Faculty Disclosures. Disclosures. Updates on the Long-Term Management of Opioid and Alcohol Use Disorders: A Focus on Medication-Assisted Treatment

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1 Updates on the Long-Term Management of Opioid and Alcohol Use Disorders: A Focus on Medication-Assisted Treatment Supported by an educational grant from Alkermes, Inc. Rakesh Jain, MD, MPH Clinical Professor Department of Psychiatry Texas Tech University School of Medicine Midland, Texas Faculty Disclosures Dr. Rakesh Jain: Paid Speaker Addrenex, Alkermes, Allergan (Actavis/Forest), Lilly, Lundbeck, Merck, Neos Therapeutics, Otsuka, Pamlab, Pfizer, Rhodes Pharmaceuticals, Shionogi, Shire, Sunovion, Takeda, Tris Pharmaceuticals; Advisory Board Addrenex, Alkermes, Forum, Lilly, Lundbeck, Merck, Neos Therapeutics, Otsuka, Pamlab, Pfizer, Shionogi, Shire, Sunovion, Takeda; Research AstraZeneca, Allergan (Actavis/Forest), Lilly, Lundbeck, Otsuka, Pfizer, Shire, Takeda; Spouse: Consultant Lilly, Otsuka, Pamlab. Disclosures The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration). Applicable CME staff have no relationships to disclose relating to the subject matter of this activity. This activity has been independently reviewed for balance.

2 Learning Objectives Compare available SUD treatments in terms of route of administration, utility in long-term management, benefits and risks, long-term safety, and impact on adherence Address barriers to medication-assisted treatment through patient-centered therapeutic strategies Implement strategies for the management of SUDs and comorbid psychiatric disorders Risks, Signs, Symptoms of Substance Use Disorder DSM-5: SUD Poor Control Social Impairment Risky Use Tolerance Withdrawal 1. Longer periods/larger amounts 2. Failure to reduce use 3. Excessive time 4. Cravings 5. Problems with work, school, or family/social obligations 6. Interpersonal problems 7. Decrease in important social and recreational activities 8. Repeated use in physically dangerous situations 9. Worsening physical and psychological problems with continued use 1. Increased amount for same desired effect 11. Response to abrupt cessation Note: Meet 2 of these criteria to be diagnosed with SUD Severity: Mild 2 3, Moderate 4 5, Severe 6 Symptoms SUD = substance use disorder. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition. Arlington, VA: American Psychiatric Publishing, Inc.; 213. Hasin DS, et al. Am J Psychiatry. 213;17(8):

3 Overdose Death Rates from Opiates: Most Important Sign of SUD Marked increase from 1999 to 214 by county Age-adjusted rate for opiate analgesic poisoning deaths nearly quadrupled from 1.4 per 1, in 1999 to 5.4 per 1, in 211 Estimated Age-adjusted Death Rates for Drug Poisoning by County, United States Centers for Disease Control and Prevention. Drug Poison Mortality: United States, blogs.cdc.gov/nchs-data-visualization/drug-poisoning-mortality/. Accessed August 23, 216. Chen LH, et al. NCHS data brief, no 166. Hyattsville, MD: National Center for Health Statistics FDA-Approved Pharmacotherapies Opiate overdose: Intranasal naloxone Opiate-relapse prevention: Methadone, naltrexone, buprenorphine Mechanisms Methadone: Full µ-opioid receptor agonist, involves cross-tolerance with high dose Naltrexone: Blocks µ-opioid receptor, blocks euphoria Buprenorphine: Partial opioid agonist, blocks euphoria at high dose Alcohol-relapse prevention: Disulfiram, naltrexone, acamprosate Mechanisms Disulfiram: Inhibits ALDH, accumulates acetaldehyde, leads to aversion Naltrexone: Blocks µ-opioid receptor, anti-craving, anti-priming Acamprosate: Stimulates GABA and inhibits glutamate systems ALDH = aldehyde dehydrogenase; GABA = γ-aminobutyric acid. US Food and Drug Administration. Stotts AL, et al. Expert Opin Pharmacother. 29;1(11): Davies M. J Psychiatry Neurosci. 23;28(4): Naloxone Administered by Nonmedical Persons to Prevent Opiate Overdose Deaths Auto-injector Take-home, hand-held, single-use Has visual and voice instructions for the user to give this injection Available without a prescription in some states To obtain a supply of naloxone: StopOverdose.org Cost (approximately $1+) Intranasal Easier Cost (approximately $37.5) Maxwell S, et al. J Addict Dis. 26;25(3): US Food and Drug Administration.

