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Management of Neuropathic Pain

Management of Neuropathic Pain. Mazen M. Dimachkie , M.D. Disclosures. Speaker Bureau Depomed Merck Pfizer Grants Pfizer. OBJECTIVES. Heterogeneity of painful peripheral neuropathy Evidence-based diagnostic approach Pain mechanisms Neuropathic pain management

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Management of Neuropathic Pain

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  1. Management of Neuropathic Pain Mazen M. Dimachkie, M.D.

  2. Disclosures Speaker Bureau • Depomed • Merck • Pfizer Grants • Pfizer

  3. OBJECTIVES • Heterogeneity of painful peripheral neuropathy • Evidence-based diagnostic approach • Pain mechanisms • Neuropathic pain management • Evidence-based guidelines

  4. Neuropathic Pain • Pain as a direct consequence of a lesion or disease affecting the somatosensory system • Descriptors and diurnal pattern • Pain carries physical and emotional burdens and leads to increased healthcare utilization • Chronic pain or mobility impairment may lead to depression, anxiety and loss of self-esteem • This becomes part of a vicious cycle that feeds into and amplifies the negatives of painful peripheral neuropathy

  5. Peripheral Neuropathies PN affects 2.4 to 7% of the population CDC National Diabetes Fact Sheet 2011: 25.8 million diabetics 60-70% mild to severe neuropathy forms 35% of U.S. adults aged > 20 years prediabetes 26.4% of diabetic patients have painful neuropathy The Neuropathy Association estimates > 20 million (6.5%), 50% markedly symptomatic, 150 causes JNNP 1997;62:310-318 http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf Diabetes Care. 2006 Jul;29(7):1518-22

  6. Peripheral Neuropathy Classification Modality: Sensory: small and/or large fiber Motor Sensori-motor Autonomic Temporal profile Symmetric or asymmetric Length-dependence or neuronopathy Proximal and / or distal Upper motor neuron signs Axon loss or demyelinating

  7. Electrodiagnostic TestingNerve Conduction Studies • Low amplitude in axon loss • Myelin loss disorders: • Prolonged distal latency • Markedly reduced NCV • Delayed F-wave latency • Conduction block

  8. North America – South America(NA – SA) Neuropathy ProjectKhan et al, AAN 2006

  9. AAN Practice ParameterEvaluation of DSPN • Screening laboratory tests may be considered for all patients with polyneuropathy(Level C) • Serum glucose, B12 with metabolites (MMA ± HC) and serum immunofixation provide the highest yield of abnormality (Level C) • Genetic testing should be conducted in hereditary neuropathies (Level A) • Genetic testing may be considered in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype (Level C) Neurology 2009;72:185-192

  10. AAN Practice ParameterEvaluation of DSPN • Autonomic testing in suspected autonomic neuropathy (Level B) & distal small fiber sensory PN (Level C) • Nerve biopsy: insufficient evidence in DSPN but is generally accepted in amyloid neuropathy, mononeuropathy multiplex, and atypical CIDP (Level U) • Skin biopsy may be considered for the diagnosis of DSPN, esp. CSPN (Level C) Neurology 2009;72:177-184

  11. Normal Epidermal Nerve fiber Density Proximal Thigh Distal Leg

  12. Small Fiber Neuropathy: Length-dependent decrease in Epidermal Nerve Fiber Density Proximal Thigh: Decreased Epidermal Nerve Fiber Density Distal Leg: Absent Epidermal Nerve Fibers To schedule a skin biopsy, please call 913-588-0656

  13. Neuropathic Pain Mechanisms Peripheral Sensitization • Lancet Neurol. 2010 Aug;9(8):807-19

  14. Neuropathic Pain Mechanisms Central Sensitization Lancet Neurol. 2010 Aug;9(8):807-19

  15. Mechanistic Approach to Treatment Brain TCAs SSRIsSNRIs (Duloxetine) NSRIsOpiates Tramadol Descending inhibition NE/Serotonin Opiate receptors Central sensitization Peripheral sensitization Ca++: GBP, OXC, LTG, LVT, PGB NMDA: Ketamine, TPM Dextromethorphan Methadone 2° neuron PNS Na+ CBZOXC PHTTCATPMLTG Mexiletine Lidocaine Spinal cord OthersCapsaicin NSAIDsCOX-2 inhibitorsLevodopa Adapted from Beydoun, 2001

