Management of Alcohol. Michael Tang DO

Transcription

1 Management of Alcohol and Opioid Detox Michael Tang DO

2 Disclosure Kaiser Permanente South San Francisco has determined that the speaker (Dr. Tang) and the planning committee (Dr. Becker, Dr. Shanteau, Dr. Alexeenko, Dr. Ducut, Rebecca Bayrer, Heather Miller) for this activity do not have any relevant financial relationships. Kaiser Permanente South San Francisco takes responsibility for the content, quality, and scientific integrity of this CME Activity. Kaiser Permanente does not endorse any brandname products.

3 Topics to discuss Alcohol withdrawal Presentation and complications DT s, Seizures, Wernicke s Encephalopathy Treatment options Opioid withdrawal Presentation Treatment options Pharmacology for alcohol use disorders and opioid use disorders Disulfiram Naltrexone (PO and IM) Acamprosate Off label: Topiramate, Gabapentin Buprenorphine Methadone

4 Management of Alcohol Withdrawal

5 Alcohol Withdrawal: onset of symptoms over 6 24 hrs after last drink Restlessness, irritability, anxiety, agitation Anorexia, nausea, vomiting Tremor, elevated heart rate, increased blood pressure Sleep disturbance Impaired concentration, memory and judgment Increased sensitivity to sound, light, and tactile sensations Delirium (disorientation to time, place, situation) Hallucinations (auditory, visual, or tactile) Delusions, usually paranoid Grand mal seizures Hyperthermia

6 Alcohol Withdrawal Clinical Effects

7 Risk factors for Severe withdrawal Symptoms even with elevated BAC High BAC on admission time since last drink at presentation Seizures, medical illness, mental status changes Best predictor of withdrawal severity is previous withdrawal severity After 3 or 4 serious withdrawals, severity increases: Kindling hypothesis

8 Becker HC. Kindling in alcohol withdrawal. Alcohol Health Res World. 1998;22(1):25 33.

9 Risk of Seizure (2 3% overall) Increases with: Previous withdrawal seizure Three or more serious withdrawal episodes Drinking for more than two decades Poor general medical health and poor nutritional status Previous head injuries Electrolyte disturbances (calcium, sodium, potassium, or magnesium)

10 DT s: mortality of 5 10% Once full DT s, meds may not alter course Generally, ICU admission is warranted Prevention: treat withdrawal early Early withdrawal: symptom triggered administration best to prevent DT s

11 Wernicke Korsakoff Syndrome Resulting from thiamine deficiency Wernicke s sx triad: Confusion Ataxia Primarily stance and gait Ophthalmoplegia typically CN VI palsy, bilateral, rarely symmetric Korsakoff: prolong deficiency permanent defect in retentive memory and learning Confabulations

12 Detox Presentation: three groups Previous history of extreme withdrawal Treatment should begin ASAP, even before significant w/d symptoms Likely need inpatient treatment Presenting in withdrawal: decision time Inpatient vs. outpatient Presenting intoxicated: withdrawal uncertain Ideally, send to ED for observation

13 Indications for Inpatient Detox (Ideally) Pregnancy Medical illness (pneumonia, pancreatitis, diabetes, heart/lung disease) Already had a withdrawal seizure Can t tolerate PO meds CIWA Ar >15 on presentation Extremely heavy daily drinking past several weeks (> 1 case beer, a gallon of wine, a fifth gallon of spirits) Previous history complicated withdrawal (withdrawal seizures, DT s) Significant mental illness Poor social support, housing, income, etc.

