1. Alcohol: Research to Practice Gail D’Onofrio MD, MS Section of Emergency Medicine Yale University School of Medicine

2. Case Study Mr. Smith is a 35 year old white male who presents with a new onset seizure this morning. He has no known past medical history, and takes no regular medications. He does not have a primary care physician

3. Initial Management History Physical Exam Laboratory tests Diagnostic Imaging

4. GABA A Receptor NMDA receptor Glycine Receptor ETHANOL VOCC L,N Ca+ + GABA glutamate CNS Neuron Cl- Ca++ NO

5. Alcohol Dependence 3 or more of these criteria in a 12-month period: 1. Tolerance 2. Withdrawal 3. More or longer consumption than intended 4. Cannot cut down or control alcohol use 5. A great deal of time getting, using, recovering 6. Activities given up or reduced 7. Use despite knowledge of health problem (3-7) Loss of control/preoccupation American Psychiatric Association DSM IV, 1994

6. Alcohol-Related Seizures Adult onset seizures occurring in the setting of chronic alcohol dependence

7. Historical perspective Hippocrates 400 B.C. - first description Isbell 1955 - first experimental study Victor and Brausch 1967 - landmark study

8. Alcohol-Related Seizures - Withdrawal Recurrent detoxifications and prior seizure are risk factors Occur 24-48 hrs after abstinence or decreased intake Often occur prior to autonomic hyperactivity Generalized, single or a few over a short time –< 3% status epilepticus –79% < 3 –86% recurrent seizure within 6 hrs Victor and Brausch. Epilepsia 1967;8:1,

9. Differential diagnosis Structural brain lesions Stroke & traumatic brain injury. Susceptibility due to cerebral atrophy and head trauma Toxic-metabolic disorders Alkalosis, hypomagnesemia, hypoglycemia & illicit drug use

10. Differential diagnosis Alcohol withdrawal – underestimated as a cause of generalized seizures Idiopathic generalized epilepsy - poor seizure control in alcohol dependence Sleep deprivation & medication compliance

11. Pathogenesis Biochemical effects of alcohol on CNS Kindling - increased susceptibility and severity of recurrent withdrawal episodes. Brown 1988 – no. of prior detoxifications a risk factor

13. Diagnostic evaluation Screening for alcohol dependence Laboratory testing –rarely changes management. Earnest 1988 - head CT indicated for all patients with new-onset alcohol-related seizures Sand 2002 – EEGs on all patients

14. Seizure Recurrence 186 subjects with alcohol withdrawal seizures RCT, double blinded 2 mg of lorazepam IV Also decreased hospital admission D'Onofrio G et al. N Engl J Med 1999;340:915-919.

15. Treatment of Alcohol Withdrawal

16. Alcohol Withdrawal (DSM-IV) Cessation or reduction in alcohol use that has been heavy/prolonged Two or more of the following, developing in hours-days, causing distress or impairment, not due to other condition –Autonomic hyperactivity (sweating, tachycardia) –Increased hand tremor –Insomnia –Nausea or vomiting –Transient tactile, visual or auditory hallucinations or illusions –Psychomotor agitation –Anxiety –Grand mal seizures

17. Detoxification: Inpatient versus Outpatient with mild/moderate alcohol withdrawal (RCT) *p<.001, **p<0.03. Hayashida et al. NEJM 1989;320:358 Completing treatment (%)*7295 Abstinence (1 month)(%)**6681 No Intoxication (1 month)(%)*7688 Abstinence (6 months)(%)4846 No Intoxication (6 mo)(%)5951 Days of treatment (mean)*4.59.2 Cost ($)* 175-388 3319-3665 No difference in Addiction Severity Scores OUTpt (N=87) INpt (N=77)

18. Pharmacologic Therapies for Alcohol Withdrawal Treatment Phase and Drug Class ExamplesMechanism & Effects Alcohol Withdrawal Benzodiazepines diazepam (10-20 mg) chlordiazepoxide (50-100 mg) lorazepam (2-4 mg every 1-2 hr until symptoms subside [e.g., CIWA-Ar score <8] for 24 hr*) Chlordiazepoxide* Diazepam* Oxazepam* Lorazepam and others Decrease hyperautonomic state by facilitating inhibitory y- aminobutyric acid receptor for transmission, which is down- regulated by long term exposure to alcohol Sedation * Drug has a Food and Drug Administration-approved indication for this use in the US O’Connor P, et al. NEJM 1998;338;9;592-602

