Naltrexone

Class: Opiate Antagonists
VA Class: CN102
Chemical Name: 17-(Cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one
Molecular Formula: C₂₀H₂₃NO₄C₂₀H₂₃NO₄•HCl
CAS Number: 16590-41-3
Brands: ReVia, Vivitrol

• Hepatic Effects


• 
  

  Possible dose-related hepatotoxicity.^{1 102 226 228 247} Margin between therapeutic and hepatotoxic dosages may be less than fivefold; hepatotoxicity not apparent at usual dosages.^{1 102 247} (See Hepatic Effects under Cautions.)

  
  


• 
  

  Contraindicated in patients with acute hepatitis or liver failure;^{1 102 247} carefully weigh potential benefits against possible hepatotoxic risks in patients with active liver disease.^{1 247}

  
  


• 
  

  Instruct patients to discontinue naltrexone and contact a clinician if manifestations of acute hepatitis occur.^{1 247} (See Advice to Patients.)

  
  

REMS:

FDA approved a REMS for naltrexone to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of naltrexone and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Essentially a pure opiate antagonist.^{1 2 3 7 17 23 102}

Uses for Naltrexone

Opiate Dependence

Used as an adjunct to a medically supervised behavior modification program^{1 35 99 102 147 160 161 162 163 164 165 166 170} in the maintenance of opiate cessation (opiate-free state) in individuals who were formerly physically dependent on opiates and who have successfully undergone detoxification^{1 14 35 102 143 147 158 162 163 164 165} (designated an orphan drug by FDA for this use).²¹⁷

Behavior modification is an integral component in maintaining opiate cessation; behavior modification programs involve supervised programs of counseling, psychologic support and therapy, education, and changes in life-style (social rehabilitation).^{1 2 35 37 102 143 147 159 160 162 170 189 192 193 204}

May diminish or eliminate opiate-seeking behavior by blocking opiate euphoria and by preventing the conditioned abstinence syndrome (i.e., heightened sensitivity to stimuli, abnormal autonomic responses, dysphoria, intense opiate craving) that occurs following opiate withdrawal.^{1 2 27 102 158 190 191}

Efficacy in maintaining long-term cessation appears to be low;^{2 11 14 15 42 123 125 135 161 182 203} poor compliance appears to be the major limiting factor.^{1 2 8 13 42 99 182 204} Because noncompliance with naltrexone is not associated with unpleasant symptoms of withdrawal, compliance depends more on voluntary efforts; successful cessation may be more likely in highly motivated individuals.^{1 2 8 13 15 35 36 99 102 130 147 162 163 167 172}

Has 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 (e.g., naltrexone and/or naloxone) to shorten the time period of detoxification.²⁴⁶

Ultrarapid detoxification is similar but involves the administration of opiate antagonists while the patient is sedated or under general anesthesia.²⁴⁶ Consider the risk of adverse respiratory and cardiovascular effects associated with this procedure, as well as the costs of general anesthesia and hospitalization.²⁴⁶

Alcohol Dependence

Management of alcohol dependence in conjunction with a behavior modification program^{1 232 233 234 235 236 237 247} involving supervised programs of counseling, psychologic support and therapy, and education and changes in life-style (social rehabilitation).^{1 232 238}

Used IM in individuals who are able to abstain from alcohol in an outpatient setting and are abstinent when treatment is initiated.^{247 249}

Behavior modification is an integral component in maintaining alcohol cessation; naltrexone 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}

When used in conjunction with behavior modification, 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}

Naltrexone is not uniformly effective; the expected effect is a modest improvement in the outcome of conventional therapy.^{1 232 233 244 245}

Naltrexone Dosage and Administration

General

REMS for Parenteral Naltrexone

• 
  

  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 is to inform patients about serious risks associated with parenteral naltrexone.²⁵⁹ (See Advice to Patients and also see Cautions.)

  
  

Verification of Opiate Abstinence Prior to Initiation of Therapy

• 
  

  Patients who are physically dependent on opiates should complete detoxification prior to initiation of naltrexone therapy.^{1 102}

  
  


• 
  

  Manufacturers recommend that at least 7–10 days elapse between discontinuance of opiates and initiation of naltrexone therapy because of the risk of precipitating opiate withdrawal (see Accidental Precipitation of Withdrawal under Cautions.)^{1 102} This waiting period may vary depending on the dose and duration of action of the opiate;^{1 102 121 162} allow 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

  
  


• 
  

  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}

  
  


• 
  

  In addition to patient verification of abstinence from opiates, perform urinalysis after the minimum 7- to 10-day waiting period, but prior to administration of naltrexone, to confirm the absence of opiates.^{1 102} If it is uncertain whether the patient is opiate free, perform a naloxone challenge test prior to administering naltrexone.^{1 102 247}

