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Naltrexone : The Magic Bullet for Alcoholism

Alfred M. Turner

Waubonsee Community College; Honors Program; 1995


Abstract

Naltrexone was ushered in by the press as "The Magic Bullet for Alcoholism", however this is not the truth of the situation. Clinical trials of naltrexone have been limited to two independent studies. The findings of these trials were that naltrexone was effective in reducing alcohol relapse and cravings by about fifty percent in the subject population. There is a need for more in depth trials, for longer periods of time, and on a wider variety of addicted populations, to further substantiate these initial conclusions.

Outline

I. Introduction
II. How Naltrexone Works
III. Naltrexone Studies on Human Subjects
IV. Treatment Implications
V. Conclusions 

Introduction

The U.S. Food and Drug Administration (FDA), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and representatives from the DuPont Merck Pharmaceutical Corporation announced the release of a new agent called naltrexone (REVIA(TM)) on January 17, 1995 as a safe and effective adjunct to psychosocial treatments for alcoholism. "While not a 'magic bullet' naltrexone promises to help many patients in their struggle against a chronic relapsing disease," said NIAAA director Enoch Gordis, MD. "Spokespeople for Dupont Merck said that naltrexone, which has been sold under the brand name Trexan since 1984 for the treatment of heroin addiction, will be renamed REVIA and marketed for both conditions. The drug, made in tablets that are taken once a day, will be expensive. With a wholesale price of $3.75 per dose, it will probably retail for just under $6.00" ( Schmidt 1995).

Naltrexone has only recently been the focus of studies to evaluate its effects on alcoholics. Joseph Volpicelli, MD., PhD., and colleagues at the University of Pennsylvania, and Stephanie O'Mally, MD, and colleagues at Yale University School of Medicine, in two separate 1992 studies funded by the NIAAA, reported that naltrexone helped to reduce relapse in a significant number of treated alcoholics. The researchers also noted that the subjects of the studies also reported less alcohol craving and fewer drinking days than patients who were administered a placebo.

DuPont Merck also reported the results of their own study and found that naltrexone was well tolerated at the recommended dosage of 50 mg a day. This study, of three months duration, looked at a large heterogeneous population of alcoholics in diverse treatment modalities and settings. Richard Fuller, MD, director of the Division of Clinical and Prevention Research at NIAAA stated "For now at least, only physicians familiar with addiction treatment probably should prescribe naltrexone, and only in the context of an alcoholism treatment program." He also added that clinical judgment must be used to decide whether to use conventional treatment , or naltrexone combined with conventional treatment (Schmidt 1995).

How Naltrexone Works

Current treatments for alcoholism can be effective in helping patients stop drinking alcohol, however they are only modestly effective in reducing relapse, or returning to excessive drinking. About half of all patients who complete an inpatient or residential psychosocial treatment relapse within the first three months of treatment, causing this period of recovery to be critical for maintaining abstinence (Miller and Hester 1986; Nathan 1986). Therefore, finding an agent that will help to maintain abstinence during early recovery would help increase treatment success rates. Currently, the most commonly used and researched pharmacological agents are disufiram (Antabuse), lithium, and those that increase the activity of the serotonin system (i.e., the system that affects mood states). The difficulty with these agents is that none have been shown to be more effective than a placebo in clinical trials. Volpicelli et al, in a 1994 article published in Alcohol Health and Research World explains a new pharmacological advance in relapse prevention:


"A promising new approach to the problem of relapse is the use of opiate antagonists. These substances block specific portions of neurons in the brain--opiate receptors--that are stimulated by opioids, such as morphine. Opiate receptors also are targets for alcohol's activity in the brain. Blocking the receptors seems to prevent many of the positive consequences of drinking alcohol, such as the alcohol "high," thereby decreasing the likelihood of excessive alcohol consumption."