14 Treatment of alcohol withdrawal General measures: Thiamine 100 mg, folate 1 mg, MVI glucose IV ( banana bag ), correct electrolyte imbalances (magnesium, potassium and phosphate) Benzodiazepine: drug of choice: Chlordiazepoxide (Librium), diazepam (Valium), oxazepam (Serax), lorazepam (Ativan) No study has shown superiority but advantages and disadvantages of each

15 Chlordiazepoxide (Librium) Advantages: long acting, active metabolites give smooth action, less frequent dosing Disadvantages: active metabolites accumulate in elderly or with impaired liver results in impaired cognition, respiratory compromise pts can have positive benzo UDS 4 5 weeks after detox

16 Valium (Diazepam) Valium advantages: Long acting, active metabolites also gives smooth action, rapid onset of action Can give IV for seizures Disadvantages: Accumulating active metabolites in elderly or liver disease: over sedation; impaired cognition; respiratory compromise More abuse potential d/t its rapid onset of action

17 Lorazepam (Ativan) Advantages: shorter acting, lack of active metabolites make it attractive for elderly and liver disease Available PO, IM, IV in similar doses Single dose after seizure proven to prevent subsequent seizures Rapid onset of action Disadvantages: Shorter acting means more frequent dosing Some evidence suggests that late seizures occur w/ short acting BZD s: have to taper

18 Oxazepam (Serax) Advantages: No active metabolites to build up No oxidation in the liver Good for elderly and those with liver impairment Disadvantages: Slow absorption in GI tract No parenteral form Short acting: can lead to breakthrough symptoms

19 Fixed dosing Example: 20 mg valium every two hours until improvement occurs Example: Ativan 2 mg IV every hour until improvement or sedation for DT s Problems: over sedation, ataxia, confusion

20 Tapering dosage: often used in outpatient treatment Advantages: less clinical skill needed Disadvantages: patient may receive more drug than needed; conversely, in early withdrawal, may not receive enough Adjust as symptoms require

21 Symptom triggered (CIWA scale) Fewer patients needing medication lower doses when needed fewer days in hospital less cost no increase in complicated withdrawal (DT s, SZ s) requires nurse training and experience Patient must be P.O. and able to communicate Not appropriate for outpatient tx Used in combination with fixed dose and taper for ICU tx of DT s

22 Saitz R, Mayo Smith MF, Roberts MS, Redmond HA, et al. Individualized treatment for alcohol withdrawal. A randomized double blind controlled trial. JAMA Aug 17;272(7):

23 CIWA Ar (document) Useful in three ways: Assess need for medical treatment Assess site for treatment <8: medical detox not needed 8 15: consider outpatient treatment >20: inpatient more appropriate Evaluate status during treatment

24 Non Benzo s for detox: Carbamazepine and Valproate Effective in: Mild to moderate withdrawal/ protracted withdrawal distress and faster return to work No abuse potential / alcohol interactions No toxicity in 7 day trials Limitations: Not better than BZDs Side effects Limited data in seizures/delirium Also some data supporting gabapentin, baclofen If used, limit to patients with mild/moderate withdrawal, at lower risks Limited data in treating delirium

25 Sample detox protocol Librium 25mg q4hr prn x 1 day, then q6hrs prn x 1 day, then q8hrs prn, then q12hrs prn, then daily prn (if using Ativan 2mg) Thiamine 100mg daily x 30 days Folate 1mg daily x 30 days MVI daily x 30 days

26 Case 1 62 y/o married man h/o DM, s/p coronary stent Employed, doesn t want to miss work Drinks 2 6 beers weeknights, 24/night weekends Presents w/ BAC 0.04, CIWA 3 Wants Antabuse to scare myself sober Detox? Inpatient or outpatient? Pharmacology recommendations?

27 Case 2 27 year old woman, drinks 6 12 beers/day Lives with her mother who is sober in recovery No other drugs No mental illness 18 weeks pregnant Detox? Inpatient or outpatient?

28 Management of Opioid Withdrawal

29 Opioid Withdrawal Withdrawal as a result of CNS noradrenergic hyperactivity Onset of symptoms dependent on half life of opioid used E.g. 4 6 hours after last heroin use; 36 hours after last methadone use Duration of symptoms also dependent on half life of opioid used E.g. heroin: symptoms peak at hours, may last 7 to 14 days Symptoms generally do not include any life threatening complications but can cause significant discomfort Clinical Opiate Withdrawal Scale

30 Clinical Opiate Withdrawal Scale (COWS) Schuckit, M. Treatment of Opioid Use Disorders. N Engl J Med 2016; 375:

31 Opioid Withdrawal (COWS cont.): Carbamazepine and Valproate Schuckit, M. Treatment of Opioid Use Disorders. N Engl J Med 2016; 375:

