duloxetine in the treatment of diabetic peripheral neuropathic pain (dpn)

Duloxetine in the Treatment of Diabetic Peripheral

Neuropathic Pain (DPN)

♦ Introduction

♦ Mechanism of Action

♦ Efficacy in DPNP

♦ Pharmacokinetics, Safety and Tolerability

♦ Conclusion

Contents

WHO Definition:A disease characterized as a progressive loss of nerve fibers leading to sensation loss, foot ulceration, and amputation

heterogeneous group of diseases that affect the autonomic and peripheral nervous systems of patients suffering from diabetes.

Definition of diabetic neuropathy

Diabetic Peripheral Nerve Damage

Axon Loss in Diabetic Neuropathy

Classification of Diabetic Neuropathy

¨ Symmetric polyneuropathy¨ Autonomic neuropathy¨ Polyradiculopathy¨ Mononeuropathy

Multiple Mechanisms of Neuropathic Pain

♦ Multiple mechanisms play a role in neuropathic pain:• Peripheral nervous system input:

- Peripheral sensitization

- Ectopic excitability

• Central nervous system processing:

- Central sensitization

- Structural reorganization

- Disinhibition

1. Woolf CJ. Ann Intern Med. 2004;140:441–451.

Distinguishing Nociceptive and Neuropathic Pain

Nociceptive pain♦ Adaptive♦ Identifiable stimuli that

normally produce tissue damage

♦ Usually self-limiting♦ Transmitted by structurally

and functionally intact pain pathways

♦ Examples: post-operative pain, burns, ischemic pain

Neuropathic pain♦ Maladaptive♦ Often spontaneous (occurring

without identifiable stimuli)♦ Often chronic♦ May involve structural and

functional changes in pain pathways

♦ 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

1. Portenoy RK and Kanner RM. Definition and assessment of pain. In: Portenoy RK and Kanner RM, eds. Pain Management: Theory and Practice;1996:4; 2. Galer BS and Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis: McGraw-Hill; 2000:8–9.

Evoked Pain

Stimulus intensity

Mag

nit

ud

e o

f p

ain

normal hyperpathia

hyperalgesia

allodynia

Prevalence of Diabetic Neuropathyas a proportion of all diabetics 20 years after diagnosis

No neuropathy 10%

Asymptomatic 40%

Symptomatic 50%

DPNP Can Negatively Impact Patients’ Quality of Life1,2

The majority of patients experience pain on a constant, daily basis1

energy

sleep

mood

“Pain is an unpleasant

sensory and emotional

experience associated

with actual or potential

tissue damage, or

described in terms of

such damage3”

mobility

work

social activities

enjoyment of life

1. Galer BS, et al. Diabetes Res Clin Pract. 2000;47:123–128; 2. Benbow SJ, et al. QJM. 1998;91:733–737;3. IASP website (http://www.iasp-pain.org/terms-p.html#Pain). Accessed October 05, 2006.

Goals of Neuropathic Pain Treatment

♦ Primary goal = reduction in pain

♦ Secondary goals• Improvement in physical function

• Reduction in affective distress

• Improvement in quality of life

♦ Achieving these goals is predicated upon• Accurate diagnosis of any underlying etiology

• Preventive treatment of underlying etiology (eg diabetes, joint inflammation, etc.), if possible

1. Turk DC. Clin J Pain. 2000;16:279–280; 2. Belgrade MJ. Postgrad Med. 1999;106:127–140.

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.

Contents

♦ Introduction




♦ Conclusion

Ectopic discharges

Nerve lesion induces hyperactivity due to changes in ion channel function

Ectopic discharges

Nerve lesion

Spinal cordNociceptive afferent fiber

Descendingmodulation

Ascendinginput

Perceived pain

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

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

Nociceptive afferent fiber

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

Nociceptive afferent fiber

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

♦ 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

*Paroxetine 1 mg/kg + Thionisoxetine

Paroxetine

Thionisoxetine

The Combination of an NRI and an SSRI is More Effective than Either Alone

1. Iyengar S, et al. J Pharmacol Exp Ther. 2004;311:576–584.

% o

f V

ehic

le C

on

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l

Les

s P

ain

Beh

avio

r

Total paw-licking time (late phase)

Drug (mg/kg)

Higher Dose

0.1 1 100

20

40

60

80

100

120

Vehicle control

* P < .05 vs thionisoxetine alone

*

N=5–12

Duloxetine is a Potent Inhibitor of Persistent Pain in the Formalin Model

Total paw-licking time (late phase)


* P < .05 vs vehicle

% o

f V

ehic

le C

on

tro

l

Les

s P

ain

Beh

avio

r

Higher Dose

Drug (mg/kg i.p. 30 min)

N=6–9

1 10 1000

25

50

75

100 Vehiclecontrol

*

*

*

*

* *

*

Vehiclecontrol

*#

*

1 100

25

50

75

100

100

*

*

*

# Rotorod effects

Duloxetine

Venlafaxine

Milnacipran

Amitriptyline

Higher Dose

Drug (mg/kg i.p. 30 min)


