khalifa abdallah.diabetic neuropathy cymbalta f

Management of Diabetic

Peripheral Neuropathic Pain

Khalifa Abdallah Prof. of Internal Medicine

Diabetes, Metabolism & Lipidology Unit

Alexandria University

Presentation Overview

• Size and costs of the problem

• Pathophysiology

• Risk factors

• Presentations

• Diagnosis

• Prevention and Treatment

Diabetic 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.



• Pathophysiology

• Risk factors

• Presentations

• Diagnosis


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



• Pathophysiology

• Risk factors

• Presentations

• Diagnosis


Risk Factors

• Glucose control

• Duration of diabetes

• Age

• Height

• Genetic susceptibility

• Lifestyle factors

– Smoking

– Alcohol



• Pathophysiology

• Risk factors

• Presentations

• Diagnosis


Classification of Diabetic

Neuropathy A. Diffuse Neuropathy

1. Distal symmetric sensorimotor neuropathy

2. Autonomic neuropathy

a. Sudomotor

b. Cardiovascular

c. Gastrointestinal

d. Genitourinary

3. Symmetrical proximal lower limb motor neuropathy (amyotrophy)

B. Focal Neuropathy

1. Cranial neuropathy

2. Radiculopathy and plexopathy

3. Entrapment neuropathy

Painful Diabetic Neuropathy

Nociceptive and Neuropathic Pain

Neuropathic pain

Nociceptive pain

Maladaptive

Adaptive

Often spontaneous (occurring without

identifiable stimuli)

Identifiable stimuli that normally

produce tissue damage

Often chronic

Usually self-limiting

May involve structural and functional

changes in pain pathways

Transmitted by structurally and

functionally intact pain pathways

Examples: Polyneuropathy

(eg, diabetic, HIV), trigeminal

neuralgia, central post-stroke pain

Examples: post-operative pain, burns,

ischemic 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 neuron

hyperexcitability

NeP

Central mechanisms

Central neuron

hyperexcitability

(central sensitization)

Loss of

inhibitory controls

Peripheral mechanisms

Abnormal

discharges

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

Noxious

stimuli

Descending

modulation

Ascending

input

Spinal cord

Perceived pain

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

Ectopic discharges

Nerve lesion induces hyperactivity due to changes

in ion channel function

Ectopic discharges

Nerve lesion

Spinal cord


Descending

modulation

Ascending

input

Perceived pain


Loss of inhibitory controls Loss of descending modulation causes exaggerated pain due to an

imbalance between ascending and descending signals


Noxious

stimuli

Ascending

input

Spinal cord

Loss of

descending

modulation

Exaggerated pain

perception


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

Ascending

input

Descending

modulation

Nerve lesion


Tactile

stimuli

Perceived pain

(allodynia)

Ascending

input

Descending

modulation

Abnormal discharges induce central sensitization


♦ Neuropathic pain is

associated with increased

excitation and decreased

inhibition of ascending

pain pathways

♦ Descending pathways

modulate ascending signals

♦ NE and 5-HT are key

neurotransmitters in

descending inhibitory

pain pathways

♦ Increasing the availability of

NE and 5-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-HT

NE



• Pathology/pathophysiology

• Risk factors

• Presentations

• Diagnosis


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

ADA Neuropathy screening and treatment

Recommendations Diagnosis of neuropathy


Press until the filament bends.

Locations To Test



• Pathology/pathophysiology

• Risk factors

• Presentations

• Diagnosis


Prevention

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

Prevention

• Aldose reductase inhibitors

• Gamma Linoleic Acid

• Vasodilators-ACE?

• AGE inhibitors

• Antioxidants

• NGFs

• ? Smoking cessation, ? BP reduction

Treatment 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 areas

for intervention including the reduction of peripheral and

central hyperexcitability or increasing spinal inhibition

by enhancing monoaminergic activity

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 DPN

Class Examples Typical doses*

Tricyclic drugs Amitriptyline 10–75 mg at bedtime

Nortriptyline 25–75 mg at bedtime

Imipramine 25–75 mg at bedtime

Anticonvulsants 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

Management 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 Groups Treatment duration (weeks)

N

Goldstein et al1

20, 60, 120 mg/day vs placebo 12 457

Wernicke et al2

60 and 120 mg/day vs placebo 12 334

Raskin et al3

60 and 120 mg/day vs 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 QD 28 449

Completed 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 Pain 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)

Duloxetine

20 mg QD

(n=111)

Duloxetine

60 mg QD

(n=334)

Duloxetine

60 mg BID

(n=333) *

* P ≤ .05 vs placebo

MMRM Weeks

Imp

rovem

en

t

*

* *

* * * * * * * *

Mean

Ch

an

ge i

n 2

4-h

ou

r

Ave

rag

e P

ain

Severi

ty S

co

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

Pati

en

ts (

%)

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

50% Reduction

in 24-hour Average Pain

Duloxetine Improves Response Rates in DPNP 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

*

*** *** ***

* **

Placebo

Duloxetine 20 mg QD

Duloxetine 60 mg QD

Duloxetine 60 mg BID † Completer analysis

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

-4

-3

-2

-1

0

Goldstein Wernicke Raskin

Mean

Ch

an

ge F

rom

Baseli

ne i

n

24-h

ou

r W

ors

t P

ain

aft

er

12 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.

* ** **

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 Pain Severity in DPNP

-4

-3

-2

-1

0

Goldstein Wernicke Raskin

Mean

Ch

an

ge F

rom

Baseli

ne i

n

Nig

ht

Pain

Aft

er

12 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 Night in DPNP

1 2 3

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

LS

Mean

Ch

an

ge f

rom

Baselin

e B

PI-

I S

co

re

BPI Avg Score

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

Decre

ased

Im

pact

/ Im

pro

ve

men

t

Placebo

Duloxetine 60 mg QD

Duloxetine 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 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 Associated 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

dve

rse

Eve

nts

Nausea Somnolence Dizziness Constipation Sweating

Duration*

4 days

5 days

6 days *Median duration data:

Placebo

Duloxetine (60 mg)

Duloxetine (120 mg)

Duration*

23 days

13 days

15 days Duration*

5 days

4 days

6 days

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.


*

Perc

en

t o

f P

ati

en

ts

Most Common Adverse Events as Reason for Discontinuation

*P ≤ .05 vs placebo

0.3 0

0.3 0 0

0.9

0

0.9

0 0

3.2

1.5

0.9 0.9 0.6

3.2

2.6

1.5 1.2 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 Adverse Events

Duloxetine 60 mg/day=4 days


Placebo=5 days



Placebo=23 days

Severity (60 mg/QD) Median Duration

% P

atients

Report

ing A

E (

New

Cases)

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



Placebo=4 days 0

10

20

30

40

50

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%

Mild Moderate

Severe

None

Weeks

Dizziness

0

10

20

30

40

50

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

Onset

50

Somnolence

0

10

20

30

40

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 Short-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 Suicidality 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 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

khalifa abdallah.diabetic neuropathy cymbalta f

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