post-study follow-up obtained by mail and telephone. Not stated whether personnel conducting telephone study or analysis were blinded to allocation.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Cross-over design. However, patients in the active group refused to cross over. Had patients crossed-over, a carry-over effect seems likely as treatment effects appear longer lasting than the authors had expected. However, pre/post analysis conducted instead of cross-over analysis.
Were the study groups comparable (in terms of patient characteristics)?
Yes
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Mostly. Some patients had an extended baseline period (6 weeks instead of 3); other disparities as listed above (refusal to cross over; half-power active treatment).
Was follow-up adequate? (to be able to observe relevant outcomes)
Yes. Two to six months, mean 2.94 months.
Were there any withdrawals and/or discontinuations?
No. However, three patients did not receive active stimulation as per protocol due to a combination of machine failure and human error.
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
Lack of crossover data due to refusal to cross over in 5/6 active patients was dealt with by conducting pre-treatment and post-treatment analysis on all patients instead. Data were analysed according to treatment received. ITT analysis was not conducted, but the main problem was due to the technical issue with the machine, rather than patient characteristics.
Was a justification of the sample size provided?
No.
Comparability to UK setting and population?
Patients recruited from large military medical centre in US. However demographics appear similar to UK population for this condition.
Reich 1989189 Was allocation concealed? How was allocation concealed?
No details.
Was study randomised? What randomisation technique was used?
Yes. Method not reported.
231
Criterion Reviewer assessment Were patients unaware of allocation (blinded)?
No.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
No.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
No.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Parallel group.
Were the study groups comparable (in terms of patient characteristics)?
Unclear. No breakdown of patient characteristics by allocation.
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
No. Number of treatments varied (54% migraine patients received 15 or fewer, 46% received >15. Among tension patients, 64% received 15 or fewer, 36% received >15). No mean, variance, or range provided. Nature of treatment varied: some patients received TENS, some received electrical neurotransmitter modulation, and some received both. No indication given as to how many fell into each category, and results are pooled. Treatment in some of other intervention arms even more variable. Patients received treatment from one of five therapists throughout their participation, but the five therapists did not have the same qualifications.
Was follow-up adequate? (to be able to observe relevant outcomes)
Yes. Up to 36 months from end of trial.
Were there any withdrawals and/or discontinuations?
Yes. 1015 patients were screened. Some of these were unsuitable for inclusion, but an unknown number were excluded for not having completed less than three of the five assessment periods (i.e. 36 month follow-up) and only 703 were followed up for 36 months. Two patients were discharged on diagnosis of brain tumours and one died of a heart attack.
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
Patients who did not complete three or more assessments were excluded from analyses. Missing data were ignored and samples reduced accordingly for all calculations. No ITT analysis was performed. Unclear how attrition rate was distributed across treatment arms.
Was a justification of the sample size provided?
No.
Comparability to UK setting and population?
Yes.
232
Appendix 7 Neuropathic pain in MS Table 34 Characteristics of included systematic reviews: neuropathic pain in MS Review Population Intervention Comparator Outcomes Cruccu 20079 Patients with any type of
neuropathic pain. Different types of neurostimulation (TENS, PNS, NRS, SCS, DBS, MCS, rTMS).
Not specified. Various depending on whether controlled/comparative or uncontrolled studies identified as evidence.
Not specified. Various depending on evidence identified.
233
Table 35 Quality of included systematic reviews: neuropathic pain in MS
Review Was the review up-to-date?
Was a clear review question defined?
Were inclusion/exclusion criteria clearly stated?
What are the implications for review validity given study types included?
Was the search strategy adopted likely to have missed many studies?
Were methods used to decide on study inclusion/exclusion stated?
Was the data extraction process adequate?
Was the validity of included studies assessed?
Cruccu 20079
Literature was searched up to May 2006.
The aim was to develop evidence based recommendations on when a patient with (any type of) neuropathic pain should try a neurostimulation procedure.
Partly. Study design was specified as all study designs except very small case-series (<8). There were no specific criteria for population, intervention, comparator or outcome. It appears that any type of patients with neuropathic pain and any neurostimulation procedure were eligible.
All levels of evidence were included (systematic reviews, RCTs, non-randomised controlled trials, observational studies case-series) and the validity of any conclusions drawn will vary depending on what was identified for different types of neurostimulation.
MEDLINE, EMBASE and the Cochrane library were searched for systematic reviews, and text books were scanned for relevant references. Additionally primary studies were sought after the cut-off dates for previous systematic reviews. It is possible that older studies not included in the systematic reviews may have been missed, but it is less likely that more recent studies would have been missed.
References were checked independently by two reviewers.
There are no details.
The evidence was graded according to study design, but it is unclear if further assessments were undertaken.
234
Table 36 Characteristics of included RCTs: neuropathic pain in MS Trial Population Intervention Comparator Outcomes Mori 201021
Patients with relapsing remitting MS in remitting phase with chronic, drug-resistant, central neuropathic pain.
Five day treatment with tDCS.
Sham tDCS. Pain VAS, Short Form McGill Pain Questionnaire (SF-MPQ), Multiple Sclerosis Quality of Life-45 (MSQOL-54), Beck Depression Inventory (BDI), anxiety VAS.
235
Table 37 Quality of included RCTs: neuropathic pain in MS Criterion Reviewer assessment Mori 201021 Was allocation concealed? How was allocation concealed?
No details.
Was study randomised? What randomisation technique was used?
Study described as randomised, but no further details.
Were patients unaware of allocation (blinded)?
Yes, as far as possible: for sham stimulation, electrodes were placed in the same position as for active stimulation, but the stimulator was turned off after 30 seconds. The patients will have therefore received the initial itching sensation. Complete blinding with 2mA (used in this study) however has been shown to be more difficult to achieve than with 1mA, and it is possible that not all patients were unaware of group assignment.
Were individuals administering the treatment/involved in patient care unaware of allocation (blinded)?
The treating physician who had to set the tDCS or sham-stimulation protocol on the stimulator was unaware of the stimulation condition.
Were the individuals undertaking the outcomes assessment unaware of allocation (blinded)?
Patient reported outcome measures. Assessing physician was blinded to group allocation.
Was the design parallel-group or crossover? Indicate for crossover trial whether a carry-over effect is likely.
Parallel.
Were the study groups comparable (in terms of patient characteristics)?
The authors state that there were no significant differences between groups at baseline in age, disease duration, pain duration and individual scores of all clinical assessments.
Was treatment of patients throughout trial comparable? (e.g. patient care, number of assessments)
Yes in terms of treatment/sham treatment periods and number of assessments.
Was follow-up adequate? (to be able to observe relevant outcomes)
Yes to observe initial changes in pain and quality of life, but not for observing how long the effect lasts or whether the treatment can be used long-term.
Were there any withdrawals and/or discontinuations?
None.
How was missing data accounted for in analysis? Was an intention-to-treat analysis undertaken?
N/A
Was a justification of the sample size provided?
No. This is a small sample size (n=19), so results are associated with uncertainty.
Comparability to UK setting and population?
This was an Italian study and the population/setting and treatment protocol is likely to be similar to the UK.
236
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