Naltrexone in the Treatment of Alcohol Joseph \s=b\ a
R.
Volpicelli, MD, PhD; Arthur I. Alterman, PhD; Motoi Hayashida, MD, ScD;
Seventy male alcohol-dependent patients participated in 12-week, double-blind, placebo-controlled trial of nal-
trexone hydrochloride (50 mg/d) as an adjunct to treatment following alcohol detoxification. Subjects taking naltrexone reported significantly less alcohol craving and days in which any alcohol was consumed. During the 12-week study, only 23% of the naltrexone-treated subjects met the criteria for a relapse, whereas 54.3% of the placebo-treated subjects relapsed. The primary effect of naltrexone was seen in patients who drank any alcohol while attending outpatient treatment. Nineteen (95%) of the 20 placebo-treated patients relapsed after they sampled alcohol, while only eight (50%) of 16 naltrexone-treated patients exposed to alcohol met relapse criteria. Naltrexone was not associated with mood changes or other psychiatric symptoms. Signif-
icant side effects (nausea) occurred in two nalterxonetreated subjects, and one naltrexone-treated subject complained of increased pain from arthritis. These results suggest that naltrexone may be a safe and effective adjunct to treatment in alcohol-dependent subjects, particularly in preventing alcohol relapse.
(Arch Gen Psychiatry. 1992;49:876-880)
Psychosocial detoxification
treatment programs for alcohol depen¬ dence have had only modest success. While alcohol programs can safely help virtually all pa¬ tients stop using alcohol, it is another matter to help patients remain abstinent. For example, reviews of treat¬ ment outcomes for alcohol rehabilitation programs1,2 re¬ port that both intensive inpatient and residential treatment programs have about a 50% relapse rate within the first 3 months after beginning treatment. The high relapse rate has inspired a search for pharmacological agents that may act as an adjunct to psychosocial alcohol rehabilitation programs. Thus far, pharmacological adjuncts to alcohol rehabilita¬ tion treatment programs have included disulfiram, lithium, and medications that inhibit serotonin reuptake. Dis¬ ulfiram blocks alcohol metabolism, producing an accumu¬ lation of acetaldehyde and a subsequent toxic reaction. Thus, patients who resume alcohol drinking experience un¬ pleasant physical symptoms such as nausea. The anticipa-
Accepted for publication February 8, 1992. From the Department of Psychiatry, University of Pennsylvania, adelphia, and the Philadelphia Veterans Affairs Medical Center.
Phil-
Presented in part at a satellite symposium associated with the annual session of the meeting of the Society of Neuroscience, November 12, 1988, Toronto, Ontario. Reprint requests to Treatment Research Center, 3900 Chestnut St, Philadelphia, PA 19104 (Dr Volpicelli).
Dependence
Charles P. O'Brien, MD, PhD
physical sickness presumably deters patients from drinking. Disulfiram has been shown to have limited clin¬ ical utility, as seen in several well-controlled clinical trials that failed to show significant differences in treatment out¬ come between groups of subjects taking disulfiram and pla¬ cebo.3,4 Disulfiram may be effective in highly motivated subgroups of alcohol-dependent patients.3 For these sub¬ jects, disulfiram decreases the total number of drinking days and amount of alcohol consumed. Lithium has also been used to treat alcohol dependence. Many coexisting mood disorders may increase the desire to drink alcohol (ie, the so-called self-medication hypoth¬ esis).5 Accordingly, as the medication alleviates the mood tion of
disorder, the motivation to drink alcohol should decrease.
