Diabetes mellitus is a common illness and the prevalence has been increasing all over the world, especially in Asia and India. Diabetes leads to several complications, affecting kidneys, nerves, eyes, brain and heart. The involvement of nerves due to diabetes is called diabetic neuropathy, which can be painful and disabling. The current presentation looks at the symptoms and diagnosis of painful diabetic neuropathy and also the treatment options.

1. Painful Diabetic peripheral neuropathy-
Diagnosis and management
DR SUDHIR KUMAR MD DM
SENIOR CONSULTANT NEUROLOGIST
APOLLO HOSPITALS, HYDERABAD

2. Diabetes is a global epidemic
Ref: IDFAtlas 5th Ed Page 1

3. Top 10 countries/territories for individuals with diabetes
(20–79 years)
High burden of disease:
5 of the top 10 countries worldwide are in Asia
International Diabetes Federation (IDF). IDF Diabetes Atlas, 5th Edition, 2012 update. Available at:
http://www.idf.org/sites/default/files/5E_IDFAtlasPoster_2012_EN.pdf. Accessed 19 March 2014.

4. Epidemiology of diabetes in Asia

5. 1. Yoon KH, et al. Lancet 2006;368:1681-1688. 2. Ramachandran A, et al. Lancet 2010;375:408-418.
3. Hu FB. Diabetes Care 2011;34:1249-1257.
 Significant increase in diabetes prevalence across the Asian region1-3
Diabetes in Asia is increasing at alarming rates
5

6. Pathophysiology of diabetes
and its complications
6

7. Progression of prediabetes to diabetes
is multifactorial
Elevated FPG and increase in FPG
High BMI
Weight gain
Younger age
High plasma insulin
Decreased insulin response to glucose
Dyslipidemia
Hypertension
Poor β-cell function
Choice of treatment
Fonseca VA, et al. Diabetes Care 2009;32(Suppl 2):S151-S156.
7

8. Diabetes is a lifelong condition associated with
serious complications
8
1. UKPDS Group. Diabetes Res 1990;13:1-11. 2. Fong DS, et al. Diabetes Care 2003;26(Suppl 1):S99-S102. 3. Hypertension
in Diabetes Study. J Hypertens 1993;11:309-317. 4. Molitch ME, et al. Diabetes Care 2003;26(Suppl 1):S94-S98. 5. Kannel
WB, et al. Am Heart J 1990;120(3):672-676. 6. Gray RP, et al. In Textbook of Diabetes 2nd Edition, 1997. 7. Mayfield JA, et al.
Diabetes Care 2003;26(Suppl 1):S78-S79. 8. American Diabetes Association (ADA). Diabetes Care 2003;26:3333-3341.
MACROVASCULARCOMPLICATIONS
MICROVASCULARCOMPLICATIONS
Diabetic
retinopathy
Leading cause
of blindness
in adults1,2
Diabetic
nephropathy
Leading cause of
endstage renal
disease3,4
Cardiovascular
disease (CVD)
Stroke
Two- to four-fold
increase in CV
mortality and
stroke5
Diabetic
neuropathy
Leading cause of
non-traumatic
lower extremity
amputations7
Eight out of ten
individuals with
diabetes die from
CV events6
A major risk factor for
lower-extremity amputation,
and is associated with
increased CVD events8
Peripheral arterial
disease (PAD)

9. Living with diabetes can be overwhelming
 On average, a patient with diabetes has had his/her
condition for ~15 years1
 Many patients use multiple medications2
 Patients commonly feel frustrated or overwhelmed by
daily requirements of disease management3
 Diabetes can lead to many complications, including
cardiovascular disease, nephropathy, retinopathy and
neuropathy, such as painful diabetic neuropathy
(PDN)4,5
9
1. Garancini MP, et al. Diabetes Care 1996;19:1279–1282.
2. Grant RW, et al. Diabetes Care 2003;26(5):1408–1412.
3. Polonsky WH. Curr Diabetes Rep 2002;2:153–159.
4. Davies M, et al. Diabetes Care 2006;29(7):1518–1522.
5. American Diabetes Association. Diabetes Care 2011;34(Suppl1):S11–S61.

