Pharmacotherapy of Alcohol Dependence Department of Surgery Grand Rounds St. Luke’s and Roosevelt Hospitals New York, Wednesday, September 7, 2005 Petros Levounis, M.D. Director, The Addiction Institute of New York Chief, Division of Addiction Psychiatry at St. Luke’s and Roosevelt Hospitals

4 HANDOUTS 1. Mayo-Smith, M.F. (2003). Management of Alcohol Intoxication and Withdrawal. In A. W. Graham, T. K. Shultz, M. F. Mayo-Smith, R. K. Ries, & B. B. Wilford (Eds.), Principles of Addiction Medicine (3 rd ed., pp ). Chevy Chase, Maryland: American Society of Addiction Medicine. 2. Fundamentals of Addiction Medicine 3. Addiction Institute Brochure 4. These slides

OUTLINE 1. Introduction 2. Alcohol Intoxication 3. Alcohol Withdrawal 4. Relapse Prevention 5. Co-Occurring Disorders 6. New Directions

1 INTRODUCTION

Epidemiology 207 million = US Population 207 million = US Population 18 million = Alcohol Use Disorders (9%) 18 million = Alcohol Use Disorders (9%) 8 million = Alcohol Dependence (45%) 8 million = Alcohol Dependence (45%) 2 million = Ever treated (24%) 2 million = Ever treated (24%) 1.2 million = Ever seen an M.D. (60%) 1.2 million = Ever seen an M.D. (60%).6 million = Ever given meds (50%).6 million = Ever given meds (50%) Grant BF et al. Arch Gen Psychiatry. 2004;61:

Neurotransmitter Systems GABA→CNS Inhibition GABA→CNS Inhibition Glutamate→CNS Excitation Glutamate→CNS Excitation Opioid→Euphoria/Reward Opioid→Euphoria/Reward Dopamine→Addiction Dopamine→Addiction Serotonin→Impulsivity Serotonin→Impulsivity

2 ALCOHOL INTOXICATION

Characteristics mg/dLWell-being mg/dLWell-being mg/dLIncoordination mg/dLIncoordination mg/dLAtaxia mg/dLAtaxia mg/dLStage I Anesthesia mg/dLStage I Anesthesia mg/dLComa mg/dLComa mg/dLDeath mg/dLDeath

Pharmacotherapy Use IV thiamine and glucose Use IV thiamine and glucose Do not use ipecac, activated charcoal, caffeine, amphetamines, or flumazenil. Do not use ipecac, activated charcoal, caffeine, amphetamines, or flumazenil. Treatment is supportive. Treatment is supportive.

3 ALCOHOL WITHDRAWAL

Characteristics 1 Following the last drink: Following the last drink: –6 to 24 hours: Autonomic Hyperactivity –24 to 48 hours:Seizures –48 to 96 hours:Delirium tremens “Kindling effect” for seizures. “Kindling effect” for seizures. Older patients are at higher risk of DTs. Older patients are at higher risk of DTs. Typically mild, occasionally severe, rarely fatal. Typically mild, occasionally severe, rarely fatal.

Characteristics 2 Autonomic Hyperactivity with: Autonomic Hyperactivity with: –Reduced GABA activity and –Enhanced glutamate activity.

Characteristics 3 Early signs of withdrawal: Early signs of withdrawal: –Tachycardia –Blood pressure elevation –Sweating –Hyperthermia –Tremor (6 to 8 cycles per second)

Assessment Clinical Institute Withdrawal Assessment for Alcohol (revised). Clinical Institute Withdrawal Assessment for Alcohol (revised). Mayo-Smith MF. JAMA. 1997;278:

CIWA-Ar Categories [ Range of Scores: 0-7* ] Neuropsych. Symptoms Physical Symptoms Perceptual Disturbances CLOUDED SENSORIUM NAUSEA/VOMITINGAUDITORY ANXIETYHEADACHEVISUAL AGITATIONTREMORSTACTILE SWEATS * except 0-4 for sensorium Adapted from

Practice Guidelines Adapted from Mayo-Smith MF. JAMA. 1997;278:

Pharmacotherapy 1 Long-acting benzodiazepines (e.g., chlordiazepoxide) are the treatment of choice. Long-acting benzodiazepines (e.g., chlordiazepoxide) are the treatment of choice. Short-acting benzodiazepines (e.g., lorazepam) are preferred in liver damage and the elderly. Short-acting benzodiazepines (e.g., lorazepam) are preferred in liver damage and the elderly. Anticonvulsants are being studied. Anticonvulsants are being studied. Holbrook AM et al. Can Med Assoc J. 1999;160: Bonnet U et al. J Clin Psychopharmacol. 2003;23:514-9.

