new treatments for painful diabetic peripheral neuropathy ... · painful dpn: scope of the problem...

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New Treatments for Painful Diabetic Peripheral Neuropathy (DPN): Clinical Data Supporting

New Options

Julio Rosenstock, MD Dallas Diabetes and Endocrine Center

Clinical Professor of Medicine University of Texas Southwestern Medical Center

at Dallas Dallas, Texas

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Presentation Outline

• Painful DPN: Scope of the problem• Screening and assessment• Hyperglycemia: a significant risk factor• Management

– Disease pathogenesis– Symptomatic management of DPN

• Algorithm• Approved agents

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Painful DPN: Scope of the Problem

• DPN and autonomic neuropathies are the most common diabetic neuropathies

• ~20% of adult diabetes patients have DPN

• Up to 50% of patients with DPN may be asymptomatic

• 10-20% of patients with DPN may experience troublesome sensory symptoms

Boulton AJM, et al. Diabetes Care. 2005;28:956-962.Boulton AJM, et al. Diabetes Care. 2004;27:1458-1486.

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Diabetic Neuropathy is Underdiagnosed

• Only 25% of symptomatic patients have been diagnosed with diabetic neuropathy

• Less than half of patients with diabetic neuropathy symptoms have been told by their doctor that the symptoms are associated with diabetes

• ~15% of those who spoke with their physician were given no cause for their symptoms and pain

ADA. What You Don't Know About Diabetic Neuropathy Can Hurt You. Available at: http://www.diabetes.org/for-media/2005-press-releases/diabeticneuropathy.jsp.

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“Not knowing you have diabetic neuropathy doesn’t mean the condition will not progress. It will still get you… Knowing about it gives you the opportunity to take care of yourself and prevent serious consequences.”

Aaron I Vinik, MD, PhD, FCP, MACPDirector, Strelitz Diabetes Research Institute

ADA. What You Don't Know About Diabetic Neuropathy Can Hurt You. Available at: http://www.diabetes.org/for-media/2005-press-releases/diabeticneuropathy.jsp.

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DPN Recommendations 2005 ADA Position Statement

• Diagnosis of exclusion of nondiabetic causes• Tight glycemic control is the only proven prevention• Type 1 DM: screen annually after 5 years of diabetes• Type 2 DM: screen annually beginning at diagnosis• Clinical history and examination both essential parts

of annual screen• Qualitative sensory testing (QST) and

electrophysiology (EP) may be useful in a few cases• Evidence-based therapies are available for

symptomatic DPN

Boulton AJM, et al. Diabetes Care. 2005;28:956-962.

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Clinical Presentation of DPN

0

25

50

75

100

Symptoms Signs

NumbnessPrickling

Aching painBurning Pain

Lancinating PainAllodynia

Up to 50% May Be

Asymptomatic

ReducedVibratorySensation

ReducedPressureSensation

ReducedReflexes

ReducedTemperature

Sensation

Perc

enta

ge o

f DPN

Pat

ient

s


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Clinical Assessment of DPN• Symptoms–may occur anytime, intermittently

– Questionnaires (MNSI, SF-MPQ)– Visual analog scales (VAS)– Numeric scales

• Signs–often not evident at disease onset– Semmes-Weinstein monofilament– Tuning fork– Pin prick– Temperature

• History–elicit neuropathic symptoms• Examination–feet and lower limbs for ulcers,

calluses, deformities, sensory function, reflexesBoulton AJM, et al. Diabetes Care. 2005;28:956-962.


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Diabetic Neuropathy Risk Factors

• Uncontrollable– Disease duration– Ethnicity– Age– Height

• Controllable– Hyperglycemia– Hypertension– Hyperlipidemia– Weight– Smoking– Alcohol intake

Shaw JE, Zimmet PZ. Diabetes Rev. 1999;7:245-252.

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Hyperglycemia is a Major Contributor to DPN Pathogenesis


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Relations of A1C to Risk of Microvascular Complications

A1C (%)

15

13

11

9

7

5

3

16 7 8 9 10 11 12

RetinopathyNephropathyNeuropathy

Rel

ativ

e R

isk

Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254.

