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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.”
3
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
4
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
5
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)
6
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.
7
8
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
9
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
10
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.
11
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)
12
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
13
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
14
Nonpharmacologic Options
• Biofeedback • Relaxation therapy• Physical and occupational therapy• Cognitive/behavioral strategies
– meditation; guided imagery
• Acupuncture• Transcutaneous electrical nerve stimulation
15
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
16
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.
17
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
18
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)
19
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
20
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.
21
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.
22
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.
23
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.
24
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
25
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
26
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.
27
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.
28
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