MPNP Handbook 2011

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A Summary of Recommendations Issued by the Multidisciplinary Panel on Neuropathic Pain (MPNP)

www.neuropainhk.org

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Handbook of Neuropathic Pain M

anagement Guidelines 2nd Edition

Endorsed by

2nd Edition

Handbook of Neuropathic Pain Management Guidelines – 2nd Edition 1

Introduction to neuropathic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Introduction to the Multidisciplinary Panel on Neuropathic Pain (MPNP) . . . . . . . . . . . . . 4

MPNP members . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Overview of contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Diagnosis and assessment of pain severity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Drugs used in the treatment of neuropathic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Drug options and dosages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Side effect profiles and management tips . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Recommendations for postherpetic neuralgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Recommendations for idiopathic trigeminal neuralgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Recommendations for painful diabetic peripheral neuropathy . . . . . . . . . . . . . . . . . . . . . . . . 18

Recommendations for neuropathic pain associated with peripheral nerve entrapment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Recommendations for central post-stroke pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Recommendations for neuropathic cancer pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Recommendations for neuropathic pain due to spinal cord pathologies . . . . . . . . . . . . . . . . . 26

Recommendations for complex regional pain syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Table of Contents

Handbook of Neuropathic Pain Management Guidelines – 2nd Edition2

Introduction to neuropathic pain

Neuropathic pain covers a diverse group of pain conditions characterized by a primary lesion or dysfunction of the sensory nervous system. It is particularly challenging for clinicians to manage because of its chronicity and severity, poor responsiveness to

traditional pain therapies, and wide individual variations in pain responsiveness.1,2 Unfortu-nately, neuropathic pain conditions are likely to increase as populations age and age-related disorders, such as herpes zoster, diabetes mellitus, cerebrovascular accidents, Parkinson’s disease and cancer, rise in prevalence.3 Medical treatment of neuropathic pain remains unsatisfactory for a substantial proportion of patients, and with the rising rates of disorders known to incite neuropathic pain syndromes, it is vital to improve patient outcomes with existing treatment options and continue to pursue new therapeutic strategies.

What is the difference between neuropathic pain and nociceptive pain?There are two types of pain: nociceptive pain and neuropathic pain. Nociceptive pain serves as a warning of ongoing tissue damage due to injury or disease (eg, a wound, thermal insult or inflammation).3 It comprises somatic pain (in skin, muscles, joints, bone) and visceral pain (in an organ or its covering), and is an acute, self-limiting symptom.

In contrast, neuropathic pain is initiated by injury or dysfunction of the peripheral or central nervous system, resulting in a delayed chronic response to damage that is no longer acute, but which continues to evoke pain.3

What causes neuropathic pain?This disorder can be caused by injury to neuronal cell bodies in the peripheral or cen-tral nervous system via compression, transection, infiltration, ischaemia or metabolic injury, or any combination of these effects. Examples of peripheral neuropathic pain conditions include diabetic peripheral neuropathy, postherpetic neuralgia, tumour infiltration neuropa-thy, phantom limb pain, complex regional pain syndrome and trigeminal neuralgia. Central neuropathic pain conditions include multiple sclerosis, spinal cord injury, central post-stroke pain and Parkinson’s disease.

Although the underlying neuronal mechanisms of neuropathic pain are not completely understood, various distinct pathophysiological mechanisms appear to be involved, resulting in both peripheral and central sensitization.4 Nerve lesions can trigger molecular changes in nociceptive neurons, making them abnormally sensitive and evoking pathological spontaneous activity. Inflammation in the damaged nerve trunk can induce ectopic no-ciceptor activity, causing spontaneous pain. This hyperactivity in nociceptors can induce

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secondary changes in processing neurons in the spinal cord and brain, so that input from mechanoreceptive A fibres is perceived as pain. In addition, neuroplastic changes in the central pain modulatory systems can lead to further hyperexcitability.4

What are the symptoms of neuropathic pain?Neuropathic pain is commonly described as burning, electric, tingling and shooting in nature. The pain may be continuous or paroxysmal in presentation. Other common symptoms include3:• Allodynia – Pain due to nonnoxious stimuli (clothing, light touch) when applied to the

affected area. May be mechanical, dynamic or thermal• Anaesthesia – Loss of normal sensation to the affected region• Dysaesthesia – Spontaneous or evoked unpleasant abnormal sensations• Hyperalgesia – Exaggerated response to a mildly noxious stimulus applied to the af-

fected region• Hyperpathia – Delayed and explosive response to a noxious stimulus applied to the

affected region• Hypoaesthesia – Reduction of normal sensation to the affected region• Paraesthesias – Nonpainful spontaneous abnormal sensations• Phantom pain – Pain from a specific site that no longer exists (eg, amputated limb) or

where there is no current injury• Referred pain – Occurs in a region remote from the source

How to assess a patient for neuropathic pain Neuropathic pain should be suspected in patients who present with pain that they describe in any of the following terms: burning, searing or scalding, cold, numbness, tingling, shoot-ing, electric shock-like, stabbing, crushing, or vise-like.

Clinical evaluation should include a history to assess pain intensity, sensory descriptions of the pain quality, temporal variations in pain intensity and functional impact. A physical examination of gross motor function, deep tendon reflexes, and the somatosensory system should be performed. The sensory examination should include assessment of responses to touch, pinprick, pressure, cold, heat, vibration and temporal summation in the area of maximal pain.2

Patient-completed neuropathic pain screening tools can assist primary care physicians in differentiating between nociceptive and neuropathic pain. Examples of screening tools include ID Pain and painDETECT.

