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

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Presentation on theme: "Management of Neuropathic Pain Mazen M. Dimachkie, M.D."— Presentation transcript:

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

2 Disclosures Speaker Bureau  Depomed  Merck  Pfizer Grants

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 Diabetes Care Jul;29(7): JNNP 1997;62:

6 ARIZONA Banner Good Samaritan Neuropathy Center ILLINOIS The Neuropathy Center at Edward Hines, Jr. VA Hospital NEW YORK Peripheral Neuropathy Center at Columbia University CALIFORNIA - LOS ANGELES Neuropathy Center at University of Southern California KANSAS The University of Kansas Neuropathy Center NEW YORK Peripheral Neuropathy Center at Weill Medical College of Cornell University CALIFORNIA - SAN FRANCISCO University of California at San Francisco Neuropathy Center LOUISIANA The Neuropathy Center of Excellence at Louisiana State University HSC OHIO The Neuropathy Center at Ohio State University FLORIDA - JACKSONVILLE University of Florida and Shands Jacksonville Neuropathy Center MICHIGAN University of Michigan Neuropathy Center TENNESSEE The Neuropathy Center of Excellence at Vanderbilt University Medical Center FLORIDA - MIAMI University of Miami Miller School of Medicine Neuropathy Center MISSOURI The Neuropathy Center at Saint Louis University UTAH The Peripheral Neuropathy Center at The University of Utah

7 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

8 Electrodiagnostic Testing Nerve Conduction Studies  Low amplitude in axon loss  Myelin loss disorders:  Prolonged distal latency  Markedly reduced NCV  Delayed F-wave latency  Conduction block

9 North America – South America (NA – SA) Neuropathy Project Khan et al, AAN 2006 PN CategoriesNA % SA % Immune-mediated2018 Diabetic1323 Hereditary2710 Infections / Inflammatory514 Systemic / Metabolic / Toxic712 Cryptogenic2823 Total # cases

10 AAN Practice Parameter Evaluation 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:

11 AAN Practice Parameter Evaluation 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:

12 Normal Epidermal Nerve fiber Density Distal Leg Proximal Thigh

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

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

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

16 PNS CBZ OXC PHT TCA TPM LTG Mexiletine Lidocaine Na + Spinal cord Brain Descending inhibition TCAs SSRIs SNRIs (Duloxetine) NSRIs Opiates Tramadol Ca ++ : GBP, OXC, LTG, LVT, PGB NMDA : Ketamine, TPM Dextromethorphan Methadone Others Capsaicin NSAIDs COX-2 inhibitors Levodopa Adapted from Beydoun, 2001 Mechanistic Approach to Treatment Central sensitization Peripheral sensitization NE/Serotonin Opiate receptors 2° neuron

17 Neuropathic pain Multidimensional management  Treatment of underlying cause of nerve damage  Pharmacological therapy  Non-pharmacological therapy

18 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 Jun 18. [Epub ahead of print]

19 Painful Peripheral Neuropathy Treatment 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

20 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 N Engl J Med May 7;326(19): Br J Clin Pharmacol Nov;30(5): Neurology Oct 8;59(7): Pain Aug;42(2): Neurology Apr;37(4): Eur J Clin Pharmacol Nov;67(11):1131-7

21 SNRI Antidepressants: Venlafaxine  Increases synaptic serotonin/NE (SNRI) by inhibiting reuptake  RCT: ER significantly reduces pain intensity in DPN  Doses of mg a day, not 75 mg  Useful as add on to GBP in DPN: improved pain, QOL, sleep and mood  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 J Clin Neuromuscul Dis Dec;3(2):53-62 Pain Aug;110(3): Neurology Apr 22;60(8):1284-9

22 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 vs PBO  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 Jan;23(1):200-5

23 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

24 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

25 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 Ca channel  Also increases CNS levels of GABA Neurology. 2002;58(3): Epilepsy Res. 2002;49(3): Life Sci May 8;80(22):

26 Gabapentin RCTs for PHN Label JAMA 1998;280:  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) Pain 2001;94:

27 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: Arch Intern Med ;159(16): Cancer 2007;110:2110

28 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  NTP2.9  Combo* 2.3  Well tolerated, most common AE dry mouth esp. with NTP Lancet Oct 10;374(9697): *p<0.05 vs. others

29 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 LTG vs 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 Neurology 2001;57:505-9 Neurology 2000;54: Cancer 2008;112:2802-8

30 Anticonvulsants: Pregabalin  Approved on 12/31/04:  DPN mg TID  PHN mg BID  Fibromyalgia mg BID Neurology 2004;63: Curr Med Res Opin. 2006;22:

31 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 ;17(6):577-85

32 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% DPN & CSPN DLX (59 mg) PGB (217 mg) Much Improved 21%33% Adverse events 38%30% Int J Neurosci. 2011;121:521-7 * Differences NS Both are probably effective for DPN & CSPN neuropathic pain

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

34 Analgesics Opiate: Oxycodone CR in DPN 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% –Somnolence40% –Nausea36% –Dizziness32% Neurology 2003; 60:

35 Morphine SR, Gabapentin or Combo  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 Dose adjusted for >60 yo or <60 kg Gilron et al. NEJM 2005;352(13):1324–34 *p<0.05 vs. others

36 6 Pain 1999;80: Moderate pain relief Substantial pain relief Complete pain relief Lidocaine patch 5% Vehicle patch No. of patients Lidocaine 5% patch in PHN ‘Enriched enrollment' study design 28 day cross-over (n=32) 78% preferred lidocaine vs. 9% placebo (p<0.001)

37 Capsaicin 8% Patch  Selectively binds TRPV1 receptor, cation channel overexpressed in intact nociceptive sensory nerves  TRPV1 receptor activation at 38 C → high levels of intracellular calcium & substance P depletion  Capsaicin cream % of limited use  8% patch mean pain score change from 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 Jun 10;70(24): J Acquir Immune Defic Syndr. 2012;59(2):126-33

38 Gabapentin ER in PHN  RCT, n= 158, enrichment design, gastric- retentive technology GBP ER x 4 weeks:  1800 mg PM vs 600 mg AM, 1200 mg PM vs PBO 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%) dizziness (11% vs PBO 2%) somnolence (5% vs PBO 3%) Clin J Pain. 2009;25(3): J Pain Res. 2012;5:

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

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

41 Painful Peripheral Neuropathy Conclusions   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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