1. Management of Diabetic
Peripheral Neuropathic Pain
Khalifa Abdallah
Prof. of Internal Medicine
Diabetes, Metabolism & Lipidology Unit
Alexandria University

2. Presentation Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment

3. Presentation Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment

4. 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.

5. Presentation Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment

6. Presentation Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment

7. 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

8. Presentation Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment

9. Presentation Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment

10. Risk Factors
• Glucose control
• Duration of diabetes
• Age
• Height
• Genetic susceptibility
• Lifestyle factors
– Smoking
– Alcohol

11. Presentation Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment

12. Presentation Overview
• Size and costs of the problem
• Pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment

13. 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

14. Painful Diabetic Neuropathy

15. Nociceptive and Neuropathic Pain
Nociceptive pain Neuropathic pain
Adaptive Maladaptive
Identifiable stimuli that normally Often spontaneous (occurring without
produce tissue damage identifiable stimuli)
Usually self-limiting Often chronic
Transmitted by structurally and May involve structural and functional
functionally intact pain pathways changes in pain pathways
Examples: post-operative pain, burns, Examples: Polyneuropathy
ischemic pain (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

16. Pathophysiology of neuropathic pain
Peripheral mechanisms
Peripheral neuron
hyperexcitability
Loss of Abnormal
inhibitory controls discharges NeP
Central mechanisms
Central neuron
hyperexcitability
(central sensitization)
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

17. Normal nerve impulses leading to pain
Perceived pain
Noxious
stimuli
Descending Ascending
modulation input
Nociceptive afferent fiber
Spinal cord
Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;165-182

18. Ectopic discharges
Nerve lesion induces hyperactivity due to changes
in ion channel function
Perceived pain
Nerve lesion
Descending Ascending
modulation 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

19. 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
Ascending
descending
input
modulation
Nociceptive afferent fiber
Spinal cord
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

20. Central sensitization
After nerve injury, increased input to the dorsal horn
can induce central sensitization Perceived pain
Nerve lesion
Descending Ascending
modulation input
Nociceptive afferent fiber
Perceived pain
Abnormal discharges induce central sensitization (allodynia)
Tactile
stimuli Descending Ascending
modulation input
Intact tactile fiber
Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;165-182

21. 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
pain pathways
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.

22. Presentation Overview
• Size and costs of the problem
• Pathology/pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment

23. Presentation Overview
• Size and costs of the problem
• Pathology/pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment

24. 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

25. ADA Neuropathy screening and treatment
Recommendations
Diagnosis of neuropathy
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
Diabetes Care January 2011 34:S11-S61

26. Press until the filament bends.

27. Locations To Test

28. Presentation Overview
• Size and costs of the problem
• Pathology/pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment

29. Presentation Overview
• Size and costs of the problem
• Pathology/pathophysiology
• Risk factors
• Presentations
• Diagnosis
• Prevention and Treatment

30. 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

31. Prevention
• Aldose reductase inhibitors
• Gamma Linoleic Acid
• Vasodilators-ACE?
• AGE inhibitors
• Antioxidants
• NGFs
• ? Smoking cessation, ? BP reduction

32. 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

33. 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

34. ADA Neuropathy screening and treatment
Recommendations-Management
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.

35. 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.

36. Completed Duloxetine Clinical Trials in DPNP
Treatment
Study Treatment Groups duration
N
(weeks)
Goldstein et al1 20, 60, 120 mg/day
12 457
vs placebo
Wernicke et al2 60 and 120 mg/day
vs placebo 12 334
Raskin et al3 60 and 120 mg/day
12 348
vs placebo
Maintenance Study4 60 mg/day 8 + 26 115
1-year, open-label safety 120 mg vs
52 867
extension of above studies5 routine care
6-month, open-label 60 mg BID vs
safety study6 28 449
120 mg QD
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.

37. 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 *
Improvement
20 mg QD
(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.

38. Duloxetine Improves Response Rates in
DPNP After 12 Weeks†
30% Reduction 50% Reduction
in 24-hour Average Pain in 24-hour Average Pain
80 80
** ** *** *** **
**
60 60 *** *** ***
Patients (%)
* **
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

39. 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
Goldstein1 Wernicke2 Raskin3
Mean Change From Baseline in
0 n=111 n=112 n=106 n=110 n=103 n=114
Placebo
Duloxetine
-1 60 mg QD
-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.

40. 60 mg QD Duloxetine Reduces Pain at
Night in DPNP
Data from three 12-week efficacy and safety studies
1 2 3
Goldstein Wernicke Raskin
Mean Change From Baseline in
0 n=111 n=112 n=106 n=109 n=103 n=114
Night Pain After 12 Weeks
Placebo
Duloxetine
-1 60 mg QD
-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.

41. 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.

42. 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
Duloxetine 60 mg/day (n=334)
40 Duloxetine 120 mg/day (n=341)
Duration*
4 days
5 days
Duration*
30 6 days
23 days *Median duration data:
13 days Placebo
Duration*
15 days Duloxetine (60 mg)
5 days
20 4 days Duloxetine (120 mg)
6 days
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.

43. 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
* 3.2
3.2
Duloxetine 120 mg/day (n=341)
3
*
2.6
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.

44. 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)
30 Duloxetine 60 mg/day=5 days
20 76%
Duloxetine 120 mg/day=6 days
10 Placebo=4 days
0
1 2 3 4 5 6 7 8 9 10 11 12
50
2%
40 Somnolence 12% 3%
30
Duloxetine 60 mg/day=13 days 85%
20 Duloxetine 120 mg/day=15 days
10 Placebo=23 days
0
1 2 3 4 5 6 7 8 9 10 11 12
50
40 Dizziness 3% 1%
6%
30
20
Duloxetine 60 mg/day=4 days 90%
Duloxetine 120 mg/day=6 days
10 Placebo=5 days
0
1 2 3 4 5 6 7 8 9 10 11 12
Weeks Mild Severe
Placebo (n=339) Cymbalta 60 mg/day (n=334) Cymbalta 120 mg/day (n=341) Moderate 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.

45. 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
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.

46. 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.

47. 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

48. Thank You