4 General Principles of Treatment Pharmacotherapy Non-pharmacologic: Psychotherapy Psychotherapy Maximize non-pharmacologic strategies Enhance self-efficacy Decrease helplessness/dependency Enhance coping strategies Prevention of Relapse Avoid high-risk situations Anticipate minor relapses Recover from relapses Identify triggers Centre for Addiction and Mental Health. 9.2 Relapse prevention for substance use problems concurrent_disorders/a_family_guide_to_concurrent_disorders/relapse_prevention/pages/ relapse_prevention_subuse.aspx. Accessed August 23, 216.

5 Pharmacotherapy: New Tools for Addictions Long-acting depot medications Depot naltrexone: Opiates or alcohol Partial agonists Buprenorphine: Opiates OPRM1 = opioid receptor µ1 gene. Hulse GK. Br J Clin Pharmacol. 213;76(5): Pharmacotherapy of Opiate Use Disorder Naltrexone, Methadone, Buprenorphine, Depot Naltrexone Choosing a Medication for OUD Methadone: Built-in structure of the program for better or for worse Naltrexone: Difficult on, easy off Buprenorphine: Easy on, difficult off Agonist vs antagonist: What does the patient/family want? Collaborative process

6 Oral vs Depot Naltrexone: Opiates Retention and opiate-free urine compared in 2 randomized trials of naltrexone Long-acting injectable (n = 42) vs oral (n = 69) Retention and opiate use at 8 weeks post-detoxification Long-acting depot vs oral naltrexone Days retained: Depot, 42 vs oral, 32 Opiate-free urines: Depot,.52 vs oral,.37 Brooks AC, et al. J Clin Psychiatry. 21;71(1): Opiate Pharmacotherapy: Buprenorphine Partial opioid agonist Reduced overdose potential and abuse liability Less severe withdrawal than methadone when stopped Comparable to methadone in treatment retention and reduced heroin abuse Can be given in the doctors office Increased availability and reduced stigma Kosten TR, et al. Am J Addict. 24;13 Suppl 1:S1-S7. Intrinsic Activity: Full Agonist (Methadone), Partial Agonist (Buprenorphine), and Antagonist (Naltrexone) 1 9 Full Agonist (Methadone) Partial Agonist (Buprenorphine) Antagonist (Naloxone) Intrinsic Activity Log Dose of Opioid Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 4. DHHS Publication No. (SMA) Rockville, MD: Substance Abuse and Mental Health Services Administration, 24.

7 Maintenance Treatment Using Buprenorphine/Naloxone Naloxone added to sublingual buprenorphine maintenance formulation to deter parenteral abuse Naloxone has low sublingual bioavailability and combination equivalent to buprenorphine alone Numerous outpatient clinical trials compare efficacy of daily buprenorphine to placebo and to methadone Buprenorphine is more effective than placebo Buprenorphine is as effective as moderate doses of methadone (eg, 6 mg/day) Kosten TR, et al. Am J Addict. 24;13 Suppl 1:S1-S7. 1 Buprenorphine vs Methadone: Opiate Urine Results All Participants Mean % Negative % Bup 39% Hi Meth 19% Lo Meth Study Week Johnson RE, et al. JAMA. 1992;267(2): Equivalent Opiate Dose: Different Withdrawal Severity Heroin Severity of Withdrawal Buprenorphine Methadone Days Since Last Opiate Dose Kosten TR, et al. Am J Addict. 24;13 Suppl 1:S1-S7.

8 Investigational: Monthly Injectable Buprenorphine 2 monthly formulations being developed Polymer based Microcapsule based Side effects of injectable buprenorphine Injection site: Pain, itching, and redness Body: Headache, depression, constipation, nausea, vomiting, back pain Advantages Dosing equal to 8 mg to 24 mg sublingual buprenorphine Easy monthly injection No removal needed (vs implant) ClinicalTrials.gov Identifier: NCT Sobel BF, et al. Drug Alcohol Depend. 24;73(1): Partial Agonists: Summary Buprenorphine for opiates (vs methadone) Reduced overdose and abuse potential Fewer withdrawal symptoms Office-based practice with lower stigma Long-acting 6-month implant and monthly injections reduce diversion, abuse, and accidental child use Insufficient physician prescribing: Education! 2.5 million treatment-seeking opiate patients Patients per prescriber limit expanded 1 => 275 Most prescribers have fewer than 1 patients Kosten TR, et al. Am J Addict. 24;13 Suppl 1:S1-S7. Turner L, et al. Am J Addict. 215;24(1): Pharmacotherapy of Alcohol Use Disorder: Relapse Prevention Naltrexone, Disulfiram, Acamprosate

