Pharmacotherapy for Alcohol Use Disorder Addiction DayCSAM - PowerPoint PPT Presentation

Pharmacotherapy for Alcohol Use Disorder Addiction Day—CSAM November 12, 2015 Banff Alberta Laura D. Evans MD CCFP Certificant International Society of Addition Medicine Diplomate American Board of Addiction Medicine

No conflicts of interest to declare — Background: — Alberta Health Services — Foothills Medical Centre Addiction Centre — Addiction Network Hospital Consults — Renfrew Recovery and Detox Centre — Opioid Dependence Program — C.U.P.S. Primary Care Clinic — Clinical Assistant Professor Department of Family Medicine University of Calgary — Board Member Canadian Society of Addiction Medicine; CSAM—SCMA

Outline Pharmacotherapy options for treatment of alcohol use disorder — (AUD) Naltrexone — Acamprosate — Disulfiram — Others? — Mechanisms of action — Current evidence — Dosing and initiation, contraindications, side effects, monitoring — Cost and availability — Cases —

Medication options — 3 Medications approved by Health Canada 1 1 st — Naltrexone line — Acamprosate — Disulfiram 2 nd line — Numerous off-label medications, some requiring further study — Moderate evidence for Topiramate, Nalmefene, 2 — Limited evidence for Gabapentin, 3 Baclofen 4,5 1 Spithoff S, Kahan M. Primary care management of alcohol use disorder and at-risk drinking. Can Fam Physician. 2015;61:515- 521. 2 Jonas D, Amick H, Feltner C, Bobashev G, Thomas K, Wines R et al. Pharmacology for adults with alcohol use disorder in outpatient settings: a systematic review and meta-analysis. JAMA. 2014; 311(18):1889-1900. 3 Uptodate. Pharmacotherapy for alcohol use disorder. 2015. 4 Addolorato G. Leggio L, Ferruli A, et al. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol- dependent patients with liver cirrhosis: randomized , double-blind controlled study. Lancet 2007. 370:1915. 5 Addolorato G, Caputo F, Capistro E, et al. Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study. Alcohol alcohol. 2002: 37:504.

Medication options — Underutilized — <1/3 of those with AUD receive treatment 1 and <10% with AUD receive pharmacotherapy 2 — Should be considered for all patients with moderate or severe alcohol use disorder 2,3,4,5,6 who: — Have current, heavy use and ongoing risk for consequences 4 — Motivated to reduce intake 4 — Prefer medication along with (ideally) or instead of psychological intervention 4 — Have no medical contraindications to the drug 4 1 Hasin D, Stinson F, Ogburn E, Grant B. Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. ArchGen Psychiatry. 2007;64(7):830-842. 2 Jonas D, Amick H, Feltner C, Bobashev G, Thomas K, Wines R et al. Pharmacology for adults with alcohol use disorder in outpatient settings: a systematic review and meta-analysis. JAMA. 2014; 311(18):1889-1900. 3 Spithoff S, Kahan M. Primary care management of alcohol use disorder and at-risk drinking. Can Fam Physician. 2015;61:515-521. 4 Uptodate. Pharmacotherapy for alcohol use disorder. 2015. 5 Jorgensen C, Pedersen B, Tonnesen H. The efficacy of disulfiram for the treatment of alcohol use disorder. Alcohol Clin Exp Res. 2011;35(10):1749-1758. 6 Substance Abuse and Mental Health Services Administration and National Institute on Alcohol Abuse and Alcoholism. Medication for the treatment of alcohol use disorder: a brief guide. HHS Publication No. (SMA) 15-4907. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2015.

Medication options — Modeling study estimated that if 40% of all individuals with alcohol {use disorder mod-severe} received pharmacotherapy, there would be a 13% reduction in alcohol-attributable mortality in the European Union 1 — Barriers: — Cost? — Availability? — Prescriber and treatment team familiarity and support? — Education re: effectiveness? 1 Rehm J, Shield K, Gmel G, Rehm M, Frick U. Modeling the impact of alcohol dependence on mortality burden and the effect of available treatment interventions in the European Union. Eur Neuropsychopharmacol. 2013. 23(2): 89-97.

Mechanism of action Naltrexone Opioid receptor antagonist Reduces rewarding effects of ETOH, by reducing dopamine release in response to ETOH 1 — May be particularly effective in those with genetic susceptibility 2 — Asp variant of the OPRM 1 gene less likely to relapse — Heterozygotes for ASP-40 allele 6x more favourable outcome 1 Maisel N, Blodgett J, Wilbourne P, Humphreys K, Finney J. Meta-analysis of naltrexone and acamprosate for treating alcohol use disorder: When are these medications most helpful?. Addiction. 2013; 108(2):275- 293. 2 Uptodate. Pharmacotherapy for alcohol use disorder. 2015

Mechanism of action Acamprosate Restores the balance between GABA and glutamate systems disrupted by chronic alcohol use. Thought to normalize hyper excitability and re- establish homeostasis. 1,2 Glutamate GABA Glutamate Glutamate GABA GABA Acute ETOH use Chronic ETOH withdrawn 1 Maisel N, Blodgett J, Wilbourne P, Humphreys K, Finney J. Meta-analysis of naltrexone and acamprosate for treating alcohol use disorder: When are these medications most helpful?. Addiction. 2013; 108(2):275-293. 2 Restrepo R. Diagram adapted from ASAM Review Course 2015.

Mechanism of action Disulfiram Blocks conversion of acetaldehyde to acetic acid, causing buildup acetaldehyde. 1 1 Krampe H, Ehrenreich H. Supervised disulfiram as adjunct to psychotherapy in alcoholism treatment. Current Pharmaceutical Design. 2010; 16:2076-2090.

Mechanism of action Topiramate — Combination of potential mechanisms: Blocks neuronal voltage-dependent sodium — channels, enhances GABA A activity, resulting in inhibitory effect 1 Gabapentin — Structurally related to GABA but doesn’t activate GABA A or GABA B . Instead may — bind to sites which correspond with voltage-gated calcium channels with the alpha- 2-delta-1 subunits. These channel are located presynapticaly, and may modulate the release of excitatory neurotransmitters 1 Baclofen — Activates GABA B , blocks monosynaptic and polysynaptic reflexes by acting as an — inhibitory neurotransmitter, blocking the release of excitatory transmitters 1 Nalmefene — Adopted in Europe but is not available in NA — Similar to naltrexone in structure and activity—opioid antagonist—but longer half — life, greater bioavailability, more effective binding to central opioid receptors and no observed dose-dependent liver toxicity 2 1 Uptodate. Drug Information, 2015 2 Uptodate. Pharmacotherapy for alcohol use disorder. 2015

Outcomes — Abstinence — Return to any drinking: Yes/No — Reduction in consumption — Return to any heavy* drinking: Yes/No — % drinking days — %heavy drinking days * ≥ 5 for males or ≥ 4 females

Evidence

Naltrexone po and Acamprosate associated with improved consumption outcomes 1 Abstinence rates compared to placebo — Both acamprosate and naltrexone po showed fewer returned to drinking — (9% and 5% fewer respectively): Inadequate evidence in well-controlled trials or no benefit for other — medication options NNT to prevent return to any drinking (abstinence) — Acamprosate: 12 — Naltrexone po: 20 — Return to heavy drinking compared to placebo — Acamprosate=no improvement — Naltrexone po=improvement with NNT: 12 — — 9% fewer returned to heavy drinking Inadequate evidence in well-controlled trials or no benefit for other — medication options 1 Jonas D, Amick H, Feltner C, Bobashev G, Thomas K, Wines R et al. Pharmacology for adults with alcohol use disorder in outpatient settings: a systematic review and meta-analysis. JAMA. 2014; 311(18):1889-1900.

Naltrexone po and Acamprosate associated with improved consumption outcomes 1 — % drinking days compared to placebo — Both acamprosate and naltrexone po showed reductions (8.8% and 5.4% respectively) — Disulfiram: No statistically significant difference — Some evidence for topiramate as discussed below — % heavy drinking days — Both acamprosate and naltrexone po showed reductions (2.6% and 4.1% respectively) — Disulfiram: No well-controlled trials looking at this — Some evidence for topiramate & nalmefene as discussed below 1Jonas D, Amick H, Feltner C, Bobashev G, Thomas K, Wines R et al. Pharmacology for adults with alcohol use disorder in outpatient settings: a systematic review and meta-analysis. JAMA. 2014; 311(18):1889-1900.

Naltrexone po and Acamprosate associated with improved consumption outcomes 1 — “Meta-analyses of head-to-head RCTs comparing acamprosate with naltrexone po found no statistically significant difference between the two medications” — COMBINE was one of the RCTs included — Naltrexone (+MM)* = Combined behavioural intervention (+MM)=Naltrexone+CBI (+MM) — All better than placebo — But acamprosate showed no evidence of efficacy over placebo with or without CBI NALTREXONE AND ACAMPROSATE ARE CONSIDERED 1 ST LINE * Medical management: comprised of up to 9 manual-guided couselling visits at weeks 0,1,2,4,6,8,10,12 &16. Initial visit 45mins; 20 mins thereafter. Includes advice for reducing ETOH, review of adverse effects of meds., & emphasis on importance of adherence. 1 1 Jonas D, Amick H, Feltner C, Bobashev G, Thomas K, Wines R et al. Pharmacology for adults with alcohol use disorder in outpatient settings: a systematic review and meta-analysis. JAMA. 2014; 311(18):1889- 1900.