  16. Neuropathic pain Multidimensional management • Treatment of underlying cause of nerve damage • Pharmacological therapy • Non-pharmacological therapy

  17. Other Treatments: Non-pharmacological therapy • Lifestyle modification, PT & OT • Podiatric care & diabetic orthopedic shoes • Pain psychologist & Cognitive Behavioral Rx • Complementary & alternative medicine: acupuncture, supplements etc • TENS • Interventional / regional anesthesia • Neuro-stimulation J Diabetes Complications. 2012 Jun 18. [Epub ahead of print]

  18. Painful Peripheral NeuropathyTreatment Goals Setting the expectation with emphasis on function: work, recreation & sleep This is addition to significant reduction of pain scores by 30-50% Types of pharmacotherapies: Antidepressants Anticonvulsants Topical agents Analgesics Opioid drugs

  19. Antidepressants: TCAs & SSRIs • >9 TCA and/or SSRI clinical trials in DPN or PHN • Tricyclic antidepressants (TCAs) highly effective: amitriptyline, nortriptyline and desipramine • TCA effect independent of depression comorbidity • Selective serotonin reuptake inhibitors (SSRIs) less effective than TCAs: • Fluoxetine no different than placebo in DPN • Paroxetine less effective than imipramine in DPN • Escitalopram rs6318 SNP in the serotonin receptor 2C gene associated with 75% moderate or better pain relief Br J ClinPharmacol. 1990 Nov;30(5):683-91. Neurology. 2002 Oct 8;59(7):1015-21 Neurology. 1987 Apr;37(4):589-96 N Engl J Med. 1992 May 7;326(19):1250-6 Pain. 1990 Aug;42(2):135-44 Eur J Clin Pharmacol. 2011 Nov;67(11):1131-7

  20. SNRI Antidepressants: Venlafaxine • Increases synaptic serotonin/NE (SNRI) by inhibiting reuptake • RCT: ER significantly reduces pain intensity in DPN • Doses of 150-225 mg a day, not 75 mg • Useful as add on to GBP in DPN: improved pain, QOL, sleep and mood • 112.5 mg bid may be as effective as imipramine 75 mg BID in a 3-way crossover, 4-wk RCT in DPN (n=15) and non-diabetic cases (n=17, CSPN = 11) • Relatively well tolerated; side effect of nausea and somnolence Pain. 2004 Aug;110(3):697-706 J Clin Neuromuscul Dis. 2001 Dec;3(2):53-62 Neurology. 2003 Apr 22;60(8):1284-9

  21. SNRI Antidepressants: Venlafaxine in Oxaliplatin Neuropathy • RCT: 50 mg 1 h prior oxaliplatin& ER 37.5 mg b.i.d. from days 2 to 11 vsPBO • N = 48, patients with oxaliplatin-induced acute neurotoxicity • Completers 20/24 venlafaxine and 22/24 PBO • Primary end point percentage of patients with a 100% pain relief based on the NRS pain scale • Full relief was more frequent in the venlafaxine arm: 31.3% versus 5.3% (P=0.03) • Venlafaxine side-effects included grade 1-2 nausea (43.1%) and asthenia (39.2%) Ann Oncol. 2012 Jan;23(1):200-5

  22. SNRI Antidepressants:Duloxetine • SNRI released in Fall 2004 with higher, more balanced affinity for NE/5HT reuptake sites • First FDA approved agent DPN (also approved for fibromyalgia) • Effective at 60 and 120 mg/d not 20 mg/d • Higher AE incidence with 120 mg dose Pain. 2005;116(1-2):109-1 Pain Med. 2005;6(5):346-56 .

  23. Duloxetine • Adverse events (largely dose-dependent) • Nausea, somnolence, dizziness, constipation, dry mouth • Drug interactions • MAOIs (wait 14 days) • TCAs, Phenothiazines, Type 1C antiarrhythmics, Quinolone antibiotics and Cimetidine • Precautions: closed-angle glaucoma and hepatotoxicity • Black box warnings: suicide risk

  24. Anticonvulsants:Gabapentin • Most commonly prescribed AED for pain • Does not bind to plasma proteins • Does not induce hepatic enzymes • Excreted unchanged in urine • Mechanisms of action: binds to 2 subunit of presynaptic voltage-dependent Cachannel • Also increases CNS levels of GABA Life Sci. 2007 May 8;80(22):2015-24 Neurology. 2002;58(3):368-72 Epilepsy Res. 2002;49(3):203-10

