AHFS Class:

• Opoid Antagonists 28:10

Generic Name(s):

• Naltrexone

• Naltrexone Hydrochloride

Naltrexone is essentially a pure opiate antagonist.1,2,3,7,17,23,102

Opiate Dependence

Naltrexone hydrochloride is designated an orphan drug by the US Food and Drug Administration (FDA)217 and is used orally for its opiate antagonist effects as an adjunct to a medically supervised behavior modification program1,35,99,102,147,160,161,162,163,164,165,166,170 in the maintenance of opiate cessation (opiate-free state) in individuals formerly physically dependent on opiates and who have successfully undergone detoxification.1,14,35,102,143,147,158,162,163,164,165 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).1,2,35,37,102,143,147,159,160,162,170,189,192,193,204 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.1,2,27,102,158,190,191 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;1,102 however, by blocking opiate-induced euphoria and potentially preventing the redevelopment of opiate dependence (opiate use disorder [OUD]), naltrexone therapy in conjunction with a medically supervised behavior modification program may contribute to the prevention of relapse in the postaddiction period.1,102

In individuals formerly dependent on opiates, naltrexone reportedly decreases opiate craving within 3-5 weeks of initiation of therapy;42,66,158,160 however, decreased opiate craving has occurred during the first week of naltrexone therapy in some individuals, with further decreases occurring in subsequent weeks.102,182 The efficacy of opiate cessation therapy that includes naltrexone on long-term cessation rates appears to be low,2,11,14,15,42,123,125,135,161,182,203 and poor compliance appears to be the major limiting factor in opiate cessation therapy that includes naltrexone.1,2,8,13,42,99,182,204 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.1,2,8,13,15,35,36,99,102,130,147,162,163,167,172 Repeated attempts at opiate cessation therapy may increase efficacy in terms of the amount of time the individual remains opiate-free;42,102,192,193,203,204 complete cessation may not be an obtainable goal in some individuals,42 and cycles of relapse to opiate use and cessation may be likely.102,161,166,182,192,203 Because of the potential risk of relapse to opiate use and subsequent opiate overdosage, clinicians should routinely discuss the availability of the opiate antagonist naloxone with all patients receiving new or reauthorized prescriptions for medications for treatment of OUD and should strongly consider prescribing naloxone for use in the event of an overdose in all such patients.750 (See Naloxone Hydrochloride 28:10.)

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.102 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.2,102,121,143,159,160,204 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.2,15,35,36,102,130,147,162,163,167,172,204 Strong external support from family and/or employer also contributes to the success of opiate cessation therapy that includes naltrexone.2,35,62,102,121,162,163,170 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.36,102,130,147 Individuals who are psychologically healthier generally are more successful in opiate cessation than those with more baseline psychologic disturbances, including mood disorders.102,166 Potential candidates for opiate cessation therapy that involves naltrexone include former opiate-dependent individuals who are employed and socially functioning,102,163 were recently detoxified from methadone maintenance,2,99,102,204 are leaving prison or residential treatment settings,99,102,141,165 are sporadically abusing opiates but are not yet dependent,102 are physically dependent on opiates secondary to medical use of the drugs,102 and/or are ineligible for methadone maintenance;102 naltrexone therapy may also be useful when the waiting period for admission into a methadone maintenance program is long.196 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.36,99,102,163 Adolescents who have only recently become physically dependent on opiates may benefit particularly well from opiate cessation therapy that includes naltrexone.2,99,121 Opiate cessation therapy that includes naltrexone may also be especially beneficial in health-care professionals physically dependent on opiates.147,163 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).102,161,162 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.121

Most clinical experience with naltrexone therapy in detoxified, former opiate-dependent individuals has been reported to date in uncontrolled studies.29,37,86,102,127,138,141,157,158,166,183 In controlled studies, patients receiving naltrexone therapy generally appeared to decrease their consumption of opiates,40,42,102 participated in opiate cessation programs longer,42,102,162,166 and had greater decreases in craving for opiates40,42,102 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.246 Rapid opiate detoxification involves the administration of opiate antagonists such as naltrexone and/or naloxone to shorten the time period of detoxification.246 When used for this purpose, naltrexone sometimes has been given in combination with clonidine,2,38,162,168,169,246 guanabenz,164 or lofexidine (not currently available in the US).174 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.246 Ultrarapid detoxification is similar, but involves the administration of opiate antagonists (i.e., naltrexone, naloxone) while the patient is sedated or under general anesthesia.246 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.246 Safety and efficacy of these therapies have not been established and further study is needed.246

Parenteral naltrexone is not approved for use for its opiate antagonist effects or for the treatment of OUD.247

Alcohol Dependence

Naltrexone is used orally or IM in the management of alcohol dependence in conjunction with a comprehensive management program that includes psychosocial support.1,232,233,234,235,236,237,247 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.247,249 Individuals who are willing to use pharmacologic therapy as part of their treatment for alcohol dependence are candidates for naltrexone therapy.1 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.1,232,234,237,239,245 These programs involve evaluation, counseling, psychologic support and therapy, and education.1,232,238,250 Although psychosocial programs alone (i.e., without drug therapy) may be associated with moderate improvement in complete cessation rates232,238,239 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.232,238,239 When pharmacologic therapy (e.g., naltrexone) is used in conjunction with a comprehensive management program, benefits of such programs may be prolonged.238

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.231,232 In addition, pharmacologic therapy for alcohol dependence should not interact with alcohol or have addictive potential.231 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.1,238,239

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.1,232,235,237,238 However, naltrexone therapy is not uniformly effective, and the expected effect is a modest improvement in the outcome of conventional therapy.1,232,233,244,245,249 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.232,235,237,238,244 (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%,1,234,242 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.1,234,242 In this study, psychologic behavior modification consisted either of learning coping skills to prevent relapse or of abstinence supportive therapy without coping skills training.233,238,242 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.233

In another controlled study in alcohol-dependent patients that evaluated oral naltrexone, rates of abstinence for naltrexone vs placebo were 54 vs 43%, respectively.232,237 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,232,238,242 reanalysis by the manufacturer found relapse rates of 21 or 41% in patients receiving the drug or placebo, respectively.1,234 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.232,236,237,238,239,242 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.1,232,235,236,239 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.1

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.244,245 As a result, it was concluded that the use of adjunctive naltrexone therapy could not be supported in men with chronic, severe alcoholism.244,245 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.244,245 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.244,245 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.245

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,1,231,232,233,234,236,237,240,241,242 and the long-term safety and efficacy of the drug for the management of this condition have not been established.231,232,237

Efficacy of an injectable extended-release formulation of naltrexone has been evaluated in a 6-month study in individuals with alcohol dependence.247,248,249 Adults were randomized to receive naltrexone 380 mg, naltrexone 190 mg, or placebo administered IM monthly in conjunction with 12 sessions of psychosocial intervention.247,248,249 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.247,248,249 Individuals receiving 380 mg of naltrexone reported a 25% greater reduction in the rate of heavy drinking relative to placebo-treated individuals.248,249 Treatment with 190 mg of naltrexone generally was not associated with a substantial reduction in the rate of heavy drinking.248,249 Subgroup analyses suggested that treatment effects were greater in men than in women248 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.247,248,249 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.247,248,249

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.240,241 Routine use of naltrexone in the management of alcohol dependence currently is not recommended.231

Obesity

For use of naltrexone hydrochloride in fixed combination with bupropion hydrochloride for weight management, see Naltrexone Hydrochloride and Bupropion Hydrochloride 28:20.08.92.

Other Uses

Naltrexone has been used in dosages up to 800 mg daily for the treatment of schizophrenic disorder,†2,24,34,142,144,145,146,171 since elevated endorphin concentrations2,19 have been observed in patients with this disorder and naltrexone may inhibit the effects of endogenous endorphins.19,20,34,62 Although a few patients with schizophrenic disorder have shown some clinical improvement during naltrexone therapy,145 patients generally showed no improvement2,24,34,142,144,145,146,171 and psychoses worsened in some patients.2,24,146 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.176

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),97,177,187,188,202 but additional study of the efficacy of these drugs in this disease is necessary.177,196 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.202

Reconstitution and Administration

Naltrexone hydrochloride is administered orally.1,102 Adverse GI effects may be minimized by taking the drug with food123 or antacids131 or after meals.9,102,131,143

Naltrexone extended-release injection is administered by deep IM injection into the upper outer quadrant of the gluteal muscle every 4 weeks or once a month.247 Subsequent injections should be made in alternate buttocks.247 To avoid inadvertent injection of the suspension into a blood vessel, the plunger of the syringe should be drawn back prior to IM administration to ensure that blood is not aspirated.247 The IM preparation should not be administered by IV or subcutaneous injection; the IM preparation should not be inadvertently administered into fatty tissue.247,257 Inadvertent subcutaneous injection may increase the likelihood of severe injection site reactions.247 Therefore, the patient's body habitus should be evaluated prior to each injection to ensure that the length of the needle supplied by the manufacturer (1.5 inches) is adequate for gluteal IM injection in that patient.247 Because the IM preparation must be administered using the manufacturer-provided needle, alternative treatment should be considered for any patient whose body habitus (i.e., thickness of gluteal adipose tissue) precludes IM injection with the provided needle.247,261 Patients should be instructed to monitor the injection site and to notify the clinician if injection site reactions (i.e., pain, swelling, tenderness, induration, bruising, pruritus, redness) worsen or if they do not improve within 2 weeks following injection.257,258 Patients should be advised to notify the clinician promptly if intense or prolonged pain, swelling, skin color changes, or signs of necrosis (e.g., hard nodule, blistering, open wound, dark scab) are present at the injection site.247,258 Patients with signs of abscess, cellulitis, necrosis, or extensive swelling at the injection site should be promptly evaluated to determine if referral to a surgeon is warranted.247

Naltrexone for extended-release injectable suspension should be reconstituted prior to administration using the components of the dose pack supplied by the manufacturer.247 The dose pack should be allowed to reach room temperature prior to reconstitution of the injection.247 The preparation should be reconstituted using only the diluent supplied by the manufacturer and administered with the needle supplied by the manufacturer.247 The vial labeled as containing 380 mg of naltrexone extended-release microspheres should be reconstituted with 3.4 mL of diluent and shaken vigorously for 1 minute.247 The resulting suspension should be administered immediately.247 The manufacturer's prescribing information should be consulted for further details on the reconstitution and administration of this preparation.247

Patients should be advised not to attempt self-administration of opiates during therapy with the drug .1,102(See Cautions: Precautions and Contraindications.)

