Neuropathic Pain in
Advanced Illness
Russell K. Portenoy, MD
Chairman and Gerald J. and Dorothy R. Friedman Chair in Pain
Medicine and Palliative Care
Department of Pain Medicine and Palliative Care
Beth Israel Medical Center
Chief Medical Officer
Continuum Hospice Care
Professor of Neurology and Anesthesiology
Albert Einstein College of Medicine
Neuropathic Pain:
Definitions
• Pain believed to be sustained by aberrant
•
somatosensory processing in the peripheral
or central nervous systems
Pain related to damage or dysfunction of
the nervous system
Neuropathic Pain:
Clinical Challenges
•
Multiple classifications
– By medical diagnosis
– By localization of neural injury
– By inferred pathophysiology
•
Diverse phenomenologies within a diagnosis
Neuropathic Pain:
Clinical Challenges
• Classification by medical diagnosis
– Examples
 Chemotherapy-induced polyneuropathy
 Malignant plexopathy
 Post-stroke central pain syndrome
 Complex regional pain syndrome
Neuropathic Pain:
Clinical Challenges
• Classification by neurological localization
–
–
–
–
–
Polyneuropathy
Mononeuropathy (ies)
Radiculopathy
Myelopathy
Encephalopathy
Neuropathic Pain:
Clinical Challenges
• Classification by inferred pathophysiology
– Based on inference about sets of mechanisms that
may be sustaining the pain
– Determined usually by phenomenology of the pain
and the clinical examination
– Best viewed as a construct that can guide treatment
– In the future, should be replaced by “mechanismbased treatment”
Neuropathic Pain:
Clinical Challenges
• Classification by inferred pathophysiology
– Distinguishes pain with “peripheral generators” and
pain with “central generators”
Neuropathic Pain:
Inferred Pathophysiologies
Peripheral
generator
Mononeuropathy
Neuroma
Nerve
sheath pain
Central
generator
Polyneuropathy
Deafferentation
syndromes
Axonopathy
myelinopathy
Sympatheticallymaintained pain
Anesthesia
dolorosa/
phantom
pain
Central pain
Neuropathic Pain:
Diverse Phenomenologies
• Some patients report dysesthesia
(“abnormal discomfort or pain”)
–
–
–
Burning, shooting, electrical
Aftersensations
Spontaneous or touch-evoked
• But some patients report familiar pain
(e.g. aching)
Neuropathic Pain:
Diverse Phenomenologies
• Some patients report neurological phenomena
–
–
–
–
Paresthesia (abnormal nonpainful sensations)
Weakness, clumsiness
Loss of sensation
Focal autonomic dysregulation (swelling, skin
changes, sweating abnormalities)
• But some patients have pain alone
Neuropathic Pain:
Diverse Phenomenologies
• Some patients have neurological signs
– Allodynia, hyperalgesia
– Hyperpathia
– Other sensory abnormalities
– Weakness, incoordination, reflex asymmetries
– Focal autonomic or trophic changes
• But some patients have normal exams
Neuropathic Pain:
Clinical Challenges
•
•
•
Multiple phenomenologies and disorders
suggest overlapping sets of mechanisms
For now….most treatment is based on limited
data, intuition, trial-and-error, and best clinical
judgment, guided by diagnosis, neurological
localization and inferred mechanisms
Goal in the future… “mechanism-based
therapy”
Neuropathic Pain:
Mechanisms
• Peripheral processes
– Transduction dysfunction
– Peripheral sensitization
– Membrane excitability at primary afferents
• Central process
– Synaptic transmission dysfunction
– Central sensitization
– Reduced inhibition
Therapeutic Strategy for
Neuropathic Pain
• Treat underlying cause, if possible and
•
appropriate
Pharmacotherapy is the mainstay
– First-line is still an opioid
– Consider other systemic and topical analgesics
• Many options, most extrapolated from noncancer pain
• Relatively few RCTs and very few comparative trials
• Other approaches is selected cases
Dworkin RH, et al, Arch Neurol. 2003;60:1524-1534.
Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Pain. 2005;118(3):289-305.
