1 / 41

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

kieran-witt
Download Presentation

Management of Neuropathic Pain

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related