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Metabolic Pathways Leading to Diabetic Microvascular Complications

Polyolpathway

Diabetic nephropathy

Diabetic retinopathy

Diabetic neuropathy

Diabetes

Ulcers/amputations

Hyperglycemia

Superoxideoverproduction

PKC βactivation

Vision loss

Renal disease

Diabetes-induced microvascular damage

GlycationDiacylglycerol

©2005 International Medical Press.

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Management of Diabetic NeuropathyProvide Symptomatic Relief• Medical

– Stable near-normoglycemia

– Tricyclics– SSNRIs– Antiepileptics– Opioids– Antiarrhythmics

• Physical– Capsaicin– Acupuncture– Electrical

Influence Natural History• Stable near-normoglycemia• ACE inhibitors• Aldose reductase inhibitors

(ARIs)*• α-lipoic acid*• Advanced glycation

endproduct receptor blockers*• PKC β inhibitors*• PARP inhibitors*• Benfotiamine*• (Gamma-linolenic acid)*• (Neurotrophic agents)**Investigational agent.

Boulton AJM, et al. Diabetes Care. 2005;28:956-962.Boulton AJM, et al. Diabetes Care. 2004;27:1458-1486.

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Fidarestat (ARI) for DPN• Double-blind, placebo-controlled study in type 1

and type 2 diabetes patients– Placebo (n = 102) and 1 mg/day fidarestat (n = 90)

groups included in efficacy analysis– 52 weeks– Efficacy: nerve function (electrophysiology), subjective

symptoms• Results

– No changes in sensory nerve function– Significant differences between groups for 2 of 6 motor

nerve function tests– Significant differences between groups for all subjective

symptom tests except temperature sensation– No difference in adverse events or laboratory values

Hotta N, et al. Diabetes Care. 2001;24:1776-1782.

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Ruboxistaurin (PKC β Inhibitor) for DPN• Multinational phase 2 trial

– Post-hoc analyses of patients with symptomatic DPN– 1 year– Placebo (n = 68), 32 mg/d (n = 66), 64 mg/ d (n = 71)– Primary endpoint: vibration detection threshold (VDT)– Secondary endpoints: Neuropathy Total Symptom Score-6

(NTSS-6), neurologic examination, nerve electrophysiology, Neuropathy Impairment Score (NIS), Clinical Global Impressions (CGI), safety

• Results– No treatment differences for VDT, NIS, or NTSS-6 in

main analysis– In post-hoc analyses, NTSS-6 (64 mg/d) and VDT (32

and 64 mg/d) significantly improved– Diarrhea slightly higher in ruboxistaurin groups

Vinik AI, et al. Clin Ther. 2005;27:1164-1180.

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Symptomatic* Management of Painful DPN

*Does not affect underlying pathophysiology or course of neuropathy.

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Algorithm for the Management of Symptomatic DPN*

Stabilize glycemic control

First-line treatment: tricyclic antidepressants†

Second-line treatment: antiepileptic drugs‡

Third-line treatment: opioid or opioid-like drugs

Consider pain clinic referral

*Nonpharmacological, topical, or physical therapies may be useful at any stage.†Not FDA approved for the treatment of DPN.‡In this class, only pregabalin is FDA approved for the treatment of DPN.


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ADA Statement:Oral Symptomatic Therapy

Drug Class Drug NNT NNH Side EffectsAmitriptyline 2.4 (2.3-3.0) 2.7 (2.1-3.9) ++++

Imipramine 2.4 (2.0-3.0) 2.7 (2.1-3.9) ++++

Paroxetine ND ND +++

Citalopram ND ND +++

Gabapentin 3.7 (2.4-8.3) 2.7 (2.2-3.4) ++

Pregabalin 3.3 (2.3-5.9) 3.7 ++

Carbamazepine 3.3 (2.0-9.4) 1.9 (1.4-2.8) +++

Topiramate 3.0 (2.3-4.5) 9.0 ++

Tramadol 3.4 (2.3-6.4) 7.8 +++

Oxycodone CR ND ND ++++Opioids

Antiepileptic drugs

SSRIs

Tricyclics

NNT = number needed to treat; NNH = number needed to harm; ND = not determined


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Pharmacologic Management of Symptomatic DPN

Newer agents with proven efficacy• Duloxetine*• Pregabalin* • Gabapentin• Lamotrigine• Topiramate• Tramadol

*FDA approved for the treatment of type 2 diabetic complications.

