Naltrexone hydrochloride is designated an orphan drug by the US Food and Drug Administration (FDA) and is used orally for its opiate antagonist effects as an adjunct to a medically supervised behavior modification program in the maintenance of opiate cessation (opiate-free state) in individuals formerly physically dependent on opiates and who have successfully undergone detoxification. Behavior modification is an integral component in maintaining opiate cessation when naltrexone is used, and such modification involves supervised programs of counseling, psychologic support and therapy, and education, and changes in life-style (social rehabilitation). The theoretical rationale for using naltrexone as an adjunct in opiate cessation therapy is that the drug may diminish or eliminate opiate-seeking behavior by blocking the euphoric reinforcement produced by self-administration of opiates and by preventing the conditioned abstinence syndrome (i.e., heightened sensitivity to stimuli, abnormal autonomic responses, dysphoria, and intense opiate craving) that occurs following opiate withdrawal. There are no data that unequivocally demonstrate a beneficial effect of naltrexone on the tendency to relapse (recidivism) to drug abuse in detoxified, former opiate-dependent individuals; however, by blocking opiate-induced euphoria and potentially preventing the redevelopment of opiate dependence, naltrexone therapy in conjunction with a medically supervised behavior modification program may contribute to the prevention of relapse in the postaddiction period.
In individuals formerly dependent on opiates, naltrexone reportedly decreases opiate craving within 3-5 weeks of initiation of therapy; however, decreased opiate craving has occurred during the first week of naltrexone therapy in some individuals, with further decreases occurring in subsequent weeks. The efficacy of opiate cessation therapy that includes naltrexone on long-term cessation rates appears to be low, and poor compliance appears to be the major limiting factor in opiate cessation therapy that includes naltrexone. Because noncompliance with naltrexone therapy, unlike methadone or levomethadyl acetate (LAAM; no longer commercially available in the US because of potentially severe adverse cardiac effects) maintenance therapy, is not associated with unpleasant symptoms of withdrawal, compliance with opiate cessation therapy that includes naltrexone depends more on the voluntary efforts of the individual, and successful cessation appears to be more likely in highly motivated individuals. Repeated attempts at opiate cessation therapy may increase efficacy in terms of the amount of time the individual remains opiate-free; complete cessation may not be an obtainable goal in some individuals, and cycles of relapse to opiate use and cessation may be likely.
Behavioral therapy, as a component of opiate cessation therapy, allows the patient to undergo a social and psychologic rehabilitation that will aid in maintaining opiate cessation. Naltrexone therapy in combination with behavioral therapy has been shown to be more effective than naltrexone or behavioral therapy alone in prolonging opiate cessation in patients formerly physically dependent on opiates. Individuals who are highly motivated, employed, and in a stable married or other relationship appear to be most successful with naltrexone therapy and able to maintain opiate cessation. Strong external support from family and/or employer also contributes to the success of opiate cessation therapy that includes naltrexone. Because naltrexone is used as an adjunct to the individual's own cessation efforts, individuals should be highly motivated to develop a life-style free of opiate dependence. Individuals who are psychologically healthier generally are more successful in opiate cessation than those with more baseline psychologic disturbances, including mood disorders. Potential candidates for opiate cessation therapy that involves naltrexone include former opiate-dependent individuals who are employed and socially functioning, were recently detoxified from methadone maintenance, are leaving prison or residential treatment settings, are sporadically abusing opiates but are not yet dependent, are physically dependent on opiates secondary to medical use of the drugs, and/or are ineligible for methadone maintenance; naltrexone therapy may also be useful when the waiting period for admission into a methadone maintenance program is long. Naltrexone may be particularly useful as maintenance therapy in the prevention of relapse in former opiate-dependent individuals during times of stress when relapse to drug abuse may be most likely. Adolescents who have only recently become physically dependent on opiates may benefit particularly well from opiate cessation therapy that includes naltrexone. Opiate cessation therapy that includes naltrexone may also be especially beneficial in health-care professionals physically dependent on opiates. However, individuals may differ in their specific needs for behavioral therapy (e.g., psychotherapy, counseling) or additional pharmacologic support (e.g., sedatives and hypnotics, GI drugs). Individuals from lower socioeconomic groups who have recently been detoxified from methadone maintenance appear to benefit less from naltrexone therapy than health-care professionals and white-collar workers; however, behavioral therapy in the form of strong family external support improves the beneficial results of naltrexone therapy observed in individuals from lower socioeconomic groups.
Most clinical experience with naltrexone therapy in detoxified, former opiate-dependent individuals has been reported to date in uncontrolled studies. In controlled studies, patients receiving naltrexone therapy generally appeared to decrease their consumption of opiates, participated in opiate cessation programs longer, and had greater decreases in craving for opiates than did patients receiving placebo.
Opiate antagonists (e.g., naltrexone, naloxone) have been used for rapid or ultrarapid detoxification in the management of opiate withdrawal in opiate-dependent individuals, both in inpatient and outpatient settings. Rapid opiate detoxification involves the administration of opiate antagonists such as naltrexone and/or naloxone to shorten the time period of detoxification. When used for this purpose, naltrexone sometimes has been given in combination with clonidine, guanabenz, or lofexidine (not currently available in the US). The reported advantage of rapid detoxification is to minimize the risk of relapse and to initiate maintenance therapy with naltrexone and psychosocial interventions more quickly. Ultrarapid detoxification is similar, but involves the administration of opiate antagonists (i.e., naltrexone, naloxone) while the patient is sedated or under general anesthesia. However, the risk of adverse respiratory and cardiovascular effects associated with this procedure must be considered as well as the costs of general anesthesia and hospitalization. Safety and efficacy of these therapies have not been established and further study is needed.
Parenteral naltrexone is not approved for use for its opiate antagonist effects or for the treatment of opiate dependence.
Naltrexone is used orally or IM in the management of alcohol dependence in conjunction with a comprehensive management program that includes psychosocial support. Naltrexone is used IM in patients with alcohol dependence who are able to abstain from alcohol in an outpatient setting prior to initiation of naltrexone therapy and are abstinent at the time such therapy is initiated.Individuals who are willing to use pharmacologic therapy as part of their treatment for alcohol dependence are candidates for naltrexone therapy. A comprehensive management program is an integral component in maintaining alcohol cessation when naltrexone is used, since the drug has not been shown to provide any therapeutic benefit except as part of an appropriate plan of addiction management. These programs involve evaluation, counseling, psychologic support and therapy, and education. Although psychosocial programs alone (i.e., without drug therapy) may be associated with moderate improvement in complete cessation rates and substantial initial rates of alcohol cessation, long-term cessation rates are low, with 50% of patients undergoing intensive inpatient and/or outpatient behavior modification usually relapsing within the first 3 months. When pharmacologic therapy (e.g., naltrexone) is used in conjunction with a comprehensive management program, benefits of such programs may be prolonged.
In general, the goals of pharmacologic therapy in alcohol dependence are to consistently reduce craving for alcohol and to reduce the motivation to drink by blunting pleasant feelings associated with alcohol consumption. In addition, pharmacologic therapy for alcohol dependence should not interact with alcohol or have addictive potential. Factors associated with positive outcomes in clinical trials in alcohol-dependent patients receiving naltrexone for alcohol dependence include type, intensity, and duration of pharmacologic therapy; use of community-based support groups; appropriate management of conditions accompanying alcoholism; and good medication compliance.
When used in conjunction with a comprehensive management program, naltrexone reportedly decreases alcohol craving, reduces alcohol consumption, decreases the number of drinking days, maintains abstinence from alcohol ingestion, and prevents, decreases, or ameliorates the severity of relapse. However, naltrexone therapy is not uniformly effective, and the expected effect is a modest improvement in the outcome of conventional therapy. The theoretical rationale for using naltrexone as an adjunct in alcohol dependence therapy is that the drug may diminish alcohol consumption by blocking the rewarding, pleasurable effects associated with alcohol ingestion.
(See Pharmacology: Opiate Antagonist Effects).
In one controlled study in alcohol-dependent patients, reported abstinence rates for naltrexone hydrochloride (50 mg orally once daily for 12 weeks) compared with placebo were 51 vs 23%, while relapse (defined as consumption of 4 or 5 drinks per occasion for women or men, respectively) within 12 weeks of the study period occurred in 31 vs 60% of patients receiving the drug or placebo, respectively. In this study, psychologic behavior modification consisted either of learning coping skills to prevent relapse or of abstinence supportive therapy without coping skills training. Further analysis of these data indicates that rates of abstinence for naltrexone vs placebo were 61 vs 19% in patients receiving supportive therapy in addition to naltrexone or placebo, respectively, while in patients undergoing coping skills training, abstinence rates were 28 vs 21% in those receiving additional naltrexone or placebo therapy, respectively.
In another controlled study in alcohol-dependent patients that evaluated oral naltrexone, rates of abstinence for naltrexone vs placebo were 54 vs 43%, respectively. Although relapse (defined as drinking during 5 or more days within 1 week, having 5 or more drinks per drinking occasion, or having an alcohol blood concentration exceeding 100 mg/dL) in this study was reported in 23 or 54% of patients receiving naltrexone hydrochloride (50 mg orally once daily for 12 weeks) or placebo, respectively, reanalysis by the manufacturer found relapse rates of 21 or 41% in patients receiving the drug or placebo, respectively. In patients who reportedly had consumed at least one drink while undergoing the study, relapse occurred in 50 or 95% of patients receiving naltrexone or placebo, respectively. Results of this study also indicate that patients receiving naltrexone experienced less pleasure after alcohol ingestion and had fewer drinking days and less alcohol craving than those receiving placebo. In an uncontrolled, large multicenter study in patients with alcohol dependence, including those with psychiatric conditions, those physically dependent on other substances, and those with human immunodeficiency virus (HIV) infection, abstinence and relapse rates were similar to those in the controlled studies.
In a study in 627 US veterans (almost all men) with chronic, severe alcoholism (history of heavy drinking at least twice in a week during the previous 30 days and a DSM-IV diagnosis of alcohol dependence but who were sober for at least 5 days prior to study entry), oral naltrexone hydrochloride therapy (50 mg daily) was not effective as an adjunct to standard psychosocial therapy in the management of alcohol dependence as evidenced by no apparent benefit after 13 weeks on days to relapse (mean: 72.3 vs 62.4 days for naltrexone and placebo, respectively) nor at 52 weeks on the percentage of days on which drinking occurred or the number of drinks per drinking day. As a result, it was concluded that the use of adjunctive naltrexone therapy could not be supported in men with chronic, severe alcoholism. Whether these findings can be extrapolated to patients with less severe or less chronic alcoholism or to women or non-veterans remains to be established. Patients in this study relative to other studies typically were older, had been drinking for longer periods, and were less likely to be married or living with a partner; although employment data were not reported, about one-third were receiving disability pensions, which may have negatively affected their motivation to stop drinking. Pending further accumulation of data, some experts recommend that naltrexone continue to be prescribed for patients considered likely to benefit from such therapy such as those who have been drinking heavily for no longer than 20 years and who have stable social support and living situations.
Efficacy of oral naltrexone therapy for alcohol dependence has been established in short-term (up to 12 weeks) clinical studies involving a limited number of patients with alcohol dependence, and the long-term safety and efficacy of the drug for the management of this condition have not been established.
Efficacy of an injectable extended-release formulation of naltrexone has been evaluated in a 6-month study in individuals with alcohol dependence. Adults were randomized to receive naltrexone 380 mg, naltrexone 190 mg, or placebo administered IM monthly in conjunction with 12 sessions of psychosocial intervention. Treatment with 380 mg of naltrexone was associated with a greater reduction in days of heavy drinking (defined as 5 or more alcohol-containing drinks per day for men and 4 or more alcohol-containing drinks per day for women) than treatment with placebo. Individuals receiving 380 mg of naltrexone reported a 25% greater reduction in the rate of heavy drinking relative to placebo-treated individuals. Treatment with 190 mg of naltrexone generally was not associated with a substantial reduction in the rate of heavy drinking. Subgroup analyses suggested that treatment effects were greater in men than in women and also were greater in individuals with lead-in abstinence (about 8% of the study population) than in those who drank during the lead-in phase. Naltrexone-associated reductions in heavy drinking were observed in men and individuals with lead-in abstinence, but the same effects were not observed in women or individuals who drank during the lead-in period.
Studies sponsored by the National Institute of Alcohol Abuse and Alcoholism (NIAAA) are ongoing in an attempt to identify which alcohol-dependent patients are most likely to benefit from naltrexone therapy, to determine optimum duration and dosage of naltrexone, and to identify potential combination therapies that are most effective for use with naltrexone in these patients.Routine use of naltrexone in the management of alcohol dependence currently is not recommended.
Naltrexone has been used in dosages up to 800 mg daily for the treatment of schizophrenic disorder, since elevated endorphin concentrations have been observed in patients with this disorder and naltrexone may inhibit the effects of endogenous endorphins. Although a few patients with schizophrenic disorder have shown some clinical improvement during naltrexone therapy, patients generally showed no improvement and psychoses worsened in some patients. Naltrexone has also been used in a patient with a psychoneurologic syndrome of unknown etiology that included some signs and symptoms similar to those associated with mast cell disease, carcinoid disease, and dermatitis herpetiformis; the drug reversed and/or suppressed flush and organic psychosis and associated mood alterations, anxiety, and severe skin, bone, and abdominal pain in this patient.
There is preliminary evidence that opiate antagonists (i.e., naloxone, naltrexone) may cause some clinical improvement in patients with dementia of the Alzheimer's type (Alzheimer's disease), but additional study of the efficacy of these drugs in this disease is necessary. In one study in a limited number of patients, there was little evidence of cognitive or behavioral improvement following oral naltrexone dosages up to 100 mg daily.