Support for this notion was provided by evidence show¬ ing that lithium reduced drinking in a subgroup of alcohol-dependent subjects who had coexisting mood dis¬ orders.6,7 Follow-up studies, however, have shown that lithium may not be an effective adjunct when compared in placebo-controlled, double-blind studies. For example, in recent multicenter double-blind trial with 457 male veterans, lithium failed to improve treatment outcome for either depressed or nondepressed a
alcohol-dependent
patients.8
There may, however, be a subgroup of highly motivated patients and occasional drinkers who derive benefit from taking lithium. Medications that enhance serotonergic activity are also being investigated for possible usefulness in the treatment of alcohol dependence. Several animal studies have shown that serotonergic drugs decrease alcohol drinking, although there is considerable debate over whether the effects of serotonergic drugs are specific for alcohol or generally decrease all appetitive behavior.9 Studies with nondependent alcohol abusers have shown that the serotonin uptake inhibitor citralopram de¬ creases the number of drinking days and the total amount of alcohol drinking.10 The efficacy of serotoner¬ gic agents in alcohol-dependent patients remains to be tested in double-blind studies. Biochemical and behavioral studies demonstrating an in¬ teraction between alcohol and opioids suggest new phar¬ macological approaches to the treatment of alcoholism. Several animal studies have shown that opiate antagonists such as naltrexone1113 or naloxone14,15 will decrease alcohol drinking. For example, following experience with inescap¬ able stress, rats will dramatically increase their preference for alcohol. This poststress increase in alcohol drinking is blocked by subcutaneous injections of 10 mg/kg naltrex¬ one.12 Furthermore, alcohol drinking in rats increases fol¬ lowing administration of small doses of opiates such as
Downloaded From: http://archpsyc.jamanetwork.com/ by a Western University User on 06/09/2015
morphine.16 These data suggest that alcohol drinking is in¬ fluenced by alterations in opiate receptor activity, and that opiate antagonists such as naltrexone may be a helpful ad¬ junct in the treatment of alcohol dependence.17 The present article is a report in which this hypothesis was evaluated in alcohol-dependent men by assessing the effectiveness of naltrexone hydrochloride in reducing alcohol craving and alcohol drinking, using a variety of subjective and objective measures. Specifically, we tested the following hypotheses: (1) naltrexone decreases alcohol craving; (2) naltrexone decreases alcohol drinking as assessed by self-reports, breath alcohol readings, and liver enzyme data; (3) naltrexone decreases clinically significant bouts of alcohol drinking (relapse rates as defined in this study); and (4) naltrexone does not have adverse emotional
Placebo
Age,
African American White
Hispanic
Employed, Married, Years
Subjects
Procedure
newly admitted alcohol-dependent patients receiving outpatient rehabilitation treatment at the Substance Abuse Treatment Unit of the Philadelphia Veterans Affairs Med¬ ical Center. In addition to receiving naltrexone or placebo for 12 weeks, all subjects received standard rehabilitation treatment at were
the Substance Abuse Treatment Unit. The first month of rehabil¬ itation for all patients consists of daily contacts with the unit in the partial day-hospitalization treatment program. Patients spend 6 hours in daily treatment, which consists of group therapy, in¬ dividual counseling for problems related to alcohol dependence, educational classes, recreation, health education, and general health care provided by staff nurse practitioners or physician as¬ sistants. Following 1 month of day treatment, patients enter after-care treatment, which involves attending group therapy twice per week for the next 11 months. New medically detoxified patients or patients whose last drink occurred within the last 21 days were checked for the above cri¬ teria. If they met all the requirements, they were informed of the study and given the opportunity to volunteer. Volunteers were then randomized into the naltrexone or placebo treatment groups using a simple randomization procedure. All subjects initially underwent a 1-week treatment with placebo. Following the baseline placebo week, they received naltrexone or placebo according to their randomized assignment. Patients who re¬ turned for the first visit following randomization were counted as subjects. This resulted in 35 placebo- and 35 naltrexonetreated subjects.
%
%
heavy drinking
AST, U/L GGT, U/L
SUBJECTS AND METHODS
Subjects
y
Naltrexone 43.5±9.3
Race, %
effects.
