PAINFUL DIABETIC NEUROPATHY

Transcription

1 PAINFUL DIABETIC NEUROPATHY

2 Content Painful diabetic neuropathy (PDN): painful consequences of diabetes Mechanisms of neuropathic pain in PDN Diagnosis and management of PDN PDN treatment: guidance from experts Addressing central sensitization in PDN Pregabalin efficacy and safety in patients with PDN Pregabalin treatment in Asian patients: 13-weeks of Treatment safety evaluation of pregabalin treatment over 52 Weeks Summary 2

3 Painful diabetic neuropathy (PDN): painful consequences of diabetes 3

4 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 thereafter 1 ~210 million people in the Asia Pacific region have diabetes 2 1 out of 5 patients with diabetes suffer from PDN % to 70% of diabetic patients have diabetic neuropathy 6 Chronic sensorimotor neuropathy Autonomic neuropathy 9 out of 10 patients with PDN report moderate or severe pain 7 PDN, painful diabetic neuropathy 1. American Diabetes Association. Diabetes Care 2011;34(Suppl1):S11 S International Diabetes Federation. IDF Diabetes Atlas, 6th edn. Brussels, Belgium: International Diabetes Federation, Available at: Accessed 19 February Bouhassira D, Letanoux M, Hartemann A. PLoS One 2013;8:e 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: Centers for Disease Control and Prevention. National Diabetes Fact Sheet, Available at: Accessed July 1, Data on file. Wave 2 Consumer DPN ATU Study Pfizer Inc, New York, NY. Focal and multifocal neuropathies 4

5 Neuropathic pain of PDN negatively affects quality of life Pain may significantly interfere with a patient s ability to exercise or walk 1 Walking has been shown to improve HbA 1C in patients with diabetes regardless of change in body mass 2,3 Pain often intensifies at night and may significantly interfere with sleep 4 Sleep debt has been shown to have a negative impact on metabolic and endocrine control 5-7 Pain is significantly correlated with depression in diabetic patients 8 PDN, painful diabetic neuropathy; HbA 1C, glycated hemoglobin 1. Novak P, et al. J Rehabil Med 2004; 36: Boule NG, et al. JAMA 2001;286: American Diabetes Association. Diabetes Care 2011;34(Suppl1):S11 S Quattrini C, et al. Diabetes Metab Res Rev 2003;19:S2 S8. 5. Zelman DC, et al. Clin J Pain 2006;22: Spiegel K, et al. Lancet 1999;354: Å kerstedt T, Nilsson PM. J Intern Med 2003;254: Raval A, et al. Indian J Med Res 2010;132:

6 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 both HCPs and patients report that PDN symptoms can be difficult to describe (69% and 56%, respectively) PDN, painful diabetic neuropathy; HCP, healthcare provider Sadosky A, Hopper J, Parsons B. Patient 2014;7:

7 Mechanisms of neuropathic pain in PDN 7

8 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 Together, these biochemical mechanisms result in structural nerve damage. Lin HC. Diabetic Neuropathy. Available at: / overview#a0104. Accessed 1 June

9 Neuropathic pain associated with diabetic neuropathy: Often due to sensory nerve damage Stocking-and-glove painful sensations are very common 1 While both small and large nerve fibers can be affected, symptoms of PDN typically indicate that small fibers are affected first Small fibers (A and C) 1,2 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 Large fibers (A / ) 1,3 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 1. Vinik AI, et al. In: Diabetes and Carbohydrate Metabolism. [E-textbook] Available at: Accessed November 11, Tavee J, Zhou L. Cleve Clin J Med 2009;76(5): Pittenger G, Vinik A. Experimental Diab Res 2003;4:

10 Small-fiber neuropathy in PDN Loss of small fibers are characterized by reduced density of intraepidermal nerve fibers (IENF) as shown by arrows 1 Arrowheads indicate dermal nerve bundles Length-dependent denervation of skin is particularly seen in distal leg Typical clinical presentation 2 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 HbA 1c levels may have small-fiber neuropathy and experience pain 3 Normal epidermis (A) Proximal thigh (B) Distal leg Diabetic patient with small-fiber neuropathy PDN, painful diabetic neuropathy; HbA 1C, glycated hemoglobin Printed with permission from Macmillan Publishers Ltd: Lauria G, Devigili G. Nat Clin Lauria G, Devigili G. Nat Clin Pract Neurol 2007;3: Pract Neurol. 2007;3: , copyright Tavee J, Zhou L. Cleve Clin J Med 2009;76(5): Tesfaye S, Selvarajah D. Current Diabetes Reports 2009;9:

