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    Khalifa abdallah.diabetic neuropathy cymbalta f Khalifa abdallah.diabetic neuropathy cymbalta f Presentation Transcript

    • Management of DiabeticPeripheral Neuropathic Pain Khalifa Abdallah Prof. of Internal Medicine Diabetes, Metabolism & Lipidology Unit Alexandria University
    • Presentation Overview• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
    • Presentation Overview• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
    • Diabetic Neuropathy: Size and Cost• DM affects about 300 million individual worldwide.• Diabetic neuropathy is one of the most common manifestations of diabetes and potentially its most debilitating.• It affects approximately 30% of all patients with diabetes.• It quietly and insidiously places its victim at high risk for devastating complications.
    • Presentation Overview• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
    • Presentation Overview• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
    • Pathogenesis of Diabetic Neuropathy• Metabolic factors – High blood glucose – Advanced glycation end products – Sorbitol pathway – Abnormal blood fat levels• Ischemia• Impaired nerve fiber repair mechanisms
    • Presentation Overview• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
    • Presentation Overview• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
    • Risk Factors• Glucose control• Duration of diabetes• Age• Height• Genetic susceptibility• Lifestyle factors – Smoking – Alcohol
    • Presentation Overview• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
    • Presentation Overview• Size and costs of the problem• Pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
    • Classification of Diabetic NeuropathyA. Diffuse Neuropathy 1. Distal symmetric sensorimotor neuropathy 2. Autonomic neuropathy a. Sudomotor b. Cardiovascular c. Gastrointestinal d. Genitourinary 3. Symmetrical proximal lower limb motor neuropathy (amyotrophy)B. Focal Neuropathy 1. Cranial neuropathy 2. Radiculopathy and plexopathy 3. Entrapment neuropathy
    • Painful Diabetic Neuropathy
    • Nociceptive and Neuropathic Pain Nociceptive pain Neuropathic pain Adaptive Maladaptive Identifiable stimuli that normally Often spontaneous (occurring without produce tissue damage identifiable stimuli) Usually self-limiting Often chronic Transmitted by structurally and May involve structural and functional functionally intact pain pathways changes in pain pathways Examples: post-operative pain, burns, Examples: Polyneuropathy ischemic pain (eg, diabetic, HIV), trigeminal neuralgia, central post-stroke painClinical pain syndromes occur along a spectrum from nociceptive to neuropathicNociceptive and neuropathic pain may coexist in the same patient
    • Pathophysiology of neuropathic painPeripheral mechanisms Peripheral neuron hyperexcitability Loss of Abnormal inhibitory controls discharges NeP Central mechanisms Central neuron hyperexcitability (central sensitization)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). Pain and central nervous system disease. 1991
    • Normal nerve impulses leading to pain Perceived pain Noxious stimuli Descending Ascending modulation input Nociceptive afferent fiber Spinal cordAdapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;165-182
    • Ectopic dischargesNerve lesion induces hyperactivity due to changesin ion channel function Perceived pain Nerve lesion Descending Ascending modulation input Nociceptive afferent fiber Spinal cord Ectopic dischargesAdapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;165-182
    • Loss of inhibitory controlsLoss of descending modulation causes exaggerated pain due to animbalance between ascending and descending signals Exaggerated pain perception Noxious stimuli Loss of Ascending descending input modulation Nociceptive afferent fiber Spinal cordAdapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;165-182Attal 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). Pain and central nervous system disease. 1991
    • Central sensitizationAfter nerve injury, increased input to the dorsal horncan induce central sensitization Perceived pain Nerve lesion Descending Ascending modulation input Nociceptive afferent fiber Perceived pain Abnormal discharges induce central sensitization (allodynia) Tactile stimuli Descending Ascending modulation input Intact tactile fiberAdapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;165-182
    • Serotonin & NorepinephrinePlay a Major Role in Pain♦ Neuropathic pain is associated with increased excitation and decreased inhibition of ascending pain pathways♦ Descending pathways modulate ascending signals 5-HT♦ NE and 5-HT are key neurotransmitters in descending inhibitory pain pathways NE♦ Increasing the availability of NE and 5-HT may promote pain inhibition centrally1. Figure adapted from: Fields HL and Basbaum AI. Central nervous system mechanisms of pain modulation. In: Wall PD and Melzack R,eds. Textbook of Pain, 4th ed. Churchill Livingstone: London, UK;1999,310.
