Key Strategies for Managing Neuropathic Pain

 Copyright © 2005 Thomson Professional Postgraduate Services®. All rights reserved.

2

IASP Definition of Pain

“Pain is an unpleasant sensory and emotional experience

associated with actual or potential tissue damage or described in

terms of such damage.”

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Acute vs Chronic Pain

Characteristic Acute Pain Chronic Pain

Cause Generally known Often unknown

Duration of pain Short, well-characterized

Persists after healing, 3 months

Treatmentapproach

Resolution of underlying cause, usually self-limited

Underlying cause and pain disorder; outcome is often pain control, not cure

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Domains of Chronic Pain

Social Consequences• Marital/family

relations• Intimacy/sexual activity• Social isolation

Socioeconomic Consequences• Healthcare costs• Disability• Lost workdays

Quality of Life• Physical functioning• Ability to perform

activities of daily living• Work• Recreation

Psychological Morbidity• Depression• Anxiety, anger• Sleep disturbances• Loss of self-esteem

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Mixed TypeCaused by a

combination of both primary injury and secondary effects

Nociceptive vs Neuropathic Pain

NociceptivePain

Caused by activity in neural pathways in

response to potentially tissue-damaging stimuli

Neuropathic Pain

Initiated or caused by primary lesion or dysfunction in the nervous system

Postoperativepain

Mechanicallow back pain

Sickle cellcrisis

ArthritisPostherpetic

neuralgia

Neuropathic low back pain

CRPS*

Sports/exerciseinjuries

*Complex regional pain syndrome

Central post-stroke pain

Trigeminalneuralgia

Distalpolyneuropathy (eg, diabetic, HIV)

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Possible Descriptions of Neuropathic Pain

• Sensations– numbness– tingling– burning– paresthetic– paroxysmal– lancinating– electriclike– raw skin– shooting– deep, dull, bonelike ache

• Signs/Symptoms– allodynia: pain from a

stimulus that does not normally evoke pain

• thermal

• mechanical

– hyperalgesia: exaggerated response to a normally painful stimulus

Physiology of Pain Perception

• Transduction

• Transmission

• Modulation

• Perception

• Interpretation

• Behavior

Injury

Descending Pathway

PeripheralNerve

Dorsal RootGanglion

C-Fiber

A-beta Fiber

A-delta Fiber

AscendingPathways

Dorsal Horn

Brain

Spinal CordAdapted with permission from WebMD Scientific American® Medicine.

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Pathophysiology of Neuropathic Pain

• Chemical excitation of nonnociceptors

• Recruitment of nerves outside of site of injury

• Excitotoxicity

• Sodium channels

• Ectopic discharge

• Deafferentation

• Central sensitization– maintained by peripheral input

• Sympathetic involvement

• Antidromic neurogenic inflammation

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Multiple Pathophysiologies May Be Involved in Neuropathic Pain

• More than one mechanism of action likely involved • Neuropathic pain may result from abnormal peripheral

nerve function and neural processing of impulses due to abnormal neuronal receptor and mediator activity

• Combination of medications may be needed to manage pain: topicals, anticonvulsants, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and opioids

• In the future, ability to determine the relationship between the pathophysiology and symptoms/signs may help target therapy

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Percentages of Herpes Zoster Patients With Persistent Pain

0

10

20

30

40

50

60

70

80

0 19 29 39 49 59 69 70

Age (y)

1 month

1 year

% o

f p

atie

nts

Adapted from DeMorgas JM, Kierland RR. Arch Dermatol. 1957;75:193-196.

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What Are the Goals of Clinical Assessment?

• Achieve diagnosis of pain• Identify underlying causes of neuropathy• Identify comorbid conditions• Evaluate psychosocial factors• Evaluate functional status (activity levels) • Set goals • Develop targeted treatment plan• Determine when to refer to specialist or

multidisciplinary team (pain clinic)

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Assessing the Patient With Pain

• Onset and duration• Location/distribution• Quality• Intensity• Aggravating/relieving factors• Associated features or secondary signs/symptoms• Associated factors

– mood/emotional distress– functional activities

• Treatment response

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Pain Treatment Continuum

Least invasive

Most invasive

Psychological/physical approaches

Topical medications

*Consider referral if previous treatments were unsuccessful.

Systemic medications*

Interventional techniques*

Continuum not related to efficacy

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Nonpharmacologic Options

• Biofeedback • Relaxation therapy• Physical and occupational therapy• Cognitive/behavioral strategies

– meditation; guided imagery

• Acupuncture• Transcutaneous electrical nerve stimulation

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Pharmacologic Treatment Options

• Classes of agents with efficacy demonstrated in multiple, randomized, controlled trials for neuropathic pain– topical analgesics (capsaicin, lidocaine patch 5%)– anticonvulsants (gabapentin, lamotrigine, pregabalin)– antidepressants (nortriptyline, desipramine)– opioids (oxycodone, tramadol)

• Consider safety and tolerability when initiating treatment

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FDA-Approved Treatments for Neuropathic Pain

• Carbamazepine– trigeminal neuralgia

• Duloxetine– peripheral diabetic neuropathy

• Gabapentin– postherpetic neuralgia

• Lidocaine Patch 5%– postherpetic neuralgia

• Pregabalin*– peripheral diabetic neuropathy– postherpetic neuralgia

*Availability pending based upon controlled substance scheduling by the DEA.

