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Management of Diabetic
Peripheral Neuropathic Pain
Khalifa Abdallah Prof. of Internal Medicine
Diabetes, Metabolism & Lipidology Unit
Alexandria University
Presentation Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment
Presentation Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment
Diabetic 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 Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment
Presentation Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment
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 Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment
Presentation Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment
Risk Factors
• Glucose control
• Duration of diabetes
• Age
• Height
• Genetic susceptibility
• Lifestyle factors
– Smoking
– Alcohol
Presentation Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment
Presentation Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment
Classification of Diabetic
Neuropathy A. Diffuse Neuropathy
1. Distal symmetric sensorimotor neuropathy
2. Autonomic neuropathy
a. Sudomotor
b. Cardiovascular
c. Gastrointestinal
d. Genitourinary
3. Symmetrical proximal lower limb motor neuropathy (amyotrophy)
B. Focal Neuropathy
1. Cranial neuropathy
2. Radiculopathy and plexopathy
3. Entrapment neuropathy
Painful Diabetic Neuropathy
Nociceptive and Neuropathic Pain
Neuropathic pain
Nociceptive pain
Maladaptive
Adaptive
Often spontaneous (occurring without
identifiable stimuli)
Identifiable stimuli that normally
produce tissue damage
Often chronic
Usually self-limiting
May involve structural and functional
changes in pain pathways
Transmitted by structurally and
functionally intact pain pathways
Examples: Polyneuropathy
(eg, diabetic, HIV), trigeminal
neuralgia, central post-stroke pain
Examples: post-operative pain, burns,
ischemic 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 neuron
hyperexcitability
NeP
Central mechanisms
Central neuron
hyperexcitability
(central sensitization)
Loss of
inhibitory controls
Peripheral mechanisms
Abnormal
discharges
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
Noxious
stimuli
Descending
modulation
Ascending
input
Spinal cord
Perceived pain
Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;165-182
Ectopic discharges
Nerve lesion induces hyperactivity due to changes
in ion channel function
Ectopic discharges
Nerve lesion
Spinal cord
Nociceptive afferent fiber
Descending
modulation
Ascending
input
Perceived pain
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
Nociceptive afferent fiber
Noxious
stimuli
Ascending
input
Spinal cord
Loss of
descending
modulation
Exaggerated pain
perception
Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th 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
Ascending
input
Descending
modulation
Nerve lesion
Nociceptive afferent fiber
Tactile
stimuli
Perceived pain
(allodynia)
Ascending
input
Descending
modulation
Abnormal discharges induce central sensitization
Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th 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
Presentation Overview
• Size and costs of the problem
• Pathology/pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment
Presentation Overview
• Size and costs of the problem
• Pathology/pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment
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
Diabetes Care January 2011 34:S11-S61
Press until the filament bends.
Locations To Test
Presentation Overview
• Size and costs of the problem
• Pathology/pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment
Presentation Overview
• Size and costs of the problem
• Pathology/pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment
Prevention
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
Prevention
• Aldose reductase inhibitors
• Gamma Linoleic Acid
• Vasodilators-ACE?
• AGE inhibitors
• Antioxidants
• NGFs
• ? Smoking cessation, ? BP reduction
Treatment 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 areas
for intervention including the reduction of peripheral and
central hyperexcitability or increasing spinal inhibition
by enhancing monoaminergic activity
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 DPN
Class Examples Typical doses*
Tricyclic drugs Amitriptyline 10–75 mg at bedtime
Nortriptyline 25–75 mg at bedtime
Imipramine 25–75 mg at bedtime
Anticonvulsants 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
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.
Study Treatment Groups Treatment duration (weeks)
N
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
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)
Duloxetine
20 mg QD
(n=111)
Duloxetine
60 mg QD
(n=334)
Duloxetine
60 mg BID
(n=333) *
* P ≤ .05 vs placebo
MMRM Weeks
Imp
rovem
en
t
*
* *
* * * * * * * *
Mean
Ch
an
ge i
n 2
4-h
ou
r
Ave
rag
e P
ain
Severi
ty S
co
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
Pati
en
ts (
%)
** ** ** *** ** ***
50% Reduction
in 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
*
*** *** ***
* **
Placebo
Duloxetine 20 mg QD
Duloxetine 60 mg QD
Duloxetine 60 mg BID † Completer analysis
Study 23 Study 12 Study 23 Study 34 Study 11 Study 31
-4
-3
-2
-1
0
Goldstein Wernicke Raskin
Mean
Ch
an
ge F
rom
Baseli
ne i
n
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
-4
-3
-2
-1
0
Goldstein Wernicke Raskin
Mean
Ch
an
ge F
rom
Baseli
ne i
n
Nig
ht
Pain
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.
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
LS
Mean
Ch
an
ge f
rom
Baselin
e B
PI-
I S
co
re
BPI Avg Score
Armstrong DG, et al. Pain Med. 2007;8(5):410-418.
Decre
ased
Im
pact
/ Im
pro
ve
men
t
Placebo
Duloxetine 60 mg QD
Duloxetine 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
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
dve
rse
Eve
nts
Nausea Somnolence Dizziness Constipation Sweating
Duration*
4 days
5 days
6 days *Median duration data:
Placebo
Duloxetine (60 mg)
Duloxetine (120 mg)
Duration*
23 days
13 days
15 days Duration*
5 days
4 days
6 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
*
Perc
en
t o
f P
ati
en
ts
Most Common Adverse Events as Reason for Discontinuation
*P ≤ .05 vs placebo
0.3 0
0.3 0 0
0.9
0
0.9
0 0
3.2
1.5
0.9 0.9 0.6
3.2
2.6
1.5 1.2 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 Adverse Events
Duloxetine 60 mg/day=4 days
Duloxetine 120 mg/day=6 days
Placebo=5 days
Duloxetine 60 mg/day=13 days
Duloxetine 120 mg/day=15 days
Placebo=23 days
Severity (60 mg/QD) Median Duration
% P
atients
Report
ing A
E (
New
Cases)
Placebo (n=339) Cymbalta 60 mg/day (n=334) Cymbalta 120 mg/day (n=341)
Duloxetine 60 mg/day=5 days
Duloxetine 120 mg/day=6 days
Placebo=4 days 0
10
20
30
40
50
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%
Mild Moderate
Severe
None
Weeks
Dizziness
0
10
20
30
40
50
1 2 3 9 10 11 12 4 5 6 7 8
Onset
50
Somnolence
0
10
20
30
40
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.
Take 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