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Cervical Afferents and Primary Headache:
An investigation of the potential role of cervical nociceptors in
sensitising the trigemino-cervical nucleus in primary
headache
Dean H Watson
Master Applied Science in Manipulative Therapy
Thesis submitted in fulfillment of requirement for the degree of Doctor of Philosophy
May 2016
School of Psychology and Exercise Science, Murdoch University Western Australia
ii
DECLARATION
I declare that this thesis is my own account of my research and contains as its
main content work that has not previously been submitted for a degree at any tertiary
education institution.
Dean H Watson. May 2016
iii
ABSTRACT
An underlying disorder in the migraine condition is an apparent subclinical
sensitization of the trigemino cervical nucleus (TCN) indicated, for example, by an
interictal deficient habituation of the nociceptive blink reflex (nBR). This has
ramifications for tension-type headache (TTH), as there is considerable support for a
pathogenesis of TTH which overlaps with that of migraine. The aim of this thesis was
to investigate the upper cervical (C1-3) afferents as a potential sensitising source of the
TCN in migraine and TTH, thereby addressing the hypothesis that upper cervical
afferents evoke sensitisation of the TCN in migraine and TTH.
Firstly, manual examination of the upper cervical (atlanto-occipital and C2-3)
joints was performed in 20 migraineurs, 14 TTH patients and 14 controls. The
reproduction of customary head pain in 100 and 95 per cent of TTH patients and
migraineurs, respectively, supports a role of the upper cervical spine in primary
headache, perhaps involving sensitization of the TCN.
The second study employed the nociceptive blink reflex (nBR) to assess
processing of trigeminal nociceptive information during reproduction and resolution of
customary head pain (as the examination technique was sustained) in 15 migraineurs
interictally. Reproduction and resolution of head pain was repeated over four 90 second
trials; each trial was separated by 30 seconds. Migraineurs reported significant
lessening of reproduction and increasing resolution of customary head pain over the
four trials. In parallel was a significant increase in latency and decrease in amplitude of
the nBR. The desensitizing effect of this examination technique on head pain implies
iv
that modulation of cervical afferent information may benefit migraineurs during manual
cervical reproduction of customary head pain.
Whiplash of the neck is considered a musculo skeletal event and subsequent
headache implies involvement of upper cervical (C1-3) afferents. The symptomatic
profile of chronic whiplash associated headache (CWAH) mirrors that of primary
headache, inviting speculation that CWAH shares a pathophysiology similar to that of
primary headache. This prompted us to assess trigeminal nociceptive processing in
CWAH patients in the third study. The symptomatic profile of 22 CWAH patients
confirmed previous studies demonstrating similar profiles to primary headache.
Furthermore, when compared to controls (n=25), CWAH patients had significant
photophobia and allodynia. In addition, analysis of the nBR revealed hyperexcitability
in central nociceptive pathways in CWAH patients, thus reinforcing the hypothesis that
CWAH could be driven by central sensitization from upper cervical afferents.
Together, these studies support the view that upper cervical (C1-3) nociceptive
information may contribute to sensitising the TCN in primary headache. Thus,
therapeutic strategies that aim to alleviate aberrant discharge of cervical afferents may
play a role in the management of primary headache.
v
PUBLICATIONS
Refereed articles
Watson DH, Drummond PD. Head Pain Referral During Examination of the Neck in
Migraine and Tension-Type Headache. Headache 2012;52:1226-1235
Watson DH, Drummond PD. Cervical Referral of Head Pain in Migraine: Effects on
the Nociceptive Blink Reflex. Headache 2014;54:1035-1045
Watson DH, Drummond PD. The Role of the Trigemino Cervical Complex in Chronic
Whiplash Associated Headache: A Cross-Sectional Study. In Press.
The following ‘STATEMENT OF AUTHORSHIP’ applies to the (3) abovementioned
referred articles.
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Peter D. Drummond; Dean H. Watson
(b) Acquisition of Data
Dean H. Watson
(c) Analysis and Interpretation of Data
Peter D. Drummond; Dean H. Watson
Category 2
(a) Drafting the Manuscript
Dean H. Watson; Peter D. Drummond
(b) Revising It for Intellectual Content
vi
Dean H. Watson; Peter D. Drummond
Category 3
(a) Final Approval of the Completed Manuscript
Peter D. Drummond; Dean H. Watson
Dean H. Watson Professor Peter D. Drummond
vii
ACKNOWLEDGEMENTS
Completion of this thesis would not have been possible without the patient
guidance, and academic support of my PhD supervisor and mentor Professor Peter
Drummond. Peter has challenged my interpretation of my clinical experience, whilst
remaining receptive and providing valuable input. Peter’s influence has gone beyond
the PhD experience - it has added another dimension to my professional and personal
life. Thank you.
I wish to express my appreciation for the financial assistance from Murdoch
University via Murdoch University Student Scholarship. Also Man and Francis, the
Labaratory Technicians at the School of Psychology, need to be acknowledged. Due to
the technical nature of this research, it would not have been possible without their
expert assistance and guidance.
My gratitude also extends to the participants who made my studies possible.
Also, a thank you to my (senior) PhD colleague, Shiree Treleavan-Hassard, and her
family for her guidance, stimulating discussion, and support.
I would also like to acknowledge people in my personal life. Unfortunately,
Phyllis and Roy (parents) and Beryl (mother-in-law) have passed. They deserve to see
their belief in me and my ‘headache journey’ reach such a milestone. Finally, without
the unconditional support, commitment and conviction of my childhood sweetheart and
partner, Jane Watson, this would not have been possible. I owe you big time!
viii
TABLE OF CONTENTS Abstract iii
Publications v
Acknowledgements vii
1.0 Literature Review and Introduction 1
2.0 Classification of Headache 14
2.1 Introduction 14
2.2 Models of Headache Classification 14
2.3 Summary 24
3.0 Role of the Upper Cervical (C1-3) Afferents in Primary (Migraine and Tension-
Type) Headache and Chronic Whiplash Associated Headache 33
3.1 Introduction 33
3.2 Cervical Signs and Symptoms in Primary Headache 35
3.3 Whiplash Headache and Primary Headache 38
3.4 Modulation of Cervical Afferents in Primary Headache 44
3.5 Zygapophyseal Joints and Animal Studies 47
3.6 Primary Headache: are Cervical Lesions Necessary? 51
3.7 Upper Cervical Joint Dysfunction in Primary Headache 52
3.8 Cervical Treatment of Primary Headache 53
3.9 Summary 57
4.0 Blink Reflex 90
4.1 Introduction 90
4.2 Anatomy and measurement of the blink reflex 90
4.3 Migraine and the ‘nociceptive specific’ blink reflex 93
4.3.1 Central sensitisation 96
4.3.2 Habituation 99
ix
4.4 Summary 100
5.0 Cervical Reproduction of Customary Head Pain in Primary Headache 107
5.1 Introduction 107
5.2 Study 1 113
6.0 The Effect of Cervical Reproduction of Head Pain on the Nociceptive Blink
Reflex 138
6.1 Introduction 138
6.2 Study 2 143
7.0 The Trigemino Cervical Complex and Chronic Whiplash Associated
Headache: a Cross-Sectional Study 170
7.1 Introduction 170
7.2 Study 3 176
8.0 Conclusion 212
8.1 Summary of the three studies 212
8.2 Limitations 213
8.3 Future research 215
8.4 Theoretical and clinical implications 217
List of tables Tables from Chapter 2 Table International Headache Society Diagnostic Criteria for Migraine and Episodic Tension-type Headache 15 Table from Chapter 4 Table Nociceptive blink reflex studies and migraine. 94 Tables from Chapter 5 (Study 1) Table 1 Tenderness Ratings Stratified by Headache Groups and Site 121 Table 2 The Intensity of Head Pain Referral 122
x
Table 3 Tenderness Ratings for Referral and Non-Referral Groups 123 Table from Chapter 6 (Study 2) Table F Ratios for the Main Effects and Interactions of the Dependent 150 Variables Tables from Chapter 7 (Study 3) Table 1 Clinical characteristics of whiplash subjects (n=22) 185 Table 2 Photophobia and Pressure pain thresholds in female patients and female controls 187 Table 3 Photophobia and Pressure pain thresholds in female and male controls 188 List of figures Figures from Chapter 2 Figure 1 A diagrammatic representation of the ‘severity’ perspective of the ‘continuum theory’ demonstrating the relationship between severity, associated symptoms, and area and quality of pain. 18 Figure 2 A diagrammatic representation of the vascular-suprapinal-myofascial (VSM) model according to Olesen.63 19 Figure 3 A diagrammatic representation of the ‘Tension Headache, Migraine Continuum’ according to Nelson.31 20
Figure 4 A diagrammatic representation of the ‘convergence hypothesis’ demonstrating a single, escalating process of sensitization. 21 Figure 5 A diagrammatic representation of the morphing of migraine to daily or almost daily headache over time. 23 Figures from Chapter 6 (Study 2) Figure 1 Referral ratings stratified by trials. Note that not only did referral ratings decrease, but the values at the end of each trial decreased progressively across the 4 trials when compared with the values at the start of each trial. 151 Figure 2 Tenderness ratings stratified by trials. Note that cervical tenderness ratings decreased progressively, while those
xi
for the arm remained unchanged. 152 Figure 3 Supraorbital ratings stratified by trials (trials 1 = baseline, ie, no intervention). Note that the ratings remained unchanged across the trials for both sites. 152 Figure 4 Number of nociceptive blink reflex stratified by trials. Note the decreasing number of blinks across the trials for both sites. 153 Figure 5 R2 areas under the curve (AUC) stratified by trials (trial 1 = baseline, ie, no intervention). Of note is the significant decrease of AUC during the cervical but not the arm intervention. 153 Figure 6 R2 latencies stratified by trials (trial 1 = baseline, ie, no intervention). Of note is the significant increase of latencies during the cervical but not the arm intervention. 154 Figures from Chapter 7 (Study 3) Figure 1 Pressure pain thresholds (PPT) ± S.E. at the different sites. Note that at all sites pressure pain thresholds were lower in the whiplash group. 186 Figure 2 ‘Glare’ and ‘Pain’ ratings ± S.E. Note the significantly higher ratings for ‘Pain’ in the Whiplash group but not for ‘Glare’. 189 Figure 3 Number of blinks (No. nBR) ± S.E. stratified by trials. The number of blinks was greater in the whiplash group. (ISI: inter stimulus interval) 190 Figure 4 R2 AUC ± S.E. stratified by trials. (ISI: inter stimulus interval) 190 Figure 5 R2 area under the curve (AUC) ± S.E. stratified by trials. Note the significant increase in AUC for the whiplash group in the 2 second ISI (inter stimulus interval) compared with the control group. 191 Figure 6 Recovery curve stratified by trials. Note the recovery curves were comparable for both groups. (ISI: inter stimulus interval) 191
1
CHAPTER 1
LITERATURE REVIEW AND INTRODUCTION
1.0 Literature Review and Introduction
Headache disorders are common:1,2 headache is one of the most frequent
medical complaints with over 10% of adults experiencing disabling headache at some
stage and three percent reporting more headache days than not.3 Whilst tension-type
headache (TTH) is more common than migraine,1,4 (global prevalence 20.1% and 17.7%
respectively),1 opinions differ as to which is more disabling. In a search of 107
epidemiological studies,3 TTH was considered more disabling than migraine whilst,
conversely, in the more recent Global Burden of Disease Survey 2010,5 migraine was
considered more disabling and considered globally as the seventh highest cause of
disability.1 Notwithstanding this discrepancy, these statistics do little more than
highlight that substantial numbers of people are disabled by headache and are not
receiving effective management. Obviously headache is a common, disabling problem;
what is required is a more comprehensive understanding of headache mechanisms so
that those affected by headache receive appropriate care.1
Currently, there is discord between the International Headache Society’s (IHS)
classification of headache,6 which describes TTH and migraine as separate entities, with
unknown pathophysiologies, and alternate models,7-9 which imply that TTH and
migraine are only different presentations of a common underlying mechanism. Initially,
therefore, this treatise will review the IHS classification and alternate models. (Chapter
2)
2
Whilst the principal cause of migraine and tension-type headache remains elusive,
the trigeminal system appears to be intimately involved.10,11 The sensory trigeminal
nerve nuclei are the largest of the cranial nerve nuclei, and extend through the whole of
the midbrain, pons and medulla, and into the cervical spinal cord. That part extending
into the upper cervical spinal cord - the spinal trigeminal nucleus - is subdivided into
three parts from rostral to caudal: pars oralis, pars interpolaris, and the pars caudalis
A significant body of research has demonstrated that the par caudalis extends to include
the C1 and C2 dorsal horns (DH).12-19 This group of cells could be regarded as the
trigemino cervical nucleus (TCN).20
Afferents of the trigeminal system21-23 and convergent synaptic input from
cervical (C2) spinal afferents21,23-31 project to second order neurons in the TCN. The
extensive convergence of trigeminal and C1 and C2 afferents demonstrated in the C1
and C2 DH23,31-33 as well as the pars caudalis34-36 supports the notion that the TCN
complex may play a critical role in headache.32,37-39 The afferent convergence from the
trigeminal and cervical afferent sources in the C1 and C2 DH and adjacent pars caudalis
supports the view that the DH of the upper cervical spinal cord (C1 and C2 spinal
segments) and pars caudalis form a functional continuum in processing sensory
information.23,31,32 Strong noxious trigeminal stimulation evokes central sensitisation of
nociceptive second order neurons.21-23,38 Similarly, stimulation of upper cervical
afferents induces central sensitisation of nociceptive second order neurons in the
TCN.19,23,24,26,28-31 Therefore, central sensitisation of the second order neurons in the
TCN could result either from noxious trigeminal or upper cervical afferents; the clinical
correlates comprising head pain referral, cephalic cutaneous allodynia and cervical
tenderness.40-43
3
Cervicogenic headache is defined as referred head and/or face pain from a
validated cervical lesion.6 Reproduction of headache when examining the upper
cervical spine is considered a key diagnostic criterion for a diagnosis of cervicogenic
headache.44 This phenomenon then invites speculation as to the presence of a peripheral
or cervical lesion. Occipital and suboccipital structures comprising deep paraspinal
cervical muscles, the atlanto occipital, atlanto axial (C1-2) and C2-3 zygapophyseal
joints are recognised as sources of head pain.37,45,46 Afferent nociceptive information
from these structures is also conveyed by the C1 and C2 nerve roots terminating in the
DH of the cervical spine extending from the C2 spinal segment cranially to the
medullary DH.31,47-51
However, reproduction of accustomed head pain does not necessarily involve a
peripheral or cervical lesion. Stimulating cervical afferents (reproduction of
accustomed head pain) may provide a neuromodulatory effect on the central mechanism
of primary headache, increasing the excitability of trigeminal input. The reproduction
and lessening of accustomed head pain in migraineurs when examining upper cervical
joints potentially diminishes cervical input and increases the threshold for pain in the
TCN.37 Cervical afferent involvement in primary headache therefore may not be reliant
on an aberrant source residing in the upper cervical spine.
A straightforward interaction between converging cervical and dural
afferents19,21-23,25-38 cannot explain the symptomatology of primary headache. However,
a sensitised state of the TCN is considered central in initiating primary headache.38
If the TCN is already sensitised then non noxious afferent cervical information
could represent a form of pathology; i.e., ordinary (sub clinical) cervical input augments
4
pain. Potentially, increased normal input could be a source of pain in the presence of a
sensitised TCN. Therefore, whilst cervical afferents may be involved, by definition, this
sequence of events does not constitute cervicogenic headache.
Undoubtedly, the TCN plays a pivotal role in migraine pathogenesis; i.e.,
stimulation of nociceptive second order neurons in the TCN, by trigeminal and C2
spinal afferents, instigates central sensitisation.19 This has implications for tension-type
headache, as there is significant support for a pathogenesis similar to that of migraine.52
Nevertheless, irrespective of whether migraine and TTH share a common pathogenesis,
both migraine and TTH are disorders conveyed by a final common pathway; the TCN.
Despite widespread acceptance of the role of the trigeminal system in the migraine
process,10 controversy engulfs the primary driver of central sensitisation of nociceptive
second order neurons in the TCN.53-55
Chapter 3 is a review of the literature investigating a potential sensitising role of
upper cervical (C1-3) afferents in primary headache. In this chapter the relationship
between cervical signs and symptoms and primary headache will be explored. Because
the profile of chronic whiplash associated headache (CWAH) mirrors that of primary
headache 56-64 and is, by definition, a consequence of a musculoskeletal event,65 a
review of the source of pain in CWAH follows. As contemporary literature implicates
the upper cervical joints (primarily the C2-3 zygapophyseal joint) as a source of pain in
CWAH,66,67 research investigating the role of the zygapohyseal joints will be considered
from the perspective of pathology, dysfunction and treatment will be presented.
In studies on trigeminal activity in primary headache syndromes, it is essential
that the accent be on nociceptive processing. Nociceptive specific (NS) and wide
5
dynamic range (WDR) neurons respond to noxious stimuli and are present in the
interstitial nucleus of the spinal trigeminal nucleus (STN).68 Animal and human studies
has demonstrated that nociceptive processing occurs within the STN, 68,69 and as NS and
WDR neurons are involved in conveyance of the blink reflex (BR), the BR and more
specifically the nociceptive BR (R2 nBR), provides a vehicle to assess trigeminal
nociceptive processing.70 Chapter 4 comprises a review of studies analyzing the BR and
employing the nBR in migraineurs.
The primary aim of this dissertation was to investigate the C1-3 afferents as a
sensitising source of the TCN in migraine, TTH and CWAH. Any affirmation of a
causal role of C1-3 afferents may substantiate the use of treatments that target these
afferents as an alternative form of care that supplements or replaces other forms of
treatment (e.g., medication).
6
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59. Stovner LJ, Obelieniene D. Whiplash headache is transitory worsening of a pre-
existing primary headache. Cephalalgia. Jul 2008;28 Suppl 1:28-31.
60. Vincent MB. Is a de novo whiplash-associated pain most commonly
cervicogenic headache? Cephalalgia. Jul 2008;28 Suppl 1:32-34.
61. Lenaerts ME. Post-traumatic headache: from classification challenges to
biological underpinnings. Cephalalgia. Jul 2008;28 Suppl 1:12-15.
62. Obermann M, Keidel M, Diener HC. Post-traumatic headache: is it for real?
Crossfire debates on headache: pro. Headache. Apr 2010;50(4):710-715.
63. Obermann M, Nebel K, Riegel A, et al. Incidence and predictors of chronic
headache attributed to whiplash injury. Cephalalgia. May 2010;30(5):528-534.
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65. Crowe H. A new diagnostic sign in neck injuries. Calif Med. Jan 1964;100:12-
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66. Lord SM, Barnsley L, Wallis BJ, Bogduk N. Third occipital nerve headache: a
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13
67. Bogduk N, Govind J. Cervicogenic headache: an assessment of the evidence on
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70. Ellrich J. Brain Stem Reflexes: Probing Human Trigeminal Nociception. News
Physiol Sci. Apr 2000;15:94-97.
14
CHAPTER 2
CLASSIFICATION OF HEADACHE
2.1 Introduction
The contemporary presiding authority for the classification of primary headache
disorders is the International Headache Society’s (IHS) Classification system which was
first published in 19881 with revisions in 20042 and 2013.3
Classifications of medical conditions discriminate between clinical-symptomatic
presentation and etiological approaches. The clinical-symptomatic approach considers
symptom clustering and ostensible characteristics, whilst the etiological system relies on
a recognised biological cause.4 The IHS system currently provides a classification based
not on biology but on clinical features and symptoms and the exclusion of other
disorders,5 and, whilst pathophysiological mechanisms remain unclear, views the
primary headache conditions, migraine, episodic tension-type headache (ETTH) and the
trigeminal autonomic cephalalgias, as separate entities.3,6-8 However, the IHS
classification continues to be revisited and challenged by alternative perspectives.
2.2 Models of Headache Classification
According to the IHS classification, migraine is characterized by unilateral,
throbbing head pain of moderate to severe intensity, accompanied by nausea, vomiting,
photo- and phono- phobia.3 (Table 1) (Fig. 1) In contrast, bilateral, mild to moderate
dull aching, pressure or tightening, and no more than either photo- or phono phobia
typifies ETTH.3 (Table 1)
15
Table International Headache Society Diagnostic Criteria for Migraine and Episodic Tension-type Headache Migraine Without Episodic Tension-type Aura Headache Duration: 4 to 72 hours 30 minutes to 7 days Pain (2 of 4): Area Unilateral Bilateral Intensity Moderate to severe Mild Quality Pulsating Pressure / ache / heaviness Physical activity Aggravates Unchanged Associated symptoms (1 or 2): Nausea or Absent Vomiting Absent Photophobia and Photophobia *
Phonophobia Phonophobia*
No evidence of organic disease * Either photo- or phono-phobia allowed.
Those contending that migraine and ETTH are separate disorders assert that
migraine is underpinned by neuro vascular mechanisms and ETTH arises from other
sources (e.g., emotional distress or abnormal muscle activity).9 However, whether the
primary headache conditions constitute heterogeneous entities with distinct
pathophysiological processes or different clinical expressions of a common
pathophysiology has been the subject of vigorous debate.7,8 At the centre of this
dissension is ETTH and migraine, the most common primary headache disorders,7,8 and
the most difficult to distinguish from each other.3,10-14
16
In the mid 1800s Willis proposed that migraine and TTH existed on a
‘continuum’.8,15 The fundamental ideology of the ‘continuum theory’ is that variable
presentations experienced by migraineurs are different manifestations of a common
pathophysiological foundation.5-45 Thus, the ‘continuum theory’ provides an alternative
perspective to the current medical model, which views migraine and episodic tension-
type headache (ETTH) presentations as distinct pathophysiologic entities.3,5-8
The continuum theory remained essentially unchallenged until the mid 1950s,19
when Wolff’s clinical and experimental investigations 46,47 elaborated on the potential
role of the intracranial vasculature in migraine. The consequence of this research
effectively partitioned migraine from TTH and weakened the ‘continuum theory’.7
The endorsement of migraine and ETTH as separate entities was strengthened in
the 1990s by studies demonstrating a limited effect of sumatriptan on ETTH when
compared with migraine.48,49 However, the IHS classification relies on symptom
presentation.3 Complexity then arises when there is either the concomitant presence of
more than one headache type, or one or more associated features of one specific
headache type are present in the other.5-45,50,51 For example, migraineurs experience a
range of headache including migraine without aura (IHS 1.1), migraine with aura (IHS
1.2), probable migraine (previously ‘migrainous disorder’) (IHS 1.5) and ETTH (IHS
2.1; 2.2).3,5,7 In the early studies investigating the effectiveness of sumatriptan,52,53
migraine and ETTH patients with precise diagnoses of migraine and ETTH were
included. However, some studies since then have included patients who, whilst not
meeting the IHS criteria for migraine, experienced clinically defined migraine and
ETTH episodes.5,21 In these studies, sumatriptan was found to be equally effective for
17
migraine, migrainous and ETTH episodes,5,21 which supports the hypothesis of the
existence of a common underlying pathophysiological process.5-45
Furthermore, numerous studies have demonstrated that not only do ETTH
patients and migraineurs share many symptoms, but also an absence of unique,
differentiating clinical features,5,6,48,49 supporting the concept that ETTH and migraine
are opposite extremes of a continuum.7,8 Another consistent, attendant finding was an
incremental increase in associated symptoms with increasing severity of pain.5-18,22-24,27-
34,42-45,54 Consequently, proponents of the ‘continuum theory’ based their perspective on
the ‘severity model’, i.e., pain intensity increases with accumulation of other symptoms,
rather than qualitative differences.9-11,13,15,23,30 That is, at one end of the continuum is
severe headache, which is more likely to be unilateral, throbbing in nature and
accompanied by nausea, vomiting, photo- and or phono- phobia and aggravated by
routine physical activity. At the opposite end is the ETTH presentation, i.e., mild to
moderate bilateral ache or dull pain, with perhaps some photo- or phonophobia.
