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

Disclosures Speaker Bureau Depomed Merck Pfizer Grants

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

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

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

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

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

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

North America – South America (NA – SA) Neuropathy Project Khan et al, AAN 2006 PN Categories NA % SA Immune-mediated 20 18 Diabetic 13 23 Hereditary 27 10 Infections / Inflammatory 5 14 Systemic / Metabolic / Toxic 7 12 Cryptogenic 28 Total # cases 1090 1034

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;72:185-192

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;72:177-184

Normal Epidermal Nerve fiber Density Proximal Thigh Distal Leg

To schedule a skin biopsy, please call 913-588-0656 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

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

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

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

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

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]

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

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 Clin Pharmacol. 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

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

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. 2012 Jan;23(1):200-5

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 .

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

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 Life Sci. 2007 May 8;80(22):2015-24 Neurology. 2002;58(3):368-72 Epilepsy Res. 2002;49(3):203-10

Gabapentin RCTs for PHN Label 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 Pain 2001;94:215-224 Mean Change (SE) *P<0.01 (for both doses of gabapentin)

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

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

Lamotrigine DPN RCT vs PBO, n=59 HIV neuropathy RCT n=42 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;54:2115-9 Cancer 2008;112:2802-8

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 Curr Med Res Opin. 2006;22:375-84.

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

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% Both are probably effective for DPN & CSPN neuropathic pain * Differences NS Int J Neurosci. 2011;121:521-7

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

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

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 *p<0.05 vs. others Gilron et al. NEJM 2005;352(13):1324–34

Substantial pain relief 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 Moderate pain relief Substantial pain relief Complete pain relief 78% preferred lidocaine vs. 9% placebo (p<0.001) Pain 1999;80:533-538

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 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 Defic Syndr. 2012;59(2):126-33

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%) Clin J Pain. 2009;25(3):185-92 J Pain Res. 2012;5:203-208

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

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):1758-65

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