Upload
anabel-hutchinson
View
222
Download
0
Tags:
Embed Size (px)
Citation preview
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
Neuropathic Pain: Neuropathic Pain: Clinical ChallengesClinical Challenges
• Classification by medical diagnosis– Examples
Chemotherapy-induced polyneuropathy Malignant plexopathy Post-stroke central pain syndrome Complex regional pain syndrome
Neuropathic Pain: Neuropathic Pain: Clinical ChallengesClinical Challenges
• Classification by neurological localization– Polyneuropathy– Mononeuropathy (ies)– Radiculopathy– Myelopathy– Encephalopathy
Neuropathic Pain: Neuropathic Pain: Clinical ChallengesClinical 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: Neuropathic Pain: Clinical ChallengesClinical Challenges
• 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
Neuropathic Pain: Neuropathic Pain: Clinical ChallengesClinical 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: 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
Opioids in Opioids in Neuropathic PainNeuropathic 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
Opioids in Opioids in Neuropathic PainNeuropathic Pain
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
Pharmacotherapy of Pharmacotherapy of Neuropathic PainNeuropathic Pain
• Opioids
• “Adjuvant analgesics”
• 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
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
• 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
NMDA-Receptor AntagonistsNMDA-Receptor Antagonists
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 AntagonistsNMDA-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
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.
Pharmacotherapy of Pharmacotherapy of Neuropathic PainNeuropathic Pain
• Opioids
• “Adjuvant analgesics”
• 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
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