Duloxetine in the Treatment of Diabetic Peripheral Neuropathic Pain .


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Duloxetine in the Treatment of Diabetic Peripheral Neuropathic Pain (DPN)
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Duloxetine in the Treatment of Diabetic Peripheral Neuropathic Pain (DPN)

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Contents Introduction Mechanism of Action Efficacy in DPNP Pharmacokinetics, Safety and Tolerability Conclusion

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Definition of diabetic neuropathy heterogeneous gathering of illnesses that influence the autonomic and fringe sensory systems of patients experiencing diabetes. WHO Definition: An infection portrayed as a dynamic loss of nerve strands prompting to sensation misfortune, foot ulceration, and removal

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Diabetic Peripheral Nerve Damage

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Axon Loss in Diabetic Neuropathy

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Classification of Diabetic Neuropathy Symmetric polyneuropathy Autonomic neuropathy Polyradiculopathy Mononeuropathy

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Multiple Mechanisms of Neuropathic Pain Multiple instruments assume a part in neuropathic torment: Peripheral sensory system input: Peripheral sharpening Ectopic edginess Central sensory system preparing: Central refinement Structural rearrangement Disinhibition 1. Woolf CJ. Ann Intern Med. 2004;140:441–451.

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Nociceptive agony Adaptive Identifiable jolts that typically deliver tissue harm Usually self-restricting Transmitted by fundamentally and practically in place torment pathways Examples: post-agent torment, smolders, ischemic torment Neuropathic torment Maladaptive Often unconstrained (happening without identifiable boosts) Often perpetual May include auxiliary and utilitarian changes in torment pathways Examples: Polyneuropathy (eg, diabetic, HIV), trigeminal neuralgia, focal post-stroke torment Distinguishing Nociceptive and Neuropathic Pain Clinical torment disorders happen along a range from nociceptive to neuropathic Nociceptive and neuropathic torment may exist together in a similar patient 1. Portenoy RK and Kanner RM. Definition and evaluation of agony. In: Portenoy RK and Kanner RM, eds. Torment Management: Theory and Practice ;1996:4; 2. Galer BS and Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis: McGraw-Hill; 2000:8–9.

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Evoked Pain hyperalgesia typical hyperpathia Magnitude of agony allodynia Stimulus power

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Prevalence of Diabetic Neuropathy as an extent of all diabetics 20 years after analysis

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The lion\'s share of patients experience torment on a consistent, everyday schedule 1 DPNP Can Negatively Impact Patients\' Quality of Life 1,2 "Torment is a repulsive tangible and enthusiastic experience related with real or potential tissue harm, or depicted as far as such harm 3 " mind-set rest vitality versatility work social exercises pleasure in life 1. Galer BS, et al. Diabetes Res Clin Pract . 2000;47:123–128; 2. Benbow SJ, et al. QJM. 1998;91:733–737;3. IASP site (http://www.iasp-pain.org/terms-p.html#Pain). Gotten to October 05, 2006.

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Goals of Neuropathic Pain Treatment Primary objective = diminishment in torment Secondary objectives Improvement in physical capacity Reduction in emotional misery Improvement in personal satisfaction Achieving these objectives is predicated upon Accurate conclusion of any fundamental etiology Preventive treatment of hidden etiology (eg diabetes, joint irritation, and so forth.), if conceivable 1. Turk DC. Clin J Pain. 2000;16:279–280; 2. Belgrade MJ. Postgrad Med. 1999;106:127–140.

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Goals of Neuropathic Pain Treatment Primary objective = decrease in agony Secondary objectives Improvement in physical capacity Reduction in full of feeling trouble Improvement in personal satisfaction Achieving these objectives is predicated upon Accurate conclusion of any basic etiology Preventive treatment of hidden etiology (eg diabetes, joint aggravation, and so on.), if conceivable 1. Turk DC. Clin J Pain. 2000;16:279–280; 2. Belgrade MJ. Postgrad Med. 1999;106:127–140.

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Management of DPNP Off-Label Agents: 1 Tricyclic antidepressants – i.e., amitriptyline Anticonvulsants – i.e., gabapentin Opioid analgesics Tramadol Other antidepressants – i.e., venlafaxine FDA-Approved Agents in US: Cymbalta 2 Lyrica 3 1. Argoff CE, et al. Mayo Clin Proc. 2006;81(4):S12–25; 2. Cymbalta US Prescribing Information; 3. Lyrica US Prescribing Information.

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Contents Introduction Mechanism of Action Efficacy in DPNP Pharmacokinetics, Safety and Tolerability Conclusion

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Nerve sore Ectopic releases Ectopic releases Nerve sore incites hyperactivity because of changes in particle channel work Perceived agony Descending balance Ascending information Nociceptive afferent fiber Spinal line Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Reading material of torment. 4 th Ed. 1999.;165-182

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Noxious boosts Loss of inhibitory controls Loss of slipping regulation causes overstated agony because of an unevenness amongst climbing and sliding signs Exaggerated torment observation Loss of dropping adjustment Ascending information Nociceptive afferent fiber Spinal line Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Reading material of torment. 4 th Ed. 1999.;165-182 Attal N et al. Acta Neurol Scand. 1999;173:12-24. Woolf CJ et al. Lancet. 1999;353:1959-1964. Roberts et al. In Casey KL (Ed). Torment and focal sensory system illness. 1991

