1. 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

2. 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

3. 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:

4. 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

5. 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)

6. 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)

7. 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

8. Painful Diabetic Neuropathy Odds Ratios and NNTs for 50% Pain Relief
Tricyclic antidepressants: (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: (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

9. 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
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

10. 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, 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 = vs placebo) and sleep disruption (p = 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: 10