Pharmacotherapy 2 For symptom triggered medication, administer every hour when CIWA- Ar >= 9: For symptom triggered medication, administer every hour when CIWA- Ar >= 9: –Chlordiazepoxide50 to 100 mg –Lorazepam 2 to 4 mg –Diazepam 10 to 20 mg Mayo-Smith MF. JAMA. 1997;278:

Pharmacotherapy 3 For standing po chlordiazepoxide: For standing po chlordiazepoxide: –Day 1:50 mgQ 4 hours –Day 2:50 mgQ 6 hours –Day 3:25 mgQ 4 hours –Day 4:25 mgQ 6 hours Garbutt JC et al. JAMA. 1999;281:

Pharmacotherapy 4 For delirium tremens: For delirium tremens: –2 to 4 mg IV lorazepam followed by –1 to 2 mg IV lorazepam every 5 minutes until patient is calm. –Taper slowly over 4 to 5 days. Adopted from Garbutt JC et al. JAMA. 1999;281:

Pharmacotherapy 5 In general, for severe withdrawal: In general, for severe withdrawal: 1.Titrate to light sedation. 2.Have flumazenil ready. 3.Calculate daily dose. 4.Decrease dose by 25% daily.

4 RELAPSEPREVENTION

DISULFIRAM Introduced in 1954

Mechanism of Action Alcohol → Acetaldehyde → Acetate Alcohol → Acetaldehyde → Acetate Disulfiram irreversibly binds to acetaldehyde dehydrogenase inhibiting the metabolism of acetaldehyde to acetate. Disulfiram irreversibly binds to acetaldehyde dehydrogenase inhibiting the metabolism of acetaldehyde to acetate. Acetaldehyde accumulates resulting in a violent reaction (nausea, vomiting, flushing). Acetaldehyde accumulates resulting in a violent reaction (nausea, vomiting, flushing).

Efficacy Double-blind, placebo-control study design is not helpful as both the medication and the placebo pills may (or may not) result in fear of drinking. Double-blind, placebo-control study design is not helpful as both the medication and the placebo pills may (or may not) result in fear of drinking. Most studies are negative, but disulfiram may be helpful in highly structured settings. Most studies are negative, but disulfiram may be helpful in highly structured settings. Fuller RK et al. JAMA. 1986;256:

Dosing and Safety mg daily mg daily. Medication costs approximately $40 a month. Medication costs approximately $40 a month. Some liver toxicity; liver function should monitored. Some liver toxicity; liver function should monitored. Inhibits hepatic microsomal enzymes and increases drug levels. Inhibits hepatic microsomal enzymes and increases drug levels. Physician’s Desk Reference. 59 th ed. Pp

NALTREXONE Introduced in 1995

Mechanism of Action Reduces positive reinforcement (reward craving). Reduces positive reinforcement (reward craving). The patient does not experience the full euphorogenic/reinforcing effect of alcohol. The patient does not experience the full euphorogenic/reinforcing effect of alcohol. Prevents a slip from becoming a full-blown relapse. Prevents a slip from becoming a full-blown relapse.

Efficacy Effective in reducing relapse to heavy drinking ( >4 in men, >3 drinks/day in women). Effective in reducing relapse to heavy drinking ( >4 in men, >3 drinks/day in women). The Srisurapanont (2005) meta- analysis found efficacy up to 12 weeks but not after 12 weeks. The Srisurapanont (2005) meta- analysis found efficacy up to 12 weeks but not after 12 weeks. Medication compliance may be a limiting factor in treatment. Medication compliance may be a limiting factor in treatment. Mason BJ. Eur Neuropsychopharmacol. 2003;13: Srisurapanont M & Jarusuraisin N. Cochrane Database Syst Rev 2005.

Dosing and Safety 50 mg daily. 50 mg daily. Medication costs $103 a month. Medication costs $103 a month. Liver toxicity; liver function should monitored closely. Liver toxicity; liver function should monitored closely. Otherwise safe and well-tolerated. Otherwise safe and well-tolerated. No significant drug-drug interactions. No significant drug-drug interactions.

ACAMPROSATE Introduced in 2005

Mechanism of Action Reduces negative reinforcement (abstinence craving). Reduces negative reinforcement (abstinence craving). Neuroadaptation and upregulation of the glutamate system in alcoholism. Neuroadaptation and upregulation of the glutamate system in alcoholism. Acamprosate interferes with the glutamatergic system. Acamprosate interferes with the glutamatergic system.

