Alcohol: Alcohol: Research to PracticeResearch to Practice

Gail D’Onofrio MD, MSSection of Emergency Medicine

Yale University School of Medicine

Case StudyCase 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

Initial ManagementInitial Management

HistoryPhysical ExamLaboratory testsDiagnostic Imaging

GABAA Receptor

NMDA receptor

Glycine Receptor

ETHANOL

VOCCL,N

Ca++

GABA

glutamate

CNS Neuron

Cl-

Cl-

Ca++

NO

Alcohol DependenceAlcohol 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

Alcohol-Related SeizuresAlcohol-Related Seizures

Adult onset seizures occurring in the setting of chronic alcohol dependence

Historical perspectiveHistorical perspective

Hippocrates 400 B.C. - first description

Isbell 1955 - first experimental study

Victor and Brausch 1967 - landmark study

Alcohol-Related Seizures - Alcohol-Related Seizures - WithdrawalWithdrawal 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,

Differential diagnosisDifferential 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

Differential diagnosisDifferential diagnosis

Alcohol withdrawal – underestimated as a cause of generalized seizures

Idiopathic generalized epilepsy - poor seizure control in alcohol dependence

Sleep deprivation & medication compliance

Pathogenesis 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

Alcohol

Exacerbation of idiopathic generalized epilepsy

Epilepsy related toother risk factorsassociated with chronicalcohol abuse, e.g.traumatic brain injury

Alcohol-intoxication seizuresAlcohol-withdrawal seizures

Other predisposingfactors causing acutesymptomatic seizures,e.g., associated drug abuse

Diagnostic evaluationDiagnostic 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

Seizure Recurrence

• 186 subjects with alcohol withdrawal seizures

• RCT, double blinded• 2 mg of lorazepam IV• Also decreased

hospital admission 3

24

0

10

20

30

40

50

lorazepam

% with2ndseizure

D'Onofrio G et al. N Engl J Med 1999;340:915-919.

Treatment of Alcohol Withdrawal

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

Detoxification: Inpatient versus Outpatient with Detoxification: Inpatient versus Outpatient with mild/moderate alcohol withdrawal (RCT)mild/moderate alcohol withdrawal (RCT)

*p<.001, **p<0.03. Hayashida et al. NEJM 1989;320:358

Completing treatment (%)* 72 95

Abstinence (1 month)(%)** 66 81No Intoxication (1 month)(%)* 76 88

Abstinence (6 months)(%) 48 46No Intoxication (6 mo)(%) 59 51

Days of treatment (mean)* 4.5 9.2Cost ($)* 175-388 3319-3665

No difference in Addiction Severity Scores

OUTpt (N=87) INpt (N=77)

Pharmacologic Therapies for Pharmacologic Therapies for Alcohol WithdrawalAlcohol Withdrawal

Treatment Phase and Drug Class

Examples Mechanism & Effects

Alcohol Withdrawal

Benzodiazepinesdiazepam (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

Pharmacological Therapies for Pharmacological Therapies for Alcohol WithdrawalAlcohol Withdrawal

Treatment Phase and Drug Class

Examples Effects

Alcohol Withdrawal

Beta-blockers AtenololPropranolol

Improvement in vital signs; reduction in craving

Alpha-agonists Clonidine Decreased withdrawal symptoms

Antiepileptics Carbamazepine Decreased severity of withdrawal; prevention of seizures

O’Connor P, et al. NEJM 1998;338;9;592-602

CIWA-ArCIWA-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.

Symptom-triggered TherapySymptom-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

Saitz R et al JAMA 1994;272:519-23

Decreased Duration of TreatmentDecreased Duration of Treatment

ASAM Practice GuidelinesTreatment 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 mgMayo-Smith and ASAM working group JAMA 1997;278:144-51Saitz and O’Malley Med Clin N A 1997;81:881-907

Treatment of Alcohol DependenceTreatment of Alcohol Dependence

Detoxification is NOT treatmentBehavioral Counseling

– Motivational– Cognitive-behavioral (Cue exposure,

contingency management, coping skills– 12 step– Psychotherapy

Pharmacotherapy

Treatment Does WorkTreatment 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

Success Rates for Addictive Success Rates for Addictive DisordersDisorders

Disorder Success Rate (%)*

Alcoholism 50 (40-70)

Opioid Dependence 60 (50-80)

Cocaine Dependence 55 (50-60)

Nicotine Dependence 30 (20-40)

* Follow-up 6 mo. Data are median (range)

O, Brien C; McLellan A. Lancet 1996;347;237-40

Compliance and Relapse in Selected Compliance and Relapse in Selected Chronic Medical DisordersChronic 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%

<30%

50-60%

AsthmaMedication 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

Self Help/Mutual HelpSelf Help/Mutual Help

Alcoholics Anonymous (AA)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.

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 AA

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)AA (continued)

Behavioral Therapy

Project MATCHProject 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

Pharmacotherapy

Pharmacologic Therapies for Pharmacologic Therapies for Alcohol Prevention RelapseAlcohol Prevention Relapse

Treatment Phase and Drug Class

Examples Effects

Prevention of Relapse

Alcohol sensitizers Disulfiram* Decreased alcohol use among those who relapse

Opioid antagonists Naltrexone* Increased abstinence, decreased # of drinking days

Homotaurine derivatives Acamprosate Increased 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

Medications for Treatment of Alcohol Medications for Treatment of Alcohol Dependence to Prevent RelapseDependence to Prevent Relapse

Medication Presumed 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

DisulfiramDisulfiram

Multicenter RCT, 12-month F/u of N=605DS 250mg, 1 mg, or none No difference in abstinenceMore 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

DisulfiramDisulfiram

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

Medications for Treatment of Alcohol Medications for Treatment of Alcohol Dependence to Prevent RelapseDependence to Prevent Relapse

Medication Presumed 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

NaltrexoneNaltrexone

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

NaltrexoneNaltrexone

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

Back to Our PatientBack to Our Patient

Treatment of ARSBrief Intervention: Goal is to link with

specialized treatment center for initial detoxification

Referral to primary careLong term treatment through

behavioral and/or pharmacotherapy

ThanksThanks

Richard Saitz MD, MPH Niels Rathlev, MD

Boston University School of Medicine