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Abnormal releases initiate focal refinement Tactile boosts Intact material fiber Central sharpening After nerve harm, i ncreased contribution to the dorsal horn can instigate focal sharpening Perceived torment Nerve sore Descending balance Ascending info Nociceptive afferent fiber Perceived torment (allodynia) Descending tweak Ascending information Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Course reading of torment. 4 th Ed. 1999.;165-182

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Serotonin & Norepinephrine Play a Major Role in Pain Neuropathic torment is related with expanded excitation and diminished hindrance of climbing torment pathways Descending pathways adjust rising signs NE and 5-HT are enter neurotransmitters in plummeting inhibitory torment pathways Increasing the accessibility of NE and 5-HT may advance torment restraint midway 5-HT NE 1. Figure adjusted from: Fields HL and Basbaum AI. Focal sensory system components of agony tweak. In: Wall PD and Melzack R, eds. Course reading of Pain , fourth ed. Churchill Livingstone: London, UK;1999,310.

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The Combination of a NRI and a SSRI is More Effective than Either Alone Total paw-licking time (late stage) 120 Paroxetine Vehicle control 100 Thionisoxetine 80 Paroxetine 1 mg/kg + Thionisoxetine Less Pain Behavior % of Vehicle Control * 60 40 N=5–12 * P < .05 20 versus thionisoxetine alone 0 0.1 1 10 Drug (mg/kg) Higher Dose 1. Iyengar S, et al. J Pharmacol Exp Ther . 2004;311:576–584.

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Less Pain Behavior % of Vehicle Control Drug (mg/kg i.p. 30 min) Drug (mg/kg i.p. 30 min) Higher Dose Higher Dose Duloxetine Venlafaxine Milnacipran Amitriptyline Duloxetine is a Potent Inhibitor of Persistent Pain in the Formalin Model Total paw-licking time (late stage) Vehicle control Vehicle control 100 * 75 * 50 * # * 25 * 0 1 10 100 1 10 100 N=6–9 * P < .05 versus vehicle # Rotorod impacts 1. Iyengar S, et al. J Pharmacol Exp Ther. 2004;311:576–584.

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Duloxetine Reverses Mechanical Allodynia in the Spinal L5/L6 Nerve Ligation Model of Neuropathic Pain 14 * Vehicle control 12 Duloxetine 30 mg/kg p.o. when every day 10 8 Less Pain Behavior Withdrawal Threshold Response (g) N=4–5 6 4 * P < .05 versus vehicle 2 0 pre base Day 1 3 hrs Time pre = pre-surgery pattern, base = post-surgery benchmark 1. Iyengar S, et al. J Pharmacol Exp Ther. 2004;311:576–584.

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Contents Introduction Mechanism of Action Efficacy in DPNP Pharmacokinetics, Safety and Tolerability Conclusion

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Completed Duloxetine Clinical Trials in DPNP 1. Goldstein DJ, et al. Torment. 2005;116:109–118; 2. Wernicke JF, et al. Neurology. 2006;67:1411–1420; 3. Raskin J, et al. Torment Med. 2005;6:346–356; 4. Information on record, Eli Lilly; 5 . Notice: Raskin J, et al. 25 th American Pain Society (APS) Annual Scientific Meeting; San Antonio, TX; May 3–6, 2006; 6. Raskin J, et al. Torment Med. 2006;7:373–385.

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Duloxetine Reduces 24-Hour Average Pain Severity in DPNP Pooled information from 3 concentrates 0.0 Placebo (n=330) Duloxetine 20 mg QD (n=111) Duloxetine 60 mg QD (n=334) Duloxetine 60 mg BID (n=333) - 0.5 * - 1.0 Mean Change in 24-hour Average Pain Severity Score - 1.5 * Improvement * - 2.0 * - 2.5 * - 3.0 * P ≤ .05 - 3.5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 versus fake treatment Weeks MMRM A decrease of around 2 focuses or 30% speaks to a clinically essential distinction (mean benchmark score was 5.83 ) Poster: Raskin J, et al. 25th American Pain Society (APS) Annual Scientific Meeting; San Antonio, TX; May 3–6, 2006.

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*** ** Placebo Duloxetine 20 mg QD Duloxetine 60 mg QD Duloxetine 60 mg BID Duloxetine Improves Response Rates in DPNP After 12 Weeks † 30% Reduction in 24-hour Average Pain half Reduction in 24-hour Average Pain *** ** * Study 1 Study 2 3 Study 3 1 Study 1 2 Study 2 3 Study 3 4 * P < .05 versus fake treatment ** P < .01 versus fake treatment *** P < .001 versus fake treatment † Completer examination 1. Introduction: Raskin J, et al. 41st European Association for the Study of Diabetes (EASD) Annual Meeting; Athens, Greece; September 12–15, 2005; 2. Goldstein DJ, et al. Torment. 2005;116:109–118; 3. Wernicke JF, et al. Neurology. 2006;67:1411–1420; 4. Raskin J, et al. Torment Med. 2005;6:346–356

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60 mg QD Duloxetine Improves Worst Pain Severity in DPNP Data from three 12-week viability and security studies 1 2 3 n=112 n=110 n=114 n=111 n=106 n=103 Placebo Duloxetine 60 mg QD ** * P ≤ .05, ** P < .001 MMRM 1. Goldstein DJ, et al. Torment. 2005;116:109–118; 2. Wernicke JF, et al. Neurology. 2006;67:1411–1420; 3. Raskin J, et al. J Pain Med. 2005;6:346–356. .

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