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BRAIN

Pharmacologic Agents Affect Pain Differently

Descending Modulation

Central SensitizationPNS

Local AnestheticsTopical AnalgesicsAnticonvulsantsTricyclic AntidepressantsOpioids

Anticonvulsants

Opioids

NMDA-Receptor Antagonists

Tricyclic/SNRI Antidepressants

AnticonvulsantsOpioidsTricyclic/SNRI Antidepressants

CNSSpinalCord

PeripheralSensitization

Dorsal

Horn

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Topical vs Transdermal Drug Delivery Systems

Systemic activityApplied away from painful site

Serum levels necessarySystemic side effects

Peripheral tissue activityApplied directly over painful site

Insignificant serum levelsSystemic side effects unlikely

Topical (lidocaine patch 5%)

Transdermal(fentanyl patch)

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Lidocaine Patch 5%

• Lidocaine 5% in pliable patch• Up to 3 patches applied once daily directly over

painful site– 12 h on, 12 h off (FDA-approved label)– recently published data indicate 4 patches (18–24 h) safe

• Efficacy demonstrated in 3 randomized controlled trials on postherpetic neuralgia

• Drug interactions and systemic side effects unlikely– most common side effect: application-site sensitivity

• Clinically insignificant serum lidocaine levels• Mechanical barrier decreases allodynia

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Anticonvulsant Drugs for Neuropathic Pain Disorders

• Postherpetic neuralgia– gabapentin*

– pregabalin *

• Diabetic neuropathy– carbamazepine

– phenytoin

– gabapentin

– lamotrigine

– pregabalin *

• HIV-associated neuropathy – lamotrigine

• Trigeminal neuralgia– carbamazepine*

– lamotrigine

– oxcarbazepine

• Central poststroke pain– lamotrigine

*Approved by FDA for this use.HIV = human immunodeficiency virus.

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Gabapentin in Neuropathic Pain Disorders

• FDA approved for postherpetic neuralgia• Anticonvulsant: uncertain mechanism• Limited intestinal absorption• Usually well tolerated; serious adverse effects rare

– dizziness and sedation can occur

• No significant drug interactions• Peak time: 2 to 3 h; elimination half-life: 5 to 7 h• Usual dosage range for neuropathic pain up to 3,600

mg/d (tid–qid)*

*Not approved by FDA for this use.

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Antidepressants in Neuropathic Pain Disorders*

• Multiple mechanisms of action• Randomized controlled trials and meta-analyses

demonstrate benefit of tricyclic antidepressants (especially amitriptyline, nortriptyline, desipramine) for postherpetic neuralgia and diabetic neuropathy

• Onset of analgesia variable– analgesic effects independent of antidepressant activity

• Improvements in insomnia, anxiety, depression• Desipramine and nortriptyline have fewer adverse effects

*Not approved by FDA for this use.

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Tricyclic Antidepressants: Adverse Effects

• Commonly reported AEs (generally anticholinergic):– blurred vision– cognitive changes– constipation– dry mouth– orthostatic hypotension– sedation– sexual dysfunction– tachycardia– urinary retention

• Desipramine

• Nortriptyline

• Imipramine

• Doxepin

• Amitriptyline

FewestAEs

Most AEs

AEs = adverse effects.

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Principles of Opioid Therapy for Neuropathic Pain

• Opioids should be titrated for therapeutic efficacy versus AEs

• Fixed-dose regimens generally preferred over prn regimens• Document treatment plan and outcomes• Consider use of opioid written care agreement• Opioids can be effective in neuropathic pain• Most opioid AEs controlled with appropriate specific

management (eg, prophylactic bowel regimen, use of stimulants)• Understand distinction between addiction, tolerance, physical

dependence, and pseudoaddiction

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Distinguishing Dependence, Tolerance, and Addiction

• Physical dependence: withdrawal syndrome arises if drug discontinued, dose substantially reduced,or antagonist administered

• Tolerance: greater amount of drug needed to maintain therapeutic effect, or loss of effect over time

• Pseudoaddiction: behavior suggestive of addiction; caused by undertreatment of pain

• Addiction (psychological dependence): psychiatric disorder characterized by continued compulsive use of substance despite harm

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Interventional Treatments for Neuropathic Pain

• Neural blockade– sympathetic blocks for CRPS-I and II

(reflex sympathetic dystrophy and causalgia)

• Neurolytic techniques– alcohol or phenol neurolysis– pulse radio frequency

• Stimulatory techniques– spinal cord stimulation– peripheral nerve stimulation

• Medication pumps

CRPS = complex regional pain syndrome.

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Summary of Advances in Treatments for Neuropathic Pain*

• Botulinum toxin: low back pain• Lidocaine patch 5%: low back pain, osteoarthritis, diabetic

and HIV-related neuropathy, with gabapentin • CR oxycodone: diabetic neuropathy• Gabapentin: HIV-related neuropathy, diabetic peripheral

neuropathy, others• Levetiracetam: neuropathic pain and migraine• Oxcarbazepine: neuropathic pain; diabetic neuropathy• Bupropion: neuropathic pain• Transdermal fentanyl: low back pain

*Applications not approved by FDA.

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Summary

• Chronic neuropathic pain is a disease, not a symptom

• “Rational” polypharmacy is often necessary– combining peripheral and central nervous system agents

enhances pain relief

• Treatment goals include:– balancing efficacy, safety, and tolerability– reducing baseline pain and pain exacerbations– improving function and QOL

• New agents and new uses for existing agents offer additional treatment options