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Virginia Opioid Addiction ECHO* Clinic Virginia Opioid Addiction ECHO*Clinic February 21, 2020 *ECHO: Extension of Community Healthcare Outcomes Helpful Reminders Rename • Rename your Zoom screen, with your name and organization Helpful Reminders • You are all on mute please unmute to talk • If joining by telephone audio only, *6 to mute and unmute Unmute Helpful Reminders • Please type your full name and organization into the chat box Chat Box • Use the chat function to speak with IT or ask questions VCU Opioid Addiction ECHO Clinics • Bi-Weekly 1.5 hour tele-ECHO Clinics • Every tele-ECHO clinic includes a 30 minute didactic presentation followed by case discussions • Didactic presentations are developed and delivered by inter-professional experts • Website Link: www.vcuhealth.org/echo Hub Introductions VCU Team Clinical Director Gerard Moeller, MD Administrative Medical Director ECHO Hub and Principal Vimal Mishra, MD, MMCi Investigator Clinical Expert Lori Keyser-Marcus, PhD Courtney Holmes, PhD Albert Arias, MD Didactic Presentation Gerard Moeller, MD Program Manager Bhakti Dave, MPH Practice Administrator David Collins, MHA IT Support Vladimir Lavrentyev, MBA Introductions: • Name • Organization Reminder: Mute and Unmute to talk *6 for phone audio Use chat function for Introduction What to Expect I. Didactic Presentation I. Gerry Moeller, MD II. Case presentations I. Case 1 I. Case summary II. Clarifying questions III. Recommendations II. Case 2 I. Case summary II. Clarifying questions III. Recommendations Lets get started! III. Closing and questions Didactic Presentation Pharmacotherapy for Methamphetamine F. Gerard Moeller, M.D. Professor and Division Chair: Addictions Department of Psychiatry VCU School of Medicine 9 Disclosures • I have received grant funding from Indivior pharmaceuticals and Nektar Therapeutics for research unrelated to this talk 10 Meth vs. Cocaine Methamphetamine Cocaine Stimulant Stimulant and local anesthetic Man-made Plant-derived Smoking produces a long-lasting high Smoking produces a brief high 50% of the drug is removed from the 50% of the drug is removed from the body in 12 hours body in 1 hour Increases dopamine release and Blocks dopamine re-uptake blocks dopamine re-uptake Limited medical use for ADHD, Limited medical use as a local narcolepsy, and weight loss anesthetic in some surgical procedures 11 Methamphetamine Brain Effects • Methamphetamine metabolized in the liver to amphetamine • Methamphetamine and amphetamine reverse the transport direction of the dopamine, norepinephrine, and serotonin transporters, increasing the levels of monamines in the synapse • Also inhibit the vesicular monoamine transporter (VMAT) increasing monoamines in the cytoplasm and inability to make monoamine vesicles for normal process for neurotransmission • Methamphetamine has been shown to cause neurotoxicity characterized by long lasting depletion of dopamine and changes in striatal dopaminergic and serotonergic nerve terminals in preclinical studies 12 Structure of Stimulants MDMA Pseudoephedrine Sulfate 13 Treatment of Stimulant Abuse • Treatment of Psychiatric complications • Depression - Antidepressants warranted if symptoms persist after drug withdrawal • Psychosis - Amphetamine induced psychosis very similar in appearance to Schizophrenia. Treatment with antipsychotics effective. 14 No FDA Approved Medication for Methamphetamine Challenges Opportunities Medication Compliance • Administer Medications in clinic Treatment Retention • Contingency Management • Inclusion Criteria Subject Heterogeneity Subject Recruitment 15 Medications Have Been Assessed for Amphetamine and Methamphetamine Use Disorders Treatments Agents Mechanisms Outcome Agonists & Inhibits DA reuptake via monoamine Methylphenidate Some evidence of benefit in reduction of use, but also negative trials Stimulants transporter Amphetamines Induce DA release and inhibits DAT No clear evidence of benefit Overall no significant effect, some evidence for response in subgroups of Neuroadaptations Bupropion Inhibits DA and NE reuptake methamphetamine users Disulfiram Inhibits dopamine β-hydroxylase No clear evidence of benefit Acts through both dopaminergic and Modafinil Inconsistent results. Some evidence that compliant patients benefit glutaminergic pathways Atomoxetine NE reuptake inhibitor No clear evidence of benefit Ibudilast Phosphodiesterase inhibitor No clear evidence of benefit in clinical trial with 125 participants Reduces glutamate by enhancing the N-acetylcysteine Large trial underway in Australia glutamate transporter Vigabatrin Inhibits GABA transaminase No clear evidence of benefit Some evidence of benefit in reduction of use, but primary outcome Topiramate Enhances GABA activity partly negative in trial of 140 participants Citicoline