The US Food and Drug Administration (FDA) required and approved a Risk Evaluation and Mitigation Strategy (REMS) for parenteral naltrexone.259 The REMS requires that a medication guide be given to the patient each time parenteral naltrexone is dispensed.259,260 The goal of the REMS is to inform patients about serious risks associated with parenteral naltrexone (see Cautions: Precautions and Contraindications).259 Patients should be advised to read the medication guide prior to initiating parenteral naltrexone therapy and before each injection of the drug.258 Clinicians should advise patients about the risks and benefits of parenteral naltrexone therapy prior to initiating such therapy and ensure that patients understand the risks.260

Dosage

Prior to initiation of naltrexone therapy in patients physically dependent on opiates, detoxification should be completed.1,102 Because of the risk of precipitating opiate withdrawal (see Cautions: Opiate Withdrawal), the manufacturers recommend that a period of at least 7-10 days elapse between discontinuance of opiates and initiation of naltrexone therapy.1,102,247 This period varies depending on the dose and duration of the opiate used,1,102,121,162 and some clinicians recommend at least 7 days in patients using relatively short-acting opiates (e.g., heroin, hydromorphone, meperidine, morphine) and at least 10-14 days in those using longer-acting opiates (e.g., methadone).237 Because of the risk of relapse to drug abuse during this period, shorter periods of opiate abstinence (e.g., 2-5 days) prior to initiation of naltrexone therapy have been used in some patients.2,14,41,121,161,162,164,196 Alternatively, clonidine has been used concomitantly with naltrexone during initiation of therapy to minimize symptoms of opiate withdrawal.38,230 Some clinicians have cautiously precipitated withdrawal using repeated naloxone injections and then rapidly initiated naltrexone therapy with incremental doses of the drug; this procedure can reduce the transition period from opiate dependence to naltrexone maintenance and generally is well accepted by patients.14,41,196,207 Detoxification from opiates may be accomplished in an outpatient or supervised (e.g., hospital) setting.102,161,162 Detoxification in a supervised setting permits closer monitoring of patients during withdrawal, control over access to illicit drugs, and the opportunity to initiate naltrexone therapy during the period when the tendency to relapse to drug abuse may be greatest.14,41,102,162 Regardless of the setting for detoxification, it generally is preferable to detoxify the patient from all drugs on which they are dependent before initiating naltrexone therapy.102 In addition to patient verification of abstinence from opiates, urinalysis should be performed after the minimum 7- to 10-day waiting period, but prior to administration of naltrexone, to confirm the absence of opiates.1,102 If urinary determination is negative, a naloxone challenge test should be performed prior to administering naltrexone if the clinician believes there is a risk of precipitating a withdrawal reaction following administration of naltrexone.1,2,102,247

Naloxone Challenge Test

To avoid precipitating opiate withdrawal following administration of naltrexone, the naloxone challenge test should be performed prior to induction of naltrexone therapy in patients formerly physically dependent on opiates who have completed detoxification and in those suspected of having been dependent on opiates.1,2,14,15,41,102,162,237 The naloxone challenge test should not be performed in patients who are exhibiting signs and/or symptoms of opiate withdrawal, those whose urine shows evidence of opiates, or those in whom there is a high degree of suspicion that opiates are still being used, since naloxone may precipitate potentially severe opiate withdrawal .1,102 If signs and/or symptoms of opiate withdrawal are evident following administration of the naloxone challenge test, naltrexone therapy should not be attempted ; the naloxone challenge test may be repeated in 24 hours in these patients.1

The manufacturer of naltrexone recommends that the naloxone challenge test be performed by administering naloxone by IV or subcutaneous injection.1 For IV or subcutaneous administration of the test, a sterile syringe containing 0.8 mg of naloxone hydrochloride should be used.1 For IV administration, the manufacturer of naltrexone recommends that an initial 0. 2-mg dose of the drug be injected IV and, while the needle remains in the vein, the patient should be observed for 30 seconds for evidence of opiate withdrawal.1 Alternatively, some clinicians recommend that an initial 0. 2-mg dose of naloxone hydrochloride be injected IV and the patient observed for 15 minutes for evidence of withdrawal.196 Signs and symptoms of withdrawal include, but are not limited to, nasal stuffiness, rhinorrhea, lacrimation, yawning, sweating, tremor, abdominal cramps, vomiting, piloerection, myalgia, and skin crawling.1,102 (See Chronic Toxicity in the Opiate Agonists General Statement 28:08.08.) If no evidence of withdrawal is observed, the remaining 0. 6-mg dose of naloxone hydrochloride should be injected IV and the patient observed for an additional 20 minutes for evidence of withdrawal.1 Some clinicians recommend that a total IV dose of 2 mg be used in the test since withdrawal has been precipitated by the first oral dose of naltrexone despite a negative naloxone challenge test using lower doses and a false-negative test rarely occurs with the 2-mg naloxone hydrochloride dose.207 For subcutaneous administration, the entire 0. 8-mg dose should be injected subcutaneously and the patient observed for 20 minutes for evidence of opiate withdrawal.1 For further information on the chemistry and stability, pharmacology, pharmacokinetics, uses, cautions, and dosage and administration of naloxone, see Naloxone Hydrochloride 28:10.

During the appropriate period (i.e., 20 or 45 minutes) in the naloxone challenge test, the patient should be closely monitored for the appearance of signs and symptoms of opiate withdrawal and vital signs should be monitored.1 Although the naloxone challenge test may precipitate opiate withdrawal in a patient physically dependent on opiates, signs and symptoms will be milder and of shorter duration than those precipitated by naltrexone.102 If signs and/or symptoms of opiate withdrawal are evident following administration of the naloxone challenge test, a potential risk for precipitating more severe and prolonged withdrawal with naltrexone exists and naltrexone therapy should not be initiated; if evidence of withdrawal is absent, naltrexone therapy may be initiated.1 (See Induction of Therapy for Opiate Cessation in Dosage and Administration: Dosage.) Some clinicians caution that even minor and/or transient GI symptoms following naloxone challenge be considered evidence of withdrawal since patients with such symptoms will often develop severe and disturbing GI symptoms if naltrexone therapy is then initiated.207 If evidence of opiate withdrawal is present, naltrexone therapy should be delayed and the naloxone challenge test repeated in 24 hours with the 0. 8-mg dose and every 24 hours until results are negative.1,196

Opiate Dependence

Induction of Therapy for Opiate Cessation

Following completion of opiate detoxification and verification that the patient is free of opiates, oral naltrexone therapy is initiated with an induction regimen.102 Naltrexone therapy should be initiated carefully by slowly titrating the dose; an initial 25-mg dose of naltrexone hydrochloride is recommended by the manufacturer.1,102 Following administration of the initial dose, the patient should be observed for 1 hour for the development of opiate withdrawal.1,102 If no evidence of withdrawal is present, the usual oral dosage of 50 mg once daily can be started the next day.1 Alternatively, some clinicians have induced therapy by administering an initial 10- or 12. 5-mg dose of naltrexone hydrochloride, followed by incremental increases of 10 or 12.5 mg daily until the usual dosage of 50 mg daily has been achieved.62,99,123,196 Therapy has also been induced by administering an initial 5-mg dose, followed by incremental increases of 10 mg hourly until the usual total daily dose of 50 mg has been achieved.14,41

Maintenance Therapy for Opiate Cessation

Following induction of therapy, an oral maintenance dosage of 50 mg of naltrexone hydrochloride daily produces adequate antagonist activity to block the pharmacologic effects of parenterally administered opiates (e.g., a 25-mg IV dose of heroin).1,2,11,24,25,28,99,102 Flexible naltrexone dosing schedules in which the dose and/or frequency of administration of the drug are altered in an attempt to improve compliance have been suggested.1,2,35,62,99,102,122,138,157,158,161,164,196 The manufacturer states that naltrexone hydrochloride may be administered in dosages of 50 mg daily Monday through Friday and 100 mg on Saturday, 100 mg every other day, or 150 mg every third day.1,102 Alternatively, the drug has been administered in a regimen of 100 mg on Monday and Wednesday and 150 mg on Friday8,35,99,102,121,122,123,157,158,164 or in a regimen of 150 mg on Monday and 200 mg on Thursday.196 Although the opiate antagonist activity may be somewhat reduced by the administration of larger doses of naltrexone hydrochloride at longer intervals, improved patient compliance may result from administration of the drug every 48-72 hours rather than daily.1,102,121 Most clinicians suggest that observed ingestion of the drug in a clinic setting or by a responsible family member generally be used to ensure compliance, in which case, regimens requiring less frequent visits may be more acceptable to the patient.8,99,102,182,194,196 Some patients, particularly those who are employed, may remain in opiate cessation programs longer if they are permitted take-home doses once they are doing well in the program.102 Some clinicians suggest that random testing of urine for naltrexone and 6-β-naltrexol or for the presence of opiates may be used to monitor patient compliance.62,102,161

The optimum duration of naltrexone maintenance therapy has not been established,121 but should be based on individual requirements and response.102 In general, patients formerly physically dependent on opiates need a minimum of 6 months to make the behavioral changes necessary to maintain opiate cessation, and naltrexone therapy may be beneficial during this period.102 For patients unable to successfully deal with the temptation of opiate use, maintenance naltrexone therapy may be necessary throughout the course of a comprehensive opiate cessation program.102 For other patients, short-term maintenance therapy with naltrexone during the early transition from opiate use to abstinence may be all that is necessary.102 For other patients who are able to remain abstinent for prolonged periods after an initial period of treatment but who may revert to opiate use during a crisis or get occasional irresistible cravings for opiates, additional naltrexone therapy may only be necessary during these periods.102 In patients who discontinue naltrexone therapy prematurely and then desire to resume therapy following a relapse to opiate abuse, urinalysis for the presence of opiates and, if necessary, a naloxone challenge test should be performed prior to resuming naltrexone therapy;161,196 if there is evidence of opiate dependence, detoxification should be conducted prior to reinitiation of naltrexone therapy.102,161

Management of Opiate Withdrawal

In studies of naltrexone for the management of opiate withdrawal†, various dosage regimens of the drug have been used for rapid or ultrarapid detoxification of opiate dependence.2,38,162,168,169,246 In one study evaluating naltrexone in combination with clonidine, an initial 0. 005-mg/kg dose of clonidine hydrochloride was administered on the first day of detoxification to attenuate opiate withdrawal; clonidine dosage was then titrated according to the severity of withdrawal and the adverse effects induced by clonidine.2,38 The highest mean dose of clonidine hydrochloride was 2.3 mg daily, administered on the third day of detoxification.38 Naltrexone therapy was initiated on the second day of detoxification and administered every 4 hours on the second and third days; the initial dose of naltrexone hydrochloride was 1 mg and was increased by 1- and 2-mg increments during the daytime on the second and third days of detoxification, respectively.38 Clonidine was also administered every 4 hours on the second and third days to attenuate the withdrawal induced by naltrexone; however, after the third day, clonidine was administered only as needed to reduce signs and symptoms of withdrawal.38 Naltrexone hydrochloride was administered at a dosage of 10 mg 3 times daily on the fourth day,38 and as single 50-mg daily doses thereafter.2,38

