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Management of Alcohol Use Disorder: Withdrawal and Pharmacotherapy

Management of Alcohol Use Disorder: Withdrawal and Pharmacotherapy. Richard Saitz MD, MPH, FACP, DFASAM Professor of Community Health Sciences & Medicine Boston University Schools of Medicine & Public Health @unhealthyalcdrg @JAM_lww. School of Public Health.

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Management of Alcohol Use Disorder: Withdrawal and Pharmacotherapy

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  1. Management of Alcohol Use Disorder:Withdrawal and Pharmacotherapy Richard Saitz MD, MPH, FACP, DFASAM Professor of Community Health Sciences & Medicine Boston University Schools of Medicine & Public Health @unhealthyalcdrg @JAM_lww School of Public Health

  2. A 43 year old man presents because he bumped his head after slipping and falling. No loss of consciousness. Breath alcohol is 210 mg/dL (0.21 g/100mL). He reports no hematemesis, hematochezia, melena, tremors, past seizures, liver disease, gastrointestinal bleeding, pancreatitis or delirium. He lives alone and reports drinking all day since he became disabled from lumbar disc disease ten years ago. He takes no medications, has no allergies, and smokes one pack of cigarettes daily. T 98, RR 18, HR 110 (regular), BP 136/82 standing, 100, 140/70 lying down. EOMI, supple neck, no tremor; frontal ecchymosis. He is awake, alert and oriented to place, time and person. Speech is fluent. Gait normal. Sensorimotor exam non-focal.

  3. Four hours later (15-20 mg/dL/hr [1 drink] elimination), the patient becomes tremulous, anxious, and complains of nausea. BP 134/84, HR 90, ethanol level 146 mg/dl. • What is the diagnosis? • What is appropriate management?

  4. ALCOHOL WITHDRAWALTRIAGE • Outpatient • Last drink >36 hrs • No other risk factors, responsible other • Consider inpatient • Past seizure, drug use, anxiety disorder, multiple detoxifications, alcohol >150 • Inpatient • Older age (>60), concurrent acute illness, seizure, moderate to severe symptoms • ICU level • DTs

  5. American Society of Addiction Medicine Practice Guidelines • Symptom-triggered (q 1 when CIWA-Ar>8) • Chlordiazepoxide 50-100 mg • Diazepam 10-20 mg • Lorazepam 2-4 mg • Fixed schedule (q 6 for 4/8 doses + PRN) • Chlordiazepoxide 50 mg/25 mg • Diazepam 10 mg/5 mg • Lorazepam 2 mg/1 mg The CIWA-Ar Mayo-Smith and ASAM working group JAMA 1997;278:144-51 Saitz and O’Malley Med Clin N A 1997;81:881-907

  6. The patient is seen having a generalized tonic-clonic convulsion. • What is the most likely etiology? • What is the appropriate work-up? • Can it be prevented?

  7. Past seizures predict future seizures 80% are single; 90% of recurrences in 6hclinical diagnosis (alternative dx if atypical) Benzodiazepines reduce incident seizuresn=389 in 5 pla-controlled trials (8% v 0.5%) Benzodiazepines reduce recurrence (to <3%) Sereny 1965, Kiam 1969, Zilm 1980, Sellers 1983, Naranjo 1983, summarized in Mayo-Smith MF & ASAM Working Group JAMA 1997;278:144-51 D’Onofrio et al NEJM

  8. The patient tells you he is at the racetrack with his friends, BP 170/100, HR 110, Temp 99. • What is the diagnosis? • What if he were febrile? • Can it be prevented? Treated? DSM-5 DEFINITION: alcohol withdrawal delirium • A disturbance in attention and awareness • Develops over hours to days, a change from baseline, and fluctuates • And a disturbance in cognition

  9. DTs: Treatment • N=34, RCT • Diazepam 10 mg IV then 5mg q 5” (mean 200mg req’d) vs. paraldehyde 30cc PR q 30” until calm but awake • Shorter time to light somnolence • All complications in paraldehyde group • sudden death (2) • apnea (2) • brachial plexus injury (2) • 3rd floor jump attempt (1) • bitten nurse (1) • bitten intern (1) Thompson, Maddrey, Osler Medical Housestaff. Ann Int Med 1978;82:175