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Introduction to the Multidisciplinary Panel on Neuropathic Pain (MPNP)

The Multidisciplinary Panel on Neuropathic Pain (MPNP) comprises local thought lead-ers dedicated to improving the awareness and understanding of neuropathic pain in Hong Kong. The panel includes specialists from a range of disciplines involved in

treating neuropathic pain: neurology, neurosurgery, geriatric medicine, anaesthesiology and orthopaedics. For some time, Hong Kong physicians lacked local guidelines for managing neuropathic pain, and were potentially unaware of the most appropriate referral pathways and treat-ments. Therefore, the MPNP has endeavoured to improve the understanding and general awareness of neuropathic pain syndromes, and to contribute to better diagnosis, manage-ment and treatment of these conditions in Hong Kong. It aims to act as an information source for medical professionals on the treatment and management of neuropathic pain and provide evidence-based resources on neuropathic pain.

The

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MPNP members

Dr Phoon Ping ChenMBBS, FHKAM(Ana), FANZCA, FFPMANZCA, DipPainMgt(HKCA), MHAConsultant and Chief of Service, Department of Anaesthesiology and Operating Services, Alice Ho Miu Ling Nethersole Hospital and North District Hospital, and Adjunct Associate Professor, The Chinese University of Hong Kong, Hong Kong SAR

Dr Josephine WY IP MBBS, MS, FRCS(Edin), FHKAM(Ortho), DipHandSurg (FESSH)Associate Professor and Chief, Division of Hand and Foot Surgery, Department of Orthopaedic Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR

Dr Joseph MK LaM MBChB, FRCS(Edin), FCSHK, FHKAM(Surg)Honorary Consultant and Honorary Clinical Associate Professor, Division of Neurosurgery, Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR

Dr Vincent MoK MBBS, FHKAM(Med), FRCP(Edin), MD(CUHK)Associate Professor and Honorary Associate Consultant, Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR

Dr Tak hong TsoIMBBS, MRCP, FRCP(Edin), FRCP(Glas), FRCP(Lond), FHKCP,

FHKAM(Med)Neurologist and Consultant Physician, Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR

Dr Chun Por WongMBBS, FRCP(Lond), FRCP(Glas), FRCP(Edin), FHKAM(Med), FHKCPChief of Service, Integrated Medical Services, Consultant and Head, Department of Geriatrics, Ruttonjee and Tang Shiu Kin Hospitals, Hong Kong SAR

Dr steven ho shan WongMBBS, FHKAM(Ana), FANZCA, DipPainMgt(HKCA)Consultant Anaesthesiologist and Head of Pain Management Team, Department of Anaesthesiology and Operating Theatre Services, Queen Elizabeth Hospital, Hong Kong SAR

L-R (standing): Steven Ho Shan Wong,

Joseph MK LaM, Tak Hong TSoi and Vincent MoK;

L-R (seated): Chun Por Wong,

Josephine WY iP and Phoon Ping CHen

The

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Dr Tsun Woon LeeMBBS, FANZCA, FFPMANZCA, FHKCA, FHKAM (Ana), DipPainMgtHospital Chief Executive, Pok Oi Hospital, Hong Kong SAR

Professor Lawrence Ks WongMBBS, MD, MRCP, FHKAM (Med), FRCPProfessor and Head, Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR

Current members

Past members


Overview of contents

Since its inception in 2001, the MPNP has published recommendations on a variety of neuropathic pain conditions. This booklet summarizes these recommendations, which are endorsed by the Hong Kong Pain Society and are updated regularly.

Particular emphasis is paid to details of appropriate treatment options.

The contents include simple tools to assist in the diagnosis and evaluation of neuropathic pain, summary tables of dosage and administration details of many of the drugs used for neuropathic pain, and notes on the most common side effects associated with neuropathic pain medications. The largest section of the handbook is devoted to reproducing the treatment algorithms recommended by the MPNP for the management of neuropathic pain conditions.

The booklet is provided as a convenient summary of the medical management options in neuropathic pain conditions, and is not meant as a comprehensive guide to the complete multidisciplinary management of patients with these conditions. For full details, physicians are encouraged to consult the original versions of the MPNP recommendations, which are available on the MPNP Web site (www.neuropainhk.org). It is important to note that not all drugs mentioned are licensed for use in neuropathic pain conditions. Full prescribing infor-mation should always be consulted before initiating therapy.

It is hoped that this concise guide will assist Hong Kong physicians in their daily manage-ment of patients suffering from neuropathic pain conditions, thus ultimately helping to improve the quality of life of patients with these disabling conditions.

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DisclaimerEvery effort has been made to ensure that the information contained in this handbook is accurate at the time of publication. As new research and clinical experience broadens medical knowledge, the diagnosis and management of neuropathic pain will undoubtedly change. The MPNP cannot be held liable for any consequence arising from inappropriate application of the information provided in this handbook.


Diagnosis and assessment of pain severity

The following patient-completed screening questionnaire, called ID Pain, can assist primary care physicians in differentiating nociceptive from neuropathic pain, and facilitate earlier and more appropriate treatment. The Chinese version has recently

been validated. The two other items can help patients describe the extent and severity of pain, and can be used to monitor the effectiveness of therapy.

Screening Questionnaire5,6

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Drugs used in the treatment of neuropathic pain

AnticonvulsantsAnticonvulsants act as membrane-stabilizing agents by altering abnormal sodium channel function and calcium channel activity, thus reducing the potential for transmission of abnor-mal pain signals. The alpha-2-delta (A2D) ligands gabapentin and pregabalin may have a number of actions, but binding to the α2-d subunit of the voltage-gated calcium channel appears to play a significant role in their antineuropathic activity.

