Transcript Duloxetine in the Treatment of Diabetic Peripheral

Duloxetine in the Treatment of
Diabetic Peripheral
Neuropathic Pain (DPN)
Contents
♦ Introduction
♦ Mechanism of Action
♦ Efficacy in DPNP
♦ Pharmacokinetics, Safety and Tolerability
♦ Conclusion
Definition of diabetic neuropathy
WHO Definition:
A disease characterized as a progressive loss of
nerve
fibers leading
toofsensation
loss,affect
foot the
heterogeneous
group
diseases that
ulceration,
autonomicand
and amputation
peripheral nervous systems of
patients suffering from diabetes.
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.
Magnitude of pain
Evoked Pain
hyperalgesia
normal
allodynia
Stimulus intensity
hyperpathia
Prevalence of Diabetic Neuropathy
as 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
“Pain is an unpleasant
sensory and emotional
experience associated
with actual or potential
tissue damage, or
described in terms of
such damage3”
mood
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.
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.
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
♦ Mechanism of Action
♦ Efficacy in DPNP
♦ Pharmacokinetics, Safety and Tolerability
♦ Conclusion
Ectopic discharges
Nerve lesion induces hyperactivity due to changes
in ion channel function
Perceived pain
Nerve lesion
Descending
modulation
Ascending
input
Nociceptive afferent fiber
Spinal cord
Ectopic discharges
Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;165-182
Loss of inhibitory controls
Loss of descending modulation causes exaggerated pain due to an
imbalance between ascending and descending signals
Exaggerated pain
perception
Noxious
stimuli
Loss of
descending
modulation
Ascending
input
Nociceptive afferent fiber
Spinal cord
Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4 th Ed. 1999.;165-182
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
Central sensitization
After nerve injury, increased input to the dorsal horn
can induce central sensitization
Perceived pain
Nerve lesion
Descending
modulation
Ascending
input
Nociceptive afferent fiber
Abnormal discharges induce central sensitization
Tactile
stimuli
Descending
modulation
Intact tactile fiber
Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;165-182
Perceived pain
(allodynia)
Ascending
input
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
♦ NE and 5-HT are key
neurotransmitters in
descending inhibitory
pain pathways
5-HT
NE
♦ 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
Total paw-licking time (late phase)
% of Vehicle Control
Less Pain Behavior
120
Vehicle control
100
Paroxetine
Thionisoxetine
80
*
60
Paroxetine
1 mg/kg +
Thionisoxetine
*
40
N=5–12
* P < .05
20
vs thionisoxetine alone
0
0.1
1
Drug (mg/kg)
Higher Dose
1. Iyengar S, et al. J Pharmacol Exp Ther. 2004;311:576–584.
10
Duloxetine is a Potent Inhibitor of
Persistent Pain in the Formalin Model
% of Vehicle Control
Less Pain Behavior
Total paw-licking time (late phase)
Vehicle
control
100
*
75
Vehicle
control
100
75
*
*
*
*
50
*
50
*
*
*
25
25
*
0
1
10
*
#
*
100
0
1
Higher Dose
N=6–9
Duloxetine
Venlafaxine
* P < .05 vs vehicle
Milnacipran
# Rotorod effects
Amitriptyline
1. Iyengar S, et al. J Pharmacol Exp Ther. 2004;311:576–584.
10
Drug (mg/kg i.p. 30 min)
Drug (mg/kg i.p. 30 min)
Higher Dose
100
Withdrawal Threshold Response (g)
Less Pain Behavior
Duloxetine Reverses Mechanical Allodynia in the Spinal L5/L6
Nerve Ligation Model of Neuropathic Pain
14
*
12
Duloxetine
30 mg/kg p.o.
once daily
10
8
6
N=4–5
4
* P < .05
vs vehicle
2
0
Vehicle control
pre
base
Day 1
3 hrs
Time
pre = pre-surgery baseline, base = post-surgery baseline
1. Iyengar S, et al. J Pharmacol Exp Ther. 2004;311:576–584.
Contents
♦ Introduction
♦ Mechanism of Action
♦ Efficacy in DPNP
♦ Pharmacokinetics, Safety and Tolerability
♦ Conclusion
Completed Duloxetine Clinical Trials in DPNP
Study
Treatment Groups
Treatment
duration
(weeks)
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
N
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.