19. Pharmacological Therapies for Alcohol Withdrawal Treatment Phase and Drug ClassExamplesEffects Alcohol Withdrawal Beta-blockersAtenolol Propranolol Improvement in vital signs; reduction in craving Alpha-agonistsClonidineDecreased withdrawal symptoms AntiepilepticsCarbamazepineDecreased severity of withdrawal; prevention of seizures O’Connor P, et al. NEJM 1998;338;9;592-602

20. CIWA-Ar CIWA-Ar denotes: Clinical Institute Withdrawal Assessment for Alcohol, revised. The scale assesses 10 domains (nausea or vomiting; anxiety; tremor; sweating; auditory, visual, and tactile disturbances; headache; agitation; and clouding of sensorium) and assigns 0 to 7 points for each item except for the last item, which is assigned 0 to 4 points, with a total possible score of 67. This scale has been validated as a measure to assess the severity of alcohol withdrawal. Higher scores indicate a higher risk of complications; patients receiving scores of 8 or more should be treated.* *Mayo-Smith MF. JAMA 1997;278:144-51.

21. Symptom-triggered Therapy 101 adults with no past seizures hospitalized for alcohol withdrawal Placebo or Chlordiazepoxide 50 mg qid X4 then 25 mg qid X8 (double- blind) ALL: Chlordiazepoxide 25-100 mg q 1 hour as needed (objective scale: CIWA-Ar) Saitz R et al JAMA 1994;272:519-23

22. Decreased Duration of Treatment

23. ASAM Practice Guidelines Treatment approaches Monitor q 4-8 hrs until symptoms improved Symptom-triggered (q 1 when CIWA>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 Mayo-Smith and ASAM working group JAMA 1997;278:144-51 Saitz and O’Malley Med Clin N A 1997;81:881-907

24. Treatment of Alcohol Dependence Detoxification is NOT treatment Behavioral Counseling –Motivational –Cognitive-behavioral (Cue exposure, contingency management, coping skills –12 step –Psychotherapy Pharmacotherapy

25. Treatment Does Work 2/3rds of patients (1-year) reduce: –Consequences of alcohol consumption (injury job loss) –Amount of consumption by > 50% 1/3 of patients treated are either abstinent or drink moderately without consequences Miller WR, Walters ST, Bennett ME. How effective is alcoholism treatment in the US? J Stud Alcohol 2001;62:211-20

26. Success Rates for Addictive Disorders DisorderSuccess Rate (%)* Alcoholism50 (40-70) Opioid Dependence60 (50-80) Cocaine Dependence55 (50-60) Nicotine Dependence30 (20-40) * Follow-up 6 mo. Data are median (range) O, Brien C; McLellan A. Lancet 1996;347;237-40

27. Compliance and Relapse in Selected Chronic Medical Disorders Compliance and Relapse IDDM (Insulin-dependent diabetes mellitus) Medication Regimen Diet and Foot Care Relapse* <50% <30% 30-50% Hypertension + Medication Regimen Diet Relapse* <30% 50-60% Asthma Medication Regimen Relapse* <30% 60-80% O, Brien C; McLellan A. Lancet 1996;347;237-40 *Retreatment within 12 mo by physician at emergency room or hospital; + Requiring medication

28. Self Help/Mutual Help

29. Alcoholics Anonymous (AA) Provides support at no charge Veteran study shows higher frequency of abstinence at 12 months than those programs with CBT (26% vs 19%) Participation in AA associated with higher rates of abstinence 7 months after inpt tx compared with no participation. Quimette PC, et al. Twelve-step and cognitive-behavioral treatment for substance abuse: a comparison of treatment effectiveness. J Consult Clin Psychol 1997;65:230-40. Montgomery HA et al. Does AA involvement predict treatment outcomes? J Subst Abuse Treat 1995;12:241-6.

30. 1.We admitted we were powerless over alcohol - that our lives had become unmanageable. 2. Came to believe that a Power greater than ourselves could restore us to sanity. 3. Made a decision to turn our will and our lives over to the care of God as we understood Him. 4. Made a searching and fearless moral inventory of ourselves. 5. Admitted to God, to ourselves and to another human being the exact nature of our wrongs. 6. Were entirely ready to have God remove all these defects of character. AA

31. 7. Humbly asked Him to remove our shortcomings. 8. Made a list of all persons we had harmed, and became willing to make amends to them all. 9. Made direct amends to such people wherever possible, except when to do so would injure them or others. 10. Continued to take personal inventory, + when we were wrong promptly admitted it. 11. Sought through prayer and meditation to improve our conscious contact with God as we understood Him, praying only for knowledge of His will for us and the power to carry that out. 12. Having had a spiritual awakening as the result of these steps, we tried to carry this message to alcoholics and to practice these principles in all our affairs. AA (continued)

