Key Strategies for Managing

Neuropathic Pain

Copyright 2005 Thomson Professional Postgraduate Services . All rights reserved.

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.

Acute vs Chronic Pain

Characteristic
Cause

Acute Pain
Generally known

Chronic Pain
Often unknown

Duration of pain

Short,
well-characterized

Persists after healing,

3 months

Treatment
approach

Resolution of
underlying cause,
usually self-limited

Underlying cause and pain

disorder; outcome is often
pain control, not cure

Domains of Chronic Pain

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

Social Consequences
Marital/family
relations
Intimacy/sexual activity
Social isolation

Socioeconomic
Consequences
Healthcare costs
Disability
Lost workdays

Nociceptive vs Neuropathic Pain

Nociceptive
Pain

MixedType

Caused by activity in
neural pathways in
response to potentially
tissue-damaging stimuli

Caused by a
combination of both
primary injury and
secondary effects

Neuropathic
Pain
Initiated or caused by
primary lesion or
dysfunction in the
nervous system
CRPS*

Postoperative
pain

Arthritis

Mechanical
low back pain

Sickle cell
crisis

Sports/exercise
injuries
5

*Complex regional pain syndrome

Postherpetic
neuralgia

Trigeminal
neuralgia

Neuropathic
low back pain

Central poststroke pain

Distal
polyneuropathy
(eg, diabetic, HIV)

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

Injury

Brain

Transmission
Modulation
Perception
Interpretation
Behavior

Descending Pathway

Dorsal
Root
Ganglion

Peripheral
Nerve

Ascending
Pathways
C-Fiber

A-beta Fiber
A-delta Fiber

Dorsal
Horn
Spinal Cord

Adapted with permission from WebMD Scientific American Medicine.

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

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

Percentages of Herpes Zoster

Patients With Persistent Pain
80

% of patients

70
1 month
1 year

60
50
40
30
20
10
0
0

19

29

39

49

59

69

70

Age (y)
10

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

What Are the Goals of

Clinical Assessment?

11

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)

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

12

Pain Treatment Continuum

Most
invasive

Least
invasive

Continuum not related to efficacy

Psychological/physical approaches
Topical medications
Systemic medications*
Interventional techniques*

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*Consider referral if previous treatments were unsuccessful.

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

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

Pharmacologic Agents
Affect Pain Differently
BRAIN

CNS

PNS

Peripheral
Sensitization

17

Descending Modulation

Spinal
Cord

Dorsal
Horn
Local Anesthetics
Topical Analgesics
Anticonvulsants
Tricyclic Antidepressants
Opioids

Anticonvulsants
Opioids
Tricyclic/SNRI Antidepressants

Central Sensitization
Anticonvulsants
Opioids
NMDA-Receptor Antagonists
Tricyclic/SNRI Antidepressants

Topical vs Transdermal
Drug Delivery Systems

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Topical
(lidocaine patch 5%)

Transdermal
(fentanyl patch)

Peripheral tissue activity

Applied directly over painful site
Insignificant serum levels
Systemic side effects unlikely

Systemic activity
Applied away from painful site
Serum levels necessary
Systemic side effects

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 (1824 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

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carbamazepine
phenytoin
gabapentin
lamotrigine
pregabalin *

*Approved by FDA for this use.

HIV = human immunodeficiency virus.

HIV-associated neuropathy
lamotrigine

Trigeminal neuralgia
carbamazepine*
lamotrigine
oxcarbazepine

Central poststroke pain

lamotrigine

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 (tidqid)*
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*Not approved by FDA for this use.

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

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*Not approved by FDA for this use.

Tricyclic Antidepressants:
Adverse Effects
Commonly reported AEs
(generally anticholinergic):

23

blurred vision
cognitive changes
constipation
dry mouth
orthostatic hypotension
sedation
sexual dysfunction
tachycardia
urinary retention

AEs = adverse effects.

Fewest
AEs

Desipramine
Nortriptyline
Imipramine
Doxepin
Amitriptyline

Most
AEs

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

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CRPS = complex regional pain syndrome.

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

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*Applications not approved by FDA.

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

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