Neuropathic pain in advanced illness
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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 Care Beth Israel Medical Center Chief Medical Officer Continuum Hospice Care

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Neuropathic pain in advanced illness

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

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

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 challenges1

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 challenges2

Neuropathic Pain: Clinical Challenges

Classification by neurological localization

Polyneuropathy

Mononeuropathy (ies)

Radiculopathy

Myelopathy

Encephalopathy


Neuropathic pain clinical challenges3

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 “mechanism-based treatment”


Neuropathic pain clinical challenges4

Neuropathic Pain: Clinical Challenges

Classification by inferred pathophysiology

Distinguishes pain with “peripheral generators” and pain with “central generators”


Neuropathic pain inferred pathophysiologies

Neuropathic Pain: Inferred Pathophysiologies

Peripheral generator

Central generator

Mononeuropathy

Polyneuropathy

Deafferentation syndromes

Neuroma

Axonopathy

Anesthesia dolorosa/

phantom pain

Central pain

Nerve sheath pain

myelinopathy

Sympathetically-maintained pain


Neuropathic pain diverse phenomenologies

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 phenomenologies1

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 phenomenologies2

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 challenges5

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

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

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

Pharmacotherapy of Neuropathic Pain

  • Opioids

  • “Adjuvant analgesics”

  • NSAIDs


Opioids in neuropathic pain

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 pain1

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 pain2

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 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 pain1

Pharmacotherapy of Neuropathic Pain

  • Opioids

  • “Adjuvant analgesics”

  • NSAIDs


Adjuvant analgesics

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 analgesics1

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 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 opioid-refractory neuropathic pain


Adjuvant analgesics for 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 pain1

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

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

Anticonvulsants

  • Gabapentinoids

    • Work via voltage-gated calcium channel, modulating alpha-2-delta protein

    • Positive RCT’s

      • Gabapentin: PHN/diabetic neuropathy, neuropathiccancer 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.


Anticonvulsants1

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


Anticonvulsants2

Anticonvulsants

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

  • Newer drugs have better safety profiles

    lamotrigine carbamazepine

    topiramate phenytoin

    oxcarbazepine valproate

    tiagabine

    levetiracetam

    zonisamide


Antidepressants

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.


Antidepressants1

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.


Antidepressants2

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.


Antidepressants3

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

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 pain1

Topical Drugs for Neuropathic Pain

Other topical compounds used for pain

Ketamine

Gabapentin and other anticonvulsants

Other antidepressants


Topical drugs for neuropathic pain2

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

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

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 Antagonists

  • NMDA receptor involved in neuropathic pain and opioid tolerance

  • Commercially-available drugs

    • Ketamine

    • Memantine

    • Dextromethorphan

    • Amantadine


Nmda receptor antagonists1

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 antagonists2

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

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

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

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 pain2

Pharmacotherapy of Neuropathic Pain

Opioids

“Adjuvant analgesics”

NSAIDs


Nsaids in neuropathic pain

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

approaches

Injections

Neural blockade

Neuraxial analgesia

Spinal cord stimulation

Psychological approaches

Rehabilitative approaches

Orthoses

PT/OT

Complementary and Alternative approaches

Acupuncture

Massage

others

Non-Drug Strategies for Neuropathic Pain


Neuropathic pain in advanced illness1

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 illness2

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


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