Updates in the Treatment of Alcohol Use Disorder
Laura Evans MD CCFP AM C.ISAM C.CSAM C.ABAM Presenter: Laura D. Evans MD • Speakers Bureau/Honoraria: Speaker - Alberta College of Family Physicians; Cummings School of Medicine University; Alberta Health Services • Consulting Fees: N/A • Grants/Research Support: Research Grant Received - University of Calgary-Addiction & Mental Health Strategic Clinical Network • Patents: N/A • Other: Board Member & Treasurer - Canadian Society of Addition Medicine (CSAM) Not-For-Profit and employee of Alberta Health Services Opioid Dependence Program • The Alberta College of Family Physicians has provided support in the form of a speaker fee and/or expenses. Background • Alberta Health Services • Addiction Inpatient Consultation Service: • FMC—Medical Lead • ARCH—PLC Staff Physician • Renfrew Recovery and Detox Centre; Co-Medical Lead • Addiction Centre Concurrent Outpatient Program (FMC) • Opioid Dependence Program, ODP • C.U.P.S. Medical—Primary Care Clinic • Clinical Assistant Professor Department of Family Medicine University of Calgary • CSAM—Canadian Society of Addiction Medicine, Board Member, Treasurer
Learning objectives
• Identify the health impacts of alcohol, and alcohol use disorder (AUD) • Recognize the indications for pharmacotherapy in AUD • Evaluate the treatment options for alcohol use disorder in a clinical context • Review the treatment effect size of pharmacotherapy in alcohol use disorder Health Impacts of Alcohol
• 7.7% of Canadian deaths related to alcohol abuse (2016)1 • Associated with 200 disease or injury conditions2 • Worldwide 3 million deaths/year (5%), more than lung cancer and HIV combined(2012)3 • Total hospitalizations directly related to ETOH: 77,000 or 212/day (2015-16)4 • More than for heart attacks: 75,000 (2015-16)4
1BCCSU 2019 2Rehm et al 2009 3Chief Public Health Officer’s Report on the State of Public Health in Canada in 2015 4Canadian Centre on Substance Use and Addiction 2017 Burden of disease shifting towards women • ED visits↑4.4 x (2003-16 in ON)1 • Women: rate of increase 86.5% Canadians • Men: rate of increase 53.2% should prepare • Visits for young women: ↑240%1 for rising • Alcohol-related deaths (Canada): alcohol-related • ↑26% women vs. harms, • ↑5% men (2001-16)2 particularly in • Admissions related to alcohol ↑3% in just 1 yr!! (2015-16)2 young girls & women2,3 • Admissions related to alcohol for girls > boys aged 10-192
1Myran 2019 2www.cihi.ca/en/alcohol-harm-on-the-rise-for-Canadian-women 3Spithoff, 2019 Health Impacts of Alcohol & AUD
• 22 million or nearly 80% of Canadians drank alcohol in the previous year
Health Canada 2015 Age distribution of the 22million or 80% of Canadians who drink
Health Canada 2015 Risky drinking:
Of the 22 million or nearly 80% of Canadians who drank in the past year: • 3.1 million or 14% at risk for immediate injury & harm • 4.4 million or 20% at risk for chronic effects such as liver cirrhosis & various types of cancer
Health Canada 2015 AUD Prevalence DSM-5 Criteria
• Canadian data: • 18% of >15 yrs. meet criteria during their lives1 • 8% of >15 yrs. meet criteria for active/current AUD2
1BCCSU 2019 2 World Health Organization, 2018. https://www.who.int/substance_abuse/publications/global_alcohol_report/profiles/can.pdf Health impacts of alcohol
Health Canada 2015 In terms of cancer risk, no safe limit is known (Canadian Cancer Society)
Health Canada 2015 Health impacts of alcohol
• Cancer: • Alcohol is considered carcinogenic • No safe amount known • Heavy ETOH strongly associated with ↑ risk of the following cancers: • Colorectal & Breast: 50% ↑ risk • Oral, pharyngeal, oesophageal: 5x ↑ risk • Laryngeal: 2.5x 5x ↑ risk
Health Canada 2015 $4.2 of $14.6 Billion are direct health care costs1
1Canadian Substance Use Costs and Harm Scientific Working Group. (2018). Canadian substance use costs and harms (2007-2014). Ottawa: Canadian Centre on Substance Use and Addiction.