Backonja MM, Galer BS. Neurol Clin. 1998;16:775-790. Morello CM, et al. Arch Intern Med. 1999;159:1931-1937.

Harati Y, et al. Neurology. 1998;50:1842-1846. Harati Y, et al. J Diabetes Complications. 2000;14:65-70.

Eisenberg E, et al. Neurology. 2001;57:505-509. Petit WA Jr, Upender RP. Clin Podiatr Med Surg. 2003;20:671-688.

Haslbeck M. MMW Fortschr Med. 2004;146:47-50.

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Pregabalin Characteristics

• Binding: α2δ subunit of voltage-gated calcium channels

• No GABAA or GABAB receptor activity

• FDA approved indications– Painful DPN

– Postherpetic neuralgia

Ben-Menachem E. Epilepsia. 2004;45(suppl 6):13-18.

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Pregabalin Study Design

• Objective: Evaluate pregabalin safety and efficacy in treating DPN-associated pain – Safety: Adverse events (AE)– Efficacy: Weekly mean pain score from daily diary

entries

• Study Design– Double-blind, randomized, placebo-controlled,

multicenter– Placebo (n = 70), 100 mg TID (n = 76)– 8 weeks treatment– Clinic visits at baseline and Weeks 1, 3, 5, and 8– Acetaminophen, aspirin, and SSRIs allowed

Rosenstock J, et al. Pain. 2004;110:628-638.

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Pregabalin Study Demographics

• Average age 59.7 ± 11.4 years• Type 1 (13%) or type 2 (87%) diabetes• Painful DPN symptoms for 1 to 5 years

– Symmetrical symptoms in distal extremities– Avg. daily pain score ≥4 on 0-10 numeric scale

• A1C ≤11% at baseline– Actual placebo group avg. at baseline = 7.9 ± 1.4% – Actual pregabalin group avg. at baseline = 8.2 ± 1.4%


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Pregabalin Study Demographics

• Exclusions– Previous failure to respond to gabapentin– Serious or unstable medical conditions (including

psychiatric disorders)– Amputations, nondiabetic neurologic disorders, skin

conditions affecting sensation– Serum creatinine clearance ≤60 ml/min OR WBC

<2500/mm3 OR neutrophil count <1500/mm3 ORplatelet count <100 x 103/mm3

– Lack of normal chest X-ray in preceding 2 years


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Pregabalin Primary Efficacy Outcome

• Weekly mean pain score– Significantly different from placebo by end

of Week 1

– 40% of pregabalin group and 14.5% of placebo group achieved ≥50% pain score reduction


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Pregabalin Secondary Efficacy Outcomes

• Secondary–pregabalin generated improvements in:– Short-Form McGill Pain Questionnaire (SF-MPQ)– Sleep score– Patient Global Impression of Change (PGIC)– Clinical Global Impression of Change (CGIC)– SF-36 Health Survey– Profile of Mood States (POMS)


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Pregabalin Primary Efficacy Outcome:Weekly Mean Pain Score

PlaceboPGB

10

8

6

4

2

0

Mea

n Pa

in S

core

s

1 2 3 4 5 6 7 8Baseline

* * * * * * * *

WorstPossible

Pain

NoPain

Week

*P <0.01.