Efficacy Effective in improving abstinence. Effective in improving abstinence. The Mann et al (2004) meta- analysis found a 50% improvement in 6-month abstinence (36% acamprosate vs. 23% placebo). The Mann et al (2004) meta- analysis found a 50% improvement in 6-month abstinence (36% acamprosate vs. 23% placebo). Three times a day dosing may compromise compliance. Three times a day dosing may compromise compliance. Sass et al. Arch Gen Psychiatry. 1996;53: Mann K et al. Alcohol Clin Exp Res. 2004;28:51-63.

Dosing and Safety 666 mg three times a day. 666 mg three times a day. Medication costs $110 a month. Medication costs $110 a month. Excreted by the kidneys - No liver metabolism. Excreted by the kidneys - No liver metabolism. Mild diarrhea (16% acamprosate vs. 10% placebo). Mild diarrhea (16% acamprosate vs. 10% placebo). No drug-drug interactions. No drug-drug interactions. Physician’s Desk Reference. 59 th ed. Pp

5 CO-OCCURRING DISORDERS

In General Co-occurring alcohol dependence and other psychiatric disorder(s) typically require treatment for both (all). Co-occurring alcohol dependence and other psychiatric disorder(s) typically require treatment for both (all). Treating patients under one roof improves both addiction and mental health outcomes. Treating patients under one roof improves both addiction and mental health outcomes. Mariani JJ, Levin FR. Harvard Rev Psychiatry. 2004;12: Kranzler HR, Jaffe JH. In: Graham TK et al, eds. Principles of Addition Medicine. 3 rd ed. Chevy Chase, MD: American Society of Addition Medicine. 2003:

Depression Antidepressants typically improve depressive symptoms. Antidepressants typically improve depressive symptoms. However, they have limited impact on alcohol use. However, they have limited impact on alcohol use. Nunez EV, Levin FR. JAMA. 2004;291:

Antidepressants’ Effect on Depression From Nunez EV, Levin FR. JAMA. 2004;291:1893.

Antidepressants’ Effect on Substance Use From Nunez EV, Levin FR. JAMA. 2004;291:1893.

6 NEW DIRECTIONS

New Delivery Systems Long-acting naltrexone injection: 100 μm diameter microspheres composed of naltrexone and PLG polymeric matrix. Long-acting naltrexone injection: 100 μm diameter microspheres composed of naltrexone and PLG polymeric matrix. Nausea, headache, and fatigue are the prominent adverse effects. Nausea, headache, and fatigue are the prominent adverse effects. FDA decision expected in late ‘05. FDA decision expected in late ‘05. Please note: This agent is not approved by the FDA for use in alcohol dependence.

Injectable Naltrexone Heavy drinking days rates during a 24 week treatment trial with injectable naltrexone 190 mg and 380 mg Qmonth. Heavy drinking days rates during a 24 week treatment trial with injectable naltrexone 190 mg and 380 mg Qmonth. Injectable naltrexone reduced the rate of heavy drinking by 25% ( P =.02). Injectable naltrexone reduced the rate of heavy drinking by 25% ( P =.02). Adapted from Garbutt et al. JAMA. 2005;293:1622.

New Combinations Acamprosate and naltrexone have different mechanisms of action and may work synergistically. Acamprosate and naltrexone have different mechanisms of action and may work synergistically. The COMBINE trial (n=1,375; 11 sites) will assess the medication combination and two behavioral interventions for a total of 9 possible treatment formulations. The COMBINE trial (n=1,375; 11 sites) will assess the medication combination and two behavioral interventions for a total of 9 possible treatment formulations. COMBINE Study Research Group. Alcohol Clin Exp Res. 2003;27:

Naltrexone/Acamprosate Abstinence rates during a 12-week treatment trial with naltrexone 50 mg QD and acamprosate 666 mg TID. Abstinence rates during a 12-week treatment trial with naltrexone 50 mg QD and acamprosate 666 mg TID. The combination of the two medications helped alcoholics stay abstinent ( P= 0.002) better than each drug alone. The combination of the two medications helped alcoholics stay abstinent ( P= 0.002) better than each drug alone. Adapted from Kiefer F et al. Arch Gen Psychiatry. 2003;60:96.

New Pharmacological Agents Anticonvulsants Anticonvulsants –Topiramate –Carbamazepine –Valproic Acid GABA agonist GABA agonist –Baclofen Selective Serotonin Reuptake Inhibitors Selective Serotonin Reuptake Inhibitors Serotonin (5-HT 3 ) antagonist Serotonin (5-HT 3 ) antagonist –Ondansetron Please note: These agents are not approved by the FDA for use in alcohol dependence.

Where you can find us You can request an addiction consultation by contacting: You can request an addiction consultation by contacting: –Galen Cooper, Ph.D., x38409/pgr at Roosevelt, or –Raisa Montalvo, M.A., x31743/pgr at St. Luke’s. Our website: Our website: Our 24-hour-line: Our 24-hour-line: