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Painful Diabetic peripheral neuropathy- Diagnosis and management
DR SUDHIR KUMAR MD DM SENIOR CONSULTANT NEUROLOGIST
APOLLO HOSPITALS, HYDERABAD
Diabetes is a global epidemic
Ref: IDF Atlas 5th Ed Page 1
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.
Epidemiology of diabetes in Asia
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
Pathophysiology of diabetes and its complications
6
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
Diabetes is a lifelong condition associated with serious complications
81. 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.
MA
CR
OVA
SCU
LAR
CO
MPLIC
ATION
SMIC
RO
VASC
ULA
R C
OM
PLIC
ATIO
NS Diabetic
retinopathyLeading causeof blindnessin adults1,2
DiabeticnephropathyLeading cause of endstage renaldisease3,4
Cardiovasculardisease (CVD)
StrokeTwo- to four-fold increase in CV mortality and stroke5
DiabeticneuropathyLeading cause ofnon-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)
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.
Diabetic neuropathy caused significant reductions in HRQoL (Japan)
Tsuji M, et al. Pain Res Treat 2013;2013:318352. 11
Painful diabetic neuropathy (PDN): painful consequence of diabetes
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
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
141. 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
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
15Sadosky A, Hopper J, Parsons B. Patient 2014;7:107-114.
PDN, painful diabetic neuropathy; HCP, healthcare provider
Mechanisms of neuropathic pain in PDN
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.
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 andhyperalgesia (first)
· Loss of sensitivity (later on)· Autonomic symptoms· Predisposes to diabetic
foot disease· Electrophysiology may not
detect nerve damage
PDN, painful diabetic neuropathy
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
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.
2. 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.
Diagnosis and management of PDN
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
HyperalgesiaAllodynia Anesthesia
Negative symptoms(due to deficit of function)1,2
Nervous system dysfunction or damage
Hypoesthesia
HypoalgesiaAnalgesia
1. Baron R, et al. Lancet Neurol 2010;9:807-819. 2. Jensen TS, et al. Eur J Pharmacol 2001;429:1-11. 22
Symptom DefinitionSpontaneous 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
Symptom DefinitionHypoesthesia 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
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
25National 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.
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
261. 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.
‘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.
The inter-relationship between neuropathic pain, sleep and anxiety/depression
28Nicholson B, et al. Pain Med 2004;5(Suppl1):S9-27.
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
291. Corbett CF. Diabetes Educator 2005;31:523-402. Freynhagen R, Bennett MI. BMJ 2009;339:391-395.
PDN, painful diabetic neuropathy
Mechanism-Based Pharmacological Treatment of Neuropathic Pain
Spinal cordNociceptive afferent fiber
SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressantAdapted 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.
Descendingmodulation
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
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.
Recommended treatments for PDN:Summary of key international guidelines
321. 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 recommendationsThe 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)
PDN treatment recommendations: Philippines
33Rosales 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.
Summary of AAN recommendationsRecommended drug and dose Not recommended
Level A • Pregabalin 300–600 mg/dayLevel 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
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 contraindicationsSecond 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
35Tesfaye S, et al. Diabetes Metab Res Rev 2011;27:629-638.
PDN, painful diabetic neuropathy; TCA, tricyclic antidepressant; SNRI, serotonin norepinephrine reuptake inhibitor
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.
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
Mea
n ch
ange
in p
ain
scor
e (%
) fr
om b
asel
ine
to e
nd p
oint *
(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
Pain
relie
f
PDN, painful diabetic neuropathy
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
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)
Pregabalin150 mg/day
(n=175)
Pregabalin300 mg/day
(n=265)
Pregabalin600 mg/day
(n=507)
Endp
oint
leas
t-squ
ares
mea
n ch
ange
in p
ain
scor
es
-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
Freynhagen R, et al. Pain 2005;115:254-263.
Efficacy in peripheral neuropathic pain: Flexible-dose study
40
4
10
5
5 8 12
Leas
t-squ
ares
mea
n pa
in s
core
7
*p<0.05 , **p≤0.01, 150-600 mg/day†p<0.05, ††p≤0.01, 600 mg/day vs placebo
01110976431 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
Chinese patients with PDN or PHN: Improvement in pain with pregabalin
Placebo (n=102) Pregabalin (n=206)0
1
2
3
4
5
6
7 Baseline Endpoint
Mea
n pa
in s
core
41
*
* p=0.005
Guan Y, et al. Clin Ther 2011;33(2):159-166.
Chinese patients with PDN or PHN: Responder rates with pregabalin
Placebo (n=102) Pregabalin (n=206)0
10
20
30
40
50
60
70
80
% o
f pat
ient
s
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.
Pregabalin: Efficacy in Japanese patients with PDN
Placebo (n=135)Pregabalin 300 mg/day (n=134)
Pregabalin 600 mg/day (n=45)
-3
-2
-1
0
Wee
kly
mea
n pa
in s
core
s m
ean
chan
ge fr
om b
asel
ine
43
***
*p<0.05, **p<0.01 vs placebo
Satoh J, et al. Diabet Med 2011;28(1):109-116.
-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
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
Patie
nts
(%)
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/daydivided 3 times daily
(n=79)
Placebo(n=95)
PDN, painful diabetic neuropathy
5%
Any worsening No change Any improvement
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
Red
uctio
n in
mea
n sc
ore
(%)
-0
R e d u c ti o n i n m e a n s c o r e ( % )
-50
-5
-10
-20
-15
-25
-30
-35
-40
-45
Pain Sleep Anxiety
-39.7%*-42.3%*-43.1%*
Japanese trial(A0081163)
Pooled data from Western trials
Placebo
(n=135)Pooled PGB
(n=179)
Placebo
(n=830)Pooled PGB(n=1,637)
DizzinessAC 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%)
SomnolenceAC 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 edemaAC 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 gainAC 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.
Pregabalin treatment in Asian patients:13-weeks of TreatmentSatoh et al. Diabet Med 2011;28:109-116
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.
Japanese DPN Study : Improvement in Pain
Placebo (n=135)Pregabalin 300mg/day
(n=134)Pregabalin 600mg/day
(n=45)
-3
-2
-1
0
Mea
n ch
ange
from
bas
elin
e
50
***
*P<0.05, **P<0.01 vs. placebo
Satoh et al. Diabet Med. 2011;28(1):109-16.
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.
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
52Satoh et al. Diabet Med. 2011;28(1):109-16.
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
53Satoh et al. Diabet Med. 2011;28(1):109-16.
Summary
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.
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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.
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