    • Presentation Overview• Size and costs of the problem• Pathology/pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
    • Presentation Overview• Size and costs of the problem• Pathology/pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
    • ADA Neuropathy screening and treatment Recommendations• All patients should be screened for distal symmetric polyneuropathy (DPN) at diagnosis and at least annually thereafter using simple clinical tests. (B)• Electrophysiological testing is rarely needed, except in situations where the clinical features are atypical. (E)• Screening for signs and symptoms of cardiovascular autonomic neuropathy should be instituted at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes. Special testing is rarely needed and may not affect management or outcomes. (E)• Medications for the relief of specific symptoms related to DPN and autonomic neuropathy are recommended, as they improve the quality of life of the patient. (E) Diabetes Care January 2011 34:S11-S61
    • ADA Neuropathy screening and treatment Recommendations Diagnosis of neuropathyDistal symmetric polyneuropathy• Patients with diabetes should be screened annually for DPN using tests such as pinprick sensation, vibration perception (using a 128-Hz tuning fork), 10-g monofilament pressure sensation at the distal plantar aspect of both great toes and metatarsal joints, and assessment of ankle reflexes.• Combinations of more than one test have >87% sensitivity in detecting DPN. Loss of 10-g monofilament perception and reduced vibration perception predict foot ulcers Diabetes Care January 2011 34:S11-S61
    • Press until the filament bends.
    • Locations To Test
    • Presentation Overview• Size and costs of the problem• Pathology/pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
    • Presentation Overview• Size and costs of the problem• Pathology/pathophysiology• Risk factors• Presentations• Diagnosis• Prevention and Treatment
    • PreventionControl• DCCT (1995) – Tight control-3% neuropathy at 5 years – Conventional-10%• UKPDS (1998) – Tight control (HbA1c 7%)-31.2% neuropathy at 15 years – Conventional (HbA1c 7.9%)-51.7% – P=0.005 – No protective effect seen for BP control
    • Prevention• Aldose reductase inhibitors• Gamma Linoleic Acid• Vasodilators-ACE?• AGE inhibitors• Antioxidants• NGFs• ? Smoking cessation, ? BP reduction
    • Treatment of diabetic neuropathic painNeuropathic pain remains one of the most challenging of all neurological diseases and presents a large unmet need for improved therapies.Mechanism-based approaches have highlighted key areasfor intervention including the reduction of peripheral and central hyperexcitability or increasing spinal inhibition by enhancing monoaminergic activity
    • ADA: Neuropathy treatment recommendations management• The first step in management of patients with DPN should be to aim for stable and optimal glycemic control and avoidance of extreme blood glucose fluctuations• Patients with painful DPN may benefit from pharmacological treatment of their symptoms Diabetes Care January 2009 32:S6-S12
    • ADA Neuropathy screening and treatment Recommendations-ManagementTable 14—Table of drugs to treat symptomatic DPNClass Examples Typical doses*Tricyclic drugs Amitriptyline 10–75 mg at bedtime Nortriptyline 25–75 mg at bedtime Imipramine 25–75 mg at bedtimeAnticonvulsants Gabapentin 300–1,200 mg t.i.d. Carbamazepine 200–400 mg t.i.d. Pregabalin 100 mg t.i.d.5-hydroxytryptamine Duloxetine 60–120 mg dailyAnd norepinephrine uptake inhibitorSubstance P inhibitor Capsaicin cream 0.025–0.075% applied t.i.d. or q.i.d.
    • 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: • Cymbalta2 • Lyrica31. Argoff CE, et al. Mayo Clin Proc. 2006;81(4):S12–25; 2. Cymbalta US Prescribing Information; 3. Lyrica US Prescribing Information.
    • Completed Duloxetine Clinical Trials in DPNP Treatment Study Treatment Groups duration N (weeks) Goldstein et al1 20, 60, 120 mg/day 12 457 vs placebo Wernicke et al2 60 and 120 mg/day vs placebo 12 334 Raskin et al3 60 and 120 mg/day 12 348 vs placebo Maintenance Study4 60 mg/day 8 + 26 115 1-year, open-label safety 120 mg vs 52 867 extension of above studies5 routine care 6-month, open-label 60 mg BID vs safety study6 28 449 120 mg QD1. Goldstein DJ, et al. Pain. 2005;116:109–118; 2. Wernicke JF, et al. Neurology. 2006;67:1411–1420; 3. Raskin J, et al. Pain Med. 2005;6:346–356;4. Data on file, Eli Lilly; 5. Poster: Raskin J, et al. 25th American Pain Society (APS) Annual Scientific Meeting; San Antonio, TX; May 3–6, 2006; 6. Raskin J, et al. Pain Med. 2006;7:373–385.
