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
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Neuropathic Pain in Advanced Illness Russell K. Portenoy, MD Chairman and Gerald J. and Dorothy R. Friedman Chair in Pain Medicine and Palliative Care.
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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 CareBeth Israel Medical Center
Chief Medical Officer Continuum Hospice Care
Professor of Neurology and AnesthesiologyAlbert Einstein College of Medicine
• 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
• 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 opioid-
refractory neuropathic pain
Adjuvant Analgesics for Adjuvant Analgesics for Neuropathic PainNeuropathic 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 Adjuvant Analgesics for Neuropathic PainNeuropathic 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.
CorticosteroidsCorticosteroids
• 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
AnticonvulsantsAnticonvulsants• Gabapentinoids
– Work via voltage-gated calcium channel, modulating alpha-2-delta protein
– Positive RCT’s • Gabapentin: PHN/diabetic neuropathy, neuropathic cancer
Sindrup et al, Basic Clin Pharmacol Toxicol. 2005;96:399-409.
• 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
AntidepressantsAntidepressants
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.
• Side effects
– 3o amine drugs > 2o amine drug > SNRIs/SSRIs/bupropion
– CNS, nausea, anticholinergic (TCAs), CV (TCAs), sexual (SSRIs, SNRIs)
AntidepressantsAntidepressants
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.
• Based on safety and likelihood of efficacy, most reasonable choices would be 2o amine drugs or SNRIs– Desipramine
– Nortriptyline
– Duloxetine
– Venlafaxine
– Also consider bupropion
AntidepressantsAntidepressants
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 Topical Drugs for Neuropathic PainNeuropathic 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 Topical Drugs for Neuropathic PainNeuropathic Pain
• Other topical compounds used for pain– Ketamine
– Gabapentin and other anticonvulsants
– Other antidepressants
Topical Drugs for Topical Drugs for Neuropathic PainNeuropathic Pain
• Conventional use– Local anesthetics first
• Lidocaine 5% patch or gel• Others
– Capsaicin
– Doxepin
– NSAIDs, including diclofenac, ibuprofen and aspirin
Sodium Channel BlockersSodium 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.
-2 Adrenergic Agonists-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 involved in neuropathic pain and opioid tolerance
• 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
CannabinoidsCannabinoids
• 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.