Importance of recognizing high-risk drinking and AUD
• Screening provides critical opportunity to intervene • Many may respond to brief counselling and interventions alone, change behavior and reduce risk of harms related to alcohol
BCCSU 2019 Saitz 2019 Many validated screening tools
• CAGE Questionnaire • Single Alcohol Screening Question • Have you ever felt you ought to Cut down (SASQ): on your drinking? • “In the past year how often have you • Have people Annoyed you by criticizing consumed more than 3 drinks (adult your drinking? women) or 4 drinks (for adult men) • Have you ever felt bad or Guilty about on any one occasion?”. your drinking? • Any answer >zero or never is a • Have you ever had a drink in the morning positive screen for high-risk drinking, (Eye-opener) to get rid of a hangover? warranting additional follow-up. • AUDIT: Alcohol Use Disorders Identification Test • AUDIT-C: Condensed AUDIT- Consumption Test DSM-5 Diagnostic Criteria for AUD
A problematic pattern of alcohol use leading to clinically significant impairment or distress, as manifested by two or more of the following within a 12-month period, indicates presence of an AUD: Specifiers: • Alcohol is often taken in larger amounts or over a longer period than was intended • Remission: • Early remission: full criteria for a AUD • Persistent desire or unsuccessful efforts to cut down or control use previously met, and none met (with the • A great deal of time is spent in activities necessary to obtain or use alcohol, or recover exception of craving) for 3-12 months • Sustained remission: full criteria for a from its effects AUD previously met, and none met (with the exception of craving) for more than 12 • Craving or strong desire to use alcohol months • In a controlled environment: If the • Recurrent use resulting in failure to fulfill major role obligations at work, school, or individual is in an environment where home access to alcohol is restricted (e.g. residential facility, incarcerated, etc.) • Continued use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of use • Severity: • Mild: 2-3 symptoms • Important social, occupational, or recreational activities are given up or reduced • Moderate: 4-6 symptoms because of use • Severe: 6 or more symptoms • Recurrent use in situations in which it is physically hazardous • Continued use despite knowledge of having persistent or recurrent physical or psychological problem that it likely to have been caused or exacerbated by alcohol • Tolerance: the need for more to get the same effect or diminished effect with similar amount • Withdrawal: typical withdrawal or use of ETOH or benzo to relieve/avoid withdrawal 5As Model for Delivering Alcohol Use Brief Intervention*
• ASK: Screen and document alcohol use for all patients. Identify those drinking above low- risk guidelines • ADVISE: that they are drinking above the low-risk limits, and that they may be at risk of alcohol-related harms • ASSESS: Is individual willing to make a change at this time? Confirm/exclude Dx of AUD since BI alone is not effective for those with AUD • ASSIST: For those willing to reduce or stop using alcohol, develop a treatment plan; provide supportive counselling and advise, and referrals to community resources • ARRANGE: Schedule a follow-up visit, preferably within a week of the planned change date
*Robust evidence for BIs in primary care: 2018 Meta-analysis showed sustained reductions in alcohol use up to 1 year later (1.5 fewer drinks on average compared to minimal or no intervention)