11 The theory of neuronal plasticity in the pathogenesis of pain Neuronal plasticity describes changes in neuron function, chemical profile or structure as a result of painful stimulation and nerve damage 1 Pain can be the result of these changes 2,3 Neuropathic pain is pain felt in absence of nociceptor stimulation, resulting from lesion or disease affecting the somatosensory system Amplified pain perception results from changes in pain processing in the central nervous system 2,4 Pain amplification is characterized by hyperalgesia and allodynia 3 1. Woolf CJ, Salter MW. Science 2000;288: Costigan M, et al. Annu Rev Neurosci 2009;32: Woolf CJ. Ann Intern Med 2004;140: Staud R. Arthritis Res Ther 2006;8:

12 Diagnosis and management of PDN 12

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

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

15 Negative sensory symptoms of peripheral neuropathy Symptom Hypoesthesia Definition Diminished sensitivity to stimulation Anesthesia Hypoalgesia Analgesia A total loss of sensation (especially tactile sensitivity) Diminished pain in response to a normally painful stimulus Absence of pain in response to stimulation that would normally be painful International Association for the Study of Pain (IASP). IASP Taxonomy. Available at: Accessed 2 August

16 Identifying and quantifying nerve damage in diabetic neuropathy Electromyography 1 Measure of electrical activity generated by muscles Diagnosis is made when there is less electrical activity than normal Skin Biopsy 2,3 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. American Diabetes Association. Available at: Accessed June 28, Lauria G, Devigili G. Nat Clin Pract Neurol 2007;3: Smith AG, et al. Diabetes Care 2006;29: Tavee J, Zhou L. Cleve Clin J Med 2009;76(5):

17 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 National Institute of Diabetes and Digestive and Kidney Diseases. Diabetic Neuropathies: The Nerve Damage of Diabetes. Available from: Accessed 15 Jul

18 Examining a diabetic patient with pain: Taking a pain history Question the patient about his/her pain 1 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 pain 2 1. Haanpää ML et al. Am J Medicine 2009;122(10 Suppl):S Gilron I et al. Can Med Assoc J 2006;175: Baron R, et al. Lancet Neurol 2010;9:

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

20 Examining a diabetic patient with pain: Assess for sensory and/or physical abnormalities Inspect painful body area and compare with corresponding healthy area: 1 Differences in color, temperature, sweating 2 Conduct simple bedside tests to confirm sensory abnormalities: 1 3 Gauze or a piece of cotton wool Pinprick Pinch Thermal (hot or cold object) Pain when straight leg is raised 1. Haanpää ML et al. Am J Medicine 2009;122(10 Suppl):S Gilron I et al. Can Med Assoc J 2006;175: Baron R, et al. Lancet Neurol 2010;9:

21 Examining a diabetic patient with pain: Assess pattern of sensory impairment In diabetic neuropathy, sensorimotor impairment may occur in a stockingand-glove pattern 1,2 1. Boulton AJ et al. Diabetes Care 2004;27: Boulton AJ et al. Diabetes Care 2005;28:

22 Neuropathic pain screening tools Name Description Sensitivity* Specificity* Author & year LANSS NPQ DN4 5 symptom items and 2 clinical examination items 10 sensory-related items and 2 affect items 7 symptom items and 3 clinical examination items 82-91% 80-94% Bennett, % 74% Krause, % 90% Bouhassira, 2005 paindetect 7 sensory items and 2 spatial characteristics items ID-Pain 5 sensory items and 1 pain location 85% 80% Freynhagen, 2006 NR NR Portenoy, 2006 *Compared with clinical diagnosis. LANSS, Leeds Assessment of Neuropathic Symptoms and Signs; NPQ, Neuropathic Pain Questionnaire; DN4, Douleur neuropathic en 4 questions; NR, not reported Bennett MI et al. Pain 2007;127:

