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Diabetic Peripheral Neuropathy Basics for Drug Selection Dave Joffe, R.Ph, CDE, FACA 1 Dave Joffe, R.Ph, CDE, FACA Conducted over 50 Diabetes Days at Eckerd, with help from Bayer, MiniMed ,Novo, Lilly, Lifescan, and Disetronic Eckerd Patient Care Pharmacist 1999- 2000. Managed Patients full time in 3 Retail Locations. Responsible for 170 Diabetes Patients with Full Therapy Rights on Over 70 Patients. Pharmacist --Madeira Beach FL President Insulin Pump Specialty Group AADE Past -President JDRF Tampa Bay Chapter Past President Florida West Coast Assoc. Diabetes Educators Diabetes Outcome Manager, currently managing over 100 diabetes patients in private practice, with primary care physicians. Certified Insulin Pump trainer Deltec, Animas and Medtronic Editor in Chief –Diabetes In Control .com 2 Poll • Do patients ever come to you complaining of intense burning or sharp pains in their feet? 3 1 Program Overview: • This program focuses on information to help pharmacists advise patients on DPN. • We give you valuable information on current methods of treatment and how these impact DPN. • Special emphasis is placed on improving outcomes and giving you the knowledge to advise patients and other diabetes medical professionals on proper therapy choices and reasons for medication selection 4 Objectives At the end of this program the pharmacist should be able to discuss: • The Neural Systems and how Neurotransmitters work • The difference between Nociceptive and Neuropathic Pain • Signs and symptoms of Diabetic Peripheral Neuropathy(DPN) • Medical Management of DPN • Advantage of newer medications for DPN • Dosing recommendations, and Patient Safety Issues. 5 The Nervous System 6 2 Neurons –Functional Systems • Sensory or Afferent • − Collect info from organs or perception − Sends info to the brain Motor or Efferent − Carry the signal from the brain and spinal cord − Signal carries to the muscles, glands, blood vessels, organs 7 Neurotransmitters Acetylcholine – Transmits impulses that signal muscles to contract Major Excitatory NT Glutamate –Major Inhibitory NT’s GABA and Glycine 8 Neurotransmission 9 3 Nociceptive vs Neuropathic Pain States Nociceptive • Pain that arises from a stimulus • • Neuropathic vs that is outside of the nervous system Proportionate to the stimulation of the receptor When acute serves a protective function • Pain initiated or caused by a • • • primary lesion or dysfunction in the nervous system No nociceptive stimulation required Disproportionate to the stimulation of receptor Other evidence of nerve damage Serra J. Acta Neurol Scand. 1999;173(suppl):7-11. 10 Poll – True or False? • An example of nociceptive pain would be arthritis. 11 Examples of Nociceptive and Neuropathic Pain Nociceptive Pain Caused by activity in neural pathways in response to potentially tissue-damaging stimuli Arthritis Postoperative pain Mechanical low back pain Sports/exercise injuries Mixed Type Caused by a combination of both primary injury or secondary effects Neuropathic Pain Initiated or caused by primary lesion or dysfunction in the nervous system Central poststroke pain Neuropathic low back pain Sickle cell crisis *Complex regional pain syndrome CRPS* Trigeminal neuralgia Postherpetic neuralgia (PHN) Distal polyneuropathy (eg, diabetic, HIV) 12 4 Stimulus-Evoked Symptoms Symptom Allodynia Hyperalgesia Hyperpathia Definition Painful response to a nonpainful stimulus Heightened response to a painful stimulus Delayed, explosive pain to a painful stimulus Merskey H and Bogduk N. Classification of Chronic Pain. 1994. 13 Mechanisms – Neuropathic Pain • Ectopic impulse generation • − Spontaneous neuronal firing − Common mechanism for DPN Peripheral/central sensitization − Lowers activation thresholds of nociceptors and increases firing rates • Sympathetically maintained pain − Nerves release NE which stimulates C nerve fibers which are responsible for nociceptive input 14 Diabetic Peripheral Neuropathy (DPN): What Is It? • Nerve damage and dysfunction secondary to diabetes mellitus type I or II − Consensus definition1: “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes” • A very common complication of diabetes • A leading cause of neuropathic pain 1. Boulton AJ, et al. Diabet Med. 1998;15:508-514. 