  10. Benzodiazepines prevent incident delirium n=358 in 4 pla-controlled trials (6% v 2%) Sedative-hypnotics (incl bzd) reduce --duration of delirium (by 1-3 DAYS)* --mortality (1 v 8 deaths)** *n=304 trials of paraldehyde v neuroleptics **n=386 in trials of sedatives v neuroleptics Guideline recommendation: Long-acting, parenteral, frequent, doubling dose as needed to achieve light somnolence Rosenfeld 1961, Sereny 1965, Kaim 1969, Zilm 1980, summarized in Mayo-Smith MF & ASAM Working Group JAMA 1997;278:144-51 Mayo-Smith et al. Arch Intern Med. 2004 Jul 12;164(13):1405-12.

  11. “He did predictably suffer from delirium tremens. This was quelled with p.o. alcohol” • Dose/therapeutic index • Effectiveness • Toxicities

  12. MANAGEMENT OF UNHEALTHY ALCOHOL USE: BEYOND WITHDRAWAL MANAGEMENT • “Detoxification” is not treatment; should be initiation/induction • Brief Intervention • Treatment • In primary care or by specialist, outpatient or inpatient • Counseling, removal from environment/access • Pharmacotherapy • Self (online, books) and mutual help (e.g. AA, Smart Recovery) • Manage comorbidity (medical and psychiatric) Friedmann PD, Saitz R, Samet JH. JAMA 1998;279(15):1227-31.

  13. Alcohol Pharmacotherapy:Long-term treatment (“relapse prevention”) Four FDA-approved drugs: • Disulfiram • Naltrexone (PO and IM) • Acamprosate Other potentials: • Topiramate • Gabapentin • Antidepressants (for co-occurring depression and AUD)

  14. Disulfiram (Antabuse) • Dose: 250 mg daily. • Randomized placebo-controlled trials have failed to demonstrate a benefit (difficult to do with this type of drug). • Appears to be effective with compared with no treatment (OR for abstinence 2.2) or when administration is supervised (OR for abstinence 3.9) • Side effects: disulfiram reaction, neuropathy. • Larger effects than other meds (NTX, ACA, TOP) Jorgensen CH, et al. Alcohol ClinExp Res 2011;35:1749.

  15. Naltrexone (Revia/Vivitrol) • Opioid antagonist, thought to reduce the reinforcing effects of alcohol. • Usual Dose: 50-100 mg po daily. • Long-acting injectable form (Vivitrol – 380 mg IM q mo). • Modestly reduces return to heavy drinking (risk difference of 9% (48% base rate) - NNT=11). • Oral vs IM effectiveness? • Side effects: nausea (14%) & dizziness (12%) Rösner S, et al. Cochrane Database Syst Rev 2010:CD001867. Jonas D, et al. JAMA 2014;311:18:1889.

  16. Opioid Antagonists: Return to Heavy Drinking Risk ratio = 0.83 51% v. 61% Cochrane Database of Systematic Reviews8 DEC 2010 DOI: 10.1002/14651858.CD001867.pub3http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001867.pub3/full#CD001867-fig-0005

  17. Acamprosate (Campral) • Enhances GABA reception & transmission, which are reduced by chronic alcohol exposure. • Usual Dose: 666 mg (2 pills) TID. • Modestly improves abstinence (risk difference of 9% - NNT = 11). • Side effects: Diarrhea (17%). Rösner S, et al. Cochrane Database Syst Rev 2010:CD004332 Jonas D, et al. JAMA 2014;311:18:1889.

  18. Acamprosate: Return to Any Drinking Risk ratio = 0.86 ~25% vs 17% abstinent Cochrane Database of Systematic Reviews7 SEP 2010 DOI: 10.1002/14651858.CD004332.pub2http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004332.pub2/full#CD004332-fig-0006

  19. NaltrexoneAcamprosate MORE Abstinence LESS Return to Heavy Drinking Maisel NC, et al. Addiction 2013;108:275.

  20. Topiramate (Topamax) • GABA enhancer, thought to reduce the rewarding effects of alcohol; 25 mg/d then increase by 25 to 50 mg/d each week to 200 mg/d max • Systematic review including 6 RCTs and total of 979 participants: • Fewer drinks/drinking day (-1.6) • Higher % days abstinent (mean difference 15.5%) • Less heavy drinking (standardized mean -0.44) • Side effects: Parasthesias (50%), taste perversion (23%), anorexia (20%), difficulty with concentration (15%) • No differences compared to other meds in head to head trials Pani PP, et al. Cochrane Database Syst Rev 2014;2:CD008544 Not FDA approved for AUD