  25. Gabapentin RCTs for PHN Label Pain2001;94:215-224 JAMA 1998;280:1837-42 • 8-week trial • 229 patients titrated up to 3600 mg/day • Average daily pain score dropped from 6.3 to 4.2 on GBP vs. 6.5 to 6.0 for placebo (p<0.001) • 33% reduction in pain score vs. 8% reduction on placebo • 43% with significant improvement vs. 12% on placebo Mean Change (SE) *P<0.01 (for both doses of gabapentin)

  26. Gabapentin: DPN & Chemo Neuropathy • RCT 8 wk in 165 DPN patients GBP vs PBO: • Mean daily pain scores lower in GBP group (p<.001) • 26% pain-free vs. 15% on placebo at 8 wks • Improved quality of life & sleep • GBP vs. amitriptyline cross-over study in DPN • No significant difference • RCT cross-over in 115 Chemo-induced neuropathy • 6 wk epochs of GBP 2700 mg vs. PBO • 2-week washout period • No benefit of GBP vs. placebo on 0-10 pain rating scale • JAMA 1998;280:1831-36 Arch Intern Med. 1999 ;159(16):1931-7 Cancer 2007;110:2110

  27. Gabapentin, Nortriptyline or Combo • Double-blind, double-dummy, crossover trial, DPN & PHN • 56 patients randomized in a 1:1:1 ratio to receive one of three sequences of daily oral GBP, nortriptyline, & combo • Duration of each treatment period 6-week, 45 completers • Primary outcome mean daily pain at maximum tolerated dose • Mean daily pain levels in 45 completers compared to baseline (5.4): • GBP 3.2 • NTP 2.9 • Combo* 2.3 • Well tolerated, most common AE dry mouth esp. with NTP *p<0.05 vs. others Lancet. 2009 Oct 10;374(9697):1252-61

  28. Lamotrigine • DPN RCT vs PBO, n=59 • Numerical pain scale reduction 6.4 to 4.2 and with PBO 6.5 to 5.3 (p < 0.001) • Effective at doses of 200 – 400 mg daily • HIV neuropathy RCT n=42 • Better pain reduction in 9 LTGvs 20 PBO • 13 drop out, 5 due to mild to moderate rash • Chemo-induced neuropathy RCT n= 131 • 300 mg vs. PBO x 10 wks • No significant difference in average pain scores (0-10) or on secondary outcomes • Neurology2001;57:505-9 Neurology 2000;54:2115-9 Cancer 2008;112:2802-8

  29. Anticonvulsants: Pregabalin • Approved on 12/31/04: • DPN 50-100 mg TID • PHN 75-300 mg BID • Fibromyalgia 75-225 mg BID Neurology 2004;63:2104-10 CurrMed Res Opin. 2006;22:375-84.

  30. Anticonvulsants: Pregabalin • Similar mechanism as gabapentin • Initiate at therapeutic dose, onset of action by day 2-3 • Linear pharmacokinetics across therapeutic doses • DPN adverse events on 150, 300 mg & 600 mg daily: • Dizziness (9, 23 & 29%) • Somnolence (6, 13 & 16%) • Peripheral edema (6, 9 & 12%) • Weight gain (4, 4 & 6%) • Dry mouth (2, 5 & 7%) • Blurry vision (1, 3 & 6%) • SAE: suicide risk Am J Ther. 2010 ;17(6):577-85

  31. DLX vs PGB in DPN & CSPN • Retrospective chart review • N=143; both drugs at different times n = 51, only one n= 92 • Majority DPN & CSPN • Overall responders: DLX 41% PGB 48% • Discontinuation DPN: DLX 66%, PGB 59% Both are probably effective for DPN & CSPN neuropathic pain * Differences NS Int J Neurosci. 2011;121:521-7

  32. Tramadol in DPN • Centrally-acting: • Binds μ-opioid receptors • Weak inhibitor of NEP/5HT reuptake • RCT tramadol (n=65; 50-400 mg) vs. PBO (n= 66): • Effective in DPN • Mean dose 210 mg/d • No effect on sleep • AEs: nausea, constipation, HA & somnolence Neurology 1998;50:1842