Seventy subjects (all male veterans) who met the following cri¬ teria were enrolled in this double-blind, placebo-controlled study. The study subjects (1) were 21 to 65 years of age; (2) met at least five of the nine DSM-III-R criteria for alcohol dependence, including physical signs of alcohol withdrawal of sufficient intensity to require medical detoxification (these criteria were evaluated on the basis of an interview by a psychiatrist); (3) scored greater than 5 on the Michigan Alcohol Screening Test; and (4) were capable of understanding the requirements of the study and completing self-rating forms. Exclusion criteria included having a major psychiatric illness associated with psychosis or dementia at the time of the evaluation or being judged by a psychiatrist to be a danger to self or others, having a history of unstable or se¬ rious medical illness, using narcotics in the past 30 days, having a drug screen positive for opiates, amphetamines, cocaine, or barbiturates, or having laboratory evidence of significant hepatocellular failure as evidenced by elevated bilirubin levels. The study was reviewed and approved by the Philadelphia (Pa) Vet¬ erans Affairs Medical Center's Human Subjects Committee, and all subjects gave written informed consent after a full under¬ standing of the study.
43.3±9.0 82.8 17.2 0
74.2 23.8 2
34.2
48.9
45.7
42.8
19.4±9.5
20.4±8.6
65.2±69.0
45.4±35.8
180.1 ±243.8
139.9±266.5
Baseline alcohol craving Baseline drinking days
3.08±2.69
2.54±2.06
0.06±0.13
0.02±0.07
BPRS
24.3±6.7
23.1 ±7.0
69.8+63.7 0.58±0.57 0.87±0.86 0.73±0.79 0.89 + 0.85 0.83 ±0.81 0.57±0.78 0.62±0.74 0.93±0.95 0.65±0.69
49.2±47.9 0.49±0.54 0.61 ±0.68 0.53±0.60 0.64±0.60 0.55±0.60 0.43±0.72 0.24±0.53t 0.61 ±0.75 0.39±0.61
SCL-90 Total Somatic
Obsessive-compulsive Interpersonal sensitivity Depression Anxiety Hostility Phobic anxiety
Paranoid ideation
Psychoticism
*Except as indicated, values are mean±SD. AST indicates aspartate aminotransferase; GGT, -y-glutamyltransferase; BPRS, Brief Psychiatric Rating Scale; and SCL-90, 90-ltem Symptom Checklist. tP
R.
Volpicelli, MD, PhD; Arthur I. Alterman, PhD; Motoi Hayashida, MD, ScD;
Seventy male alcohol-dependent patients participated in 12-week, double-blind, placebo-controlled trial of nal-
trexone hydrochloride (50 mg/d) as an adjunct to treatment following alcohol detoxification. Subjects taking naltrexone reported significantly less alcohol craving and days in which any alcohol was consumed. During the 12-week study, only 23% of the naltrexone-treated subjects met the criteria for a relapse, whereas 54.3% of the placebo-treated subjects relapsed. The primary effect of naltrexone was seen in patients who drank any alcohol while attending outpatient treatment. Nineteen (95%) of the 20 placebo-treated patients relapsed after they sampled alcohol, while only eight (50%) of 16 naltrexone-treated patients exposed to alcohol met relapse criteria. Naltrexone was not associated with mood changes or other psychiatric symptoms. Signif-
icant side effects (nausea) occurred in two nalterxonetreated subjects, and one naltrexone-treated subject complained of increased pain from arthritis. These results suggest that naltrexone may be a safe and effective adjunct to treatment in alcohol-dependent subjects, particularly in preventing alcohol relapse.
(Arch Gen Psychiatry. 1992;49:876-880)
Psychosocial detoxification
treatment programs for alcohol depen¬ dence have had only modest success. While alcohol programs can safely help virtually all pa¬ tients stop using alcohol, it is another matter to help patients remain abstinent. For example, reviews of treat¬ ment outcomes for alcohol rehabilitation programs1,2 re¬ port that both intensive inpatient and residential treatment programs have about a 50% relapse rate within the first 3 months after beginning treatment. The high relapse rate has inspired a search for pharmacological agents that may act as an adjunct to psychosocial alcohol rehabilitation programs. Thus far, pharmacological adjuncts to alcohol rehabilita¬ tion treatment programs have included disulfiram, lithium, and medications that inhibit serotonin reuptake. Dis¬ ulfiram blocks alcohol metabolism, producing an accumu¬ lation of acetaldehyde and a subsequent toxic reaction. Thus, patients who resume alcohol drinking experience un¬ pleasant physical symptoms such as nausea. The anticipa-
Accepted for publication February 8, 1992. From the Department of Psychiatry, University of Pennsylvania, adelphia, and the Philadelphia Veterans Affairs Medical Center.