  21. Gabapentin (Neurontin) • Enhances GABA activity • In a 12-week trial (N=150), gabapentin 1800 mg/day was associated with: • Reduction in heavy drinking (55% vs. 77%; NNT=5) • Increase in abstinence (17% vs. 4%; NNT=8) • 2 other smaller studies (N = 60, 21) with positive results. • 1 study reported that a combination of gabapentin with naltrexone was superior to naltrexone alone (over 6 weeks) • Not FDA approved, potential for misuse Mason BJ, et al. JAMA Intern Med 2014;174:70. Leung JG, et al. Ann Pharmacotherapy 2015;49:897. Not FDA approved for AUD

  22. N=346 10-site trial • No differences in ‘no heavy drinking days’ (28% v. 22%) • No differences in other drinking measures or consequences • Fatigue, dizziness, somnolence Alcohol Clin Exp Res. 2019 (2018 Nov 7 Ahead of print) doi: 10.1111/acer.13917

  23. Baclofen • A placebo-controlled trial found a large increase in abstinence. • Subsequent studies did not confirm efficacy. • A physician reported his successful self-titrated treatment with high-dose baclofen, confirmed in a small trial, but adverse effects are prominent (e.g. drowsiness) and efficacy has not been replicated Addolorato G et al. The Lancet VOLUME 370, ISSUE 9603, P1915-1922, DECEMBER 08, 2007 Not FDA approved for AUD

  24. Antidepressants • For patients with co-occurring depression and AUD • In a systematic review that included 8 RCTs with a total of 389 subjects followed for 8-24 weeks, antidepressant medications had beneficial effects on measures of alcohol use with an effect size of 0.51 • Medications: sertraline, fluoxetine, desipramine, imipramine, nefazodone. • Many individuals seeking treatment for SUD are depressed and their depression often gets better with treatment of their SUD. NB: high placebo response rates; lower when were limited to individuals with at least a week of abstinence Nunes EV, Levin FR. JAMA 2004;291:15:1887. None FDA approved for AUD

  25. Pharmacotherapy:Unanswered questions • Should it be offered to everyone? • Counseling (specialized, med mgt, none) • What meds/choices? • Combinations? • Clinical outcomes? • Your cases? Latt NC, et al. Med J Australia 2002;176:530-534. Kranzler & Soyka. JAMA. 2018;320(8):815-824. doi:10.1001/jama.2018.11406 Saitz R. JAMA. 2018;320(8):766-768. doi:10.1001/jama.2018.10061

  26. Summary • Benzodiazepines for withdrawal; individualize • Pharmacotherapy, for as long as needed (see figure) • Efficacious though modest • Future promise for individualization • Targeted may be effective • Psycho-social or medical-type counseling • Address depression and anxiety, social needs

  27. How do I teach this? INTEGRATE • Morning report case of WD • Ambulatory case for pharmacological management • Journal club re RCTs TEACHING POINTS • BZD for WD • Prescribe pharmacotherapy • Keep current

  28. extras

  29. ALCOHOL WITHDRAWAL SEIZURES • Recurrent detox and prior seizure are risk factors • Generalized • Single or a few (79% <3, <3% status) • 86% in the 1st 6 hrs • Imaging unhelpful if clinical picture consistent • Fever • Delirium • Focal exam, focal seizure • Head trauma • 1st or multiple seizures, status

  30. LORAZEPAM PREVENTS RECURRENCE • 186 subjects with alcohol withdrawal seizures • RPCDBT • 2 mg of lorazepam IV • Also decreased hospital admission D’Onofrio G et al New Engl J Med

  31. DTs: Recommendation • Parenteral benzodiazepines, prefer long-acting • Example regimen: • Diazepam, 5 mg intravenously (2.5 mg/min) • If not effective, repeat in 5 to 10“ • if not satisfactory, use 10 mg for the third and fourth doses • if not effective, use 20 mg for the fifth and subsequent doses until sedation • Then 5 to 20 mg q 1h PRN to maintain light somnolence

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