15 5 Diabetic Peripheral Neuropathy 16 Distal Symmetric Polyneuropathy • • • • Most common form of DPN Gradual onset “glove-stocking” distribution Acute or chronic 17 Open-Ended Question Please use the chat window to respond. • What do you recommend OTC for your patients who complain of neuropathy? 18 6 Treatment of DPN: Satisfaction with Medication is Inadequate Patient Satisfaction With Prescription Medications Extremely dissatisfied 5.1% A little dissatisfied 7.5% Somewhat satisfied 29.8% Very satisfied 14.1% Extremely satisfied 8.2% NA 23.5% 0% 5% 10% 15% 20% 25% 30% Percent of Patients Few patients (22.3%) were extremely or very satisfied with their prescription medications Gore M, et al. Presented at: American Diabetes Association 64th Annual Scientific Sessions; June 4, 2004; Orlando, Fla. 19 Management of Neuropathic Pain Associated With DPN and PHN Pharmacotherapy Neurostimulatory Interventional regional anesthesia Treatment approaches Complementary/ alternative Physical rehabilitation Psychological Lifestyle Belgrade MJ. Postgrad Med 1999;106:127-140 Orza et al. NeuroRehabilitation 2000;14:15-23 Ashburn and Staats. Lancet 1999;353:1865-1869 20 Poll • Do you recommend prescription therapy for DPN to your patients who ask? 21 7 Management of Neuropathic Pain Associated With DPN and PHN • Gabapentin • Opioids • TCAs • Cymbalta • Topamax • NSAIDs • Carbamazepine • Other AEDs • All Others 46.6% 19.8% 12.9% 3.9% 1.6% 1.3% 1.2% 1.0% 11.7% 22 Clinical Management - Anticonvulsants • Mechanisms of Action − Block / modulate sodium, calcium channels • Decrease action potential frequency • Decrease excitation or decrease NT release − Increase GABA-ergic transmission • Increase inhibition − Decrease Glutamatergic transmission • Decrease excitation 23 Clinical Management – Anticonvulsant agents − First generation • Carbamazepine • Phenytoin • Valproate − Second generation • Gabapentin* (Neurontin) • Lamotrigine (Lamictal) • Topiramate (Topamax) • Pregabalin* (Lyrica) 24 8 Clinical Management Anticonvulsant agents • Gabapentin , Pregabalin − Modulate the release of excitatory neurotransmitters from the presynaptic cell − MORE ON THIS LATER! 25 Pharmacological Options: Firstgeneration Anticonvulsants • Phenytoin − Mechanism unclear; may stabilize sodium channels1 − Effectiveness less clear than with carbamazepine − May be limited by adverse effects and drug interactions • Valproate − Increases CNS GABA concentrations1 − Limited evidence of efficacy in DPN2 − Generally well tolerated1 • Carbamazepine • • • • Inhibits sodium channels Inhibits calcium channels Blocks NMDA glutamate receptors Increases extracellular serotonin levels 1. Physician’s Desk Reference. Montvale, NJ: Thomson PDR; 2004. 2. Kochar DK, et al. Acta Neurol Scand. 2002;106:248-252. 3.Engel J, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott-Raven; 1997. . 26 Carbamazepine: Efficacy • Indicated for trigeminal neuralgia1 • Significant pain relief compared with placebo shown in DPN trials2-3 − 4-week double blind cross-over (N=40)2 − 6-week double blind cross-over (N=30)3 Safety and Tolerability Black box warning for aplastic anemia and agranulocytosis1 Rare hypersensitivity reactions Hyponatremia Most frequent adverse events Dizziness Drowsiness Unsteadiness Nausea/vomiting 1. Tegretol [prescribing information]. East Hanover, NJ: Novartis; 2003. 2. Wilton TD. S Afr Med J. 1974;48:869-872. 3. Rull JA, et al. Diabetologia. 1969;5:215-218. 27 9 Carbamazepine: Dosing Recommendations • Beginning dosage: 200 mg/d (2 divided doses) • Titration: 100-mg increments every 12 hours • Maximum dosage: 1200 mg/d Tegretol [prescribing information]. East Hanover, NJ: Novartis; 2003. 28 Pharmacological Options: Second Generation Anticonvulsants • Lamotrigine − Interacts with sodium channels and inhibits glutamate release1 − Limited evidence of efficacy in DPN2 and PHN − Published data in other neuropathic pain states (ie, HIV3,4 and trigeminal neuralgia5) • Gabapentin − − − − α 2 δ ligand6 FDA-approved for postherpetic neuralgia1 Evidence for efficacy in DPN7 Generally well tolerated1 • Topiramate − Small study suggested efficacy8 1. Physician’s Desk Reference. Montvale, NJ: Thomson PDR; 2004. 2. Eisenberg E, et al. Neurology 2001;57:505-9. 3. Simpson DM, et al. Neurology. 2000;54:21152119. 4. Simpson DM, et al. Neurology. 2003; 60:1508-1514. 5. Zakrzewska JM, et al. Pain. 1997;73:223-230. 6.Gee NS, et al. J Biol Chem. 1996;271:5768-5776. 7. Backonja M, et al. JAMA. 1998;280:1831-1836. 8. Edwards KR, et al. Neurology 2000; 54: A81(abstract). 29 Clinical Management - Antidepressants • Tricyclic Antidepressants − Block reuptake of NE, serotonin at presynaptic neurons − Block postsynaptic receptors − Thought to enhance the descending inhibitory pathway, and decrease pain signaling − Analgesic effects are independent of antidepressant effects − Low dose 30 10 TCAs: Efficacy • Meta-analysis of 13 studies of TCAs across pain conditions • Number needed to treat (NNT) for 50% pain relief: 2.9 • • (95% CI, 2.4-3.7) − Imipramine (4 reports): NNT=3.7 (2.3-9.5) − Desipramine (2 reports): NNT=3.2 (1.9-9.7) Analysis of DPN trials only: NNT=3.4 (2.6-4.7) Analysis of PHN trials only: NNT=2.1 (1.7-3.0) McQuay HJ, et al. Pain 1996;68:217-227. Collins SL, et al. J Pain Symptom Manage. 2000;20:449-458. 31 TCAs: Mechanism of Action • Block reuptake of noradrenaline and serotonin by • • presynaptic neurons1 − Raises synaptic neurotransmitter concentrations Analgesic effects independent of antidepressive effects2 − Analgesia usually occurs at a lower dose Inhibition of noradrenaline and serotonin reuptake is thought to enhance the descending inhibitory pathway3,4 1. Reisner L. Curr Pain Headache Rep. 2003;7:24-33. 2. Vaillancourt PD, Langevin HM. Med Clin North Am. 1999;83:627-643. 3. Ashburn MA, Rice LJ, eds. The Management of Pain. New York: Churchill Livingstone; 1998 4. Belgrade MJ. Postgrad Med. 1999;106:127-140. 32 TCAs: Safety and Tolerability • Up to 5% of patients experience significant adverse effects of TCAs • Anticholinergic effects • • • • • − − − − − − Blurred vision Dry mouth Sinus tachycardia Constipation Urinary retention Confusion/memory impairment Sedation, potentiation of CNS depressants Orthostatic hypotension, dizziness Hypotension Weight gain Reflex tachycardia Hardman JG, Limbird LE, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw Hill; 2001. Andreasen NC, Black DW. Introductory Textbook of Psychiatry. 3rd ed. Washington, DC: American Psychiatric Press; 2001. 33 11 TCAs: Dosing Recommendations • Beginning dosage: 10-25 mg every night • Titration: increase by 10-25 mg/d every 3-7 days as tolerated • Maximum dosage: 75-150 mg/d • Duration of adequate trial: 6-8 wk with at least 1-2 wk at maximum tolerated dosage Dworkin RH, et al. Arch Neurol. 2003;60:1524-1534. 34 Clinical Management - Antidepressants • SNRIs − Venlafaxine (Effexor XR) − Duloxetine* (Cymbalta) − Specifically inhibit norepinephrine reuptake •SSRIs –Sertraline (Zoloft) –Fluoxetine (Prozac) –Paroxetine (Paxil) –Specifically inhibit serotonin reuptake 35 Poll • Do you feel that clinicians are more likely to accept your recommendation for a topical product than for an oral medication? 36 12 Clinical Management - Topicals • Capsaicin − OTC, PHN/DPN labeling − Depletes substance P from the peripheral nerve endings − Takes time for optimal response • Lidocaine Patch − Blocks the movement of Na across neuronal cell membranes − Prevents the APs from being transmitted − Can be worn up to 12 hours a day 37 Local and Regional Treatment Measures • Lidocaine patch − Indicated for PHN1 − Favorable side effect profile1 • Erythema, edema, abnormal sensation at application site − Suggested efficacy in pilot studies in DPN2 have not been − confirmed in controlled trials Limitations • Topical route of administration • Application of the patch is painful • Capsaicin − One study found effective pain relief compared with amitriptyline3 − Other studies have given mixed results4,5 1. Lidoderm [prescribing information]. Chadds Ford, Penna: Endo Pharmaceuticals; 2004. 