There have been several suggested methods of alcohol's indirect affect upon opioid receptor activity. Studies have shown that in humans alcohol stimulates the release of endogenous opioids, including beta-endorphin, which is under normal circumstances used by the body to diminish pain. Also included in the studies are other endorphins that will produce pleasurable effects upon release by alcohol (Gianoulakis 1993, Volpicelli 1994). The activity of these endorphins may be the explanation for excessive alcohol consumption in some rat strains as well as in some humans. Volpicelli elaborates:

"For example, rats bred to have a high preference for alcohol show enhanced beta- endorphin release when they consume alcohol compared with rats bred for a low preference for alcohol (deWaele et al. 1992). Similarly, in a study conducted by Gianoulakis and colleagues (1990), male social drinkers who were at increased risk for alcohol abuse, because they had alcohol dependent parents, experienced a 170-percent increase in peripheral beta-endorphin levels after consuming moderate doses of alcohol. In contrast, male social drinkers without alcohol dependent parents did not show any increase in beta-endorphin levels after drinking the same amount of alcohol. Thus, enhanced release of endorphins induced by even small amounts of alcohol may increase the risk for alcohol abuse, and the more a person drinks, the more endorphins appear to be released."(1994)

Several studies show that opioid consumption affects alcohol consumption. Sinclair (1974) demonstrated that rats given a high dose of morphine reduced alcohol intake but not water intake. This showed that morphine's' effect was limited to alcohol. In another related study rats were found to reduce alcohol consumption as larger doses of morphine were administered. (Ho et al., 1976) Opiate use can reduce the intake of alcohol, however, the inverse is true during opiate withdrawal. Volpicelli and colleagues found in 1991 (compared to a control group) that rats given free access to both alcohol and water decreased alcohol consumption when injected with morphine. The next day, however, the rats alcohol consumption was nearly doubled. These studies and others support the hypothesis that an increase in activity at opioid receptor sites can result in reduced alcohol consumption. On the other side of this equation, reduced opioid receptor activity results in increased alcohol intake. As with most research findings there are exceptions to the rule:

"An important exception to this relationship comes from the research conducted by Reid and associates (1991), in which small doses of morphine were found to increase alcohol transiently in rats given limited access to alcohol or water. For example, rats with 2-hour access to alcohol or water that received a low dose of morphine (generally less than 2.5 mg/kg) typically drank more of an alcohol solution than did rats injected with saline (Volpicelli, 1994)."

The sum of the above shows that opiates can have an effect equal to that of having an appetizer before dinner. A small dose of a substance that affects the opiate receptor sites can increase the drive to consume more of the same. This "priming effect" (Volpicelli 1994), is shown to be consistent across a wide variety of addictive substances (Stewert, 1983; Jaffe et al. 1989). While no studies have shown this particular effect to hold true in human alcohol consumption, Volpicelli (1994) draws the correlation, " These people (such as the high-risk subjects mentioned above in the study by Gianoulakis and colleges [1990]) may find that one drink increases the motivation and craving for the next drink, and this may explain why some alcohol-dependent people find it difficult to control their alcohol consumption once they have begun to drink." This "appetizer" or "priming" effect provides good reason to look at opiate receptor blocking pharmacological agents in the battle to reduce relapse in early recovery. Using the studies on animals and the concurrent studies done on the effects of alcohol on opioid receptor sites in humans, the NIAAA funded two initial studies on the effects of naltrexone on alcoholics seeking recovery.

Naltrexone Studies on Human Subjects

The Volpicelli et al. (1992) study:
Setting 


Volpicelli and colleagues used a double-blind, twelve week, outpatient, clinical trial on seventy male veterans, predominately African-American and unemployed, who had been drinking an average of twenty years. The Subjects (Ss) were administered either a fifty mg. dose of naltrexone or a placebo. Ss also were referred to AA meetings, and received psychosocial therapy in the form of supportive alcoholism counseling and relapse prevention therapy. Outcome measures were self-reported on alcohol drinking and craving. Alcohol relapse was differentiated from "slipping" in this study. Relapse was defined as consuming five or more drinks on one occasion, and/or presenting for treatment with a BAC of 1.0 or greater, and/or consuming alcohol five or more times during the previous week.

Results

Relapse rates for the naltrexone treated Ss were approximately one half of those Ss who were administered placebos. Effects on craving (measured on a scale of one to ten) in Ss given placebos was negligent and Ss given naltrexone reported a gradual decline in self- reported craving. Volpicelli explains the effects:

"Possibly as a consequence of their reduced desire to drink, naltrexone-treated subjects reported less alcohol consumption than the placebo-treated subjects. Although the percentage of naltrexone-treated patients who drank any alcohol during the study was equal to the percentage of placebo-treated subjects who drank, the naltrexone-treated subjects who slipped consumed alcohol on fewer days than did placebo-treated subjects. Of the subjects who slipped, the placebo-treated group drank alcohol on nearly four times as many days as the naltrexone-treated subjects (14.0 percent of the study days versus 3.6 of the study days)." (1992).