Alcohol Dependence

Following verification that the patient is free of opiates (see Dosage: Naloxone Challenge Test, in Dosage and Administration), oral naltrexone hydrochloride therapy may be initiated for alcohol dependence.1 A dosage of 50 mg once daily has been recommended for patients with alcohol dependence.1,234,237 Since about 5-15% of patients reportedly have experienced adverse effects (mainly GI effects) with this dosage, some clinicians have recommended an initial dose of 25 mg, dividing the daily dosage, or adjusting the time of dosing in an effort to minimize such effects; however, naltrexone-associated adverse effects did not appear to be alleviated by such alterations in the recommended dosage.1,237 Safety and efficacy of naltrexone hydrochloride for alcohol dependence have been established only in short-term (up to 12 weeks) clinical studies using an oral naltrexone hydrochloride dosage of 50 mg daily,1,231,232,233,234,236,237 and the optimum duration of naltrexone therapy for this condition currently is not known.237

When naltrexone extended-release injection is used for the treatment of alcohol dependence in patients who are free of opiates (See Dosage: Naloxone Challenge Test, in Dosage and Administration), the recommended dosage is 380 mg of naltrexone IM every 4 weeks or once a month.247 The IM preparation should not be administered by IV or subcutaneous injection; the IM preparation should not be inadvertently administered into fatty tissue (see Dosage and Administration: Reconstitution and Administration).247,257

If the patient misses a dose, the next dose should be administered as soon as possible.247 Dosage adjustment is not needed in patients with mild to moderate (Child-Pugh class A or B) hepatic impairment or mild renal impairment (creatinine clearance of 50-80 mL/minute).247 Patients initiating therapy with naltrexone for alcohol dependence may initiate therapy with the parenteral preparation; it is not necessary to initiate therapy with oral naltrexone and then switch to the parenteral preparation.247 Information regarding reinitiation of naltrexone therapy in patients who discontinued such therapy is lacking; data needed to support recommendations for switching patients from oral to parenteral naltrexone therapy have not been systematically collected.247

At usual oral dosages, adverse effects of naltrexone are generally mild to moderate in severity2,11,17,37,42,102,122,125,147 and usually subside within a few days.11,17,37 Because of the potential for naltrexone to precipitate or exacerbate withdrawal in patients formerly physically dependent on opiates and who are not completely free of the drugs,1,31,122,124,125,126,129 adverse effects associated with naltrexone in some patients may have been secondary to opiate withdrawal.2,3,11,15,17,31,37,62,102,122,137,139 Many adverse effects reported during administration of naltrexone have occurred prior to as well as during administration of the drug1,32,102,127,139 and may be the result of alcohol and drug abuse and poor nutrition;1,102 in some patients, adverse effects improved or resolved during administration of the drug.1,102 Therefore, a causal relationship for many adverse reactions to naltrexone has not been clearly established.102,132

When administered to opiate-free individuals in usual oral dosages (i.e., 50 mg daily), naltrexone generally has not caused serious adverse effects or abnormal laboratory test results (e.g., liver function).1,102 In several controlled studies, the incidence of naltrexone-associated adverse effects was similar to that reported with placebo.1,102,129,131,137,141 In addition, in uncontrolled studies, the incidence of naltrexone-induced adverse effects (e.g., lymphocytosis, increases in serum aminotransferase [transaminase] concentrations, GI effects) was similar to that expected in individuals not receiving the drug.1,37,102,130,132

In controlled studies in alcohol-dependent patients receiving oral therapy with naltrexone hydrochloride 50 mg daily for 12 weeks, the drug was well tolerated.1 In these studies, nausea required discontinuance of therapy in about 5% of patients; however, no serious adverse effects were reported.1

Adverse effects reported in patients with alcohol dependence receiving naltrexone extended-release IM injection generally have been described as mild to moderate.247 The most common adverse effects associated with IM therapy with the drug are injection site reactions, nausea, and headache.247,257 (See Cautions: Precautions and Contraindications.)

GI Effects

The most frequent adverse effects reported in individuals receiving oral naltrexone are GI effects.2,28,132,134,138,141,147 Abdominal pain and cramps,1,3,8,9,11,17,32,62,102,122,126,127,128,129,130,132,134,135,138,141,143,144,242 nausea,1,2,3,8,9,11,17,21,25,26,37,43,62,71,125,127,134,137,144,145,146,242 and vomiting1,3,11,37,125,127,134,144,242 reportedly occur in more than 10% of patients receiving naltrexone for opiate dependence1,102 and may occasionally be severe enough to require discontinuance of the drug.102,127,129,143 Adverse GI effects reported in 1-10% of patients receiving the drug for opiate dependence include constipation1,3,37,137,141,145 and anorexia.1,2,3,37,46,62,121,134,138,139,141 Other adverse GI effects reported in less than 1% of patients receiving the drug for opiate dependence include diarrhea,1,217 flatulence,1,122,141 upset stomach,128,129,130,137 hemorrhoids,1 epigastric pain or heartburn,14,37,123,131,135 and ulcer.1,37 Nausea and vomiting were reported in 10 and 3%, respectively, of patients receiving naltrexone for the management of alcohol dependence, and were among the most common adverse effects reported in these patients.1,232,237

Nausea247,248 (most commonly following the initial dose247 ), vomiting,247,248 or diarrhea247,248 occurred in 33, 14, or 13%, respectively, of individuals receiving naltrexone extended-release IM injection in a dosage of 380 mg every 4 weeks in clinical studies.247 Abdominal pain,247 dry mouth,247 or anorexia (appetite disorder)247,248 was reported in 11, 5, or 14%, respectively, of these individuals.247 Nausea has required discontinuance of the drug in about 2% of patients.247

Hepatic Effects

Naltrexone reportedly can cause dose-related hepatocellular injury, manifested as increases in serum hepatic enzyme concentrations.1,102,226,228,247 Liver function abnormalities have been observed mainly in patients receiving high dosages (e.g., 300 mg daily) of the drug investigationally for the treatment of obesity1,102,196,206,217,226,228 or dementia of the Alzheimer's type (Alzheimer's disease),1,196,206 but increases in serum aminotransferase concentrations have also occurred following administration of dosages 2 times that recommended for blockade of pharmacologic effects of opiates.1,217 Following naltrexone hydrochloride dosages of 300 mg daily for 3-8 weeks in obese patients in one placebo-controlled study, serum ALT (SGPT) concentrations increased to up to 3-19 times the baseline values in about 20% of patients receiving the drug, but not in those receiving placebo, and decreased to or near baseline values within several weeks following discontinuance of the drug.1,228 In another placebo-controlled study in obese patients, increases in serum ALT, AST (SGOT), and/or LDH concentrations occurred in about 15% of patients receiving 50 or 100 mg of naltrexone hydrochloride daily for 8 weeks and in about 25% of those receiving placebo; in the naltrexone-treated group, hepatic enzymes decreased to at or less than baseline values over several weeks to months following discontinuance of the drug.197 Clinical symptoms of hepatotoxicity generally were not present in patients with liver function abnormalities.1 Mild liver function abnormalities are common in very obese patients, probably secondary to fatty infiltration of the liver,197,215,216 and were present in about 50% of obese patients at baseline in one naltrexone study.197 Increases in serum aminotransferase concentrations have also occurred in several patients with a history of alcohol dependence or of hepatitis.127,130

The manufacturer states that naltrexone-induced hepatocellular injury appears to be a direct toxic rather than an idiosyncratic effect of the drug.1 However, some clinicians suggest that liver function abnormalities associated with naltrexone use may be caused by noroxymorphone, a minor metabolite of naltrexone that has opiate agonist activity,196,206 since opiate agonists have been shown to cause increases in serum hepatic enzyme concentrations and hepatocellular injury in animals206,211,212,213,214 and humans.196,206,208,209,210 In addition, opiate antagonists, including naltrexone, have been shown to block the increases in serum hepatic enzymes and hepatocellular injury caused by opiates.206,212 Therefore, additional study to more fully elucidate the hepatotoxic potential of naltrexone and its metabolites and any possible dose relationship is necessary.196,197,206

Hepatotoxicity reportedly has not occurred at dosages recommended for blockade of pharmacologic effects of opiates, and serum concentrations of liver enzymes observed following recommended dosages of the drug have been reported to be similar to those observed in the same patients prior to administration of naltrexone.1,196,206,217 In one short-term study, the incidence of serum AST elevations in individuals receiving parenteral naltrexone was similar to the incidence in those receiving oral naltrexone (1.5% each) and higher than the incidence in those receiving placebo (0.9%).247 Deterioration in pretreatment liver function abnormalities in former opiate-dependent patients has not been reported to date following initiation of naltrexone therapy.196,206 However, the manufacturers state that the margin between therapeutic and hepatotoxic dosages may be less than fivefold,1,247 and the hepatotoxic potential of naltrexone must be considered prior to initiation of and during therapy with the drug.1,102 (See Cautions: Precautions and Contraindications.)

