ueda2012 diabetic-neuropathy cymbalta f-d.khalifa

Management of Diabetic Peripheral Neuropathic Pain

Management of Diabetic Peripheral Neuropathic Pain

Khalifa AbdallahProf. of Internal Medicine

Diabetes, Metabolism & Lipidology Unit

Alexandria University

Presentation OverviewPresentation Overview

• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment



Diabetic Neuropathy: Size and CostDiabetic Neuropathy: Size and Cost

• DM affects about 300 million individual worldwide.

• Diabetic neuropathy is one of the most common

manifestations of diabetes and potentially its most

debilitating.

• It affects approximately 30% of all patients with diabetes.

• It quietly and insidiously places its victim at high risk for

devastating complications.





Pathogenesis of Diabetic Neuropathy

Pathogenesis of Diabetic Neuropathy

• Metabolic factors– High blood glucose– Advanced glycation end products– Sorbitol pathway– Abnormal blood fat levels

• Ischemia• Impaired nerve fiber repair mechanisms





Risk FactorsRisk Factors

• Glucose control• Duration of diabetes• Age• Height• Genetic susceptibility• Lifestyle factors

– Smoking– Alcohol





Classification of Diabetic Neuropathy

Classification of Diabetic Neuropathy

A. Diffuse Neuropathy1. Distal symmetric sensorimotor neuropathy2. Autonomic neuropathy

a. Sudomotorb. Cardiovascularc. Gastrointestinald. Genitourinary

3. Symmetrical proximal lower limb motor neuropathy (amyotrophy)B. Focal Neuropathy

1. Cranial neuropathy2. Radiculopathy and plexopathy3. Entrapment neuropathy

Painful Diabetic Neuropathy

Nociceptive and Neuropathic PainNociceptive and Neuropathic Pain

Nociceptive pain Neuropathic pain

Adaptive Maladaptive

Identifiable stimuli that normally produce tissue damage

Often spontaneous (occurring without identifiable stimuli)

Usually self-limiting Often chronic

Transmitted by structurally and functionally intact pain pathways

May involve structural and functional changes in pain pathways

Examples: post-operative pain, burns, ischemic pain

Examples: Polyneuropathy (eg, diabetic, HIV), trigeminal

neuralgia, central post-stroke pain

Clinical pain syndromes occur along a spectrum from nociceptive to neuropathic Nociceptive and neuropathic pain may coexist in the same patient

Pathophysiology of neuropathic pain

Peripheral neuronhyperexcitability

NeP

Central mechanisms

Central neuron hyperexcitability

(central sensitization)

Loss ofinhibitory controls

Peripheral mechanisms

Abnormaldischarges

Attal N et al. Acta Neurol Scand. 1999;173:12-24. Woolf CJ et al. Lancet. 1999;353:1959-1964. Roberts et al. In Casey KL (Ed). Pain and central nervous system disease. 1991

Nociceptive afferent fiber

Normal nerve impulses leading to pain

Noxiousstimuli

Descendingmodulation

Ascendinginput

Spinal cord

Perceived pain

Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4 th Ed. 1999.;165-182

Ectopic discharges

Nerve lesion induces hyperactivity due to changes in ion channel function

Ectopic discharges

Nerve lesion

Spinal cordNociceptive afferent fiber


Ascendinginput

Perceived pain


Loss of inhibitory controlsLoss of descending modulation causes exaggerated pain due to an imbalance between ascending and descending signals


Noxiousstimuli

Ascendinginput

Spinal cord

Loss ofdescendingmodulation

Exaggerated painperception


Attal N et al. Acta Neurol Scand. 1999;173:12-24. Woolf CJ et al. Lancet. 1999;353:1959-1964. Roberts et al. In Casey KL (Ed). Pain and central nervous system disease. 1991

Intact tactile fiber

Central sensitization

After nerve injury, increased input to the dorsal horn can induce central sensitization

Perceived pain

Ascendinginput


Nerve lesion


Tactilestimuli

Perceived pain(allodynia)

Ascendinginput


Abnormal discharges induce central sensitization


♦ Neuropathic pain is associated with increased excitation and decreased inhibition of ascending pain pathways

♦ Descending pathways modulate ascending signals

♦ NENE and 5-HT5-HT are key neurotransmitters in descending inhibitory pain pathways

♦ Increasing the availability of NENE and 5-HT5-HT may promote pain inhibition centrally

Serotonin & Norepinephrine Play a Major Role in Pain

1. Figure adapted from: Fields HL and Basbaum AI. Central nervous system mechanisms of pain modulation. In: Wall PD and Melzack R, eds. Textbook of Pain, 4th ed. Churchill Livingstone: London, UK;1999,310.