Side effects were negligible on all Ss. Two Ss dropped out ofinduced by the administration of naltrexone.

The O'Mally et al. (1992) study:
Setting

A double-blind, twelve week, outpatient, clinical trial on 97 Ss (72 men and 25 women), predominately white and employed full time. The Subjects (Ss) were administered either a fifty mg. dose of naltrexone or a placebo. Ss received one of two different types of therapy (coping skills reported on alcohol drinking and craving. Alcohol relapse was differentiated from "slipping" in this study. Relapse, in this study, was defined as consuming five or more drinks on one occasion for men and four or more for women.

Results

Findings in this study were similar to those of Volpicelli's 1992 study. O'Mally and colleagues found that naltrexone reduced relapse rates by about one half. Ss administered naltrexone reported drinking on 4.3 percent of the study days whereas Ss given a placebo reported drinking on 9.9 percent of the study days. Another interesting outcome of this particular study was that Ss who received naltrexone and supportive therapy were less likely to sample a drink for the first time after beginning treatment as compared to other treatment groups. Ss treated with naltrexone and coping skills therapy were just as likely to slip as control Ss, however, they were less likely to relapse. This suggests that naltrexone combined with coping skills therapy is the most effective treatment approach to reducing craving and relapse.

Treatment Implications

Counselors considering using naltrexone as an adjunct to chemical dependency treatment would be well advised to consider the following criteria in determining Ss who may be good prosp 1) Ss should be actively participating in comprehensive psychosocial treatment. 
2) Ss MUST be opioid free for seven days prior to initiation of naltrexone treatment. 
3) Ss MUST have completed opioid or alcohol withdrawal completely.
4) Ss should demonstrate a high degree of commitment to abstinence and avoidance of high risk situations.
5) Ss with acute hepatitis and/or liver failure are not eligible for naltrexone treatment.
Ss should be given complete information on thenaltrexone as an adjunct to treatment. Naltrexone can only be prescribed by a physician and the clinician would be wise to instruct the Ss to undergo a complete physical as well wheexcellent judgment when deciding which Ss to recommend for naltrexone treatment. Excessive consumption of opioids or alcohol to negate naltrexone's "blocking" effect can resuldistress. This appeared in a minor percentage of the Ss studied.

Conclusions

While Naltrexone was effective for some Ss within these studies, it is highly improbable that this will hold true for all addicted Ss. Additional research is needed in the following areas: 1) determine which sub-populations naltrexone might benefit most; 2) determine the most effective dosages for these Ss; 3) determine naltrexone's efficacy beyond the three month time frame. Currently the NIAAA is funding nine research studies, some of which are looking at these specific criteria. The prudent counselor may opt to wait for the extended research to become available before deciding to adopt naltrexone as a part of their particular treatment program. The press at large was quick to dub naltrexone a "magic bullet" despite the warnings of experts in the field that this was not the case. However, giving credit where it is due, the press has since published more accurate and restrained claims as to naltrexone's informed, may have misconceptions as to naltrexone's method of action, effectiveness,limitations. The future of naltrexone may depend, in part, on the clinician's prudent judgment as to who should be eligible to receive naltrexone as an adjunct to therapy.

I haven't had time to update my research on Naltrexone lately so I've included this letter that I recently recieved from Dr. Volpicelli. He has graciously given his permission to post his email address if you would like to contact him directly for further information. Simply click on his name to send him email. 

Addendum

Date: Sat, 26 Oct 1996 02:15:59 -0400
From: ">Joseph R. Volpicelli To: Al Turner 

Al,

I have read your web page and it is good. There are now more data to show that naltrexone is helpful for patients. I am currently submitting a study which shows that naltrexone is helpful for patients who are motivated for treatment. We found that overall naltrexone had only modest effects but when we compared patients who were reliable with taking naltrexone compared to placebo we found an interesting interaction. Naltrexone had a latreatment effect size compared to placebo patients. Also, this finding has been replicated in another study in England.