9 Naltrexone and Alcohol: Background Case History Lars Sweden: 45-year-old white man with 3 years of AUD and in his third marriage After 5 to 7 drinks, he gets loud and sometimes violent, including abusing his wife He failed multiple detoxifications and trial of disulfiram He got sick once after drinking and then refused disulfiram Mechanism of Naltrexone for Reducing Alcohol Relapse Alcohol raises β-endorphin Naltrexone raises β-endorphin through blocking feedback inhibition via presynaptic µ-opioid receptors Naltrexone reduces alcohol stimulation and craving by maximal β-endorphin stimulation of postsynaptic µ-opioid receptors Because β-endorphin levels are maximized, alcohol cannot further raise β-endorphin or increase µ-opioid receptor stimulation, thereby reducing high and priming effect from alcohol Haile CN, et al. Am J Drug Alcohol Abuse. 28;34(4): Krishnan-Sarin S, et al. Biol Psychiatry. 27;62(6): Gianoulakis C. Eur J Pharmacol. 199;18(1): Dai X, et al. Alcohol Clin Exp Res. 25;29(11): Setiawan E, et al. Alcohol Clin Exp Res. 211;35(6): Naltrexone for Alcohol: Advantages and Disadvantages Advantages Reduces priming effect of alcohol lapse, which reduces craving for more alcohol Few interactions with other medications Few side effects and 4 years of safety data Disadvantages Limitations primarily centered on oral naltrexone s poor pharmacokinetic profile and need for daily or 3 weekly adherence Opiates (precipitated withdrawal/block analgesia) Witkiewitz K, et al. Ther Clin Risk Manag. 212;8: US Department of Health and Human Services. Substance Abuse and Mental Health Services Administration. Substance Abuse Treatment Advisory. 25;4(1):1-8.

10 Cumulative Proportion with No Relapse Oral Naltrexone in the Treatment of AUD Naltrexone (n = 35) Placebo (n = 35) Weeks Receiving Medication Volpicelli JR, et al. Arch Gen Psychiatry. 1992;49(11): Jonas DE, et al. JAMA. 214;311(18): Naltrexone (ng/ml) Plasma Concentration (ng/ml) The Poor Pharmacokinetic Profile of Naltrexone Plasma Levels from Daily Dose Time (hours) Fluctuations per Month Therapeutic consequences Suboptimal efficacy associated with daily nadir in drug plasma levels Adverse events associated with high drug levels Adherence problems compounded by the requirement to take medication daily All contribute to relapse Galloway GP, et al. BMC Psychiatry. 25;5:18. 3 Pharmacokinetics of Depot Naltrexone Mean Naltrexone Concentration Naltrexone (ng/ml) Increased and consistent therapeutic concentrations Fluctuating, dose-dependent plasma concentrations Naltrexone 38 mg Intramuscular Injection Oral Naltrexone 5 mg Time (days) Naltrexone mean plasma concentrations over 1 month following 1 depot naltrexone dose Dunbar JL, et al. Alcohol Clin Exp Res. 26;3(3):48-49.

11 Disulfiram Mechanism of action: Inhibits aldehyde dehydrogenase, an enzyme in the metabolism of alcohol Leads to acetaldehyde poisoning when alcohol is ingested Reaction occurs 5 to 15 minutes after drinking Reaction can be quite severe, occasionally fatal Severity is related to dose and individual characteristics Koppaka V, et al. Pharmacol Rev. 212;64(3): Borja-Oliveira CR. J Pharmacovigilance. 214;2:145. Disulfiram: Advantages Built-in impulse control because of prolonged elimination time (up to 2 weeks) May indirectly reduce desire to drink Best used in careful, impulsive, situational drinkers May be used as needed later Importance of adherence strategies: Observed administration DARA Thailand. Alcoholrehab.com. Accessed August 23, 216. Carroll KM, et al. Am J Drug Alcohol Abuse. 27;33(3): Disulfiram: Disadvantages Side effects, including the 2 side effects of greatest concern Liver toxicity Risk of unintentional or intentional alcohol reaction Other disadvantage is possible over-reliance on disulfiram, under-reliance on other supports Center for Substance Abuse Treatment. Incorporating Alcohol Pharmacotherapies Into Medical Practice. Treatment Improvement Protocol (TIP) Series 49. HHS Publication No. (SMA) Rockville, MD: Substance Abuse and Mental Health Services Administration, 29.

