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Management of Diabetic Peripheral Neuropathic Pain
Management of Diabetic Peripheral Neuropathic Pain
Khalifa AbdallahProf. of Internal Medicine
Diabetes, Metabolism & Lipidology Unit
Alexandria University
Presentation OverviewPresentation Overview
• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
Presentation OverviewPresentation Overview
• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
Diabetic Neuropathy: Size and CostDiabetic 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.
Presentation OverviewPresentation Overview
• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
Presentation OverviewPresentation Overview
• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
Pathogenesis of Diabetic Neuropathy
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
Presentation OverviewPresentation Overview
• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
Presentation OverviewPresentation Overview
• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
Risk FactorsRisk Factors
• Glucose control• Duration of diabetes• Age• Height• Genetic susceptibility• Lifestyle factors
– Smoking– Alcohol
Presentation OverviewPresentation Overview
• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
Presentation OverviewPresentation Overview
• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
Classification of Diabetic Neuropathy
Classification of Diabetic Neuropathy
A. Diffuse Neuropathy1. Distal symmetric sensorimotor neuropathy2. Autonomic neuropathy
a. Sudomotorb. Cardiovascularc. Gastrointestinald. Genitourinary
3. Symmetrical proximal lower limb motor neuropathy (amyotrophy)B. Focal Neuropathy
1. Cranial neuropathy2. Radiculopathy and plexopathy3. Entrapment neuropathy
Painful Diabetic Neuropathy
Nociceptive and Neuropathic PainNociceptive and Neuropathic Pain
Nociceptive pain Neuropathic pain
Adaptive Maladaptive
Identifiable stimuli that normally produce tissue damage
Often spontaneous (occurring without identifiable stimuli)
Usually self-limiting Often chronic
Transmitted by structurally and functionally intact pain pathways
May involve structural and functional changes in pain pathways
Examples: post-operative pain, burns, ischemic pain
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
Pathophysiology of neuropathic pain
Peripheral neuronhyperexcitability
NeP
Central mechanisms
Central neuron hyperexcitability
(central sensitization)
Loss ofinhibitory controls
Peripheral mechanisms
Abnormaldischarges
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
Noxiousstimuli
Descendingmodulation
Ascendinginput
Spinal cord
Perceived pain
Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4 th Ed. 1999.;165-182
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
♦ NENE and 5-HT5-HT are key neurotransmitters in descending inhibitory pain pathways
♦ Increasing the availability of NENE and 5-HT5-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-HT5-HT
NENE
Presentation OverviewPresentation Overview
• Size and costs of the problem• Pathology/pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
Presentation OverviewPresentation Overview
• Size and costs of the problem• Pathology/pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
ADA Neuropathy screening and treatment Recommendations
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
ADA Neuropathy screening and treatment Recommendations
Diagnosis of neuropathy
Diabetes Care January 2011 34:S11-S61
Press until the filament bends.
Locations To Test
Presentation OverviewPresentation Overview
• Size and costs of the problem• Pathology/pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
Presentation OverviewPresentation Overview
• Size and costs of the problem• Pathology/pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
PreventionPrevention
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
PreventionPrevention
• Aldose reductase inhibitors• Gamma Linoleic Acid• Vasodilators-ACE?• AGE inhibitors• Antioxidants • NGFs• ? Smoking cessation, ? BP reduction
Treatment of diabetic neuropathic painTreatment 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 areasfor intervention including the reduction of peripheral andcentral hyperexcitability or increasing spinal inhibition
by enhancing monoaminergic activity
ADA: Neuropathy treatment recommendations management
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
Diabetes Care January 2009 32:S6-S12
Table 14—Table of drugs to treat symptomatic DPNClass Examples Typical doses*
Tricyclic drugs Amitriptyline 10–75 mg at bedtime Nortriptyline 25–75 mg at bedtime Imipramine 25–75 mg at bedtimeAnticonvulsants 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
ADA Neuropathy screening and treatment Recommendations-Management
Management of DPNPManagement 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 GroupsTreatment duration(weeks) N
Goldstein et al1 20, 60, 120 mg/dayvs placebo 12 457
Wernicke et al2
60 and 120 mg/dayvs 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 QD28 449
Completed Duloxetine Clinical Trials in DPNPCompleted 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 Duloxetine Reduces 24-Hour Average Pain Severity in DPNPPain 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 Duloxetine Improves Response Rates in DPNP After 12 WeeksDPNP 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
-4
-3
-2
-1
0
Goldstein Wernicke Raskin
Mea
n C
han
ge
Fro
m B
asel
ine
in24
-ho
ur
Wo
rst
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.
* ** **
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 60 mg QD Duloxetine Improves Worst Pain Severity in DPNPPain Severity in DPNP
-4
-3
-2
-1
0
Goldstein Wernicke Raskin
Mea
n C
han
ge
Fro
m B
asel
ine
inN
igh
t P
ain
Aft
er 1
2 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 60 mg QD Duloxetine Reduces Pain at Night in DPNPNight in DPNP
1 2 3
n=111 n=112 n=106 n=109 n=103 n=114
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 Duloxetine Decreased the Impact of Pain on Daily Activity, Function, and Enjoyment of Life (BPI-I)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
0
10
20
30
40
50
Appetite
Most Common Adverse Events Most Common Adverse Events Associated with Duloxetine in DPNPAssociated 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
*
Per
cen
t o
f P
atie
nts
Most Common Adverse Events as Most Common Adverse Events as Reason for DiscontinuationReason for Discontinuation
*P ≤ .05 vs placebo
0.30
0.30 0
0.9
0
0.9
0 0
3.2
1.5
0.9 0.90.6
3.2
2.6
1.51.2 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)
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 Clinical Profile of the 3 Most Common Adverse EventsAdverse 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 Nausea on Duloxetine is Common, but is Short-Lived and Mostly Mild or ModerateShort-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 No Evidence of an Increased Risk of Suicidality with DuloxetineSuicidality 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 messageTake 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