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Diabetic Peripheral
Neuropathic Pain (DPNP)
SUMMARY SLIDE SET
Contents
♦ Introduction
♦ Mechanism of Action
♦ Efficacy in DPNP
♦ Conclusion
Contents
♦ Introduction
♦ Mechanism of Action
♦ Efficacy in DPNP
♦ Conclusion
Neuropathic Pain is a Frequent
Complication of Diabetes
1. Clark CM, et al. N Engl J Med. 1995;332:1210–1217; 2. Boulton AJM, et al. Diabetes Care. 2004;27:1458–1486; 3. Eastman RC.
Neuropathy in Diabetes. In: Diabetes Data Group, eds. Diabetes in America, 2nd ed. NIH Publication: Washington, DC;1995:339–348.
4. Argoff CE, et al. Mayo Clin Proc. 2006; 81(4):S3–11; 5. Sullivan SD, et al. Pharmacoeconomics. 2002;20:1079–1089.
DPNP Can Negatively Impact Patients’
Quality of Life1,2
“Pain is an unpleasant
sensory and emotional
experience associated
with actual or potential
tissue damage, or
The majority described in terms of
of patients such damage3”
experience pain
on a constant, mood
daily basis1
sleep
energy
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.
Multiple Mechanisms of Neuropathic Pain
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
♦ Mechanism of Action
♦ Efficacy in DPNP
♦ Conclusion
Serotonin & Norepinephrine
Play a Major Role in Pain
♦ Neuropathic pain is
associated with increased
excitation and decreased
inhibition of ascending
pain pathways
♦ Descending pathways
modulate ascending signals 5-HT
♦ NE and 5-HT are key
neurotransmitters in
descending inhibitory NE
pain pathways
♦ Increasing the availability of
NE and 5-HT may promote pain
inhibition centrally
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.
The Combination of an NRI and an SSRI is
More Effective than Either Alone
Vehicle control
100
% of Vehicle Control
Thionisoxetine
80
Paroxetine
60 * * 1 mg/kg +
Thionisoxetine
40 N=5–12
* P < .05
20 vs thionisoxetine alone
0
0.1 1 10
Drug (mg/kg)
Higher Dose
Vehicle Vehicle
Less Pain Behavior
100 control
100
control
75 * * 75
*
*
* *
50 50
* * *
#
25 * 25
* *
0 0
1 10 100 1 10 100
Drug (mg/kg i.p. 30 min) Drug (mg/kg i.p. 30 min)
Higher Dose Duloxetine Higher Dose
N=6–9 Venlafaxine
* P < .05 vs vehicle Milnacipran
# Rotorod effects Amitriptyline
14
* Vehicle control
Less Pain Behavior
12
Duloxetine
10 30 mg/kg p.o.
8 once daily
6 N=4–5
4
* P < .05
2
vs vehicle
0
pre base Day 1
3 hrs
Time
pre = pre-surgery baseline, base = post-surgery baseline
♦ Introduction
♦ Mechanism of Action
♦ Efficacy in DPNP
♦ Conclusion
Completed Duloxetine Clinical Trials in DPNP
Treatment
Study Treatment Groups duration
(weeks) N
Wernicke et al2
60 and 120 mg/day
vs placebo 12 334
dstein 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;
a 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.
Duloxetine Reduces 24-Hour Average
Pain Severity in DPNP
Pooled data from 3 studies
0.0
Average Pain Severity Score
Placebo
Mean Change in 24-hour
-0.5 (n=330)
Duloxetine
-1.0 * 20 mg QD
Improvement
(n=111)
-1.5
* * Duloxetine
-2.0 * 60 mg QD
* * (n=334)
* * * * *
-2.5 * * *
* * Duloxetine
-3.0
* * * 60 mg BID
* * * (n=333)
* *
-3.5 * P ≤ .05
0 1 2 3 4 5 6 7 8 9 10 11 12 13 vs placebo
Weeks MMRM
♦ A reduction of approximately 2 points or 30% represents a clinically
important difference (mean baseline score was 5.83)
Poster: Raskin J, et al. 25th American Pain Society (APS) Annual Scientific Meeting; San Antonio, TX; May 3–6, 2006.
Duloxetine Improves Response Rates in
DPNP After 12 Weeks†
* **
40 40
*
20 20
0 0
Study 11 Study 23 Study 31 Study 12 Study 23 Study 34
Placebo
Duloxetine 20 mg QD * P < .05 vs placebo
Duloxetine 60 mg QD ** P < .01 vs placebo
Duloxetine 60 mg BID
†
Completer analysis *** 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
60 mg QD Duloxetine Improves Worst
Pain Severity in DPNP
24-hour Worst Pain after 12 Weeks Data from three 12-week efficacy and safety studies
0
n=111 n=112 n=106 n=110 n=103 n=114
Placebo
Duloxetine
-1 60 mg QD
-2
-3
** **
*
-4
0
Night Pain After 12 Weeks
-2
-3
* ** **
-4
Very
Much Worse/ A Little No A Little Much Very Much
30 Much Worse Worse Change Better Better Better
% Change in BPI Average
Pain Score at Endpoint
10
Improvement
-10
-30
-50
-70
-90
Study 1: Duloxetine 20, 60, 120 mg; placebo (N=457)
Study 2: Duloxetine 60 and 120 mg; placebo (N=334)
Study 3: Duloxetine 60 and 120 mg; placebo (N=348)
Poster: Farrar J, et al. Presented at: 25th American Pain Society (APS) Annual Meeting; San Antonio, TX; May 3–6, 2006.