23 Examining a diabetic patient with pain: Making a differential diagnosis Are verbal descriptors suggestive of neuropathic pain? 1 Yes No Can you detect sensory abnormalities using simple bedside tests? 1-3 Yes Probable nociceptive pain No Consider specialist referral and, if neuropathic pain is still suspected, consider treatment in the interim period 3 Can you identify the responsible nervous system lesion/dysfunction? 3 No Yes Neuropathic pain syndrome likely: Initiate treatment 3 1. Freynhagen R, Bennett MI. BMJ 2009;339: Haanpää ML et al. Am J Medicine 2009;122(10 Suppl):S

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

25 Treatment of PDN Treatment of PDN is both preventative and symptomatic, and is based on: 1. Stabilizing glycemic levels 1 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 PDN, painful diabetic neuropathy 1. Corbett CF. Diabetes Educator 2005;31: Freynhagen R, Bennett MI. BMJ 2009;339:

26 Pharmacological treatments for PDN: Hypothesized mechanisms of action Predominant mechanism Binding to α2δ subunit of voltage-dependent calcium channels with reduced release of transmitters Dual serotonin/noradrenaline reuptake inhibition μ-opioid (or К 2 -opioid) receptor agonist Voltage-gated sodium channel inhibition Voltage-gated sodium-channel block; inhibition of glutamate release via activity at AMPA/kainate receptors Increase of GABA levels in brain and potentiation of GABA-mediated responses NMDA (N-methyl-D-aspartate) antagonists Drugs pregabalin, gabapentin amitriptyline, nortriptyline, duloxetine, imipramine, venlafaxine oxycodone; tramadol (also has monoamine reuptake inhibition) lamotrigine, carbamazepine, oxcarbazepine topiramate valproate memantine; dextromethorphan (weak) PDN, painful diabetic neuropathy. Venlafaxine is not approved for the treatment of neuropathic pain. 1. Zin CS, et al. CNS Drugs 2008;22: Attal N, et al. Eur J Neurol 2010;17:1113-e88. 26

27 Non-pharmacological treatment of neuropathic pain Given their presumed safety, non-pharmacological treatments should be considered whenever appropriate 1 In general, non-pharmacological treatment is complementary to drug therapy 2 Non-pharmacological treatment options include: 2 Physiotherapy Pain management programs Acupuncture Transcutaneous electrical nerve stimulation (TENS) 1. Gilron I et al. Can Med Assoc J 2006;175: Bennett MI, Closs SJ. Pain Clinical Updates 2010;18:

28 PDN treatment: guidance from experts 28

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

30 PDN treatment recommendations: Hong Kong The Multidisciplinary Panel on Neuropathic Pain. Handbook of Neuropathic Pain Management Guidelines. Hong Kong: UBM Medica,

31 PDN guidelines: Singapore Yeo A, et al. Pain Management Guidelines for General Practitioners Singapore: Pfizer Pte Ltd,

32 PDN treatment recommendations: Philippines Agent type Reason for recommendation Agents First tier Second tier 2 RCTs on PDN, functional outcomes 1 RCT on PDN; 1 RCT on other painful neuropathies Topical Mechanism of action Lidocaine Pregabalin, gabapentin, duloxetine Venlafaxine XR, oxycodone CR, tramadol, amitriptyline 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. The availability and relative affordability of vitamin B complex makes this drug a frequent choice for treating peripheral neuropathy. 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. Rosales RL, et al. In: Compendium of Philippine Medicine Manila: PPD Healthcare Publishing,

33 Treatment of PDN: Guidance from the AAN Joint report of the American Academy of Neurology (AAN), the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation Report designates pregabalin as the only Level A recommendation, citing robust evidence of its efficacy in the treatment of PDN Level B recommendations ( probably effective and should be considered ) included gabapentin, duloxetine, amitriptyline and transcutaneous electric nerve stimulation 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. Bril V, et al. Neurology 2011;76:

34 Summary of AAN recommendations Level A Level B Recommended drug and dose Pregabalin mg/day Gabapentin 900 3,600 mg/day Valproate 500 1,200 mg/day Venlafaxine mg/day Duloxetine mg/day Amitriptyline 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 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: Lyrica maximum dose for PDN treatment in Taiwan is 300mg/day Not recommended Oxcarbazepine Lamotrigine Lacosamide Clonidine Pentoxifylline Mexiletine Magnetic field treatment Low-intensity laser therapy Reiki therapy Gabapentin and venlafaxine are not approved for the treatment of neuropathic pain. 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