10. Diabetic neuropathy caused significant
reductions in HRQoL (Japan)
Tsuji M, et al. Pain Res Treat 2013;2013:318352.
11

11. Painful diabetic neuropathy (PDN):
painful consequence of diabetes
12

12. Assessing diabetic neuropathy is a critical
part of overall diabetes management
 The American Diabetes Association recommends screening for diabetic neuropathy
in all patients at diagnosis and annually thereafter1
13
9 out of 10 patients with PDN report
moderate or severe pain7
1 out of 5 patients with diabetes
suffer from PDN3-5
60% to 70% of diabetic patients
have diabetic neuropathy6
1. American Diabetes Association. Diabetes Care 2011;34(Suppl1):S11–S61.
2. International Diabetes Federation. IDF Diabetes Atlas, 6th edn. Brussels, Belgium: International Diabetes Federation,
2013. Available at: http://www.idf.org/diabetesatlas. Accessed 19 February 2014.
3. Bouhassira D, Letanoux M, Hartemann A. PLoS One 2013;8:e74195.
4. Kim SS, Won JC, Kwon HS, et al. Diabetes Res Clin Pract 2013 Dec 25. [Epub ahead of print]
5. Tsuji M, Yasuda T, Kaneto H, et al. Pain Res Treat 2013;2013:318352.
6. Centers for Disease Control and Prevention. National Diabetes Fact Sheet, 2007. Available at:
http://apps.nccd.cdc.gov/DDTSTRS/FactSheet.aspx. Accessed July 1, 2008.
7. Data on file. Wave 2 Consumer DPN ATU Study. 2007. Pfizer Inc, New York, NY.
~210 million people in the Asia Pacific region have diabetes2
Chronic sensorimotor neuropathy
Autonomic neuropathy
Focal and multifocal neuropathies
PDN, painful diabetic neuropathy

13. Neuropathic pain of PDN negatively affects
quality of life
 Pain may significantly interfere with a patient’s ability to
exercise or walk1
 Walking has been shown to improve HbA1C in patients with diabetes
regardless of change in body mass2,3
 Pain often intensifies at night and may significantly interfere
with sleep4
 Sleep debt has been shown to have a negative impact on metabolic
and endocrine control5-7
 Pain is significantly correlated with depression in diabetic
patients8
14
1. Novak P, et al. J Rehabil Med 2004; 36:249–252.
2. Boule NG, et al. JAMA 2001;286:1218–1227.
3. American Diabetes Association. Diabetes Care 2011;34(Suppl1):S11–S61.
4. Quattrini C, et al. Diabetes Metab Res Rev 2003;19:S2–S8.
5. Zelman DC, et al. Clin J Pain 2006;22:681–685.
6. Spiegel K, et al. Lancet 1999;354:1435–1339.
7. Åkerstedt T, Nilsson PM. J Intern Med 2003;254:6–12.
8. Raval A, et al. Indian J Med Res 2010;132:195-200.
PDN, painful diabetic neuropathy; HbA1C, glycated hemoglobin

14. PDN is a complication of diabetes
that often is undertreated
 83% of people with diabetic neuropathy report
experiencing pain, but HCPs estimate that fewer than
half (41%) of their diabetic neuropathy patients
experience pain
 Fewer than half of those with PDN say they speak about
it with their HCP
 More than half of patients (56%) report that PDN
symptoms can be difficult to describe
15
Sadosky A, Hopper J, Parsons B. Patient 2014;7:107-114.
PDN, painful diabetic neuropathy; HCP, healthcare provider

15. Mechanisms of
neuropathic pain in PDN

16. Development of diabetic neuropathy:
A multifactorial process
Hyperglycemia leads to:
 Activation of the polyol pathway
 With saturation of the normal glycolytic
pathway, extra glucose is shunted into the
poyol pathway and converted to sorbitol and
fructose. Accumulation of these sugars leads
to reduced nerve myoinositol, impaired
axonal transport and structural breakdown of
nerves
 Production of advance glycation end-
products (AGEs)
 AGEs interfere with neuronal metabolism and
axonal transport, leading to disruption of
neuronal integrity
 Increased production of free radicals
 Free radicals induce direct damage to blood
vessels leading to nerve ischemia and
facilitation of AGE reactions
Lin HC. Diabetic Neuropathy. Available at: http://emedicine.medscape.com/article/1170337-
overview#a0104. Accessed 1 June 2011.
Together, these biochemical mechanisms result in structural nerve damage.

17. Neuropathic pain associated with diabetic
neuropathy: Often due to sensory nerve damage
 “Stocking-and-glove” painful sensations are very common1
 While both small and large nerve fibers can be affected, symptoms of
PDN typically indicate that small fibers are affected first
1. Vinik AI, et al. In: Diabetes and Carbohydrate Metabolism. [E-
textbook]. 2002. Available at: http://www.endotext.org. Accessed
November 11, 2009.
2. Tavee J, Zhou L. Cleve Clin J Med 2009;76(5):297–305.
3. Pittenger G, Vinik A. Experimental Diab Res 2003;4:271–285.
Large fibers (A/)1,3Small fibers (A and C)1,2
 Sensory and/or motor nerves
 Feet usually affected first
 Loss of vibration perception
and proprioception
 Deep-seated gnawing and
aching pain
 Muscle wasting (hammer toes)
 Abnormalities readily detected
by electromyography
 Pain amplification and
hyperalgesia (first)
 Loss of sensitivity (later on)
 Autonomic symptoms
 Predisposes to diabetic
foot disease
 Electrophysiology may not
detect nerve damage
PDN, painful diabetic neuropathy

18. Small-fiber neuropathy in PDN
 Loss of small fibers are characterized
by reduced density of intraepidermal
nerve fibers (IENF) as shown by
arrows1
 Arrowheads indicate dermal
nerve bundles
 Length-dependent denervation of skin
is particularly seen in distal leg
 Typical clinical presentation2
 Burning and superficial pain; allodynia
and hyperalgesia
 May have normal strength, reflexes and
conduction velocity
 Abnormal thresholds for warm thermal
perception and pain
 Patients with prediabetes glucose
intolerance and normal HbA1c levels
may have small-fiber neuropathy and
experience pain3
1. 1. Lauria G, Devigili G. Nat Clin Pract Neurol 2007;3:546–557.
2. 2. Tavee J, Zhou L. Cleve Clin J Med 2009;76(5):297–305.
3. Tesfaye S, Selvarajah D. Current Diabetes Reports 2009;9:432–434.
Diabetic patient with
small-fiber neuropathy
(A) Proximal thigh
(B) Distal leg
Printed with permission from Macmillan Publishers Ltd: Lauria G,
Devigili G. Nat Clin Pract Neurol. 2007;3:546–557, copyright 2007.
PDN, painful diabetic neuropathy; HbA1C, glycated hemoglobin
Normal
epidermis

19. Identifying and quantifying nerve damage
in diabetic neuropathy
 Electromyography1
 Measure of electrical activity generated by muscles
 Diagnosis is made when there is less electrical activity than normal
 Skin Biopsy2,3
 Quantification of intraepidermal nerve fibers (IENF)
 Diagnosis is made if IENF density is lower than normal
 Quantitative Sudomotor Axon Reflex Testing (QSART)4
 Autonomic study measures sweat output in response to acetylcholine
 Diagnosis is made when sweat gland output is lower than normal
1. 1. American Diabetes Association. Available at:
http://www.diabetes.org/diabetes-basics/common-terms/. Accessed June 28, 2010.
1. 2. Lauria G, Devigili G. Nat Clin Pract Neurol 2007;3:546–557.
3. Smith AG, et al. Diabetes Care 2006;29:1294–1299.
4. Tavee J, Zhou L. Cleve Clin J Med 2009;76(5):297–305.

20. Diagnosis and management of PDN
21

21. Neuropathic pain:
Positive and negative sensory symptoms
Positive symptoms
(due to excessive activity)1,2
Dysesthesia
Sensory abnormalities and pain paradoxically co-exist1,2
Each patient may have a combination of symptoms
that may change over time (even within a single etiology)
Paresthesia
Spontaneous pain
Hyperalgesia
Allodynia Anesthesia
Negative symptoms
(due to deficit of function)1,2
Nervous system dysfunction or damage
Hypoesthesia
Hypoalgesia
Analgesia
1. Baron R, et al. Lancet Neurol 2010;9:807-819.
2. Jensen TS, et al. Eur J Pharmacol 2001;429:1-11.
22

22. Symptom Definition
Spontaneous pain Painful sensations felt with no evident stimulus
Allodynia Pain due to a stimulus that does not normally provoke
pain (eg, touching, movement, cold, heat)
Hyperalgesia An increased response to a stimulus that is normally
painful (eg, cold, heat, pinprick)
Dysesthesia An unpleasant abnormal sensation, whether
spontaneous or evoked (eg, shooting sensation)
Paresthesia An abnormal sensation, whether spontaneous or
evoked (eg, tingling, buzzing, vibrating sensations)
Positive sensory symptoms
of peripheral neuropathy
International Association for the Study of Pain (IASP). IASP Taxonomy. Available at:
http://www.iasp-pain.org/Content/NavigationMenu/GeneralResourceLinks/PainDefinitions/default.htm.
Accessed 2 August 2011.
23