2.Dworkin R, et al. Presented at: American Pain Society 22nd Annual Meeting. March 20, 2003. 3. Biesbroeck R, et al. Adv Ther 1995;12:111-20. 4. Low PA, et al. Pain 1995;62:163−168. 5. Capsaicin Study Group. Arch Intern Med 1991;151:2225−2229. 38 Pharmacological Options: Other Agents • • • • • Opioids NSAIDs Tramadol Baclofen − Anecdotal reports suggest some benefit Antiarrhythmics − Mexiletine effective in some but not all trials1,2 1. Oskarsson P, et al. Diabetes Care 1997;20:1594-1597. 2. Jarvis B, Coukell AJ. Drugs 1998;56:691-707. 39 13 Opioids: Mechanism of Action • Bind to opioid receptors − G-protein linked cell signaling molecules − Endogenous ligands are the enkephalins, endorphins, and dynorphins − Physiological role not completely understood • Opioid analgesia produced at the spinal and supraspinal levels • Enhance activity of the descending pain modulation pathway Hardman JG, Limbird LE, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw Hill; 2001. 40 Opioids: Efficacy • Efficacy in neuropathic pain remains controversial1-4 • Some opioids have shown benefit in PHN5-8 • Doses needed for neuropathic pain may be higher than those needed to treat nociceptive pain3,9,10 1. Wall PD, Melzack R, eds. Textbook of Pain. 4th ed. Edinburgh: Churchill Livingstone; 1999. 2. Vaillancourt PD, Langevin HM. Med Clin North Am. 1999;83:627-643. 3. Benedetti F, et al. Pain. 1998;74:205-211. 4. Galer BS. Neurology. 1995;45(Suppl 9): S17-S25. 5. Raja SN, et al. Neurology. 2002;59:1015-1021. 6. Rowbotham MC, et al. Neurology 1991;41:1024-1028. 7. Max MB, et al. Clin Pharmacol Ther. 1988;68:217227. 8. Watson C, Babul N. Neurology. 1998;50:1837-1841. 9. Cherny NI, et al. Neurology. 1994;44:857-861. 10. Jadad AR, et al. Lancet. 1992;339:1367-1371. 41 Opioids: Dosing Recommendations • Extended-release opioids should be given by the clock, not on an as-needed basis • Initiate at a low dosage • Titrate based on response • Maximum dosage based on adequate pain relief and tolerability Kalso E, et al. Eur J Pain. 2003;7:381-386. 42 14 Mechanisms of Action – AEDs Multiple and overlapping Mechanisms • Block Na channels − Decreases frequency of the AP • Block Ca channels − Decrease excitation, release of excitatory NTs • Attenuation of Ca influx into Presyn. Terminal − Reduction of Ca influx decreases the release of excitatory NTs − Decrease # of APs 43 Mechanisms of Action – AEDs Multiple and overlapping Mechanisms • Decrease Glutamatergic Transmission − Inhibit glutamate receptor − Decrease glutamate synthesis/release • Increase GABA-ergic Transmission − Increase GABA receptor activity − Increase GABA synthesis/release − Decrease GABA reuptake 44 Pregabalin and Gabapentin • Binds to the alpha2-delta subunit of voltagegated calcium channels (N-type and P/Q-type) − Modulates the calcium channel and reduces calcium influx − Reduces the release of NTs from hyperexcited presynaptic neurons 45 15 46 Pregabalin and GabapentinRationale for Newer Therapy • Are NOT: − Calcium channel blockers!! − Calcium channel blockers (amlodipine) bind to the alph1 subunit of L-type calcium channels • Directly blocks the channel pore • Effect the peripheral vascular smooth muscle • DO NOT: − Bind to GABA − Augment GABA responses − Act like GABA uptake inhibitors 47 Different Chemical Structures CO2H NH2 Pregabalin H2N CO2H GABA NH2 CO2H Gabapentin Lyrica® (pregabalin) capsules CV [package insert]. New York, NY: Pfizer Inc; 2005; Neurontin® (gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004. 