35 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) If pain control is inadequate and considering contraindications Second line TCA or SNRI TCA or α2δ agonist (pregabalin or gabapentin) If pain control is still inadequate Third line Add opioid agonist as combination therapy TCA SNRI or α2δ agonist (pregabalin or gabapentin) PDN, painful diabetic neuropathy; TCA, tricyclic antidepressant; SNRI, serotonin norepinephrine reuptake inhibitor Gabapentin is not approved for the treatment of neuropathic pain. Tesfaye S, et al. Diabetes Metab Res Rev 2011;27:

36 Addressing central sensitization in PDN 36

37 Central sensitization: Underlying cause of amplified pain perception associated with PDN Central sensitization is believed to be the underlying cause of amplified pain perception that results from dysfunction in the CNS 1,2 This is believed to result from excessive release of two important neurotransmitters, substance P and glutamate 3 Neurotransmitters (eg, substance P, glutamate) Excessive neurotransmitter release in hyperexcited neuron Presynaptic Ca 2+ channel Ca 2+ ion PDN, painful diabetic neuropathy; CNS, centralnervous system Postsynaptic 1. Costigan M, et al. Annu Rev Neurosci 2009;32: Staud R. Arthritis Res Ther [serialonline] 2006;8: Costigan M, et al. In: Siegel GJ, et al, eds. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 7 th ed. Burlington, MA: Elsevier Academic Press;2006:

38 Pregabalin is believed to impact central sensitization Binds with high affinity to α2δ subunit of voltage-gated calcium channels at dorsal horn Reduces excessive calciumdependent release of substance P and glutamate Although exact mechanism of action of pregabalin is unknown, results from animal models suggest binding to α2δ subunit may be associated with anti-hyperalgesic and antiallodynic effects of pregabalin Pregabalin reduces excessive neurotransmitter release Presynaptic Neurotransmitters (eg, substance P, glutamate) PREGABALIN Postsynaptic Ca 2+ ion α2δ subunit Ca 2+ channel The clinical significance of these observations in humans is currently unknown Costigan M, et al. In: Siegel GJ, et al, eds. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 7 th ed. Burlington, MA: Elsevier Academic Press;2006:

39 Pregabalin works differently than antidepressants and opioids* Pregabalin works at a different point along the pain pathway compared with opioids, TCAs and SNRIs Dampens Pain Perception Blocks TCAs and SNRIs are believed to dampen pain signals by increasing availability of norepinephine and serotonin within the descending pathway 2 *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. Descending Pathway Pain Stimulus Ascending Pathway Some opioids are believed to work in the brain to block pain perception 1 Reduces 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 1. Way WL, et al. In: Basic & Clinical Pharmacology, 8th ed. New York, NY: Lange Medical Books/McGraw-Hill; 2001: Smith T, et al. Vasc Health Risk Manag 2007;3(6):

40 Pregabalin efficacy and safety in patients with PDN 40

41 Pain relief Mean change in pain score (%) from baseline to end point In clinical trials, pregabalin provided pain relief in patients with PDN Pregabalin provided greater pain relief vs placebo in an 8-week study * 39% *p= PDN, painful diabetic neuropathy 5 0 Rosenstock J, et al. Pain 2004;110: (n=76) Pregabalin 300 mg/day 13% (n=70) Placebo 41

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

43 Endpoint least-squares mean change in pain scores Pregabalin: Efficacy in patients with PDN Lyrica maximum dose for PDN treatment in Taiwan is 300mg/day 0 Placebo (n=550) Pregabalin 150 mg/day (n=175) Pregabalin 300 mg/day (n=265) Pregabalin 600 mg/day (n=507) *p=0.007 vs placebo p< vs placebo -2.05* 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 PDN, painful diabetic neuropathy Freeman R, et al. Diabetes Care 2008;31:

44 Least-squares mean pain score Efficacy in peripheral neuropathic pain: Flexible-dose study Baseline * *p<0.05, **p 0.01, mg/day p<0.05, p 0.01, 600 mg/day vs placebo 1 2 * 3 ** 4 Lyrica maximum dose for PDN treatment in Taiwan is 300mg/day In an 8-week study, both flexible- and fixed-dose pregabalin significantly reduced endpoint mean pain score versus placebo ** ** ** ** ** ** ** Placebo (n=65) Week Pregabalin mg/day (n=141) Pregabalin 600 mg/day (n=132) ** ** Endpoint Freynhagen R, et al. Pain 2005;115: ( Maximum dose for DPNP treatment in Taiwan is 300mg/day ) 44

45 Weekly mean pain scores mean change from baseline Pregabalin: Efficacy in Japanese patients with PDN Lyrica maximum dose for PDN treatment in Taiwan is 300mg/day 0 Placebo (n=135) Pregabalin 300 mg/day (n=134) Pregabalin 600 mg/day (n=45) -1-2 ** * -3 *p<0.05, **p<0.01 vs placebo Satoh J, et al. Diabet Med 011;28(1):

46 Pregabalin: Efficacy up to 52 weeks in Japanese patients with PDN PDN, painful diabetic neuropathy; VAS, visual analog scale; PPI, present pain intensity Satoh J, et al. J Diabetes Invest 2011;6:

47 Pregabalin: Most effective in reducing PDN pain No head-to-head comparison study was conducted in those products PDN, painful diabetic neuropathy; VAS, visual analog scale; CrI, credible interval Pregabalin 300 mg Mexiletine Amitriptyline Tramadol Gabapentin Capsaicin (topical 0.075%) Zonisamide Venlafaxine Lacosamide Oxcarbazepine Topiramate Mean VAS reduction over placebo (95% CrI) Snedecor SJ, et al. Pain Pract 2014;14: Favors treatment Favors placebo 47

48 Patients (%) Pregabalin helped patients with PDN feel better In a 5-week study, pregabalin helped the majority of patients feel better 1, % *p= % Placebo (n=95) 56% 5% 5% 15% * 80% Pregabalin 300 mg/day divided 3 times daily (n=79) Results based on pregabalin 300 mg/day, according to the Patient Global Impression of Change (PGIC), a secondary endpoint measure 1,2 Any worsening Worsening No change Change Any improvement Improvement PDN, painful diabetic neuropathy 1. Data on file. pdpn trial of 3 dosages of pregabalin. Protocol Pfizer Inc, New York, NY. 2. Lesser H, et al. Neurology 2004;63:

49 Reduction Reduction in in mean mean score score (%) (%) Pregabalin: Effect on the components of the triad of pain Open-label, non-comparative, flexible-dose study Pain Sleep Anxiety %* -43.1%* -42.3%* *p< vs baseline Baron R et al. Eur J Pain 2008;12:

50 Pregabalin: Warnings and precautions summary* Angioedema (eg, swelling of throat, head and neck) can occur, and may be associated with life-threatening respiratory compromise requiring emergency treatment. Pregabalin should be discontinued immediately in these cases Hypersensitivity reactions (eg, hives, dyspnea, and wheezing) can occur. Pregabalin should be discontinued immediately in these patients Increased seizure frequency may occur in patients with seizure disorders if pregabalin is rapidly discontinued. Withdraw pregabalin gradually over minimum of 1 week Antiepileptic drugs, including pregabalin, increase risk of suicidal thoughts or behavior Pregabalin may cause peripheral edema. Exercise caution when co-administering pregabalin and thiazolidinedione antidiabetic agents Pregabalin may cause dizziness and somnolence and impair patients ability to drive or operate machinery LYRICA (pregabalin) capsules [package insert]. New York, NY: Pfizer Inc, December Please refer to your local approved prescribing information. 50

51 Incidence (%) of most common* adverse events in pregabalin PDN studies PGB 150 mg/day (n=212) PGB 300 mg/day (n=321) PGB 600 mg/day (n=369) PGB all doses (n=979) Placebo (n=459) Dizziness Somnolence Peripheral edema Asthenia Dry mouth Blurry vision Constipation Weight gain *Incidence 4% and at least twice the rate observed with placebo. PDN, painful diabetic neuropathy. Includes 75 mg/day group. Investigator term; summary level term is amblyopia. Please refer to your local approved prescribing information. Lyrica maximum dose for PDN treatment in Taiwan is 300mg/day LYRICA (pregabalin) capsules [package insert]. New York, NY: Pfizer Inc, December ( Maximum dose for DPNP treatment in Taiwan is 300mg/day ) 51