23. Symptom Definition
Hypoesthesia Diminished sensitivity to stimulation
Anesthesia A total loss of sensation (especially tactile sensitivity)
Hypoalgesia Diminished pain in response to a normally painful
stimulus
Analgesia Absence of pain in response to stimulation that would
normally be painful
Negative sensory symptoms
of peripheral neuropathy
International Association for the Study of Pain (IASP). IASP Taxonomy. Available at:
http://www.iasp-pain.org/Content/NavigationMenu/GeneralResourceLinks/PainDefinitions/default.htm.
Accessed 2 August 2011.
24

24. Diabetic peripheral neuropathy
 Numbness or insensitivity to pain or
temperature
 Tingling, burning or prickling
sensation
 Sharp pains or cramps
 Extreme sensitivity to touch, even
light touch
 Loss of balance and coordination
 Muscle weakness and loss of
reflexes
 Symptoms are often worse at night
25
National Institute of Diabetes and Digestive and Kidney Diseases. Diabetic Neuropathies: The Nerve
Damage of Diabetes. Available from: http://diabetes.niddk.nih.gov/dm/pubs/neuropathies/neuropathies.pdf.
Accessed 15 Jul 2009.

25. Examining a diabetic patient with pain:
Taking a pain history
Question the patient about his/her pain1
 Duration
 Frequency
 Quality
 Intensity
Be alert and ask for common verbal descriptors
of neuropathic pain (eg, tingling, electric shock-like,
numbness, burning, shooting)2,3
Use analogue or numerical scales to quantify the pain2
26
1. Haanpää ML et al. Am J Medicine 2009;122(10 Suppl):S13-21.
2. Gilron I et al. Can Med Assoc J 2006;175:265-275.
3. Baron R, et al. Lancet Neurol 2010;9:807-819.

26. ‘Numbness’
‘Shooting’ ‘Burning’
Patients with neuropathic pain may use
these pain descriptors
27
Be alert for common verbal descriptors
of neuropathic pain1,2
‘Electric shock-like’
‘Tingling’
1. Gilron I et al. Can Med Assoc J 2006;175:265-275.
2. Baron R, et al. Lancet Neurol 2010;9:807-819.

27. The inter-relationship between neuropathic pain,
sleep and anxiety/depression
28
Nicholson B, et al. Pain Med 2004;5(Suppl1):S9-27.

28. Treatment of PDN
Treatment of PDN is both preventive and symptomatic,
and is based on:
1. Stabilizing glycemic levels1
2. Therapeutic agents specific to neuropathic pain, such as alpha-
2-delta ligands (pregabalin, gabapentin), tricyclic
antidepressants (TCAs) and serotonin-norepinephrine reuptake
inhibitors (SNRIs)2
29
1. Corbett CF. Diabetes Educator 2005;31:523-40
2. Freynhagen R, Bennett MI. BMJ 2009;339:391-395.
PDN, painful diabetic neuropathy

29. Mechanism-Based Pharmacological
Treatment of Neuropathic Pain
Spinal cordNociceptive afferent fiber
SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant
Adapted from: Attal N et al. Eur J Neurol 2010; 17(9):1113-e88; Beydoun A, Backonja MM. J Pain Symptom Manage 2003; 25(5 Suppl):S18-30;
Jarvis MF, Boyce-Rustay JM. Curr Pharm Des 2009; 15(15):1711-6; Gilron I et al. CMAJ 2006; 175(3):265-75; Moisset X, Bouhassira D. NeuroImage 2007;
37(Suppl 1):S80-8; Morlion B. Curr Med Res Opin 2011; 27(1):11-33; Scholz J, Woolf CJ. Nat Neurosci 2002; 5(Suppl):1062-7.
Descending
modulation
Central
sensitization
Ectopic
discharge
Peripheral
sensitization
Brain
Medications affecting
descending modulation:
• SNRIs
• TCAs
• α2δ ligands
• Tramadol, opioids
Medications
affecting central
sensitization:
• α2δ ligands
• TCAs
• Tramadol, opioids
Medications affecting
peripheral sensitization:
• Capsaicin
• Local anesthetics
• TCAs
Nerve lesion/disease Nerve lesion/disease
Central
sensitization
Nerve lesion/disease

