Duloxetine in the Treatment of Diabetic Peripheral Neuropathic Pain (DPN)
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Transcript of 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.
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
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
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
Intact tactile fiber
Central sensitization
After nerve injury, increased input to the dorsal horn can induce central sensitization
Perceived pain
Ascendinginput
Descendingmodulation
Nerve lesion
Nociceptive afferent fiber
Tactilestimuli
Perceived pain(allodynia)
Ascendinginput
Descendingmodulation
Abnormal discharges induce central sensitization
Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4 th Ed. 1999.;165-182
♦ 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
tro
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)
1. Iyengar S, et al. J Pharmacol Exp Ther. 2004;311:576–584.
* 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)
1. Iyengar S, et al. J Pharmacol Exp Ther. 2004;311:576–584.
* 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
ns
e (
g)
N=4–5
*
Contents
♦ Introduction
♦ Mechanism of Action
♦ Efficacy in DPNP
♦ Pharmacokinetics, Safety and Tolerability
♦ 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
****** ***
***
***
***
******
*****
****
** ******
***
Pooled data from 3 studies
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
♦ 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
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)
Duration*23 days 13 days15 days
Duration*5 days 4 days6 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.
Pooled data from 3 studies
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
Duloxetine 60 mg/day=13 daysDuloxetine 120 mg/day=15 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)
Duloxetine 60 mg/day=5 daysDuloxetine 120 mg/day=6 days
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
Pooled data from 3 studies
♦ 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%
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.
Pooled data from 3 studies
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
♦ 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