  33. Analgesics Opiate: Oxycodone CR in DPN • RCT n=159 • Dose 10 mg BID increased Q 3 d to maximum 60 mg BID • Primary efficacy was pain intensity at days 28 & 42 • Results at mean dose of 37 mg/d (10-100): • Effective in moderate to severe DPN pain • Adverse events in 96% vs. 68% on PBO! • Constipation 42% • Somnolence 40% • Nausea 36% • Dizziness 32% Neurology 2003; 60:927-934

  34. Morphine SR , Gabapentin or Combo Dose adjusted for >60 yo or <60 kg • Four-period (5 wks) crossover trial (35 DPN; 22 PHN) • Active placebo (lorazepam 1.6 mg/d) • Morphine SR 120 mg/d (60 mg/d) • Gabapentin 3200 mg /d (2400 mg/d) • Morphine SR 60 mg/d + gabapentin 2400 mg/d • Mean daily pain levels over 7 days at maximally tolerated dose in 41 completers (N=57) compared to baseline (5.72): • Active PBO 4.49 (1.38 mg) • Morphine SR 3.70 (45.3 mg) • Gabapentin 4.15 (2207 mg) • Morphine SR + GBP* 3.06 (34.3 mg; 1705 mg) • Combination had lower mood interference, higher vitality & social functioning scores than morphine alone • AEs Combination: • more constipation than gabapentin • more dry mouth than morphine *p<0.05 vs. others Gilron et al. NEJM 2005;352(13):1324–34

  35. Lidocaine 5% patch in PHN‘Enriched enrollment' study design 28 day cross-over (n=32) 12 Lidocaine patch 5% 11 Vehicle patch 10 9 8 7 No. of patients 6 5 4 3 2 1 0 Moderate pain relief Substantial pain relief Complete pain relief 78% preferred lidocaine vs. 9% placebo (p<0.001) Pain 1999;80:533-538

  36. Capsaicin 8% Patch • Selectively binds TRPV1 receptor, cationchannel overexpressed in intact nociceptive sensory nerves • TRPV1 receptor activation at 38 C → high levels of intracellular calcium & substance P depletion • Capsaicin cream 0.075-0.1% of limited use • 8% patch mean pain score change from baseline @ wk 2-12: -33.8% NGX-4010 vs +4.9% PBO in PHN • AE: pain, transient burning, itch, skin irritation & HTN • 2 RCTs in HIV DSPN: • mean pain reduction of 22.8% vs. 10.7% PBO • mean pain reduction of 29.5% vs. 24.5% PBO Pain Med. 2010;11:600-8 Neurology. 2008 Jun 10;70(24):2305-13 J Acquir Immune DeficSyndr. 2012;59(2):126-33

  37. Gabapentin ER in PHN • RCT, n= 158, enrichment design, gastric-retentive technology GBP ER x 4 weeks: • 1800 mg PM vs600 mg AM, 1200 mg PM vsPBO 1 or 2 x daily • ≥50% decrease from baseline in ADP score: 25.5%, 28.8%, and 11.8% (p<0.05) • Sleep interference scores improved • AE: dizziness (22.2%, 11.3%, and 9.8%) somnolence (9.3%, 7.5%, and 7.8%) • Pooled data analysis from 2 clinical trials: dizziness (11% vs PBO 2%) somnolence (5% vs PBO 3%) Clin J Pain. 2009;25(3):185-92 J Pain Res. 2012;5:203-208

  38. PHN Pain Pharmacotherapy 2012 AAN Practice Parameter 2004 (Level A) TCA, GBP, PGB, opioids & lidocaine patch Capsaicin 8% patch Gabapentin ER Nerve block Neurology. 2004 Sep 28;63(6):959-65 Pain Med. 2010;11:600-8 Clin J Pain. 2009;25(3):185-92

  39. DPN Pain Pharmacotherapy 2012 PGB (Level A) Amitriptyline, DLX, GBP, venlafaxine, Na valproate Opioids (tramadol, morphine, oxycodone CR) Capsaicin, isosorbidedinitrate Percutaneous electrical stimulation (Level B) Venlafaxine add-on to GBPLidocaine patch (Level C) Desipramine or imipramine, fluoxetine, NTP+fluphenazine, topiramate, vitamins & ALA (Level U) Neurology. 2011;76(20):1758-65

  40. Painful Peripheral NeuropathyConclusions Discuss patient expectations in managing chronic neuropathic pain Selection based on efficacy, AE and comorbidity Multiplicity of drugs A variety of mechanisms Indications limited to PHN, DPN & fibromylagia Comparative effectiveness studies are needed in a wider variety of neuropathic pain etiologies

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