12 Acamprosate (N-acetyl homotaurine) Mechanism of action: Interacts with glutamate and GABA neurotransmitters systems May reduce protracted withdrawal symptoms Witkiewitz K, et al. Ther Clin Risk Manag. 212;8: Center for Substance Abuse Treatment. Acamprosate: A new medication for alcohol use disorders. Substance Abuse Treatment Advisory. 25;4(1):1-8. Acamprosate in the Treatment of AUD (continued) Acamprosate Calcium (n = 136) Placebo (n = 136) 1 Treatment Period* Follow-up Period Abstinent Patients (%) % 21% 37% 17% Weeks *P =.1; P =.3; 272 patients were entered into the study over 2 years; Kaplan-Meier survival analysis (survival function estimate); continuous abstinence for the treatment and follow-up periods. Sass H, et al. Arch Gen Psychiatry. 1996;53(8): Acamprosate: Advantages Will not make you sick if you drink May reduce desire to drink Helpful for those with liver disease Increases likelihood of abstinence Center for Substance Abuse Treatment. Acamprosate: A new medication for alcohol use disorders. Substance Abuse Treatment Advisory. 25;4(1):1-8.

13 Acamprosate: Disadvantages Relatively small effect size Recent negative trials, though very recent positive trial from Japan Requires 3 /day dosing Center for Substance Abuse Treatment. Acamprosate: A new medication for alcohol use disorders. Substance Abuse Treatment Advisory. 25;4(1):1-8. Choosing an AUD Medication Goal of treatment, patient wishes Current status (ie, duration of abstinence) Liver, kidney function Other medications (eg, opiates) VA Pharmacy Benefits Management Services, Medical Advisory Pane, and VISN Pharmacist Executives. Alcohol use disorder pharmacotherapy: recommendations for use. December Alcohol_Use_Disorder_Pharmacotherapy_Acamprosate_Naltrexone_Disulfiram_Recommendations_f or_use.docx. Accessed August 23, 216. Pharmacotherapy Conclusions Address patient and physician-centric barriers Patient s treatment adherence: depot medications Providers poor adoption of effective pharmacotherapy: education needed! Individualized care of patients with SUD Pharmacogenetics is evolving Individualized dosing and duration of medications Behavioral interventions, including contingencies

14 Combining Medications to Treat SUDs and Psychiatric Comorbidities Depression Co-occurring Disorder Pharmacotherapy Typically focuses on treatment of the psychiatric disorder, although more recent studies have focused on SUD as well Choice of medication is typically based on the typical considerations Profile of side effects Family history of medication response Likelihood of medication adherence Pharmacotherapy of SUD and Depression Tricyclic antidepressants have the most robust effect SSRIs most helpful in late-onset alcoholics and may worsen early-onset alcoholics Less improvement in SUD (often correlated with mood improvement), but not worsening (ie, not enabling) Buprenorphine has efficacy for treatment-resistant depression independent of OUD But adding SSRI to buprenorphine has no added benefit SSRI = selective serotonin reuptake inhibitor. Nunes EV, et al. JAMA. 24;291(15): Pani PP, et al. Cochrane Database Syst Rev. 21; (9):CD8373. Fava M, et al. Am J Psychiatry. 216;173(5): Nunes EV, et al. Arch Gen Psychiatry. 1998;55(2):

15 Sertraline + Naltrexone for Depressed Alcoholics First-Drink Day and Heavy-Drinking Day Proportion of Participants without a Heavy-Drinking Day Proportion of Participants Remaining Abstinent Days Days Placebo Sertraline Naltrexone Sertraline + Naltrexone Pettinati HM, et al. Am J Psychiatry. 21;167(6): Practical Take-Aways Intranasal naloxone prevents opiate overdose deaths in communities Depot naltrexone has better adherence than oral naltrexone for AUD and OUD Partial opioid agonist buprenorphine has excellent safety and efficacy results with less withdrawal when stopped; long-acting depot available Pharmacogenetics can match alcoholics with medications such as naltrexone SUD with depression, psychosis, or PTSD: Limited data on combination pharmacotherapies Buprenorphine +/- tricyclic antidepressants for depression and OUD Valproate for bipolar disorder and alcoholism Sertraline + naltrexone for major depression and alcoholism Naltrexone for depression or psychosis with alcoholism Disulfiram for PTSD and alcoholism