Between these extremes lies a wide range of clinical presentations, including
combinations of one feature or another. (Fig. 1)
An alternative model to explain the variable and overlapping headache
presentations was based upon the convergence of vascular, supraspinal and myofascial
(e.g. temporalis muscle) factors upon the trigemino cervical nucleus (TCN); the
vascular-supraspinal-myofascial (‘VSM’) model.55 In this model, headache
presentation was hypothesized to depend on the magnitude of contribution from each of
these three sources. For example, if the vascular component was predominant, a
headache of migrainous quality results; conversely ETTH, if the major input was
myofascial. (Fig. 2) Potentially, these three factors are likely to vary between patients,
18
and within patients, over time, accounting for the overlap and variable severity of
symptoms and different types of headache. Whilst uncertainty surrounded the extent of
supraspinal influences, the ‘VSM’ model considered the supraspinal input to play a
prominent, facilitatory role.55
Figure 1. A diagrammatic representation of the ‘severity’ perspective of the ‘continuum theory’ demonstrating the relationship between severity, associated symptoms, and area and quality of pain. Note the ‘grey’ area representing the variable, inconsistent clinical presentations, including combinations of one feature or another.
Another hypothesis, the ‘Tension Headache, Migraine continuum’,28 also
considers the convergence and integration of several factors on the TCN. Like the
‘VSM’ model, these factors include vascular and somatic influences, but this model
differs in that the somatic sources of pain are postulated to reside in the upper cervical
spine (e.g. muscles, ligaments, disc of the upper cervical spine), instead of
‘supraspinally’, in the serotoninergic system.28 (Fig. 3)
19
An important distinction, therefore, is that this model incorporates the spinal C1-
3 (cervical) afferents, whilst the ‘VSM’ model is essentially confined to the trigeminal
system.
Figure 2. A diagrammatic representation of the vascular-suprapinal-myofascial (VSM) model according to Olesen.63 Note: that the myofascial contribution is considered to be trigeminally mediated e.g. temporalis muscle; also the significant but variable supraspinal influences. Those headaches without a predominance of either vascular or myofascial contributions in the ‘grey’ area are likely to be diagnosed as IHS Probable Migraine.
Accordingly, if a patient had a significant vascular component their headache
would present with migrainous characteristics, whereas if the somatic component
prevailed an ETTH results. Advocates of this theory consider that both cervicogenic
headache and ETTH are part of the somatic end of the continuum and use ‘cervicogenic
headache’ as a descriptor and not a diagnosis.28 Whilst ETTH, migraine and
cervicogenic headache are considered separate entities,3 there is evidence that cervical
factors are involved in the pathogenesis of TTH 25,56-68 and migraine.25,62,63,67,69,70
20
Figure 3. A diagrammatic representation of the ‘Tension Headache, Migraine Continuum’ according to Nelson.31 Note: the somatic contribution comprises the C1-3 spinal afferents; also the variability in serotonin levels. Those headaches without a predominance of either vascular or somatic contributions in the ‘grey’ area are likely to be diagnosed as IHS Probable Migraine.
Incorporating and building on converging influences on the TCN is the
‘convergence hypothesis’.7,8 Instrumental in the development of this hypothesis were
studies demonstrating uniform effectiveness of sumatriptan, not only in patients with
IHS criteria for migraine with and without aura, but also non-IHS migraine i.e., IHS
criteria for probable migraine (previously ‘migrainous’ headache) and ETTH.5,21 This
hypothesis, as in the ‘continuum model’, postulates that a single, escalating,
pathophysiological process is responsible for the vacillating presentations evident in
migraine. (Fig.4)
Subsumed in this process is the merging and integration of afferent information
from ophthalmic, maxillary and mandibular branches of the trigeminal nerve and upper
21
cervical dermatomes in the TCN. Equally significant is that the TCN is influenced by a
range of supraspinal inhibitory and excitatory effects.7 In the event of continuing central
disinhibition or sensitisation extending to second order neurons in the TCN, trigeminal
and C1-3 spinal afferent information is amplified. If the process ceases soon after
commencing, the resultant headache would resemble ETTH headache, whilst if it
continues uninterrupted, IHS migraine results replete with associated symptoms. If the
process terminates in the mid range then IHS probable migraine eventuates.7 (Fig 4)
This process embodies the increasing severity and associated symptoms elucidated in
earlier studies suggesting a ‘severity’ continuum. 5-18,22-24,27-34,42-49,52-54,71,72
Figure 4. A diagrammatic representation of the ‘convergence hypothesis’ demonstrating a single, escalating process of sensitisation. Note the symptom overlap between migraine and ETTH in the ‘probable migraine’ group.
Because afferent information from visceral, trigeminal and spinal fields
converges on the nucleus tractus solitarius, an escalating process of sensitisation could
22
explain nausea and vomiting associated with migraine.73 This has been supported by a
study in which recurring head pain (induced by an ice block applied to the temple)
provoked nausea in migraineurs, but not in controls.74 Furthermore, this effect was
magnified during and after provocation of motion sickness. Potentially this finding
represents hyper excitability within the emetic or trigeminal nociceptive pathways.74,75
The ‘convergence hypothesis’ also describes ETTH assuming a unilateral
presentation - a feature of migraine. This could suggest an asymmetric activation of the
TCN.76 This possibility has been supported by a study demonstrating ipsilateral
activation of the dorsolateral pons in unilateral headache episodes induced by glyceryl
trinitrate.76 Ipsilateral activation also occurred in bilateral headache with a unilateral
predominance.76
Furthermore, as in the aforementioned ‘VSM’ model and ‘Tension Headache,
Migraine continuum’, the variability of symptoms could be a manifestation of the
magnitude of the various afferent inputs.7 For instance, if disinhibition affects
primarily the ophthalmic contribution, IHS migraine results; conversely if disinhibition
of the mandibular and/or upper cervical afferents prevail, ETTH develops.7 Another
common headache presentation, erroneously interpreted as ‘sinus headache’ could
occur, should disinhibition of maxillary afferents be more profound.7
An additional feature reinforcing the concept that migraine and TTH are
intimately related is the morphing of migraine into daily or near daily headache. Many
of these patients have a history of migraine, intimating a consequential relationship
between migraine and near daily headache.7,9 In this transformation, episodic migraine
often assumes a similar presentation to chronic tension-type headache (CTTH) (IHS
23
2.3),3 i.e., increased duration of episodes, with decreased severity and diminution of
associated features. 35,36 (Fig 5) This metamorphosis (chronification) of episodic
migraine to CTTH presentation accentuates progression of a common underlying
pathophysiological process.9
Figure 5. A diagrammatic representation of the morphing of migraine to daily or almost daily headache over time. Note decreasing severity and associated symptoms and increased frequency and duration of episodes.
Initially the only classification describing frequent daily headache was chronic
tension-type headache (CTTH).1 However this was considered inappropriate as most
patients classifiable as CTTH also experience migraine or migrainous symptoms.
Furthermore, these daily headaches often evolved from episodic migraine; thus, to
consider them as an embodiment of TTH was deemed to be incongruous.9 Currently,
after various terminologies were proposed, notably, ‘transformed’ or ‘evolutive
migraine’,35 this ‘chronic daily headache’ group is classified as ‘chronic migraine’ (IHS
24
1.3).3 Notably, in the description of chronic migraine, headache resembling ‘tension-
type’ is allowed.3
2.3 Summary
Substantial research has demonstrated significant symptomatic overlap between
migraine and ETTH, the existence of modified forms, the dual experience of migraine
and ETTH, and transformation of migraine to headache resembling CTTH. Thus,
migraine and TTH, based on a set of signs and symptoms, represent different points on
a continuum rather than being discrete entities. This is recognized by the IHS, as
evidenced by subsequent revisions of the classification system.2,3
However, the conundrum of whether a single common mechanism underlies this
headache spectrum, or whether two or more mechanisms interact to produce head pain,
can only be determined by further studies of the pathophysiology of headache.50 The
aim of this thesis was to examine the potential role of C1-3 afferents in TTH, migraine
and chronic whiplash associated headache, to determine whether cervical input might be
a source of pain in all three clinical conditions.
25
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33
CHAPTER 3
ROLE OF THE UPPER CERVICAL (C1-3) AFFERENTS IN PRIMARY
(MIGRAINE AND TENSION-TYPE) HEADACHE AND CHRONIC WHIPLASH
ASSOCIATED HEADACHE
3.1 Introduction
The Primary Headache syndromes are characterised by hyperalgesia, allodynia
and referral of pain into trigeminal and cervical sclerotomes.1-6 This constellation of
symptoms is thought to be underpinned by anatomical convergence of afferents from
the trigeminal 7-9 and cervical fields,10,11 and sensitisation of second order neurons in the
trigemino cervical nucleus (TCN).12-15
Corroborating earlier observations,7,8 anatomical convergence of trigeminal and
cervical afferents was confirmed when neurons in the C2 dorsal horn were shown to
have characteristics common to the ophthalmic division of the trigeminal nerve, the
C2-3 dermatome and cervical musculature innervated by the greater occipital nerve
(GON).9 Animal studies 16-18 have established that convergence in the TCN extends
distally to the second and third cervical spinal (C2-3) segment.
Therefore, whilst stimulation of the supratentorial dura refers sensations to the
ophthalmic division of the trigeminal nerve,19 the convergence phenomenon accounts
for referral to the upper cervical sclerotomes.20 Conversely, stimulation of the upper
cervical nerve roots,8,21 subcutaneous tissue innervated by the GON22,23 and the atlanto-
occipital-axial (O-C1-C2)24 and C2-325 spinal segments results in head pain.
34
These studies confirm anatomic and functional coupling between nociceptive
dural afferents and cervical afferents onto neurons in the TCN. Therefore, neurons in
the TCN may be considered the principal conduit for nociceptive input from the
trigeminal and cervical fields. Consequently, the TCN is likely to govern head pain in
primary headache conditions.12,26,27
The presence of hyperalgesia, allodynia and referral of pain into trigeminal and
cervical sclerotomes in primary headache conditions implies facilitation or sensitisation
of neurons in the TCN.14,15 This process could account for pain referral from trigeminal
to cervical structures and vice versa without necessarily involving pathology in the
cervical or trigeminal innervation territories respectively.5
The notion of central sensitisation considers an increased barrage of afferent
information from nociceptive C-fibers onto second-order neurons as pivotal in the
development of this hyper excitability, effectively increasing their response to afferent
information. 28-30 In addition, it is recognised that pain modulating circuits in the
brainstem also influence the degree of second-order neuron excitability.13
Accordingly, sensitisation of nociceptive second-order neurons in the TCN
could result from two pathophysiological mechanisms: facilitatory (noxious)
neurotransmission from the trigeminal12,31-33 or cervical regions;33-41 or dysfunctional
central pain-modulatory controls that disinhibit 42-44 or facilitate 45-47 afferent
neurotransmission into the TCN. This review focuses on the potential sensitizing role
of converging cervical afferent discharge41 in primary headache.26,48,49
35
Hence, the relationship between cervical signs and symptoms and primary
headache will be explored. Because the profile of chronic whiplash associated
headache (CWAH) mirrors that of primary headache and is, by definition, a
consequence of a musculoskeletal event, a review of the source of pain in CWAH
follows. As contemporary literature implicates the upper cervical joints (primarily C2-3
zygapophyseal) as the primary source of pain in CWAH, research investigating the role
of the zygapohyseal joints will be considered. The effect of various interventions
(including manual cervical treatments) that potentially mitigate noxious afferent
cervical discharge will also be reviewed.
3.2 Cervical Signs and Symptoms in Primary Headache
As early as 1917 a causal relationship between headache and neck symptoms
was inferred.50 However, despite the common occurrence of concomitant neck pain in
the primary headache syndromes,48,49,51-76 cervical symptoms are often considered to be
an epiphenomenon of activation of the TCN. 13,26,77,78
Although neck pain is highly prevalent in the general population79 it is even
more prevalent in individuals with primary headaches49 and, whilst the extent of
reported associated cervical symptoms in primary headache varies, their presence is
nevertheless significant. For example, in an extensive population survey, 73 self
reported migraineurs were 2.3 times more likely to experience neck pain than
participants without headache whilst, in a similar survey,74 38 per cent of migraineurs
reported neck pain compared to 11 per cent of controls.
36
This compares to studies 56,60,65 in tertiary settings which established that 40 to
64 % of migraine patients reported accompanying neck and occipital symptoms.
Furthermore, in a cross sectional study in which participants were assigned to migraine,
TTH and combined migraine and TTH groups, neck pain was reported by 76, 88 and
89 % of those with migraine, TTH and coexistent migraine and TTH respectively.49
Aside from the prevalence of neck pain, a causal role is strengthened by reports
that when compared to controls, the intensity of neck pain in a cohort of headache
patients increased appreciably during headache.72 The authors suggested that rather
than concomitant cervical symptoms being an epiphenomenon, 13,26,77,78 they were likely
to be instrumental in headache pathogenesis.53 This is supported by another study in
which 69.4% of migraineurs (n=487) reported neck pain during the migraine phase.80 In
addition, the significance of concomitant neck pain has been underscored by its
preeminence above nausea, which is considered to be a key feature of migraine.72
Reinforcing the relevance of cervical symptoms, not only in migraine but also
TTH, are studies of neck function in migraineurs inferring a comorbid relationship;
perhaps facilitating the chronification of migraine.72 Utilising the CROM (Performance
Attainment Associates, St Paul, MN) device, a validated device providing a
3-dimensional measure of cervical range of movement, a tertiary based study
demonstrated comparable decreased cervical movement in women with episodic and
transformed migraine when compared to controls.71
Self-reported headache frequency, severity, and symptomatic days significantly
predict disability independent of headache characteristics.69 The Neck Disability Index
(NDI) is a validated questionnaire assessing functional impairment related to neck
37
pain.81 This instrument was used to assess neck disability in 91 patients with episodic
migraine and 34 with chronic migraine.75 Cervical range of motion was measured using
a CROM. Not only was the prevalence of cervical symptoms in migraineurs confirmed,
but neck pain disability also increased with increased frequency of migrainous episodes
and correlated with the probability of migraine chronification. 72,75 This was more
pronounced in individuals with chronic migraine and in those with symptoms during
neck movements, when compared to those with episodic migraine.75 These findings
were confirmed in another NDI study in which disability due to neck pain was apparent
in 69 and 92 % of individuals with episodic and chronic migraine respectively.82
Clearly, concomitant cervical symptoms and dysfunction are common in
primary headache. However, speculation surrounds the source of symptoms and their
role; are they epiphenomena, i.e., trigeminal referral (a result of the bidirectional TCN
pathway), or instrumental in primary headache conditions?
There is a dearth of literature investigating the source of neck symptoms and
signs in primary headache (as indicated by a search in CINHAL, Cochrane, Medline,
Ovid, Pubmed (≤ 2015), using the terms, cervical symptoms, cervical pain, neck
symptoms, neck pain, migraine, tension headache, tension-type headache pain). This is
not surprising, because it is the absence of demonstrable cervical lesions in primary
headache13,26,83,84 which primarily is responsible for the assumption that cervical
dysfunction plays no role in primary headache conditions.13 However, given that the
symptomatic profile of chronic whiplash associated headache (CWAH) mirrors the
profiles of primary headache and that, by definition, whiplash headache involves
cervical trauma, extrapolation to primary headache may be drawn from an appreciation
of the source of symptoms in whiplash-associated headache.
38
3.3 Whiplash Headache and Primary Headache
The term ‘Whiplash’ describes a musculoskeletal mechanical event85 with
pathophysiological considerations including micro trauma to the musculoskeletal
systems of the neck.86 Thus, it is not surprising that concomitant cervical symptoms are
characteristic of chronic whiplash associated headache (CWAH).87-89 Furthermore,
acute90 and CWAH patients, 66,91 like migraineurs,82 exhibit comparable neck disability
on the NDI. In addition, surveys92-100 have shown that the profile of CWAH mirrors that
of primary headache. This feature, coupled with the high prevalence of concomitant
cervical symptoms and comparable neck disability, raises the possibility that CWAH
may share a common mechanism with primary headache.97
Clinical 86-89,101-103 and biomechanical 104-115 studies have identified the cervical
zygapophyseal joints as the most common source of injury and accompanying neck and
head pain in CWAH. However, other sub occipital structures at risk during the
whiplash mechanism include the deep cervical paravertebral muscles and intervertebral
discs.116,117 Human subject and biomechanical modeling has predicted that potentially
injurious 118,119 muscle fascicle strains in cervical paravertebral muscles could occur as a
result of forced lengthening during reflex neck muscle activation during trauma.120,121
Furthermore, MRI based studies have demonstrated the extensive presence of fatty
infiltrates in neck muscles of chronic whiplash patients.122-125 However, these were not
evident in patients with chronic spontaneous onset neck pain,124 and whilst it is
acknowledged that muscles reside within areas of pain,126 no research has produced
clinical evidence for compromised muscles as determinants of CWAH.126,127
39
Similarly, whilst lesions of the anterior longitudinal ligament and anterior aspect
of the annulus fibrosis (of the intervertebral disc) have been demonstrated in cadavers
127 and post mortem studies of patients with CWAH, 128,129 their nociceptive role has not
been ascertained.130 Furthermore, determining the incidence of disc injury in the
whiplash mechanism is problematic,131 because of the high prevalence of asymptomatic
intervertebral disc disease.132 Therefore, conceivably the primary nociceptive focus lies
with other vulnerable structures in the neck.133
It has been hypothesised that neuromuscular abnormalities observed in
CWAH,134,135 for example, altered range of cervical movement,136,137 originate from
muscle spasm triggered by abnormal afferents from compromised zygapophyseal joint
capsules and associated ligaments.118,138-140 This is supported by evidence of increased
laxity of zygapophyseal joint capsules after exposure to the whiplash mechanism.141
The capsular innervation by nerve fibres, particularly nociceptors,139,140,142,143 and the
mechanical vulnerability of the zygapophyseal joints,144 support the joint’s nociceptive
role.
Further incriminating the zygapophyseal joints and associated capsules are
biomechanical studies demonstrating that movements of the upper cervical segments
can exceed physiological limits during motor vehicle trauma.112-114 Indeed, of the
purported structures responsible for neck pain and headache, the C2-3 zygapophyseal
joint and capsule is the only validated source.116,126,145 Whilst atlanto axial (C1-2)
24,146,147 and atlanto occipital joints 24 have been shown to refer head pain, C1-2
involvement is relatively uncommon,147 and a dearth of studies investigating the atlanto
occipital joints precludes any consequential discussion.
40
The C2-3 zygapophyseal joint is innervated by the third occipital nerve.148
Accordingly, stimulation to the C2-C3 zygapophyseal joint provokes head pain;25
conversely, cervical medial branch blocks anaesthetize afferents from the
zygapophyseal joints,25 and ameliorate headache not only in CWAH patients but in
atraumatic headache patients.149 Consequently, because this form of headache is
alleviated by anaesthetizing the third occipital nerve, it became known as ‘third
occipital headache’.90,150-154
To determine the prevalence of C2-3 zygapophyseal joint involvement in
CWAH, a search of CINHAL, Cochrane, Medline, Ovid, Pubmed (≤ 2015), using the
terms, whiplash headache, C2-3 zygapophyseal joint, C2-3 facet joint, C2-3 z-joint,
third occipital headache, was undertaken. As different methodologies and outcome
variables were employed in the studies identified, each study is reviewed separately
below.
A cohort of 100 patients with chronic neck pain post whiplash underwent
diagnostic anaesthetic blocks of the third occipital nerve (medial branch of C3 nerve).89
Seventy-one patients reported headache; of those, headache was the predominant
symptom in 41. Anaesthetic blockade of the C2-3 zygapophyseal joint was successful in
27% of all patients and 53% in which headache was the dominant feature. In a similar
study,88 the C2-3 zygapophyseal joint was incriminated in 50% of post whiplash
patients in whom headache was the predominant symptom.
Both the presence of cervical pain and response to anaesthetic blocks of the third
occipital nerve in whiplash patients is paralleled in patients with neck pain who had not
been subject to overt trauma. In a study of mild to moderate neck pain, whiplash
41
patients (n=133) and atraumatic neck pain patients (n=691) were assessed.152 After
considering perceived neck pain, functional limitation (NDI) and prognosis, there were
no relevant differences between the two groups.152 Fifty-four and 48.4% of the whiplash
and atraumatic neck pain patients respectively reported associated headache. There was
no attempt to classify headache type. Similarly, studies in which the third occipital
nerve was anaesthetized in patients with atraumatic neck pain reflect the results in
whiplash patients; anaesthetic blockade afforded complete relief in 36% to 67% of
atraumatic neck pain patients.153,155,156 The authors of the study153 in which prevalence
of pain relief was relatively low (36%) accept that their result was conservative because
many patients declined a second confirmatory anaesthetic block.
Furthermore, denervation of the zygapophyseal joint utilising percutaneous
radiofrequency medial branch neurotomy of the third occipital nerve has been shown to
produce complete and long-lasting relief from cervical (below C2-3) zygapophyseal
joint (neck) pain. 157-161 In a consummate study,161 radio frequency neurotomy of the
C2-3 zygapophyseal joints provided complete relief from headache for around 297 days
in 43 of 49 patients. In addition, neurotomies were repeated in 14 patients, 12 of whom
achieved further relief for a median duration of 217 days. It was not clear how many
patients had symptoms that were attributable to trauma, but 33 were involved in
litigation.