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Pregabalin Safety/Adverse Events

• More in pregabalin than placebo group (62% vs 29%)

• Dizziness, somnolence, infection, and peripheral edema


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Duloxetine Characteristics• Balanced norepinephrine/serotonin reuptake

inhibitor1-2

• No significant affinity for the following receptors3:– Cholinergic– Histamine– α-adrenergic– Dopamine– Glutamate– GABA– Opioid

• FDA-approved indications3

– Major depressive disorder– Neuropathic pain associated with DPN

1Detke MJ, et al. J Clin Psychiatry. 2002;63:308-315.2Detke MJ, et al. J Psychiatr Res. 2002;36:383-390.

3Cymbalta® (duloxetine hydrochloride) package insert. Indianapolis, Ind: Eli Lilly and Company;2005.

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Duloxetine Study Design• Objective: Evaluate duloxetine safety and

efficacy in treating DPN-associated pain – Safety: AE, blood chemistry and hematology,

glycemic control and lipids, hypertension, QT interval– Efficacy: weekly mean change from baseline to

endpoint on 24-hour avg. pain scale• Study Design

– Double-blind, randomized, placebo-controlled– Placebo (n = 115), 20 mg QD (n = 115), 60 mg QD

(n = 114)– 12 weeks– Only acetaminophen ( ≤4g/d) allowed for analgesia– Regression analysis for effect due to mood and

anxiety symptom improvementGoldstein DJ, et al. Pain. 2005;116:109-118.

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Duloxetine Study Demographics

• Average age 60.1 ± 10.9 years

• Type 1 (11.6%) or type 2 (88.4%) diabetes

• Daily diabetic neuropathic pain for ≥6 months

• Exclusions:– MDD, depression-partial remission, dysthymic

disorder, generalized anxiety disorder, alcohol or eating disorders, mania, bipolar disorder, psychosis

– Pain or neurological disorders unrelated to diabetic neuropathy

Goldstein DJ, et al. Pain. 2005;116:109-118.

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Duloxetine Primary Efficacy Outcomes

• Dose-related efficacy relative to placebo– 20 mg/d → nonsignificant ↓ in pain severity

– 60 and 120 mg/d → significant ↓ in pain severity

– No difference between 60 and 120 mg/d

• <10% of treatment effect due to indirect effect on mood or anxiety symptoms


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Duloxetine Primary Efficacy Outcome: Weekly Mean Change in 24-hour Average Pain Severity

PlaceboDuloxetine 20 mg/dDuloxetine 60 mg/dDuloxetine 120 mg/d

0

-0.5

-1

-1.5

-2

-2.5

-3

-3.50 1 5432 76 8 10 11 129

Mea

n C

hang

e in

24

hr A

vera

gePa

in S

ever

ity S

core

Week*P ≤0.01.**P ≤0.001.


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Duloxetine Secondary Efficacy Outcomes

• 16 pain and health outcome measures including:– SF36 Health status survey

– Beck Depression Inventory-II, Anxiety Inventory

– Avg. daily dose of supplemental analgesic

• 60 and 120 mg/d doses significantly improved all pain outcomes except dynamic allodynia

• Also Clinical Global Impressions of Severity (CGI-Severity), Short-Form (SF) McGill total score, supplemental analgesic use


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Duloxetine Safety/Adverse Events

• No treatment group differences in severe AEs(chest pain, hyperglycemia, myocardial infarction)

• Percentage of patients experiencing the following AEs was significantly higher in the 120 mg/day duloxetine group:– Nausea, somnolence*, dizziness, constipation*, dry

mouth, ↑sweating, ↓appetite, anorexia, weakness

• Significant mean decrease in QT interval*Also significantly higher in 60 mg/day group.


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Summary• Diabetic neuropathy is a significant problem that

is underdiagnosed

• The ADA has developed an algorithm for the management of painful DPN

• Many oral agents currently used for painful DPN have limitations due to poor risk:benefit ratios and side effects

• Pregabalin and duloxetine are approved by the US FDA for the treatment of painful DPN

• Long-term controlled trials are still needed

new treatments for painful diabetic peripheral neuropathy ... · painful dpn: scope of the problem...

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