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Management of Neuropathic Pain

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Presented by Dr.Perry Fine at Pain Management for the Elderly Course, 2010. …

Presented by Dr.Perry Fine at Pain Management for the Elderly Course, 2010.
Scribe medical events Egypt. www.scribeofegypt.org

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  • 1. Management of Neuropathic Pain Perry G. Fine, MD Professor of Anesthesiology Pain Research Center School of Medicine University of Utah Salt Lake City, Utah
  • 2. Pathophysiology of Neuropathic Pain • Chemical excitation of non-nociceptors • Recruitment of nerves outside of site of injury • Excitotoxicity • Sodium channels • Ectopic discharge • Deafferentation • Central sensitization – maintained by peripheral input • Sympathetic involvement • Antidromic neurogenic inflammation
  • 3. Multiple Pathophysiologies May Be Involved in Neuropathic Pain • More than one mechanism of action likely involved • Neuropathic pain may result from abnormal peripheral nerve function and neural processing of impulses due to abnormal neuronal receptor and mediator activity • Combination of medications may be needed to manage pain: topicals, anticonvulsants, tricyclic antidepressants, serotonin- norepinephrine reuptake inhibitors, and opioids • In the future, ability to determine the relationship between the pathophysiology and symptoms/signs may help target therapy
  • 4. Pain Treatment Continuum Least invasive Most invasive Psychological/physical approaches Topical medications *Consider referral if previous treatments were unsuccessful. Systemic medications* Interventional techniques* Continuum not related to efficacy
  • 5. Nonpharmacologic Options • Biofeedback • Relaxation therapy • Physical and occupational therapy • Cognitive/behavioral strategies – meditation; guided imagery • Acupuncture • Transcutaneous electrical nerve stimulation
  • 6. Dorsal Horn BRAIN Pharmacologic Agents Affect Pain Differently Descending Modulation Peripheral Sensitization Central Sensitization PNS Local Anesthetics Topical Analgesics Anticonvulsants Tricyclic Antidepressants Opioids Anticonvulsants Opioids NMDA-Receptor Antagonists Tricyclic/SNRI Antidepressants Anticonvulsants Opioids Tricyclic/SNRI Antidepressants SPINAL CORD CNS
  • 7. Mechanisms of Action: Analgesic Agents • Anticonvulsants – sodium-channel blockade (oxcarbazepine [Trileptal]) – calcium-channel blockade (gabapentin) • Antidepressants – inhibit reuptake of norepinephrine and serotonin into presynaptic neurons (duloxetine) – sodium-channel blockade (tricyclics) • Opioids – block neurotransmitter-release by nociceptive fibers, thus decreasing transmission of pain-producing signals (oxycodone) • Topical Analgesics – sodium-channel blockade (lidocaine patch 5%) – vanilloid receptor (capsaicin)
  • 8. FDA-Approved Treatments for Neuropathic Pain • Carbamazepine – trigeminal neuralgia • Duloxetine – peripheral diabetic neuropathy • Gabapentin – postherpetic neuralgia • Lidocaine Patch 5% – postherpetic neuralgia • Pregabalin – peripheral diabetic neuropathy – postherpetic neuralgia
  • 9. Treatment Guidelines for Diabetic Peripheral Neuropathic Pain Reason for Agent Type Recommendation Agent Names First tier ≥2 RCTs in DPN Duloxetine, oxycodone CR, pregabalin, TCAs Second tier 1 RCT in DPN and ≥1 in other painful neuropathies Carbamazepine, gabapentin, lamotrigine, tramadol, venlafaxine ER (Effexor) Topical Mechanism of action Capsaicin, lidocaine Other ≥1RCTs in other painful neuropathies or other evidence Bupropion (Wellbutrin), citalopram (Celexa), methadone (Dolophine), paroxetine (Paxil), phenytoin (Dilantin), topiramate (Topamax) Adapted from Argoff CE, et al. Mayo Clin Proc. 2006;81:S12-S25. CR = controlled release; DPN = diabetic peripheral neuropathy; ER = extended release RCT= randomized controlled trial; TCAs = tricyclic antidepressants.
  • 10. Interventional Treatments for Neuropathic Pain • Neural blockade – sympathetic blocks for CRPS-I and II (reflex sympathetic dystrophy and causalgia) • Neurolytic techniques – alcohol or phenol neurolysis – pulse radio frequency • Stimulatory techniques – spinal cord stimulation – peripheral nerve stimulation • Medication pumps CRPS = complex regional pain syndrome.
  • 11. Comparison of Neuropathic Pain Treatment Guidelines, Excluding Trigeminal Neuralgia* Medication Class NeuPSIG Guidelines CPS Guidelines EFNS Guidelines TCAs First line First line First line for PPN, PHN, and CP Calcium channel α2-δ ligands (gabapentin and pregabalin) First line First line First line for PPN, PHN, and CP SNRIs (duloxetine and venlafaxine) First line Second line Second line for PPN *Only nontopical medications and nonopioid drugs considered first- or second-line in 1 of the guidelines are presented. CP = central pain. CPS = Canadian Pain Society. EFNS = European Federation of Neurological Societies. NeuPSIG = Neuropathic Pain Special Interest Group. NP = neuropathic pain. PHN = postherpetic neuralgia. PPN = painful polyneuropathy. SNRI = serotonin-norepinephrine reuptake inhibitor. TCAs = tricyclic antidepressants. Adapted from: O’Connor AB, Dworkin RH. Am J Med. 2009;122:S22-S32.
  • 12. Efficacy of Anticonvulsants in Treating Neuropathic Pain: Older Anticonvulsants Condition Carbamazepine Oxcarbazepine Phenytoin Sodium Valproate Diabetic neuropathy Yes (mod) ? (high) ? (mod) Yes (high) Postherpetic neuralgia Yes (mod) 0 0 Yes (high) Trigeminal neuralgia Yes (high) 0 0 0 Spinal cord injury pain 0 0 0 No (mod) Poststroke pain No (mod) 0 0 0 HIV neuropathy 0 0 0 0 Pain in patients with Guillain- Barré syndrome Yes (mod) 0 0 0 Cancer-related neuropathic pain 0 0 ? (mod/high) 0 Stomatodynia 0 0 0 0 TMJ dysfunction and associated myofascial pain 0 0 0 0 Chronic lumbar radicular pain 0 0 0 0 Postamputation phantom limb pain 0 0 0 0 Fibromyalgia syndrome 0 0 0 0 CRPS I 0 0 0 0 Neuropathic pain not otherwise specified ? (mod) 0 Yes (mod) No (high) CRPS = complex regional pain syndrome. HIV = human immunodeficiency virus. TMJ = temporomandibular joint. Adapted from: Goodyear-Smith F, Halliwell J. Clin J Pain. 2009;25:528-536.
  • 13. Efficacy of Anticonvulsants in Treating Neuropathic Pain: Newer Anticonvulsants Condition Lamotrigine Vigabatrin Tiagabine Topiramate Levetiracetam Diabetic neuropathy ? (high) 0 0 No (high) 0 Postherpetic neuralgia 0 0 0 0 ? (low) Trigeminal neuralgia Yes (mod) 0 0 No (mod) 0 Spinal cord injury pain ? (high) 0 0 0 0 Poststroke pain Yes (high) 0 0 0 0 HIV neuropathy Yes* (high) 0 0 0 0 Pain in patients with Guillain-Barré syndrome 0 0 0 0 0 Cancer-related neuropathic pain 0 0 0 0 0 Stomatodynia 0 0 0 0 0 TMJ dysfunction and associated myofascial pain 0 0 0 0 0 Chronic lumbar radicular pain 0 0 0 No (mod) 0 Postamputation phantom limb pain 0 0 0 0 0 Fibromyalgia syndrome 0 0 0 0 0 CRPS I 0 0 0 0 0 Neuropathic pain not otherwise specified No (mod) 0 ? (mod) 0 0 *Efficacious in patients on antiretroviral therapy but evidence is inconclusive for patients not receiving antiretroviral therapy. Adapted from: Goodyear-Smith F, Halliwell J. Clin J Pain. 2009;25:528-536.