While in 1992, we were cautious in our interpretation of the efficacy for naltrexone, I believe the tide has changed. Naltrexone is a safe medicine and there are several studies which show its efficacy in treating patients. Also the results of dozens of animal studies show that naltrexone reduces alcohol drinking in a variety of conditions. Finally studies of social drinkers show that naltrexone reduces alcohol stimulation. At this time I believe that to withhold the option of naltrexone for motivated patients is poor clinical practice. As I look at the cost-benefit ratio, for me the benefits clearly outweigh the costs.

While I am generally cautious in my interpretations of the data, there are times when caution carries a risk. As I think about people who may be helped with naltrexone who are not receiving help because of being too cautious I wonder if we are doing more harm then good.

">Joe

Web of Addictions's Naltrexone Pages which include some case studies and a FAQ.

Naltrexone in the treatment of Autism.

References

deWaele, J.P.; Papachristou, D.N. and Gianoulakis, C. The alcohol-preferring C57Bl/6 mice present an enhanced sensitivity of the hypothalamic B-endorphin systhan the alcohol avoiding DBA/2 mice. Journal of Pharmacology and Experimental Therapeutics 261:788-794, 1992.

Enoch,G. Open letter to the press, Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute on Alcohol, Abuse and Alcoholism. Feb. 1995.

Gianoulakis, C.; Angelogianni, P.; Meany, M.; Thavundayil, J.; and Tawar, V. endorphins in individuals with high and low risk for development of alcoholism. In; Reid, L.D., ed. Opioids, Bulimia, and Alcohol Abuse and Alcoholism. New York; Springer-Verlag, 229- 246 1990.

Gianoulakis, C. Endogenous opioids and excessive alcohol consumption. Journal of Psychiatric Neuroscience 18(4): 148-156, 1993 

Ho, A.K.S.; Chen, R.C.A.; and Morrison, J.M. Interaction of narcotics, narcotic antagonists, and ethanol during acute, chronic, and withdrawal states. Annals of the New York Academy of Sciences 281:297-310, 1976 

Jaffe, J.H.; Cascella, N.G.; Kumor, K.M.; and Sherer, M.A. Cocaine-induced cocaine craving. Psychopharmacology 97(1):59-64, 1989.

Miller, W.R., and Hester, R.K. The effectiveness of alcoholism treatment: What the research reveals. In: Miller, W.R., and Heather, N., eds. Treating Addictive Disorders: Processes of Change. New York: Plenum Press, Nathan, P.E. Outcomes of treatment for alcoholism: Current Data. Annals of Behavioral Medicine 8:40-46, 1986.

O'Mally, S.S.; Jaffe, A.J.; Chang, G.; Schottenfeld, R.S.; Meyer, R.E.; and Rounsaville, B. Naltrexone and coping skills therapy for alcohol dependence: A controlled study. Archives of General Psychiatry 49(11):881-887, 1992. 

Reid, L.D.; Delconte, J.D.; Nichols, M.L.; Bilsky, E.J.; and Hubbard, C.L. Tests of opioid deficiency hypothesis of alcoholism. Alcohol 8(4);247-257, 1991.

Sinclair, J.D. Morphine suppresses alcohol drinking regardless of prior alcohol access duration. Pharmacology, Biochemistry, and Behavior 2:409-412, 1974.

Schmidt, L. Naltrexone 10, 1994.

Stewert, J. reinstatement of heroin and cocaine self-administration behavior in the rat by intracerebral application of morphine in the ventral tegmental area. Pharmacology, Biochemistry, and Behavior 20:917-923, 1983.

Volpicelli, J.R.; Ulm, R.R.; and Hopson, N. alcohol drinking in rats during and following morphine injections. Alcohol 8(11):289-292, 1991.

Volpicelli, J.R.; Alterman, A.I.; Hayashida, M.; and O'Brian, C.P. Naltrexone in the treatment of alcohol dependence. Archives of General Psychiatry 49(11):876- 880,1992.

Volpicelli, JR..; Clay, K.L.; Watts, NT; Volpicelli, L. Naltrexone and the treatment of alcohol dependence. Alcohol Health and Research World 1: 272, 1994. 

 


Alexander DeLuca, M.D., FASAM.
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Revised: June 16, 2001.
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