Moreover, reflecting the effect of anaesthetic blockade of the third occipital
nerve in whiplash patients is the amelioration of headache following this procedure in
seven or 10 atraumatic headache patients.149 Furthermore, the characteristics of
headache resembled TTH, implying that other forms of (primary) headache may be
masquerading as ‘third occipital headache’.149,162
42
In addition to the positive effect of medial branch blocks of the third occipital
nerve on headache and neck pain, further evidence of zygapophyseal joint involvement
is furnished by reduction of sensory hypersensitivity (pressure pain and cold pain
thresholds) in patients with chronic whiplash associated disorders (WAD) following
anaesthetic blockade of the joint.163 As with pressure pain thresholds, cold
hyperalgesia is usually related to altered sensory processing,164 and has been associated
with poor prognosis in patients with chronic WAD.165
In another study,166 increased pressure pain thresholds in patients with chronic
WAD resulted from anaesthetic blockade of myofascial trigger points in the upper
fibres of the trapezius. Furthermore, symptoms of photophobia resolved in all but two of
the 11 subjects for the duration of the anaesthetic block. This result suggests a central
mechanism as the mediator between the myofascial trigger points and sensitivity to
light. However, the increase in pressure pain thresholds in this study conflicts with an
earlier study,165 leading to speculation that other cervical structures were responsible for
central sensitisation.165 This contrary result was considered to be due to the difference in
technique used to identify trigger points, for in the earlier study165 anaesthetic
infiltration of ‘tender’ as opposed to ‘trigger’ points was administered.166 Nevertheless,
the reduction in pain,163 reduced sensory hypersensitivity163,166 and photophobia166
following modulation of cervical afferents reflects decreased nociceptive input into the
central nervous system165 with probable decreased excitability of central nociceptive
pathways and/or facilitation of inhibitory pathways.167
In favour of the former possibility (i.e., decreased nociceptive input into the
central nervous system) were the results of a recent study in which sensory processing
43
in the head in chronic neck pain patients was investigated.168 The organisation of
sensory processing is considered to be a result of functional transmission via the
functional interaction between trigeminal and upper cervical afferents. 169-172 This
allows bidirectional transmission and processing of nociceptive afferents between the
cervical and trigeminal sensory receptive fields of the face and head.7,8,25,26,147,169-172
Using a multi modal quantitative sensory testing protocol (incorporating pressure pain,
thermal and electrical threshold testing), along with assessment of descending inhibitory
controls using the conditioned pain modulation (CPM) paradigm, the sensory
organisation in cervicogenic headache patients with associated chronic zygapophyseal
joint pain was compared to patients with chronic zygapophyseal joint pain without
headache.168 Pressure hyperalgesia and accompanying cold and warm hyperaesthesia on
the headache side in cervicogenic headache patients compared to the non headache
group implied ongoing sensitisation of the TCN driven by cervical afferents.168
Alternatively, generalized hyperalgesia could be due to dysfunctional
supraspinal, descending inhibitory controls.165,167,173 However, the finding that CPM
was unimpaired in both the cervicogenic headache and non headache groups implies
that descending inhibitory controls were fully operational and therefore unlikely to be
responsible for central sensitisation in the cervicogenic headache patients.168
This conclusion is strengthened by a review of 16 studies investigating the
nociceptive flexion reflex (NFR) in subjects with chronic musculoskeletal pain.174 The
NFR is considered to be a more diametrical measure of spinal cord excitability relying
less on psychological factors175-177 when compared to quantitative sensory testing.178
The reviewers included studies of primary headache, fibromyalgia, knee pain and
whiplash subjects. All groups demonstrated central hyperexcitability evidenced by
44
impairment of NFR.174,178 Notably, this review included studies of migraineurs179 and
tension headache patients179-181 and supports the possibility of a sensitisation from
noxious cervical afferents. This is mirrored by studies revealing impaired NFR in acute
whiplash headache182 and chronic whiplash associated disorders.175
Whilst not employing traditional joint blockades, a study of 229 occipital
migraine patients undergoing ‘migraine surgery’ investigated the effect of third
occipital nerve resection.183 Excision of the third occipital nerve (n=111), effectively
blocking C2-3 zygapophyseal joint afferents, did not affect ‘migraine surgery’
outcomes. Given that the C2-3 zygapophyseal joint is innervated by the third occipital
nerve,148 this suggests that afferents from the C2-3 zygapophyseal joint are not directly
involved in the migraine process. However, the effect of zygapophyseal joint
anaesthetic blockade on primary headache per se has not been investigated145 and a
search of the subsequent literature (CINHAL, Cochrane, Medline, Ovid, Pubmed (2004
- 2015), using the terms, C2-3 zygapophyseal joint, anaesthetic blockade, migraine,
tension headache, tension-type headache, chronic tension-type headache) failed to
uncover any studies.
3.4 Modulation of Cervical Afferents in Primary Headache
Because primary headache often includes pain in the back of the head,
anaesthetic blockade of the greater occipital nerve (GON) has become an increasingly
common practice,184 despite denunciation of its value on the basis that it supplies only
the skin, muscles and vessels of the scalp which are not established sources of pain.145
The predominant interventions include anaesthetic blockade of the GON (GON block)
and occipital nerve stimulation (ONS).
45
Whilst some studies support the efficacy of anaesthetizing the GON in acute and
chronic migraine,4,185-199 the great heterogeneity of published studies renders their
evaluation difficult. In an extensive review of eleven studies, 4,186,188,190-198 the authors199
highlight inconsistencies surrounding patient selection, timing of the procedure i.e. inter
/ ictally, variability of technique (including bilateral / unilateral), inclusion of other
nerves and / or the presence of trigger points, local anaesthetic agent alone or combined
with different types and dosages of steroids, and variable outcome measures.
Unfortunately, randomized, double-blinded, placebo-controlled studies of GON
block in migraine have produced conflicting results.196,197 Supporting the benefit of
GON block outcomes in open-label studies or case series4,185-193 in addition to the
perception of benefit among clinicians145,200 was the larger (n=73) of two studies,197
whilst the smaller (n=33)196 found no benefit of GON block in the management of
migraine. Thus, the role of GON block in migraine remains uncertain.
Comparatively few studies have investigated the effect of anaesthetic blockade
of the GON in TTH. Furthermore, these studies190,201,202 were plagued by similar (to
migraine) inconsistencies with contrasting results. As with migraine, whether GON
blocks are an effective treatment for TTH will require additional clinical trials.
Regardless of the ambivalence surrounding GON block in primary headache,
GON block provides relief for some patients; however, the relief is mostly only
temporary. This has led to increasing interest in occipital nerve stimulation (ONS).203
Subsequent to the first published (1999) ONS study204 for intractable occipital
neuralgia, ensuing studies205,206 have reported promising results for chronic migraine
46
which, in turn, encouraged randomised trials.207-209 Of these, only one study209 met its
primary end point, demonstrating 39% of 29 patients with chronic migraine at three
months follow-up experienced a three point or more decrease in severity from baseline
or greater than 50% decrease in headache days per month.
Whilst these studies failed to meet expectations, results from subsequent
studies210,211 have been more promising. Although investigating primarily the
significance of paraesthesia and possible placebo effects, the first of the double-blinded
trials (n=8)210 reported consistent stimulation dependent benefit. In the second and
larger (n= 157) study,211 59.5% and 47.8% of chronic migraine patients reported a
corresponding 30% and 50% reduction in headache days and / or pain severity over 12
months. After completing the randomised, double blinded section of the study (three
months), patients continued with open-label ONS for the remaining 40 weeks.
Therefore, in both studies the effect appears to be stimulation dependent; further
investigations are required to determine long-term efficacy in a non stimulation
environment.210
A search of the CINHAL, Cochrane, Medline, Ovid, and Pubmed databases (≤
2015), using the terms, occipital nerve stimulation, ONS, tension headache, tension-type
headache, chronic tension-type headache failed to disclose any studies on the effect of
ONS in TTH.
Debate continues as to whether the modulatory effect of the GON block or ONS
on migraine is peripherally driven or activates central inhibitory mechanisms.145,210
However, GON afferent information arises from structures not considered as sources of
pain in migraine and in itself the GON is not compromised. Therefore, modulation
47
cannot be interpreted as ‘anaesthetizing’ the source of pain.145 Conceivably the ongoing
relief provided by neurotomy or (to a lesser extent) medial branch blocks, supports the
assertion that targeting the GON as the primary source of pain in migraine is sub
optimal.145
3.5 Zygapophyseal Joints and Animal Studies
As in humans, histological studies of zygapophyseal joints in rats and goats have
identified nociceptive nerve fibres in the joint’s capsular ligament.143,212,213 Mechanical
hyperalgesia or allodynia represents enhanced nociceptive processing and as such is
commonly used as an indicator of pain outcomes in animal studies.214,215
A substantial body of evidence from animal models has demonstrated the
development of mechanical hyperalgesia from controlled, non injurious loading of the
zygapophyseal joint capsule.214-225 Conversely, after removal of the capsule, stressing
the joint resulted in no pain,219 indicating that capsular tension is a requirement for pain
from zygapophyseal joint loading.218,219 Furthermore, intra-articular injection of
ketorolac, a non-steroidal anti-inflammatory drug, attenuated zygapophyseal joint
pain.222 This was considered to be due to a concomitant reduction (which had increased
in parallel with mechanical hyperalgesia) in astrocytic Protease-activated receptor -1.222
Protease-activated receptor -1 is considered instrumental in the maintenance of
pain.226-228
Substance P is a common nociceptive mediator, both locally and spinally, for
joint pain.229 The potential for Substance P to influence nociceptive signalling has been
demonstrated in a study in which lumbar zygapophyseal joint proprioceptive and
48
nociceptive afferents in rabbits were enhanced by application of substance P.229
Similarly, in the rat, increased substance P expression in the dorsal root ganglia
(associated with mechanical hyperalgesia) was detected after capsular loading of
cervical joints.215 Furthermore, increased substance P was still evident seven days
later.215 In addition to increased expression in the spinal cord of prostaglandin (E2) and
interleukin-1α, other markers associated with joint inflammation and pain229-234 were
observed within a day224 and persisted for seven days223 after loading of cervical
zygapophyseal joints,223,224 implying that spinal inflammation not only initiates but also
contributes to maintenance of pain after joint compromise.
In addition, extracellular recordings of spinal dorsal horn neuronal activity were
taken seven days after capsular loading. The presence of increased neuronal firing was
interpreted as direct evidence of neuronal modulation and in part likely to be
responsible for central sensitisation underpinning chronic pain.221
Furthermore, in a recent study, intra articular zygapophyseal joint injections of
saline induced nociceptor activation (as measured by mechanical hyperalgesia), dorsal
horn hyper excitability and up-regulation of excitatory signaling proteins.225 These
changes were attenuated by intra articular bupivacaine only within (and not after spinal
modifications develop) four hours, implying that initial afferent activity induces spinal
sensitisation via spinal glutamatergic signaling.225
Conspicuously, mechanical hyperalgesia and associated aforementioned
neurophysiological changes result from relatively small loads;214-217,223,225 joint
distractions ranging from 0.35 mm224 to 0.9 mm214 have been shown to elicit
mechanical allodynia in rats. Reflecting the relatively low consequential distraction
49
loads, capsular loading was quantified in terms of strain, with mechanical hyperalgesia
evident at as low as 11.1% of maximum capsular strain.216 This finding raises the
possibility of pain-initiating events occurring before joint tensile strain threshold is
reached.216
This hypothesis is supported by evidence of capsular fibre realignment at 0.51
mm distraction, preceding the capsular yield (defined by a decrease in stiffness).235
Ligament yield is defined by any decrease in the maximum tangent stiffness of at least
10%. 236 By definition, for any data point where failure is detected, yield will also be
detected because the tangent stiffness during failure decreases enough to become
negative. Therefore, it is possible that anomalous fibre realignment may occur at lower
thresholds than detected in this study. Furthermore, because yield forces correspond
with joint distractions producing mechanical hyperalgesia and associated cellular
responses,214,216,217 yield may also provide a barometer for pain,217 and therefore may be
a superior measure of injury thresholds more relevant to pathophysiological
events.217,236
These results imply that the aforementioned neurophysiological phenomena,
notably zygapophyseal joint139,143,237 mediated spinal hyperexcitability, plasticity of
dorsal horn neuronal activity and pain,220,221,223 occur in response to abnormal
alterations in fibre patterns of the capsule’s collagen matrix during loading occurring at
or preceding capsular yield.235
Pathophysiological effects identified in mechanistic studies of the
zygapophyseal joint in animal studies may be important in human pain processes.238-240
In particular, animal studies indicate that nociceptive afferent information from
50
zygapophyseal joints contribute to central sensitisation; moreover, when considered
with the ameliorating effect of anaesthetizing86-89,101-103,150-156 or neurotomy158-161 of the
medial branch of the third occipital nerve, animal data provide a compelling argument
for cervical zygapophyseal joints as a source of neck pain and/or headache.
Additional extrapolation from animal research suggests that symptomatic
compromise of the zygapophyseal joint may occur in the absence of any macroscopic
lesion. When considered with studies demonstrating parallel profiles of neck pain,
functional limitation and prognosis152 and the effect of anaesthetic blockade of the third
occipital nerve in CWAH and atraumatic patients, 153-156 this implies that overt trauma
is not a prerequisite for cervical zygapophyseal joint compromise.
This in part explains why whiplash remains one of the most debated and
controversial painful musculoskeletal conditions,91,95,99,100,152-155 for whilst it is generally
acknowledged that an initial cervical injury occurs during a whiplash event, 241 specific
patho anatomical lesions are, in the main, not evident.125,152,155-160
Notwithstanding the absence of clinical evidence for compromised cervical
muscles in the CWAH,126,127 and the focus on zygapophyseal joints,116,118,126,138-140,144,145
studies using animal models have demonstrated that algesic chemical stimulation of
deep cervical paraspinal muscles evokes effects in the trigeminal field. These include
prolonged increased activity of the ipsilateral jaw musculature38,242 and alterations in the
jaw opening reflex,35 an established model for the investigation of sensorimotor
processing of the trigeminal brainstem.36 These findings are supported by studies in
which neuronal brainstem activity was recorded during cervical intervention. In one
study, long-term increased neuronal excitability in the brainstem resulted from a single
51
intra muscular injection of low dose adenosine 5'-triphosphate (ATP) into murine neck
musculature.36 (ATP is an algogenic molecule which is used widely for experimental
induction of noxious input from muscles.)39,40 This finding was replicated by research in
which inflammatory irritant mustard oil was injected into deep paraspinal structures
adjacent to the C1-2 spinal segment - 70 per cent of neurons exhibited increased
excitability.41 Another pertinent finding reflecting central sensitisation was the
expansion post injection of the orofacial and cervical neuronal receptive fields.41 This
body of research involving cervical musculature provides additional support for cervical
afferent sensitisation of the TCN.
3.6 Primary Headache: are Cervical Lesions Necessary?
The fact that neurophysiological phenomena result from non injurious loading of
the zygapophyseal joint capsule has significant implications. Not the least is that these
findings are incongruent with the biomechanical premise that the degree of symptoms
would be proportional to magnitude of soft tissue loading.125,243 Accordingly, there is
general agreement that conventional medical imaging lacks sensitivity for capsular and
intra-articular injuries of the spine.125,131,152,155-158,160,161 Consequently, computed
tomography and magnetic resonance imaging are not appropriate tests to rule out
pathology.125,131,152,157,160,161 Instead, identifying lesions is likely to require more
sophisticated and specialised methods. For example, in a positron emission tomography
study, tracer uptake in proximity to the second cervical vertebra was significantly
greater in CWAH patients than controls, indicating local persistent peripheral tissue
inflammation.244
52
Secondly, and conspicuously in relation to whiplash disorders, the inability of
customary medical imaging to identify pathology implies that the source of patients’
symptomatology is not always clinically detectable;126,155-158,160 that is, the absence of
extensive, conspicuous zygapophyseal joint capsular damage does not rule out
nociceptive relevance.125,152,155 However the exact pathophysiology of CWAH and
associated neck pain remains an enigma for many.245-248
This puts CWAH in the same category as cervicogenic headache and primary
headache conditions. Cervicogenic headache, like CWAH, is considered a
musculoskeletal condition but its purported existence continues to be debated.249,250
Underpinning this debate is the lack of identifiable pathology. In this respect diagnoses
of migraine,83 and tension-type headache,84 suffer from the same limitations.
3.7 Upper Cervical Joint Dysfunction in Primary Headache
Notwithstanding the lack of identifiable spinal pathology, noxious afferent
cervical information has been linked to TTH49,54,59,251-261 and migraine.49,54,56,72,261,262 In
a recent observational, case-control study,262 significant hypomobility of the atlanto
occipital and C1-2 segments in a cohort of 20 migraineurs was demonstrated. In an
earlier larger study of 90 patients,261 comprising 39 migraine, 11 TTH and nine patients
with combination headache (the remaining 31 patients were assigned cluster, post-
traumatic or drug rebound headache diagnoses), manual palpation detected dysfunction
of the C1-2, C2-3 and C3-4 segments in 86% of migraineurs, while in 78% of TTH
patients dysfunction was demonstrated at atlanto occipital, C1-2, and C2-3 segments.
Furthermore, there were no statistically significant differences in cervical dysfunction
between groups. Similarly in another study,54 84% of patients with either TTH or
53
migraine without aura exhibited hypomobility of the atlanto occipital and C1-2
segments.
Corroborating the manual findings was the radiological assessment which
confirmed reduced segmental motion at the atlanto occipital segment in 90% and 70%
of participants in flexion and extension, respectively.54 However, in stark contrast,
another study found no evidence of palpable upper cervical segmental dysfunction in
TTH patients or migraineurs.252 The dissimilarity in results is likely to be due to
different examination approaches and underlines the importance of developing a
standardized protocol for assessing the cervical spine; currently, reliable and valid
testing methods have not been established.263
A symptomatic (and potentially more relevant), non manual correlate is
provided by studies demonstrating referral of head pain from symptomatic upper
cervical facet and C2-3 zygapophyseal joints.24,89,146,147,264-266 This suggests that head
pain referral is a pivotal characteristic of cervical afferent involvement in
headache.84,267-269
3.8 Cervical Treatment of Primary Headache
Randomized controlled trials (RCTs) are considered an optimal method with
which to assess the efficacy of any intervention. 270 Furthermore, it is now recognised
that for unambiguous interpretation of the efficacy of RCTs in headache, assessment
using a primary end-point (headache frequency) and secondary end-points (duration and
intensity) are mandatory.271
54
The first systematic and comprehensive review assessing the efficacy of manual
therapy RCT for primary headache in which headache frequency and duration and
intensity were used as primary and secondary endpoints respectively was conducted in
2014 272 and considering its currency provides the basis of this overview. In a search of
the CINHAL, Cochrane, Medline, Ovid and PubMed databases using the terms
migraine, chronic migraine, chronic tension-type headache combined with spinal
mobilisation, spinal manipulative therapy, manipulative therapy, physiotherapy,
osteopathic treatment, chiropractic, massage therapy, six RCTs were identified, all
addressing CTTH;260,273-277 no available studies assessed migraine.272 Five studies
applied physiotherapy260,274-277 and the other, massage therapy.273 The methodological
quality of the RCTs was evaluated using the PEDro scale - four studies were considered
of good quality.260,273,276,277
Additionally, of particular relevance is the upper three cervical (C1-3) afferents
from the apposite spinal joints. Furthermore, if additional interventions were involved,
results were inconclusive; determining which intervention was effective is problematic.
None of the studies identified 260,273-277 focused exclusively on the atlanto occipital, C1-
2 and C2-3 spinal segments and only two avoided co-intervention; headache and neck
massage275 and biofeedback only.276 By way of example, in one study manual therapy
intervention comprised mobilisation of the thoracic and cervical (segmental levels not
specified) spines, craniocervical exercises and postural correction.277 At each treatment
session the therapist, depending on the outcome from previous sessions, selected the
intervention. Typically, mobilisation commenced with exercises and, if necessary,
progressed to spinal mobilisation, complemented by muscle stretching and massage.
Whilst this study demonstrated that manual therapy is more effective in the
55
management of chronic tension type headache than standard general medical
practitioner care,277 the role of C1-3 afferents is uncertain.
However, a later double blind, randomised, placebo controlled trial addressed
the atlanto occipital segment specifically and also avoided co-intervention.278 Patients
with either chronic or episodic tension type headache were divided into four groups;
atlanto occipital manipulation, sub occipital soft tissue massage, a combination of both
and a placebo-control group. Those patients who had received manipulation only, and
also combined with sub occipital massage, reported significant improvement in
frequency and intensity of headache; the latter group showing greater improvement.278
Whilst patients completed headache diaries, it is unclear whether the interventions also
impacted on duration. Possibly the inclusion of both (and not discriminating between)
episodic and chronic tension type headache patients precluded any meaningful analysis
of duration.
While the underlying pathophysiology of tension type headache is
uncertain,84,279 the most accepted theory is that tension type headache is underpinned by
central sensitisation due to prolonged afferent nociceptive inputs from peripheral
tissues.280 Moreover, peripheral factors are implicated in episodic tension-type
headache, whereas central factors are considered to be instrumental in chronic tension-
type headache.279 Therefore, in patients with episodic tension type headache where the
peripheral input is probably dominant, manual therapy is likely to be more effective
than in those with chronic tension type headache.281 Conceivably, then, the
amalgamation of episodic and chronic tension-type headache patients could have
blurred interpretation of results.
56
Whilst the results of this study278 are promising, the four week follow-up period,
as the authors conceded, could be considered to be a limitation; longer periods of
observation after treatment are necessary to adequately judge the value of atlanto
occipital, C1-2 and C2-3 mobilisation/manipulation as a potential first line of therapy
for tension-type headache.278
In relation to TTH, the available RCTs 260,273-277 suggest that massage and
physiotherapy are effective treatment options in the management of CTTH,272 without
specifically identifying, with the exception of one study,278 a potential causative role of
the upper cervical afferents.
Building on the 2014 review,272 another comprehensive 2015 systematic review
and meta-analysis of physiotherapy clinical trials in primary headache282 identified
trials for TTH277,283,284 and migraine.285-289 (for search terms and strategy, the reader is
referred Luedtke et al 282). However all trials used aerobic exercise or a
multidisciplinary approach and as such provide no meaningful information as to the role
of upper cervical afferents in primary headache. The authors of the latter review
concluded that whilst there was low level evidence for appreciable reduction in the
severity of TTH and duration of migrainous episodes,282 unequivocal evidence for a
beneficial effect of physiotherapy /cervical intervention on primary headache conditions
can only be provided by future RCTs of incontrovertible methodological rigor and
adequate sample sizes.272,282
57
3.9 Summary
The significant presence of neck pain and cervical dysfunction in TTH and
migraine suggests that cervical afferents are instrumental in primary headache
pathophysiology. This relationship is reinforced by impairment of the nociceptive
flexion reflex in migraineurs and TTH patients. Additional support is afforded by the
similar profile of CWAH to that of primary headache (including the incidence of neck
pain) and that the C2-3 zygapophyseal joint has been validated as a source of neck pain
and headache in CWAH. Furthermore, minor stress on zygapophyseal joints can lead
to zygapophyseal joint mediated spinal hyperexcitability, plasticity of dorsal horn
neuronal activity and pain. That the C2-3 zygapophyseal joint could play a causal role
in primary headache conditions is strengthened by the significant relief following
neurotomy of the C2-3 zygapophyseal joint.