BCCSU 2019 Indications for pharmacotherapy ✓Diagnosis of AUD moderate- Alongside information and severe as per DSM-5; or referrals for psychosocial treatment, community-based ✓Regardless of severity, offer to supports, peer and family support any patient who stopped or groups, and recovery support reduced & has cravings or is at services risk of relapse ; and ✓Interested in medication Considerations for referral to inpatient treatment programs • Not benefitted from multiple previous outpatient tx attempts • Severity of AUD • Co-occurring mental health disorder • Unstable social environment or circumstances • Pregnant • Consider programs offering cultural interventions and tailored programs for indigenous people Saitz 2019; BCCSU 2019; Spithoff 2017; Goals of pharmacotherapy—abstinence vs. reduction
• Traditionally abstinence was primary goal of treatment • Not all patients view abstinence as realistic, acceptable, or desirable • Abstinence only models can prevent some from seeking care or result in disengagement from care • More likely to achieve self-identified goals, whether abstinence, or reduced drinking
Rehm 2013 BCCSU 2019 Naltrexone First-line Mu-opioid receptor antagonist pharmacotherapies Reduces rewarding effects of ETOH, by reducing dopamine release in response to ETOH1, reduces cravings for alcohol in some individuals1,2
• BCCSU Guidelines Acamprosate (2019) Restores the balance between GABA and glutamate systems disrupted by chronic • American Psychiatric alcohol use. Thought to normalize hyper excitability and re-establish homeostasis.1,3 Association4 Glutamate GABA • Up-to-date5 GABA GABA Glutamate
Acute ETOH use Chronic ETOH withdrawn
1Maisel et al 2013 2BCCSU 2019 3Restrepo R. Diagram adapted from ASAM Review Course 2015. 4 Reus et al 2018 5 Saitz, 2019 Efficacy naltrexone vs. placebo & acamprosate vs. placebo Return to any drinking/relapse: Return to heavy drinking:
Naltrexone 50mg PO daily: ✔️ NNT to prevent relapse: 20 ✔️ NNT to prevent return to heavy consumption: 12
• # Studies: 16 19 • # Participants 2,347 2,875 • Results effect size (95%CI): RD: -0.05 RD: -0.09
Acamprosate: ✔️ NNT to prevent relapse: 12 ✖️Not statistically significant, thus NNT not calculated
• # Studies: 16 7 • # Participants 4,847 2,496 • Results effect size (95%CI): RD: -0.09 RD: -0.01
Jonas et al 2014 Other meta-analyses echo these findings:
Relative to placebo both exert statistically significant (although modest) effect in preventing relapse; with Acamprosate tending to be slightly superior Ntx for Abstinence; and only Ntx preventing return to heavy drinking1,2,3,4,5
1Jonas et al 2014 2Maisel et al 2013 3Rosner et al. 2010. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev ; CD001867. 4Rosner et al 2010. Acamprosate for alcohol dependence. Cochrane Database Syst Rev ; CD004332. 5Rosner et al 2008 Effect size Return to any Return to heavy Effect size: drinking/relapse: drinking:
Naltrexone 50mg ✔️ NNT to prevent ✔️ NNT to prevent return PO daily: relapse: 20 to heavy consumption: 12
• # Studies: 16 19 Cohen 1977 cited in McLeod 2019 • # Participants 2,347 2,875 • Results effect RD: -0.05 RD: -0.09 Effect size: size (95%CI): v. small v. small Very small= 0.01 Acamprosate: Small= 0.2 ✔️ NNT to prevent return ✖️Not statistically Medium= 0.5 to heavy drinking: 12 significant, thus NNT not Large= 0.8 calculated Very large= 1.2 • # Studies: 16 7 Sawilowsky 2009 • # Participants 4,847 2,496 • Results effect RD: -0.09 RD: -0.01 size (95%CI): v. small Interpreting effect size • Caution in using the small, medium, large effect size rule of thumb1 • Small and large effects can mean different things in different contexts • Whereas a “small” reduction in suicide rates is invaluable • A “small” reduction in weight loss may be meaningless • Refer to bigger picture and other studies to see significance of results2 • Given the tremendous burden disease for AUD and challenge to find impactful treatments, even a small or v. small effect size can have significant impact