AntidepressantsTricyclic antidepressants (TCAs) enhance the descending pain inhibitory system by preventing cellular reuptake of noradrenaline (NA) and serotonin (5-HT). Other possible mechanisms of action include α–adrenergic blockade, sodium channel effects and N-methyl D-aspartate (NMDA) receptor antagonism. Duloxetine, a 5-HT and NA reuptake inhibitor (SNRI), is thought to relieve neuropathic pain by increasing NA and 5-HT activity in the central ner-vous system.

OpioidsDespite the initial belief that neuropathic pain was opioid-resistant, it appears that reduced sensitivity to systemic opioids is present, necessitating the use of higher doses. Opioids relieve neuropathic pain in some patients; however, on average, pain relief appears to be only moderate and treatment-limiting side effects are common. The molecular mechanisms of opioid action in neuropathic pain are not yet fully understood.

Local anaestheticsThe local anaesthetic lignocaine is used systemically and topically in neuropathic pain. The local anaesthetic mexiletine is structurally similar to lignocaine, orally active and has antiarrythmic activity. The assumed analgesic mechanism of action of these drugs is acute inhibition of sodium channels, which has a membrane-stabilizing effect and disrupts trans-mission of pain signals. The topical application of local anaesthetics (eg, 5% lignocaine patch, EMLA) may be useful for patients who have small areas of hyperaesthesia.

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Drug options and dosagesThis table covers most of the first- and second-line drugs mentioned in the treatment al-gorithms included in this booklet, but does not represent an exhaustive list of treatment options. Full prescribing information should be consulted before initiating therapy.

Drug Recommended for starting dosage Dose titration (if necessary) Maximum dosage Duration of adequate trial

anticonvulsants

Pregabalin* PHN (1st line)DPN (1st line)TN (2nd line)

150 mg/day as 75 mg bid Increase to 300 mg daily after 3–7 days, then by 150 mg/d every 3–7 days as tolerated

600 mg daily (200 mg tid or 300 mg bid) 4 wks

Gabapentin* PHN (1st line)DPN (1st line)TN (2nd line)

300 mg at bedtime on Day 1; 300 mg bid on Day 2; 300 mg tid on Day 3

Increase by 300 mg tid every 1–7 days as tolerated

3,600 mg daily (1,200 mg tid) 3–8 wks for titration plus 2 wks at maximum tolerated dosage

Carbamazepine† TN (1st line)PHN (2nd line)

100 mg bid 100 mg every 3–7 days 1,600 mg/day 8-12 wks

Lamotrigine TN (2nd line) 25 mg/day for 2 weeks Increase to 50 mg/day for 2 wks, then increase by 50–100 mg every wk

200–400 mg/day 12 wks (including titration period)

antidepressants

Amitriptyline PHN (1st line)DPN (1st line)TN (2nd line)

10–25 mg daily at bedtime Increase by 10 to 25 mg weekly Up to 75 mg daily 3 months at maximum tolerated dosage

Nortriptyline, desipramine

PHN (1st line)DPN (1st line)TN (2nd line)

10–25 mg at bedtime Increase by 25 mg daily every 3–7 days as tolerated

150 mg daily 6–8 wks with at least 2 wks at maximum tolerated dosage

Duloxetine DPN (1st line) 60 mg/day – 60 mg/day –

opioids

Morphine, oxycodone, methadone, levorphanol

PHN (2nd line) 10–15 mg morphine q4h or as needed (equianalgesic dosages should be used for other opioid analgesics)

After 1–2 wks, convert total daily dosage to long-acting opioid analgesic and continue short-acting medication as needed

No maximum dosage with careful titration

4–6 wks

Tramadol DPN (2nd line) 50 mg daily or bid Increase by 50–100 mg daily in divided doses every 3–7 days as tolerated

400 mg daily (100 mg qid); 300 mg daily in patients >75 years

4 wks

Local anaesthetics

IV lignocaine 5 mg/kg over 30–60 min Titrated based on symptoms of cyclic antidepressant toxicity, eg, perioral numbness, slurring of speech, tinnitus, dizziness, diplopia, convulsions

–

Mexiletine 150 mg daily to 200 mg bid Increase by 50 mg every 2 to 3 days prn 1,200 mg/day –

5% lignocaine patch PHN (1st line) Apply patch for a maximum of 12 h

None needed 3 patches daily for no more than 12 h in 24 h

2–4 wks

EMLA® PHN (1st line) tid, under occlusive dressing if possible

– – –

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Drug Recommended for starting dosage Dose titration (if necessary) Maximum dosage Duration of adequate trial

anticonvulsants

Pregabalin* PHN (1st line)DPN (1st line)TN (2nd line)

150 mg/day as 75 mg bid Increase to 300 mg daily after 3–7 days, then by 150 mg/d every 3–7 days as tolerated

600 mg daily (200 mg tid or 300 mg bid) 4 wks

Gabapentin* PHN (1st line)DPN (1st line)TN (2nd line)

300 mg at bedtime on Day 1; 300 mg bid on Day 2; 300 mg tid on Day 3

Increase by 300 mg tid every 1–7 days as tolerated

3,600 mg daily (1,200 mg tid) 3–8 wks for titration plus 2 wks at maximum tolerated dosage

Carbamazepine† TN (1st line)PHN (2nd line)

100 mg bid 100 mg every 3–7 days 1,600 mg/day 8-12 wks

Lamotrigine TN (2nd line) 25 mg/day for 2 weeks Increase to 50 mg/day for 2 wks, then increase by 50–100 mg every wk

200–400 mg/day 12 wks (including titration period)

antidepressants

Amitriptyline PHN (1st line)DPN (1st line)TN (2nd line)