  • 14. Efficacy of Anticonvulsants in Treating Neuropathic Pain: GABA Analogs GABA = gamma aminobutyric acid. GBP = gabapentin. Adapted from: Goodyear-Smith F, Halliwell J. Clin J Pain. 2009;25:528-536. Condition GBP Pregabalin Diabetic neuropathy Yes (high) Yes (high) Postherpetic neuralgia Yes (high) Yes (high) Trigeminal neuralgia 0 0 Spinal cord injury pain Yes (high) Yes (high) Poststroke pain 0 0 HIV neuropathy Yes (high) 0 Pain in patients with Guillain- Barré syndrome Yes (mod) 0 Cancer-related neuropathic pain Yes (high) 0 Stomatodynia 0 0 TMJ dysfunction and associated myofascial pain 0 0 Chronic lumbar radicular pain 0 0 Postamputation phantom limb pain Yes (high) 0 Fibromyalgia syndrome 0 Yes (high) CRPS I No (high) 0 Neuropathic pain not otherwise specified Yes (high) 0
  • 15. Are Serotonergic Antidepressants Effective in Diabetic Peripheral Neuropathic Pain (DPNP)? Author, Year Number of Patients Active Drug Dose (mg/day) Placebo Controlled ? Effective for Pain? Goodnick P, et al. 2000 12 Sertraline 62 No Yes (100% patients) Goodnick P, et al. 1997 8 Sertraline 150 No Yes Wilson RC. 1999 31 Trazodone 50-100 No 22.6% complete relief and 61.3% symptomatic relief
  • 16. Are TCAs Effective in DPNP? Author, Year Number of Patients Active Drug Dose (mg/day) Placebo Controlled? Effective for Pain? Sindrup RH, et al. 1989 9 IMI Variable Yes Yes Sindrup RH, et al. 1990 14 IMI Variable No Yes, if concentration >400-500 mmol/L Max MB, et al. 1987 29 AMI Variable Yes Yes Young RJ, Clarke BF. 1985 71 IMI or AMI Variable No Yes in 72.3% of patients Kvinesdal B, et al. 1984 12 IMI Variable Yes Yes Langohr HD, et al. 1982 48 CLO vs ASA 150 1500 Active Control Yes CLO>ASA Turkington RW. 1980 59 IMI and AMI 100 100 Active Control 100% response to drug vs 0% response to active control AMI = amitriptyline. ASA = acetylsalicylic acid. CLO = clomipramine. IMI = imipramine.
  • 17. Is Venlafaxine Effective in DPNP? VEN = venlafaxine. XR = extended release. Author, Year Number of Patients Active Drug Dose (mg/day) Placebo Controlled? Effective for Pain? Davis JL, Smith RL. 1999 11 VEN 37.5-75 No 100% patients, 75-100% reduction in pain Lithner F. 2000 11 VEN 225 No Yes Kiayias J, et al. 2000 8 VEN 75 Yes Yes 100% patients Rowbotham MC, et al. 2004 244 VEN XR 75, 150, 225 vs placebo Yes Yes at 150 and 225 mg
  • 18. Is Duloxetine Effective in DPNP? Author, Year Number of Patients Active Drug Dose (mg/day) Placebo Controlled? Drug Effective for Pain? Goldstein DJ, et al. 2005 457 Duloxetine 20, 60, 120 Yes Yes, at 60 and 120 mg
  • 19. Head-to-head Trials for DPNP: Antidepressants vs Anticonvulsants Author, Year Number of Patients Active Drug Dose (mg/day) Placebo Controlled? Drug Effective for Pain? Dallocchio C, et al. 2000 13 GBP 12 AMI GBP vs AMI 2400 30-90 N/A GBP>AMI Morello CM, et al. 1999 27 GBP vs AMI 225 N/A GBP = AMI
  • 20. Head-to-head Trials for DPNP: Antidepressants vs Antidepressants CIT = citalopram. DESIP = desipramine. FLUOX = fluoxetine. MAP = maprotiline. MIA = mianserin. Author, Year Number of Patients Active Drug Dose (mg/day) Placebo Controlled? Effective for Pain? Vrethem M, et al. 1997 37 AMI vs MAP 75 75 Yes Yes AMI>Map>Placeb o Max MB, et al. 1992 38 46 AMI vs DESIP vs FLUOX vs Placebo 105 111 40 Yes AMI = DESIP AMI>Placebo DESIP>Placebo FLUOX = Placebo Sindrup SH, et al. 1992 18 IMI vs MIA vs Placebo Variable 60 Yes IMI>Placebo MIA = Placebo Sindrup SH, et al. 1992 15 CIT vs IMI vs Placebo 40 Yes IMI>CIT>Placebo
  • 21. NNTs for Anticonvulsants vs Antidepressants in DPNP • 12 trials of 9 antidepressants (including SSRIs) • 4 trials of anticonvulsants (phenytoin, carbamazepine, GBP) • NNT antidepressants = 3.4 • NNT anticonvulsants = 2.7 SSRI = selective serotonin reuptake inhibitor. Collins SL, et al. J Pain Symptom Manage. 2000;20:449-458.