52 Manage patient expectations when prescribing pregabalin Lyrica maximum dose for PDN treatment in Taiwan is 300mg/day Two of the most common adverse reactions in controlled PDN/PHN trials Placebo (n=857) PGB 150 mg/day (n=514) PGB 300 mg/day (n=633) PGB 600 mg/day (n=523) PGB all doses (n=1,831) Dizziness 7% 14% 27% 31% 23% Somnolence 4% 10% 16% 19% 14% If present, dizziness and somnolence typically occurred early and were often transient and dose-related; in some patients, dizziness and somnolence persisted throughout the course of treatment PGB, pregabalin; PDN, painful diabetic neuropathy; PHN, postherpetic neuralgia. Pregabalin was administered in divided doses, given twice or 3 times daily. Includes all doses of pregabalin that were studied in PDN and PHN (eg, 75 mg/day). Please refer to your local approved prescribing information. LYRICA (pregabalin) capsules [package insert]. New York, NY: Pfizer Inc, December ( Maximum dose for DPNP treatment in Taiwan is 300mg/day ) 52

53 Pregabalin safety profile in Japanese patients similar to that in Western patients Dizziness Somnolence Peripheral edema Weight gain Placebo (n=135) Japanese trial (A ) Pooled PGB (n=179) Pooled data from Western trials Placebo (n=830) Pooled PGB (n=1,637) AC 9 (6.7%) 44 (24.6%) 48 (5.4%) 376 (23.0%) TR 9 (6.7%) 43 (24.0%) 34 (4.1%) 338 (20.6%) 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%) 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%) 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%) Data presented as number of events (% of group) PGB, pregabalin; AC, all cause; TR, treatment related Ogawa S, et al. Drug Saf 2012;35:

54 Weight gain in clinical trials Pregabalin-treated diabetic patients gained an average of 1.6 kg, compared to an average 0.3 kg weight gained in placebo patients 1 Weight gain appeared to be dose- and duration-related Effects of pregabalin-associated weight gain on glycemic control have not been systematically assessed In accordance with current clinical practice, some diabetic patients who gain weight on pregabalin treatment may need to adjust hypoglycemic medicinal products 2 In clinical trials with diabetic patients, pregabalin treatment did not appear to be associated with loss of glycemic control (as measured by HbA 1c ) 1 Weight gain was not associated with clinically important changes in blood pressure in these studies; the long-term cardiovascular effects of pregabalin-associated weight gain are unknown 1 HbA 1C, glycated hemoglobin 1. LYRICA (pregabalin) capsules [package insert]. New York, NY: Pfizer Inc, December LYRICA (pregabalin) Summary of Product Characteristics. Kent: Pfizer Ltd, February

55 Pregabalin has low potential for pharmacokinetic drug interactions (I) Drug interactions are an important consideration for patients with diabetes who are taking multiple medications Medications having low potential for pharmacokinetic interactions with pregabalin* Insulin Antidiabetics Opioids Benzodiazepines Oral Antiepileptic contraceptives Diuretics drugs Glyburide Oxycodone Lorazepam Ethinyl estradiol Furosemide Carbamazepine Metformin Norethindrone Lamotrigine Phenobarbital Phenytoin Tiagabine Topiramate Valproic acid Pregabalin may exacerbate the effects of oxycodone, lorazepam or ethanol on cognitive and gross motor functioning *Confirmed in vivo and/or in vitro studies. Based on a population pharmacokinetic analysis. Please refer to your local approved prescribing information. LYRICA (pregabalin) capsules [package insert]. New York, NY: Pfizer Inc, December

56 Pregabalin has low potential for pharmacokinetic drug interactions (II) No blood monitoring required for patients taking pregabalin Is not associated with loss of glycemic control, as measured by HbA 1c Does not inhibit or induce major CYP450 enzymes Negligibly hepatically metabolized Is renally excreted as unchanged drug Not protein bound HbA 1C, glycated hemoglobin Please refer to your local approved prescribing information LYRICA (pregabalin) capsules [package insert]. New York, NY: Pfizer Inc, December