increases NE, DA, and serotonin levels No clear evidence of benefit in clinical trial with 104 participants Varenecline Nicotinic receptor partial agonist No clear evidence of benefit Other Mirtazapine, Inhibit monoamine reuptake, other Reduction in use in small trial in MSM treated with mirtazapine which was Antidepressants Sertraline mechanisms confirmed with larger trial Inconsistent findings. One study with reduced positive urine drug screens, Opioid Antagonist Naltrexone Antagonist at mu opioid receptor others negative Antipsychotics Aripiprazole Dopamine antagonist/partial agonist No clear evidence of benefit, possibility of increased harm Muscle Relaxant GABA, Voltage Dependent Calcium Baclofen, gabapentin No clear evidence of benefit and anticonvulsants Channels Anti- Monoclonal antibody to neutralize Immunotherapy methamphetamine Phase 1 study underway methamphetamine activities antibody Note. DAT = dopamine transporter; GABA = γ-aminobutyric acid; BBB = blood brain barrier; MSM = cis or transgender men who have sex with men; NE = norepinephrine; TCA = tricyclic antidepressants; CUD = cocaine use disorder. 16 Recent Reviews • Chan B, Freeman M, Kondo K, et al. Pharmacotherapy for methamphetamine/amphetamine use disorder-a systematic review and meta-analysis. Addiction. 2019;114(12):2122-2136 • Lee NK, Jenner L, Harney A, Cameron J. Pharmacotherapy for amphetamine dependence: A systematic review. Drug Alcohol Depend. 2018;191:309-337. 17 Methylphenidate • Stimulant that blocks reuptake of DA, NE • Has abuse/diversion potential • Hypertension/cardiac effects limit use • Five randomized clinical trials studying effects of methylphenidate for MUD have been reported • Based on randomized trials completed to date, there is low strength evidence supporting methylphenidate reducing methamphetamine use (based on systematic reviews) 18 Methylphenidate • Ling et al., 2014: 110 methamphetamine dependent participants – sustained release methylphenidate vs. placebo showed no difference in the primary outcome measure of self-reported days of methamphetamine use in the last 30 days of active treatment – planned secondary analyses there were fewer self-reported methamphetamine use days from baseline through the active phase of treatment and lower craving scores compared to placebo (MPH-SR (Concerta®) 18 mg daily for week 1, 36 mg for week 2 and 54 mg for weeks 3–10) DOSE TITRATION IMPORTANT • Miles et al., 2013: Trial of sustained release methylphenidate vs. placebo in 79 methamphetamine/amphetamine users – No difference from placebo in positive urine drug screens – Better retention in methylphenidate treated participants 19 Topiramate • Anticonvulsant • Sodium, Calcium channel and GABA effects • No abuse potential. Cognitive side effects limit use. • Two recent reviews (above) conclude there is some evidence to support topiramate for methamphetamine use • Evidence is limited to a few clinical trials 20 Topiramate • Elkashef 2012: 140 MUD participants treated with slow titration over 35 days to target dose of 200mg per day of topiramate – No difference in abstinence from methamphetamine in weeks 6-12 of the 13-week study, – Secondary analysis showed reduced weekly median urine methamphetamine levels and observer rated severity of dependence • Rezaie et al., 2016: 62 MUD participants with target dose of 200mg topiramate – Reduction in positive methamphetamine urine drug screen results at week 6 of a 10 week study compared to placebo (but no significant difference at all other weeks) 21 Bupropion • Antidepressant • Weak DA reuptake inhibition, antagonist at nicotinic receptors • Seizure risk at higher doses • Several clinical trials • Some evidence of subgroup effects 22 (From Elkashef et al., 2009) 23 Bupropion • Elkashef 2008: 151 MUD participants treated 150 mg bupropion twice daily – No significant difference in abstinence from methamphetamine overall – Subgroup analysis showed male patients with lower levels of methamphetamine use responded better to bupropion • Anderson et al., 2015: 204 MUD participants who used less than daily 150mg sustained release bupropion daily – No difference with bupropion – Medication compliance poor 24 Mirtazapine • Antidepressant • 5-HT2, NE, H1 antagonist • Sedation significant side effect • Two studies showing potential efficacy 25 Mirtazapine • Colfax et al., 2011: 60 MUD participants treated 30 mg mirtazapine once daily (titrated up from 15mg daily after one week) – Sexually active; men who had sex with men and had methamphetamine use disorder – Participants were randomized to receive the study drug or placebo for 12 weeks – Mirtazapine group had fewer methamphetamine-positive urine test results compared with participants assigned to the placebo group. – Risky sexual behavior reduced in mirtazapine
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