1Cohen 1977 2Durlak 2009 Importance of pharmacotherapy
• Despite burden of disease, few with AUD receive treatment:1,2,3 • <8% in U.S. in the past 12 months1 • <10% in European countries2 • <1% with AUD receive pharmacotherapy • Only 0.4% (37 of 10,394) public drug beneficiaries filled Rx for Naltrexone or Acamprosate in the year following AUD hospital visit in ON3 • Only 0.9% (493 of 53,625) diagnosed with AUD filled Rx for Naltrexone, Acamprosate or Disulfirum in 2018 in MB1
1BCCSU 2019 2 Rehm 2013 3Spithoff 2017 Importance of pharmacotherapy
• Modeling study estimated that if 40% of all individuals with alcohol dependence (DSM-5: use disorder mod-severe) received pharmacotherapy along with psychosocial supports*, there would be a 13% reduction in males and 9% reduction in females in alcohol- attributable mortality in the European Union1
1Rehm et al 2013 *CBT, MI, Brief Intervention; Pharmacotherapy is most effective overall (Rehm 2013) Based on Cochrane 2010 reviews, assumes pharmacotherapy (acamprosate & ntx) would result in the following: for 55% of reduction of drinking by 13%; for 18% a reduction of 50%; and abstinence for 26.8% Other pharmacotherapy options? • Approved by Health Canada for treatment in AUD • 1st line: • Naltrexone • Acamprosate • 2nd line: • Disulfiram • Off-label medications • Limited evidence—Consider as 2nd Line: • Topiramate1,2 • Gabapentin3,4,5 • Very limited evidence—Inadequate evidence to recommend for use • Baclofen6 • Ondansetron7,8 • 38-70% treated with naltrexone or acamprosate do not benefit, or only partially benefit9,10
1Jonas et al, 2014 2Blodgett et al 2019 3Mason et al 2014 4Falk et al 2018 5Kranzler et al 2019 6Rose et al 2018 7Johnson et al 2000 8Sellers et al 1994. 9 Cited in BCCSU 2019 10Raistrick et al 2006 Disulfirum • Aversive agent; no effect unless alcohol ingested • 2014 meta-analysis (2 trials n=492)1 • No difference from placebo in abstinence Disulfiram • Meta-analysis (5 blinded RCTs vs. 17 open-label 2 trials) Blocks conversion of acetaldehyde to acetic acid, • 1st 12 weeks supervised causing buildup acetaldehyde.4 • Disulfiram >ntx and acamp for abstinence, and ↓consumption • Subsequent unsupervised 52 weeks, more similar to real world, benefits dissipated • Only consider if • Strong patient preference over meds with better evidence • Additional support in high risk situations? e.g. vacations, special celebrations • Structured, supervised conditions available3 1Jonas et al, 2014 2Cited in BCCSU 2019 3 Aubin et al, 2015 4 Krampe 2010 Topiramate • 2014 meta-analysis of 7 placebo-controlled trials (n=1,125)1 • May be superior to Ntx for heavy drinking and cravings • May be equal to Ntx for abstinence outcome • But: • Requires titration over 5-8 weeks • AE significantly more common in tx vs. placebo:2 • Paresthesia 51% vs. 11% • Dysgeusia 23% vs. 5% • Anorexia 20% vs. 7% • ↓ concentration or attention 15% vs. 3% • Nervousness 14% vs. 8% • Dizziness 12% vs. 5% • Pruritis 10% vs. 1%