30. Pharmacological treatments for PDN:
Hypothesized mechanisms of action
Predominant mechanism Drugs
Binding to α2δ subunit of voltage-dependent calcium
channels with reduced release of transmitters
pregabalin, gabapentin
Dual serotonin/noradrenaline reuptake inhibition amitriptyline, nortriptyline,
duloxetine, imipramine, venlafaxine
μ-opioid (or К2-opioid) receptor agonist oxycodone; tramadol (also has
monoamine reuptake inhibition)
Voltage-gated sodium channel inhibition lamotrigine, carbamazepine,
oxcarbazepine
Voltage-gated sodium-channel block; inhibition of
glutamate release via activity at AMPA/kainate
receptors
topiramate
Increase of GABA levels in brain and potentiation of
GABA-mediated responses
valproate
NMDA (N-methyl-D-aspartate) antagonists memantine; dextromethorphan
(weak)
1. Zin CS, et al. CNS Drugs 2008;22:417-442.
2. Attal N, et al. Eur J Neurol 2010;17:1113-e88.PDN, painful diabetic neuropathy.
Venlafaxine is not approved for the treatment of neuropathic pain.

31. Recommended treatments for PDN:
Summary of key international guidelines
32
1. Attal N et al. Eur J Neurol 2010;17:1113-e88.
2. Dworkin RH et al. Mayo Clin Proc 2010;85(3Suppl):S3-14.
3. Moulin DE et al. Pain Res Manag 2007;12:13-21.
*Guidelines did not distinguish between peripheral and central neuropathic pain.
PDN, painful diabetic neuropathy; TCAs, tricyclic antidepressants; ER, extended release; SNRIs, serotonin-
norepinephrine reuptake inhibitors. Venlafaxine is not approved for the treatment of neuropathic pain.
Guideline 1st line recommendations 2nd line recommendations
The European Federation
of Neurological Societies
(EFNS)1
Pregabalin, gabapentin, TCAs,
duloxetine, venlafaxine ER
Tramadol, opioids, capsaicin
The International
Association for the Study
of Pain (IASP)*2
Pregabalin, gabapentin, TCAs,
duloxetine, venlafaxine,
lidocaine (topical)
Opioid analgesics, tramadol
The Canadian Pain
Society (CPS)*3
Pregabalin, TCAs, gabapentin SNRIs, lidocaine (topical)

32. PDN treatment recommendations:
Philippines
33
Rosales RL, et al. In: Compendium of Philippine Medicine 2009.
Manila: PPD Healthcare Publishing, 2009.
Agent type Reason for recommendation Agents
First tier ≥2 RCTs on PDN, functional
outcomes
Pregabalin, gabapentin, duloxetine
Second tier 1 RCT on PDN; ≥1 RCT on other
painful neuropathies
Venlafaxine XR, oxycodone CR,
tramadol, amitriptyline
Topical Mechanism of action Lidocaine
Other Insufficient evidence for any
recommendation
Alpha-lipoic acid, vitamin B complex,
SSRIs, capsaicin
RCTs, randomized controlled trials; PDN, painful diabetic neuropathy; XR, extended release; CR, controlled release;
SSRIs, selective serotonin reuptake inhibitors. Venlafaxine is not approved for the treatment of neuropathic pain.
There is a paucity of high quality studies on the efficacy of vitamin B complex
for neuropathic pain. Cautious consideration should be made because vitamin B6
in high doses has a potential to induce neuropathy.
The availability and relative affordability of vitamin B complex makes this drug a
frequent choice for treating peripheral neuropathy.

33. Summary of AAN recommendations
Recommended drug and dose Not recommended
Level A • Pregabalin 300–600 mg/day
Level B • Gabapentin 900–3,600 mg/day
• Valproate 500–1,200 mg/day
• Venlafaxine 75–225 mg/day
• Duloxetine 60–120 mg/day
• Amitriptyline 25–100 mg/day
• Dextromethorphan 400 mg/day
• Morphine sulfate, titrated to 120 mg/day
• Tramadol 210 mg/day
• Oxycodone, mean 37 mg/day, maximum
120 mg/day
• Capsaicin 0.075% four times per day
• Isosorbide dinitrate spray
• Electrical stimulation, percutaneous nerve
stimulation for 3–4 weeks
• Oxcarbazepine
• Lamotrigine
• Lacosamide
• Clonidine
• Pentoxifylline
• Mexiletine
• Magnetic field treatment
• Low-intensity laser therapy
• Reiki therapy
34
“Based on consistent Class I evidence, pregabalin is established as effective in lessening the pain
of PDN. If clinically appropriate, pregabalin should be offered for the treatment of PDN (Level A).”
Bril V, et al. Neurology 2011;76:1758-1765.
The AAN recognizes that specific care decisions are the prerogative of the patient and the physician caring for
the patient, based on all of the circumstances involved. Venlafaxine is not approved for the treatment of
neuropathic pain. PDN, painful diabetic neuropathy; AAN, American Academy of Neurology

