Learning objectives

After reading this article, you should be able to:

C explain the general principles of pharmacological treatment in

chronic pain

C outline the evidence base for the most commonly used

PAIN

The place of pharmacologicaltreatment in chronic painUsman Bashir

Lesley A Colvin

pharmacological agents

C describe the mechanisms of action of these drugs

C list side effects from chronic use of these pharmacological

agents

AbstractPharmacological treatment may be required for the successful manage-

ment of chronic pain. The use of drugs should be considered alongside

other multidisciplinary strategies including active physical rehabilita-

tion, psychological support to assist self-management and, if appro-

priate, targeted injections. In clinical practice there may be a

substantial overlap in drug management options for neuropathic and

nociceptive pain. We present an overview of clinical use and

associated problems of commonly used pharmacological agents in cur-

rent practice.

Keywords Chronic non-cancer pain; common agents; multidisciplinary;

pharmacology; rationale; role

Royal College of Anaesthetists CPD matrix: 2E03

Chronic non-cancer pain is typically defined as pain lasting

longer than 3 months or beyond the expected period of healing of

tissue pathology.1 The mechanisms underlying chronic pain

display a complex interplay of physiological, emotional, cogni-

tive, social and environmental factors.2 To understand and

effectively treat patients with chronic pain consideration should

be given to all these facets; therefore the focus of treatment ap-

proaches must be multimodal and multidisciplinary. In this

broad context, the role of pharmacological treatment is only part

of a spectrum of approaches that seek to minimize pain and

improve function. Pharmacotherapy for chronic pain should aim

to improve health-related quality of life by balancing the benefits

gained from analgesics with unwanted adverse effects, both in

the short and long term.

The use of drugs to treat pain has expanded exponentially in

recent years, with increases in expenditures of 188% between

1996 and 2005.3 Despite advances in the understanding of the

neurophysiology and psychology of pain, drug therapy alone is

usually inadequate to eliminate chronic pain.

Usman Bashir FRCA is a Specialty Registrar in the Department of

Anaesthesia, Intensive Care and Pain Management at the Western

General Hospital, Edinburgh, UK. Conflicts of interest: none declared.

Lesley A Colvin PhD FRCA FFPMRCA FRCPE is Consultant and Reader in

Anaesthesia and Pain Medicine at the Western General Hospital,

Edinburgh, UK. Conflicts of interest: none declared.

ANAESTHESIA AND INTENSIVE CARE MEDICINE 14:12 528

General principles of drug therapy

� Discuss drug treatment limitations and manage expecta-

tions of pain relief as part of the overall management

plan.

� Be aware of unpredictable responses to analgesia, both in

terms of efficacy and side effects.

� Regular review and reassessment is important.

� Stop or change medication that is not working effectively.

For the purpose of this review, pharmacological agents are

grouped by therapeutic class, although it is recognized that this

can set artificial limits on their usage.

Paracetamol (acetaminophen)

Paracetamol is a simple analgesic, which is used widely due to its

low side effect profile, and antipyretic and analgesic properties.

Its exact mechanism of action remains unclear. Paracetamol is

less effective than non-steroidal anti-inflammatory drugs

(NSAIDs) for pain relief in osteoarthritis and generalized chronic

low back pain, but has a better safety profile. While generally

ineffective in neuropathic pain, paracetamol has been found to

be effective when used in combination with tramadol and

codeine.4

Non-steroidal anti-inflammatory drugs

NSAIDs are one of the most commonly used analgesics. They

work by inhibiting the cyclooxygenase (COX) enzyme. Inhibition

of COX not only reduces inflammatory prostaglandin synthesis,

but also decreases other eicosanoids that have protective ho-

meostatic functions in platelet function, the intestinal mucosa

and kidney, resulting in a number of potentially severe adverse

effects.

NSAIDs are mainly useful in conditions with an inflammatory

component (e.g. rheumatoid arthritis), although they also show

modest beneficial effects in non-specific low back pain.4

With the exception of naproxen, NSAIDs are associated with

a one-third increase in the risk of major vascular events. The

Medicines and Healthcare products Regulatory Agency (MHRA)

have issued a drug safety warning against using these drugs in

patients at risk of developing a major vascular event. Gastro-

intestinal (GI) complications are also increased by NSAIDs,

however COX-2 selective NSAIDs are less problematic in this

regard.

� 2013 Elsevier Ltd. All rights reserved.

PAIN

Anticonvulsants

The mechanisms of analgesic action of anticonvulsant drugs are

via, sodium channel blockade (carbamazepine, oxcarbazepine),

calcium channel blockade (pregabalin, gabapentin, carbamaze-

pine, lamotrigine), suppression of glutamatergic transmission

(gabapentin, pregabalin, lamotrigine, carbamazepine) or a com-

bination of these effects.5 Pregabalin and gabapentin share a

novel and specific high-affinity binding site at a 2-d proteins of

voltage-gated calcium channels. These binding sites are localized

particularly at synapses in the superficial dorsal horn of spinal

cord where their analgesic action is probably due to inhibition of

excitatory neurotransmitter release (Tables 1 and 2).