32. Behavioral Therapy

33. Project MATCH Subjects recruited after inpatient treatment or outpatient treatment Randomized to MET, CBT or 12-step facilitation, over 12-week period Little difference in outcomes by type of Treatment Aftercare after inpatient stay: 12-month continuous abstinence 35%, 40% relapsed to 3 consecutive heavy drinking days Outpatients, 19% abstained, and 46% relapsed Project MATCH Research Group. J Stud Alcohol 1997;58:7-29

34. Pharmacotherapy

35. Pharmacologic Therapies for Alcohol Prevention Relapse Treatment Phase and Drug Class ExamplesEffects Prevention of Relapse Alcohol sensitizersDisulfiram*Decreased alcohol use among those who relapse Opioid antagonistsNaltrexone*Increased abstinence, decreased # of drinking days Homotaurine derivativesAcamprosateIncreased abstinence * Drug has a Food and Drug Administration-approved indication for this use in the US O’Connor P, et al. NEJM 1998;338;9;592-602

36. Medications for Treatment of Alcohol Dependence to Prevent Relapse MedicationPresumed Mechanism of Action Side Effects DISULFIRAM Antabuse (Initial dose, 250 mg daily; therapeutic dose, 500 mg daily) Blocks acetaldehyde dehydrogenase; blockade allows acetaldehyde to accumulate with alcohol consumption, causing unpleasant symptoms (e.g., flushing, headache, vomiting, dyspnea, confusion) Idiosyncratic fulminant hepatitis, neuropathy (at doses >500mg), psychosis, and symptoms that generally resolve on discontinuation of drug (headache, drowsiness, fatigue, rash, pruritus, dermatitis, garlicky taste in mouth) Contraindications: wait 24 hours after drinking, elderly, varices, confusion, HTN Rx Saitz R NEJM 2005;352;6;596-607

37. Disulfiram Multicenter RCT, 12-month F/u of N=605 DS 250mg, 1 mg, or none No difference in abstinence More abstinence in those adherent to DS (43% vs. 8%,p<0.001) Fewer drinking days in the 162 assigned to DS, adhered, and completed F/u, compared to other groups (p=0.05) Fuller RK JAMA 1986;256:1449

38. Disulfiram Daily or just prior to risky situation –Duration of action: 4-7 days, up to 14 Monitor LFTS (2 wks, 3,6 Mo, 1yr), avoid alcohol in OTC meds, interacts with warfarin, INH and anticonvulsants Contraindications –alcohol within 24 hours –Elderly, pregnancy, varices, confusion, seizures, heart disease, anti-HTN therapy, (ie. anti-adrenergics

40. Medications for Treatment of Alcohol Dependence to Prevent Relapse MedicationPresumed Mechanism of Action Side Effects NALTREXONE ReVia (initial dose 12.5 mg daily or 25 mg daily; therapeutic dose 50 mg daily) Acts as an opiate agonist; decreases heavy drinking by blocking endogenous opioids, a process that attenuates craving and the reinforcing effects of alcohol Nausea, headache, dizziness, nervousness, fatigue, insomnia, vomiting, anxiety, somnolence, dry mouth, dyspepsia, elevated liver- enzyme levels (dose-related), difficult pain management Contraindicated: opiate dependence, pregnancy, liver disease ACAMPROSATE Campral (666 mg 3 times a day) Increases abstinence by stabilizing activity in the glutamate system, which is affected by long-term heavy consumption Diarrhea Contraindications: Renal insufficiency Saitz R NEJM 2005;352;6;596-607

41. Naltrexone A meta-analysis showed that in RCTs of a short duration (< 3 months) – decreased the risk of a return to heavy drinking from 48% to 37% –Decreased drinking days by 4.5% –Proportion of patients who were abstinent was higher with naltrexone than placebo (35% vs. 30%); borderline significance Carmen B et al. Addiction 2004:99:811-28

42. Naltrexone Can be prescribed in the context of psychosocial treatments for those with alcohol dependence, not drinking. Last drink 5-30 days ago, LFTs < 3x normal, no opiates Less drinking, less relapse 12.5 mg →25mg →50mg over first few days Med Alert bracelet, stop 3 days pre-op Monitor LFTs, drinking and SEs monthly ? Duration of treatment

43. Back to Our Patient Treatment of ARS Brief Intervention: Goal is to link with specialized treatment center for initial detoxification Referral to primary care Long term treatment through behavioral and/or pharmacotherapy

44. Thanks Richard Saitz MD, MPH Niels Rathlev, MD Boston University School of Medicine