34. Treatment of PDN: Guidance from the
Toronto Consensus Panel on Diabetic Neuropathy
Consideration of contraindications and comorbidities
First line α2δ agonist
(pregabalin or
gabapentin)
SNRI (duloxetine) TCA
If pain control is inadequate and considering contraindications
Second line TCA or SNRI TCA or α2δ agonist
(pregabalin or
gabapentin)
SNRI or α2δ agonist
(pregabalin or
gabapentin)
If pain control is still inadequate
Third line Add opioid agonist as combination therapy
35
Tesfaye S, et al. Diabetes Metab Res Rev 2011;27:629-638.
PDN, painful diabetic neuropathy; TCA, tricyclic antidepressant; SNRI, serotonin norepinephrine
reuptake inhibitor

35. Although the mechanism of
action of pregabalin is unknown,
it is believed to work in the
cortex and prior to the
ascending pathway to reduce
release of pain-related
neurotransmitters
Pregabalin works differently than
antidepressants and opioids*
Pregabalin works at a different point along the pain pathway compared
with opioids, TCAs and SNRIs
Blocks
Reduces
Dampens
Descending Pathway
Ascending Pathway
Some opioids are believed
to work in the brain to block
pain perception1
1. Way WL, et al. In: Basic & Clinical Pharmacology, 8th ed. New York,
NY: Lange Medical Books/McGraw-Hill; 2001:513.
2. Smith T, et al. Vasc Health Risk Manag 2007;3(6):833–844.
TCAs and SNRIs are
believed to dampen pain
signals by increasing
availability of norepinephine
and serotonin within the
descending pathway2
Pain
Perception
Pain
Stimulus
*These findings are derived from work in preclinical experimental
animal models. The clinical significance in humans is currently
unknown.
TCA, tricyclic antidepressant; SNRI, serotonin-norepinephrine
reuptake inhibitor.

36. In clinical trials, pregabalin provided pain relief
in patients with PDN
37
39%
13%
0
5
10
15
20
25
30
35
40
45
Pregabalin Placebo
Meanchangeinpainscore(%)
frombaselinetoendpoint
*
(n=76) (n=70)
300 mg/day
Pregabalin provided greater pain relief vs placebo in an 8-week study
Rosenstock J, et al. Pain 2004;110:628–638.
*p=0.0001
Painrelief
PDN, painful diabetic neuropathy

37. Pregabalin reduced pain by half
in more than 40% of patients
38
 Efficacy was also demonstrated at the 30% responder rate1
 30% reduction is considered clinically meaningful pain reduction3
16%
42%
0 10 20 30 40 50
Patients (%)
*
*p=0.0002
In a 5-week study, PDN patients had their pain cut in half (50% responder rate)1,2
1. Data on file. Pooled logistic regression of BOCF pain responders (50% and ≥30% response) at endpoint (DPN study 1008-029).
Pfizer Inc, New York, NY. 2. Lesser H, et al. Neurology 2004;63:2104–2110. 3. Farrar JT, et al. Pain 2001;94:149–158.
Pregabalin
300 mg/day
(n=81)
Placebo
(n=97)
PDN, painful diabetic neuropathy

38. Pregabalin: Efficacy in patients with PDN
39
 Pooled data from 7 randomized, double-blind, placebo-controlled trials showed that
pregabalin significantly reduced pain associated with diabetic peripheral neuropathy
 Pain reductions were positively correlated with dosage
 Pain-related sleep interference was also significantly improved
-3
0
-1.5
-2.5
-1
Placebo
(n=550)
Pregabalin
150 mg/day
(n=175)
Pregabalin
300 mg/day
(n=265)
Pregabalin
600 mg/day
(n=507)
Endpointleast-squares
meanchangeinpainscores
-2
-0.5
-1.49
-2.05*
-2.36†
-2.75†
*p=0.007 vs placebo
†p<0.0001 vs placebo
Freeman R, et al. Diabetes Care 2008;31:1448-1454.
PDN, painful diabetic neuropathy