  
  

Naloxone Challenge Test

• 
  

  Perform test 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}

  
  


• 
  

  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}

  
  


• 
  

  Do not attempt naltrexone therapy if signs and/or symptoms of opiate withdrawal (e.g., nasal stuffiness, rhinorrhea, lacrimation, yawning, sweating, tremor, abdominal cramps, vomiting, piloerection, myalgia, skin crawling) are evident following administration of the naloxone challenge test;^{1 102} instead, repeat the naloxone challenge test in 24 hours.¹

  
  


• 
  

  Naloxone may be administered IV or sub-Q in the challenge test.¹

  
  


• 
  

  IV challenge test: Draw 0.8 mg of naloxone hydrochloride into a syringe.¹ Administer 0.2 mg initially; while the needle remains in the vein observe the patient for 30 seconds¹⁹⁶ for evidence of opiate withdrawal.¹ Alternatively, some clinicians recommend 15 minutes for the period of observation. If no evidence of withdrawal is observed, inject the remaining 0.6-mg dose and observe the patient for an additional 20 minutes for evidence of withdrawal.¹

  
  


• 
  

  Sub-Q challenge test: Draw 0.8 mg of naloxone hydrochloride into a syringe.¹ Inject the entire 0.8-mg dose and observe the patient for 20 minutes for evidence of opiate withdrawal.¹

  
  


• 
  

  If evidence of opiate withdrawal is present, delay naltrexone therapy and repeat the naloxone challenge test in 24 hours with the 0.8-mg dose; repeat the test every 24 hours until results are negative.^{1 196}

  
  


• 
  

  If it is uncertain whether the patient is opiate free or is undergoing opiate withdrawal following an initial test, repeat the naloxone challenge test with a 1.6-mg IV dose.¹

  
  

Administration

Administer orally or by IM injection.^{1 102 247}

Do not administer parenteral preparation by IV or sub-Q injection; do not administer into fatty tissue.^{247 257}

Oral Administration

Administer orally;^{1 102} minimize adverse GI effects by taking with food¹²³ or antacids¹³¹ or after meals.^{9 102 131 143}

Patients should take naltrexone as directed and not attempt self-administration of opiates during therapy with the drug.^{1 102} (See Risks Associated with Self-administration of Opiates During Naltrexone Therapy under Cautions.)

IM Administration

IM preparation may be used in individuals who are able to abstain from alcohol in an outpatient setting and are abstinent when treatment is initiated.^{247 249}

Administer by deep IM injection into the upper outer quadrant of the gluteal muscle every 4 weeks (or once a month); alternate buttocks for subsequent injections.²⁴⁷

Administer only with needle and other components of dose pack supplied by manufacturer.²⁴⁷

Use aspiration to avoid inadvertent injection into a blood vessel.^{247 257}

Do not administer by IV or sub-Q injection; do not inadvertently administer into fatty tissue.^{247 257} Inadvertent sub-Q injection may increase likelihood of severe injection site reactions.²⁴⁷ (See Local Reactions under Cautions.)

Evaluate the patient's body habitus prior to each injection to ensure that the 1.5-inch needle supplied by the manufacturer is adequate for gluteal IM injection in that patient.²⁴⁷ Consider alternative treatment for any patient whose body habitus (i.e., gluteal fat thickness) precludes IM injection with the provided needle.^{247 261}

Reconstitution

Consult manufacturer’s labeling for instructions for using components of dose pack for reconstitution.²⁴⁷

Allow dose pack to reach room temperature before reconstituting.²⁴⁷

Reconstitute vial labeled as containing 380 mg of naltrexone extended-release microspheres with 3.4 mL of diluent; shake vigorously for 1 minute.²⁴⁷ Use only the diluent supplied by the manufacturer.²⁴⁷ Administer immediately.²⁴⁷

Dosage

Available for oral administration as naltrexone hydrochloride; dosage expressed in terms of the salt.¹

Available for IM administration as naltrexone.²⁴⁷

Adults

Opiate Dependence

Induction of Therapy for Opiate Cessation

Oral

Initiate induction regimen following completion of opiate detoxification and verification that the patient is free of opiates.¹⁰² (See General under Dosage and Administration.)