Duloxetine Reduces 24-Hour Average
Pain Severity in DPNP
Mean Change in 24-hour
Average Pain Severity Score
Improvement
Pooled data from 3 studies
0.0
Placebo
(n=330)
-0.5
Duloxetine
20 mg QD
(n=111)
*
-1.0
-1.5
*
-2.0
*
*
-2.5
*
*
-3.0
-3.5
0
1
2
3
Duloxetine
60 mg QD
(n=334)
*
* * * *
* * *
*
*
* * *
* * *
* *
4
5
6
7
8
9
10
11
12
Duloxetine
60 mg BID
(n=333)
* P ≤ .05
13
Weeks
♦ 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.
vs placebo
MMRM
Duloxetine Improves Response Rates in
DPNP After 12 Weeks†
30% Reduction
in 24-hour Average Pain
80
** **
**
***
*** **
50% Reduction
in 24-hour Average Pain
80
60
40
40
20
20
Patients (%)
60
0
Study 11
Study 23
Study 31
Placebo
Duloxetine 20 mg QD
Duloxetine 60 mg QD
Duloxetine 60 mg BID
† Completer analysis
0
*** ***
*
Study 12
***
**
*
Study 23
Study 34
* 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
60 mg QD Duloxetine Improves Worst
Pain Severity in DPNP
Mean Change From
Baseline in
24-hour Worst Pain after 12
Weeks
Data from three 12-week efficacy and safety studies
0
1
2
3
Goldstein
Wernicke
Raskin
n=111 n=112
n=106 n=110
n=103 n=114
Placebo
Duloxetine
60 mg QD
-1
-2
-3
-4
*
**
**
* P ≤ .05, ** P < .001 MMRM
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.
60 mg QD Duloxetine Reduces Pain at
Night in DPNP
Data from three 12-week efficacy and safety studies
Mean Change From
Baseline in
Night Pain After 12 Weeks
1
0
2
3
Goldstein
Wernicke
Raskin
n=111 n=112
n=106 n=109
n=103 n=114
Placebo
Duloxetine
60 mg QD
-1
-2
-3
*
**
**
-4
* P ≤ .05, ** P < .05
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.
Do Improvements in Pain Ratings Correspond
to Patients Actually Feeling Better?
♦ 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
Please rate your pain by circling the one number
that best describes your pain on average
No
Pain
0
1
2
3
4
5
6
7
Pain as bad
as you can
imagine
8
9
10
♦ 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 better
2 Much better
3 A little better
4 No change
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.
5 A little worse
6 Much worse
7 Very much worse
Duloxetine Decreased the Impact of Pain on Daily
Activity, Function, and Enjoyment of Life (BPI-I)
0
LS Mean Change from
Baseline BPI-I Score
Decreased Impact / Improvement
Pooled data from 3 studies
BPI Avg
Score
General
Activity
Mood
Walking
Ability
Normal
Work
Relationship
With Others
Sleep
Enjoyment
of Life
-0.5
-1
-1.5
*
-2
-2.5
-3
***
***
***
***
***
***
***
**
***
***
***
***
***
** ***
-3.5
Placebo
Duloxetine 60 mg QD
Duloxetine 60 mg BID
Armstrong DG, et al. Pain Med. 2007;8(5):410-418.
* P < .05 vs placebo
** P < .01 vs placebo
*** P < .001 vs placebo
PGI-Improvement at Endpoint of Maintenance Phase
3.5
Improvement
3
2.5
2
1.5
1
0.5
0
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
♦ Mechanism of Action
♦ Efficacy in DPNP
♦ Pharmacokinetics, Safety and Tolerability
♦ 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
♦ 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
1. Cymbalta US Prescribing Information.
Most Common Adverse Events
Associated with Duloxetine in DPNP
Pooled data from 3 studies
Cymbalta Adverse Events that Occurred 5% and Twice Placebo
% Incidence of Adverse Events
50
40
Duration*
30
4 days
5 days
6 days
20
Placebo (n=339)
Duloxetine 20 mg/day (n=115)
Duloxetine 60 mg/day (n=334)
Duloxetine 120 mg/day (n=341)
Duration*
23 days
13 days
15 days
Duration*
5 days
4 days
6 days
*Median duration data:
Placebo
Duloxetine (60 mg)
Duloxetine (120 mg)
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.
% Patients Reporting AE (New Cases)
Clinical Profile of the 3 Most Common
Adverse Events
50
40
30
20
10
0
50
40
30
20
10
0
50
40
30
20
10
0
Pooled data from 3 studies
Onset
Median Duration
Severity (60 mg/QD)
13%
Nausea
9% 2%
Duloxetine 60 mg/day=5 days
Duloxetine 120 mg/day=6 days
Placebo=4 days
1
2
3
4
5
6
7
8
76%
9 10 11 12
2%
12% 3%
Somnolence
Duloxetine 60 mg/day=13 days
Duloxetine 120 mg/day=15 days
Placebo=23 days
1
2
3
4
5
6
7
8
85%
9 10 11 12
Dizziness
6%
3% 1%
90%
Duloxetine 60 mg/day=4 days
Duloxetine 120 mg/day=6 days
Placebo=5 days
1
2
3
4
5
6
7
8
9 10 11 12
Weeks
Placebo (n=339)
Cymbalta 60 mg/day (n=334)
Cymbalta 120 mg/day (n=341)
Mild
Moderate
Severe
None
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
Severity of Treatment-emergent Nausea on Duloxetine 60 mg QD
Mild 13%
Moderate 9%
Severe 2%
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.
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.
♦
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.
Data on file.
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
♦ Mechanism of Action
♦ Efficacy in DPNP
♦ Pharmacokinetics, Safety and Tolerability
♦ 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