Alcohol: Research to Practice

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Alcohol Research to Practice

• Gail DOnofrio MD, MS
• Section of Emergency Medicine
• Yale University School of Medicine

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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

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Initial Management

• History
• Physical Exam
• Laboratory tests
• Diagnostic Imaging

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ETHANOL
CNS Neuron
GABA
GABAA Receptor
glutamate
Cl-
NMDA receptor
NO
Ca
Ca
Cl-
VOCCL,N
Glycine Receptor
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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
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Alcohol-Related Seizures

• Adult onset seizures occurring in the setting of
  chronic alcohol dependence

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Historical perspective

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

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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
• lt 3 status epilepticus
• 79 lt 3
• 86 recurrent seizure within 6 hrs

Victor and Brausch. Epilepsia 196781,
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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

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Differential diagnosis

• Alcohol withdrawal underestimated as a cause of
  generalized seizures
• Idiopathic generalized epilepsy - poor seizure
  control in alcohol dependence
• Sleep deprivation medication compliance

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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

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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

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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
1999340915-919.
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• Treatment of Alcohol Withdrawal

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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

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Detoxification Inpatient versus Outpatient with
mild/moderate alcohol withdrawal (RCT)
OUTpt (N87) INpt (N77)
Completing treatment () 72 95 Abstinence (1
month)() 66 81 No Intoxication (1
month)() 76 88 Abstinence (6
months)() 48 46 No Intoxication (6
mo)() 59 51 Days of treatment
(mean) 4.5 9.2 Cost () 175-388
3319-3665 No difference in Addiction Severity
Scores
plt.001, plt0.03. Hayashida et al. NEJM
1989320358
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Pharmacologic Therapies for Alcohol Withdrawal
Treatment Phase and Drug Class Examples Mechanism 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 lt8 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
OConnor P, et al. NEJM 19983389592-602
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Pharmacological Therapies for Alcohol Withdrawal
Treatment Phase and Drug Class Examples Effects
Alcohol Withdrawal
Beta-blockers Atenolol Propranolol Improvement in vital signs reduction in craving
Alpha-agonists Clonidine Decreased withdrawal symptoms
Antiepileptics Carbamazepine Decreased severity of withdrawal prevention of seizures
OConnor P, et al. NEJM 19983389592-602
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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 1997278144-51.
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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 1994272519-23
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Decreased Duration of Treatment
Saitz R et al JAMA 1994272519-23
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ASAM Practice GuidelinesTreatment approaches

• Monitor q 4-8 hrs until symptoms improved
• Symptom-triggered (q 1 when CIWAgt8)
• 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
1997278144-51 Saitz and OMalley Med Clin N A
199781881-907
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Treatment of Alcohol Dependence

• Detoxification is NOT treatment
• Behavioral Counseling
• Motivational
• Cognitive-behavioral (Cue exposure, contingency
  management, coping skills
• 12 step
• Psychotherapy
• Pharmacotherapy

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Treatment Does Work

• 2/3rds of patients (1-year) reduce
• Consequences of alcohol consumption (injury job
  loss)
• Amount of consumption by gt 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
200162211-20
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Success Rates for Addictive Disorders
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 1996347237-40
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Compliance and Relapse in Selected Chronic
Medical Disorders
Compliance and Relapse
IDDM (Insulin-dependent diabetes mellitus) Medication Regimen Diet and Foot Care Relapse lt50 lt30 30-50
Hypertension Medication Regimen Diet Relapse lt30 lt30 50-60
Asthma Medication Regimen Relapse lt30 60-80
Retreatment within 12 mo by
physician at emergency room or hospital
Requiring medication
O, Brien C McLellan A. Lancet 1996347237-40
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Self Help/Mutual Help
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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 199765230-40. Montgomery
HA et al. Does AA involvement predict treatment
outcomes? J Subst Abuse Treat 199512241-6.
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AA

• 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.

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AA (continued)

• 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.

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Behavioral Therapy
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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
1997587-29
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Pharmacotherapy
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Pharmacologic Therapies for Alcohol 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
OConnor P, et al. NEJM 19983389592-602
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Medications for Treatment of Alcohol Dependence
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 gt500mg), 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 20053526596-607
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Disulfiram

• Multicenter RCT, 12-month F/u of N605
• DS 250mg, 1 mg, or none
• No difference in abstinence
• More abstinence in those adherent to DS (43 vs.
  8,plt0.001)
• Fewer drinking days in the 162 assigned to DS,
  adhered, and completed F/u, compared to other
  groups (p0.05)

Fuller RK JAMA 19862561449
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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

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Medications for Treatment of Alcohol Dependence
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 20053526596-607
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Naltrexone

• A meta-analysis showed that in RCTs of a short
  duration (lt 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 200499811-28
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Naltrexone

• Can be prescribed in the context of psychosocial
  treatments for those with alcohol dependence, not
  drinking. Last drink 5-30 days ago, LFTs lt 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

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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

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Thanks

• Richard Saitz MD, MPH
• Niels Rathlev, MD
• Boston University School of Medicine