Initially, 25 mg; if no evidence of withdrawal is present, begin 50 mg daily.¹

Alternatively, some clinicians have administered 12.5 mg initially, followed by incremental increases of 12.5 mg daily until the usual dosage of 50 mg daily has been achieved.^{62 99 123 196}

Maintenance Therapy for Opiate Cessation

Oral

50 mg daily following induction of therapy.^{1 2 11 24 25 28 99 102}

Alternatively, flexible dosing schedules have been suggested in an attempt to improve compliance.^{1 2 35 62 99 102 122 138 157 158 161 164 196} Administration of larger doses at longer intervals (e.g., 48–72 hours) may reduce opiate antagonist activity somewhat, but may improve compliance.^{1 102 121} Single doses >50 mg may increase risk of hepatic injury; weigh possible risks against probable benefits of flexible dosing.¹

• Flexible Naltrexone Hydrochloride Dosing Schedules for Maintenance Therapy for Opiate Cessation


• 
  

  50 mg daily Monday through Friday and 100 mg on Saturday^{1 102}

  
  


• 
  

  100 mg every other day^{1 102}

  
  


• 
  

  150 mg every third day^{1 102}

  
  


• 
  

  100 mg on Monday and Wednesday and 150 mg on Friday^{1 8 35 99 102 121 122 123 157 158 164}

  
  


• 
  

  150 mg on Monday and 200 mg on Thursday¹⁹⁶

  
  

Ingestion of the naltrexone dose generally should be observed in a clinic setting or by a responsible family member to ensure compliance, in which case, regimens requiring less frequent visits may be more acceptable to the patient.^{8 99 102 182 194 196}

Monitor patient compliance by random testing of urine for naltrexone and 6-β-naltrexol or for the presence of opiates.^{62 102 161}

Optimum duration of maintenance therapy not established;¹²¹ base on individual requirements and response.¹⁰²

In patients who discontinue naltrexone prematurely and then desire to resume therapy following a relapse to opiate abuse, perform urinalysis for the presence of opiates and, if necessary, a naloxone challenge test prior to resuming therapy.^{161 196} If there is evidence of opiate dependence, conduct detoxification prior to reinitiation of naltrexone therapy.^{102 161}

Opiate Detoxification†

Oral

Various dosage regimens have been used for rapid or ultrarapid detoxification† of opiate dependence.^{2 38 162 168 169 246}

The following regimen of naltrexone, given in conjunction with clonidine to attenuate withdrawal manifestations, has been studied.³⁸

Day of Detoxification Therapy	Clonidine Hydrochloride	Naltrexone Hydrochloride
Day 1	0.005 mg/kg initially; then titrated according to the severity of withdrawal and the adverse effects induced by clonidine2 38
Day 2	Administered every 4 hours to attenuate the withdrawal induced by naltrexone38	Administered every 4 hours; 1 mg initially; then increased in 1-mg increments during the daytime on day 2 38
Day 3	Administered every 4 hours to attenuate the withdrawal induced by naltrexone; highest mean dosage was 2.3 mg daily on day 338	Administered every 4 hours; dosage increased in 2-mg increments during the daytime on day 338
Day 4	Administered only as needed to reduce signs and symptoms of withdrawal38	10 mg 3 times daily38
Day 5	Administered only as needed to reduce signs and symptoms of withdrawal38	50 mg once daily2 38

Alcohol Dependence

Oral

50 mg once daily,^{1 234 237} following verification that the patient is free of opiates.¹ (See General under Dosage and Administration.)

Optimum duration of therapy not established;²³⁷ safety and efficacy established only in short-term (up to 12 weeks) studies.^{1 231 232 233 234 236 237}

IM

380 mg every 4 weeks or once a month following verification that the patient is free of opiates. ²⁴⁷ (See General under Dosage and Administration.)

If a dose is missed, reschedule administration with a health-care professional as soon as possible.²⁴⁷

Therapy may be initiated with parenteral preparation; not necessary to initiate therapy with oral naltrexone and then switch to parenteral preparation.²⁴⁷

Special Populations

Hepatic Impairment

Alcohol Dependence

IM

Dosage adjustment not needed in patients with mild to moderate (Child-Pugh class A or B) hepatic impairment.²⁴⁷

Renal Impairment

Alcohol Dependence

IM

Dosage adjustment not needed in patients with mild renal impairment (Cl_cr of 50–80 mL/minute).²⁴⁷

Cautions for Naltrexone

Contraindications

• 
  

  Patients receiving opiate agonists (except for emergency situations).^{1 102 247}

  
  


• 
  

  Nondetoxified patients physically dependent on opiates, including those receiving maintenance treatment with opiates (e.g., methadone).^{1 102 247}

  
  


• 
  

  Patients experiencing acute opiate withdrawal.^{1 102 247}

  
  


• 
  

  Patients who experience opiate withdrawal following administration of the naloxone challenge test or in patients in whom urinalysis for the presence of opiates is positive.^{1 102 247}

  
  


• 
  

  Patients with acute hepatitis or hepatic failure.^{1 247}

  
  


• 
  

  Patients with known hypersensitivity to the drug or any ingredient in the formulation.^{1 247} Not known whether cross-sensitivity exists between naltrexone and naloxone or phenanthrene-derivative opiate agonists (e.g., codeine, morphine, oxymorphone).¹

  
  

Warnings/Precautions

Warnings

Hepatic Effects

Possible dose-related hepatocellular injury, manifested as increases in serum hepatic enzyme concentrations.^{1 102 226 228 247} (See Boxed Warning.)