Pharmacotherapy of
Neuropathic Pain
• Opioids
• “Adjuvant analgesics”
• NSAIDs
Opioids in
Neuropathic Pain
• NOT correct: “Neuropathic pain is ‘resistant’
•
to opioids”
Limited data suggest
– Neuropathic pain is less responsive than
nociceptive pain
– Poorly responsive syndromes are more likely
to be neuropathic
• But opioids are clearly efficacious
Opioids in
Neuropathic Pain
• Positive trials of oxycodone in DPN and PHN
• Positive trial of methadone in mixed types of
neuropathic pain
• Positive trial of morphine in PHN
• Positive trial of levorphanol in peripheral and
central neuropathic pain
Gimbel JS et al: Neurology. 2003;60:927-934. Watson CP, Babul N: Neurology. 1998;50:1837-1841.
Morley JS et al: Palliat Med. 2003;7:576-587.
Raja SN et al: Neurology. 2002;59:1015-1021.
Rowbotham MC, et al: NEJM. 2003;348:1223-1232.
Opioids in
Neuropathic Pain
• Positive systematic review of tramadol
(5 trials)
• Positive trial of morphine + gabapentin, and
morphine alone, relative to gabapentin in
patients with DPN or PHN
Duhmke RM, et al. Cochrane Database Syst Rev. 2004:CD003726.
Gilron I, et al: NEJM. 2005;352:1324-1334.
Opioids in Neuropathic Pain:
Conventional Practice
• Opioids remain first-line for most patients with
•
moderate to severe neuropathic pain related
to serious medical illness
In most cases, the opioid regimen should
optimized before addition of other drugs
Pharmacotherapy of
Neuropathic Pain
• Opioids
• “Adjuvant analgesics”
• NSAIDs
Adjuvant Analgesics
• Traditional definition
Drugs with indications other than pain which
may be analgesic in specific circumstances
• Numerous drugs in diverse classes,
•
some now specifically indicated for pain
Use in neuropathic pain in the medically
ill extrapolated from observations in
other populations
Adjuvant Analgesics
•
•
•
•
•
Multipurpose analgesics
Drugs used for neuropathic pain
Drugs used for bone pain
Drugs used for bowel obstruction
Drugs used for muscle spasm
Multipurpose Adjuvant
Analgesics
• Multipurpose analgesics based on number and
types of studies
–
–
–
–
Corticosteroids
Antidepressants
Alpha-2 adrenergic agonists
Topical therapies
• In populations with serious or life-threatening
illness
– Corticosteroids most used for multiple purposes
– With some exceptions, other drugs used for opioidrefractory neuropathic pain
Adjuvant Analgesics for
Neuropathic Pain
• Initial Strategy
– Treat etiology, if possible and appropriate, and
titrate opioid
– First-line drugs are corticosteroids, anticonvulsants,
antidepressants, and topical agents
• Corticosteroid depending on clinical setting
• Then gabapentin or pregabalin, unless comorbid
depression is present
• If comorbid depression is present, consider
desipramine, nortriptyline, or duloxetine
• Always consider co-administered topical drug
Adjuvant Analgesics for
Neuropathic Pain
• Initial Strategy
– If first-line drug unsatisfactory, consider sequential trials of
adjuvant analgesics, starting with other antidepressants or
anticonvulsants
– Then consider second-line and third-line drugs
– Combination therapy is appropriate as long as each drug is
demonstrably effective and tolerated
Dworkin RH, et al, Pain, 2007;132:237-251.
Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Pain. 2005;118(3):289-305.
Corticosteroids
• Multipurpose: Despite limited data, widely
accepted as analgesic in
Neuropathic pain
Bone pain
Capsular pain
Lymphedema
Headache
Other conditions
• High dose regimen with rapid taper used for
•
very severe pain
Low dose regimen continued indefinitely
Anticonvulsants
• Gabapentinoids
– Work via voltage-gated calcium channel, modulating
alpha-2-delta protein
– Positive RCT’s
Gabapentin: PHN/diabetic neuropathy, neuropathic cancer
pain
Pregabalin: PHN/diabetic neuropathy/fibromyalgia
– NNT less favorable than TCAs, but first-line drug
because of safety
• Not hepatically metabolized
• No drug-drug interactions
• Side effects usually tolerable
Backonja et al, JAMA. 1998;280:1831-1836. Rowbotham M, JAMA. 1998;280:1837-1842.