Antidepressants

Antidepressants include tricyclic antidepressants (TCA) (such as

amitriptyline, imipramine, nortriptyline, doxepin), selective se-

rotonin reuptake inhibitors (SSRI) (such as fluoxetine, paroxe-

tine) and serotoninenoradrenaline reuptake inhibitors (SNRI)

(such as duloxetine, venlafaxine).

Antidepressants enhance descending inhibitory control

mechanisms by boosting serotonin and noradrenaline neuro-

transmitter concentration. There is additional clinical rationale

for using antidepressants in chronic pain to improvement mood

and sleep disturbances (Tables 2 and 3).

Opioids

See articles (Opioids in the management of persistent, non-

cancer pain) and (Pharmacology of opioids) elsewhere in this

journal.

Topical agents

Topical treatments are used to treat a variety of painful

conditions, including arthritis, localized peripheral

Clinical use of anticonvulsants

Drug name Clinical condition

Gabapentin All neuropathic conditions6

Prevention of chronic pain (CP

Pregabalin8 Post-herpatic neuralgia

Painful diabetic neuropathy

Central Neuropathic pain

Fibromyalgia

Prevention of chronic pain (CP

Carbamazepine/oxcarbazepine9 Trigeminal neuralgia

NNT, number of patients who need to receive an analgesic to achieve at least 50% p

efficient drugs have low NNTs; PGIC, patients’ global impression of change; IMMPACT,

chronic post-surgical pain.

Table 1

ANAESTHESIA AND INTENSIVE CARE MEDICINE 14:12 529

neuropathies, musculoskeletal injuries and painful cutaneous

ulcers.11

Topical medications exert their effects close to the site of

application with little systemic uptake or distribution. Skin

penetration depends upon several factors, including lipid and

aqueous solubility and formulation type (cream vs gel vs

microemulsion). Table 4 lists some commonly used topical

agents.

Capsaicin is active compound present in chilli peppers. It

binds to transient receptor potential vanilloid 1 channels (TRPV1)

where its agonist action produces analgesia. A single-dose

application of high concentration (8%) capsaicin patch for 30e90

minutes showed significant pain relief for up to 12 weeks in

chronic pain arising from post-herpetic neuralgia or HIV

neuropathy.12

Guidelines and new developments

Neuropathic pain is defined as ‘pain caused by a lesion or disease

of the somatosensory system’. Assessment and management of

neuropathic pain is challenging and several guidelines exist to

support treatment approaches.17e19 Most of these guidelines

recommend TCAs, SNRIs or gabapentinoids as first- and/or

second-line therapies in most neuropathic pain states. The British

Pain Society (BPS) has recently produced a detailed neuropathic

pain pathway.20

Over the past few decades, a better understanding of the

mechanisms of pain at cellular, molecular and synaptic levels has

allowed the development of new analgesic targets, providing

new hope for better pain management. Cannabinoid agonists

(Sativex), kinin receptor antagonists (AMG379, SSR240612),

cytokines and chemokines antagonists (anti-TNF a antibody:

tanezumab), transient receptor potential cation channel sub-

family V member 1 (TRPV1) antagonists and Nav selective

channels blockers are a few such examples of ongoing novel

targets.4

Clinical usefulness (NNT/result comments)

9.6(For PGIC ‘very much improved’)

6.1(for PGIC ‘much or very much improved’)

6.8(IMMPACT: substantial pain relief more than 50%)

SP)7 Moderate to large reduction in development of CPSP

3.9

5.0

5.6

11e21

SP)7 Moderate-to-large reduction in development of CPSP

1.7e1.9

ain relief in one patient more than in the placebo group. This implies that most

Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials. CPSP,

� 2013 Elsevier Ltd. All rights reserved.

Adverse drug reactions and prescribing recommendations for antidepressants and anticonvulsants in chronic painmanagement

Drug Major adverse effects/contraindications (CI) Dosing regime/duration of adequate trial

Common anticonvulsants

Gabapentin Sedation, dizziness, oedema, weight gain,

blurred vision

Start with 100e300 mg three times a day, increase by

100e300 mg three times a day every 1e7 days as

tolerated to a maximum of 3600 mg daily (1200 mg three

times a day). 3e8 weeks’ trial duration plus 2 weeks on

maximum dose

Pregabalin Same as gabapentin Start with 50 mg three times daily or 75 mg twice daily.