48 16 Gabapentin and Pregabalin Binds to the α 2 - δ Subunit of Voltage-Gated Ca2+ Channels in the Central Nervous System Presynaptic Α2- δ subunit Ca2+ channel Neurotransmitters Postsynaptic Schematic representation of pregabalin’s proposed mechanism of action • Pregabalin selectively binds to α2 - δ subunit of calcium channels • • • • Modulates calcium influx in hyperexcited neurons Reduces neurotransmitter release Pharmacologic effect requires binding at this site The clinical significance of these observations in humans is currently unknown 49 Taylor. CNS Drug Rev. 2004;10:183-188. Pharmacokinetic Profile The Logic for a New Drug Variable Gabapentin Absorption Bioavailability Dosage increases Exposure Plasma half-life Steady state Protein binding Metabolized Renal excretion Pregablin Slow Rapid Food affects absorption Various No food effect Dose proportional Non-Linear Linear and Predictable Dose related Predictable levels BID or TID dosing BID or TID dosing Slow dose adjustment Fast dose adjustment Varied Predictable levels Yes Predictable levels Removed by dialysis Adjust in renal impairment Removed by dialysis Adjust in renal impairment Lyrica® (pregabalin) capsules CV [package insert]. New York, NY: Pfizer Inc; 2005 Neurontin® (gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004;. 50 Poll – True or False? • A medication that has dose dependent absorption rates is safer for a patient than one that has linear absorption. 51 17 Dose Response Pregabalin Versus Gabapentin High Bioavailability Linear PK Profile 18 Steady State Cmax (µg/mL) 16 Pregabalin 14 Gabapentin 900 mg 60% 12 10 All doses 8 ≥ 9 0% 2400 mg 34% 3600 mg 33% 6 4 1800 mg Recommended dose Pregabalin Gabapentin 2 0 1200 mg 47% 0 600 1200 1800 2400 3000 3600 4200 4800 Dose (mg/d) Lyrica® (pregabalin) capsules CV [package insert]. New York, NY: Pfizer Inc; 2005; Neurontin® (gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004; Wesche, Bockbrader. Presented at: 24th Annual Scientific Meeting of the American Pain Society; 2005. 52 Open-Ended Question Please use the chat window to respond. • What do you recommend a patient do if they are not sure a medication is working? 53 Refractory Pain Study —Design Overview Treatment period 1 Drug holiday 1 Treatment period 2 Drug holiday 2 Treatment period 3 Drug holiday 3 Treatment period 4 Drug holiday 4 Treatment period 5 3 months 3-28 days 3 months 3-28 days 3 months 3-28 days 3 months 3-28 days 3 months Relapse Relapse Relapse Relapse “How much has your pain worsened since discontinuing study medication?” Not at all = 1 A little worse =2 √ Moderately worse =3 √ Much worse =4 √ Very much worse =5 Relapse Treatment period = 3-month open-label treatment period with pregabalin 150-600 mg/day ADA, June 2005 54 18 Pregabalin treatment Relapse visit (drug holiday) Moderate Baseline 100 90 80 70 60 50 40 30 20 10 0 Severe Mild Mean SF-MPQ VAS/Relapse VAS scores Pain Reported on Pregabalin Treatment* and During Drug Holidays 3 months DH 1 6 months DH 2 9 months DH 3 12 months DH 4 15 months DH = drug holiday *15-month open-label pregabalin treatment analysis 55 ADA, June 2005 % of patients Distribution of Pain Severity at Baseline and 15 Months 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 1 36 41 None/mild Moderate Severe 36 63 23 Baseline 15 months No/Mild Pain: 0 – 39; Moderate Pain: 40 – 69; Severe Pain: ≥70 on SF-MPQ pain VAS 15-month analysis (LOCF). 56 ADA, June 2005 Dizziness / Somnolence • Mild, moderate • Occurred soon after initiation of therapy • Majority resolved before end of the study • Most common reason for discontinuation − Dizziness 3% − Somnolence 2% 57 19 In Conclusion • DPN is a painful, debilitating complication of diabetes • Patients have difficulty finding relief • Current medications are somewhat effective and duration of effectiveness is varied • Newer medications have been focused on improving outcomes without side effects • Patients need to be counseled on medication expectations, dosing and side effects • Pharmacists are in a unique position to counsel patients. 58 20