1. Diabetic Neuropathy

3. Nociceptive vs Neuropathic Pain Mixed Type Caused by a combination of both primary injury and secondary effects Nociceptive Pain Caused by activity in neural pathways in response to potentially tissue-damaging stimuli Neuropathic Pain Initiated or caused by primary lesion or dysfunction in the nervous system Postoperative pain Mechanical low back pain Sickle cell crisis Arthritis Postherpetic neuralgia Neuropathic low back pain CRPS* Sports/exercise injuries *Complex regional pain syndrome Central post- stroke pain Trigeminal neuralgia Distal polyneuropathy (eg, diabetic, HIV)

11. Management of Diabetic Neuropathy

12. Goals of Neuropathic Pain Management Treat/prevent recurrence of pain-causing condition Reduce pain Improve physical/psychologic function Improve quality of life

13. Diabetic Neuropathy- Pain Assessment Scales

15. DIABETIC NEUROPATHY MANAGEMENT - ALGORITHM

16. APPROACHES TO THE MANAGEMENT OF NEUROPATHIC PAIN Monotherapy Combinations Additional Measures First-line TCA Low-dose TCA+ AE Paracetamol Acupuncture Physiotherapy Anti-epileptic (AE) Second-line Alternative antidepressant Opioid with TCA or AE Opioid Capsaicin Third-line Alternative opioids Intrathecal drug delivery Neuromodulation

17. Management of Diabetic Peripheral Neuropathy Managing Neuropathic Pain: New Approaches For Today's Clinical Practice Charles E. Argoff, MD, www.medscape.com Parameters Significance Tight glucose control Can reverse the changes but only if the neuropathy and diabetes is recent in onset. Tricyclic antidepressants (TCA’s) e.g. Amitriptyline, Nortriptyline Effective but suffer from multiple side effects that are dosage dependent Serotonin reuptake inhibitor (SSRI’s) e.g. Fluoxetine, Paroxetine, Sertraline and Citalopram FDA not approved, no more efficacious than placebo in several controlled trials. Antiepileptic drugs (AED’s) e.g. Gabapentin & Pregabalin Emerging as first line treatment for painful neuropathy. Methylcobalamin Exerts neuroprotective effects, regenerates myelin sheath

18. Latest Guidelines on Neuropathy Management Neurology® 2011;76:1–1

19. Summary of Recommendations

21. Pregabalin in the management of DPNP

22. How does Pregabalin work??? Pregabalin binds with high affinity to the alpha2-delta site ( voltage-gated calcium channels) in Neurons Reduces the calcium-dependent release of several neurotransmitters (Glutamate , Substance P) Increases neuronal GABA levels Reduces neuropathic pain & also exerts anticonvulsive and anxiolytic effects

27. Results – Weekly least-squares mean pain scores Improvement in the Pregabalin group was evident at week 1 and this improvement was maintained at every weekly time point through week 13 Research article, Joseph C Arezzo* et.al, BMC Neurology 2008, 8:33 doi:10.1186/1471-2377-8-33

28. Results – Responder rate 49% patients in Pregabalin group responded to ≥50% reduction in mean pain score from baseline to endpoint as compared to 23% in placebo group. Research article, Joseph C Arezzo* et.al, BMC Neurology 2008, 8:33 doi:10.1186/1471-2377-8-33

29. Results - Global improvement On both the clinician-rated and the patient-rated instruments, there was a response favoring Pregabalin compared with placebo CGIC – Clinical Global Impression of Change scales PGIC – Patient Global Impression of Change scales Research article, Joseph C Arezzo* et.al, BMC Neurology 2008, 8:33 doi:10.1186/1471-2377-8-33

32. Results – Change in least-squares mean pain score Significant reductions in end point least-squares mean pain score were observed for all three dosages of Pregabalin i.e.150, 300, and 600 mg/day ROY FREEMAN, MD, et.al, Diabetes Care 31:1448–1454, 2008

33. Results - Proportion of patients meeting improvement from baseline in mean pain score Significant improvements from baseline was observed for all three dosages of Pregabalin i.e.150, 300, and 600 mg/day ROY FREEMAN, MD, et.al, Diabetes Care 31:1448–1454, 2008

34. Results – Survival curve analysis The median time to onset of a sustained (≥ 30% at end point) 1-point improvement was 4 days in patients treated with Pregabalin 600 mg/day, 5 days in patients treated with Pregabalin 300 mg/day, 13 days in patients treated with Pregabalin 150 mg/day, and 60 days in patients receiving placebo. ROY FREEMAN, MD, et.al, Diabetes Care 31:1448–1454, 2008

37. Results – Effect on Mean Weekly Pain scores in DPN Pregabalin produced significant improvements for mean pain scores; mean sleep interference scores; and Total Mood Disturbance versus placebo Rosenstock J, Tuchman M, LaMoreaux L, Sharma U et.al, Pain. 2004 Aug;110(3):628-38.

41. Pregabalin better than Gabapentin…. Feature Pregabalin Gabapentin T max 1 h., Pregebalin SR (3-4 hr) 3.5 h. Absorption Fast Slow Oral Bioavailability > 90 % independent of dose 35% - 57 % dependent of dose Plasma concentrations Predictable & Linear Unpredictable & non-linear Potency based on Plasma conc . 2.5 times more potent - Drug-Drug interactions No Known drug-drug interactions Oral antacids reduce bioavailability by 20 – 30 % Dosage (starting dose) 2 times a day ( 75 to 150 mg/day ), Pregebalin SR (150, 300 mg / day) 3 times a day ( 300 to 900 mg/day ) Overall Pharmacokinetic More stable Less stable At high dosage Fast absorption Less absorption Onset of action 1 – 2 days ≥ 9 days Dose increases Non – linear Linear and predictable Protein binding Varied Predictable levels

42. Antidepressants in DPNP

48. SNRI – AN OVERVIEW

54. Methylcobalamin in Management of Diabetic Neuropathy

60. Nitroglycerine Spray in Management of DPNP

64. THANK YOU