39. Freynhagen R, et al. Pain 2005;115:254-263.
Efficacy in peripheral neuropathic pain:
Flexible-dose study
40
4
10
5
5 8 12
Least-squaresmeanpainscore
7
*p<0.05 , **p≤0.01, 150-600 mg/day
†p<0.05, ††p≤0.01, 600 mg/day vs placebo
0
1110976431 2
Week
Placebo
(n=65)
Pregabalin 150-600 mg/day
(n=141)
Pregabalin 600 mg/day
(n=132)
Baseline Endpoint
9
8
6
3
2
†
*
†
†
*
†
†
**
†
†
**
††
**
†
†
**
†
†
**
††
**
††
**
††
**
††
**
†
†
**
††
1
In an 12-week study, both flexible- and fixed-dose pregabalin
significantly reduced endpoint mean pain score versus placebo

40. Chinese patients with PDN or PHN:
Improvement in pain with pregabalin
0
1
2
3
4
5
6
7
Placebo (n=102) Pregabalin (n=206)
Meanpainscore
Baseline Endpoint
41
*
* p=0.005
Guan Y, et al. Clin Ther 2011;33(2):159-166.

41. Chinese patients with PDN or PHN:
Responder rates with pregabalin
0
10
20
30
40
50
60
70
80
Placebo (n=102) Pregabalin (n=206)
%ofpatients
42
* p=0.041
Responders with a 30% reduction in mean pain score at endpoint
52%
64%
*
Guan Y, et al. Clin Ther 2011;33(2):159-166.

42. Pregabalin:
Efficacy in Japanese patients with PDN
-3
-2
-1
0
Placebo (n=135)
Pregabalin 300 mg/day
(n=134)
Pregabalin 600 mg/day
(n=45)
Weeklymeanpainscores
meanchangefrombaseline
43
***
*p<0.05, **p<0.01 vs placebo
Satoh J, et al. Diabet Med 2011;28(1):109-116.

43. -13.38
-21.88
-15.53
-10.72
-6.92
-9.43
-18.84
-13.39
-12.56
-5.93
Pregabalin: Most effective in reducing PDN pain
Snedecor SJ, et al. Pain Pract 2014;14:167-184.
Mean VAS reduction over placebo (95% CrI)
Topiramate
Oxcarbazepine
Lacosamide
Venlafaxine
Zonisamide
Capsaicin (topical 0.075%)
Gabapentin
Tramadol
Amitriptyline
Mexiletine
Pregabalin ≥300 mg
-10.0-20.0-30.0 0.0
-3.09
Favors placeboFavors treatment
PDN, painful diabetic neuropathy;
VAS, visual analog scale;
CrI, credible interval
44

44. Pregabalin helped patients with PDN feel better
45
Results based on
pregabalin 300 mg/day,
according to the Patient
Global Impression of
Change (PGIC), a
secondary endpoint
measure1
11%
5%
34%
15%
56%
80%
0
20
40
60
80
100
Any Worsening No Change Any Improvement
**p=0.001
Patients(%)
1. Lesser H, et al. Neurology 2004;63:2104–2110.
In a 5-week study, pregabalin helped the majority of patients feel better1
Pregabalin 300 mg/day
divided 3 times daily
(n=79)
Placebo
(n=95)
PDN, painful diabetic neuropathy
5%
Any worsening No change Any improvement

45. Pregabalin:
Effect on the components of the triad of pain
46
*p<0.0001 vs baseline
Baron R et al. Eur J Pain 2008;12:850-858.
-50
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
Reductioninmeanscore(%)
-0
Reductioninmeanscore(%)
-50
-5
-10
-20
-15
-25
-30
-35
-40
-45
Pain Sleep Anxiety
-39.7%*
-42.3%*-43.1%*

