Diagnosis and Management of Diabetic Neuropathies Part 4 Aaron I. Vinik, MD, PhD, FCP, MACP Professor of Medicine/Pathology/Neurobiology Director of Research and Neuroendocrine Unit Eastern Virginia Medical School Strelitz Diabetes Center for Endocrine and Metabolic Disorders Norfolk, Virginia

What Are the Advantages of fMRI? Noninvasive, no exposure to radiation Allows repetitions, follow-ups, longitudinal studies Task and rest in the same session Good spatial and temporal resolution Can be used to study brain, brain stem, and spinal cord 2.3 8.0 Brain response to noxious heat

Increased Cerebral Activation as a Result of Central Sensitization in Healthy Subjects Functional MRI Normal nociceptive transmission (no hyperalgesia) Central sensitization (secondary hyperalgesia) 60 g monofilament after 45° C + capsaicin Zambreanu L, et al. Pain. 2005;114:397-407.

Reduced IENF density in painful diabetic neuropathy Skin Biopsies Skin biopsy determines damage to small nerve fibers allows quantification of somatic IENFs has a diagnostic efficiency of 88.4% is an invasive technique requiring local anaesthesia 20 Reduced IENF density in painful diabetic neuropathy 15 IENF/mm 10 Permissions needed for Figure in slide—Devigli 3B, only the “dot” graph, not line graph– For photomicrograph, permissions needed from Kennedy figs 2 and 3 5 Neuropathy Controls Devigili G et al. Brain. 2008;131:1912. Sorensen L et al. Diabetes Care. 2006;29:883. Kennedy WR. Muscle Nerve. 2004;756:756. Pittenger GL et al. Diabetes Care. 2004;27:1974. IENF, intra-epidermal nerve fibers 4

Generic Scales Commonly Used in Clinical Trials Pain Quality of Life/Outcomes 11-point numeric rating scale 4-point verbal rating scale (VRS) Visual analog scale (VAS) McGill Pain Questionnaire (MPQ) Brief Pain Inventory (BPI) Medical Outcomes Survey Short Form-36 (MOS SF-36) Sleep interference scales Quality of life (QoL)

Neuropathic Pain Scales Commonly Used in Clinical Trials 11-point Neuropathy Pain Scale (NPS) Neuropathic Pain Symptom Inventory (NPSI) Brief Pain Inventory (BPI) Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) Neuropathic Pain Questionnaire (NPQ) Neuropathy Total Symptom Score (NTSS) Total Symptom Score (TSS) Neuropathy Symptom Score (NSS) Neuropathy Impairment Score (NIS) Michigan Neuropathy Screening Instrument (MNSI)

Painful Diabetic Polyneuropathy EFNS Canadian IASP 1st Line TCA Gabapentin Pregabalin TCA, Gabapentin SNRIs 2nd Line SNRI Lamotrigine Opioids Tramadol Top. lidocaine 3rd Line CR opioid Antiepileptics Mexiletine NMDA antagonist Top. capsaicin 4th Line Cannabinoid, methadone, lamotrigine, topiramate, valproic acid Fact check: Canadian/IASP-Same as previous slide similar to this EFNS- pgs 1156 (bottom)-1175 (top) Topiramate- 3 controlled trials negative, but 1 positive multi-center study Raskin et al. Neurol 2004 7

Painful Diabetic Neuropathy Odds Ratios and NNTs for 50% Pain Relief Tricyclic antidepressants: 22.24 (NNT=3.4) (desipramine, imipramine, amitriptyline) Traditional ACDs: 5.33 (6.0) (carbamazepine, valpraote, oxcarbazepine) Opioids and tramadol: 4.25 (3.1) Newer-generation ACDs: 3.25 (gabapentin, pregabalin 300−600 mg*) (3.3−4.1) SNRI (duloxetine 60/120 mg*): 2.55/2.1 (7.2/4.2) Fact Check: OR (Wong): Traditional ACD/new generation ACD: right column, page 5 TCA: pg 6 bottom of right column SNRI: pg 7, top of left column Opioids: top of right column NNT (Chong) TCA: pg 577, bottom of left column New generation ACD: pg 580, left column, middle of pregabalin section Tramadol/Opioid- table 2 SNRI: avg of values in table 2 Traditional ACD: ? Odds ratio: Higher the odds ratio the better the drug The odds ratio is a measure of effect size particularly important in Bayesian statistics and logistic regression. It is defined as the ratio of the odds of an event occurring in one group to the odds of it occurring in another group, or to a sample-based estimate of that ratio. These groups might be men and women, an experimental group and a control group, or any other dichotomous classification. If the probabilities of the event in each of the groups are p (first group) and q (second group), then the odds ratio is: An odds ratio of 1 indicates that the condition or event under study is equally likely in both groups. An odds ratio greater than 1 indicates that the condition or event is more likely in the first group. And an odds ratio less than 1 indicates that the condition or event is less likely in the first group. The odds ratio must be greater than or equal to zero. As the odds of the first group approaches zero, the odds ratio approaches zero. As the odds of the second group approaches zero, the odds ratio approaches positive infinity. Treatment algorithm suggested: see fig 16 Wong M et al. BMJ. 2008;335:87. Chong MS, Hester J. Drugs. 2007;67:569. *FDA-approved indication. 8