Phil-
Presented in part at a satellite symposium associated with the annual session of the meeting of the Society of Neuroscience, November 12, 1988, Toronto, Ontario. Reprint requests to Treatment Research Center, 3900 Chestnut St, Philadelphia, PA 19104 (Dr Volpicelli).
Dependence
Charles P. O'Brien, MD, PhD
physical sickness presumably deters patients from drinking. Disulfiram has been shown to have limited clin¬ ical utility, as seen in several well-controlled clinical trials that failed to show significant differences in treatment out¬ come between groups of subjects taking disulfiram and pla¬ cebo.3,4 Disulfiram may be effective in highly motivated subgroups of alcohol-dependent patients.3 For these sub¬ jects, disulfiram decreases the total number of drinking days and amount of alcohol consumed. Lithium has also been used to treat alcohol dependence. Many coexisting mood disorders may increase the desire to drink alcohol (ie, the so-called self-medication hypoth¬ esis).5 Accordingly, as the medication alleviates the mood tion of
disorder, the motivation to drink alcohol should decrease.
Support for this notion was provided by evidence show¬ ing that lithium reduced drinking in a subgroup of alcohol-dependent subjects who had coexisting mood dis¬ orders.6,7 Follow-up studies, however, have shown that lithium may not be an effective adjunct when compared in placebo-controlled, double-blind studies. For example, in recent multicenter double-blind trial with 457 male veterans, lithium failed to improve treatment outcome for either depressed or nondepressed a
alcohol-dependent
patients.8
There may, however, be a subgroup of highly motivated patients and occasional drinkers who derive benefit from taking lithium. Medications that enhance serotonergic activity are also being investigated for possible usefulness in the treatment of alcohol dependence. Several animal studies have shown that serotonergic drugs decrease alcohol drinking, although there is considerable debate over whether the effects of serotonergic drugs are specific for alcohol or generally decrease all appetitive behavior.9 Studies with nondependent alcohol abusers have shown that the serotonin uptake inhibitor citralopram de¬ creases the number of drinking days and the total amount of alcohol drinking.10 The efficacy of serotoner¬ gic agents in alcohol-dependent patients remains to be tested in double-blind studies. Biochemical and behavioral studies demonstrating an in¬ teraction between alcohol and opioids suggest new phar¬ macological approaches to the treatment of alcoholism. Several animal studies have shown that opiate antagonists such as naltrexone1113 or naloxone14,15 will decrease alcohol drinking. For example, following experience with inescap¬ able stress, rats will dramatically increase their preference for alcohol. This poststress increase in alcohol drinking is blocked by subcutaneous injections of 10 mg/kg naltrex¬ one.12 Furthermore, alcohol drinking in rats increases fol¬ lowing administration of small doses of opiates such as
Downloaded From: http://archpsyc.jamanetwork.com/ by a Western University User on 06/09/2015
morphine.16 These data suggest that alcohol drinking is in¬ fluenced by alterations in opiate receptor activity, and that opiate antagonists such as naltrexone may be a helpful ad¬ junct in the treatment of alcohol dependence.17 The present article is a report in which this hypothesis was evaluated in alcohol-dependent men by assessing the effectiveness of naltrexone hydrochloride in reducing alcohol craving and alcohol drinking, using a variety of subjective and objective measures. Specifically, we tested the following hypotheses: (1) naltrexone decreases alcohol craving; (2) naltrexone decreases alcohol drinking as assessed by self-reports, breath alcohol readings, and liver enzyme data; (3) naltrexone decreases clinically significant bouts of alcohol drinking (relapse rates as defined in this study); and (4) naltrexone does not have adverse emotional