57 Pregabalin has predictable absorption across its dosing range Pregabalin Gabapentin Pregabalin displays linear plasma absorption 1 Plasma concentration is dose proportional Gabapentin, in contrast, displays saturable absorption Low intersubject variability 2 Oral bioavailability is 90%, regardless of dose 1 1. Brockbrader HN, et al. Clin Pharmacokinet 2010;49: ; 2. Sabatowski R, et al. Pain 2004;109:

58 Pregabalin provides flexible dosing within the approved dosing range Diagnosis of PDN Start with 150 mg/day (75 mg twice daily) Increase to 300 mg/day within 1 week if needed Selected safety information 150 mg per day Pregabalin should be discontinued gradually over a minimum of 1 week 300 mg per day Pregabalin should be discontinued immediately in patients with symptoms of hypersensitivity or angioedema Patients with a creatinine clearance of 30 to 60 ml/min had a greater incidence of discontinuation due to adverse reactions than patients with normal creatinine clearance Cases of abuse have been reported. Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of pregabalin abuse Please refer to your local approved prescribing information 1. LYRICA (pregabalin) capsules [package insert]. New York, NY: Pfizer Inc, December LYRICA (pregabalin) Summary of Product Characteristics. Kent: Pfizer Ltd, February ( Maximum dose for DPNP treatment in Taiwan is 300mg/day ) 58

59 Pregabalin dose adjustment based on renal function Creatinine clearance (CLcr) (ml/min) Total pregabalin daily dose (mg/day)* Dose regimen BID or TID BID or TID QD or BID < QD Supplementary dosage following hemodialysis (mg) Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the mg QD regimen: take one supplemental dose of 75 mg or 100 mg Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg TID, 3 divided doses; BID, 2 divided doses; QD, single daily dose. *Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. Supplementary dose is a single additional dose. Please refer to your local approved prescribing information. LYRICA (pregabalin) capsules [package insert]. New York, NY: Pfizer Inc, December ( Maximum dose for DPNP treatment in Taiwan is 300mg/day ) 59

60 Manage patient expectations Remind your patients that: Pregabalin is not a PRN pain medication; it must be taken as prescribed Some patients may see improvement within 1 week, while it may take longer for others Pregabalin dose may be adjusted within approved dose range: 150 mg/day starting dose for PDN May be increased to 300 mg/day as early as 1 week if needed Maximum dose 300 mg/day for PDN Pregabalin may cause adverse reactions. Discuss: Common reactions and what to do if they occur How they should not stop taking pregabalin abruptly PDN, painful diabetic neuropathy 60

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

62 Japanese DPN Study: Background 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 = years (35-85) Mean duration of DPN: years Mean baseline pain score = Lyrica maximum dose for PDN treatment in Taiwan is 300mg/day Satoh et al. Diabet Med. 2011;28(1):

63 Mean change from baseline Japanese DPN Study : Improvement in Pain Lyrica maximum dose for PDN treatment in Taiwan is 300mg/day 0 Placebo (n=135) Pregabalin 300mg/day (n=134) Pregabalin 600mg/day (n=45) -1-2 ** * -3 *P<0.05, **P<0.01 vs. placebo Satoh et al. Diabet Med. 2011;28(1):

64 Japanese DPN Study : Improvement in Pain & Sleep Lyrica maximum dose for PDN treatment in Taiwan is 300mg/day *P<0.05, P<0.01 vs. placebo Satoh et al. Diabet Med. 2011;28(1):

65 Japanese DPN Study : Key Results Lyrica maximum dose for PDN treatment in Taiwan is 300mg/day 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 Satoh et al. Diabet Med. 2011;28(1):

66 Japanese DPN Study : Safety Lyrica maximum dose for PDN treatment in Taiwan is 300mg/day The incidence of patients with one or more treatmentrelated 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 Satoh et al. Diabet Med. 2011;28(1):

67 Japanese DPN Study : Treatment-related Adverse Events Occurring Lyrica maximum dose for PDN treatment in Taiwan is 300mg/day In >3% Of Any Treatment Group And Discontinuations Adverse event; n (%) Placebo (n = 135) Pregabalin 300 mg/day (n=134) Pregabalin 600 mg/day (n=45) Incidence Discont'n Incidence Discont'n Incidence Discont'n Somnolence 11 (8.1) 0 28 (20.9) 0 18 (40.0) 2 (4.4) Dizziness 9 (6.7) 2 (1.5) 26 (19.4) 3 (2.2) 17 (37.8) 5 (11.1) Peripheral oedema 6 (4.4) 0 17 (12.7) 0 6 (13.3) 0 Weight increased 3 (2.2) 0 15 (11.2) 1 (0.7) 5 (11.1) 0 Constipation 1 (0.7) 0 4 (3.0) 0 2 (4.4) 0 Oedema 1 (0.7) 0 3 (2.2) 0 2 (4.4) 1 (2.2) Face oedema (3.7) 0 1 (2.2) 0 Blood creatine phosphokinase increased (1.5) 0 2 (4.4) 0 Hot flush 1 (0.7) 0 1 (0.7) 0 2 (4.4) 0 Muscular weakness (4.4) 0 Satoh et al. Diabet Med. 2011;28(1):

68 Pregabalin treatment in Asian patients: safety evaluation of pregabalin treatment over 52 Weeks Satoh et al. J Diabetes Invest 2011;6:

69 Pregabalin effective in DPN Japanese Study 52 weeks: Background Lyrica maximum dose for PDN treatment in Taiwan is 300mg/day Study treatment Pregabalin 150 to 600 mg/day vs. placebo BID dosing Patients who had completed 13 weeks of Tx in the preceding study were enrolled to an open label study Baseline characteristics 123 patients treated Mean age = 61.7 years (36-85) Mean duration of DPN: 4.4 years Mean baseline pain score = 7.4 Satoh et al. J Diabetes Invest 2011;6:

70 Pregabalin effective in DPN Japanese Study 52 weeks: Improvement in Pain (mm) Baseline Baseline 4 4 VAS value Mean ± SD At final evaluation Week PPI score Mean ± SD At final evaluation Week Satoh et al. J Diabetes Invest 2011;6:

71 Pregabalin Japanese DPN Study 52 weeks: Most Frequent Treatment-Associated Adverse Events Nº Subjects included in safety evaluation Incidence >3% 123 % Nº Subjects with adverse event (%) 87 (70.7) Somnolence 28 (22.8) Weight gain 27 (22.0) Dizziness 25 (20.3) Peripheral edema 19 (15.4) Face edema 8 (6.5) Edema 6 (4.9) Satoh et al. J Diabetes Invest 2011;6:

72 Pregabalin effective in DPN Japanese Study 52 weeks: Conclusion Improvements continued during 52 week treatment period; suggesting a long-term analgesic effect of pregabalin. 30 and 50% improvement rates in VAS value from baseline (a well-known efficacy measurement method) were 65.9 and 56.1%, respectively which supported the efficacy of pregabalin Somnolence, weight gain, dizziness and peripheral edema occurred as treatment-related adverse events, but they were of mild to moderate severity and did not result in study discontinuation in most subjects No new concerns about safety as a result of long-term administration of pregabalin were identified The findings from this trial suggest that long-term treatment with pregabalin is beneficial for pain relief in patients with DPN Satoh et al. J Diabetes Invest 2011;6:

73 Summary 73

74 Treat the neuropathic pain associated with diabetic neuropathy Living with diabetes can be deeply overwhelming and it may lead to PDN 1,2 PDN may complicate diabetes management 3 Pregabalin effectively manages the neuropathic pain associated with PDN 4 Global and regional guidelines recommend pregabalin in the treatment of PDN (level A recommendation) 5-8 PDN, painful diabetic neuropathy 1. Polonsky WH. Curr Diabetes Rep 2002;2: American Diabetes Association. Diabetes Care 2011;34(Suppl1):S11 S Novak P, et al. J Rehabil Med 2004; 36: Freeman R, et al. Diabetes Care 2008;31: Attal N et al. Eur J Neurol 2010;17:1113-e Dworkin RH et al. Mayo Clin Proc 2010;85(3Suppl):S Moulin DE et al. Pain Res Manag 2007;12: Bril V, et al. Neurology 2011;76: