Pharmacodynamic Actions: REVIA (naltrexone) is a pure opioid antagonist. It markedly attenuates or completely blocks, reversibly, the subjective effects of intravenously administered opioids.

When co-administered with morphine, on a chronic basis, REVIA (naltrexone) blocks the physical dependence to morphine, heroin and other opioids.

REVIA (naltrexone) has few, if any, intrinsic actions besides its opioid blocking properties. However, it does produce some pupillary constriction, by an unknown mechanism.

The administration of REVIA (naltrexone) is not associated with the development of tolerance or dependence. In subjects physically dependent on opioids, REVIA (naltrexone) will precipitate withdrawal symptomatology.

Clinical studies indicate that 50 mg of REVIA (naltrexone) will block the pharmacologic effects of 25 mg of intravenously administered heroin for periods as long as 24 hours. Other data suggest that doubling the dose of REVIA (naltrexone) provides blockade for 48 hours, and tripling the dose of REVIA (naltrexone) provides blockade for about 72 hours.

REVIA (naltrexone) blocks the effects of opioids by competitive binding (i.e., analogous to competitive inhibition of enzymes) at opioid receptors. This makes the blockade produced potentially surmountable, but overcoming full naltrexone blockade by administration of very high doses of opiates has resulted in excessive symptoms of histamine release in experimental subjects.

The mechanism of action of REVIA (naltrexone) in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. REVIA (naltrexone) , an opioid receptor antagonist, competitively binds to such receptors and may block the effects of endogenous opioids. Opioid antagonists have been shown to reduce alcohol consumption by animals, and REVIA (naltrexone) has been shown to reduce alcohol consumption in clinical studies.

REVIA (naltrexone) is not aversive therapy and does not cause a disulfiram-like reaction either as a result of opiate use or ethanol ingestion.

Pharmacokinetics:

REVIA (naltrexone) is a pure opioid receptor antagonist. Although well absorbed orally, naltrexone is subject to significant first pass metabolism with oral bioavailability estimates ranging from 5 to 40%. The activity of naltrexone is believed to be due to both parent and the 6-(beta)-naltrexol metabolite. Both parent drug and metabolites are excreted primarily by the kidney (53% to 79% of the dose), however, urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose and fecal excretion is a minor elimination pathway. The mean elimination half-life (T-1/2) values for naltrexone and 6-(beta)-naltrexol are 4 hours and 13 hours, respectively. Naltrexone and 6-(beta)-naltrexol are dose proportional in terms of AUC and C _max over the range of 50 to 200 mg and do not accumulate after 100 mg daily doses.

Absorption:

Following oral administration, naltrexone undergoes rapid and nearly complete absorption with approximately 96% of the dose absorbed from the gastrointestinal tract. Peak plasma levels of both naltrexone and 6-(beta)-naltrexol occur within one hour of dosing.

Distribution:

The volume of distribution for naltrexone following intravenous administration is estimated to be 1350 liters. In vitro tests with human plasma show naltrexone to be 21% bound to plasma proteins over the therapeutic dose range.

Metabolism:

The systemic clearance (after intravenous administration) of naltrexone is ~3.5 L/min, which exceeds liver blood flow (~1.2 L/min). This suggests both that naltrexone is a highly extracted drug (>98% metabolized) and that extra-hepatic sites of drug metabolism exist. The major metabolite of naltrexone is 6-(beta)-naltrexol. Two other minor metabolites are 2-hydroxy-3-methoxy-6-(beta)-naltrexol and 2-hydroxy-3-methyl-naltrexone. Naltrexone and its metabolites are also conjugated to form additional metabolic products.

Elimination:

The renal clearance for naltrexone ranges from 30-127 mL/min and suggests that renal elimination is primarily by glomerular filtration. In comparison, the renal clearance for 6-(beta)-naltrexol ranges from 230-369 mL/min, suggesting an additional renal tubular secretory mechanism. The urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose; urinary excretion of unchanged and conjugated 6-(beta)-naltrexol accounts for 43% of an oral dose. The pharmacokinetic profile of naltrexone suggests that naltrexone and its metabolites may undergo enterohepatic recycling.

Hepatic and Renal Impairment:

Naltrexone appears to have extra-hepatic sites of drug metabolism and its major metabolite undergoes active tubular secretion (see Metabolism above). Adequate studies of naltrexone in patients with severe hepatic or renal impairment have not been conducted (see PRECAUTIONS : Special Risk Patients ).

Clinical Trials:

Alcoholism:

The efficacy of REVIA (naltrexone) as an aid to the treatment of alcoholism was tested in placebo-controlled, outpatient, double blind trials. These studies used a dose of REVIA (naltrexone) 50 mg once daily for 12 weeks as an adjunct to social and psychotherapeutic methods when given under conditions that enhanced patient compliance. Patients with psychosis, dementia, and secondary psychiatric diagnoses were excluded from these studies.

In one of these studies, 104 alcohol-dependent patients were randomized to receive either REVIA (naltrexone) 50 mg once daily or placebo. In this study, REVIA (naltrexone) proved superior to placebo in measures of drinking including abstention rates (51% vs. 23%), number of drinking days, and relapse (31% vs. 60%). In a second study with 82 alcohol-dependent patients, the group of patients receiving REVIA (naltrexone) were shown to have lower relapse rates (21% vs. 41%), less alcohol craving, and fewer drinking days compared with patients who received placebo, but these results depended on the specific analysis used.

The clinical use of REVIA (naltrexone) as adjunctive pharmacotherapy for the treatment of alcoholism was also evaluated in a multicenter safety study. This study of 865 individuals with alcoholism included patients with comorbid psychiatric conditions, concomitant medications, polysubstance abuse and HIV disease. Results of this study demonstrated that the side effect profile of REVIA (naltrexone) appears to be similar in both alcoholic and opioid dependent populations, and that serious side effects are uncommon.

In the clinical studies, treatment with REVIA (naltrexone) supported abstinence, prevented relapse and decreased alcohol consumption. In the uncontrolled study, the patterns of abstinence and relapse were similar to those observed in the controlled studies. REVIA (naltrexone) was not uniformly helpful to all patients, and the expected effect of the drug is a modest improvement in the outcome of conventional treatment.

Treatment of Opioid Addiction:

REVIA (naltrexone) has been shown to produce complete blockade of the euphoric effects of opioids in both volunteer and addict populations. When administered by means that enforce compliance, it will produce an effective opioid blockade, but has not been shown to affect the use of cocaine or other non-opioid drugs of abuse.

There are no data that demonstrate an unequivocally beneficial effect of REVIA (naltrexone) on rates of recidivism among detoxified, formerly opioid-dependent individuals who self-administer the drug. The failure of the drug in this setting appears to be due to poor medication compliance.

The drug is reported to be of greatest use in good prognosis opioid addicts who take the drug as part of a comprehensive occupational rehabilitative program, behavioral contract, or other compliance-enhancing protocol. REVIA (naltrexone) , unlike methadone or LAAM (levo-alpha-acetylmethadol), does not reinforce medication compliance and is expected to have a therapeutic effect only when given under external conditions that support continued use of the medication.

Individualization of Dosage:

DO NOT ATTEMPT TREATMENT WITH REVIA (naltrexone) UNLESS, IN THE MEDICAL JUDGEMENT OF THE PRESCRIBING PHYSICIAN, THERE IS NO REASONABLE POSSIBILITY OF OPIOID USE WITHIN THE PAST 7-10 DAYS. IF THERE IS ANY QUESTION OF OCCULT OPIOID DEPENDENCE, PERFORM A NALOXONE CHALLENGE TEST.

Treatment of Alcoholism:

The placebo-controlled studies that demonstrated the efficacy of REVIA (naltrexone) as an adjunctive treatment of alcoholism used a dose regimen of REVIA (naltrexone) 50 mg once daily for up to 12 weeks. Other dose regimens or durations of therapy were not studied in these trials.

Physicians are advised that 5-15% of patients taking REVIA (naltrexone) for alcoholism will complain of non-specific side effects, chiefly gastrointestinal upset. Prescribing physicians have tried using an initial 25 mg dose, splitting the daily dose, and adjusting the time of dosing with limited success. No dose or pattern of dosing has been shown to be more effective than any other in reducing these complaints for all patients.

Treatment of Opioid Dependence:

Once the patient has been started on REVIA (naltrexone) , 50 mg once a day will produce adequate clinical blockade of the actions of parenterally administered opioids. As with many non-agonist treatments for addiction, REVIA (naltrexone) is of proven value only when given as part of a comprehensive plan of management that includes some measure to ensure the patient takes the medication.

A flexible approach to a dosing regimen may be employed to enhance compliance. Thus, patients may receive 50 mg of REVIA (naltrexone hydrochloride) every weekday with a 100 mg dose on Saturday or patients may receive 100 mg every other day, or 150 mg every third day. Several of the clinical studies reported in the literature have employed the following dosing regimen: 100 mg on Monday, 100 mg on Wednesday, and 150 mg on Friday. This dosing schedule appeared to be acceptable to many REVIA (naltrexone) patients successfully maintaining their opioid-free state.

Experience with the supervised administration of a number of potentially hepatotoxic agents suggests that supervised administration and single doses of REVIA (naltrexone) higher than 50 mg may have an associated increased risk of hepatocellular injury, even though three-times a week dosing has been well tolerated in the addict population and in initial clinical trials in alcoholism. Clinics using this approach should balance the possible risks against the probable benefits and may wish to maintain a higher index of suspicion for drug-associated hepatitis and ensure patients are advised of the need to report non-specific abdominal complaints (see Information for Patients ).

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.