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1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. This online publication has been corrected. The corrected version first appeared at thelancet.com on September 9, Supplement to: Connor JP, Haber PS, Hall WD. Alcohol use disorders. Lancet 2015; published online Sept 4.

2 Web Appendix Table 1: DSM-5 Diagnostic Criteria 1 Broad Domain DSM-5 Diagnostic Criteria DSM-IV Impaired Control 1. Drinking larger amounts or over longer periods than intended. 2. Desire or unsuccessful attempts to cut down or control alcohol use. 3. A great deal of time spent obtaining, using or recovering from alcohol 4. Craving, or a strong desire or urge to use alcohol New for DSM-5 Social Dysfunction 5. Failure to fulfil major role obligations as a result of Abuse and Physical Risk alcohol use 6. Continued drinking despite social or interpersonal Abuse problems 7. Diminished social, occupational or recreational activities due to drinking 8. Recurrent alcohol use in physically hazardous Abuse situations 9. Continued drinking despite physical or psychological problems Physiological 10. Tolerance, as evidenced by a markedly diminished effect 11. Withdrawal Syndrome, or drinking to prevent withdrawal Threshold for Diagnosis of an Alcohol Use Disorder (AUD) At least 2 symptoms Severity AUD Index Mild=2 to 3 symptoms; Moderate=4 to 5 symptoms; Severe=6 or more symptoms Specifiers Early remission 3 to 12 months without AUD criteria met (except craving) Sustained remission >12 months without AUD criteria met (except craving) Page 1 of 4

3 Table 2: Emerging Medications for the Treatment of Alcohol Use Disorders Medication Drug Class Approved Proposed Mechanism Adverse Reactions Current Evidence (key findings) Indication Topiramate Anticonvulsant Paediatric epilepsy, migraine, weight loss Inhibits mesolimbic dopamine release, via GABAergic function plus antagonism of AMPA and KARs Paraesthesiae, tiredness, cognitive dulling, dizziness, weight loss Single site 2 and multi-site 3 blinded controlled trials show reductions in heavy drinking days and increased abstinence. Equivalent to naltrexone in a blinded study and superior in an open label study metaanalysis concluded that there is insufficient evidence for use in AUDs 6 Gabapentin Anticonvulsant Epilepsy, neuropathic pain Calcium channel/gabamodulator Clumsiness, eye movement, muscle coordination Blinded controlled trials showed reduced drinking in patients with 7 and without 8 comorbid insomnia. When combined with naltrexone it improved drinking outcomes but only while adjunctively prescribed. 9 A meta-analysis concluded that there is insufficient evidence for use in AUDs. 6 Baclofen Muscle relaxant and antispasticity agent Reversible spasticity, neuropathic pain GABA-B receptor agonist Somnolence, dizziness, fatigue, potential tolerance, nausea Several small, open label trials. Largest (n=84) blinded controlled trial in cirrhotic patients reported improved abstinence rates and reduced consumption. 10 Not superior to placebo in alcohol dependent (non-cirrhotic) patients in subsequent study. 11 A recent study suggests that baclofen may be more effective at reducing Page 2 of 4

4 drinking in patients with comorbid anxiety. 12 Varenicline Nicotinic Smoking Partial α4β2 nicotinic Nausea, dizziness, Two blinded controlled studies have included alcohol receptor cessation acetylcholine receptor agitation dependent smokers and non-smokers (remaining partial agonist agonist studies exclusively smoking, alcohol users). Largest study (n=200) found reduced heavy drinking days but not increased abstinence. 13 This was not the case in a smaller study (n=40). 14 Largest blind controlled sample of (non-dependent) drinking smokers (n=64) 15 found reduced alcohol consumption, but not increased abstinence. References 1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC: APA; Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet 2003; 361(9370): Johnson BA, Rosenthal N, Capece JA, et al. Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA 2007; 298(14): Baltieri DA, Daro FR, Ribeiro PL, de Andrade AG. Comparing topiramate with naltrexone in the treatment of alcohol dependence. Addiction 2008; 103(12): Florez G, Saiz PA, Garcia-Portilla P, Alvarez S, Nogueiras L, Bobes J. Topiramate for the treatment of alcohol dependence: comparison with naltrexone. Eur Addict Res 2011; 17(1): Pani PP, Trogu E, Pacini M, Maremmani I. Anticonvulsants for alcohol dependence. Cochrane Database Syst Rev 2014; 2: CD Brower KJ, Myra Kim H, Strobbe S, Karam-Hage MA, Consens F, Zucker RA. A randomized double-blind pilot trial of gabapentin versus placebo to treat alcohol dependence and comorbid insomnia. Alcohol Clin Exp Res 2008; 32(8): Mason BJ, Quello S, Goodell V, Shadan F, Kyle M, Begovic A. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med 2014; 174(1): Page 3 of 4

5 9. Anton RF, Myrick H, Wright TM, et al. Gabapentin combined with naltrexone for the treatment of alcohol dependence. Am J Psychiatry 2011; 168(7): Addolorato G, Leggio L, Ferrulli A, et al. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcoholdependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet 2007; 370(9603): Garbutt JC, Kampov-Polevoy AB, Gallop R, Kalka-Juhl L, Flannery BA. Efficacy and safety of baclofen for alcohol dependence: a randomized, double-blind, placebo-controlled trial. Alcohol Clin Exp Res 2010; 34(11): Morley KC, Baillie A, Leung S, Addolorato G, Leggio L, Haber PS. Baclofen for the treatment of alcohol dependence and possible role of comorbid anxiety. Alcohol Alcohol 2014; September 21: /alcalc/agu Litten RZ, Ryan ML, Fertig JB, et al. A double-blind, placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence. J Addict Med 2013; 7(4): Plebani JG, Lynch KG, Rennert L, Pettinati HM, O'Brien CP, Kampman KM. Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence. Drug Alcohol Depend 2013; 133(2): Mitchell JM, Teague CH, Kayser AS, Bartlett SE, Fields HL. Varenicline decreases alcohol consumption in heavy-drinking smokers. Psychopharmacology (Berl) 2012; 223(3): Page 4 of 4

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