Nervous System Effects

Adverse nervous system effects reported in more than 10% of patients receiving oral naltrexone for opiate dependence1 include headache,1,3,8,11,17,62,102,144,147,242 lassitude,1,11,17,37,132,138,141,143 low energy,242 difficulty sleeping,1,11,17,28,37,125,135,138,140,143,144,145,242 anxiety,1,28,37,125,129,143,242 and nervousness.1,11,17,37,129,144,242 Increased energy,1,147 mental depression,1,2,128,132,138 irritability,1,2,11,25,37,62,138,143,144 and dizziness1 have been reported in 1-10% of patients receiving oral naltrexone for opiate dependence.1 Other adverse nervous system effects reported in less than 1% of patients receiving the drug for opiate dependence1 include paranoia,1 akathisia,145 fatigue,1,2,26,37,138 restlessness,1,133,138,144 confusion,1,2,31,133,138 dysphoria,26,62,147 disorientation,1,26,33,138 hallucinations,1,25,31,133 lightheadedness,26,43,138 nightmares and bad dreams,1,135 talkativeness,133 yawning,1,25,139 drowsiness or somnolence,1,17,26,32,37,62,138,144 and malaise.144 In some patients receiving the drug for opiate dependence, severe lethargy and somnolence have developed after only one or two doses of naltrexone and persisted for 12-36 hours;1,219,220,221,222 several such patients were receiving a phenothiazine antipsychotic agent (thioridazine) concomitantly.1,220,221,222

Depression, suicide, attempted suicide, and suicidal ideation (possibly associated with substance abuse) have been reported in patients receiving oral naltrexone for opiate or alcohol dependence, but the risk of suicide is known to be increased in substance abusers with or without depression, and a causal relationship to the drug has not been established.1 Clinicians should consider that naltrexone has not been associated with a decrease in the risk of suicide.1 Depression has been reported in up to 15% of patients receiving oral naltrexone for alcohol dependence.1 Suicidal ideation or attempted suicide has been reported in up to 1% of these individuals.1 Headache occurred in 7% and dizziness, nervousness, fatigue, insomnia, anxiety, and somnolence have been reported in 2-4% of patients receiving oral naltrexone for the treatment of alcohol dependence.1

Headache,247,248 dizziness,247,248 and somnolence247 have occurred in 25, 13, and 4%, respectively, of individuals receiving naltrexone extended-release IM injection in a dosage of 380 mg every 4 weeks in clinical studies.247 Insomnia or sleep disorder,247,248 anxiety,247 and depression247 have been reported in 14, 12, and 8-10%, respectively, of these individuals.247 Headache has required discontinuance of the drug in about 1% of patients.247 Suicidality (i.e., suicidal ideation, suicide attempt, completed suicide) was reported more frequently in individuals receiving parenteral naltrexone than in those receiving placebo (1 versus 0%).247 Two completed suicides, both in naltrexone-treated individuals, occurred in controlled clinical studies.247

Musculoskeletal Effects

Joint and muscle pain1,37,122,139,242,247 reportedly occur in more than 10% of patients receiving oral or parenteral naltrexone.1,247 Other adverse musculoskeletal effects reported in less than 1% of patients receiving oral naltrexone include tremors, twitching, and painful shoulders, legs, or knees.1 Back pain or stiffness247 and muscle cramps247 have occurred in 6-8% of patients receiving parenteral naltrexone in the recommended dosage.247

Dermatologic Effects

Rash1,2,3,8,15,43,102,140 has been reported in 1-10% of patients receiving oral naltrexone.1 Oily skin,1 pruritus,1,15,25,133,140 acne,1,122 athlete's foot,1 cold sores,1 and alopecia1 have been reported in less than 1% of these patients.1

Local Reactions

Injection site reactions,247,248 including tenderness,247 induration,247 pain,247,248 pruritus,247 ecchymosis,247 nodules,247 and swelling,247 have been reported in 65% of patients receiving parenteral naltrexone in the recommended dosage and have required discontinuance of the drug in about 3% of patients.247 Cellulitis,247 hematoma,247 abscess,247 sterile abscess,247 and necrosis247 also have been reported during postmarketing surveillance of parenteral naltrexone.247 Some injection site reactions may be very severe, result in substantial scarring, or require surgical intervention, including debridement of necrotic tissue.247 Injection site reactions have occurred predominantly in females.247 Inadvertent subcutaneous injection may increase the likelihood of a severe injection reaction.247 (See Cautions: Precautions and Contraindications and see Dosage and Administration: Reconstitution and Administration.)

Respiratory and Cardiovascular Effects

Respiratory symptoms, including nasal congestion,1 rhinorrhea,1,37 sneezing,1 sore throat,1 excessive mucus or phlegm production,1 sinus trouble,1 labored breathing,1 hoarseness,1 cough,1 epistaxis,1,143 and dyspnea,1 have been reported in less than 1% of patients receiving oral naltrexone.1 Adverse cardiovascular effects reported in less than 1% of these patients1 include phlebitis,1 edema,1 increased systolic2,9,32,33,35,102,131 and/or diastolic blood pressures,1,17,25,29,32,33,35,94,102,122,133 nonspecific ECG changes,1,32,102 palpitation,1 and tachycardia.1 Systolic pressures have returned to pretreatment levels after the first week of therapy in some patients.9,102

Upper respiratory tract infection247,248 and pharyngitis247,248 have occurred in 11-13 % of patients receiving the recommended dosage of parenteral naltrexone.247 Eosinophilic pneumonia247 has been reported in at least one individual receiving parenteral naltrexone.247 Clinicians should consider eosinophilic pneumonia in the differential diagnosis of patients with pneumonia that has not responded to anti-infective therapy.247

Opiate Withdrawal

Naltrexone may precipitate mild to severe signs and symptoms of withdrawal in some patients physically dependent on opiates.1,2,7,11,15,31,35,38,42,82 The manufacturers recommend that a period of at least 7-10 days elapse between discontinuance of opiates and initiation of naltrexone therapy, and patients should be adequately evaluated to confirm that they are free of opiates prior to initiating therapy with the drug.1,102,247 (See Cautions: Precautions and Contraindications.)

Accidental ingestion of naltrexone has precipitated severe withdrawal in some patients physically dependent on opiates; signs and symptoms of withdrawal usually appeared within 5 minutes of ingestion of naltrexone and continued for up to 48 hours.1,31,102,124 Signs and symptoms of opiate withdrawal vary in severity depending on the specific opiate used, its dose and duration of use, and individual physiologic and psychologic characteristics of the patient.102 Signs and symptoms of opiate withdrawal reported in patients receiving naltrexone have included drug craving, confusion, drowsiness, visual hallucinations, abdominal pain, and vomiting and diarrhea which resulted in substantial fluid loss requiring IV fluid replacement therapy in some patients.1,31,102 Other signs and symptoms of withdrawal included fever, chills, tachypnea, perspiration, salivation, lacrimation, rhinorrhea, and mydriasis.31,124 Opiate-like withdrawal symptoms, including lacrimation, nasal symptoms, mild nausea, abdominal cramps, restlessness, bone or joint pain, and myalgia have been reported in a few healthy individuals and alcohol-dependent patients receiving naltrexone.1 It is not known if these symptoms were associated with occult opiate use or with naltrexone therapy.1

Other Adverse Effects

Chills1,122,144 have been reported in less than 10% of patients receiving oral naltrexone.1 Increased thirst reportedly occurs in more than 1% of these patients.1

Other adverse effects of oral naltrexone reportedly occur in less than 1% of patients.1 Adverse genitourinary effects include urinary frequency1,37 and dysuria.1 Adverse ocular effects include blurred vision,1,37,122 sensitivity to light,1 burning,1 swelling,1 and aching and strained eyes.1 Adverse otic effects include congestion,1 tinnitus,1 and aching ears.1 Other adverse effects include lymphocytosis,1,102,122,129,130 decreased hematocrit,129 increased appetite,1 weight loss1,46,62,102,121,143 or gain,1 fever,1,31 diaphoresis,26,138,139 dry mouth,1 throbbing head,1 inguinal pain,1 swollen glands,1 cold feet,1 and hot flushes (flashes).1

Idiopathic thrombocytopenic purpura reportedly occurred in one patient receiving oral naltrexone; however, the patient improved without additional complications following discontinuance of the drug and initiation of corticosteroid therapy.1,15,35,102 Although the patient may have developed hypersensitivity to naltrexone during previous therapy,1,102 standard antigen-antibody studies failed to clearly establish a causal relationship to the drug.15,35,102

A hypersensitivity reaction, characterized by an allergic rash, occurred in one patient receiving oral naltrexone but disappeared 5 days after discontinuance of the drug; palmar erythema, pruritus, and exfoliative dermatitis reappeared upon rechallenge with low doses of the drug.15,35

Altered plasma proteins and increases in IgM, IgA, and IgG levels have been reported in patients receiving oral naltrexone but may have been the result of alcohol abuse or a history of hepatitis.127

Asthenia247 has occurred in 23% of patients receiving the recommended dosage of parenteral naltrexone.247

Although the manufacturers state that a dose-related causal relationship between naltrexone and abnormal liver function test results has been established (see Cautions: Hepatic Effects),1,102 other abnormal laboratory test results observed during oral naltrexone therapy have not been directly attributed to the drug.1 Increases in eosinophil counts (which returned to normal over several months with continued use of the drug), decreases in platelet count not associated with bleeding, and serum creatine kinase (CK, creatine phosphokinase, CPK) abnormalities have occurred in individuals receiving parenteral naltrexone.247 Changes in baseline concentrations of some hypothalamic, pituitary, adrenal, or gonadal hormones have occurred in patients receiving opiate antagonists; however, the clinical importance of such changes has not been established.1

Precautions and Contraindications

Naltrexone reportedly can cause dose-related hepatotoxicity.1,102,226,228,247 (See Cautions: Hepatic Effects.) Baseline determinations of liver function should be performed in all patients prior to initiation of naltrexone.102 The manufacturers state that the potential benefits of naltrexone therapy should be weighed carefully against the possible hepatotoxic risks of the drug in patients with active liver disease (e.g., liver function test values exceeding 3 times the upper limit of normal).1,247 However, some clinicians have questioned the need for considering withholding naltrexone therapy in most opiate or alcohol-dependent individuals with marginal evidence of hepatic injury or disease,196,229,237 since baseline serum concentrations of liver enzymes are frequently elevated in opiate- or alcohol-dependent individuals205,206,237 and evidence of hepatotoxic risk of naltrexone therapy at usual dosages has not been demonstrated in these individuals.196,206,229 Naltrexone is contraindicated in patients with acute hepatitis or liver failure.1,102,247 Naltrexone should be discontinued if manifestations of acute hepatitis (e.g., abdominal pain lasting more than a few days, light-colored [e.g., white] stools, dark urine, yellowing of the eyes) develop.1,247 Patients receiving naltrexone therapy should be instructed to contact a clinician if such manifestations occur and to discontinue therapy with the drug (if receiving oral therapy).1,247,258 Although naltrexone-associated hepatic failure has not been reported, clinicians are advised to consider the risk of naltrexone-associated hepatic failure and to use the drug with caution similar to that employed with other drugs that may cause hepatic injury.1 In addition, some clinicians state that the possibility that naltrexone might have synergistic toxic effects in patients with alcohol-induced hepatic disease has not been ruled out.237 The manufacturer of oral naltrexone recommends that liver function be monitored at regular intervals in all patients during naltrexone therapy to detect hepatic injury or disease that may develop secondary to the drug.1,102,121 The manufacturer states that the risk of naltrexone-induced toxicity may be increased when flexible naltrexone hydrochloride dosing schedules that involve administration of single doses greater than 50 mg (e.g., 100 mg every other day, 150 mg every third day) are used, and clinicians should balance the benefits of improved patient compliance against possible risks.1

Naltrexone may precipitate mild to severe withdrawal in patients physically dependent on opiates.1,2,7,11,15,31,35,38,42,82,247 (See Cautions: Opiate Withdrawal.) If signs and/or symptoms of withdrawal are precipitated by naltrexone in a patient physically dependent on opiates, the patient should be closely monitored and therapy adjusted according to individual requirements and response.1,102 To minimize the risk of developing acute withdrawal, opiate-dependent individuals who are candidates for naltrexone therapy should be instructed to remain free of opiates for a minimum of 7-10 days prior to initiating therapy with the drug.1,102,247,258 A urinalysis to confirm the absence of opiates should be performed after the minimum 7- to 10-day waiting period but prior to administration of naltrexone; however, the absence of opiates in urine is frequently insufficient evidence that a patient is free of opiates, and, if opiates are absent, a naloxone challenge test should also be performed prior to administering naltrexone if the clinician believes there is a risk of precipitating a withdrawal reaction following administration of naltrexone.1,102,247 (See Naloxone Challenge Test in Dosage and Administration: Dosage.)

Although naltrexone is a potent opiate antagonist with a dose-dependent duration of activity that ranges from 24-72 hours following oral administration, the opiate antagonist activity produced by oral or parenteral naltrexone can be overcome by administration of opiates; overcoming the blockade of pharmacologic effects produced by naltrexone may be useful in certain patients in whom opiate analgesia is necessary.1,247 Generally, if analgesia is necessary in patients receiving naltrexone, a nonopiate analgesic, regional analgesia, conscious sedation with a benzodiazepine, or general anesthesia should be used whenever possible.1,102,247 In an emergency situation when adequate analgesia can only be achieved by administration of an opiate agonist in naltrexone-treated patients, cautious administration of an opiate may afford adequate analgesia, but higher than usual dosages may be required.1,102 If an opiate agonist is used in these patients, the possibility that the respiratory depression produced by the opiate may be deeper and more prolonged should be considered.1,102 If an opiate is required as a component of anesthesia or analgesia, the patient should be continuously monitored in an anesthesia care setting by individuals who are trained in the use of anesthetic agents and in the management of respiratory depressant effects of potent opiates and who are not involved in the conduct of the surgical or diagnostic procedure.247 In addition, patients receiving naltrexone and analgesic therapy with opiate agonists may also experience apparent non-opiate receptor-induced effects such as facial swelling, pruritus, generalized erythema, or bronchoconstriction that are probably caused by opiate-induced histamine release and/or other mechanisms.1 Since methods for reversing opiate overdosage in patients receiving naltrexone have not been established, use of a short-acting opiate with minimal respiratory depression is preferable and dosage of the opiate agonist should be carefully adjusted according to individual requirements and response.1,102 However, regardless of the opiate agonist used, the patient should be closely monitored in a setting equipped and staffed by health-care personnel appropriately trained in cardiopulmonary resuscitation.1,247 Prior to elective surgery in which analgesia can only be achieved by administration of an opiate, oral naltrexone should be discontinued at least 48 hours prior to the surgical procedure.121 Use of other opiate-agonist-containing preparations such as those used for the management of cough or diarrhea should generally be avoided, since adequate therapeutic benefit may be difficult to achieve with an opiate.1,102,247

Self-administration of large doses of opiates may produce serum opiate concentrations sufficient to overcome the antagonist effects of naltrexone and may produce signs and symptoms of acute opiate overdosage, including respiratory arrest, circulatory collapse, and possibly death.1,247 For a complete discussion of opiate overdosage, see Acute Toxicity in the Opiate Agonists General Statement 28:08.08. Self-administration of smaller doses of opiate agonists than previously used may produce signs and symptoms of opiate overdosage and toxicity.1,247

Patients undergoing naltrexone therapy should be carefully instructed that naltrexone has been prescribed as part of a comprehensive program for the treatment of their drug dependence and to carry some form of medical identification that can alert medical personnel that they are taking a long-acting opiate antagonist.1,102,247,258 Patients should be instructed to take oral naltrexone as directed;1,102 patients receiving parenteral naltrexone should be advised of the frequency of administration.247 Patients should be warned of the serious consequences of self-administration of opiates in an attempt to overcome the antagonist activity of naltrexone.1,247,258 They should be advised that self-administration of small doses of opiates (e.g., heroin) during naltrexone therapy will not result in any pharmacologic effect and that large doses may result in serious pharmacologic effects, including coma and death.1,102,258 Patients also should be advised that if they previously self-administered opiates, they may be more sensitive to lower doses of opiates after naltrexone therapy is discontinued.1,247,258 Because of the potential for relapse to opiate use and subsequent opiate overdosage to occur, patients should be advised of the benefits of naloxone administration following an opiate overdose and of their options for obtaining the drug.750

Because naltrexone and its metabolites are eliminated principally in urine, naltrexone should be used with caution in patients with moderate to severe renal impairment.1,247

Injection site reactions have been reported in patients receiving parenteral naltrexone.247 Patients should be instructed to monitor the injection site and to notify the clinician if injection site reactions (i.e., pain, swelling, tenderness, induration, bruising, pruritus, redness) worsen or if they do not improve within 2 weeks following injection.257,258 Patients should be advised to notify the clinician promptly if intense or prolonged pain, swelling, skin color changes, or signs of necrosis (e.g., hard nodule, blistering, open wound, dark scab) are present at the injection site.247,258 Patients with signs of abscess, cellulitis, necrosis, or extensive swelling at the injection site should be promptly evaluated to determine if referral to a surgeon is warranted.247

As with any preparation administered IM, parenteral naltrexone should be used with caution in patients with thrombocytopenia or other coagulation disorder (e.g., hemophilia).247

Because eosinophilic pneumonia has been reported rarely in patients receiving parenteral naltrexone, patients receiving this preparation should be advised to seek medical attention if symptoms of pneumonia develop.247,258

Depression and suicidality have occurred in naltrexone-treated individuals.1,247 Patients receiving naltrexone should be closely monitored for symptoms of depression and suicidal thinking and should be advised to contact their clinician immediately if they experience new or worsening symptoms of depression or suicidal thoughts.1,247,258

Because naltrexone may cause dizziness, patients should be advised to avoid driving or operating heavy machinery until they know how the drug affects them.1,247,258

The US Food and Drug Administration (FDA) required and approved a Risk Evaluation and Mitigation Strategy (REMS) for parenteral naltrexone.259 The REMS requires that a medication guide be given to the patient each time parenteral naltrexone is dispensed.259,260 The goal of the REMS is to inform patients about serious risks associated with parenteral naltrexone.259 Patients should be advised to read the medication guide prior to initiating parenteral naltrexone therapy and before each injection of the drug.258 Clinicians should advise patients about the risks and benefits of parenteral naltrexone therapy prior to initiating such therapy and ensure that patients understand the risks.260

Naltrexone is contraindicated in patients receiving opiate agonists (except for emergency situations), nondetoxified patients physically dependent on opiates (including those receiving methadone), patients experiencing acute opiate withdrawal, patients who experience opiate withdrawal following administration of the naloxone challenge test, and patients in whom urinalysis for the presence of opiates is positive.1,102,247 Naltrexone is also contraindicated in patients with acute hepatitis or hepatic failure and in patients with known hypersensitivity to the drug or any ingredient in the formulation.1,247 It is not known whether cross-sensitivity exists between naltrexone and naloxone or phenanthrene-derivative opiate agonists (e.g., codeine, morphine, oxymorphone).1

Pediatric Precautions

Safety of naltrexone in children younger than 18 years of age has not been established.1,102,121,247,248

Geriatric Precautions

Clinical studies of parenteral naltrexone did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger adults.247

Mutagenicity and Carcinogenicity

Mutagenic changes and chromosomal damage have occurred in vitro in human lymphocytes148 and Chinese hamster ovarian cells,149 in the Drosophila recessive lethal assay,1,102,150,247 and in nonspecific DNA repair tests with Escherichia coli 1,102,151,247 and WI-38 cells.151,247 However, the importance of these findings has not been determined1,102,247 and naltrexone did not show evidence of mutagenic potential in many other tests using bacterial, mammalian, or tissue culture systems.1,102,151

In a 2-year study of the carcinogenic potential of naltrexone, there was an increase in the frequency of mesotheliomas in male rats and tumors of vascular origin in both male and female rats.1,69,102,247 No evidence of carcinogenicity was observed in several other 2-year studies in mice or rats receiving naltrexone dosages of 30 or 100 mg/kg daily (47 or 150 times greater than the usual dosage in humans), respectively.152

The possible mutagenic and carcinogenic effects of 6-β-naltrexol (an active metabolite) are unknown.1

Pregnancy, Fertility, and Lactation

Pregnancy

In reproduction studies in rats and rabbits, oral naltrexone was shown to increase the incidence of early fetal loss.1,247 There are no adequate and controlled studies to date using naltrexone in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1,247 It is not known whether naltrexone affects the duration of labor and delivery.1,102,247

Fertility

Naltrexone dosages of 100 mg/kg daily in rats (about 16 times the usual human oral dosage based on body surface area) produced an increase in pseudopregnancy and a decrease in the pregnancy rate in mated rats,1,45,102 but the relevance of these findings to human fertility is not known.1,102 Use of the drug has been associated with delayed ejaculation1 and decreased1,135,143 or increased sexual potency62 in less than 10% of patients.1 Increased1,26,52,138 (see Pharmacology: Other Effects) or decreased1,37,139 libido has been reported in less than 1% of patients.1

Lactation

Naltrexone and its major metabolite, 6-β-naltrexol, are distributed into human milk.247,254 Because of the potential for serious adverse effects in nursing infants, a decision should be make whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.247

The manufacturer states that concomitant administration of naltrexone with drugs other than opiate agonists has not been studied; therefore, naltrexone should be used with caution in patients receiving other drugs.1,247

Opiate Agonists

Patients receiving naltrexone may not benefit therapeutically from opiate-containing preparations, including those used for the management of cough and cold, diarrhea, and pain.1,102,247 Use of these preparations should generally be avoided during naltrexone therapy.1 (See Cautions: Precautions and Contraindications.) Because naltrexone can precipitate potentially severe opiate withdrawal, naltrexone should not be used in patients receiving opiates or in nondetoxified patients physically dependent on opiates (including those receiving methadone maintenance treatment).1,102,247

Effects on Hepatic Clearance of Drugs

Since naltrexone is metabolized principally in the liver, other drugs that alter hepatic metabolism may increase or decrease serum naltrexone concentrations.121 In animals and in vitro, naltrexone and 6-β-naltrexol (an active metabolite) have been shown to inhibit hepatic metabolism of aminopyrine and aniline via hepatic microsomal mixed-function oxidase enzymes;2,4 the importance of this effect on metabolism of other drugs in humans requires further study.4 Naltrexone reportedly does not induce its own metabolism.72,79,101,102

Other Drugs

Naltrexone has been administered concurrently with non-opiate drugs (e.g., disulfiram, antidepressants, lithium) frequently used in the treatment of drug dependence without evidence of unusual adverse effects; however, these drug interactions have not been examined closely under a controlled clinical environment.121,247

Because the safety and efficacy of concomitant use of naltrexone and disulfiram currently are not known but potentially hepatotoxic drugs usually are not administered concomitantly, the manufacturer recommends that the drugs be used together only if the potential benefits justify the possible risks to the patient.1 Augmentation of naltrexone-induced lethargy and somnolence have been reported following initial doses of naltrexone in several patients stabilized on phenothiazine therapy (thioridazine).1,220,221,222,237 (See Cautions: Nervous System Effects.)

In a study in healthy individuals, concomitant use of acamprosate (1 g every 12 hours) and naltrexone hydrochloride (50 mg orally once daily) resulted in an increase in the rate and extent of absorption of acamprosate but did not alter the pharmacokinetics of naltrexone or 6-β-naltrexol.256 Area under the plasma concentration-time curve (AUC) and peak plasma concentration of acamprosate were increased by 25 and 33%, respectively, and time to peak plasma concentration was reduced by 33% when acamprosate and naltrexone were given concomitantly.256 Cognitive testing indicated that, although each drug alone was associated with some adverse effects on cognitive performance, combined use of the drugs did not appear to enhance these effects.256

Following abrupt discontinuance of methadone, concomitant administration of naltrexone and clonidine hydrochloride has attenuated withdrawal symptoms generally precipitated or exacerbated by naltrexone.38,230 Clonidine alone reduces the severity of opiate withdrawal symptoms by stimulation of presynaptic α₂-adrenergic receptors resulting in attenuation of rebound increases in noradrenergic activity in the CNS, which may be responsible for the behavioral symptoms of opiate withdrawal.38,168,184,185,230 Concomitant administration of clonidine and naltrexone may reduce the duration of opiate withdrawal by decreasing opiate-induced postsynaptic supersensitivity.38,168,230

Laboratory Test Interferences

Naltrexone reportedly does not interfere with the determination of urinary morphine, methadone, or quinine using thin-layer (TLC), gas-liquid (GLC), or high-pressure liquid (HPLC) chromatography.1 Naltrexone may interfere with some immunoassay or enzymatic methods used for the detection of urinary opiates.1,247

Acute Toxicity

The manufacturers state that there has been limited experience to date with overdosage of naltrexone in humans.1,102,247

Pathogenesis

The oral LD₅₀ of naltrexone has been reported to be 1.1-1.55,1,10,69,102 1.45,1,10,69,102 1.49,1,102 and 3 g/kg10,69 in mice, rats, guinea pigs, and monkeys, respectively; death usually occurred within 4 hours after administration.10 The IV LD₅₀ has been reported to be 180 mg/kg in mice,10 and the subcutaneous LD₅₀ has been reported to be 550-590,10,155,156 1930,10 and 200 mg/kg10 in mice, rats, and dogs, respectively. Acute toxicity from naltrexone in mice, rats, and dogs resulted in death secondary to tonic-clonic seizures and/or respiratory failure.1,10,102 Weight loss occurred in monkeys following subcutaneous administration of 100-mg/kg doses, and prostration, seizures, and death occurred following subcutaneous administration of 300-mg/kg doses.10 Hypoactivity, salivation, and emesis occurred in monkeys following oral administration of 1-g/kg doses, and seizures and death occurred following oral administration of 3-g/kg doses.10

Patients receiving 800 mg of naltrexone hydrochloride daily for up to 1 week in one study showed no evidence of toxicity.1,86,102,142,247 However, lower dosages reportedly have been hepatotoxic in some patients.1,102 (See Cautions: Hepatic Effects.) No serious adverse effects were observed following administration of single naltrexone doses of up to 784 mg (as the extended-release IM injection) in several healthy individuals.247

Treatment

There has been limited experience to date in the treatment of naltrexone overdosage, but supportive and symptomatic treatment should be initiated as necessary.1,102,247 When the drug has been ingested orally, usual measures to decrease GI absorption of the drug (e.g., induction of emesis, gastric lavage) should also be employed.196 Clinicians should consider contacting a poison control center for the most current information on treatment of naltrexone overdosage.1,102

Pharmacology

Opiate Antagonist Effects

Naltrexone hydrochloride is essentially a pure opiate antagonist.1,2,3,7,17,23,102 In contrast to levallorphan or nalorphine6 but like naloxone,2,6,73 naltrexone generally has little or no agonist activity.2,7,12,17,23,36,94 The opiate antagonist activity of naltrexone on a weight basis is reportedly 2-9 times that of naloxone,2,17,24,25,29,136,175 17 times that of nalorphine,2,24,25,31,102 and about one-tenth that of cyclazocine (not currently available in the US).24,25,28 The major metabolite of naltrexone, 6-β-naltrexol, is also an opiate antagonist and may contribute to the antagonist activity of the drug.1,62,102 (See Pharmacokinetics: Elimination.) When administered in usual doses to patients who have not recently received opiates, naltrexone exhibits little or no pharmacologic effect.7,18,25,41 At oral doses of 30-50 mg daily,25,31,40 naltrexone generally produces minimal analgesia,1,23,30 only slight drowsiness,1,17,25 and no respiratory depression.1,21,23 Psychotomimetic effects1,23,39 or circulatory changes1,11 are generally absent following administration of naltrexone. However, pharmacologic effects, including psychotomimetic effects,25,26,43 increased systolic and/or diastolic blood pressure,1,9,17,23,25,29,32,33,35,94,102,122,131,133 respiratory depression,2,33,43,94,133,178 and decreased oral temperature,2,33,43,94,178 which are suggestive of opiate agonist activity,2,43,94 have reportedly occurred in a few individuals. The drug has also occasionally produced a small degree of miosis in some individuals, suggesting some opiate agonist activity,1,2,11,17,22,25,33,37,43,67,72,94,102,103,178 but the exact mechanism of this effect is not known.1 It has been suggested that a metabolite of naltrexone (e.g., noroxymorphone) may be responsible for any opiate agonist activity observed with the drug.102,103,104 (See Pharmacokinetics: Elimination.)

In patients who have received single or repeated large doses of morphine or other opiate agonists, naltrexone attenuates or produces a complete but reversible block of the pharmacologic effects (e.g., physical dependence, analgesia, euphoria, tolerance) of the opiate.1,3,13,14,22,23,25,31 The drug antagonizes most of the subjective and objective effects of opiates,3,14,25,102,103 including respiratory depression,72,102,103 miosis,14,25,72,102,103 euphoria,14,72,102,103 and drug craving.3,25,72,102,103 Like naloxone,7,23 naltrexone probably also antagonizes the psychotomimetic effects of opiate partial agonists (e.g., pentazocine).196 Because the duration of action of naltrexone may be shorter than that of the opiate, the effects of the opiate may return as the effects of naltrexone dissipate.15,33,36 The degree of opiate antagonism produced by naltrexone depends on the dose and the time elapsed since the last dose of naltrexone and the dose of the opiate.1,11,32,102,122 Doses of up to 3 g daily of oral naloxone are necessary to produce the degree of antagonist activity produced by 30- to 50-mg daily doses of oral naltrexone.25,102,195

Naltrexone does not produce physical or psychologic dependence, and tolerance to the drug's opiate antagonist activity reportedly does not develop.1,7,8,11,13,22,27,33,39,40,79 Naltrexone may precipitate mild to potentially severe withdrawal in individuals physically dependent on opiates1,2,7,11,15,31,35,38,42,82 or pentazocine.196

The precise mechanism of the opiate antagonist effects of naltrexone is not known.1 However, naltrexone reportedly shares the actions of naloxone and is thought to act as a competitive antagonist at µ, κ, and δ receptors in the CNS;1,7,16,28,34,78,102,218 the drug appears to have the highest affinity for the µ receptor.7,16,19,218 The drug may displace opiates from opiate-occupied receptor sites by competitive binding at the receptors,1,3,41 and displacement of naltrexone from these receptors by opiates is also reportedly possible.1,7,36 In one study in dogs, naltrexone failed to antagonize the agonist effect of N -allylnormetazocine at the Σ receptor.199 Naltrexone may antagonize the pharmacologic effects of endorphins,19,34,62 but the effect of the drug on endorphins has not been fully elucidated.9 Sensitivity to the analgesic effects of morphine and the number of opiate receptors in the CNS has reportedly increased in rats following chronic subcutaneous administration of naltrexone for 8 days; sensitivity and number of receptors returned to pretreatment levels within 6 days after withdrawal of naltrexone.78,88

The mechanism of action of naltrexone in alcohol dependence is not known.1,231,235,237,239,240,247 Evidence from studies in animals suggests that alcohol ingestion stimulates release of endogenous opiate agonists,1,235,237,238,239,242 which may increase some of the rewarding effects associated with alcohol ingestion through agonist activity at opiate (e.g., µ) receptors.237,238 In animals and humans, opiate antagonists (e.g., naltrexone) that competitively bind to opiate receptors may reduce alcohol consumption by blocking the effects of endogenous opiates and thus making alcohol ingestion less pleasurable.1,232,233,235,236,237,238,241,247 In addition, naltrexone appears to decrease substantially the subjective alcohol “high”236,237,238,239 and increase the negative or dysphoric effects associated with alcohol consumption.235 The drug also may decrease alcohol-associated stimulant effects and increase alcohol-associated sedative effects without altering psychomotor performance in individuals receiving an intoxicating dose of alcohol.235,237 Naltrexone does not cause disulfiram-like reactions following ingestion of alcohol.1,238,242,247