Placebo
Age,
African American White
Hispanic
Employed, Married, Years
Subjects
Procedure
newly admitted alcohol-dependent patients receiving outpatient rehabilitation treatment at the Substance Abuse Treatment Unit of the Philadelphia Veterans Affairs Med¬ ical Center. In addition to receiving naltrexone or placebo for 12 weeks, all subjects received standard rehabilitation treatment at were
the Substance Abuse Treatment Unit. The first month of rehabil¬ itation for all patients consists of daily contacts with the unit in the partial day-hospitalization treatment program. Patients spend 6 hours in daily treatment, which consists of group therapy, in¬ dividual counseling for problems related to alcohol dependence, educational classes, recreation, health education, and general health care provided by staff nurse practitioners or physician as¬ sistants. Following 1 month of day treatment, patients enter after-care treatment, which involves attending group therapy twice per week for the next 11 months. New medically detoxified patients or patients whose last drink occurred within the last 21 days were checked for the above cri¬ teria. If they met all the requirements, they were informed of the study and given the opportunity to volunteer. Volunteers were then randomized into the naltrexone or placebo treatment groups using a simple randomization procedure. All subjects initially underwent a 1-week treatment with placebo. Following the baseline placebo week, they received naltrexone or placebo according to their randomized assignment. Patients who re¬ turned for the first visit following randomization were counted as subjects. This resulted in 35 placebo- and 35 naltrexonetreated subjects.
%
%
heavy drinking
AST, U/L GGT, U/L
SUBJECTS AND METHODS
Subjects
y
Naltrexone 43.5±9.3
Race, %
effects.
Seventy subjects (all male veterans) who met the following cri¬ teria were enrolled in this double-blind, placebo-controlled study. The study subjects (1) were 21 to 65 years of age; (2) met at least five of the nine DSM-III-R criteria for alcohol dependence, including physical signs of alcohol withdrawal of sufficient intensity to require medical detoxification (these criteria were evaluated on the basis of an interview by a psychiatrist); (3) scored greater than 5 on the Michigan Alcohol Screening Test; and (4) were capable of understanding the requirements of the study and completing self-rating forms. Exclusion criteria included having a major psychiatric illness associated with psychosis or dementia at the time of the evaluation or being judged by a psychiatrist to be a danger to self or others, having a history of unstable or se¬ rious medical illness, using narcotics in the past 30 days, having a drug screen positive for opiates, amphetamines, cocaine, or barbiturates, or having laboratory evidence of significant hepatocellular failure as evidenced by elevated bilirubin levels. The study was reviewed and approved by the Philadelphia (Pa) Vet¬ erans Affairs Medical Center's Human Subjects Committee, and all subjects gave written informed consent after a full under¬ standing of the study.
43.3±9.0 82.8 17.2 0
74.2 23.8 2
34.2
48.9
45.7
42.8
19.4±9.5
20.4±8.6
65.2±69.0
45.4±35.8
180.1 ±243.8
139.9±266.5
Baseline alcohol craving Baseline drinking days
3.08±2.69
2.54±2.06
0.06±0.13
0.02±0.07
BPRS
24.3±6.7
23.1 ±7.0
69.8+63.7 0.58±0.57 0.87±0.86 0.73±0.79 0.89 + 0.85 0.83 ±0.81 0.57±0.78 0.62±0.74 0.93±0.95 0.65±0.69
49.2±47.9 0.49±0.54 0.61 ±0.68 0.53±0.60 0.64±0.60 0.55±0.60 0.43±0.72 0.24±0.53t 0.61 ±0.75 0.39±0.61
SCL-90 Total Somatic
Obsessive-compulsive Interpersonal sensitivity Depression Anxiety Hostility Phobic anxiety
Paranoid ideation
Psychoticism
*Except as indicated, values are mean±SD. AST indicates aspartate aminotransferase; GGT, -y-glutamyltransferase; BPRS, Brief Psychiatric Rating Scale; and SCL-90, 90-ltem Symptom Checklist. tP