1Blodgett et al 2014 2Cited in BCCSU 2019 Gabapentin • 2019 meta-analysis (7 RCTs n=751) • May be more effective than Ntx for reducing percentage of heavy drinking days1 • But no effect on: abstinence, relapse to heavy drinking, percentage of abstinent days, mean # drinks per day • AE vs. placebo:1 • Dizziness 19% vs. 7% • Somnolence 14% vs. 5% • Ataxia or gait disorder 14% vs. 2% • Peripheral edema 7% vs. 2% • Renally excreted • Safe in severe liver disease • Diversion risks2 • 1% in general pop • 2% of those prescribed gabapentin • 12-22% among opioid-users where access to alcohol & other drugs is restricted (treatment facilities, incarceration)2 • Safety risks • Detected in 22% of all overdose deaths and 26% of all opioid-related overdose deaths3
1Kranzler et al 2019 2Smith et al 2016 3Cited in BCCSU 2019 Baclofen • Early trials showed promise; later trials mixed results • 2018 meta-analysis (12 RCTs)1: • May increase abstinence rates compared to placebo (6 RCTs, n=590) • 2.67 times more likely to be abstinent at end of tx than placebo • NNT: 8 for 1 to achieve abstinence • Small # of trials, and large positive effect of one of the trials • But no improvement on • # days abstinent • % of heaving drinking days • Cravings • 2018 Cochrane review (12 RCTs, n=1,128) • No difference from placebo on any outcome • Increased side effects compared to placebo: • Vertigo, drowsiness, paresthesia, muscle spasms or rigidity • 53% drop out rate reported in larger study, due to persistent AEs2 • “Use of baclofen as a treatment for AUD is premature”1
1Rose, 2018 2Rigal et al 2015 Ondansetron • Small pilot & small clinical trials only; no clear benefit1 • Possibly effective in subset with greater genetic or biological basis • AUD developed
1Jonas et al 2014 2BCCSU 2019 DSM-5 Confirmed AUD: Is patient interested in medication? First-line pharmacotherapies • Goal Abstinence: • Naltrexone • Acamprosate • Goal Reduced Drinking: • Naltrexone (can be initiated while still drinking)
Saitz, 2018 https://www.bccsu.ca/wp-content/uploads/2019/12/AUD-Guideline.pdf Naltrexone vs. acamprosate: other considerations • CI to Ntx: • Opioid use • Liver failure or acute hepatitis • CI to Acamprosate: • Severe renal impairment Regular benefit for Income Support,C AISH, Coverage via Special Auth. Process when • Breast feeding NIHB without Special Auth. Naltrexone CI or ineffective • Acamprosate TID vs. daily dosing • Coverage: Ntx > Acamp • Acamp Spec auth: For CI to Ntx such as severe hepatic disease, failure on Ntx, and must be abstinent 4+ days) • Ok to start Ntx if still drinking • Acamp safe to start if drinking, but likely < effective
https://www.bccsu.ca/wp-content/uploads/2019/12/AUD-Guideline.pdf Combining Medications? • Ntx + acamprosate: • RCT 160 participants; Relapse rates1: • Placebo: 75% • Acamprosate: 50% • Naltrexone: 35.3% • Acamp & Ntx: 27.5% • Conclusion: combo better acamp alone, but not significantly superior to Ntx alone for relapse or heavy drinking • Conversely: COMBINE Study2: • Combo ntx & acamp not more effective than either alone • Ntx + gabapentin • RCT 150 participants1 • Some benefit in early stages of alcohol withdrawal • Overall benefits not well established; premature to recommend
1Cited in BCCSU 2019 2 Anton 2006 Duration of treatment?
• Not well-defined in literature • Medications at least 6-12 months1 • Psychosocial treatment at least 6 months and ideally 12 months1 • Longer if well tolerated and beneficial; sometimes indefinite1
1Saitz 2018 References page 1 of 2
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Addressing rising alcohol-related harms in Canada. CMAJ, 191:E02-3, doi:10.1503/cmaj.190818 Appendix Sample scripts to discuss alcohol use
BCCSU 2019 Alcohol Use Disorder Identifications Test (AUDIT) Screening Tools
AUDIT-Consumption (Audit-C) Tool
BCCSU 2019 C
hBCCSU 2019 BCCSU 2019