Conversely, modulating cervical afferents by anaesthetizing or influencing the
GON in primary headache has produced inconsistent results, reinforcing the notion that
targeting the GON is sub optimal. Similarly, manual cervical treatment of primary
headache conditions suffers the same fate, perhaps because rigorously designed clinical
trials have not focused specifically on the C2-3 zygapophysial and adjacent joints.
58
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painful upper cervical joint dysfunction. Aust J Physiother. 1997;43(2):125-129.
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Effectiveness of an intensive multidisciplinary headache treatment program.
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2009;49(4):563-570.
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CHAPTER 4
BLINK REFLEX
4.1 Introduction
In studies on trigeminal activity in primary headache syndromes, it is mandatory
that the emphasis be on nociceptive processing. Wide dynamic range (WDR) and
nociceptive specific (NS) neurons respond to noxious stimuli and are present in the
interstitial nucleus of the spinal trigeminal tract and the spinal trigeminal nucleus
(STN).1 The STN comprises 3 sub-nuclei; the nucleus oralis (SNo), interpolaris (SNi)
and caudalis (SNc).
Data from animal and human studies have demonstrated that nociceptive
processing occurs predominantly within the medullary SNi and SNc of the STN.1,2
Furthermore WDR and NS neurons are involved in mediation of the blink reflex (BR),
and therefore the BR provides a model by which to assess trigeminal pain processing.3
4.2 Anatomy and Measurement of the Blink Reflex
The BR can be evoked by electrical stimulation of the supra orbital nerve and is
measured from responses of the obicularis oculi muscle. The BR response comprises 3
components: an early ipsilateral component (R1); a bilateral late component (R2) and a
bilateral ultra late component (R3).4
Innocuous electrical and mechanical stimuli elicit R1 and R2, implying
mediation by Aβ afferents,4 whereas R3 is evoked by strong electrical stimuli. The ultra
91
late R3 response is not always present and because it cannot be elicited unconditionally
is considered to be part of the ‘startle’ response.5,6
Whilst initially R2 and R3 were considered nociceptive components of the BR,7
it has been demonstrated that R3 is not a suitable measure of trigeminal nociceptive
processing.8 The electrical threshold of R3 is mainly determined by activation of Aβ
fibres (and to a lesser extent nociceptive Aδ fibres). However, application of local
anaesthetic in the supra orbital region failed to alter R3,8 implying that nociceptive Aδ
fibres were probably not involved in R3 and therefore R3 is an inappropriate measure of
nociception.
Because both nociceptive and non-nociceptive afferents can elicit R2, two reflex
paths are possible.3 The first involves Aβ afferents converging onto low threshold
mechano receptive (LMT) neurons and Aδ onto nociceptive specific neurons. The
second reflex path involves both Aβ and Aδ afferents projecting onto common WDR
neurons. That is, both reflex paths share the same interneurons.3 Activation of the
DNIC system (WDR neurons) involves nociceptive specific neurons in the sub nucleus
reticularis dorsalis inhibiting WDR in the trigeminal system and spinal cord. 9 R2 was
inhibited, demonstrating that Aβ and Aδ afferents converge onto WDR neurons in the
medullary spinal trigeminal nucleus.9 Furthermore, noxious stimulation to the forehead
facilitated R2, consistent with convergence of low-threshold mechanoreceptive and
nociceptive afferents onto medullary WDR neurons.10
Another assessment technique developed to measure trigeminal brainstem
nociception is the corneal reflex (CR). This reflex involves applying noxious heat or air
puff stimulation of the cornea to evoke selective stimulation of trigeminal nociceptive
92
fibers, thus increasing the nociceptive sensitivity of the blink reflex response. 11,12 The
CR consists of two late bilateral symmetrical components, analogous to the R2
component.13 That is, the BR comprises R1, 2 and 3; the CR R2 only. Further, the BR
is essentially a cutaneous reflex elicited by mechanoreceptors from afferent Aβ and
nociceptive Aδ fibres, whilst the CR results from stimulation of nociceptive Aδ afferent
fibres in the corneal epithelium. In addition, the CR nociceptive afferents project onto
the second order neurons of laminae I and II, and V, and VI of the SNc, whereas the Aβ
afferents of the BR terminate on laminae III and VI of the SNc with tactile and
nociceptive information converging on WDR neurons at more rostral levels of the
trigeminal system.14 These characteristics of the BR, along with findings demonstrating
fewer fibres and inter neurons in the CR, have led to the thesis that the BR affords
greater stability than the CR.15,16
Because approximately 90% of the R2 reflex response of a BR to standard
electrical stimuli depends on non-nociceptive Aβ fibre input,17 the possibility of
selective stimulation of superficial nociceptive fibres in the area of the supra orbital
nerve to elicit a ‘nociception specific’ blink reflex (R2 nBR) was explored.18 Blink
reflex responses elicited by the standard parallel electrode were compared to those
elicited by a custom built concentric electrode (R2) before and after local anaesthetic
cream was applied to the supra orbital area. Importantly, the R2 component was reduced
by 12 and 90% respectively. The authors concluded that the almost total inhibition of
R2 nBR after local anaesthetic using the novel electrode demonstrated selective
stimulation of nociceptive fibres at a low current intensity in the region of the
supraorbital nerve that was more tolerable than stimulation of the cornea.18 A
subsequent study investigating the optimal parameters of the R2 nBR confirmed the R2
nBR to be a reliable, non invasive electrophysiological technique to assess activity of
93
the trigeminal system in primary headache conditions.19 Therefore, those studies
investigating migraine utilising the R2 nBR are reviewed below.
4.3 Migraine and the ‘nociceptive specific’ blink reflex
A search of the literature comprising the search terms ‘R2, migraine, nBR’ from
2000 to 2015 identified seven studies employing the nBR.17,19-24 (Table 3.1) Researchers
have assessed various properties of the nBR, namely habituation, onset latencies, area
under the curve (AUC) and, to a lesser degree, the recovery cycle (RC).
Habituation is a complex, multi factorial phenomenon. The dual process theory
considers two separate divergent processes that influence the response profile to
repetitive stimuli.25 Habituation, considered to be a rudimentary and omnipresent form
of behavioural plasticity, has been defined as “a response decrement as a result of
repeated stimulation”26 (cited by 27) and therefore is a measure of decreased
responsiveness. The opposing process comprises facilitation or sensitisation i.e.,
increased responsiveness.25
Sensitisation, when present, occurs during the initial stages of exposure to
repeated stimuli, accounting for an increase in response amplitude; conversely,
habituation prevails subsequently. As with habituation, sensitisation is considered an
elementary form of behavioural plasticity, and as such is regarded with equal
importance.28 Therefore, habituation and sensitisation are considered to reflect activity
in neuronal substrates of information processing in the CNS.28
94
Table 1 Nociceptive blink reflex studies and migraine.
Authors & Year
Experimental Groups (n) Modus operandi Results Conclusions
Kaube et al 200217
Migraineurs=17 (Ictal & interictal)
R2 latencies & AUC ictally & post treatment (lysine acetylsalicylate (ACA) or zolmatriptan) i.e. interictally
↓ latencies & ↑ AUC R2nBR 680% ictally; ↑latencies & ↓ AUC posttreatment
Temporary central trigeminal sensitisation during migraine
Katsavara et al 200220
Migraine=14 (Ictal & interictal); Controls with sinusitis headache=14
R2 nBR during migraine & sinusitis headache
R2 nBR facilitated ipsilaterally during migraine
Facilitation in migraine not peripherally mediated
Katsavara et al 200319
Migraineurs=17 (Ictal & interictal); Controls=15
AUC R2 nBR ictally & interictally to repeated stimulation
↑ AUC in migraineurs butnot controls interictally
Interictal deficit of habituation in migraineurs
Katsavara et al 200421
Migraineurs=28 (Ictal & interictal) Controls=30
R2 nBR ictally and post treatment (ACA or zolmatriptan) i.e. interictally
↑ latencies R2 nBR andsuppression of AUC posttreatments ictally but notinterictally
Medication inhibited R2 nBR ictally but not interictally
95
Table. Nociceptive blink reflex studies and migraine. (cont.)
Di Clemente et al 200522
Migraineurs=15 (Interictally) Controls=15
AUC R2 nBR interictally to repeated stimulation
↑ AUC R2 nBR in migraineurs butnot controls interictally
Interictal deficit of habituation in migraineurs not due to trigeminal sensitisation
Di Clemente et al 200723
Migraineurs=16 (Interictally) Controls=15
AUC R2 nBR interictally to repeated stimulation
↑ AUC R2 nBR in migraineurs butnot in controls interictally
Interictal deficit of habituation in migraineurs not due to trigeminal sensitisation
Coppola et al 200724
Migraineurs=14 (Interictally) Controls=15
R2 nBR recovery curve (paired stimuli) interictally
No difference in onset latencies and AUC R2 nBR between migraine & controls; R2 nBR recovery curves normal
Interictal sensitisation of trigeminal system non existent; descending brainstem pathways are normal in migraineurs interictally
96
4.3.1 Central sensitisation
Central sensitisation refers to plastic changes in neural structures belonging to
the “pain matrix” that result in decreased nociceptive thresholds and increased
responsiveness to noxious and innocuous peripheral stimuli, and expansion of the
receptive fields of CNS nociceptive neurons.29
In an early ictal study utilising both BR and R2 nBR responses in migraineurs,17
sensitisation of the trigemino cervical nucleus (TCN) was demonstrated. Seventeen
patients were assessed within 6 hours of migraine onset, and after treatment with either
acetylsalicylic acid (ASA) or oral zolmitriptan, i.e., interictally. No differences were
evident for onset latencies or AUC at any time on the non headache side. However, on
the headache side, R2 nBR demonstrated significant shortening of latencies ictally,
which lengthened following either drug treatment. The AUC increased significantly,
and similarly was attenuated by either ASA or zolmitriptan.17 (Table 1)
In a similar drug intervention study,21 the effects of ASA and zolmitriptan were
found to be different ictally versus interictally. The R2 nBR was used to investigate 28
migraine patients ictally and interictally in a double blind crossover study. Patients were
assessed before, 0 and 90 minutes after treatment comprising either ASA or oral
zolmitriptan. Thirty non migrainous participants (controls) received either ASA,
zolmitriptan or placebo. Neither of the drug treatments inhibited R2 nBR in the control
97
group, whereas both ASA and zolmitriptan inhibited nBR response ictally, but not
intertictally.21 (Table 1)
These findings demonstrate corresponding effects of ASA and zolmitriptan on
both headache resolution and inhibition of amplified AUC of R2 nBR. It has been
shown that both the triptans30-32 and ASA33,34 arrest transmission of nociceptive
impulses in the TNC.
Furthermore, in a study contrasting migraineurs and patients with sinusitis
headache, an interictal habituation deficit was demonstrated in migraineurs only.20 Thus,
the facilitation of trigeminal nociception was considered to be specific for the migraine
process rather than a product of peripheral (sinusitis) pain.20
The R2 nBR can be inhibited by preceding stimulations of the supraorbital
nerve.35 Increasing the intervals between the first (conditioning or inhibitory) stimulus
and second stimulus (i.e., paired stimuli) enables determination of a ‘recovery curve’
(RC) i.e., a representation of recovery of the second (inhibited) R2 response with
increasing interstimulus intervals. Therefore, the RC of R2 nBR after paired supra
orbital stimuli is considered to be a reflection of the excitability of the R2 nBR at a
segmental level.4
Only one study investigating the RC of R2 nBR in migraine was identified.24
This interictal study, employing paired supra orbital stimuli, did not demonstrate any
98
difference in the R2 AUC between 14 migraineurs and 15 controls. This result does not
support interictal sensitisation of the TCN. Additionally, participants were also
subjected to (pre conditioning) electrical stimulation of the index finger. Similarly,
changes in R2 AUC were similar in migraineurs and controls, implying normal
interictal control of nociceptive neurotransmission by descending brainstem pathways in
migraineurs.24
Two other studies investigating RC have been identified, but because one used
the BR36 and the other R2 nBR in cluster headache, direct extrapolation is not possible.
In the BR study, the effects of attention and habituation on the BR in (interictal)
migraineurs were investigated. Perhaps surprisingly (given evidence that facilitation
occurs ictally), an increase (areas of averaged R2 responses generated by the
conditioning stimulus expressed as a percentage of that of the averaged test responses)
in R2 RC after the conditioning stimulus was demonstrated.36 The authors postulated
that this finding reflected ongoing hyperexcitability of the TCN after the last migrainous
episode.36 The other study investigated RCs in ten cluster headache patients ictally,37
and revealed increased ipsilateral (to headache) RCs after paired supra orbital stimuli.
The authors concluded that the unilateral decrease of R2 nBR inhibition was a
manifestation of TCN sensitisation.37
The paucity of studies investigating RC behaviour of R2 nBR in migraineurs
prevents any meaningful discussion. However, deficient habituation is considered the
most consistent and prevalent interictal abnormality of the migraine condition.27
99
4.3.2 Habituation
The expected effect of habituation on the AUC of the R2 nBR is decreasing
amplitude during repetitive electrical stimulation.36,38,39 In migraine, R2 nBR has
demonstrated an interictal habituation deficit during short19,20 as well as long time
courses.22,23 (Table 1)
Habituation of R2 nBR was investigated interictally in a group of 15
migraineurs.22 The findings included a tendency for shorter (sensitised) mean R2
latencies in migraineurs in the first stimulation block compared to (15) controls.
Habituation in this study was defined as the percentage difference of the R2 AUC
between the first and tenth block of five averaged responses. The difference in R2 AUC
habituation between migraineurs and controls was not only significant in most blocks,
but also increased progressively with the number of blocks. In addition, the frequency
of migrainous episodes correlated with R2 AUC responses. This revealed increasing R2
nBR habituation with increased frequency of episodes, implying that the interictal
habituation deficit was unlikely to be the result of trigeminal sensitisation.22
This finding was confirmed in a later study from the same group. Using similar
methodology, in which habituation was measured as percentage AUC decrease in 10
consecutive blocks of five averaged rectified responses, 16 migraineurs were found to
have an interictal deficit of habituation of R2 nBR.23
100
However, uncertainty surrounding the neural mechanisms underlying the
interictal habituation deficit in migraine means agreement has not been reached as to the
interpretation of this characteristic.40,41
4.4 Summary
It appears that migraine can influence R2 nBR. The R2 nBR has reliably
demonstrated an interictal habituation deficit19,22,23,27,28 and facilitation
(sensitisation)17,20,21,42 during migrainous episodes.
101
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by an exclusively neural mechanism. Brain. Oct 1996;119 ( Pt 5):1419-1428.
32. Levy D, Jakubowski M, Burstein R. Disruption of communication between
peripheral and central trigeminovascular neurons mediates the antimigraine
action of 5HT 1B/1D receptor agonists. Proc Natl Acad Sci U S A. Mar 23
2004;101(12):4274-4279.
105
33. Buzzi MG, Sakas DE, Moskowitz MA. Indomethacin and acetylsalicylic acid
block neurogenic plasma protein extravasation in rat dura mater. Eur J
Pharmacol. Jun 20 1989;165(2-3):251-258.
34. Kaube H, Hoskin KL, Goadsby PJ. Intravenous acetylsalicylic acid inhibits
central trigeminal neurons in the dorsal horn of the upper cervical spinal cord in
the cat. Headache. Nov-Dec 1993;33(10):541-544.
35. Rossi A, Scarpini C. Gating of trigemino-facial reflex from low-threshold
trigeminal and extratrigeminal cutaneous fibres in humans. J Neurol Neurosurg
Psychiatry. Sep 1992;55(9):774-780.
36. de Tommaso M, Murasecco D, Libro G, et al. Modulation of trigeminal reflex
excitability in migraine: effects of attention and habituation on the blink reflex.
Int J Psychophysiol. Jun 2002;44(3):239-249.
37. Lozza A, Schoenen J, Delwaide PJ. Inhibition of the blink reflex R2 component
after supraorbital and index finger stimulations is reduced in cluster headache:
an indication for both segmental and suprasegmental dysfunction? Pain. May
1997;71(1):81-88.
38. Boelhouwer AJ, Brunia CH. Blink reflexes and the state of arousal. J Neurol
Neurosurg Psychiatry. Jan 1977;40(1):58-63.
39. De Marinis M, Pujia A, Natale L, D'Arcangelo E, Accornero N. Decreased
habituation of the R2 component of the blink reflex in migraine patients. Clin
Neurophysiol. May 2003;114(5):889-893.
40. Coppola G, Pierelli F, Schoenen J. Is the cerebral cortex hyperexcitable or
hyperresponsive in migraine? Cephalalgia. Dec 2007;27(12):1427-1439.
106
41. Aurora SK, Wilkinson F. The brain is hyperexcitable in migraine. Cephalalgia.
Dec 2007;27(12):1442-1453.
42. Tajti J, Pardutz A, Vamos E, et al. Migraine is a neuronal disease. J Neural
Transm. Apr 2011;118(4):511-524.
107
CHAPTER 5
CERVICAL REPRODUCTION OF CUSTOMARY HEAD PAIN IN PRIMARY
HEADACHE
5.1 Introduction
The symptomatic profile of CWAH mirrors that of primary headache,1-9 and
cervical symptoms and neck disability are similar in CWAH and primary headache
syndromes.6 Furthermore, the C2-3 zygapophyseal joint appears to play a primary role
in neck pain and associated headache both in CWAH10-31 and in patients with atraumatic
headache.32 In addition to the C2-3 zygapophyseal joint, the AO and C1-2 joints are
also capable of referring head pain.33-35
Whilst the IHS classification system of headache questions the significance of
customary head pain referral during examination of the neck in primary headache
patients,36 others consider this to be a cornerstone of cervical relevance.36-39
Therefore, we sought to investigate the incidence of head pain referral during
examination of the AO and C2-3 joints in primary headache patients and non headache
volunteers.
108
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113
5.2 Study 1.
This is a reprint of an article accepted for publication in Headache: Journal of
Head and Face Pain. Copyright is owned by the American Headache Society.
Head Pain Referral During Examination of the Neck in
Migraine and Tension-Type Headache
Dean H. Watson, MAppSc; Peter D. Drummond, PhD
Objective.—To investigate if and to what extent typical head pain can be
reproduced in tension-type headache (TTH), migraine without aura sufferers, and
controls when sustained pressure was applied to the lateral posterior arch of C1
and the articular pillar of C2, stressing the atlanto occipital and C2-3 segments
respectively.
Background.—Occipital and neck symptoms often accompany primary
headache, suggesting involvement of cervical afferents in central pain processing
mechanisms in these disorders. Referral of head pain from upper cervical
structures is made possible by convergence of cervical and trigeminal nociceptive
afferent information in the trigemino-cervical nucleus. Upper cervical segmental
and C2-3 zygapophysial joint dysfunction is recognized as a potential source of
noxious afferent information and is present in primary headache sufferers.
Furthermore, referral of head pain has been demonstrated from symptomatic
114
upper cervical segments and the C2-3 zygapophysial joints, suggesting that head
pain referral may be a characteristic of cervical afferent involvement in headache.
Methods.—Thirty-four headache sufferers and 14 controls were examined
interictally. Headache patients were diagnosed according the criteria of the
International Headache Society and comprised 20 migraine without aura (females
n = 18; males n = 2; average age 35.3 years) and 14 TTH sufferers (females n = 11;
males n = 3; average age 30.7 years). Two techniques were used specifically to
stress the atlantooccipital segments (Technique 1 – C1) and C2-3 zygapophysial
joints (Technique 2 – C2). Two techniques were also applied to the arm – the
common extensor origin and the mid belly of the biceps brachii. Participants
reported reproduction of head pain with “yes” or “no” and rated the intensity of
head pain and local pressure of application on a scale of 0 -10, where 0 = no pain
and 10 = intolerable pain.
Results.—None of the subjects reported head pain during application of
techniques on the arm. Head pain referral duringthe cervical examination was
reported by 8 of 14 (57%) control participants, all TTH patients and all but 1
migraineur (P < .002). In each case, participants reported that the referred head
pain was similar to the pain they usually experienced during TTH or migraine.
The frequency of head pain referral was identical for Techniques 1 and 2. The
intensity of referral did not differ between Technique 1 and Technique 2 or
between groups. Tenderness ratings to thumb pressure were comparable between
the Techniques 1 and 2 when pressure was applied to C1 and C2 respectively and
across groups. Similarly, there were no significant differences for tenderness
115
ratings to thumb pressure between Technique 1 and Technique 2 on the arm or
between groups. While tenderness ratings to thumb pressure for Technique 2 were
similar for both referral (n = 41) and non-referral (n = 7) groups, tenderness
ratings for Technique 1 in the referral group were significantly greater when
compared with the non-referral group (P = .01).
Conclusions.—Our data support the continuum concept of headache, one in
which noxious cervical afferent information may well be significantly
underestimated. The high incidence of reproduction of headache supports the
evaluation of musculoskeletal features in patients presenting with migrainous and
TTH symptoms. This, in turn, may have important implications for understanding
the pathophysiology of headache and developing alternative treatment options.
______________________________________________________________________
From the School of Psychology, Murdoch University, Perth, WA, Australia.
Address all correspondence to D.H. Watson, School of Psychology, Murdoch
University, South Street Campus, 90 South Street,Perth, WA 6150, Australia,
email: dean@watsonheadache.com
Accepted for publication March 5, 2012.
Conflict of Interest: Dean H. Watson presents training programs to manual therapists in
the assessment of the upper cervical spine in primary headache conditions; Peter D.
Drummond has nothing to disclose.
116
Key words: migraine, tension-type headache, cervicogenic headache, mechanical
precipitation of head pain
Abbreviations: AO atlantooccipital, TTH tension-type headache
(Headache 2012;52:1226-1235)
______________________________________________________________________
Occipital and neck symptoms often accompany headache.1 Furthermore,
occipital nerve injections are effective in tension-type headache (TTH)2 and migraine,3,4
and occipital nerve stimulation is also effective in migraine.5,6 Together, these
observations suggest the involvement of afferent cervical nociceptive inputs in these
primary headache disorders.
Cervical musculoskeletal abnormalities recognized as potential sources of
noxious afferent cervical information have been linked to TTH7-19 and migraine.20,21
Mercer et al14 investigated the presence of cervical dysfunction in 90 consecutive
patients with chronic headache. The sample comprised 39 migraineurs, 11 patients with
TTH and 9 with combination headache. Other diagnoses (eg, cluster, posttraumatic, or
drug rebound headache) were assigned to the remaining 31 patients. Eighty-six percent
of migraineurs had dysfunction at C1-2, C2-3, and C3-4 segments, while 78% of TTH
patients had dysfunction of the atlantooccipital (AO), C1-2, and C2-3 segments. There
were no statistically significant differences in cervical dysfunction between groups.
Similarly, in another study,15 84% of patients with TTH or migraine without aura had
hypomobility of the upper 2 spinal segments, while radiological assessment
117
demonstrated reduced segmental motion at the AO segment in 90% and 70% of
participants in flexion and extension, respectively. Hypomobility was most pronounced
at the AO segment.15 Interestingly, these findings mirror those of Pfaffenrath et al17
who, using functional roentgenograms, demonstrated significantly reduced sagittal
mobility of the AO and C1-2 segments in 15 cervicogenic headache sufferers when
compared with 18 controls.
Referral of head pain from upper cervical structures is made possible by
convergence of cervical and trigeminal nociceptive afferent information in the
trigemino-cervical nucleus where second-order neurons receive nociceptive information
from the C1, C2, and C3 spinal nerves and from the first division ofthe trigeminal
nerve.22 The anatomical and functional nature of this convergence has been
demonstrated in laboratory animal experiments23-25 and also in humans.26-31
Furthermore, in studies involving asymptomatic participants, pain referral to the head
was demonstrated during noxious stimulation of the basal-occipital area (corresponding
to the AO segment), C1-2, and C2-3 interspinous spaces26; the AO joints32; and C2-3
zygapophysial joints.33 These studies, along with a substantive body of research
demonstrating referral of head pain from symptomatic upper cervical facet and C2-3
zygapophysial joints,34-39 suggest that head pain referral is a pivotal characteristic of
cervical afferent involvement in headache.40,41
What has not been determined is if, and to what extent, head pain can be
reproduced in TTH sufferers and migraine without aura patients during manual
118
examination of the upper cervical spine. Therefore, we sought to investigate the
incidence of reproduction of typical head pain in these patients when sustained pressure
was applied to the lateral posterior arch of C1 and the articular pillar of C2, stressing the
AO and C2-3 segments respectively.We hypothesized that manual examination of the
upper cervical spine would precipitate greater referral of head pain in these patients than
in controls without a history of migraine or frequent TTH.
MATERIALS AND METHODS
Participants.—Thirty-four headache sufferers and 14 controls were examined.
Participants in the non-headache group experienced mild non-migrainous headache no
more than 6 times per year – 4 could not recall ever having experienced headache.
Participants were recruited from the general population and from patients attending a
headache clinic. Headache sufferers were diagnosed according to the criteria of the
International Headache Society.42 Eleven females and 3 males (average age 30.7 years)
fulfilled the diagnostic criteria of TTH, and 20 patients met the criteria for migraine
without aura (average age 35.3 years; 18 females and 2 males). All 14 patients in the
TTH group had bilateral headache in various areas including frontal, temporal, and
occipital. Nineteen migraineurs experienced unilateral headache with side-shift, and
while headache was bilateral in the remaining patient, the other features fulfilled the cri-
teria for migraine without aura. Nine females and 5 males, with an average age of 32.8
years, represented the control group.All participants signed an informed consent form.
Ethical approval was obtained from the Ethics Committee of Murdoch University.
119
Passive Accessory Intervertebral Movement Examination.—The data
examination was performed by a single clinician (D.H.W. – musculoskeletal phys-
iotherapist) with 20 years experience, whose practice is limited to examination and
treatment of the upper cervical spine in primary headache conditions. Intra-examiner
reliability was analyzed using Cohen’s Kappa in a previous study7 in which 11 passive
accessory intervertebral movement techniques were employed. Intervertebral mobility
was graded on a 5-point scale, ranging from hypomobile to very hypermobile. Grade 3
was considered normal, while grade 4 was classified as hypomobile; very hypomobile
was graded as 5. Conversely, grade 2 indicated hypermobility and 1 considerably
hypermobile. A symptomatic response was also recorded – no discomfort, local pain,
local pain and headache, and headache only. There was perfect agreement in 17 of 22
passive accessory intervertebral movement tests (k = 1.0).7 Of the 5 remaining tests, the
lowest Kappa score was k = 0.667, P = .01, which indicated good agreement.43
Two techniques were used with the intention of passively stressing a specific
intervertebral segment either on the side of headache (in the case of unilateral
headache), the side of greatest frequency of headache (in the case of alternating
headache), and in the case of bilateral headache, on the side that the spinous process of
axis (C2) was deviated toward. In those participants who had never experienced head-
ache, the side of technique was randomly assigned. Technique 1 comprised applying
pressure on the posterior arch of the atlas (C1) with the participant’s head in
approximately 20 degrees of contralateral rotation, with the other hand rotating the
participant’s head ipsilaterally, thereby stressing the AO segment. The second technique
120
involved applying pressure to the articular pillar of the axis (C2) with the participant’s
head in approximately 30 degrees of contralateral rotation, in this instance stressing the
C2-3 segment.
On a separate occasion, thumb pressure was applied at 2 sites on the ipsilateral
arm. Technique 1 comprised pressure on the common extensor origin (lateral
epicondyle of the humerus); Technique 2 involved pressure over the mid belly of the
biceps brachii.
All participants were examined interictally and in the supine position. The order
of the examination (ie, arm vs cervical) alternated from 1 participant to the next within
each group. Technique 1 was always performed first. In each technique, the pressure
was applied and sustained for 5 seconds. The interval between each technique exceeded
3 minutes. Participants reported reproduction of head pain with “yes” or “no” and rated
the intensity of head pain and local tenderness to thumb pressure on a scale of 0-10,
where 0 = no pain and 10 = intolerable pain.
Statistical Approach.—Data were analyzed using SPSS Version 16 software
(SPSS Inc., Chicago, IL, USA). Ratings for arm tenderness were investigated in a 2 X 3
(Technique [Technique 1, Technique 2] X Group [Migraine, TTH, Control]) analysis of
variance. Values for tenderness over C1 and C2 and referred head pain intensity were
investigated insimilar analyses. The incidence of head pain referral was compared
across the 3 groups using chi-square analysis. Participants without head pain referral
were excluded from analyses of referred head pain intensity. Tenderness ratings for the
referral and non-referral participants were investigated in a 2 X 2 (Technique X Referral
vs Non-referral) analysis of variance.
121
P < .05 was considered to be statistically significant in all analyses, and tests of
statistical significance were 2-tailed.
RESULTS
None of the participants reported head pain during application of techniques on
the arm. In all participants who experienced referral of head pain when pressure was
applied to the neck, the pain eased immediately on cessation of the technique. Pre-
liminary inspection of the data revealed that the frequency of head pain referral was
identical for Techniques 1 and 2.
Table 1.—Tenderness Ratings Stratified by Headache Groups and Site
Control (n = 14) TTH (n = 14) Migraine (n = 20) Tenderness ratings (arm) Common extensor origin 5.500 ± 0.419 5.400 ± 0.351 6.214 ± 0.419 Biceps brachii 5.357 ± 0.440 5.350 ± 0.368 5.786 ± 0.440 Tenderness ratings (cervical) AO segment (C0-1) 6.071 ± 0.479 6.429 ± 0.479 6.700 ± 0.401 C2-3 zygapophysial joint 6.143 ± 0.457 6.786 ± 0.457 7.250 ± 0.383 AO = atlantooccipital; TTH = tension-type headache.
There were no significant differences for tenderness ratings to thumb pressure
between sites on the arm (F[2,45] = 0.403; P = .67) or between groups (F[2,45] = 0.822;
P = .45) (Table 1). Similarly, values for tenderness ratings to thumb pressure were
comparable when pressure was applied to C1 and C2 respectively (F[2,45] = 3.43; P =
.07) and across groups (F[2,45] = 1.145; P = .33) (Table 1). These results suggest that
122
thumb pressure was applied consistently across groups and also that there was no
evidence of primary hyperalgesia in either of the headache groups.
In each case, participants reported that the referred head pain was similar to the
pain they usually experienced during TTH or migraine. Head pain referral was reported
by 8 of 14 (57%) control participants, 100% of TTH participants (n = 14), and 19 of 20
(95%) migraineurs (c2 = 12.85; P < .002). The intensity of referral did not differ
between sites (F[1,38] = 0.178; P = .675) or groups (F[2,38] = 0.480; P = .622) (Table
2). Table 2.—The Intensity of Head Pain Referral Control (n = 8) TTH (n = 14) Migraine (n = 19) Head pain referral AO segment (C0-1) 5.875 ± 0.863 4.500 ± 0.645 5.474 ± 0.553 C2-3 zygapophysial joint 5.500 ± 0.815 5.000 ± 0.616 5.000 ± 0.529
AO = atlanto occipital; TTH = tension-type headache.
Tenderness ratings to thumb pressure were significantly greater in the referral
group (n = 41) than the non-referral group (n = 7) for both techniques (F[1,46] = 6.597;
P = .014), and ratings were greater when pressure was applied to C2 than C1
(F[1,46] = 4.231; P = .045 (Table 3).
123
DISCUSSION
The aim of this study was to investigate the incidence of reproduction of typical
head pain in TTH, migraine without aura, and controls when stressing the AO segments
and C2-3 zygapophysial joints.
The reproduction of usual head pain in 85% of participants in our study provides
a manual, clinical parallel with previous research supporting convergence of cervical
afferents on trigeminal nuclei.22-25,44
Table 3.—Tenderness Ratings for Referral and Non-Referral Groups
Referral (n = 41) Non-Referral (n = 7)
Tenderness ratings (cervical)
AO segment (C0-1) 6.707 ± 0.260 4.857 ± 0.629
C2-3 zygapophysial joint 7.000 ± 0.262 5.571 ± 0.635
AO = atlanto occipital.
More specifically, the findings indicate that head pain can be referred by
stimulating the AO joints32,34 and the C2-3 zygapophysial joints.35,36,38,39 Furthermore, it
is interesting to consider that referral occurred only in headache sufferers; ie, every TTH
participant, all but 1 migraineur and 8 of the 10 control participants who experienced
infrequent headache (6 or less/year, resembling TTH). In the non-referral participants (n
= 7), 4 had never experienced headache, 2 had infrequent headache, and 1 had migraine.
124
The high incidence of headache reproduction in both symptomatic groups is in
stark contrast to the findings of earlier studies in which passive accessory
intervertebral movement examinations were used and which did not demonstrate
significant abnormalities in TTH or migraine.8,19 However, both passive accessory
intervertebral movement assessment techniques used in this study not only involved
movement of C2 in relation to C3 and of the occiput relative to C1, but also sustaining
thumb pressure at the end of a segment’s range of movement for 5 seconds. This
contrasts with the traditional, standard movement examination generally employed by
manual therapists,8,19 in which thumb pressure is applied in an oscillatory manner.
Variation in application pressure across studies may also account for differing rates of
headache reproduction.The dissimilarity in results is likely to be due to the different
examination approaches and underlines the importance of developing a standardized
protocol for assessing the cervical spine.
The pressure was applied for 5 seconds, and the referred pain on all occasions
ceased immediately or within seconds of release of thumb pressure. Predictably,
therefore, the symptoms usually associated with typical migraine were not reported.
Nevertheless, the pain generally referred to the usual site of headache; sometimes of
greater intensity than usual “attacks.”
The relatively high incidence of production of head pain in the control group is
perhaps surprising. This group comprised 4 participants who had not experienced
headache, and 10 who experienced non-migrainous headache no more than 6 times per
year. Not only was head pain produced in 8 of the 10 participants who experienced
headache infrequently, but also the intensity of referral in these 8 controls did not
125
differ from the migraine or TTH groups. This suggests that a “primary headache”
mechanism may lie dormant in infrequent headache sufferers. Because of difficulties
recruiting participants who had never experienced headache, past practice has allowed
the inclusion of participants experiencing mild non-migrainous headache (resembling
TTH) up to 6 times per year. However, our findings suggest that these participants had
more in common with the TTH group than the other controls and imply the existence of
an “infrequent” headache group. This raises concerns over the composition of “control”
groups in headache studies.
Mechanical precipitation of head pain with neck movements or manual pressure
over the upper cervical area is a pivotal diagnostic criterion for cervicogenic
headache.4,12,13,40 Furthermore, side-locked unilaterality is also considered a cornerstone
of the cervicogenic headache diagnostic criteria,40-42 and therefore, participants were
meticulously selected to rule out this symptom. Nineteen of the 20 migraine
experienced alternating headache, whereas the other had bilateral headache. All 14
TTH sufferers presented with bilateral headache. Assuming therefore that misdiagnosis
is unlikely, this could suggest that mechanical precipitation of usual head pain as a
diagnostic criterion is not specific to cervicogenic headache, but rather is a non-specific,
homogeneous pain reaction pattern in headache sufferers.
The results of our study not only are consistent with convergence of cervical
afferents onto neurons in the trigeminal nuclei, but also imply that this mechanism
might contribute both to migraine and TTH. The significant reproduction of head pain
in the TTH and migraine groups concurs with the relatively high incidence of segmental
dysfunction found previously.14,15 Furthermore, while TTH is considered to be a
126
separate entity of unknown pathophysiology,42 cervical dysfunction is becoming
increasingly implicated in the TTH mechanism, thus blurring the distinction between
TTH and cervicogenic headache.14,15,18,19 Recent research, in which rehabilitation of
cranio-cervical flexors significantly reduced symptoms of TTH,18 supports the notion
that cervical dysfunction may play a role in the TTH mechanism. The existence
of a “shared” mechanism supports the “Convergence Theory” postulated by Cady et
al,45 which places TTH and migraine on the same etiological spectrum,45-50 perhaps with
an underlying cervicogenic basis for central sensitization of nociceptive second-order
neurons in the trigemino-cervical nucleus and subsequent hyperexcitability to afferent
stimulation.51
The notion of central sensitization considers an increased barrage of afferent
noxious information from C-fibers onto second-order neurons as crucial in the
development of this hyperexcitability. Moreover, it has been demonstrated that
stimulation of afferents from deep somatic tissues such as joints and muscles is more
effective than cutaneous input in generating central hyperexcitability.52,53 Given the
nature of examination techniques used in this study, it is reasonable to assume that,
among other structures, the deep articular restraining anatomy (eg, joint capsules
and ligaments of the AO articulation and the C2-3 zygapophysial joint) was stressed.
These structures are innervated by the upper cervical roots and are recognized as
sources of head pain.44,54,55 Accordingly, our findings suggest that hyperexcitability of
nociceptive second-order neurons in the trigemino-cervical nucleus could result from
noxious afferent information from dysfunctional spinal segments, thereby increasing the
sensitivity to subclinical afferent information from the trigeminal field. The ensuing
127
exaggerated information is perceived as a noxious event that results in pain. This
possibility has been demonstrated by increased excitability to dural input after central
sensitization evoked by stimulation of the greater occipital nerve23 and is supported by
modulation of the nociceptive blink reflex following blockade of the greater occipital
nerve.30,31 Conceivably, this represents the cervicogenic equivalent to application of an
“inflammatory soup” onto the dura which has been shown to induce central sensitization
and ensuing increased sensitivity to trigeminal inputs.24 Alternatively, the incidence of
reproduction of head pain in migraine and TTH participants could reflect a state of
primary hyperalgesia.51,56-58 However, we believe that this is unlikely as tenderness
ratings to thumb pressure were similar across the groups.
Another interesting finding was that in every participant with head pain referral,
both of the cervical techniques precipitated their usual head pain. If the assumption is
that reproduction of usual head pain is indicative of cervical involvement in headache,
this result supports the prominence of the C2-3 zygapophysial joint in headache
reported by others.36,38,59,60 However, what is surprising is the frequency with which
referral occurred when the AO joint was stressed. This mirrors the high incidence of
dysfunction at the AO segment in earlier studies7,14,15,17 and provides a manual parallel
of referral from intra-articular injections of the AO joint demonstrated by Dreyfuss and
colleagues.32,34 Multi-joint involvement in headache has important implications,
because this indicates that when the C2-3 zygapophysial joint is symptomatic, the AO
joint will also be involved. Speculation then arises as to a course of action if blocking
the third occipital nerve (innervating the C2-3 zygapophysial joint)36,59-61 only partially
relieves headache. According to guidelines established by Bogduk, anesthetizing a
128
neighboring joint should alleviate all of the pain.62 Our result suggests that the AO joint
should be investigated as a potential source of pain.
If the assumption that local tenderness is a reflection of relevant pathology or
dysfunction, our finding that tenderness ratings to thumb pressure were greater for both
techniques in the referral group isnot surprising. While this result challenges a recent
study which demonstrated that local tenderness is not diagnostic of cervical
zygapophysial joint pain,63 it does confirm the findings of Lord et al,36 who reported that
patients with “third occipital nerve headache” were more likely to be tender over the
ipsilateral C2-3 zygapophysial joint. Direct (thumb) access to the deeply situated AO
joint is not possible, while the C2-3 zygapophysial joint is more readily palpable and
would explain the increased local tenderness ratings for stimulation of this site.
Limitations.—The examiner was not blinded when assessing controls.
However, the lack of significant difference between tenderness ratings to thumb
pressure between the controls and symptomatic groups lessens this potential influence.
In addition, there was no prior expectation that head pain referral would differ between
those in the control group with infrequent headache and those without a history of
headache; thus, this difference is unlikely to be due to examiner bias. Although
standardization of pressure clearly is important, for it to be achieved during application
of techniques used in this study and in a passive accessory intervertebral movement
examination, pressure algometers would need to be devised which not only attach to the
thumb but are sufficiently fine to allow for skilled palpation and perception of mobility.
The absence of such a device in our study could be regarded as a shortcoming. Sample
sizes could also be considered a limitation. However, the very high incidence of
129
reproduction of headache questions whether the result would differ in a larger group.
We followed standard clinical protocol by examining the AO joint before examining
C2-3. Although this might have facilitated referral of head pain during the examina-
tion of C2-3, this seems unlikely because each technique was applied for no more than 5
seconds. In addition, the referred head pain eased within a few seconds of cessation of
the examination in all cases, and the interval between techniques exceeded 3 minutes.
Furthermore, if the initial examination had facilitated subsequent responses, the
frequency or intensity of head pain referral should have increased during the second
examination. Neither was the case.
CONCLUSIONS
According to Antonaci and Sjaastad,40 a common misunderstanding is that one
can provoke head pain by exerting external pressure (eg, over identified tendon
insertions in the occipital area) in individuals who have never experienced headache to
the same degree as in some headache conditions. This was borne out in the current
study – referral of usual head pain occurred only in the symptomatic groups includ-
ing those in the control group with a history of infrequent headache.
Our data support the continuum concept of headache, one in which noxious
cervical afferent information may well be significantly underestimated. The high
incidence of reproduction of headache during cervical examination supports the
evaluation of musculoskeletal features in patients presenting with migrainous and TTH
symptoms. This, in turn, may have important implications for understanding the
pathophysiology of headache and developing alternative treatment options.
130
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Peter Drummond, Dean Watson
(b) Acquisition of Data
Dean Watson
(c) Analysis and Interpretation of Data
Peter Drummond, Dean Watson
Category 2
(a) Drafting the Article
Dean Watson, Peter Drummond
(b) Revising It for Intellectual Content
Dean Watson, Peter Drummond
Category 3
(a) Final Approval of the Completed Article
Peter Drummond, Dean Watson
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CHAPTER 6
THE EFFECT OF CERVICAL REPRODUCTION OF HEAD PAIN ON THE
NOCICEPTIVE BLINK REFLEX
6.1 Introduction
Previously we demonstrated a high incidence of customary head pain referral in
migraineurs and TTH patients. (Section 5.2) Whilst our findings support the role of
cervical afferent nociceptors in primary headache, confirmation of cervical involvement
in the pathophysiological mechanisms of primary headache is uncertain.1 The author’s
clinical observation is that as the examination technique, which reproduces accustomed
head pain, is sustained, head pain resolves within a varied but relatively short
timeframe, e.g., 30 - 90 seconds. Furthermore, some patients also report that
longstanding ‘tenderness’ in the trigeminal field resolves.
Allodynia is a common accompaniment of migraine,2-8 and is thought to be the
consequence of sensitisation of central second-order neurons, which receive dual input
from the trigeminal and cervical fields.6,9 Clinical deduction, therefore, could suggest
that reproduction and resolution of customary head pain has a positive effect on the
status of the trigemino cervical nucleus (TCN).
Referral of head pain when examining upper cervical structures is mediated by
convergence of cervical and trigeminal afferents in the TCN of the brainstem.
Convergence, when coupled with sensitisation of central trigeminal neurons, accounts
for perception of pain distant from the site of origin. 10 The nociceptive blink reflex (R2
nBR) has been used extensively to assess the status of the TCN.11-19 This body of
139
research has demonstrated an interictal habituation deficit15,17,18,20,21 and facilitation
(sensitisation) during migrainous episodes.12,14,16,22
Therefore, to elucidate further the potential role of cervical afferent nociceptors
in the pathophysiology of migraine, R2 nBR was used to assess activity in the TCN
during cervical reproduction and resolution of customary head pain in migraineurs.
140
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142
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nociceptive blink reflex: an endophenotypic marker for presymptomatic
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blink reflex after supraorbital or index finger stimulation is normal in migraine
without aura between attacks. Cephalalgia. Jul 2007;27(7):803-808.
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143
6.2 Study 2.
This is a reprint of an article accepted for publication in Headache: Journal of
Head and Face Pain. Copyright is owned by the American Headache Society.
Cervical Referral of Head Pain in Migraineurs: Effects on the
Nociceptive Blink Reflex
Dean H. Watson, MAppSc; Peter D. Drummond, PhD
Objective.—To investigate cervical, interictal reproduction of usual head
pain and its effect on the nociceptive blink reflex in migraineurs.
Background.—Anatomical and neurophysiological studies in animals and
humans have confirmed functional convergence of trigeminal and cervical afferent
pathways. Migraineurs often present with occipital and neck symptoms, and
cervical pain is referred to the head in most cases, suggesting that cervical afferent
information may contribute to headache. Furthermore, the effectiveness of greater
occipital nerve blockade in migraine and demonstrable modulation of trigeminal
transmission following greater occipital nerve blockade suggest an important role
for cervical afferents in migraine. However, to what extent cervical afferents
contribute actively to migraine is still unknown.
Methods.—The passive accessory intervertebral movements of the atlanto-
occipital and C2-3 spinal segments of 15 participants (14 females, 1 male; age 24-
44 years, mean age 33.3 years) with migraine were examined interictally. During
1session, either the atlanto-occipital or C2-3 segment was examined, resulting in
referred usual head pain, while in another session, pressure was applied over the
144
common extensor origin (lateral epicondyle of the humerus) of the ipsilateral arm.
Each intervention was repeated 4 times. The nociceptive blink reflex to a
supraorbital electrical stimulus was elicited ipsilaterally during both sessions
before and during each intervention. The main outcome variables were the
number of recorded blinks, area under the curve and latencies of the R2
components of the nociceptive blink reflex. Participants also rated the intensity of
referred head pain and the supraorbital stimulus on a scale of 0-10, where 0 = “no
pain” and 10 = “intolerable pain,” and rated the intensity of applied pressure
where 0 = “pressure but no pain” and 10 = “intolerable pain.”
Results.—Participants reported a significant reduction in local tenderness
ratings across the 4 trials for the cervical intervention but not for the arm (P =
.005). The cervical intervention evoked head pain in all participants. As the
cervical intervention was sustained, head pain decreased significantly from the
beginning to the end of each trial (P = .000) and from the beginning of the first trial
to the end of the last (P = .000). Pain evoked by the supraorbital stimulus was
consistent from baseline to across the 4 trials (P = .635) and was similar for the
cervical and arm interventions (P = .072). The number of blinks decreased
significantly across the experiment (P = .000) and was comparable in the cervical
and arm interventions (P = .624). While the R2 area under the curve decreased
irrespective of intervention (P = .000), this reduction was significantly greater for
the cervical intervention than when pressure was applied to the arm (P =
.037).Analysis of the R2 latencies revealed a notable increase across the experiment
(P = .037). However, this increase was significantly greater following the cervical
than arm intervention (P = .012).
Conclusions.—Our findings corroborate previous results related to
anatomical and functional convergence of trigeminal and cervical afferent
145
pathways in animals and humans, and suggest that manual cervical modulation of
this pathway is of potential benefit in migraine.
Key words: migraine, nociceptive blink reflex, central sensitization, cervical
headache
Abbreviations: AO atlanto-occipital, AUC area under the curve, DNIC diffuse
noxious inhibitory control, GON greater occipital nerve, nBR
nociceptive blink reflex, PAIVM passive accessory intervertebral
movement, TCN trigemino cervical nucleus
(Headache 2014;54:1035-1045)
____________________________________________________________________________________
From the School of Psychology, Murdoch University, Perth, WA, Australia
Address all correspondence to D.H. Watson, South Street, Murdoch, WA 6150,
Australia, email:dean@watsonheadache.com
Accepted for publication January 16, 2014
Temporary reproduction of usual head pain when examining structures of the
cervical spine is considered to be one of the key diagnostic criteria for cervicogenic
headache,1,2 but this might also be important in other forms of headache. For example,
we recently demonstrated reproduction of usual head pain in 95% of migraineurs3
fulfilling the International Headache Society’s Classification criteria for migraine2 when
examining the passive accessory intervertebral movements (PAIVMs) of the atlanto-
146
occipital (AO) and C2-3 spinal segments.
The extremely high incidence of reproduction of headache in migraineurs could
suggest an underlying cervicogenic basis for central sensitization of nociceptive second-
order neurons in the trigeminocervical nucleus (TCN) with subsequent hyperexcitability
to afferent stimulation.4 The notion of central sensitization considers an increased
barrage of afferent noxious information from C-fibers onto second-order neurons as
crucial in the development of this hyperexcitability.5,6 Moreover, it has been
demonstrated that stimulation of afferents from deep somatic tissues such as joints and
muscles is more effective than cutaneous input in generating central hyperexcitability.7,8
More specifically, provocation of the deep paraspinal tissues at the level of the atlanto-
axial (C1-2) spinal segment was shown to induce central sensitization in medullary and
C1-C2 dorsal horns.9
Together, these findings suggest that hyperexcitability of nociceptive second-
order neurons in the TCN could result from noxious afferent information from
dysfunctional spinal segments, thereby increasing sensitivity to subclinical afferent
information from the trigeminal field. The ensuing exaggerated information is perceived
as noxious and results in pain. In support of this possibility, central sensitization evoked
by stimulation of the greater occipital nerve (GON) resulted in occipital afferent
activation of second-order neurons in the TCN10,11 and increased excitability to dural
input.12 Further support was provided by modulation of the nociceptive blink reflex
(nBR) following blockade of the GON.13,14
The nBR is a trigeminofacial brainstem reflex and has been established as a
valid technique for assessing central trigeminal transmission.15-18 Recently, the R2
component of the nBR was examined before and after unilateral GON blocks where it
was found that the R2 latency increased and area under the curve (AUC) decreased after
GON blockade.13,14 This result provides empirical evidence for a functional influence on
147
trigeminal nociceptive inputs from cervical afferents. Conceivably, occipital activation
of the TCN represents the cervicogenic equivalent to application of an “inflammatory
soup” onto the dura that has been shown to induce central sensitization and ensuing
increased sensitivity to trigeminal inputs.19
Notwithstanding the effectiveness of GON blockades for migrainuers,20-22 the
mechanism(s) for the successful outcome remain uncertain.23 It has been postulated that
GON blockade influences central pain processing mechanisms by modulating
responses to convergent synaptic input from cervical and trigeminal nociceptive
afferents.23
In our clinical experience, patients often report lessening of their referred, usual
pain as the examination of the cervicospinal segment is sustained. The pain usually
lessens (to a variable degree, but often with complete resolution) within 90 seconds.
Moreover, sustaining the examination repeatedly results not only in decreasing intensity
of head pain referral but also in more expeditious resolution. Furthermore, patients
presenting with allodynia frequently report that after lessening of their referred pain, the
allodynia has decreased or resolved,24-26 perhaps indicating that a pre-existing central
sensitization state had diminished.
The purpose of the present study was to investigate cervical, interictal referral of
usual head pain and its effect on the nBR in migraineurs. In particular, effects of
PAIVMs of the AO and C2-3 spinal segments on referred head pain and trigeminal
nociceptive activity were examined interictally. It was hypothesized that as referred
head pain decreased, there would be a corresponding increase in latency and decrease in
the AUC of R2, reflecting a decrease in excitability of the TCN.
MATERIALS AND METHODS
Participants.—Fifteen volunteers participated in the study (14 females, 1 male;
age 24-44 years, mean age 33.3 years). All participants met the International
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Headache Society’s diagnostic classification criteria for migraine with or without aura,
experiencing 2-8 attacks of migraine within the previous 3 months.2 Each participant
had been free from migraine for at least 24 hours. Informed consent was obtained from
all participants, and the study was approved by the Ethics Committee of Murdoch
University.
PAIVM Examination.—The PAIVM examination was performed by a single
clinician (D.H.W. – Musculoskeletal Physiotherapist) with 22 years of experience,
whose practice is limited to examination and treatment of the upper cervical spine in
primary headache conditions. Intra-examiner reliability was analyzed using Cohen’s
Kappa in a previous study27 that demonstrated perfect agreement in 17 of 22 PAIVM
techniques. Of the 5 remaining tests, the lowest Kappa score was k = 0.667, P = .01,
which indicated good agreement.
Critical to our study was that usual head pain could be reproduced during the
cervical examination. Therefore, to exclude participants who did not develop head pain
during this procedure, an “inclusion/exclusion” examination was performed prior to
commencing the study. This examination also established which of the AO or C2-3
spinal segments referred usual head pain most clearly and therefore which segment
would be examined further. The PAIVM techniques have been described previously.3
In brief, this involves applying thumb pressure to the AO or C2-3 spinal segments.
All participants were examined in the supine position in 2 sessions. Each session
comprised 5 trials that were 90 seconds long and separated by 30 seconds. The nBR
was recorded during the first trial of each session, but no manual pressure was applied.
Thereafter, manual pressure was applied to either the ipsilateral common extensor
origin (lateral epicondyle of the humerus) of the arm or the AO or C2-3 segments and
was sustained for the length of each trial. The order of the examination (ie, cervical vs
arm) alternated from 1 participant to the next. Participants reported reproduction of head
149
pain with “yes” or “no” and rated the intensity of head pain ona scale of 0-10, where 0 =
“no pain” and 10 = “intolerable pain.” Participants also rated the intensity of applied
pressure where 0 = “pressure but no pain” and 10 = “intolerable pain.”
Trigeminal Nociception and Transmission.—To study trigeminal brainstem
nociception and transmission, the nBR was elicited ipsilaterally using a custom-made
planar concentric electrode. The electrode comprised a central wire cathode (diameter
0.5 mm), an isolation insert and an external anode ring, both 5 mm in diameter
providing a stimulation area of 235.5 mm.2 The electrode was placed on the forehead
10 mm above the supraorbital groove, and the nBR was recorded by 2 surface
electrodes attached below the lower eyelid and 2-3 cm laterally.18 Current intensity
(monopolar square wave pulses, 0.3 ms duration) was 2.3 mA. Main outcome variables
were the number of recorded blinks, and AUC and latencies of the R2 component of the
nBR.
The nBR was recorded during both sessions, which were separated by 30
minutes. Each session comprised 5 trials of 8 stimuli; the interstimulus interval varied
between 12 and 18 seconds. The intertribal interval was 30 seconds.
After subtracting background noise from raw blink reflex data, latencies were
established for each blink. Blinks were identified individually by inspecting each blink
in the raw data files and were defined as present if the AUC was greater than
background noise. Areas under the curve were assessed in the time window 27-87 ms
after the stimulus.28,29
Statistical Approach.—Data were analyzed using SPSS Version 16 software (SPSS,
Inc., Chicago, IL, USA). Local tenderness ratings were investigated in a 2 × 4 × 2 (site
[arm, neck]) × trial [trials 1-4] × time [start, end of each trial]) analysis of variance.
Similar analyses were computed for supraorbital pain ratings, head pain referral,
number of blinks, and R2 latency and AUC. P < .05 was considered to be statistically
150
significant in all analyses, and tests of statistical significance were 2-tailed. Where
appropriate, the Huynh–Feldt correction was used to correct for violation of the
sphericity assumption.
RESULTS
In each case, headache was reproduced during preliminary assessment of the AO
and C2-3 segments, and this referred pain ceased immediately after release of cervical
pressure. None of the participants reported head pain during application of pressure to
the arm.
F values for all main effects of interactions for all of the independent variables
are included in the Table.
Table.—F Ratios for the Main Effects and Interactions of the Dependent Variables F Ratios ______________________________________________________________________________________________ Tenderness Referred Supraorbital No. of Ratings Head pain Ratings Blinks Latency AUC ____________________________________________________________________________________ Site (cervical/arm) 0.00 – 0.80 0.59 1.31 0.78 Trials 2.32† 31.01†*** 0.64‡ 25.23‡*** 3.02‡* 13.41‡*** Time (start/end of each intervention trial) – 40.46*** – – – – Trials x time – 3.11* – – – – Site x trials 4.92** – 2.49 0.66 4.07* 2.91* ______________________________________________________________________________________________ *P < .05; **P < .01; ***P < .001. †4 intervention trials. ‡Baseline + 4 intervention trials. AUC = area under the curve.
During the cervical session, each participant reported referred head pain. As the
examination technique was sustained, head pain lessened in all participants, decreasing
significantly from the beginning to the end of each trial (main effect for time, F[1,42] =
40.46; P = .000) and from the beginning of the first trial to the end of the last (main
effect for trials, F[2.27,31.71] = 31.01; P = .000) (Fig. 1). Also notable is that referred
151
head pain at the end of each trial decreased progressively across the 4 trials when
compared with ratings at the beginning of each trial (trial × time interaction,
F[2.49,34.91] = 3.11, P =.047). The referred head pain eased immediately on cessation
of the technique at the end of each trial in all participants.
Fig 1.—Referral ratings stratified by trials. Note that not only did referral ratings decrease, but the values at the end of each trial decreased progressively across the 4 trials when compared with the values at the start of each trial.
When averaged across the 4 trials, mean ratings of tenderness to thumb pressure
were identical across the 4 trials for both interventions (F[3,42] = 0.00; P = 1.0).
However, participants reported a significant reduction in tenderness across trials during
the cervical but not the arm intervention (site X trial interaction, F[3,42] = 4.92; P =
.005) (Fig. 2).
Mean ratings of the supraorbital stimulus were similar across the 5 trials
(F[4,56] = 0.64; P = .635) and were comparable for cervical and arm interventions (site
X trial interaction, F[3.07,42.92] = 2.49; P = .072) (Fig. 3).
152
Fig 2.—Tenderness ratings stratified by trials. Note that cervical tenderness ratings decreased progressively, while those for the arm remained unchanged.
Fig 3.—Supraorbital ratings stratified by trials (trials 1 = base- line, ie, no intervention). Note that the ratings remained unchanged across the trials for both sites.
To establish a baseline for R2, blinks were elicited in the absence of either the
cervical or arm intervention during the first trial. Cervical and arm interventions were
then applied in the ensuing 4 trials. The number of blinks decreased significantly across
the 5 trials (main effect for trials, F[4,56] = 25.23; P = .000) and was comparable for
the cervical and arm interventions (site × trial interaction, F[4,56] = 0.66; P =.624) (Fig.
4).
153
Fig 4.—Number of nociceptive blink reflex stratified by trials. Note the decreasing number of blinks across the trials for both sites.
While the R2 AUC decreased irrespective of intervention (main effect for trial,
F[4,32] = 13.41; P = .000), this reduction was significantly greater for the cervical than
arm intervention (site × trial interaction, F[4,32] = 2.91; P = .037) (Fig. 5).
Fig 5.—R2 areas under the curve (AUC) stratified by trials (trial 1 = baseline, ie, no intervention). Of note is the significant decrease of AUC during the cervical but not the arm intervention.
154
Analysis of the R2 latencies revealed a notable increase across the 5 trials (main
effect for trials, F[4,24] = 3.02; P = .037). However, this increase was significantly
greater for the cervical than arm intervention (site X trial interaction, F[4,24] = 4.07; P
=.012) (Fig. 6).
No participant experienced a migraine attack for at least 48 hours following the
study.
Fig 6.—R2 latencies stratified by trials (trial 1 = baseline, ie, no intervention). Of note is the significant increase of latencies during the cervical but not the arm intervention.
DISCUSSION
In our previous study, local and referred head pain was reproduced during
manual pressure over the atlas or C2 in 95% of migraineurs.3 Similarly, in the
present study, head pain was reproduced during this procedure in all 15 participants.
Thus, referral of head pain from upper cervical structures could be an important but
underrecognized characteristic of migraine. Furthermore, after repeated application of
manual pressure, local and referred head pain decreased in parallel with decreases in the
trigeminal nBR (ie, a decrease in the AUC and increase in latency of the ipsilateral R2
waveform). To our knowledge, this is the first time a manual cervical examination
155
technique has been shown to influence trigeminal nociceptive neurotransmission.
Spinal mobilization is typically applied when dysfunctional areas of the
vertebral column are found. Clinicians utilizing manual therapy identify spinal dys-
function based on various features; among these are the ability to reproduce local and
referred pain, and restrictions in spinal joint motion.30,31 The clinician’s objective in
applying manual techniques is to restore normal motion and normalize afferent input
from the neuromusculoskeletal system.29 Despite clinical evidence for the benefits of
spinal mobilization, the biological mechanisms underlying the effects of spinal
mobilization are not known.32-34 One of the principal rationales for manual therapy
intervention is that an ongoing barrage of noxious sensory input from biomechanical
spinal dysfunction increases the excitability of neurons or circuits in the spinal cord.35-37
Mechanoreceptors including proprioceptors (muscle spindles, both primary and
secondary endings and Golgi tendon organs), low- and high-threshold
mechanoreceptors, high-threshold mechano-nociceptors, and high-threshold polymodal
nociceptors38 within deep paraspinal tissues react to mechanical deformation of these
tissues.39 A significant effect of this “biomechanical remodeling” could be restoration of
zygapophyseal joint mobility and joint “play,”40 precisely the intention of the
techniques used in this study. Thus, biomechanical remodeling resulting from
mobilization may have physiological ramifications, ultimately reducing nociceptive
input from receptive nerve endings in innervated paraspinal tissues.35,36,39
Our findings of decreased AUC and increased latency of R2 during the cervical
intervention are supported by a functional magnetic resonance imaging study in which
manual therapy was administered to the ankle joints of rats following capsaicin
injection. Subsequent to mobilization,there was decreased activation of the dorsal
horn.41 By analogy, upper cervical afferents may have an excitatory influence on
156
trigeminal circuits in migraine sufferers that can be reduced by reproduction and
lessening of usual head pain.
The reduction in the nBR during spinal mobilization is consistent with previous
studies demonstrating a functional connectivity between the cervical and the trigeminal
system in the trigeminocervical complex of the brainstem.9-12,42-44 This inhibitory effect
may be due to a general reduction of afferent cervical nociceptive/excitatory input in
the trigeminocervical complex as result of biomechanical remodeling, perhaps restoring
joint mobility and joint play,40 as inhibition of R2 was more significant than during the
arm intervention. Therefore, the highly significant reduction in head pain referral
during the cervical intervention could be a clinical correlate of lessening central
sensitization of the TCN. In particular, it is conceivable that palpation and stretch of
dysfunctional cervical paraspinal tissues elicits tenderness that lessens as remodeling
occurs.35,36,39 This could explain why tenderness ratings decreased during the cervical
intervention and not the arm for, presumably, participants’ arm tissues were not
dysfunctional and subject to remodeling.
However, the perception of pain is not only determined by the intensity of the
afferent pain signal (nociception).45 Nociceptive inputs to the dorsal horn of the spinal
cord are also influenced by potent endogenous descending inhibitory and facilitatory
processes from supraspinal regions. This bidirectional, central control incorporates a
frontal, limbic, brainstem, and spinal cord neuronexus46-49 that is driven primarily by
noxious inputs and associated emotional responses. Importantly, this includes spinal
cord activity because the spinally mediated nociceptive flexion reflex is influenced by
central pain modulation processes.50 While the exact mechanisms responsible for
emotional modulation of pain are not fully understood, heightened anxiety appears to
increase sensitivity to pain (hyperalgesia),51-68 whilemoderate fear inhibits pain
(hypoalgesia).51,69-77 This suggests that anticipation of an unpredictable, threatening
157
intervention could result in enhanced pain, while hypoalgesia results from exposure to a
predictable, threatening event (fear).51
As we did not assess the participants’ psychological state, we are unsure whether
this changed over the course of the experiment. Nevertheless, it seems unlikely that
psychological factors had a major influence on our findings for the following reasons.
First, participants were included only if usual head pain could be produced when
stressing either the AO or C2-3 segments – the “inclusion/exclusion” session. In the
case of head pain referral, both segments were examined (prior to the experimental
sessions) to ascertain which segment reproduced usual head pain most clearly.Thus,
participants experienced reproduction of their usual head pain, which ceased
immediately on cessation of the technique (ie, essentially, participants were “cued” to
believe that the procedures were not threatening). Second, participants, armed with the
knowledge that they could terminate the experimental session at any time, were in
control, further lessening the role of psychological factors.78-83 Third, pain ratings to the
supraorbital stimuli were comparable for the cervical and arm interventions, and
remained unchanged across the trials. This dissociation between pain perception and R2
activity supports the possibility that the reductions in referred head pain, cervical
tenderness, and inhibition of R2 were due to a specific “cervical,” neurophysiological
effect, rather than psychological influences.
Another possible mechanism for the inhibitory effect on pain demonstrated in
our study is that of placebo. Previous work has shown that the prospect of reduced pain
can reduce the pain reported in response to a noxious stimulus.84-88 The “inclusion/
exclusion” session provided an expectation that head pain would increase during the
interventions and cease immediately after cessation of the technique. However,
participants had no prior expectation of the likely course of referred head pain as the
technique was sustained. Accordingly, we considered that any placebo effect was
158
minimal.
An additional potential inhibitory mechanism is diffuse noxious inhibitory
controls (DNICs).The DNIC process involves inhibition of neurons in the dorsal
horn of the spinal cord in response to nociceptive stimuli applied to any part of the
body, unconnected to their facilitatory fields.89-91 However, if DNICs were
operational, we would have expected identical effects on the nBR during the arm and
cervical interventions as mean ratings of local tenderness were the same.
Limitations.—Although standardization of pressure clearly is important, for it
to be achieved during application of techniques used in this study and in a PAIVM
examination, pressure algometers would need to be devised, which are not only attach
to the thumb but are sufficiently fine to allow for skilled palpation and perception of
mobility. The absence of such a device in our study could be regarded as a shortcoming.
The sample size could also be considered a limitation; nevertheless, effects of the
cervical intervention were strong enoughto be detected even in our small sample.
Perception and self-reporting of pain clearly involve psychological influences such as
anxiety and fear. These influences need to be investigated in future studies.
CONCLUSIONS
To our knowledge, this is the first time cervical manual examination techniques
have been shown to influence trigeminal nociceptive neurotransmission. Our results
suggest that cervical spinal input contributed to lessening of referred head pain and
cervical tenderness, and inhibition of R2. These findings support the concept that
noxious cervical afferent inputs contribute to headache in migraine sufferers. They
corroborate previous results related to anatomical and functional convergence of
trigeminal and cervical afferent pathways in animals and humans, and suggest that
manual modulation of the cervical pathway is of potential benefit in migraine.
159
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Peter D. Drummond; Dean H. Watson
(b) Acquisition of Data
Dean H. Watson
(c) Analysis and Interpretation of Data
Peter D. Drummond; Dean H. Watson
Category 2
(a) Drafting the Manuscript
Dean H. Watson; Peter D. Drummond
(b) Revising It for Intellectual Content
Dean H. Watson; Peter D. Drummond
Category 3
(a) Final Approval of the Completed Manuscript
Peter D. Drummond; Dean H. Watson
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170
CHAPTER 7
THE TRIGEMINO CERVICAL COMPLEX AND CHRONIC WHIPLASH
ASSOCIATED HEADACHE: A CROSS-SECTIONAL STUDY
7.1 Introduction
It has been established that the symptomatic profile of chronic whiplash
associated headache (CWAH) mirrors that of primary headache.1-9 A substantial body
of evidence suggests that cervical afferent nociceptors (C2-3 zygapophyseal joint) play
a pivotal role in the genesis of CWAH.10-31
Studies utilising R2 (the nociceptive blink reflex) have demonstrated deficient
habituation32-36 and facilitation (sensitisation)37-40 in migraine. These features are
recognised to be genuine traits of the migraine condition. Therefore, we sought to
investigate whether, along with similar symptomatic profiles, migraine and CWAH
share these characteristics, thereby supporting cervical afferent nociceptors as a
potential sensitising source of the TCN in migraineurs.
171
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7.2 Study 3.
This is a reprint of an article accepted for publication in Headache: Journal of
Head and Face Pain. In Press. Copyright is owned by the American Headache Society.
The Trigemino Cervical Complex And Chronic Whiplash Associated Headache: A
Cross-Sectional Study.
Dean H. Watson, MAppSc; Peter D. Drummond, PhD
Objective.—To investigate signs of central sensitization in a cohort of
patients with chronic whiplash associated headache (CWAH).
Background.— Central sensitization is one of the mechanisms leading to
chronicity of primary headache, and thus might contribute to CWAH. However,
the pathophysiological mechanism of CWAH is poorly understood and whether it
is simply an expression of the primary headache or has a distinct pathogenesis
remains unclear. Thus, the factors involved in the genesis of CWAH require
further investigation.
Methods.—Twenty-two patients with CWAH (20 females, 2 males; age 25-
50 years, mean age 36.3 years) and 25 asymptomatic participants (13 females, 12
males; age 18-50 years, mean age 35.6 years) rated glare and light-induced
discomfort in response to light from an ophthalmoscope. Hyperalgesia evoked by a
pressure algometer was assessed bilaterally on the forehead, temples, occipital base
and the middle phalanx of the third finger. The number, latency, area under the
curve and recovery cycle of nociceptive blink reflexes elicited by a supraorbital
electrical stimulus were also recorded.
177
Results.—Eight and 6 CWAH patients had migrainous and tension-type
headache (TTH) profiles respectively; the remainder had features attributable to
both migraine and TTH. Patients in the whiplash group reported significantly
greater light-induced pain than controls (8.48 ± .35 versus 6.66 ± .43 on a 0-10
scale; p=0.001). The CWAH patients reported significantly lower pressure pain
thresholds at all sites. For stimuli delivered at 20 second intervals, whiplash
patients were more responsive than controls (4.8 ± .6 blinks versus 3.0 ± .6 blinks
in a block of 10 stimuli; p=0.036). Whilst R2 latencies and the AUC for the 20
second interval trials were comparable in both groups, there was a significant
reduction of the area under the curve from the first to the second of the 2-second
interval trials only in controls (99 ± 8 percent of baseline in whiplash patients
versus 68 ± 7 percent in controls; p=.009). The recovery cycle was comparable for
both groups.
Conclusions.— Our results corroborate previous findings of mechanical
hypersensitivity and photophobia in CWAH patients. The neurophysiological data
provide further evidence for hyperexcitability in central nociceptive pathways, and
endorse the hypothesis that CWAH may be driven by central sensitization.
Key words: Whiplash, Chronic whiplash associated headache, migraine, Tension-
type headache, nociceptive blink reflex, central sensitization, sensory
hyperalgesia, photophobia, recovery cycle
Abbreviations: CWAH chronic whiplash associated headache, TTH tension-type
headache, CTTH chronic tension-type headache, AUC area under
the curve
______________________________________________________________________
178
From the School of Psychology and Exercise Science, Murdoch University, Perth,
WA, Australia
Address all correspondence to D.H. Watson, South Street, Murdoch, WA 6150,
Australia, email:dean@watsonheadache.com
Accepted for publication 15th February 2016
Chronic whiplash associated headache (CWAH) is a relatively new diagnostic
entity in the ICHD-2 (5.4).41 To fulfill the criteria for this diagnosis, headache and neck
pain must develop within 7 days of a whiplash trauma (i.e., an extension of the neck
followed by flexion), which persists for at least 3 months. Whiplash associated
disorders are controversial concepts, primarily because a lack of objective biomarkers
prevents a precise diagnosis.3,7,42-44
Whiplash trauma may generate CWAH. It would seem plausible, therefore, to
assume that the trauma produces a permanent disorder that preserves the pain.7 Chronic
whiplash associated headache resembles various forms of primary headache, for
example chronic tension-type headache (CTTH), chronic migraine, or cluster
headache,1-6,45 and neck pain often accompanies the most prevalent primary headaches.1
Therefore, as CWAH and primary headache share similar symptomatic profiles,
potentially CWAH could share a common mechanism with primary headache
syndromes.9 Central sensitization is one of the mechanisms leading to chronicity of
headache,5,46-49 and thus might contribute to CWAH. However, the pathophysiological
mechanism of CWAH is poorly understood and whether it is simply an expression of
179
the primary headache or has a distinct pathogenesis remains unclear.5 Thus, the factors
involved in the genesis of CWAH require further investigation.
Cutaneous allodynia is a notable feature of migraine and other primary
headaches,48,50-55 and is thought to be caused by sensitization of central second-order
neurons, which receive dual input from the trigeminal and cervical fields.53,56 Cutaneous
allodynia is considered a manifestation of central sensitization and a risk factor for the
chronification of migraine 48,49 and tension-type headache.54 Chronic pain following
injury is often associated with centrally mediated hyperalgesia or allodynia. 57 Not
surprisingly, therefore, allodynia and hyperalgesia have been demonstrated in patients
with chronic whiplash associated disorders and, as in migraine and CTTH, occurs not
only in the cervical region but also at distant sites.58-65 This characteristic of chronic
whiplash associated disorders is attributed to hyperexcitability of nociceptive circuits
within the central nervous system.66-68
Photophobia is also a feature of primary headache,69,70 and is a fundamental aspect
of the diagnostic criteria for migraine.1 Photophobia can be evaluated in two ways – the
perception of ‘brightness’ or ‘glare’, and the level of discomfort evoked by light.71
Photophobia may result from a lack of sub cortical inhibitory influences which
ordinarily modulate sensations of glare and light induced pain.72 This is supported by a
recent study which demonstrated activation of neurons in the trigemino cervical nucleus
in response to a bright light stimulus.73 Studies eliciting the nociception specific R2
component of the nociceptive blink reflex have demonstrated a lack of habituation in
the interictal phase of migraine, which implies abnormal trigeminal nociceptive
processing in migraine patients. 34,74 This deficient habituation seems to reflect a
consistent interictal trait of migraine patients.75,76 The R2 response can be inhibited by a
180
preceding conditioning stimulus, and its recovery-curve after paired stimuli is thought
to reflect the excitability of the trigemino-brainstem-facial circuit.77,78 In a study of the
classical R2 blink reflex79 faster recovery for migraineurs than controls was thought to
demonstrate trigeminal hyperexcitability.
The aim of the present study was to investigate signs of central sensitization of the
trigemino cervical nucleus in CWAH patients. It was hypothesised that CWAH patients
would manifest photophobia, sensory hyperalgesia and alterations of R2 concomitant
with hyperexcitability of the trigemino cervical nucleus.
MATERIALS AND METHODS
Participants. – Patients fulfilling the International Headache Society’s
classification diagnostic criteria of chronic post whiplash headache41 were invited to
participate in the study. Furthermore, in accordance with the diagnostic criteria of
chronicity of TTH1 and migraine,1 patients experienced headache on at least 15 days per
month. Twenty-two headache patients (20 females; age range 25-50 years, mean age =
36.3 years) who had experienced whiplash trauma in a motor vehicle accident, were
recruited from various physiotherapy clinics. Friends, family and associates of patients
attending the first author’s clinic were invited to participate as non headache controls.
Participants in the non-headache group (N=25; 13 females; age range 18-50 years, mean
age = 35.6 years), were either headache-free or experienced mild non-migrainous
headache no more than six times per year. Sample sizes were based on similar previous
studies investigating allodynia in chronic whiplash patients,58,61,62,80 photophobia
(chronic whiplash patients),80 glare and light induced pain (migraineurs),71 and the
nociceptive blink reflex (migraineurs).34-36,38,39,81
181
Participants were enrolled independently of the experimenter (DW) to ensure
that he remained blind to the participant’s diagnostic category. Data collection
commenced in March 2009 and was completed in September 2009. Every endeavour
was made to examine patients interictally. All participants signed an informed consent
form. Ethics approval was obtained from the Ethics Committee of Murdoch University.
Photophobia. – In the first part of the experiment, an ophthalmoscope light
(WelchAllyn PocketScope) was shone directly into participants’ eyes for 10 seconds
from a distance of 10 cm. Each eye was tested separately, with ~60s between tests.
Initially the ophthalmoscope was adjusted to 50% intensity and subjects rated the glare
on a scale of 0-10 where 0 corresponded to “not glary”, 1 to ‘glary’ and 10 to ‘the most
dazzling light they had ever seen’. Then the ophthalmoscope was adjusted to maximum
intensity and participants rated light induced pain on a 0-10 scale where 0 corresponded
to ‘not at all painful’ and 10 to ‘extremely painful’. 71
Sensory hyperalgesia. – Next, a pressure algometer (Wagner Force Gage FPX
50; (flat) surface area = .5 inch) was applied bilaterally to the forehead, temples, base of
the occiput and the posterior aspect of the middle phalanx of the third finger. Pressure
was increased at one pound force per second. Participants were asked to report
immediately when the sensation of pressure became uncomfortable. Sites were tested in
random order, with a recovery period of at least 3 minutes between each application.
The reliability of pressure algometry has been found to be high [intraclass correlation
coefficient (ICC) 0.91, 95% confidence interval 0.82, 0.97].82
Trigeminal nociception. – In the final part of the study, the nociceptive blink
reflex was elicited with a custom-built planar concentric electrode, placed on the
forehead, ipsilateral to the side of headache or worst side of headache, 10 mm above the
supraorbital groove. Blink reflexes were recorded from surface electrodes placed below
182
the lower eyelids and 2-3 cm laterally.39 Current intensity was 2.3 mA (mono polar
square wave pulses, 0.3 ms duration). This current intensity elicits R2, but not R1,
consistent with excitation of superficial nociceptors but not of the deeper A-beta non
nociceptive fibres.83 Outcome variables were the number of recorded blinks, the
recovery curve, the response area under the rectified curve (AUC), and latency of the
R2 component of the nociceptive blink reflex.
After subtracting background noise from raw blink reflex data, latencies were
established for each blink. Blinks were identified individually by inspecting each
waveform in the raw data files and were defined as present if the R2 component of the
AUC was greater than background noise. Areas under the curve were assessed in the
time window 27-87 ms after the stimulus.83,84
The recovery curve was examined by delivering paired shocks at different inter
stimulus intervals. 77,79 The initial component of the recovery curve was established
using eight pairs of stimuli; inter stimulus interval 100 ms; each pair separated by two
seconds. Five minutes later this was repeated except that the inter stimulus interval was
500 ms. The recovery curve was calculated as a percentage of the second of the paired
stimuli to the conditioning stimulus.
This was followed 10 minutes later by four blocks of 10 stimuli; each block was
separated by 40 seconds. The inter stimulus interval in the first two blocks was two
seconds and 20 seconds in the remaining two blocks.
Statistical Approach.— Data were analyzed using SPSS Version 16 software
(SPSS, Inc., Chicago, IL, USA). Pressure pain thresholds were investigated in a 4 x 2 x
2 (site [forehead, temples, occiput, fingers] x (group [whiplash, control] x side [left,
right]) analysis of variance (ANOVA). Tests of statistical significance were based on
183
Pillai’s trace (VPillai), and significant effects were investigated further in ANOVAs for
each site. Differences between female patients and female controls, between male and
female controls, and between phenotypic subgroups (chronic migraine, CTTH, or a
combination of both) were investigated in exploratory analyses. Sensitivity to light
(glare, and light induced discomfort ratings) was examined in a multivariate ANOVA
using a similar approach. The number of blinks to nociceptive stimuli (defined as an R2
component greater than background noise) was investigated in a group [whiplash,
control] x block [number of blinks in the first ten trials versus the number of blinks in
the next ten trials] x inter-stimulus interval [2 s, 20 s] repeated measures ANOVA. As
some patients did not blink in response to the nociceptive stimuli, R2 AUC and R2
latency were each investigated separately for stimuli presented at 2 s and 20 s intervals
to allow most use of the available data. R2 latency was investigated in 2 x 2 (group
[whiplash, control] x block [first 10 stimuli, second 10 stimuli]) ANOVAs for stimuli
presented at 2 s and 20 s intervals. As R2 AUC was expressed as the percent change
from baseline (the first block of stimuli or the first of two paired stimuli), differences
between patients and controls were investigated at each inter-stimulus interval with
Student’s t-test. To limit type 1 errors in analyses of R2 latency and R2 AUC for stimuli
presented at 2 s and 20 s intervals, the criterion of statistical significance was adjusted
using Bonferroni’s correction (i.e., p<0.025 was considered to be statistically
significant). For all other tests, p < .05 was considered to be statistically significant;
tests of statistical significance were 2-tailed. Results are reported as the mean ± standard
error (SE).
RESULTS
Group characteristics.— Eight patients fulfilled the requirements for chronic
migraine;1 alternating head pain was a feature in five. Six patients met the criteria for
184
CTTH,1 whilst the remainder (n = 8) presented with features attributable to both TTH
and migraine. The number of headache days per month ranged from 15 to 30 (M=22.1,
SD=6.0). Two of the migraine patients, one in the TTH group and another with
symptoms common to TTH and migraine, had suffered direct head trauma. The mean
history was 6.16 years.
Two patients reported a previous history of migraine. Both reported significantly
increased frequency after the whiplash injury; one also reported that her previously
side-locked migraine now alternated and that she had also developed daily lesser
headache resembling TTH. Similarly, two patients with features of TTH reported
substantial increases in frequency of pre-existing infrequent episodic TTH. Of the
remaining 18 patients, 10 experienced mild non-migrainous headache no more than six
times per year before the whiplash injury and eight could not recall ever having
experienced headache.
Three patients from each of the TTH cohort and the group comprising patients
presenting with a combination of TTH and migrainous symptoms presented with
headache at the time of assessment. The intensity of headache on a visual analogue
scale (0 = no pain; 10 = intolerable pain) ranged from 2 to 4.
Eighty-six percent of patients reported associated neck symptoms (pain and/or
stiffness) (Table 1). Bilateral headache was described by 63.6% of patients, and 54.5%
reported unilateral headache; 66.6% of these alternated. Head pain occurred most
commonly frontally (63.6%). Aching/pressure was reported by 63.6% of patients,
pulsating (45.5%) and sharp/stabbing in 9.1%. Sixty-eight percent and 45.5% of patients
reported nausea and vomiting respectively; photo and/or phonophobia occurred in
54.5% of patients.
185
Table 1. Clinical characteristics of whiplash subjects (n=22)
Clinical characteristics
Tension-type
headache (n = 6)
Migraine (n = 8)
Mixed (n = 8)
Cervical symptoms
4
7
8
Bilateral
6
8
Unilateral
8
4
Alternating
6
2
Temporal 3
1
4
Frontal 6 4 4
Retro orbital 4 3
Occipital 4 2 2
Ache/Pressure
6
8
Pulsating
8
2
Sharp/stabbing
2
Nausea
8
7
Vomiting
4
6
Photo/phonophobia
6
6
Sensory hyperalgesia. – Pressure pain thresholds differed across sites [VPillai =
0.91, multivariate F(3,43) = 150.4, p<0.001] (Figure 1). Follow-up tests with
Bonferroni’s adjustment indicated that pressure pain thresholds were lower in the
temples than at all other sites, and higher in the fingers than at all other sites. However,
pressure pain thresholds were similar in the forehead and occipital region.
186
At all sites, pressure pain thresholds were significantly lower in CWAH patients
than controls [main effect for group F(1,45) = 17.3, p<0.001; forehead (3.93 ± .29
versus F(1,45)=30.5; p=0.001); occiput (4.2 ± .41 versus 5.41 ± .51 lbf; F(1,45)=13.31;
4.84 ± .33 lbf; F(1,45)=14.61; p=0.001)] temples (2.15 ± .19 versus 3.10 ± .24 lbf;
p=0.001); finger (11.77 ± .94 versus 14.34 ± 1.17 lbf; F(1,45)=9.40; p=0.004] (Figures
1a, b, c, and d respectively). In exploratory analyses, pressure pain thresholds were
similar at all sites in patients with chronic migraine, CTTH or a combination of both.
Figure 1. — Pressure pain thresholds (PPT) ± S.E. at the different sites. Note that at all sites pressure pain thresholds were lower in the whiplash group.
Pressure pain thresholds were lower for the left temple than the right (2.5 ± .14
versus 2.75 ± .20 lbf; F(1,45)=8.52; p=0.005) (Figure 1b) but there were no other
significant differences between sides [site x side interaction VPillai = 0.33, multivariate
F(3,43) = 6.95, p=0.001].
187
By-and-large, pressure pain thresholds were lower in female patients than
female controls [main effect for group F(1,31) = 4.65, p=0.039] (Table 2). Within the
control group, pressure pain thresholds were significantly lower at all sites in females
than males [main effect for gender F(1,23) = 8.73, p=0.007] (Table 3).
Photophobia. – Overall, sensitivity to light was greater in patients than controls
[VPillai = 0.34, multivariate F(2,44) = 11.1, p<0.001]. Univariate analyses indicated that
Table 2. Photophobia and Pressure pain thresholds in female patients and female controls.
Mean ± S.E.
Patients (N = 20) Controls (N = 13)
Photophobia (0-10)** Glare 4.79 ± 0.4 4.5 ± 0.5
Discomfort
8.48 ± 0.35
6.66 ± 0.43*
Pressure pain thresholds (lbf)***
Forehead 3.93 ± 0.29 4.84 ± 0.36
Temples 2.15 ± 0.19 3.1 ± 0.24*
Occipital 4.2 ± 0.41 5.41 ± 0.51
Finger 11.77 ± 0.94 14.34 ± 1.17
* p<0.01 between patients and controls ** rated on a 0-10 scale *** units of force measured in pounds force (lbf)
glare ratings were similar in patients and controls (4.79 ± .4 versus 4.5 ± .5 on a 0-10
scale; F(1,45)=1.68; p=0.202) (Figure 2a). However, the CWAH group reported
significantly greater light-induced pain than controls (8.48 ± .35 versus 6.66 ± .43 on a
188
0-10 scale; F(1,45)=22.61; p=0.001) (Figure 2b). In exploratory analyses, ratings of
glare and light-induced pain were similar in patients with chronic migraine, CTTH or a
combination of both.
Glare (4.95 ± .33 versus 4.34 ± .33 on a 0-10 scale; F(1,45)=5.85; p=0.020) and
light-induced pain (7.0 ± .29 versus 7.43 ± .33 on a 0-10 scale; F(1,45)=6.02; p=0.018)
were greater on the right than left side in both groups [VPillai = 0.17, multivariate F(2,44)
= 4.61, p=0.015].
Table 3. Photophobia and Pressure pain thresholds in female and male controls.
Mean ± S.E.
Females (N=13)
Males (N=12)
F values
P values
Photophobia (0-10)*
Glare
4.50 ± 0.42
4.20 ± 0.44
F(1,23) = 0.17
P = 0.69
Discomfort
6.65 ± 0.48
6.30 ± 0.50
F(1,23) = 0.57
P = 0.57
Pressure pain thresholds (lbf)**
Forehead
4.48 ± 0.38
6.24 ± 0.40
F(1,23) = 6.45
P = 0.02
Temples
3.10 ± 0.24
4.28 ± 0.25
F(1,23) = 11.88
P < 0.002
Occiput
5.41 ± 0.56
7.47 ± 0.58
F(1,23) = 6.49
P = 0.02
Finger
14.34 ± 1.26
18.14 ± 1.31
F(1,23) = 4.42
P = 0.05
* rated on a 0-10 scale ** units of force measured in pounds force (lbf)
In general, female patients were more sensitive to light than female controls
[VPillai = 0.27, multivariate F(2,30) = 5.42, p=0.010]. Specifically, ratings of light-
189
induced discomfort were greater in female patients than in female controls (8.5 ± 0.35
versus 6.7 ± 0.43 on a 0-10 scale; F(1,31)=10.8; p=0.003) (Table 2). Glare and light-
induced discomfort were comparable in female and male controls (Table 3).
Nociceptive Blink Reflex. – The number of blinks decreased significantly
across the two 10-trial blocks of stimuli when stimuli were delivered at two-second
intervals (4.19 ± .46 versus 2.78 ± .4; F(1,38)=33.26; p=0.001) but remained stable
Figure 2. — ‘Glare’ and ‘Pain’ ratings ± S.E.. Note the significantly higher ratings for ‘Pain’ in the Whiplash group but not for ‘Glare’.
when stimuli were delivered at 20-second intervals [main effect for block, F(1,38) =
17.7, p<0.001; block x interval interaction, F(1,38) = 6.94, p = 0.012]. By-and large, the
number of blinks was greater for patients than controls [main effect for group, F(1,38) =
4.75, p = 0.036]. (Figure 3). This may have been due, in part, to gender differences
between groups because the number of blinks was similar in female patients and
controls [main effect for group, F(1,26) = 0.43, p = 0.519]. Nevertheless, any gender
effect appeared to be small because the number of blinks was similar in male and
female controls [main effect for gender, F(1,19) = 3.73, p = 0.069]. In an exploratory
analysis, the number of blinks was similar in patients with chronic migraine, CTTH or a
combination of both.
190
R2 latencies were similar in both groups (Figure 4). Similarly, the change in R2
AUC from the first to the second block of trials was comparable in both groups for the
20-second inter stimulus interval trials.
However, in the two-second inter stimulus interval trials, R2 AUC decreased from
the first to the second block of stimuli only in controls [99 ± 8 percent of baseline in
whiplash patients vs 68 ± 7 percent in controls; t(28)= 2.804; p=0.009] (Figure 5).
Figure 3. — Number of blinks (No. nBR) ± S.E. stratified by trials. The number of blinks was greater in the whiplash group. (ISI: inter stimulus interval)
Figure 4. — R2 latencies ± S.E. stratified by trials. (ISI: inter stimulus interval)
191
The RC of R2 was comparable for the CWAH and control groups across both
the100 ms (Figure 6a) and 500 ms trials (Figure 6b).
As some of the females did not respond to the nociceptive stimuli, numbers were
insufficient to compare R2 latency or AUC in female patients and controls. Similarly,
numbers were insufficient to compare R2 latency or AUC across groups with chronic
migraine, CTTH or their combination.
Figure 5. — R2 area under the curve (AUC) ± S.E. stratified by trials. Note the significant increase in AUC for the whiplash group in the 2 second ISI (inter stimulus interval) trial compared with the control group.
Figure 6. — Recovery curve (RC) stratified by trials. Note the recovery curves were comparable for both groups. (ISI: inter stimulus interval)
192
DISCUSSION
We identified sensory hyperalgesia, photophobia, and modifications of R2 in the
CWAH group. These features are consistent with central sensitization and are
comparable to primary headache conditions. In addition, there were no differences
between the separate headache phenotypes when pressure pain threshold, glare, light
induced pain ratings and number of blinks were considered. This supports a common
pathogenesis to migraine, TTH 85-87 and CWAH. Indeed, the shared clinical features of
patients in our study (Table 1) and primary headache is in accordance with previous
studies,1,2,4-7,42,45,46 and reinforces the possibility that CWAH shares a common
mechanism with primary headache.4 In contrast to previous studies, in which the
majority of patients presented with profiles similar to TTH,3,7 our patients favoured a
migrainous presentation (Table 1).