  • 22. Consensus Treatment Guidelines for DPNP Agent Type Reason for Recommendation Agent Names First tier >2 RCTs in DPNP • Duloxetine • Pregabalin • Oxycodone CR • TCAs Second tier 1 RCT in DPNP >1 RCT neuropathic pain • GBP • Tramadol • Lamotrigine • VEN XR CR = controlled-release. RCT = randomized controlled trial. Modified from: Argoff CE, et al. Mayo Clin Proc. 2006;81:S12-S25.
  • 23. First Tier: Duloxetine • SNRI • FDA-approved for DPNP – 3 RCTs: 60-120 mg/day – N=1139; 12 weeks – Positive studies FDA = US Food and Drug Administration.
  • 24. Study Duration Treatment Groups N Duloxetine 60 mg/day Duloxetine 120 mg/day Goldstein DJ, et al.1* 12 weeks 20, 60, 120 mg/day vs placebo 457 P<0.001** P<0.001** Wernicke JF, et al.2* 12 weeks + 1 week taper 60, 120 mg/day vs placebo 334 P<0.001** P<0.001** Raskin J, et al.3* 12 weeks + 1 week taper 60, 120 mg/day vs placebo 348 P<0.001** P<0.001** Duloxetine: Clinical Trials in DPNP Study Duration Treatment Groups N 1-year, open-label safety studies – extension of studies 1, 2, and 34* 52 weeks 120 mg vs routine care 867 6-month, open-label safety study5 28 weeks 60 mg BID vs 120 mg QD 449 *Patients with mood disorders excluded. **Duloxetine vs placebo on primary endpoint: 24-hour average pain severity in 12 weeks. †Duloxetine is not indicated for long-term treatment in DPNP; the efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials. 1. Goldstein DJ, et al. Pain. 2005;116:109-118. 2. Wernicke JF, et al. Neurology. 2006;67:1411-1420. 3.Raskin J, et al. Pain Med. 2005;6:346-356. 4. Hardy T, et al. Diabetes Care. 2007;30:21-26. 5. Raskin J, et al. Pain Med. 2006;7:373-385. Long-term Safety Studies† Short-term Efficacy and Safety Studies
  • 25. Adverse Events: Duloxetine • Anorexia • Asthenia • Constipation • Cough • Decreased appetite • Diarrhea • Dizziness • Dry mouth • Dyspepsia • Erectile dysfunction • Fatigue • Headache • Hyperhidrosis • Insomnia • Loose stool • Muscle cramp • Myalgia • Nasopharyngitis • Nausea • Pharyngolaryngeal pain • Pollakiuria • Pyrexia • Somnolence • Tremor • Vomiting Observed in at least 3% of patients Gremillion SW, et al, eds. Drug Facts And Comparisons® Pocket Version 2010. St. Louis, MO: Wolters Kluwer; 2010.
  • 26. First Tier: Pregabalin • α2-δ calcium channel modulator • FDA-approved for DPNP • 3 RCTs: – 75 mg/day and 150 mg/day; same as placebo – 300 mg/day and 600 mg/day; good efficacy Lesser H, et al. Neurology. 2004;63:2104-2110. Richter RW, et al. J Pain. 2005;6:253-260. Rosenstock J, et al. Pain. 2004;110:628-638.