Caraceni et al, J Clin Oncol, 2004;22:2909-2914.
Anticonvulsants
• Gabapentinoids
– Pregabalin has more stable PK than gabapentin,
with easier titration and faster onset of effect than
gabapentin
– Pregabalin has established positive effects on sleep
and anxiety
– Individual variation in the response to gabapentin
and pregabalin
Anticonvulsants
• Other anticonvulsants have limited data
•
and are selected by trial and error
Newer drugs have better safety profiles
lamotrigine
topiramate
oxcarbazepine
tiagabine
levetiracetam
zonisamide
carbamazepine
phenytoin
valproate
Antidepressants
• Classes
– Tricyclic antidepressants
3o amine drugs: amitriptyline, imipramine, doxepin
2o amine drugs: desipramine, nortriptyline
– SNRIs: duloxetine, venlafaxine, minalcipran
– SSRIs: paroxetine, citalopram, others
– Others: bupropion
Sindrup et al, Basic Clin Pharmacol Toxicol. 2005;96:399-409.
Antidepressants
• Analgesic efficacy
– Studies suggest TCAs > SNRIs> SSRIs
Of the tricyclics: 3o amine drugs (amitriptyline) >
2o amine drugs (imipramine)
But not all drugs have been studied
No comparative studies against duloxetine—
now indicated for pain in diabetic neuropathy
Of the SSRIs, limited data in support of
paroxetine and citalopram
Dworkin RH, et al, Arch Neurol. 2003;60:1524-1534.
Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Pain. 2005;118(3):289-305.
Antidepressants
• Side effects
– 3o amine drugs > 2o amine drug >
SNRIs/SSRIs/bupropion
– CNS, nausea, anticholinergic (TCAs), CV (TCAs),
sexual (SSRIs, SNRIs)
Dworkin RH, et al, Arch Neurol. 2003;60:1524-1534.
Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Pain. 2005;118(3):289-305.
Antidepressants
• Based on safety and likelihood of efficacy,
most reasonable choices would be 2o amine
drugs or SNRIs
–
–
–
–
–
Desipramine
Nortriptyline
Duloxetine
Venlafaxine
Also consider bupropion
Dworkin RH, et al, Arch Neurol. 2003;60:1524-1534.
Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Pain. 2005;118(3):289-305.
Topical Drugs for
Neuropathic Pain
• RCTs support benefit from diverse drugs
classes in acute and chronic pain
– Local anesthetics, including lidocaine 5% patch
or gel
– Capsaicin
– Doxepin
– NSAIDs, including diclofenac, ibuprofen and
aspirin
– Nitrates
– Opioids
Galer et al, Pain. 1999;80:533-538; Ellison et al, JCO. 1997;15:2974-2980;
Mcleane, Br J Clin Pharm. 2000;49:574-579; Rowbotham et al, Ann Neurol.
1995;37”246-253; De Benedittis and Lorenzetti, Pain. 1996; 65:45-51.
Topical Drugs for
Neuropathic Pain
• Other topical compounds used for pain
– Ketamine
– Gabapentin and other anticonvulsants
– Other antidepressants
Topical Drugs for
Neuropathic Pain
• Conventional use
– Local anesthetics first
Lidocaine 5% patch or gel
Others
– Capsaicin
– Doxepin
– NSAIDs, including diclofenac, ibuprofen and
aspirin
Sodium Channel Blockers
• Oral mexiletine, tocainide, flecainide are
analgesic in neuropathic pain
• Efficacy of IV lidocaine supported by RCTs
• High side effect liability from oral drugs—
generally considered third-line
• IV lidocaine is an option for severe
neuropathic pain
Oskarsson P et al, Diabetes Care, 1997;20:1594-1597.