Painful Diabetic Neuropathy Lamotrigine Last Observation Carried Forward Study 1 Study 2 Placebo −1.5 −2.0 −2.5 −0.5 −0.5 Lamotrigine 200 mg Lamotrigine 300 mg −1.0 −1.0 Lamotrigine 400 mg * −1.5 Pain Intensity Change From Baseline * * −2.0 * * * * −2.5 −3.0 *P<0.05 vs placebo −3.0 −3.5 Fact Check: Vinik: fig 2, LOCF data– Permissions necessary −3.5 1 2 3 4 5 6 7 8 9 11 13 15 17 19 1 2 3 4 5 6 7 8 9 11 13 15 17 19 Dose Escalation Maintenance Dose Escalation Maintenance Used with permission from IASP Post-hoc analysis of data from patients who reached their target dose Mean reduction in pain intensity: Greatest for lamotrigine 400 mg (P<0.05 vs placebo) −2.7 for lamotrigine 400 mg −2.5 for lamotrigine 300 mg −2.0 for placebo Vinik AI et al. Pain. 2007;128:169. 9

Painful Diabetic Neuropathy Topiramate 3 RCTs that were negative1 50% vs 34% with >30% relief of pain, decreased pain, and improved sleep2 Topiramate Placebo 75 3.2 Mean Pain Score Worst Pain 70 3.0 65 2.8 60 2.6 Pain Visual Analog Scale Score (0−100 mm) Score Over Past Week (0−4) 55 2.4 Fact Check: Thienel: see conclusion section of article abstract Raskin: Figs 2a and 2b ---permission needed Background: Using identical methods, three simultaneous placebo-controlled trials of topiramate for painful diabetic neuropathy (PDN) did not reach significance. This independent yet concurrent placebo-controlled trial used different methods to assess topiramate efficacy and tolerability in PDN. Methods: This 12-week, multicenter, randomized, double-blind trial included 323 subjects with PDN and pain visual analog (PVA) score of at least 40 on a scale from 0 (no pain) to 100 (worst possible pain). Topiramate (n = 214) or placebo (n = 109) was titrated to 400 mg daily or maximum tolerated dose. Short-acting rescue analgesics were permitted only during the first 6 weeks. Results: Baseline characteristics were comparable between groups except for mean body weight (topiramate, 101.4 kg; placebo, 95.7 kg; p = 0.028). Twelve weeks of topiramate treatment reduced PVA scale score (from 68.0 to 46.2 mm) more effectively than placebo (from 69.1 to 54.0 mm; p = 0.038). Fifty percent of topiramate-treated subjects and 34% of placebo-treated subjects responded to treatment, defined as >30% reduction in PVA scale score (p = 0.004). Topiramate monotherapy also reduced worst pain intensity (p = 0.003 vs placebo) and sleep disruption (p = 0.020 vs placebo). Diarrhea, loss of appetite, and somnolence were the most commonly reported adverse events in the topiramate group. Topiramate reduced body weight (–2.6 vs +0.2 kg for placebo; p < 0.001) without disrupting glycemic control. Conclusions: Topiramate monotherapy reduced pain and body weight more effectively than placebo in patients with painful diabetic neuropathy. 50 2.2 45 2.0 P=0.028 P=0.026 P=0.038 P=0.003 40 1.8 4 8 12 4 8 12 Week Week 1. Thienel U et al. Acta Neurol Scand. 2004;110:221. 2. Raskin P et al. Topiramate vs placebo in painful diabetic neuropathy: analgesic and metabolic effect. Neurology. 2004;63:865-873. 10