32 Opioid Withdrawal (COWS cont.): Schuckit, M. Treatment of Opioid Use Disorders. N Engl J Med 2016; 375:

33 Medication Options Opioid Agonists: Methadone, buprenorphine Alpha 2 adrenergics: Block activation of locus caeruleus

34 Methadone Full opioid agonist; Peak effect: 2 4 hours, half life: hours For temporary maintenance or detox when patient is medically admitted to a hospital for an illness other than opioid use d/o Can also be used in outpatient setting for maximum of three days while patient awaiting for admission to methadone treatment program

35 Methadone Give 5mg increments based on symptoms or give single dose of 20 30mg Should not exceed 30mg in first 24 hours Sample protocol: taper every 24hours 30mg 20mg 10mg 5mg d/c

36 Buprenorphine Partial opioid agonist Peak effect 2 4 hours; half life 4 6 hours No opioid use for hours Mild moderate withdrawal with objective signs First dose should not exceed 4mg Sample protocol: taper every 24 hours 8mg 6mg 4mg 2mg d/c

37 Sample detox protocol Day 1: buprenorphine/naloxone 4/1 mg SL, may repeat in 2 to 4 hrs, up to 8/2 mg SL DAY 2: 8/2 to 12/3 mg SL DAY 3: 6/1.5 mg SL final dose may also taper 2 3 days 7 day protocol may be more effective (Ling, 2009)

38 Sample protocol #2 Suboxone 2/0.5mg q2 hrs prn sx's of withdrawal, first dose at 4/1mg max daily dose of 8/2mg on day 1 max daily dose of 12/3mg on day 2 and 3 max daily dose of 8/2mg on day 4 max daily dose of 4/1mg on day 5 max daily dose of 2/0.5mg on day 6 provided pt with 20 tabs

39 Which opioid agonist to choose? Efficacy of symptoms resolution is equivalent Buprenorphine: Faster resolution of symptoms with buprenorphine Lower risk for adverse outcomes Methadone may be better option: Patients requiring narcotic analgesia Patients already on methadone maintenance Must call and confirm dose If missed 2 days, give ½ daily dose If missed 3 days, re induct starting at 30mg

40 Schuckit, M. Treatment of Opioid Use Disorders. N Engl J Med 2016; 375:

41 Schuckit, M. Treatment of Opioid Use Disorders. N Engl J Med 2016; 375:

42 Sample detox protocol Clonidine 0.1mg q6hrs prn x 4 days, then 0.05mg q6hrs prn x 3 days Hydroxyzine 25 50mg q4hrs prn anxiety/sleep Ibuprofen 400mg q6hrs prn muscle aches/pain Prn Loperamide for diarrhea Can also use: Dicyclomine 20mg q4hrs prn abdominal cramps/discomfort; trazodone prn

43 Case 1 59 y/o divorced man w/ BPAD, most recent hypomanic Recently moved here from Colorado Drinks six pack to fifth daily Also uses 5 bags of heroin daily CIWA 12, BAC 0.00 Detox issues? Inpatient or outpatient? Level of care? Pharmacotherapy recommendations?

44 Case 2 22 y/o single woman 20 weeks pregnant Snorting 10 oxycodone tablets a day Wants to stop her use for the baby Detox? Level of care?

45 Pharmacology of Alcohol Use Disorder Disulfiram (Antabuse) Naltrexone Revia (oral) Vivitrol (injectable) Acamprosate (Campral) Topiramate (Topamax) Gabapentin (Neurontin)

46 Disulfiram (Antabuse) Strictly a deterrent Dose: 250 or 500 mg/d, hours after last drink ALDH blocker: accumulation of acetaldehyde Symptoms of disulfiram etoh reaction: Facial flushing, headache, nausea/vomiting, bp, HR: cau on in CAD, CVD, elderly, impulsivity Hepatotoxicity: rare but fatalities reported; CBC, LFT s baseline, 2wks, then periodically

