Neuropathic Pain in Advanced Illness Russell K. Portenoy, MD Chairman and Gerald J. and Dorothy R....

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

Neuropathic Pain: Neuropathic Pain: DefinitionsDefinitions

• 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: Neuropathic Pain: Clinical ChallengesClinical Challenges

• Multiple classifications– By medical diagnosis– By localization of neural injury– By inferred pathophysiology

• Diverse phenomenologies within a diagnosis


• Classification by medical diagnosis– Examples

Chemotherapy-induced polyneuropathy Malignant plexopathy Post-stroke central pain syndrome Complex regional pain syndrome


• Classification by neurological localization– Polyneuropathy– Mononeuropathy (ies)– Radiculopathy– Myelopathy– Encephalopathy


• 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 “mechanism-

based treatment”


• Classification by inferred pathophysiology– Distinguishes pain with “peripheral generators” and

pain with “central generators”

Neuropathic Pain: Inferred Pathophysiologies

Peripheral generatorPeripheral generator

Central generatorCentral generator

MononeuropathyMononeuropathy PolyneuropathyPolyneuropathy Deafferentation syndromesDeafferentation syndromes

NeuromaNeuroma

Nerve sheath painNerve sheath pain

AxonopathyAxonopathy

myelinopathymyelinopathyAnesthesia dolorosa/

phantom pain

Anesthesia dolorosa/

phantom pain

Central painCentral pain

Sympathetically-maintained pain Sympathetically-maintained pain

Neuropathic Pain: Neuropathic Pain: Diverse PhenomenologiesDiverse 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: Neuropathic Pain: Diverse Phenomenologies 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: Neuropathic Pain: Diverse Phenomenologies 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


• 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: Neuropathic Pain: MechanismsMechanisms

• Peripheral processes

– Transduction dysfunction

– Peripheral sensitization

– Membrane excitability at primary afferents

• Central process

– Synaptic transmission dysfunction

– Central sensitization

– Reduced inhibition

Therapeutic Strategy for Therapeutic Strategy for Neuropathic PainNeuropathic 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 Pharmacotherapy of Neuropathic PainNeuropathic Pain

• Opioids

• “Adjuvant analgesics”

• NSAIDs

Opioids in Opioids in Neuropathic PainNeuropathic 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

• 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.

• 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: Opioids in Neuropathic Pain: Conventional PracticeConventional 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


• Opioids


• NSAIDs

Adjuvant AnalgesicsAdjuvant 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

• Multipurpose analgesics• Drugs used for neuropathic pain• Drugs used for bone pain• Drugs used for bowel obstruction• Drugs used for muscle spasm

Adjuvant AnalgesicsAdjuvant Analgesics

Multipurpose Adjuvant Multipurpose Adjuvant AnalgesicsAnalgesics

• 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

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.

AnticonvulsantsAnticonvulsants

• 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

• Other anticonvulsants have limited data and are selected by trial and error

• Newer drugs have better safety profileslamotrigine carbamazepine

topiramate phenytoin

oxcarbazepine valproate

tiagabine

levetiracetam

zonisamide

AnticonvulsantsAnticonvulsants

• Classes

– Tricyclic antidepressants• 3o amine drugs: amitriptyline, imipramine, doxepin

• 2o amine drugs: desipramine, nortriptyline

– SNRIs: duloxetine, venlafaxine, minalcipran

– SSRIs: paroxetine, citalopram, others

– Others: bupropion

AntidepressantsAntidepressants

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



• Side effects

– 3o amine drugs > 2o amine drug > SNRIs/SSRIs/bupropion

– CNS, nausea, anticholinergic (TCAs), CV (TCAs), sexual (SSRIs, SNRIs)



• Based on safety and likelihood of efficacy, most reasonable choices would be 2o amine drugs or SNRIs– Desipramine

– Nortriptyline

– Duloxetine

– Venlafaxine

– Also consider bupropion



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.


• Other topical compounds used for pain– Ketamine

– Gabapentin and other anticonvulsants

– Other antidepressants


• 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

• Commercially-available drugs– Ketamine – Memantine– Dextromethorphan– Amantadine

NMDA-Receptor AntagonistsNMDA-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.


• 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

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.

GABAergic Adjuvant GABAergic Adjuvant AnalgesicsAnalgesics

• 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 AdministrationDrugs 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.


• Opioids


• NSAIDs

NSAIDs in Neuropathic PainNSAIDs 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 Non-Drug Strategies for Neuropathic Painfor Neuropathic Pain

• Interventional

approaches– Injections– Neural blockade– Neuraxial

analgesia– Spinal cord

stimulation

• Psychological approaches

• Rehabilitative approaches– Orthoses– PT/OT

• Complementary and Alternative approaches– Acupuncture– Massage– others


• 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


• 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

Neuropathic Pain in Advanced Illness Russell K. Portenoy, MD Chairman and Gerald J. and Dorothy R....

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Transcript of Neuropathic Pain in Advanced Illness Russell K. Portenoy, MD Chairman and Gerald J. and Dorothy R....