Naltrexone the Efficacy of Naltrexone

Naltrexone

The Efficacy of Naltrexone in the Treatment of Alcoholism

The economic, social and physical toll exacted by alcoholism is enormous by any measure, and identifying effective ways to treat this condition has been the focus of an increasing amount of research in recent years. While there has been a consensus among healthcare providers, clinicians and researchers alike that alcoholism is in fact a disease, there are some environmental and behavioral issues that have been shown to play a significant role as well. One approach that may offer some potential for treating many of the symptoms typically associated with alcoholism, as well as some of the concomitant behaviors, is the use of naltrexone. It is the hypothesis of this study that Naltrexone will reduce the cravings associated with alcoholism, as well as related relapse rates, and episodes of heavy drinking compared to a placebo with alcoholics based on a preponderance of evidence in the peer-reviewed and scholarly literature. The critical review of the literature used for this purpose is followed by a summary of the research in the conclusion, together with recommendations for policymakers and healthcare providers alike.

Review and Discussion

Background and Overview.

The impact of alcohol abuse and alcoholism is well documented and need be mentioned only to establish the extent of the problem considered herein. In this regard, Bhagar and Schmetzer (2006) report that, "Alcohol dependence is a problem that affects about 10% of the general population. It not only impacts the affected individual with disorders such as cirrhosis of the liver, pancreatitis, dementia, and others, but also affects the whole family from issues related to abuse, drunken driving, divorce, or loss of employment" (p. 29). Likewise in her essay, "Rationale for Combining Acamprosate and Naltrexone for Treating Alcohol Dependence," Mason (2005) emphasizes that the alcoholism is a prevalent, chronic disorder that carries with it profound worldwide public health consequences. Therefore, the identification of safe and effective medications has assumed new importance in recent years in an effort to augment the modest efficacy of current behavioral treatments designed to reduce the high risk of drinking relapse after an initial period of abstinence.

Treatments for this purpose have traditionally focused primarily on support groups with behavioral interventions such as Alcoholics Anonymous (AA) (Bhagar & Schmetzer, 2006). Antidipsotropics, or drugs that decrease drinking like disulfiram (which is an acetaldehyde dehydrogenase inhibitor) and naltrexone (which is an opioid antagonist), have been shown to be effective in certain settings; however, poor compliance continues to restrict their general efficacy (Bhagar & Schmetzer, 2006). According to Mason, "Primary goals for alcoholism pharmacotherapy typically include maintaining abstinence, increasing the duration of an abstinent interval prior to a lapse and reducing the intensity of drinking if a relapse occurs. Such drug effects may also serve to increase retention in behavioral treatment, thereby facilitating behavioral changes supportive of an alcohol-free lifestyle" (p. 148). A wide range of treatment modalities are available for substance abuse, with most authorities recommending a combination of approaches to help improve chances for success in recovering from alcohol dependence and alcoholism, which studies have shown remain meager despite the best efforts of all concerned, including the patients themselves. In this regard, Bean and Nimitz (2004) emphasize that, "Withdrawal and detoxification regimes [sic] have a high failure rate unless linked to long-term rehabilitation" (p. 24).

First and foremost, patients that stop drinking heavily all at once are at increased risk of seizures and the other symptoms that go hand in hand with alcohol withdrawal syndrome, and this is where naltrexone could provide a patient with the ability to withstand the nightmarish aspects of this condition in order to progress further in the treatment regimen. In this regard, Heather and Stockwell (2004) report that pharmacological agents such as naltrexone are, of course, the main method of treatment for the alcohol withdrawal syndrome, but its use has been questioned by healthcare providers and family members alike: "Treating an addiction with another drug sometimes alarms sufferers, their families and therapists. Is it not substituting one addiction with another?" (Heather & Stockwell, 2004, p. 53). These authors emphasize, though, that therapies using naltrexone to reduce relapse during outpatient treatment have not been shown to be abused for their psychotropic effects, and do not prolong a dependent state because of cross-tolerance with alcohol, as occurs with benzodiazepines. Moreover, and given the high rate of relapse among recovering alcoholics, naltrexone does not produce the same type of adverse physical reactions characterized by disulfiram or intensify the effects of alcohol should a person decide to drink while taking it (Heather & Stockwell, 2004).

Efficacy of Naltrexone.

A number of early studies suggested that the opioid-antagonist naltrexone was nontoxic and appeared to represent a good tool in the clinician's repertoire to help reduce craving for alcohol and post-treatment alcohol consumption for their patients; these findings led to more widespread application of naltrexone pharmacotherapy with alcoholics (Howard & Vaugh, 2004). There have been an increasing number of scientific studies conducted in recent years concerning the efficacy of naltrexone. A good overview of these studies is provided in the recent study, "Behavioral Therapy to Augment Oral Naltrexone for Opioid Dependence: A Ceiling on Effectiveness?," wherein Carpenter, Kleber, Nunes, Rothenburg and Sullivan (2006) report that, "The opioid antagonist naltrexone is a theoretically promising treatment for opioid dependence that has never lived up to its potential. A recent meta-analysis and accompanying editorial support the conclusion that oral naltrexone is effective" (p. 503). In their randomized trial among opioid-dependent patients, the researchers found that, "Patients retained on naltrexone three months or more achieved high rates of abstinence" (Carpenter et al., 2006, p. 503).