  • 27. Adverse Events: Pregabalin Most common reactions that lead to discontinuation • Dizziness • Somnolence • Asthenia • Ataxia • Blurred vision • Confusion • Incoordination • Peripheral edema • Abnormal thinking Most common reactions in controlled clinical trials • Blurred vision • Dizziness • Dry mouth • Edema • Somnolence • Abnormal thinking • Weight gain Gremillion SW, et al, eds. Drug Facts And Comparisons® Pocket Version 2010. St. Louis, MO: Wolters Kluwer; 2010.
  • 28. First Tier: TCAs • Amitriptyline has been studied the most extensively – Limitations due to anticholinergic adverse effects • Constipation and pseudodementia – Potential cardiac conduction abnormalities1 • Nortriptyline and desipramine – Better adverse effect profiles – High doses cause anticholinergic side effects • Affects cardiac conduction – Desipramine is an alternative if patient has an amitriptyline intolerance2 1. Max MB, et al. Pain. 1991;45:3-9. 2. Duby JJ, et al. Am J Health Syst Pharm. 2004;61:160-173.
  • 29. TCAs: Mechanisms • Relief of pain through serotonin (5-HT) and norepinephrine (NE) reuptake blockade1 • Blockade of -adrenergic receptors2 • Sodium and potassium channel modulation • Modulation of monoamine neurotransmitters • NMDA receptor antagonism? NMDA = N-methyl-D-aspartate 1. Lawson K. Expert Opin Investig Drugs. 2002;11:1437-1445. 2. Sindrup SH, Jensen TS. Pain. 1999;83:389-400.
  • 30. TCAs: Adverse Events • Commonly reported AEs (generally anticholinergic) – Blurred vision – Cognitive changes – Constipation – Dry mouth – Orthostatic hypotension – Sedation – Sexual dysfunction – Tachycardia – Urinary retention – Weight gain Most AEs desipramine nortriptyline imipramine doxepin amitriptyline Fewest AEs AEs = adverse events
  • 31. Postherpetic Neuralgia
  • 32. Efficacy of Pregabalin in PHN *≥50% and ≥30% reduction from baseline. †P≥0.001 vs placebo. ‡600 mg/day arm stratified according to CLcr. Patients either CLcr >30 and ≤60 mL/min received 300 mg/day; patients with CLcr >60 mL/min received 600 mg/day. CLcr = creatinine clearance. van Seventer, RV et al. Curr Med Res Opin. 2006;22:375-384. Patients(%) 10 20 30 40 50 60 Responders (≥50%*) Placebo (n=93) Responders (≥30%*) 0 150 (n=87) 300 (n=98) 600‡ (n=98) 600‡ (n=98) Placebo (n=93) 150 (n=87) 300 (n=98) Pregabalin dose (mg/day) Pregabalin dose (mg/day) † ††† † Proportion of Responders to Treatment
  • 33. Pregabalin Improves Sleep Disturbance in Patients with PHN *P≤0.01 vs placebo.†600 mg/day arm stratified according to CLcr patients with CLcr >30 and ≤60mL/min received 300 mg/day pregabalin; patients with CLcr >60 mL/min received 600 mg/day. van Seventer R, et al. Curr Med Res Opin. 2006;22:375-384. WeeklyMeanSleep InterferenceScore * 1 2 3 4 5 6 0 Endpoint Treatment (Weeks) Mean Weekly Pain-related Sleep-interference in PHN at All Doses 1 2 4 7 11 131210 Placebo (n=93) Pregabalin 150 mg/day (n=87) Pregabalin 300 mg/day (n=98) Pregabalin 600† mg/day (n=88) ********** * * * * * * * * * * * * * * **** * * * *** * * * * ** * 98653
  • 34. Efficacy of Gabapentin in PHN RespondersatEndpoint(%) 25 30 35 40 45 50 PBO 0 Study 1 *P<0.01 **P<0.001 Study 2 GBP 3600 mg/day GBP 1800 mg/day GBP 2400mg/day PBO 12% * ** ** 20 15 10 5 29% 14% 32% 34% Proportion of Responders (Patients with ≥50% Reduction in Pain Score) at Endpoint Controlled PHN Studies Neurontin [package insert]. New York, New York: Pfizer Inc; 2009.
  • 35. Conclusions • Irrespective of the neuropathic pain condition under treatment, the central pathways involved in these conditions remain the same; hence, the use of antidepressants and anticonvulsants that modulate pathways in patients with chronic pain will be very effective.