    • Duloxetine Reduces 24-Hour Average Pain Severity in DPNP Pooled data from 3 studies 0.0 Average Pain Severity Score Placebo Mean Change in 24-hour -0.5 (n=330) Duloxetine -1.0 *Improvement 20 mg QD (n=111) -1.5 * * Duloxetine -2.0 * 60 mg QD * * (n=334) * * * * * -2.5 * * * Duloxetine * * -3.0 * * * 60 mg BID * * * (n=333) * * -3.5 * P ≤ .05 0 1 2 3 4 5 6 7 8 9 10 11 12 13 vs placebo Weeks MMRM ♦ A reduction of approximately 2 points or 30% represents a clinically important difference (mean baseline score was 5.83) Poster: Raskin J, et al. 25th American Pain Society (APS) Annual Scientific Meeting; San Antonio, TX; May 3–6, 2006.
    • Duloxetine Improves Response Rates in DPNP After 12 Weeks† 30% Reduction 50% Reduction in 24-hour Average Pain in 24-hour Average Pain 80 80 ** ** *** *** ** ** 60 60 *** *** ***Patients (%) * ** 40 * 40 20 20 0 0 Study 11 Study 23 Study 31 Study 12 Study 23 Study 34 Placebo Duloxetine 20 mg QD * P < .05 vs placebo Duloxetine 60 mg QD ** P < .01 vs placebo Duloxetine 60 mg BID † Completer analysis *** P < .001 vs placebo 1. Presentation: 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. Pain. 2005;116:109–118; 3. Wernicke JF, et al. Neurology. 2006;67:1411–1420; 4. Raskin J, et al. Pain Med. 2005;6:346–356
    • 60 mg QD Duloxetine Improves WorstPain Severity in DPNP 24-hour Worst Pain after 12 Weeks Data from three 12-week efficacy and safety studies Goldstein1 Wernicke2 Raskin3 Mean Change From Baseline in 0 n=111 n=112 n=106 n=110 n=103 n=114 Placebo Duloxetine -1 60 mg QD -2 -3 ** ** * -4 * P ≤ .05, ** P < .001 MMRM1. Goldstein DJ, et al. Pain. 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.
    • 60 mg QD Duloxetine Reduces Pain atNight in DPNP Data from three 12-week efficacy and safety studies 1 2 3 Goldstein Wernicke Raskin Mean Change From Baseline in 0 n=111 n=112 n=106 n=109 n=103 n=114 Night Pain After 12 Weeks Placebo Duloxetine -1 60 mg QD -2 -3 ** * ** -4 * P ≤ .05, ** P < .051. Goldstein DJ, et al. Pain. 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.
    • Duloxetine Decreased the Impact of Pain on DailyActivity, Function, and Enjoyment of Life (BPI-I) Pooled data from 3 studies BPI Avg General Walking Normal Relationship Enjoyment Score Activity Mood Ability Work With Others Sleep of Life 0Decreased Impact / Improvement -0.5 LS Mean Change from Baseline BPI-I Score -1 -1.5 * -2 *** -2.5 *** *** *** ** *** *** -3 *** *** *** *** *** *** -3.5 ** *** Placebo * P < .05 vs placebo Duloxetine 60 mg QD Duloxetine 60 mg BID ** P < .01 vs placebo *** P < .001 vs placebo Armstrong DG, et al. Pain Med. 2007;8(5):410-418.