Some of the barriers to adherence with the naltrexone regimen identified by these researchers included the following:

Difficulty with induction, which requires patients to be detoxified and off opioids for at least 7 days to avoid precipitated withdrawal; and,

The ease with which patients can discontinue oral naltrexone and relapse to opioid use, after which naltrexone cannot be resumed without repeat detoxification; however, behavioral interventions, such as contingency management or couples therapy, have shown promise in improving adherence to oral naltrexone (Carpenter et al., 2006). According to these authors, "Oral naltrexone depends on daily compliance, and just a few missed doses is all that is needed to permit relapse to occur, at which point naltrexone is not easily resumed. This may be a fundamental limiting factor" (Carpenter et al., 2006, p. 503).

The most commonly reported endpoint of the naltrexone trials conducted to date has been relapse to heavy drinking which is typically defined as more than 5 drinks per day in men, and more than 4 drinks per day in women, and it is on this measure that Mason (2005) suggests that the efficacy has been most consistently demonstrated as shown by the recapitulation of studies concerning the use and effects of naltrexone to date in Table 1 below.

Table 1.

Recapitulation of selected findings from naltrexone studies to date.

Author/Date

Key findings

Comments

Bhagar & Schmetzer (2006)*

Naltrexone is extensively metabolized and its main active metabolite is 6-beta naltrexol. Because of a lack of first pass metabolism with the long-acting intramuscular formulation, significantly less 6-beta naltrexol is generated than with the oral formulation of naltrexone.

No comparative data between the 2 formulations is available. It is excreted by the kidneys, and mild renal insufficiency has no impact on its pharmacokinetics. Its clearance in moderate and severe renal insufficiency has not been evaluated.

Ait-Daoud & Johnson (1999)*

Naltrexone has been shown to decrease alcohol consumption; however, its practical effective-ness may be compromised by poor patient compliance and other factors.

Human laboratory studies exploring the effects of naltrexone on alcohol-induced mood and craving have produced mixed results; one factor that may contribute to the discrepancy among research results is a person's genetic susceptibility to alcoholism. Nevertheless, alcohol consumption by laboratory animals is reduced by naltrexone.

Krystal et al. (2001)

The demonstration of a decrease in relapse has not been observed in all studies, including the largest to date (N = 627)

There are a number of factors that could explain this; i.e., because the effect of naltrexone may be to reduce consumption when drinking, potential treatment effects in the clinical trials may be diluted by patients who remain abstinent throughout.

Morris et al. (2001)

If the analysis is restricted to patients that resume drinking during the trials, then the size of the treatment effect may be increased.

Chick et al. (2000)*

No significant difference was found between control group using placebo and naltrexone to time to first heavy drinking or time to first drink outcomes. Alcohol consumption for naltrexone group was lower in last 4 weeks of 12-week trial but was not significant; however, naltrexone group reported significantly less craving for alcohol.

Oslin et al. (1997)

14.3% of subjects in the naltrexone group relapsed versus 34.8% in the placebo group. No significant differences in treatment compliance or reported craving were found.

This study revealed an effect where none existed before.

O'Malley, Jaffe, Rode & Rounsaville (1996)*

The naltrexone group reported significantly lower levels of craving compared with the placebo group.

Croop et al. (1997).

The overall safety profile of naltrexone is good; however, care must be taken in prescribing the drug to certain patient populations; e.g., naltrexone shows a dose-dependent hepatotoxicity (package insert) and is therefore contraindicated in patients with significant hepatic impairment, which is frequently encountered in alcohol-dependent populations.

The clinical trials of naltrexone have typically been conducted in patients without significant impairment in hepatic function. Another consequence of the hepatic impact of naltrexone is the possibility of drug-drug interactions.

Kim et al. (2001) potentially clinically significant interaction has been reported between naltrexone and nonsteroidal anti-inflammatory drugs; these researchers found elevated liver function tests in study participants receiving both medications, although the doses of naltrexone used in this study were higher than the typical 50 mg daily dose.

Naltrexone is not appropriate for use with patients taking prescribed or illicit opioid drugs. Antagonism of the effects of these drugs at opiate receptors will generally precipitate an opiate withdrawal syndrome. As a result, naltrexone would be contraindicated for methadone-maintained patients with alcohol dependence or those patients with needs for narcotic analgesics, and a small proportion of patients will not be able to tolerate naltrexone, primarily because of nausea.

Pettinati et al. (2000)* combined medication management and motivational enhancement regimen was used to provide individualized clinical care while monitoring pharmaco-therapy or individualized counseling. The study found that for compliant subjects, much lower relapse rates were experienced in the naltrexone group compared to the control group; however, for noncompliant subjects there was no advantage to naltrexone over placebo.