47 Disulfiram (cont.) Studies mixed: # drinking days, cravings No : abstinence, time to first drink Works best with supervised administration Good relationship builder to restore trust (Couples Behavioral Therapy for SUD) Department of Justice for probation or parole Adverse SE s: neuropathy (including optic), elevated LFt s, psychosis

48 Naltrexone oral or long acting injectable Endorphin release + some dopamine release stimulated by mu receptor high, craving blocked by naltrexone Type B alcoholic: + family history, male, started young # drinking days, #drinks/day; days to 1 st drink, heavy drinking Start 4 7 days after last drink IM: more compliance Improved results combined with Acamprosate

49 Naltrexone Side Effects Nausea/Diarrhea Headache Insomnia Possible Hepatic toxicity Opioid analgesics will not be effective Anhedonia? Hasn t been a problem

50 Acamprosate (Campral) Blocks glutamate release, NMDA excitability European trials: small but significant effect (15 18%); less so here (COMBINE, eg) Pill burden, TID dosing, compliance, GI S.E. s Think late onset, type A, female, negative family hx, anxious, physiologic dep.

51 Topiramate GABA ergic antiepileptic Several trials: effectiveness to Naltrexone Side effects intolerable with rapid induction Cognitive, paresthesias, motor slowing Slow weekly up titration: Optimal dose/duration not well defined: 200mg? May start while still drinking

52 Topiramate cont. Johnson et al, Ma et al: up to 300 mg/d Improved: # drinking days, #drinks/day, # days to first drink Improved quality of life Moderate effect (% drinking days: 0.63) Miranda et al: 76 heavy drinkers not seeking treatment: Both 200 and 300 mg/d decreased % heavy drinking days

53 Topiramate Significant Cumulative effect Max effect ~ 80 days Johnson et al # drinking days #drinks/days # days to 1 st drink Moderate effect (% drinking days: 0.63) Johnson et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet 361,

54 Gabapentin (Mason JAMA 2014) 12 week PCT, n=150 Placebo, GABA 900mg/d, GABA 1800mg/d Abstinence: 4.1%, 11.1%, 17% resp. No heavy drinking days: 22.5%, 29.6%, 44.7% avg # heavy drinking days/wk; # drinks/wk No sig side effects Risk of abuse, especially among opioid SUD

55 Gabapentin for Relapse Prevention Mason et al, Jama Internal Med 2014

56 Pharmacology of Opioid Use Disorder Methadone Buprenorphine Naltrexone

57 Evolution of Opioid Agonist Therapy: Methadone Research project 1964: Rockefeller University Dole, Nyswander: only 6 patients Findings: HD (60 120mg) better than LD (<60) Relieves narcotic craving Suppress withdrawal for hrs Blocks reinforcing effect of heroin Pt develops tolerance to euphoria, sedation Pro social behaviors, school, employment, health Coined Methadone Maintenance (MMT) 1972: approved by FDA; regulations for OTP

58 Challenges of MMT Identified problems Regional programs, not local: impractical for many ~1200 OTP US clinics serve ~20% of opioid addicts Safety: Overdose possible, side effects, interactions Daily witnessed dosing: burden of care Reinforced negative attitudes and stereotypes toward opioid addicts in recovery

59 Office-Based Treatment of Opioid Dependence Drug Addiction Treatment Act of 2000 (DATA): Provider qualifications: physician only Waiver: 8 hour course, research, specialists Medication qualifications: Buprenorphine Suboxone, Subutex, (generic), Zubsolv, Bunavail Partial agonist: safer Schedule III (refills, call-in) Office-based treatment

60 Buprenorphine Partial Agonist Strong receptor affinity (binding strength) > displace full agonists (e.g. heroin, methadone) Receptor dissociation slow > block full agonist binding 36 hours or more

61 Full Agonist heroin/methadone A Net Decrease in Receptor Activity if a Partial Agonist displaces Full Agonist % Mu Receptor Intrinsic Activity Partial Agonist buprenorphine no drug low dose high dose DRUG DOSE