Eighty-six percent of patients reported accompanying cervical pain, which is a
common feature of primary headache.3,88 The term ‘Whiplash’ describes a mechanical
event.89 Accordingly, clinical and biomechanical studies have identified the cervical
zygapophyseal joints as the most common source of injury and accompanying neck and
head pain,10,14-16,18,20,21 and have demonstrated that movements of the upper cervical
segments during motor vehicle accidents can exceed physiological limits. 25-27 Indeed,
the location of symptomatic joints is consistent with the location predicted by
biomechanical studies: joints at C5-6 or C6-7 and at C2-3 are most commonly affected.
11,24,27,28 Furthermore, in a positron emission tomography study, tracer uptake in
proximity to the second cervical vertebra was significantly greater in CWAH patients
than controls, indicating local persistent peripheral tissue inflammation.90 In-vivo
animal models indicate that tissue injury leads to modifications in nociceptor activation,
immediate and sustained dysfunction in afferents and spinal neurons, neuroplastic
193
changes and pain.91-97 Together, these findings provide a compelling case for cervical
afferents being a peripheral driver of CWAH.
Sensitivity to mechanical stimulation 48,50-55,98-102 and light 41,69,70 are considered
intrinsic characteristics of the primary headaches. In accordance with previous studies,
58-63,103-105 pressure-pain thresholds were lower in CWAH patients than in controls,
including sites remote from the cervical and trigeminal fields. Our finding of decreased
pressure pain thresholds in female patients is consistent with previous findings of
mechanical hypersensitivity in female migraineurs.18 Whilst in our cohort of participants
females outnumbered males significantly (i.e. 33:14), only two (CWAH females)
reported a prior history of migraine. Therefore, although we cannot exclude the
possibility of sensory hyperalgesia (and photophobia) being present pre injury, the
absence of significant previous histories lessens potential gender bias of our findings.
The mechanism for asymmetrical perception is unknown, but perhaps indicates
asymmetry of pain modulation processes 106-108 and could explain our finding of lower
pressure-pain thresholds on the left at the temples (Figure 1). The significant presence
of cephalic, cervical and remote sensory hyperalgesia in patients with CWAH mirrors
the presentation of primary headache 48,50-55,98-102,109 and is considered a clinical
manifestation of central sensitization. 52,110,111
Given this centrally-sensitized environment, the augmentation of light-induced
pain in our CWAH group is not surprising. This combination of sensory hyperalgesia
and light-induced pain suggests that, in those with CWAH, light may have a relevant
role in trigeminal and cervical pain perception thresholds for, whilst the mechanism of
photophobia remains unclear, 71-73 involvement of converging visual and trigeminal
nociceptive activity is likely.71,112 Because of converging trigeminal and retinal afferents
194
on thalamic neurons, these neurons interpret light as a nociceptive signal.113 This is
supported by an animal study in which increased activity of neurons in the trigemino
cervical nucleus was noted when exposed to light, a finding that was interpreted as a
nociceptive (photophobic) response.73 Glare and light-induced pain were greater on the
right side than the left, possibly because headaches had a right-sided bias in most of our
patients. This is in accordance with an early study in which light-induced pain was
greater on the symptomatic side in 19 of 25 patients with unilateral headache.70
Symptoms of trigeminal excitability, such as ice cream headache and icepick-like pains,
are often most intense at the habitual site of headache,114 suggesting that trigeminal
hyperexcitability persists between headache episodes. Thus, it is intriguing that
sensitivity to blunt pressure was greater in the left temple than the right, despite the
opposite trend for visual discomfort.
That central sensitization could be responsible for the sensory hypersensitivity and
photophobia demonstrated in our CWAH patients is supported by our
neurophysiological findings of a significant delay in habituation in area under the curve
in the two-second inter stimulus interval trial, and more blinks to trigeminal nociceptive
stimuli in CWAH patients. These findings reinforce those of an earlier study
demonstrating altered central pain control in CWAH patients.115 Furthermore, the larger
number of blinks in the CWAH patients parallels migraine, as deficient habituation of
R2 interictally is considered a trait of the migraine condition. 34,74-76 However, these
findings should be interpreted cautiously as latencies were similar in CWAH patients
and controls, as was AUC in the 20 second inter stimulus interval and recovery curve
trials.
195
Whilst the mechanisms underlying sensory hypersensitivity and photophobia
remain unclear, peripheral, spinal, and supraspinal involvement has been
proposed.67,80,116 However, consistent with cervical musculoskeletal involvement in the
‘whiplash’ mechanism and the considerable evidence incriminating the cervical
zygapophyseal joints, 10,14-21 it seems plausible that a peripheral mechanism drives
central hyperexcitability.57,117 This is reinforced by demonstrable alterations in neuronal
excitability in the spinal cord secondary to ongoing peripheral nociception. 92,95,96,118
Furthermore, a recent study has demonstrated significant concomitant diminution of
recognised central sensitization measures in association with improved cervical
movement.119 This finding strengthens the notion that chronic pain in cervical whiplash
patients could be maintained by peripheral nociceptive input.57,119 In addition,
amelioration of widespread sensory hyperalgesia has occurred following medial branch
blocks of cervical zygapophyseal joints 61 and anesthetic injections of cervical
myofascial trigger points.80 Moreover, anesthetic injections of cervical myofascial
trigger points also resolved photophobia.80
Psychological distress is considered a feature of chronic whiplash.120 As we did
not assess participants’ psychological state, we cannot be certain of the influence of
psychological factors on our data. However, some evidence suggests that whilst
psychological distress may be present it is not solely responsible for central
sensitization. 61,80,119-121
Nine of our CWAH patients were involved in litigation. It has been suggested
that litigation or monetary issues may amplify chronic symptoms of whiplash,122 and
whilst we cannot exclude litigation factors we think this was unlikely to have had a
major influence on our findings given our neurophysiological data.
196
Limitations.— The sample size could be considered a limitation; nevertheless,
significant differences between groups in the pressure-pain threshold and light induced
pain suggest that the complexion of our data would be unaffected by a larger sample.
Whilst we surmise that augmentation of light induced pain suggests central
sensitisation, we acknowledge that there have been no formal studies validating this.
Perception and self-reporting of pain clearly involve psychological influences, and these
need to be investigated in future studies. Controls and patients were not matched for
gender and therefore we investigated (i) photophobia and pressure pain thresholds in
men and women in the control group and also (ii) ran separate analyses for female
patients versus female controls. Despite women being more sensitive to pressure-pain
than men, nevertheless tenderness was greater in female patients than female controls.
We inferred central sensitization by the presence of photophobia and hyperalgesia to
pressure-pain in the forehead, temples, neck and fingers, and of delayed habituation to
trigeminal nociceptive stimuli. However, this could be investigated further using
additional tests (e.g., of temporal summation to punctate or thermal stimuli, and the
integrity of conditioned pain modulation). Furthermore, additional support for central
sensitisation in CWAH may be furnished by future studies comparing CWAH patients
with a group of patients with acute whiplash associated headache. Phenotyping our
cohort of CWAH patients using dependent variables employed in this study failed to
differentiate between patients with features of chronic migraine, CTTH or their
combination. Whilst this could suggest a common mechanism across chronic migraine,
CTTH and CWAH, larger samples would be needed to corroborate this finding.
CONCLUSIONS
Our data confirm previous findings of sensory hypersensitivity and photophobia
in CWAH patients, providing further evidence for hyperexcitability in central
197
nociceptive pathways. To our knowledge, this the first study to investigate R2 in
CWAH patients. Our neurophysiological data provide additional endorsement for the
hypothesis that CWAH may be driven by central sensitization. Furthermore, whilst
additional mechanisms are probably involved in CWAH, considerable evidence
supports the role of spinal afferents as the primary driver of CWAH.
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Peter D. Drummond; Dean H. Watson
(b) Acquisition of Data
Dean H. Watson
(c) Analysis and Interpretation of Data
Peter D. Drummond; Dean H. Watson
Category 2
(a) Drafting the Manuscript
Dean H. Watson; Peter D. Drummond
(b) Revising It for Intellectual Content
Dean H. Watson; Peter D. Drummond
Category 3
(a) Final Approval of the Completed Manuscript
Peter D. Drummond; Dean H. Watson
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212
CHAPTER 8
CONCLUSION
8.1 Summary of the three studies
The aim of the three studies (sections 5.2, 6.2, 7.2) was to investigate a potential
sensitizing role of the upper cervical (C1-3) afferents on the trigemino cervical nucleus
(TCN) in primary headache.
In the study presented in Chapter 5 (section 5.2), the incidence of manual
cervical referral of accustomed head pain was investigated in migraine and tension-type
headache (TTH) patients. Referral of accustomed head pain was reported by 95 and 100
percent of 20 migraineurs and 14 TTH patients respectively. In addition, reproduction
of accustomed head pain occurred from both the (cervical) C2-3 and atlanto occipital
segments in all subjects who experienced head pain referral.
The second study (section 6.2) investigated the clinical phenomenon of manual
cervical reproduction and resolution (while the examination technique was sustained) of
accustomed head pain in 15 migraineurs and its effect on a TCN reflex, the nociceptive
blink reflex. Sustaining the examination technique over four 90 second trials resulted in
significant lessening of referred accustomed head pain and local tenderness. In parallel,
a significant increase and decrease of nociceptive blink reflex (R2 nBR) latencies and
area under the curve (AUC) respectively, was demonstrated.
The symptomatic profiles of chronic whiplash associated headache (CWAH)
mimic those of primary headache, implying a shared pathophysiological mechanism. If
213
this were the case, then given ‘whiplash’ is considered a musculoskeletal event, a
sensitizing role of cervical afferents in primary headache becomes a possibility. This
was the subject of the third study (section 7.2). The symptomatic profiles of 22 CWAH
patients confirmed previous studies, mimicking profiles of primary headache. Patients
with CWAH reported significant photophobia and hyperalgesia when compared to
controls (n=25). Analysis of R2 nBR was consistent with hyperexcitability in central
nociceptive pathways in CWAH patients.
8.2 Limitations
The sample sizes in all three studies (sections 5.2, 6.2, 7.2) could be considered
a limitation. However the very high incidence of head pain referral in study one
suggests that the result would be replicated in a larger cohort. Similarly, in study two
(section 6.2) the effects of the cervical intervention were convincing, and in study three
(section 7.2), highly significant differences between the CWAH and control group in
the pressure pain thresholds and light induced pain were demonstrated regardless of
small sample sizes.
In study one (section 5.2), the examiner was not blinded when assessing head
pain referral in patients and controls, which could be considered a limitation. However,
tenderness ratings for thumb pressure between controls and symptomatic groups were
comparable, lessening this possibility. Furthermore, there was no prior assumption that
head pain referral would be different between those in the control group with infrequent
headache and those without a history of headache. Accordingly, this difference is
unlikely to be due to examiner bias.
214
Examination of the atlanto occipital and C2-3 segments in succession in study
one (section 5.2) could suggest facilitation of head pain during examination of the
subsequent segment (C2-3), potentially distorting our result. This appears unlikely
because each technique was applied for no longer than five seconds, referred head pain
eased within seconds of ceasing the examination technique, and the interval between
each technique was greater than three minutes. In addition, if the initial technique had
facilitated succeeding responses, the frequency and severity of head pain referral should
have increased during the second (C2-3) examination. This was not the case.
The standardisation of thumb pressure during cervical intervention in studies
one and two (sections 5.2 and 6.2) is clearly desirable. Examination of passive
accessory intervertebral movement requires skilled palpation, which includes perception
of mobility. Therefore, pressure algometers would need to be developed which not only
attach to the thumb but are sufficiently fine to allow for perception of mobility. An
absence of such a device in both studies could be considered a shortcoming.
In study three (section 7.2), controls and patients were not matched for gender,
and as a result female participants outnumbered males. This might have influenced our
result. Recognising that females are more sensitive to pressure-pain than males, we
investigated photophobia and pressure pain thresholds in men and women in the control
group and also compared findings in female patients and controls. Our finding that
tenderness was greater in female patients than female controls lessens a potential gender
bias in our results. Furthermore, only two (CWAH females) reported a prior history of
migraine. Therefore, whilst it is not possible to exclude the possibility of sensory
hyperalgesia (and photophobia) being present before injury, the absence of previous
histories further diminishes the likelihood of gender influence on our data.
215
Other limitations in these studies included reliance on perception and self-report
of pain. Clearly, these involve psychological influences such as anxiety and fear, and as
we did not assess participants’ psychological state, we cannot be certain of the effect of
psychological factors on our findings.
8.3 Future research
Pivotal to this thesis has been the investigation of cervical nociceptors in
sensitization of the brainstem in primary headache utilising manual cervical
reproduction of customary head pain when examining the atlanto occipital and C2-3
segments (sections 5.2 and 6.2). Perception and self-reporting of pain clearly involve
psychological influences such as anxiety and fear. Moderate fear inhibits pain
(hypoalgesia),1-10 while heightened anxiety appears to increase sensitivity to pain
(hyperalgesia).1,11-27 This implies that anticipation of an unpredictable, threatening
intervention could result in enhanced pain, while diminished pain results from exposure
to a predictable, threatening event (fear).1 An additional potential inhibitory mechanism
is diffuse noxious inhibitory controls (DNICs), expressed as ‘conditioned pain
modulation’ in humans. The DNIC process involves inhibition of neurons in the dorsal
horn of the spinal cord in response to nociceptive stimuli applied to any part of the
body.28-30 Whilst is has been shown that DNICs are impaired in tension headache31,32
and migraine, 32,33 it remains to be determined whether DNIC impairment is responsible
for the development of central sensitisation in nociceptive pathways or is a nonspecific
neuro physiological manifestation of chronic pain. A recent study investigating
menstrual migraineurs found no impairment of DNICs,34 prompting the authors to
speculate as to whether the DNICs play a patho physiological role in migraine or
216
whether migraine compromises DNIC.34 Furthermore, an animal study35 demonstrated
concomitant DNIC impairment and sensitisation of the TCN. Perhaps then, another
explanation needs to be explored; could it be that the magnitude of central sensitization
during a severe migraine attack defeats the inhibitory capacity DNICs, thereby reducing
their effectiveness?36 Studies investigating potential influences of these processes (fear,
anxiety, DNICs) on sensitization of the TCN in primary headache, utilising R2 nBR, are
warranted.
A further study to supplement the findings of study 1 (section 5.2) in which
migraineurs and TTH patients were examined could include a cohort of patients from
the third primary headache group i.e., the trigeminal autonomic cephalalgias (TACs),
comprising cluster headache, chronic paroxysmal hemicrania and short lasting unilateral
neuralgiform headache attacks with conjunctival injection. In both the first and second
studies (sections 5.2 and 6.2), the clinical experience of the author directed examination
of the atlanto occipital and C2-3 segments. However, referral of head pain from the
atlanto axial (C1-2) segment is also possible. Whilst not a specific aim of this thesis, a
future study comparing the incidence of head pain referral from each of the atlanto
occipital, C1-2 and C2-3 segments could benefit clinicians.
The results of study 2 (section 6.2), could be supplemented by replicating
studies in cohorts of TTH and TAC patients. If similar effects on the nBR were
demonstrated, this would support the role of cervical nociception across the primary
headache spectrum.
In the third study (section 7.2) the presence of widespread hyperalgesia to
pressure-pain, photophobia and delayed habituation of nBR in chronic whiplash
217
associated headache (CWAH) patients suggests a state of central sensitisation.
However, future studies using additional tests (e.g., of temporal summation to punctate
or thermal stimuli and the integrity of conditioned pain modulation) would provide
further information about sensitization of the TCN in CWAH. Also, additional support
for central sensitisation in CWAH may be furnished by studies comparing a cohort of
patients with acute whiplash associated headache to others with CWAH. In addition,
assessing the incidence of reproduction of customary head pain (study 1) and the effect
of reproduction and resolution of head pain on the nBR (study 2; section 6.2) in CWAH
patients could provide further support for the relevance of cervical nociception in
CWAH. Also replicating study 3 (section 7.2) in which participants were matched for
age and gender would help to clarify whether these characteristics moderate
vulnerability to sensitization of the TCN in CWAH.
8.4 Theoretical and clinical implications
Differentiating migraine without aura, TTH and cervicogenic headache patients
on the basis of symptoms alone is problematic.37-39 Whilst abolition of head pain
following anaesthetic blocks of a cervical structure or its nerve supply (notably the C2-3
zygapophyseal joint / third occipital nerve) is considered the ‘gold standard’ for a
diagnosis of cervicogenic headache,40-43 these blocks are invasive, placebo responses
also need to be considered, and many practitioners do not have facilities for such
procedures.43,44 However, manual cervical reproduction of accustomed head pain is also
considered an important diagnostic criterion of cervicogenic headache.40-42
The high incidence of temporary reproduction of accustomed head pain in
migraineurs and TTH patients during palpation of the upper cervical spine (section 5.2)
218
reinforces the importance of assessing musculoskeletal features of the upper cervical
spine45 - notably the C2-3 zygapopohyseal and atlanto occipital segments - in patients
presenting with TTH and migrainous symptoms. This, in turn, potentially provides an
alternative treatment option for those primary headache patients in whom headache
referral occurs during examination of the upper cervical spinal segments.
However, controversy surrounds the interpretation of temporary reproduction of
head pain as a diagnostic criterion of cervicogenic headache, for this also occurs in
primary headache i.e., reproduction in this manner is not unique to cervicogenic
headache.
Although the pathophysiology of primary headache remains unclear,46 the
assumption that C1-3 afferents are merely a bystander in primary headache47-49 must
now be seriously questioned. It seems reasonable that the opposite perspective be
considered i.e., manual cervical reproduction of accustomed head pain in primary
headache could suggest that C1-3 afferents play a pivotal role in the pathophysiology of
primary headache. In our second study (section 6.2) we sought to investigate this
phenomenon further by exploring the relationship between manual cervical referral and
lessening of accustomed head pain in migraine, and its effect on trigeminal nociceptive
processing. Migraine is characterised by an interictal habituation deficit of R2 nBR.50-54
Our finding of concomitant lessening of referred pain and cervical tenderness with
increased latencies and decreased AUC of R2 nBR, mirrors earlier findings of the
effects of drug interventions on R2 nBR in migraineurs. These ictal studies55,56
demonstrated increased R2 nBR latencies and decreased R2 nBR AUC in migraine
patients following successful administration of acetylsalicylic acid or oral zolmitriptan.
219
To our knowledge, this is the first time that manual cervical intervention has been
shown to influence trigeminal nociceptive neurotransmission.
Taken together, these results support the hypothesis that C1-3 afferent inputs
contribute to headache in migraine; and that manual cervical referral and resolution in
migraineurs is more than a reflection of convergence of C1-3 afferents on trigeminal
nuclei. That is, hyperexcitability of nociceptive second-order neurons in the TCN could
result from noxious afferent information from dysfunctional spinal segments, thereby
increasing sensitivity to subclinical afferent information from the trigeminal field.
Therefore, whilst interpretation of temporary reproduction of customary head
pain remains contentious, perhaps a more convincing (than temporary reproduction)
diagnostic criterion of cervical relevance could be ‘reproduction and resolution’ of
customary head pain. Furthermore, study 2 (section 6.2) demonstrates that manual
modulation of C1-3 afferents may be of potential benefit in migraine patients in whom
manual cervical referral and resolution of accustomed head pain occurs.
Another interesting finding in study 1 (section 5.2) with potential clinical
implications was that in every participant with head pain referral, examination of both
the atlanto occipital and C2-3 segments reproduced their usual head pain. This has
important ramifications, because this indicates that when the C2-3 zygapophyseal joint
is symptomatic, the atlanto occipital joint will also be involved. Confirmation of
cervical afferent involvement in headache requires at least 90 percent resolution of head
pain subsequent to anaesthetic blocks of a cervical structure or its nerve supply.41,57
According to established guidelines, in the event of partial resolution, anaethetising
spinal segments adjacent to C2-3 should alleviate all of the pain.57 Whilst the C1-2
220
segment has been implicated in head pain referral58,59 and headache,60 another study61 in
symptomatic subjects suggests minimal involvement of C1-2. The result of the second
study (section 5.2) suggests that the atlanto occipital segment should be investigated as
a potential source of pain.
‘Whiplash’ is defined as a (traumatic cervical) musculoskeletal event.62 All
studies incriminating the C2-3 zygapophyseal joint as a source of headache have
involved patients with a history of trauma.61,63-65 Therefore, it seems plausible that
C1-3 (notably the third occipital nerve) afferents are instrumental in the development of
CWAH. Furthermore, the symptomatic profile of CWAH resembles various forms of
primary headache, for example chronic tension-type headache, chronic or transformed
migraine, or cluster headache,66-72 and neck pain often accompanies the most prevalent
primary headaches.68 Therefore, CWAH may share a common pathophysiology with
primary headache syndromes.69-71 As central sensitization is one of the mechanisms
leading to chronicity of headache,67,73-76 we investigated this possibility in our third
study (section 7.2).
The results of our study not only confirmed previous studies demonstrating
common symptomatic profiles, but also identified sensory hyperalgesia, photophobia,
and delayed habituation of R2 nBR in the CWAH group. These features are consistent
with central sensitization and are comparable to primary headache conditions.
Whilst the mechanisms underlying sensory hypersensitivity, photophobia and
altered trigeminal nociception remain unclear, peripheral, spinal, and supraspinal
involvement has been proposed.77-79 However, consistent with upper cervical
musculoskeletal involvement in the ‘whiplash’ mechanism and the substantial evidence
221
implicating the cervical zygapophyseal joints,64,80-87 it seems logical that a peripheral
(C1-3) mechanism is responsible for central hyperexcitability.88,89 This is reinforced by
concomitant modifications of neuronal excitability in the spinal cord with ongoing
peripheral nociception.90-93 Furthermore, a recent study has demonstrated significant
moderation of recognised signs of central sensitization in association with improved
cervical movement.94
Our findings strengthen the hypothesis that CWAH - headache that resembles
primary headache - could be maintained by peripheral nociceptive input.88,94 In turn,
shared symptomatic profiles, clinical and neurophysiological (R2) modifications
support the role of C1-3 afferents in primary headache.
Taken together, the findings of this thesis reinforce a sensitising role of the
upper cervical afferents on the TCN in primary headache. In addition, from a clinical
perspective, the findings also imply that in those primary headache patients in whom
manual cervical examination refers accustomed head pain, cervical intervention
comprising sustained reproduction and resolution of head pain, is of potential benefit.
222
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