* P < .05vs vehicle

Vehicle control

Duloxetine 30 mg/kg p.o.once daily

pre = pre-surgery baseline, base = post-surgery baseline

Duloxetine Reverses Mechanical Allodynia in the Spinal L5/L6 Nerve Ligation Model of Neuropathic Pain

Les

s P

ain

Beh

avio

r

Time

pre base Day 13 hrs

0

2

4

6

8

10

12

14

Wit

hd

raw

al

Th

res

ho

ld R

es

po

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e (

g)

N=4–5

*

Contents

♦ Introduction




♦ Conclusion

Study Treatment GroupsTreatment duration(weeks) N

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

Wernicke et al260 and 120 mg/day

vs 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 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)

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 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

*

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

PlaceboDuloxetine 20 mg QDDuloxetine 60 mg QDDuloxetine 60 mg BID

† Completer analysis

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

Goldstein Wernicke Raskin

-4

-3

-2

-1

0

Mea

n C

han

ge

Fro

m

Bas

elin

e in

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

Goldstein Wernicke Raskin

-4

-3

-2

-1

0

Mea

n C

han

ge

Fro

m

Bas

elin

e in

Nig

ht

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.

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

♦ Global assessment of improvement assessed in Cymbalta DPNP Clinical Trials: Patient Global Impression of Improvement (PGI-I) Scale2

Check one box that best describes how you have felt overall since you began taking this medication

1 Very much better2 Much better

3 A little better4 No change

5 A little worse6 Much worse7 Very much worse

♦ In clinical trials, efficacy is often measured with numerical or categorical pain scales

♦ Scales used in the Cymbalta DPNP clinical trials include• 24-hour Average Pain Likert Scores • Brief Pain Inventory (BPI) Average Pain Score1

Do Improvements in Pain Ratings Correspond to Patients Actually Feeling Better?

0

NoPain

Pain as badas you can

imagine

Please rate your pain by circling the one number that best describes your pain on average

1. Cleeland CS and Ryan KM. Ann Acad Med Singapore. 1994;23:129–138; 2. Guy W. ECDEU Assessment Manual for Psychopharmacology. 1976;217–222:313–331.

1 2 3 4 5 6 7 8 9 10

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 Activity, Function, and Enjoyment of Life (BPI-I)

* P < .05 vs placebo

** P < .01 vs placebo

*** P < .001 vs placebo

****** ***

***

***

***

******

*****

****

** ******

***


PGI-Improvement at Endpoint of Maintenance Phase

0

0.5

1

1.5

2

2.5

3

3.5

Imp

rov

eme

nt

Responders (60 mg)

Non-Responders (120 mg)

Responders defined as ≥30% reduction on BPI average pain during acute phase.PGI-Improvement = Patient’s Global Impression of Improvement

Data on File

Contents

♦ Introduction




♦ Conclusion

Duloxetine Pharmacokinetic Data

♦ Clinical pharmacology1-7:• t1/2 about 12 hours (in plasma)• Protein binding >90%

♦ Observed duration of action with once-daily dosing suggests:• Therapeutic effects may persist after drug is cleared• Brain concentration may differ from plasma concentration

♦ No need for dose adjustment based on• Age, gender and/or smoking• Excretion data

1. Sharma A, et al. J Clin Pharmacol. 2000;40:161–167; 2. Skinner MH, et al. Clin Pharmacol Ther. 2000;67:129; 3. Takahashi A, et al. Neuropsychopharmacology. 1994;10 (Supp 3 Pt 1):S651; 4. Johnson JT, et al. Pharm Res. 2001;12 (Supp 9):S387; 5. Cymbalta SPC.

Hepatic Safety Profile of Duloxetine

1. Cymbalta US Prescribing Information.

♦ Metabolized by CYP2D6 and 1A21

• Moderate inhibitor of 2D6• No clinically significant inhibition of 1A2, 3A, 2C9, or 2C19• No induction of CYP isoenzymes

♦ In the overall duloxetine clinical trial database (N=3,372), just three duloxetine-treated patients met laboratory thresholds predictive of liver injury1

♦ No specific laboratory tests are recommended, although duloxetine should ordinarily not be prescribed to patients with substantial alcohol use nor patients with any hepatic insufficiency1

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

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.



Clinical Profile of the 3 Most Common Adverse 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 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.

Depression as co-morbidity in patients with diabetes:

¨ People with diabetes are twice as likely to be depressed as people without chronic disease.

¨ Depression is a risk factor for onset of type 2 diabetes.

¨ Improvement of depression ↔ improvement in glycemic control.

¨ Psychological maladjustment or depression in diabetes can result from diabetes complications

Contents

♦ Introduction




♦ Conclusion

Summary

♦ DPNP is a relatively widespread condition that significantly impacts patients’ functioning and quality of life

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

♦ Following 8 weeks of acute therapy, duloxetine 60 mg once daily maintained its efficacy in the management of diabetic peripheral neuropathic pain for 26 weeks.

♦ Duloxetine is safe and well-tolerated

duloxetine in the treatment of diabetic peripheral neuropathic pain (dpn)

Documents

pain management

assessment of pain

postoperative pain

clin j pain

drugs slide

intact pain pathways

energy sleep mood pain

potential tissue damage