5-HT5-HT

NENE


• Size and costs of the problem• Pathology/pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment



ADA Neuropathy screening and treatment Recommendations


• All patients should be screened for distal symmetric polyneuropathy (DPN) at diagnosis and at least annually thereafter using simple clinical tests. (B)

• Electrophysiological testing is rarely needed, except in situations where the clinical features are atypical. (E)

• Screening for signs and symptoms of cardiovascular autonomic neuropathy should be instituted at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes. Special testing is rarely needed and may not affect management or outcomes. (E)

• Medications for the relief of specific symptoms related to DPN and autonomic neuropathy are recommended, as they improve the quality of life of the patient. (E)

Diabetes Care January 2011 34:S11-S61

Distal symmetric polyneuropathy• Patients with diabetes should be screened annually for

DPN using tests such as pinprick sensation, vibration perception (using a 128-Hz tuning fork), 10-g monofilament pressure sensation at the distal plantar aspect of both great toes and metatarsal joints, and assessment of ankle reflexes.

• Combinations of more than one test have >87% sensitivity in detecting DPN. Loss of 10-g monofilament perception and reduced vibration perception predict foot ulcers


Diagnosis of neuropathy


Diagnosis of neuropathy


Press until the filament bends.

Locations To Test





PreventionPrevention

Control• DCCT (1995)

– Tight control-3% neuropathy at 5 years

– Conventional-10%

• UKPDS (1998)– Tight control (HbA1c 7%)-31.2% neuropathy at 15

years

– Conventional (HbA1c 7.9%)-51.7%

– P=0.005

– No protective effect seen for BP control

PreventionPrevention

• Aldose reductase inhibitors• Gamma Linoleic Acid• Vasodilators-ACE?• AGE inhibitors• Antioxidants • NGFs• ? Smoking cessation, ? BP reduction

Treatment of diabetic neuropathic painTreatment of diabetic neuropathic pain

Neuropathic pain remains one of the most challenging of all neurological diseases and presents a large

unmet need for improved therapies.

Mechanism-based approaches have highlighted key areasfor intervention including the reduction of peripheral andcentral hyperexcitability or increasing spinal inhibition

by enhancing monoaminergic activity

ADA: Neuropathy treatment recommendations management

ADA: Neuropathy treatment recommendations management

• The first step in management of patients with DPN should be to aim for stable and optimal glycemic control and avoidance of extreme blood glucose fluctuations

• Patients with painful DPN may benefit from

pharmacological treatment of their symptoms


Table 14—Table of drugs to treat symptomatic DPNClass Examples Typical doses*

Tricyclic drugs Amitriptyline 10–75 mg at bedtime Nortriptyline 25–75 mg at bedtime Imipramine 25–75 mg at bedtimeAnticonvulsants Gabapentin 300–1,200 mg t.i.d. Carbamazepine 200–400 mg t.i.d. Pregabalin 100 mg t.i.d.5-hydroxytryptamine Duloxetine 60–120 mg daily And norepinephrine uptake inhibitor Substance P inhibitor Capsaicin cream 0.025–0.075% applied t.i.d. or q.i.d.

ADA Neuropathy screening and treatment Recommendations-Management

ADA Neuropathy screening and treatment Recommendations-Management

Management of DPNPManagement of DPNP

♦ Off-Label Agents:1

• Tricyclic antidepressants – i.e., amitriptyline

• Anticonvulsants – i.e., gabapentin

• Opioid analgesics

• Tramadol

• Other antidepressants – i.e., venlafaxine

♦ FDA-Approved Agents in US:

• Cymbalta2

• Lyrica3

1. Argoff CE, et al. Mayo Clin Proc. 2006;81(4):S12–25; 2. Cymbalta US Prescribing Information; 3. Lyrica US Prescribing Information.

Study Treatment GroupsTreatment duration(weeks) N

Goldstein et al1 20, 60, 120 mg/dayvs placebo 12 457

Wernicke et al2

60 and 120 mg/dayvs placebo 12 334

Raskin et al3 60 and 120 mg/dayvs placebo 12 348

Maintenance Study4 60 mg/day 8 + 26 115

1-year, open-label safety extension of above studies5

120 mg vs routine care 52 867

6-month, open-label safety study6

60 mg BID vs

120 mg QD28 449

Completed Duloxetine Clinical Trials in DPNPCompleted Duloxetine Clinical Trials in DPNP

1. Goldstein DJ, et al. Pain. 2005;116:109–118; 2. Wernicke JF, et al. Neurology. 2006;67:1411–1420; 3. Raskin J, et al. Pain Med. 2005;6:346–356; 4. Data on file, Eli Lilly; 5. Poster: Raskin J, et al. 25th American Pain Society (APS) Annual Scientific Meeting; San Antonio, TX; May 3–6, 2006;

6. Raskin J, et al. Pain Med. 2006;7:373–385.

******

*

****

*

Poster: Raskin J, et al. 25th American Pain Society (APS) Annual Scientific Meeting; San Antonio, TX; May 3–6, 2006.