46. Japanese trial
(A0081163)
Pooled data from
Western trials
Placebo
(n=135)
Pooled PGB
(n=179)
Placebo
(n=830)
Pooled PGB
(n=1,637)
Dizziness
AC 9 (6.7%) 44 (24.6%) 45 (5.4%) 376 (23.0%)
TR 9 (6.7%) 43 (24.0%) 34 (4.1%) 338 (20.6%)
Somnolence
AC 12 (8.9%) 46 (25.7%) 32 (3.9%) 219 (13.4%)
TR 11 (8.1%) 46 (25.7%) 31 (3.7%) 210 (12.8%)
Peripheral edema
AC 8 (5.9%) 27 (15.1%) 56 (6.7%) 168 (10.3%)
TR 6 (4.4%) 23 (12.8%) 46 (5.5%) 131 (8.0%)
Weight gain
AC 5 (3.7%) 24 (13.4%) 13 (1.6%) 115 (7.0%)
TR 3 (2.2%) 20 (11.2%) 9 (1.1%) 97 (5.9%)
Pregabalin safety profile in Japanese patients
similar to that in Western patients
47
Data presented as number of events (% of group)
PGB, pregabalin; AC, all cause; TR, treatment related
Ogawa S, et al. Drug Saf 2012;35:793-806.

47. Pregabalin treatment in Asian patients:
13-weeks of Treatment
Satoh et al. Diabet Med 2011;28:109-116

48. Japanese DPN Study:
Background
49
Study treatment
• Pregabalin 300 and 600 mg/day vs. placebo
• BID dosing
• 13 weeks treatment: 1 week dose escalation, 12 weeks fixed
dose
Baseline characteristics
• 314 patients treated
• Mean age = 61-62 years (35-85)
• Mean duration of DPN: 4.2-4.5 years
• Mean baseline pain score = 6.0-6.1
Satoh et al. Diabet Med. 2011;28(1):109-16.

49. Japanese DPN Study :
Improvement in Pain
-3
-2
-1
0
Placebo (n=135)
Pregabalin 300mg/day
(n=134)
Pregabalin 600mg/day
(n=45)
Meanchangefrombaseline
50
*
**
*P<0.05, **P<0.01 vs. placebo
Satoh et al. Diabet Med. 2011;28(1):109-16.

50. Japanese DPN Study :
Improvement in Pain & Sleep
51
*P<0.05, †P<0.01 vs. placebo
Satoh et al. Diabet Med. 2011;28(1):109-16.

51. Japanese DPN Study :
Key Results
Pain
• Significant improvement in weekly mean pain scores in both
pregabalin treatment groups throughout the study
• ≥50% responders: placebo =21.5%, pregabalin 300 mg/day =
29.1%, pregabalin 600 mg/day = 35.6% (no significant differences)
Sleep
• Significant improvement in weekly mean pain-related sleep
interference scores in both pregabalin treatment groups throughout
the study
• Significant improvements on some MOS-sleep subscales
observed with pregabalin
52
Satoh et al. Diabet Med. 2011;28(1):109-16.

52. Japanese DPN Study : Safety
 The incidence of patients with one or more treatment-
related adverse events in placebo, 300 and 600 mg⁄ day
groups was 36, 57 and 80%, respectively
 Somnolence (26%), dizziness (24%), peripheral oedema
(13%) and increased weight (11%) occurred most
frequently in patients treated with pregabalin and
appeared to be dose related.
 In all treatment groups,most of the adverse events were
reported as mild or moderate
53
Satoh et al. Diabet Med. 2011;28(1):109-16.

53. Summary
54

54. Treat the neuropathic pain associated
with diabetic neuropathy
 Living with diabetes can be deeply overwhelming and it
may lead to PDN1,2
 PDN may complicate diabetes management3
 Pregabalin effectively manages the neuropathic pain
associated with PDN4
 Global and regional guidelines recommend pregabalin in
the treatment of PDN (level A recommendation)5-8
 Other treatment options include gabapentin, amitriptyline
and SNRIs.
55
1. Polonsky WH. Curr Diabetes Rep 2002;2:153–159.
2. American Diabetes Association. Diabetes Care 2011;34(Suppl1):S11–S61.
3. Novak P, et al. J Rehabil Med 2004; 36:249–252.
4. Freeman R, et al. Diabetes Care 2008;31:1448-1454.
5. Attal N et al. Eur J Neurol 2010;17:1113-e88.
6. Dworkin RH et al. Mayo Clin Proc 2010;85(3Suppl):S3-14.
7. Moulin DE et al. Pain Res Manag 2007;12:13-21.
8. Bril V, et al. Neurology 2011;76:1758-1765.

55. Queries/Comments?
THANKS
Email: drsudhirkumar@yahoo.com
Whatsapp: 9866193953
Facebook: http://www.facebook.com/bestneurologist