10–25 mg daily at bedtime Increase by 10 to 25 mg weekly Up to 75 mg daily 3 months at maximum tolerated dosage

Nortriptyline, desipramine

PHN (1st line)DPN (1st line)TN (2nd line)

10–25 mg at bedtime Increase by 25 mg daily every 3–7 days as tolerated

150 mg daily 6–8 wks with at least 2 wks at maximum tolerated dosage

Duloxetine DPN (1st line) 60 mg/day – 60 mg/day –

opioids


PHN (2nd line) 10–15 mg morphine q4h or as needed (equianalgesic dosages should be used for other opioid analgesics)

After 1–2 wks, convert total daily dosage to long-acting opioid analgesic and continue short-acting medication as needed

No maximum dosage with careful titration

4–6 wks

Tramadol DPN (2nd line) 50 mg daily or bid Increase by 50–100 mg daily in divided doses every 3–7 days as tolerated

400 mg daily (100 mg qid); 300 mg daily in patients >75 years

4 wks

Local anaesthetics

IV lignocaine 5 mg/kg over 30–60 min Titrated based on symptoms of cyclic antidepressant toxicity, eg, perioral numbness, slurring of speech, tinnitus, dizziness, diplopia, convulsions

–

Mexiletine 150 mg daily to 200 mg bid Increase by 50 mg every 2 to 3 days prn 1,200 mg/day –

5% lignocaine patch PHN (1st line) Apply patch for a maximum of 12 h

None needed 3 patches daily for no more than 12 h in 24 h

2–4 wks

EMLA® PHN (1st line) tid, under occlusive dressing if possible

– – –

wks, weeks; IV, intravenous; EMLA, eutectic mixture of local anesthetics; –, information unavailable/incomplete; DPN, diabetic poly-neuropathy; PHN, postherpetic neuralgia; TN, trigeminal neuralgia

N.B. There is no evidence that paracetamol and NSAIDs are effective for the treatment of neuropathic pain.

* Pregabalin and gabapentin are licensed in Hong Kong for the treatment of neuropathic pain.

† Carbamazepine is licensed in Hong Kong for the treatment of trigeminal neuralgia and diabetic polyneuropathy.

Sources: American Medical Association. Assessing and Treating Neuropathic Pain. Module 9. September 2007. Available at: http://www.amacmeonline.com/pain_mgmt/printver-sion/ama_painmgmt_m9.pdf. Accessed April 18; 2008; Gilron I, Watson CPN, Ca-hill CM, Moulin DE. Neuropathic pain: a practical guide for the clinician. CMaJ 2006;175:265-275; Leicestershire Medi-cines Strategy Group. Guideline for treat-ing patients with neuropathic pain. May 2007. Available at: http://www.lmsg.nhs.uk/Guidelines/pdfdocs/NeuropathicPainGuide-line200711.pdf. Accessed April 18, 2008; The Merck Manual for Healthcare Profession-als. Neurological Disorders. Pain. Available at: http://www.merck.com/mmpe/sec16/ch209/ch209a.html#CACIDGIH. Accessed April 18, 2008.

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Side effect profiles and management tipsThis table summarizes some of the more commonly encountered adverse effects associated with neuropathic pain treatments. The list is not exhaustive and full prescribing information should be consulted before initiating any therapy.

Drug Potential adverse effects Comments

anticonvulsants

Pregabalin Dizziness, somnolence, weight gain, blurred vision, dry mouth, constipation, peripheral oedema, euphoric mood, disturbed attention, increased appetite, balance disorder

Dose adjustment needed in renal dysfunction

Gabapentin Dose adjustment needed in renal dysfunction

Carbamazepine Sedation, dizziness, gait abnormalities, nausea & vomiting; serious AEs: hyponatraemia, agranulocytosis, aplastic anaemia, Stevens-Johnson syndrome*

Monitor CBC, liver enzymes and sodium levels for 1 year; contraindicated in porphyria, AV block or with concomitant MAO inhibitors; patients should seek immediate medical assistance if fever, sore throat, rash or mouth ulcers, bruising/bleeding develop

Lamotrigine Skin rash (potentially severe), irritability, headache, drowsiness, insomnia, dizziness, tremor, nystagmus, ataxia, diplopia, blurred vision, nausea, vomiting, diarrhoea, constipation, tiredness, arthralgia, painful menses, back pain

Very slow dose titration minimizes risk of rash; most cases of rash occur within first 8 weeks

antidepressants

Amitriptyline

Dry mouth, sweating, sedation, disturbed vision, cardiotoxicity, palpitations, postural hypotension, urinary retention, constipation, drowsiness

Give dose at bedtime to minimize effect of sedation; titrate dose slowly; may be poorly tolerated by the elderly; CI in patients with glaucoma and those taking MAO inhibitors

Nortriptyline, desipramine Nortriptyline causes less sedation and anticholinergic effects than amitriptyline; CI in patients with glaucoma and those taking MAO inhibitors

Duloxetine Nausea, dry mouth, constipation, GI distress, nausea/vomiting, decreased appetite, insomnia, dizziness, somnolence, blurred vision, increased sweating, fatigue

–

opioids


Constipation, sedation, nausea, dizziness, vomiting, respiratory depression Coadminister pre-emptive stool softeners and antiemetics

Tramadol Dizziness, dry mouth, nausea, constipation, somnolence; risk of seizures/ epilepsy; risk of serotonergic syndrome if combined with SSRIs

Initiate therapy at low dose and titrate as tolerated; use with caution in epileptic patients

Local anaesthetics

IV lignocaine Tremor, insomnia or drowsiness, lightheadedness, slurred speech, ataxia, depression, agitation, change in sensorium, a change in personality, nystagmus, hallucinations, memory impairment, emotional lability