Increase to 300 mg/day after 3e7 days, then increase

again by 150 mg/day every 3e7 days until maximum

dose of 600 mg/day (300 mg twice a day or 200 mg three

times a day)

Carbamazepine Hepatotoxicity, thrombocytopenia, leukopenia,

hyponatraemia, somnolence, dizziness, headache,

ataxia, nystagmus, diplopia, blurred vision

CI: AV block, concomitant use of MAO inhibitors

Start with 100e200 mg daily, increase weekly by

100e200 mg daily to reach a maximum dose of 1600 mg

daily. Trial period of 6 to 8 weeks

Oxcarbazepine Somnolence, dizziness, headache, diplopia, nausea,

fatigue, hyponatraemia

Comon antidepressants

TCAs:

Amitryptyline,

Nortryptline,

Desipramine

Cardiac conduction block, sedation, confusion,

anticholinergic effects (dry mouth, constipation,

urinary retention, blurred vision), orthostatic

hypotension, weight gain;

CI: recovery phase after myocardial infarction.

Arrhythmias, concomitant use of MAO inhibitors

Start with 25 mg at bed time. Increase by 25 mg daily

every 3e7 days to a maximum to 150 mg daily. Trial

duration 6e8 weeks with at least 2 weeks at maximum

tolerated dose

SNRIs:

Duloxetine

Nausea, loss of appetite constipation, sedation, dry

mouth, hyperhidrosis, anxiety

CI: Concomitant use of MAO inhibitors, uncontrolled

hypertension

Start with 30 mg once daily. Increase to 60 mg after one

week to a maximum of 120 mg. Trial duration 4 weeks

Venlafexin Nausea, loss of appetite, hypertension, sedation,

insomnia, anxiety, dry mouth, hyperhidrosis, constipation

CI: concomitant use of MAO inhibitors.

Start with 37.5 mg once or twice daily. Increase by 75 mg

each week to a maximum of 225 mg daily. Trial duration

4e6 weeks

AV, atrioventricular; TCAs, tricyclic antidepressants; SNRIs, serotoninenorepinephrine reuptake inhibitors; SSRIs, serotonin selective reuptake inhibitors; MAO, mono-

amine oxidase. CI,contraindications.Source: Adapted from5

Table 2

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ANAESTHESIA AND INTENSIVE CARE MEDICINE 14:12 530 � 2013 Elsevier Ltd. All rights reserved.

Clinical use of antidepressants

Clinical condition Clinical usefulness (NNTs/summary results)

Chronic musculoskeletal pain10 Antidepressants followed by pain management programme:

C Global improvement in pain: 47.2% in treatment group vs 12.6% in usual care

C More than 50% reduction in depression: 37% in treatment group vs 16% in usual care

Neuropathic pain treatment5 (including diabetic

painful neuropathy, post-herpetic neuralgia and

central post-stroke pain)

TCAs: imipramine: 2.2, desipramine:2.6, amitryptyline: 3.1

SNRIs: 5e6 (venlafexin, duloxetine)

SSRIs: 6.8*

Failed to demonstrate efficacy of TCAsLumbar radiculopathy/HIV-related neuropathy

Fibromyalgia5 Variable efficacy for pain: effect size for pain reduction large for TCAs, medium

for MAO inhibitors and small for SSRIs/SNRIs

Benefits for depressed mood, fatigue, sleep disturbance

Low back pain5 No significant effect on pain or depression

Prevention of chronic pain5 Amitriptyline: 90 days use with the onset of varicella zoster reactivation rash

reduced the incidence of post-herpetic neuralgia at 6 months

Venlafexin: use for 10 days post-mastectomy reduced pain at 6 months postoperatively

HIV, human immunodeficiency virus; TCAs, tricyclic antidepressants; SNRIs, serotoninenorepinephrine reuptake inhibitors; SSRIs, serotonin selective reuptake inhib-

itors; MAO, monoamine oxidase.

Table 3

Clinical use of topical agents

Topical agent Comments on clinical use

Topical capsaicin

C Low concentration(<1%)13

C High concentration (8%)12Insufficient evidence to draw conclusion for use in neuropathic pain conditions

Significant pain relief for up to 12 weeks in chronic pain arising from post-herpetic

neuralgia or HIV neuropathy (NNTs 6e9 at 8e12 weeks)

Topical lidocaine14,15 Shown to be better than placebo in post-herpetic neuralgia.

Little evidence for use of lidocaine plaster in other refractory neuropathic pain conditions.

Topical NSAIDs (topical diclofenac)16 Benefit over placebo in patients with painful osteoarthritis of knee or hand (50% pain relief:

NNT of 6.4 for solution and 11 for gel)

HIV, human immunodeficiency virus; NNT, number needed to treat; NSAID, non-steroidal anti-inflammatory drug.

Table 4

PAIN

Summary

It can often be a process of trial and error in clinical practice to

find effective agents that are tolerable for the patient. While the

proportion of people obtaining a high degree of treatment-

specific pain relief is small, the benefits in terms of improve-

ments in quality of life may be considerable. The pharmacolog-

ical management of chronic pain should be managed within a

multidisciplinary framework. A

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� 2013 Elsevier Ltd. All rights reserved.