Endocrine Effects

Like naloxone,7,47,62,63,65,85,179,180,181 naltrexone has been shown to increase plasma concentrations of luteinizing hormone (LH),2,26,47,51,52,53,54,55,56,57,58,61,62,94,102,138,178 corticotropin (ACTH),20,47,60,102,178,180 and cortisol.2,20,47,60,94,102,178 Since corticotropin has been shown to have partial antagonist activity at opiate receptors, it has been suggested that increases in plasma concentrations of corticotropin and cortisol following administration of naltrexone may result from displacement of corticotropin and endorphins from opiate receptors by naltrexone,102,178 although other mechanisms may be responsible (e.g., naltrexone-induced release of adrenocorticotropic releasing factor).196 Naltrexone has been shown to have little, if any, effect on plasma concentrations of follicle-stimulating hormone (FSH)47,52,53,62 and to produce minimal increases in serum testosterone concentrations.51,53,56,58,61,62,102 It is believed that naltrexone may influence plasma concentrations of LH by enhancing the secretion of gonadotropin releasing hormone.47,57 When administered prior to heroin (diacetylmorphine), naltrexone prevents the decrease in plasma concentrations of LH and testosterone usually produced by heroin.26 However, in one study, chronic administration of naltrexone in obese individuals was shown to have little, if any, effect on plasma concentrations of LH, FSH, testosterone, estradiol, cortisol, prolactin, glucose, or insulin.47 Like naloxone,47,48,49,50,62,63,179,180,181 naltrexone generally has been shown to have little, if any, effect on plasma growth hormone (GH)47 or serum prolactin concentrations.2,56,59,61,102,178

Naloxone does not affect serum concentrations of basal or stimulated glucagon.47,63 The drug does not affect serum concentrations of basal or stimulated thyrotropin (TSH) or TSH concentrations in hypothyroid patients;47,63,180,181 in animals, naltrexone has reversed the decrease in plasma TSH concentrations usually observed following exposure to acute or chronic stress.81 Naloxone and naltrexone indirectly block the effect of thyrotropin releasing hormone (TRH) on GI transit and fluid accumulation in rabbits and rats, presumably by blocking TRH-induced release of serotonin.80

Naltrexone has increased sensory-stimulated release of acetylcholine (ACh) from the cerebral cortex in rats, but spontaneous release of ACh was unaffected by the drug.95 The effect of naltrexone on antidiuretic hormone (ADH, vasopressin) in humans has not been studied;196,217 in animals, naltrexone did not affect changes in plasma ADH concentrations induced by most stimuli (i.e., nicotine, osmotic stimuli, hypovolemia, hemorrhage, tail pinch, overhydration).83 Basal plasma concentrations of ADH have not been affected by high doses (10 mg) of naloxone.47,63 The effect of naltrexone on GI secretions has not been studied;196 however, naloxone has reduced basal and meal-stimulated gastric acid secretion but not postprandial gastric acid secretion or basal, meal-stimulated, or postprandial gastrin and pancreatic polypeptide secretion.47

Other Effects

The effect of naltrexone on catecholamines in humans has not been studied;196,217 however, in rats, naltrexone produced a decrease in the midbrain and hippocampal concentrations of norepinephrine.87 Increased plasma concentrations of epinephrine and norepinephrine have been reported following high (10 mg) but not low (0.4 mg) doses of naloxone.47

Naltrexone has produced recurrent, spontaneous sexual arousal (i.e., penile erections) associated with dysphoric sexual ideation in several individuals.26,52,138 However, one study failed to confirm this finding.178

In a limited number of schizophrenic patients, naltrexone hydrochloride reportedly enhanced electrical evoked potentials to somatosensory stimuli and visual evoked potentials;30,44 following administration of naltrexone (average daily dose of 500 mg at time of testing) for 8 days in schizophrenic patients, electrical evoked potentials were characterized by larger amplitude at higher stimulus intensities.30 These effects on evoked potentials may result from the drug's inhibition of the effects of endogenous endorphins19,20,34,44,62 and reversal of endorphin suppression of noradrenergic activity in the CNS.44,196

Naltrexone, in single doses of 50 or 100 mg in healthy individuals, produced EEG patterns characterized by alpha waves of decreased frequency; in addition, 1 hour after administration of 100 mg of the drug, the EEG pattern in the fast frequency band was characterized by less power than after placebo.94,178

Inhibition of weight gain45 or decreased food consumption96 has occurred in rats following administration of naltrexone hydrochloride in single doses ranging from 0.3-10 mg/kg96 or daily doses of 100 mg/kg for 1-8 weeks.45 Anorexia and/or weight loss have occurred in several patients following oral administration of usual dosages of naltrexone for the treatment of opiate addiction.46 Although the exact mechanism of the anorexic effect has not been fully determined,2,46 the drug may inhibit the effects of endogenous endorphins,19,20,34,62 and decreased concentrations of endorphins in the CNS have been associated with fasting and starvation.2,46,62,64 It has also been suggested that the anorexic effect of the drug may be characteristic of withdrawal from chronic use of opiates rather than secondary to a direct effect of naltrexone.47 Naltrexone, administered to mice in doses of 10 mg/kg, blocked the lack of weight gain and growth inhibition produced by 5- to 20-mg/kg doses of pentazocine administered daily for 3 weeks; in these same animals, naltrexone alone did not produce growth inhibition.92 In the same study, protein synthesis in brain, liver, and muscle was substantially depressed by pentazocine but was unaffected by naltrexone.92

Like naloxone,89 naltrexone increases mean arterial pressure, cardiac output, stroke volume, and left ventricular contractility in dogs with hypovolemic shock following administration of naltrexone hydrochloride doses ranging from 2.5-10 mg/kg as a rapid IV injection or 2 mg/kg rapidly IV followed by an IV infusion of 2 mg/kg per hour for 4 hours.90 Pretreatment with naltrexone has blocked the potentiating effect of morphine in mice with anaphylactic shock.200 The effects of naltrexone in shock in humans requires further study.90

Bradycardia has occurred following IV naltrexone hydrochloride doses of 5-80 mcg/kg in unanesthetized dogs; respiratory rate, blood pressure, arterial blood gases, and EEG remained unchanged throughout the dose range.93 Within 20 minutes of 1-mg/kg IV doses in cats, total brain oxygen consumption decreased by about 48% and blood flow to the entire brain and the pons decreased by about 40%;91 however, the effect of naltrexone on total oxygen consumption and blood flow in humans has not been determined.196

Pharmacokinetics

Absorption

Naltrexone hydrochloride is rapidly and almost completely (about 96%) absorbed from the GI tract following oral administration,1,2,3,22,67,71,72,100,102,105 but the drug undergoes extensive first-pass metabolism in the liver.1,2,3,33,62,71,102 (See Pharmacokinetics: Elimination.) Only 5-40% of an orally administered dose reaches systemic circulation unchanged.1,2,67,71,72,74,102 Considerable interindividual variation in absorption of the drug during the first 24 hours after a single dose has been reported.62,71,72 The bioavailability of naltrexone hydrochloride tablets is reportedly similar to that of an oral solution of the drug (not commercially available in the US).1,71,102

Peak plasma concentrations of naltrexone and 6-β-naltrexol (the major metabolite of naltrexone) usually occur within 1 hour following oral administration of the tablets and 0.6 hours following oral administration of the solution.1,71,72,251,256 Because orally administered naltrexone undergoes substantial first-pass metabolism, plasma concentrations of 6-β-naltrexol following oral administration are substantially higher than corresponding concentrations of naltrexone.251,256 Following oral administration, the area under the serum concentration-time curve (AUC) for 6-β-naltrexol is 10-30 times greater than the AUC for naltrexone.71,251,252 Following single- or multiple-dose (i.e., once daily) oral administration of naltrexone hydrochloride 50 mg in healthy individuals, peak plasma concentrations of naltrexone and 6-β-naltrexol averaged 10.6-13.7 and 109-139 ng/mL, respectively.251,256

Plasma concentrations of naltrexone and 6-β-naltrexol increase with increasing doses of the drug.1,71,86,100 The AUC and peak plasma concentrations of naltrexone and 6-β-naltrexol increase proportionally with single naltrexone hydrochloride doses of 50-200 mg.1 Following oral administration of single doses of a 50-mg tablet, two 50-mg tablets, or 100 mg of a solution in a study in healthy individuals, mean peak plasma naltrexone concentrations were 8.6, 19.6, or 20.7 ng/mL, and mean peak plasma concentrations of 6-β-naltrexol were 99.3, 206.8, or 206.2 ng/mL, respectively.71

Little, if any, accumulation of naltrexone and/or 6-β-naltrexol appears to occur following chronic administration of the drug.1,62,70,71,72,74,101 Following chronic administration of naltrexone, plasma concentrations of 6-β-naltrexol are at least 40% higher than those following administration of a single dose of the drug;1,72 however, plasma concentrations of naltrexone and 6-β-naltrexol 24 hours after each dose of chronically administered drug are similar to concentrations 24 hours after a single dose of the drug in most patients.70,72

The onset of opiate antagonism following oral administration of naltrexone has been reported to be 15-30 minutes in a limited number of patients who had been receiving morphine chronically.25 Administration of a single 15-mg oral dose of naltrexone hydrochloride immediately following a single 30-mg subcutaneous dose of morphine has been reported to produce opiate antagonism that is prominent within 6 hours, maximal within 12 hours, and persists for at least 24 hours.25 The extent and duration of antagonist activity of naltrexone appear to be directly related to plasma and tissue concentrations of the drug.62 Plasma naltrexone concentrations of 2 ng/mL have been reported to be associated with an 87% blockade of the pharmacologic effects of a 25-mg IV dose of heroin.62,72 In one study in former opiate-dependent individuals receiving 100 mg of naltrexone hydrochloride daily and subsequently challenged with a 25-mg IV dose of heroin, the extent of blockade of the effects of heroin was 96, 87, and 47% at 24, 48, and 72 hours after naltrexone, respectively;62,72,103 corresponding plasma naltrexone concentrations were 2.4, 2, and 1.7 ng/mL, respectively.62,72,103

The duration of the opiate antagonist activity of naltrexone appears to be dose dependent1,7,12,102 and is longer than that of equipotent doses of naloxone.5,7,22,25,33,72 A single 50-mg oral dose of naltrexone hydrochloride effectively antagonizes the pharmacologic effects of 25 mg of IV heroin1,12,102 or subcutaneous morphine25,99 for up to 24 hours.1,25,99,102 Increasing the dose of naltrexone hydrochloride to 100 or 150 mg reportedly antagonizes the effects of 25 mg of IV heroin for up to 481,7,12,68,72,74,102 or 72 hours,1,7,28,102 respectively.

Bioavailability of orally administered naltrexone is altered in individuals with hepatic impairment.1,252,253 Following oral administration of naltrexone in patients with compensated (Child-Pugh class A or B) or decompensated liver cirrhosis (Child-Pugh class C), naltrexone AUC values are fivefold or tenfold higher, respectively, than values in individuals with normal hepatic function.1 Although peak plasma concentrations of 6-β-naltrexol were delayed in patients with hepatic impairment, systemic exposure to the metabolite in these patients was not altered substantially compared with that in healthy individuals.252,253

Following IM administration of naltrexone extended-release injection, the drug is released slowly and gradually from the microspheres by diffusion and erosion as the polylactide co-glycolide polymer degrades.247,249,251,252 Following IM administration of naltrexone 380 mg, peak plasma naltrexone concentrations of 12.9 ng/mL occur in 2-3 days (there is a transient initial peak 2 hours after injection); plasma concentrations start to decline after 14 days but remain detectable for 1 month or longer.247,251,252 Following IM administration of naltrexone 380 mg, peak plasma concentrations of 6-β-naltrexol (the major metabolite of naltrexone) generally occur in 3 days.251 Exposure to 6-β-naltrexol is about twofold higher than the corresponding naltrexone exposure.251 Following administration of a single IM dose of naltrexone 380 mg, total naltrexone exposure is threefold to fourfold higher and 6-β-naltrexol exposure is 3.4-fold lower than exposure following oral administration of naltrexone 50 mg daily for 28 days.247,251 Steady-state plasma concentrations of naltrexone and 6-β-naltrexol are attained by the end of the dosing interval after the first injection.247,251 Minimal accumulation of naltrexone and/or 6-β-naltrexol appears to occur following repeated IM administration.247,251

Following IM administration of naltrexone extended-release injection, plasma concentrations of naltrexone and 6-β-naltrexol achieved in individuals with mild to moderate hepatic impairment (Child-Pugh class A and B) are similar to those in healthy individuals with normal hepatic function.247,252

Distribution

Naltrexone hydrochloride is widely distributed throughout the body,69,75 but considerable interindividual variation in distribution parameters during the first 24 hours following a single oral dose has been reported.62,71,72 Following subcutaneous administration of radiolabeled drug in rats, the drug distributes into CSF within 30 minutes.75 In animals, CSF naltrexone concentrations are reported to be approximately 30% of concurrent peak plasma concentrations.75 The drug and its metabolites have been shown to distribute into saliva84,117 and erythrocytes84 following oral administration in humans. Following IV injection of a single 1-mg dose of the drug in healthy adults with normal renal and hepatic function, the volume of distribution of naltrexone was estimated to be 1350 L.1,102,105 The volume of distribution of the drug in former opiate-dependent individuals with normal renal and hepatic function reportedly averages 16.1 L/kg following oral administration of a single 100-mg dose2,67,72,74 and 14.2 L/kg following oral administration of 100 mg daily for at least 18 days.72,74

Naltrexone is approximately 21-28% protein bound.1,2,76,77,102,247

It is not known if naltrexone and/or its metabolites cross the placenta.217 Naltrexone and its major metabolite, 6-β-naltrexol, are distributed into human milk.247,254

Elimination

Plasma concentrations of naltrexone and 6-β-naltrexol, the major metabolite, appear to decline in a biphasic manner during the first 24 hours following a single oral dose or during chronic administration of the drug.2,67,72,102 Following oral administration of single or multiple doses of naltrexone hydrochloride, the plasma half-lives of naltrexone1,71,72,101,102,104 and 6-β-naltrexol in the initial phase (t_½α) average 1.1-3.9 and 2.3-3.1 hours,72 respectively, and the plasma half-lives in the terminal phase (t_½β) average 9.7-10.372,74,101 and 11.4-16.8 hours,71,72,101,104 respectively. Plasma concentrations of naltrexone and 6-β-naltrexol have also been reported to decline in a triphasic manner2,67,72 following oral administration, with a terminal elimination half-life after the first 24 hours of 96 hours for naltrexone and 18 hours for 6-β-naltrexol, possibly resulting from initial distribution into body tissues and subsequent redistribution into systemic circulation.67,72

Naltrexone is metabolized in the liver principally by reduction of the 6-keto group of naltrexone to 6-β-naltrexol (6-β-hydroxynaltrexone).1,2,33,62,67,72,84,100,101,102,103,104,105,106,107,109,112,113,115,116,117,118 Naltrexone also undergoes metabolism by catechol- O -methyl transferase (COMT) to form 2-hydroxy-3-methoxy-6-β-naltrexol (HMN)1,2,62,67,72,84,100,101,102,103,105,107,108,111,114,117,118 and 2-hydroxy-3-methoxynaltrexone.62,101,103,108 Several minor metabolites have also been identified, including noroxymorphone2,62,100,102,103 and 3-methoxy-6-β-naltrexol.100,105 Because oral but not IM administration of naltrexone results in substantial first-pass hepatic metabolism of the drug, 6-β-naltrexol concentrations following IM administration are substantially lower than concentrations of the metabolite obtained following oral administration.247,251,252 Naltrexone does not appear to inhibit or induce its own metabolism following chronic administration.72,79,101,102 Cytochrome P-450 (CYP) isoenzymes are not involved in the metabolism of naltrexone.247 Naltrexone and its metabolites undergo conjugation with glucuronic acid.2,62,101,103 The major fraction of total drug and metabolites in both plasma and urine consists of conjugated metabolites.2,67,72,100,102,103,104,105,116 The drug and its metabolites may undergo enterohepatic circulation.1,71

Metabolites of naltrexone may contribute to the opiate antagonist activity of the drug.1,72,102 Like naltrexone, 6-β-naltrexol is an essentially pure opiate antagonist,1,102 with a potency of 6-8% that of naltrexone in precipitating withdrawal symptoms in dogs physically dependent on morphine101,104,110,112 and 1.25-2% that of naltrexone in mice.106,110 Because of its weak affinity for opiate receptors, HMN may not contribute appreciably to the opiate antagonist activity of naltrexone;103 however, the in vivo opiate antagonist activity of HMN or 2-hydroxy-3-methoxynaltrexone has not been studied.2,101 Noroxymorphone, a minor metabolite of naltrexone, is a potent opiate agonist and may be responsible for the agonist activity (e.g., miosis) that occurs infrequently in individuals receiving naltrexone.102,103

Naltrexone and its metabolites (unconjugated and conjugated) are excreted principally in urine via glomerular filtration;1,102,257 6-β-naltrexol,1,62,67,72,101,102,105 conjugated 6-β-naltrexol,105 and conjugated naltrexone105 are also excreted via tubular secretion. Naltrexone may also undergo partial reabsorption by the renal tubules.72,100,101 Following single- or multiple-dose oral administration of naltrexone hydrochloride, respectively, approximately 38-60 or 70% of a dose has been recovered in urine, principally as 6-β-naltrexol (conjugated and unconjugated). 2,33,62,67,72,100,101,102,105,109,110,116 Most urinary excretion of naltrexone occurs within the first 4 hours after oral administration.72,104,105,107,109,114 Less than 2% of an orally administered dose is excreted unchanged in urine within 24 hours.1,33,102,104,109,116 Approximately 5-10,102,103,104,119 19-35,102,103,104,116 7-16,102,103,104,116 3.5-4.6,102,103,108 and 0.45%108 of an oral dose are excreted in urine as conjugated naltrexone, 6-β-naltrexol, conjugated 6-β-naltrexol, HMN, and 2-hydroxy-3-methoxynaltrexone, respectively, within 24 hours. Less than 5% of a dose is excreted in feces, principally as 6-β-naltrexol, within 24 hours following single- or multiple-dose oral administration of the drug.67,72,101,102,103 Following oral administration of 50 mg of radiolabeled naltrexone in one patient, approximately 93% of the radiolabeled dose was excreted within 133 hours; about 79 and 14% were excreted in urine and feces, respectively.119

Following oral administration of a single 100-mg dose in individuals formerly dependent on opiates and in healthy individuals, renal clearance of naltrexone and 6-β-naltrexol is reported to be 67-1371,67,71,72,102 and 283-318 mL/minute,1,67,71,72,102 respectively. Renal clearance of naltrexone and 6-β-naltrexol is reported to be 30 and 369 mL/minute, respectively, following administration of 100 mg daily for at least 18 days.67,72 Total body clearance of naltrexone following oral administration is reported to be 1.5 L/minute,1,71,102 while systemic clearance following IV administration reportedly is about 3.5 L/minute.1 Since systemic clearance exceeds hepatic blood flow, it appears that the drug also is metabolized at extrahepatic sites.1

Following IM administration of naltrexone extended-release injection, the half-life of naltrexone and 6-β-naltrexol is 5-10 days.247,251,252

Pharmacokinetics of parenterally administered naltrexone do not appear to be substantially altered in patients with mild renal impairment (creatinine clearance of 50-80 mL/minute).247

Limited data suggest that orally administered naltrexone is not removed by hemodialysis.255

Chemistry and Stability

Chemistry

Naltrexone is a synthetic opiate antagonist that is derived from thebaine.1 Naltrexone differs structurally from oxymorphone only in that the methyl group on the nitrogen atom of oxymorphone is replaced by a cyclopropylmethyl group.1,7,102 This structural modification results in naltrexone having essentially pure opiate antagonist activity, rather than the pure opiate agonist activity of oxymorphone.7,102 Naltrexone differs structurally from naloxone, another opiate antagonist, in that the allyl group on the nitrogen atom of naloxone is replaced by a cyclopropylmethyl group.1,4,7,102 This structural modification results in increased oral activity and duration of action of naltrexone compared with naloxone.7,25,29,102

Naltrexone hydrochloride occurs as white crystals1,2,10 having a bitter taste1,2,8,9 and has a solubility of 100 mg/mL in water at 25°C.1,2,217 The drug has a pK_a of 8.13 at 37°C.2,5

Commercially available naltrexone for extended-release injectable suspension (Vivitrol^®) contains naltrexone incorporated into microspheres composed of polylactide co-glycolide, a biodegradable polymer matrix.247,251,252 Following reconstitution with the diluent provided by the manufacturer, naltrexone suspension is milky white, does not contain clumps, and moves freely down the wall of the vial.247 The diluent provided by the manufacturer provides an appropriate vehicle for reconstitution and delivery of the drug and contains carboxymethylcellulose sodium, polysorbate 20, and sodium chloride in sterile water for injection.247

Stability

Naltrexone hydrochloride tablets should be stored in well-closed containers at 15-30°C.217

The entire dose pack containing naltrexone for extended-release injectable suspension should be refrigerated at 2-8°C; the dose pack can be stored at room temperature (i.e., room temperatures not exceeding 25°C) for up to 7 days.247 Storage at temperatures above 25°C or freezing should be avoided.247

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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