Decrease the infusion rate or discontinue treatment if signs of toxicity

Mexiletine Lightheadedness, dizziness, nervousness, inco-ordination, GI distress, nausea/vomiting, trembling, unsteady gait, tremor, ataxia; proarrhythmia, impaired haemodynamics

Consider cardiac evaluation before initiating therapy in patients with a significant heart disorder; monitor blood pressure; monitor and adjust dose to prevent QTc prolongation; administer with food or prescribe antacids to reduce GI AEs; has a narrow therapeutic index

5% lignocaine patch Mild localized skin reactions around application site Only apply to healed intact skin; apply to affected area

EMLA® Pale skin, redness or swelling at the application site, burning, change in hot or cold sensation

–

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Drug Potential adverse effects Comments

anticonvulsants

Pregabalin Dizziness, somnolence, weight gain, blurred vision, dry mouth, constipation, peripheral oedema, euphoric mood, disturbed attention, increased appetite, balance disorder

Dose adjustment needed in renal dysfunction

Gabapentin Dose adjustment needed in renal dysfunction

Carbamazepine Sedation, dizziness, gait abnormalities, nausea & vomiting; serious AEs: hyponatraemia, agranulocytosis, aplastic anaemia, Stevens-Johnson syndrome*

Monitor CBC, liver enzymes and sodium levels for 1 year; contraindicated in porphyria, AV block or with concomitant MAO inhibitors; patients should seek immediate medical assistance if fever, sore throat, rash or mouth ulcers, bruising/bleeding develop

Lamotrigine Skin rash (potentially severe), irritability, headache, drowsiness, insomnia, dizziness, tremor, nystagmus, ataxia, diplopia, blurred vision, nausea, vomiting, diarrhoea, constipation, tiredness, arthralgia, painful menses, back pain

Very slow dose titration minimizes risk of rash; most cases of rash occur within first 8 weeks

antidepressants

Amitriptyline

Dry mouth, sweating, sedation, disturbed vision, cardiotoxicity, palpitations, postural hypotension, urinary retention, constipation, drowsiness

Give dose at bedtime to minimize effect of sedation; titrate dose slowly; may be poorly tolerated by the elderly; CI in patients with glaucoma and those taking MAO inhibitors

Nortriptyline, desipramine Nortriptyline causes less sedation and anticholinergic effects than amitriptyline; CI in patients with glaucoma and those taking MAO inhibitors

Duloxetine Nausea, dry mouth, constipation, GI distress, nausea/vomiting, decreased appetite, insomnia, dizziness, somnolence, blurred vision, increased sweating, fatigue

–

opioids


Constipation, sedation, nausea, dizziness, vomiting, respiratory depression Coadminister pre-emptive stool softeners and antiemetics

Tramadol Dizziness, dry mouth, nausea, constipation, somnolence; risk of seizures/ epilepsy; risk of serotonergic syndrome if combined with SSRIs

Initiate therapy at low dose and titrate as tolerated; use with caution in epileptic patients

Local anaesthetics

IV lignocaine Tremor, insomnia or drowsiness, lightheadedness, slurred speech, ataxia, depression, agitation, change in sensorium, a change in personality, nystagmus, hallucinations, memory impairment, emotional lability

Decrease the infusion rate or discontinue treatment if signs of toxicity

Mexiletine Lightheadedness, dizziness, nervousness, inco-ordination, GI distress, nausea/vomiting, trembling, unsteady gait, tremor, ataxia; proarrhythmia, impaired haemodynamics

Consider cardiac evaluation before initiating therapy in patients with a significant heart disorder; monitor blood pressure; monitor and adjust dose to prevent QTc prolongation; administer with food or prescribe antacids to reduce GI AEs; has a narrow therapeutic index

5% lignocaine patch Mild localized skin reactions around application site Only apply to healed intact skin; apply to affected area

EMLA® Pale skin, redness or swelling at the application site, burning, change in hot or cold sensation

–

CI, contraindicated; MAO, monoamine oxidase; AEs, adverse effects; CBC, complete blood count; AV, atrioventricular; SSRI, selective serotonin reuptake inhibitor; EMLA, eutectic mixture of local anesthetics; IV, intravenous; GI, gastrointestinal; –, information unavailable/incomplete

* Genetic susceptibility for Stevens-Johnson syndrome (HLA-B1502) should be assessed in Asian patients before commencing treatment with carbamazepine.

Sources:American Medical Association. Assessing and Treating Neuropathic Pain. Module 9. September 2007. Available at: http://www.amacmeonline.com/pain_mgmt/printversion/ama_painmgmt_m9.pdf. Accessed April 18; 2008; Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain. Evidence-based recommenda-tions. Pain 2007;132:237-251; Gilron I, Watson CPN, Cahill CM, Moulin DE. Neuropathic pain: a practi-cal guide for the clinician. CMaJ 2006;175:265-275; Leicestershire Medicines Strategy Group. Guideline for treating patients with neuropathic pain. May 2007. Available at: http://www.lmsg.nhs.uk/Guide-lines/pdfdocs/NeuropathicPainGuideline200711.pdf. Accessed April 18, 2008; The Merck Manual for Healthcare Professionals. Neurological Disorders. Pain. Available at: http://www.merck.com/mmpe/sec16/ch209/ch209a.html#CACIDGIH. Accessed April 18, 2008.

Drug

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Postherpetic neuralgia14

Recommendations for postherpetic neuralgia7

TCA, tricyclic antidepressant; A2D, alpha-2-delta; EMLA, eutectic mixture of local anaesthetics; TENS, transcutaneous electrical nerve stimulation; NMDA, N-methyl D-aspartateThe A2D ligands are pregabalin and gabapentin


Post

herp

etic

neu

ralg

ia

Postherpetic neuralgia is a neuropathic pain syndrome

that occurs following acute herpes zoster infection

or shingles.

Postherpetic neuralgia 15

• Start low-dose amitriptyline or nortriptyline therapy (10 to 25 mg at night) and titrate weekly up to the maximum tolerated dose or a maximum of 150 mg.

• For patients older than 60 years, or in cases where TCAs are not tolerated or are contra-indicated, the A2D ligands pregabalin or gabapentin may be used.8-13 In some practices, pregabalin and gabapentin are considered first-line therapy.

• Add a topical local anaesthetic, such as a lignocaine patch14-16 or EMLA cream.17,18 This can be first-line treatment if antidepressants and anticonvulsants are contraindicated.

• Carbamazepine is commonly used, but there is little evidence to support its use.

• Consider tramadol19 or opioids20 if antidepressants and anticonvulsants are ineffective or are contraindicated.

• Consider transcutaneous electrical nerve stimulation (TENS) as adjunctive therapy.

• If adequate pain control is not achieved after 8 weeks, consider referring the patient to a pain medicine specialist for alternative therapies, such as NMDA receptor antagonists,21 intrathecal steroids,22 intravenous adenosine 5’-triphosphate (ATP),23,24 or combination therapy.25,26 A multidisciplinary approach to managing these difficult-to-treat patients may be necessary.

Post

herp

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Painful diabetic peripheral neuropathy16

Diab

etic

neu

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thy

Recommendations for idiopathic trigeminal neuralgia27

A2D, alpha-2-delta; PRFR, percutaneous radiofrequency rhizotomy; BCR, balloon compression rhizotomy; PRGR, percutaneous retro-Gasserian glycerol rhizotomyThe A2D ligands are pregabalin and gabapentin


The second or third division of the trigeminal nerve is

affected in most trigeminal neuralgia patients.

Painful diabetic peripheral neuropathy 17

Diab

etic

neu

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thy

• The primary care physician should try carbamazepine first.28

• If the response is not satisfactory or the patient cannot tolerate treatment, one or two second-line drugs may be tried. The second-line drugs include pregabalin,11-13,29-31 gabapentin,32 phenytoin,33 sodium valproate,33 clonazepam,34,35 baclofen,36 lamotrigine33 and antidepressant agents.37

• For chronic, intractable pain, a patient should be referred to a multidisciplinary pain management centre.

• Peripheral trigeminal nerve block is a useful adjunctive therapy, and may be used while pharmacotherapy is being optimized.38-40

• If treatment is not successful following a trial of two or three medications for an adequate period (3 to 6 months), an operation or interventional treatment should be considered.

• Selecting a procedure is both difficult and controversial. Patients should be allowed to consider all of the available options.

– In general, for patients younger than 70 years who have a low surgical risk and prefer to preserve trigeminal nerve function, microvascular decompression should be recommended.41

– Percutaneous radiofrequency rhizotomy (PRFR) can be considered for patients who have failed medical treatment and suffer from intractable TN.42

– In cases involving the ophthalmic division or all three divisions, balloon compression rhizotomy (BCR) should be considered over PRFR.43

– Gamma knife radiosurgery (GKR) should be reserved for patients who have failed both surgical and percutaneous procedures.44,45

Idiopathic trigeminal neuralgia18

Trig

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Recommendations for painful diabetic peripheral neuropathy46

TCA, tricyclic antidepressant; A2D, alpha-2-delta; NMDA, N-methyl-D-aspartate; PENS, percutaneous electrical nerve stimulation; TENS, transcutaneous electrical nerve stimulation; SNRI, serotonin–norepinephrine reuptake inhibitorThe A2D ligands are pregabalin and gabapentin

Approximately 20 to 40% of diabetic patients develop some

sort of neuropathy. Diabetic neuropathy may lead to foot

ulceration and even the need for amputation.

Idiopathic trigeminal neuralgia 19

Trig

emin

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• A2D ligands (eg, pregabalin and gabapentin) should be considered as first-line treatment options due to their efficacy and safety.28-31,47 In addition, A2D ligands are generally associ-ated with fewer side effects compared with TCAs, carbamazepine or phenytoin. Also, the side effects can be further minimized by slow dosage titration.

• For chronic pain, TCAs (eg, amitriptyline, nortriptyline, desipramine) should be considered first-line therapies.28 Pain relief may not be apparent for up to 3 weeks. TCAs are contra-indicated in patients with cardiac and hepatic disease. Some patients cannot tolerate the side effects of TCAs, but these can be minimized by starting with a low dose at night and increasing gradually. Nortriptyline, imipramine and desipramine are less sedating than amitriptyline.

• For acute pain, start with simple analgesics and progress to TCAs or other adjuvant analgesics, if necessary.

• If TCAs are contraindicated , ineffective and/or not well tolerated, SNRIs should also be considered as an alternate first-line choice, or as an add-on therapy to A2D ligands.48-50

• Tramadol may be an effective alternative for some patients.51

• Patients remaining refractory to a reasonable trial of pharmacotherapy (eg, 2 to 3 months with two to three different agents) should be referred to a multidisciplinary pain clinic for further therapeutic initiatives.

• Physical stimulation, such as TENS52 and acupuncture, may counteract painful sensations. However, acupuncture and topical treatments should be used with caution in the lower leg in patients with diabetes, as these may aggravate the skin and lead to infection. More invasive stimulatory interventions, such as spinal cord stimulation, may be considered as a last option.53

• Pain management programmes and behavioural therapy can also be used with pharma-cological approaches to teach patients how to live with pain. Regular walking, warm baths or elastic stockings may also help to relieve leg pain.