    • Most Common Adverse Events Associated with Duloxetine in DPNP Pooled data from 3 studies Cymbalta Adverse Events that Occurred 5% and Twice Placebo 50 Placebo (n=339) Duloxetine 20 mg/day (n=115)% Incidence of Adverse Events Duloxetine 60 mg/day (n=334) 40 Duloxetine 120 mg/day (n=341) Duration* 4 days 5 days Duration* 30 6 days 23 days *Median duration data: 13 days Placebo Duration* 15 days Duloxetine (60 mg) 5 days 20 4 days Duloxetine (120 mg) 6 days 10 0 Nausea Somnolence Dizziness Constipation Sweating Dry Mouth Appetite Poster: Robinson M, et al. Presented at: 8th International Conference on the Mechanisms and Treatment of Neuropathic Pain (ICMTNP); San Francisco, CA; Nov 5, 2005.
    • Most Common Adverse Events asReason for Discontinuation Pooled data from 3 studies 5 Placebo (n=339) Duloxetine 20 mg/day (n=115) 4 Duloxetine 60 mg/day (n=334) * Percent of Patients * 3.2 3.2 Duloxetine 120 mg/day (n=341) 3 * 2.6 2 1.5 1.5 1.2 1.2 0.9 0.9 0.9 0.9 1 0.6 0.3 0.3 0 0 0 0 0 0 0 Nausea Somnolence Dizziness Fatigue Vomiting *P ≤ .05 vs placeboPoster: Robinson M, et al. Presented at: 8th International Conference on the Mechanisms and Treatment of Neuropathic Pain (ICMTNP);San Francisco, CA; Nov 5, 2005.
    • Clinical Profile of the 3 Most Common Adverse Events Pooled data from 3 studies Onset Median Duration Severity (60 mg/QD) 50 9% 2% 40 Nausea 13%% Patients Reporting AE (New Cases) 30 Duloxetine 60 mg/day=5 days 20 76% Duloxetine 120 mg/day=6 days 10 Placebo=4 days 0 1 2 3 4 5 6 7 8 9 10 11 12 50 2% 40 Somnolence 12% 3% 30 Duloxetine 60 mg/day=13 days 85% 20 Duloxetine 120 mg/day=15 days 10 Placebo=23 days 0 1 2 3 4 5 6 7 8 9 10 11 12 50 40 Dizziness 3% 1% 6% 30 20 Duloxetine 60 mg/day=4 days 90% Duloxetine 120 mg/day=6 days 10 Placebo=5 days 0 1 2 3 4 5 6 7 8 9 10 11 12 Weeks Mild Severe Placebo (n=339) Cymbalta 60 mg/day (n=334) Cymbalta 120 mg/day (n=341) Moderate None Poster: Robinson M, et al. Presented at: 8th International Conference on the Mechanisms and Treatment of Neuropathic Pain (ICMTNP); San Francisco, CA; Nov 5, 2005.
    • Nausea on Duloxetine is Common, but isShort-Lived and Mostly Mild or Moderate Pooled data from 3 studies Severity of Treatment-emergent Nausea on Duloxetine 60 mg QD Moderate 9% Severe 2% Mild 13% None 76%♦ Of all the DPNP patients reporting nausea, 92% reported it as mild to moderate♦ Nausea occurred primarily during the first week of treatment and resolved rapidly with continued treatment (median duration 5 days)Poster: Robinson M, et al. Presented at: 8th International Conference on the Mechanisms and Treatment of Neuropathic Pain (ICMTNP);San Francisco, CA; Nov 5, 2005.
    • No Evidence of an Increased Risk of Suicidality with Duloxetine♦ The data from studies of adult patients with MDD demonstrate that duloxetine significantly reduces the risk of worsening suicidal ideation and significantly increases the chances for improvement in ideation for patients who had suicidal ideation at baseline.♦ The data from studies of adult patients with nonpsychiatric indications (including SUI, FM and DPNP) support the conclusion that duloxetine is not associated with the development of suicidal ideation in depressed or non-depressed adult patients receiving duloxetine for any of the indications.NOTE: The duloxetine FDA black box warning about suicidality in adults is derived from a meta-analysis of all drugs in this class. Although primarily based on studies of MDD, the warning applies to all indications. Data on file.
    • Take home message• Diabetic neuropathy is one of the most common manifestations of diabetes and potentially its most debilitating• All patients should be screened for distal symmetric polyneuropathy (DPN) at diagnosis and at least annually thereafter using simple clinical tests• Patients who can not feel the 10-g monofilament should receive advice about foot care• Duloxetine, a potent and balanced dual 5-HT and NE reuptake inhibitor, has been shown to significantly decrease pain in DPNP patients
    • Thank You