Duloxetine Reduces 24-Hour Average Duloxetine Reduces 24-Hour Average Pain Severity in DPNPPain Severity in DPNP

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12

Placebo(n=330)

Duloxetine20 mg QD(n=111)

Duloxetine60 mg QD(n=334)

Duloxetine60 mg BID(n=333)

** P ≤ .05vs placebo

MMRMWeeks

Imp

rove

men

t

*

**

* * * * * * * *

Mea

n C

han

ge

in 2

4-h

ou

rA

vera

ge

Pai

n S

ever

ity

Sco

re

♦ A reduction of approximately 2 points or 30% represents a clinically important difference (mean baseline score was 5.83)

13

Pooled data from 3 studies

30% Reduction in 24-hour Average Pain

0

20

40

60

80

Pat

ien

ts (

%)

** ** ***** *****

50% Reductionin 24-hour Average Pain

Duloxetine Improves Response Rates in Duloxetine Improves Response Rates in DPNP After 12 WeeksDPNP After 12 Weeks††

* P < .05 vs placebo

** P < .01 vs placebo

*** P < .001 vs placebo

1. Presentation: Raskin J, et al. 41st European Association for the Study of Diabetes (EASD) Annual Meeting; Athens, Greece; September 12–15, 2005; 2. Goldstein DJ, et al. Pain. 2005;116:109–118; 3. Wernicke JF, et al. Neurology. 2006;67:1411–1420; 4. Raskin J, et al. Pain Med. 2005;6:346–356

0

20

40

60

80

*

*** *** **** **

PlaceboDuloxetine 20 mg QDDuloxetine 60 mg QDDuloxetine 60 mg BID

† Completer analysis

Study 23 Study 12 Study 23 Study 34Study 11 Study 31

-4

-3

-2

-1

0

Goldstein Wernicke Raskin

Mea

n C

han

ge

Fro

m B

asel

ine

in24

-ho

ur

Wo

rst

Pai

n a

fter

12

Wee

ks

1. Goldstein DJ, et al. Pain. 2005;116:109–118; 2. Wernicke JF, et al. Neurology. 2006;67:1411–1420; 3. Raskin J, et al. J Pain Med. 2005;6:346–356.

* ** **

Data from three 12-week efficacy and safety studies

1 2 3

* P ≤ .05, ** P < .001 MMRM

n=111 n=112 n=106 n=110 n=103 n=114

Placebo

Duloxetine 60 mg QD

60 mg QD Duloxetine Improves Worst 60 mg QD Duloxetine Improves Worst Pain Severity in DPNPPain Severity in DPNP

-4

-3

-2

-1

0

Goldstein Wernicke Raskin

Mea

n C

han

ge

Fro

m B

asel

ine

inN

igh

t P

ain

Aft

er 1

2 W

eeks

1. Goldstein DJ, et al. Pain. 2005;116:109–118; 2. Wernicke JF, et al. Neurology. 2006;67:1411–1420; 3. Raskin J, et al. J Pain Med. 2005;6:346–356.

Placebo

Duloxetine 60 mg QD

* ** **

Data from three 12-week efficacy and safety studies

* P ≤ .05, ** P < .05

60 mg QD Duloxetine Reduces Pain at 60 mg QD Duloxetine Reduces Pain at Night in DPNPNight in DPNP

1 2 3

n=111 n=112 n=106 n=109 n=103 n=114

LS

Mea

n C

han

ge

fro

m

Bas

elin

e B

PI-

I Sco

re

BPI Avg Score

Armstrong DG, et al. Pain Med. 2007;8(5):410-418.