Neuropathic pain associated with peripheral nerve entrapment20

Cervical radiculopathy

Lumbar radiculopathy

Carpal tunnel syndrome

Cubital tunnel syndrome

Conservative treatment

• Cervical collar• Oral NSAIDs• Physiotherapy/neck

care exercises• Anticonvulsants or

antidepressants• Epidural

corticosteroid injection

• Lumbar corset • Oral NSAIDs• Physiotherapy• PENS/TENS• Anticonvulsants

or antidepressants• Epidural

corticosteroid injection

• Chemonucleolysis

• Physiotherapy• Wrist splinting• Oral steroids

and local steroid injections

• Diuretics

• Educate patient on how to avoid provoking symptoms

• Conservative treatment does not have a great role in management

surgical interventions

• Anterior discectomy with spinal fusion

• Microforaminotomy• Cervical arthroplasty

• Discectomy• Microdiscectomy• Percutaneous

discectomy• Lumbar

foraminotomy• Lumbar spinal

fusion

• Carpal tunnel release (open or endoscopic)

• Simple neurolysis• Anterior transposition

of ulnar nerve• Medial

epicondylectomy of distal humerus

• Cubital tunnel release (open or endoscopic)

Recommendations for neuropathic pain associated with peripheral nerve entrapment54

NSAIDS, nonsteroidal anti-inflammatory drugs; PENS, percutaneous electrical nerve stimulation; TENS, transcutaneous electrical nerve stimulation

Perip

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Carpal tunnel syndrome results from compression of the median nerve at the carpal tunnel.

Neuropathic pain associated with peripheral nerve entrapment 21

Cervical radiculopathy• Mild cases may improve without treatment, or may benefit from short-term use of a cer-

vical collar, nonsteroidal anti-inflammatory drugs (NSAIDs), neck-care exercises, postural training and activity modification, and intermittent cervical traction. Pregabalin has dem-onstrated some benefit in cervical radiculopathy.55

• Surgery (eg, decompression via an anterior cervical approach with spinal fusion or a posterior approach with laminectomy) is indicated for more severe cases or when other treatments have failed.

Lumbar radiculopathy• Bed rest is not recommended; mobility must be maintained.56

• Oral NSAIDs57 and physiotherapy may be beneficial. Epidural corticosteroids and percu-taneous or transcutaneous electrical nerve stimulation may give short-term relief.58-60

• Gabapentin was effective in patients with chronic radiculopathy (L4-5 and/or L5-S1 bulg-ing and/or protrusion).61 Pregabalin as monotherapy or add-on therapy improved patient-reported clinical outcomes in painful lumbar or cervical radiculopathy.55

Carpal tunnel syndrome• Conservative strategies that may be of benefit include good ergonomics, splinting of the

wrist in a neutral position, rest at intervals and minimizing hand or wrist movements. Acupuncture and ultrasound may also reduce pain.62

• NSAIDs, diuretics and oral corticosteroids are options for mild-to-moderate carpal tunnel syndrome. Local steroid injection may be superior to oral corticosteroids.63,64

• Carpal tunnel release surgery (open or endoscopic) is indicated when conservative thera-py has failed, or motor involvement or severe numbness is present.

Cubital tunnel syndrome• Frequently requires a release operation, such as simple neurolysis, anterior transposition

of the ulnar nerve or medial epicondylectomy of the distal humerus.

Perip

hera

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ve e

ntra

pmen

t

Central post-stroke pain

Recommendations for central post-stroke pain65

A2D, alpha-2-delta; TCA, tricyclic antidepressant; CPSP, central post-stroke painThe A2D ligands are pregabalin and gabapentin

Cent

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ost-s

troke

pai

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CPSP is characterized by constant or intermittent pain

following a stroke. Around 8% of stroke patients will develop CPSP.

Central post-stroke pain 23

• TCAs such as amitriptyline or nortriptyline should be considered as first-line therapy for central post-stroke pain (CPSP). To minimize side effects, commence at a low dose and titrate to a higher maintenance dose.

• The A2D ligand pregabalin is a first-line treatment option as it has been shown to significantly reduce pain and improve health status in patients with central pain, including CPSP.66

• Lamotrigine may be used as a second-line agent or an alternative first-line treatment to TCAs.67

• Gabapentin, another A2D ligand, is approved for the treatment of neuropathic pain and may be effective in treating CPSP.68

• Central pain appears to be poorly responsive, but not totally unresponsive, to opioids.69

• Intravenous lignocaine may provide pain relief in some patients with CPSP.70,71

• Mexiletine may be used as an adjunct to TCAs when patients do not respond to TCAs alone.72

• Patients remaining refractory to a reasonable trial of pharmacotherapy should be referred to a multidisciplinary pain clinic for further therapeutic initiatives.

• Intrathecal baclofen may be effective in some patients with CPSP,73,74 but should only be considered after the failure of other pharmacologic therapies.

• Surgical interventions can be considered for patients unresponsive to pharmacological therapy, but may be associated with morbidity and mortality. Motor cortex stimulation, spinal cord stimulation and stereotactic mesencephalic tractotomy may be beneficial.75,76

Cent

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Neuropathic cancer pain24

Recommendations for neuropathic cancer pain77

Neu

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can

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ain

A2D, alpha-2-delta; TCA, tricyclic antidepressant; CPSP, central post-stroke painThe A2D ligands are pregabalin and gabapentin

Neuropathic cancer pain 25

• For neuropathic pain caused by direct tumour involvement, first-line management is oncologic treatment and may include surgery, radiation therapy or chemotherapy.78 For example, radiotherapy can relieve neuropathic pain due to tumour-induced neural compression or irritation.79

• Correctable causes of neuropathic pain (eg, spinal cord compression) should be managed appropriately.