62 Rationale for Buprenorphine/Naloxone Combination When taken sublingually Buprenorphine will be well absorbed Naloxone absorption will be minimal If taken intravenously Naloxone now 100% bioavailable In theory: precipitated withdrawal occurs In practice: need > 10mg Nx IV to precipitate w/d Focus on diversion rather than aversion

63 Dosing Bioavailability is lower than initially thought Significant variability Cochrane report 2014: higher doses( 16mg) = better results Dosing limits may be compromising overall effectiveness Balance against diversion risk Avoid split dosing: may contribute to dosing positive reinforcement and overuse

64 Naltrexone Sustained Release (SRX) Naltrexone works : blocks opioids, no reinforcement, opioid use decreases Oral naltrexone: poor compliance, retention No better than placebo; OD deaths on relapse SRX: fewer dropout opportunities: compliance? Industry sponsored study in Russia: effective (graphs) No agonist treatment available Craving decreased No data on compliance in US: limited uptake in practice

65 Naltrexone IM (Vivitrol) Opioid Free Patients Change in Craving score Retention in Treatment May be skewed by lack of other available tx in Russia, promise of drug if study completed Krupitsky E, et al. Injectable extended release naltrexone for opioid dependence: a double blind, placebo controlled, multicentre randomised trial. Lancet Apr 30; 377:

66 Medication assisted Therapy (MAT) Characteristic Methadone Buprenorphine Naltrexone Brand names Dolophine, Methadose Suboxone, Subutex, Zubsolv ReVia, Vivitrol Class Agonist full Partial agonist Antagonist Use, effects Once daily orally to reduce cravings and withdrawal Sublingual daily to reduce cravings and withdrawal Oral daily or monthly injection to block opioid effect Pros Gold standard, structured format, witnessed dosing, 40 years experience Doctor s office, by prescription, more available, less stigma Non addicting, no physical dependence, once monthly dosing (IM) Cons Official OTP only: limited availability; daily dosing; full agonist: overdose possible Abuse, diversion liability; difficult to arrange psychosocial support Poor compliance; 7 day abstinence required; overdose risk high M. Tang, 2017

67 Questions?

68 References Becker HC. Kindling in alcohol withdrawal. Alcohol Health Res World. 1998;22(1): Dole VP. Implications of methadone maintenance for theories of narcotic addiction. JAMA 1988; 260: Johnson BA, Ait Daoud N. Topiramate in the new generation of drugs: efficacy in the treatment of alcoholic patients. Curr Pharm Des. 2010;16(19): Kreek MJ, Reisinger M. The addict as patient. In: Lowinson JH, Ruiz P, Millman RB, Langrod JG, editors. Substance abuse: A comprehensive textbook. 3rd ed. Baltimore (MD): Williams & Wilkens; pp Krupitsky E, Nunes EV, Ling W, et al. Injectable extended releasenaltrexonefor opioid dependence: a double blind, placebo controlled, multicentre randomised trial. Lancet Apr 30; 377: Ling W, et al.: Buprenorphine tapering schedule and illicit opioid use. Addiction. 2009; 104: Mason B, Quello S, Goodell V, et al. Gabapentin Treatment for Alcohol Dependence A Randomized Clinical Trial. JAMA Intern Med. 2014; 174(1): Maldonado JR, An approach to the patient with substance use and abuse. Med Clin North Am Nov;94(6): Miranda R Jr, MacKillop J, Treloar H, et al. Biobehavioral mechanisms of topiramate's effects on alcohol use: an investigation pairing laboratory and ecological momentary assessments. Addict Biol Jan;21(1): Saitz R, Mayo Smith MF, Roberts MS, Redmond HA, et al. Individualized treatment for alcohol withdrawal. A randomized double blind controlled trial. JAMA Aug 17;272(7): Schuckit, M. Treatment of Opioid Use Disorders. N Engl J Med 2016; 375: Johnson, B.A., Ait Daoud, N., Bowden, C.L., DiClemente, C.C., Roache, J.D., Lawson, K.,Javors, M.A., Ma, J.Z., Oral topiramate for treatment of alcohol dependence:a randomised controlled trial. Lancet. 2003, 361,