Dec

reas

ed Im

pac

t / I

mp

rove

men

t

PlaceboDuloxetine 60 mg QDDuloxetine 60 mg BID

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

General Activity Mood

Walking Ability

Normal Work

Relationship With Others Sleep

Enjoyment of Life

Duloxetine Decreased the Impact of Pain on Daily Duloxetine Decreased the Impact of Pain on Daily Activity, Function, and Enjoyment of Life (BPI-I)Activity, Function, and Enjoyment of Life (BPI-I)

* P < .05 vs placebo

** P < .01 vs placebo

*** P < .001 vs placebo

****** ***

***

***

***

******

*****

****

** ******

***


0

10

20

30

40

50

Appetite

Most Common Adverse Events Most Common Adverse Events Associated with Duloxetine in DPNPAssociated with Duloxetine in DPNP

Cymbalta Adverse Events that Occurred 5% and Twice Placebo

Dry Mouth

Placebo (n=339)Duloxetine 20 mg/day (n=115)Duloxetine 60 mg/day (n=334)Duloxetine 120 mg/day (n=341)

% I

nc

ide

nc

e o

f A

dv

ers

e E

ve

nts

Nausea Somnolence Dizziness Constipation Sweating

Duration*4 days 5 days6 days

*Median duration data:PlaceboDuloxetine (60 mg) Duloxetine (120 mg)



Poster: Robinson M, et al. Presented at: 8th International Conference on the Mechanisms and Treatment of Neuropathic Pain (ICMTNP); San Francisco, CA; Nov 5, 2005.


*

Per

cen

t o

f P

atie

nts

Most Common Adverse Events as Most Common Adverse Events as Reason for DiscontinuationReason for Discontinuation

*P ≤ .05 vs placebo

0.30

0.30 0

0.9

0

0.9

0 0

3.2

1.5

0.9 0.90.6

3.2

2.6

1.51.2 1.2

0

1

2

3

4

5

Nausea Somnolence Dizziness Fatigue Vomiting

Placebo (n=339)Duloxetine 20 mg/day (n=115)Duloxetine 60 mg/day (n=334)Duloxetine 120 mg/day (n=341)



**


Clinical Profile of the 3 Most Common Clinical Profile of the 3 Most Common Adverse EventsAdverse Events

Duloxetine 60 mg/day=4 daysDuloxetine 120 mg/day=6 days

Placebo=5 days


Placebo=23 days

Severity (60 mg/QD)Median Duration

% P

atie

nts

Rep

ortin

g A

E (

New

Cas

es)

Placebo (n=339) Cymbalta 60 mg/day (n=334) Cymbalta 120 mg/day (n=341)


Placebo=4 days0

1020304050

1 2 3 4 5 6 7 8 9 10 11 12

Nausea

90%

6%1%3%

3% 2%12%

85%

13%

76%

9% 2%

MildModerate

SevereNone

Weeks

Dizziness

01020304050

1 2 3 9 10 11 124 5 6 7 8

Onset

50

Somnolence

010203040

1 2 3 4 5 6 7 8 9 10 11 12


♦ Of all the DPNP patients reporting nausea, 92% reported it as mild to moderate♦ Nausea occurred primarily during the first week of treatment and resolved

rapidly with continued treatment (median duration 5 days)

Nausea on Duloxetine is Common, but is Nausea on Duloxetine is Common, but is Short-Lived and Mostly Mild or ModerateShort-Lived and Mostly Mild or Moderate

Severity of Treatment-emergent Nausea on Duloxetine 60 mg QD

Mild 13%

None 76%

Moderate 9% Severe 2%



No Evidence of an Increased Risk of No Evidence of an Increased Risk of Suicidality with DuloxetineSuicidality with Duloxetine

Data on file.

♦ The data from studies of adult patients with MDD demonstrate that duloxetine significantly reduces the risk of worsening suicidal ideation and significantly increases the chances for improvement in ideation for patients who had suicidal ideation at baseline.

♦ The data from studies of adult patients with nonpsychiatric indications (including SUI, FM and DPNP) support the conclusion that duloxetine is not associated with the development of suicidal ideation in depressed or non-depressed adult patients receiving duloxetine for any of the indications.

NOTE: The duloxetine FDA black box warning about suicidality in adults is derived from a meta-analysis of all drugs in this class. Although primarily based on studies of MDD, the warning applies to all indications.

Take home messageTake home message

• Diabetic neuropathy is one of the most common manifestations of diabetes and potentially its most debilitating

• All patients should be screened for distal symmetric polyneuropathy (DPN) at diagnosis and at least annually thereafter using simple clinical tests

• Patients who can not feel the 10-g monofilament should receive advice about foot care

• Duloxetine, a potent and balanced dual 5-HT and NE reuptake inhibitor, has been shown to significantly decrease pain in DPNP patients

Thank You

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ueda2012 diabetic-neuropathy cymbalta f-d.khalifa