Duloxetine Decreased the Impact of Pain on Daily
Activity, Function, and Enjoyment of Life (BPI-I)
Pooled data from 3 studies
BPI Avg General Walking Normal Relationship Enjoyment
Score Activity Mood Ability Work With Others Sleep of Life
0
Decreased Impact / Improvement
-0.5
LS Mean Change from
Baseline BPI-I Score
-1
-1.5
*
-2
***
-2.5 ***
*** *** **
*** ***
-3 *** *** *** ***
*** ***
-3.5 ** ***
Placebo * P < .05 vs placebo
Duloxetine 60 mg QD
Duloxetine 60 mg BID ** P < .01 vs placebo
*** P < .001 vs placebo
Armstrong DG, et al. Pain Med. 2007;8(5):410-418.
Maintenance Study Design
Study Study Study Study
Period I Period II Period III Period IV
60 mg once daily
60 mg once daily
Visit 1 2 3 4 5 6 7 8 8 or ED 301
Week -1 0 1 8 12 16 24 34 34 or ED 36
* Responders are defined as patients with a ≥30% reduction from Visit 2 on the BPI 24-hour
average pain item at Visit 4. All other patients are considered nonresponders. Patients who
have been taking duloxetine 60 mg once daily for at least 7 days entered the taper phase
Data on File
Patient Disposition
Enrolled Patients
N = 216
Completed
Completed
N = 9 (75.0%)
N = 77 (74.8%)
Data on File
BPI 24-hour Average Pain Score
BPI Average Pain Score
8
5.85 Acute Duloxetine
LOCF 30/60 mg
6
4 3.36
***
2
0
0 4 8
Weeks on Therapy
*** P ≤ .001
BPI = Brief Pain Inventory;
LOCF = Last observation carried forward
Data on File
BPI 24-hour Average Pain Score
2
MMRM
1.5 Duloxetine
*** 60 mg
1
LS Mean Change
Responders
Improvement
* Duloxetine
0.5
120 mg
0
8 12 16 20 24 28 32 36
-0.5
***
-1 *
3.5
2.5
Improvement
1.5
0.5
0
Responders Non-Responders
(60 mg) (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
BPI 24-Hour Average Pain Score - 50%
Response Rates at Endpoint
Duloxetine
N n (%)
Responders 114 76 (66.7)
Nonresponders 66 21 (31.8)
Data on File
Contents
♦ Introduction
♦ Mechanism of Action
♦ Efficacy in DPNP
♦ 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
*
10.8
10
5.3
4.3
0
Placebo Duloxetine Duloxetine Duloxetine
(n=339) 20 mg QD 60 mg QD 60 mg BID
(n=115) (n=344) (n=341)
*P ≤ .05 vs placebo
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.
Most Common Adverse Events
Associated with Duloxetine in DPNP
Pooled data from 3 studies
Cymbalta Adverse Events that Occurred 5% and Twice Placebo
50
Placebo (n=339)
Duloxetine 20 mg/day (n=115)
% Incidence of Adverse Events
10
0
Nausea Somnolence Dizziness Constipation Sweating Dry Mouth Appetite
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.
Most Common Adverse Events as
Reason for Discontinuation
Pooled data from 3 studies
5
Placebo (n=339)
Duloxetine 20 mg/day (n=115)
4 Duloxetine 60 mg/day (n=334)
* *
Percent of Patients
2
1.5 1.5
1.2 1.2
0.9 0.9 0.9 0.9
1 0.6
0.3 0.3
0 0 0 0 0 0
0
Nausea Somnolence Dizziness Fatigue Vomiting
*P ≤ .05 vs placebo
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
Pooled data from 3 studies
Onset Median Duration Severity (60 mg/QD)
50 9% 2%
40 Nausea 13%
% Patients Reporting AE (New Cases)
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.
Nausea on Duloxetine is Common, but is
Short-Lived and Mostly Mild or Moderate
Pooled data from 3 studies
Moderate 9% Severe 2%
Mild 13%
None 76%
♦ 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)
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.
Duloxetine Causes Minimal Long-term
Weight Change in DPNP
1.5
0.51
0.5
0.31
Poster: Raskin J, et al. 25th American Pain Society (APS) Annual Scientific Meeting; San Antonio, TX; May 3–6, 2006.
Effects on Fasting Glucose Levels and
Hemoglobin A1c
0.5
Mean Change
0.004
0
0.002
0.002
-0.5
-0.64
-1 0
Fasting Glucose Hemoglobin A1c
Routine Care (n=559) Routine Care (n=265)
Duloxetine 60 mg BID (n=269) Duloxetine 60 mg BID (n=548)
Poster: Raskin J, et al. 25th American Pain Society (APS) Annual Scientific Meeting; San Antonio, TX; May 3–6, 2006.
No Clinically Significant Long-term
Blood Pressure Changes with Duloxetine
Pooled data from three 52-week studies
Supine Systolic BP Supine Diastolic BP
5
Blood Pressure (mm Hg)
4
Mean Change in
2
*
1.41
1.35 1.38 * P < .05 vs routine care
1
0
-0.15
-1
Routine Care (N=287) Duloxetine 60 mg BID (N=577)
Poster: Raskin J, et al. 25th American Pain Society (APS) Annual Scientific Meeting; San Antonio, TX; May 3–6, 2006.
No Evidence of an Increased Risk of
Suicidality with Duloxetine
♦ 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.
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.
Data on file.
Contents
♦ Introduction
♦ Mechanism of Action
♦ Efficacy in DPNP
♦ Conclusion
Summary
♦ DPNP is a relatively widespread condition that significantly
impacts patients’ functioning and quality of life