• Anticonvulsants should be considered if neuropathic pain is unresponsive to conventional analgesics. Neuropathic pain specifically due to cancer treatment may be treated with gabapentin.80 Pregabalin after epidural anaesthesia significantly improved visual analogue scale (VAS) and quality-of-life scores in chronic cancer patients.81 Anticonvulsants should be initiated at a low dose and slowly titrated until the patient achieves adequate pain relief or side effects develop.82

• Antidepressants such as TCAs or selective serotonin reuptake inhibitors are alternative options for management of neuropathic pain.83,84 Antidepressants may be given together with anticonvulsants when there is unsatisfactory response to either medication.85

• Systemic ketamine may be effective, but because of its adverse effects should be limited to experienced teams.86,87

• Other adjunctive therapies include systemic lignocaine.82

• Interventional therapy may also be effective for neuropathic cancer pain.88 However, certain interventional techniques for neuropathic pain should only be considered when pharmacologic interventions have failed, are poorly tolerated or inappropriate.87

• Patients with postsurgical neuropathic pain may also benefit from topical capsaicin cream when appropriate.89

Neu

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Neuropathic pain due to spinal cord pathologies26

Recommendations for neuropathic pain due to spinal cord pathologies90

A2D, alpha-2-delta; TCA, tricyclic antidepressantThe A2D ligands are pregabalin and gabapentin

Spin

al c

ord

path

olog

y Pain develops in around 60 to 70% of patients with spinal cord injury, and about one third will report severe pain.

Neuropathic pain due to spinal cord pathologies 27

• Treatment of neuropathic pain due to spinal cord lesions includes primary treatment of the underlying cause (eg, surgery for certain structural abnormalities) and other neuro-logical sequelae (eg, motor deficits, incontinence).

• Spinal cord injury (SCI) causing compression should be treated within 8 hours of com-pression, if possible.91 Methylprednisolone may be given as a 30 mg/kg-bolus dose, then maintained at a dose of 5.4 mg/kg/h. If initiated within 3 hours, treatment should be maintained for 24 hours; maintain treatment for 48 hours if initiated between 3 and 8 hours after injury. If neuropathic pain is due to direct compression by tumour, anti-neoplastic treatment may reduce tumour size and provide pain relief.92

• There is very little evidence that NSAIDs have benefit for pain due to spinal cord lesions.93,94

• A2D ligands (eg, pregabalin, gabapentin) may be used in conjunction with physical and psychological therapy as first-line treatments for neuropathic pain due to spinal cord le-sions.95,96 Alternatively, TCAs may also be considered as a first-line management option despite limited evidence.28 Patients may also be given other anticonvulsants or opioids to improve pain control.93,96-100

• Intravenous ketamine may be used as third-line therapy, but requires meticulous monitoring for side effects.100,102,103

• Patients who respond poorly to oral, transdermal or intravenous analgesics may be considered for invasive procedures, such as intrathecal drug administration, neurostimula-tion (eg, spinal cord stimulation, electroacupuncture) and dorsal root entry zone lesioning (DREZotomy).104-114

• A multidisciplinary approach should be taken to rehabilitation.91 Many patients achieve significant pain relief from physical therapy.94

Spin

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Complex regional pain syndrome28

Recommendations for complex regional pain syndrome115

*Primarily diagnostic and/or to facilitate physical rehabilitation. The efficacy of sympathetic blocks in the treatment of CRPS is still poorly defined. CRPS, complex regional pain syndrome; NSAID, nonsteroidal anti-inflammatory drug; TCA, tricyclic antidepressant; TENS, transcutaneous electrical nerve stimulationAdapted from treatment algorithm proposed by the International Coalition on Neuropathic Pain.116

Com

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Complex regional pain syndrome 29

• Patient outcomes are improved if treatment is started at an early stage: patients should be referred as soon as possible to pain specialists or physicians with experience in managing complex regional pain syndrome (CRPS).117

• An early programme of physical and occupational therapy, especially for at-risk patients, is essential to treat the secondary complications of CRPS, such as decreased joint and tendon movement. This will improve pain control and mobility.117

• Psychological support and cognitive behavioural management programmes can help patients manage their pain, and reduce depression and dependence on health care.

• For patients with sympathetic maintained pain (SMP), sympathetic blocks provide effec-tive pain relief to facilitate physical rehabilitation.

• Whenever appropriate, anti-inflammatory medications are useful in the acute phase following injury to minimize pain and swelling.118,119

• Primary pain management should include tricyclic antidepressants ([TCAs] eg, amitripty-line)120,121 or anticonvulsants (eg, gabapentin, pregabalin).66,122,123 Slow dosage titration (up to 8 weeks) is necessary to minimize side effects of both TCAs and anticonvulsants; pain relief may not be apparent for 3 weeks at the maximum tolerated dosage.

• When the response to TCAs and anticonvulsants is unsatisfactory, a trial of combined TCA and anticonvulsant may be effective.116

• Rescue therapy with opioids may be necessary, but this should only be used for short-term treatment.124

• For patients remaining refractory to trials of pharmacotherapy and physiotherapy, invasive procedures can be considered. Neurostimulation of the spinal cord or peripheral nerves may be effective,125,126 but may not improve long-term prognosis. Destructive or ablative surgery is not recommended127 and only has a limited role in providing relief for patients with a short life expectancy.

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