Challapalli et al, Cochrane Database Sys Rev. 2005;CD003345.
a-2 Adrenergic Agonists
• Multipurpose analgesics but little evidence in
the medically ill
• In RCT, intrathecal clonidine worked for
cancer-related neuropathic pain
• Tizanidine usually better tolerated than
clonidine
• Consider tizanidine if muscle spasm is
present
Eisenach JC, et al, Pain. 1995;61:391-399.
NMDA-Receptor Antagonists
• NMDA receptor involved in
neuropathic pain and opioid tolerance
• Commercially-available drugs
Ketamine
Memantine
Dextromethorphan
Amantadine
NMDA-Receptor Antagonists
• 37 RCTs of ketamine plus opioids by single
bolus or infusion show mixed but generally
favorable results
• 4 RCTs of co-administration to opioids in
cancer pain: no conclusion possible
• RCT of dextromethorphan positive in DPN
and negative in PHN
• Very limited positive data for memantine and
amantadine; several negative RCTs of
memantine
Subramaniam K, Anesth Analg. 2004;99:482-495.
Bell R, Cochrane Database Syst Rev. 2003;(1):CD003351.
Nelson et al, Neurology. 1997;48:1212.
NMDA-Receptor Antagonists
• Conclusion: Limited data, conflicting
•
findings
Ketamine is used in refractory pain
Brief, hours-days, infusion by IV or SQ
Oral use of injectable or compounded drug
Co-administered benzodiazepine or
neuroleptic to reduce risk of side effects
• Ketamine is used for palliative sedation
Cannabinoids
• Strong preclinical support for analgesic
efficacy of both CB1 and CB2 agonists
• RCTs of THC in central pain
• Recent positive RCTs of new formulation
(THC plus cannabidiol) in central pain and
in cancer pain
• Empirical use of THC and nabilone as
third-line agents
Svendsen et al, BMJ. 2004;329:253.
Berman et al, Pain. 2004;112:299-306.
GABAergic Adjuvant
Analgesics
• Baclofen
RCT in trigeminal neuralgia
Intrathecal baclofen may relieve
neuropathic pain apart from spasticity
Used empirically for neuropathic pain
as third-line agent
• Benzodiazepines
– Clonazepam used for neuropathic pain
despite lack of data
Fromm et al, Ann Neurol, 1984;15:240-244.
Drugs for IT Administration
• Ziconotide
Selective N-type calcium channel blocker for use
by subarachnoid infusion
RCTs support analgesic efficacy
• Local Anesthetics
• Clonidine
• Others
Staats et al, JAMA. 2004;291:63.
Pharmacotherapy of
Neuropathic Pain
• Opioids
• “Adjuvant analgesics”
• NSAIDs
NSAIDs in Neuropathic Pain
• Generally viewed to be inefficacious but…
– Commonly used (e.g., 20% of patients with
SCI pain)
– Strong evidence of prostaglandin-mediated
mechanisms in some preclinical models
– Limited positive clinical trial
– Conclusion: NSAIDs have a role
Wlderstrom et al, Spinal Cord. 2003;41:600.
Cohen et al, Arch Intern Med. 1987;147:1442.
Non-Drug Strategies
for Neuropathic Pain
• Interventional
• Rehabilitative
approaches
approaches
– Injections
– Neural blockade
– Neuraxial
analgesia
– Spinal cord
stimulation
• Psychological
approaches
– Orthoses
– PT/OT
• Complementary and
Alternative approaches
– Acupuncture
– Massage
– others
Neuropathic Pain in
Advanced Illness
• Conclusions and overall strategy
– Neuropathic pain is common, diverse, poorly
understood, newly studied, target of future
mechanism-based therapy, now treated by
trial-and-error based on limited data
– Treatment part of the broader palliative plan
of care
Neuropathic Pain in
Advanced Illness
• Conclusions and overall strategy
– Management strategy
• Treat etiology, if possible
• Use opioids
• Add systemic and topical adjuvant analgesics
• Have a first-line, second-line, third-line
strategy for drug
• Have a first-line and second-line strategy for
non-drug approaches, including
interventional pain treatments