Manufacturers state that naltrexone-induced hepatocellular injury appears to be a direct toxic rather than an idiosyncratic effect.¹ Some clinicians suggest that liver function abnormalities may be caused by noroxymorphone, a minor metabolite of naltrexone that has opiate agonist activity.^{196 206}

Manufacturer of oral naltrexone recommends monitoring liver function at intervals deemed appropriate for the naltrexone dosage employed and the clinical status of the patient.¹

Local Reactions

IM injection associated with injection site reactions (e.g., tenderness, induration, pain, pruritus, ecchymosis, nodules, swelling) in most patients.²⁴⁷ Cellulitis,²⁴⁷ hematoma,²⁴⁷ abscess,²⁴⁷ sterile abscess,²⁴⁷ and necrosis²⁴⁷ also reported.²⁴⁷ Injection site reactions occur predominantly in females.²⁴⁷

Some reactions may be very severe, result in substantial scarring, or require surgery, including debridement of necrotic tissue.²⁴⁷ Inadvertent sub-Q injection may increase likelihood of a severe injection reaction.²⁴⁷

Patients should monitor the injection site and contact clinician if injection site reactions worsen or persist.^{257 258} (See Advice to Patients.) Promptly evaluate patients with signs of abscess, cellulitis, necrosis, or extensive swelling to determine if referral to a surgeon is warranted.²⁴⁷

Verification of Opiate Abstinence Prior to Initiation of Therapy

Naltrexone may precipitate mild to severe withdrawal in patients physically dependent on opiates.^{1 2 7 11 15 31 35 38 42 82 247}

To minimize the risk of precipitating signs and symptoms of withdrawal, instruct opiate-dependent individuals who are candidates for naltrexone therapy to remain free of opiates for a minimum of 7–10 days prior to initiating therapy with the drug.^{1 102 247}

Absence of opiates in urine is frequently insufficient evidence that a patient is free of opiates.^{1 102 247} If it is uncertain whether the patient is opiate free, perform a naloxone challenge test prior to administering naltrexone.^{1 102 247} (See Naloxone Challenge Test under Dosage and Administration.)

Risks Associated with Self-administration of Opiates During Naltrexone Therapy

Self-administration of large doses of opiates in an attempt to overcome the antagonist activity of naltrexone may produce signs and symptoms of acute opiate overdosage (e.g., respiratory arrest, circulatory collapse, death).^{1 247}

Signs and symptoms of opiate overdosage also may occur following administration of smaller doses of opiate agonists relatively long after the last naltrexone dose or in an amount that results in a longer duration of agonist activity than the antagonist activity of naltrexone and its metabolites.^{1 247}

Advise patients of the serious consequences of self-administration of opiates during naltrexone therapy.^{1 102 247} (See Advice to Patients.)

Eosinophilic Pneumonia

Eosinophilic pneumonia reported rarely in patients receiving parenteral naltrexone.²⁴⁷ Consider eosinophilic pneumonia in patients with pneumonia who have not responded to anti-infective therapy.²⁴⁷

General Precautions

Therapeutic Use of Opiates in Naltrexone-treated Patients

In an emergency situation when adequate analgesia can be achieved only 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} Whenever possible, use nonopiate analgesics, regional analgesia, conscious sedation with a benzodiazepine, or general anesthesia.^{1 102 247}

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

Respiratory depression produced by the opiate may be deeper and more prolonged.^{1 102} Patients may experience apparent nonopiate 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

Use of a short-acting opiate with minimal respiratory depression is preferable; adjust dosage of the opiate agonist carefully according to individual requirements and response.^{1 102} Closely monitor the patient in a setting equipped and staffed by health-care personnel appropriately trained in CPR.^{1 247}

Discontinue oral naltrexone ≥48 hours prior to elective surgical procedures requiring opiate analgesia.¹²¹

Avoid use of other opiate-agonist-containing preparations (e.g., those used for the management of cough or diarrhea) when alternative nonopiate therapy is available, since adequate therapeutic benefit may be difficult to achieve with an opiate.^{1 102}

Accidental Precipitation of Withdrawal

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 naltrexone ingestion and continued for up to 48 hours.^{1 31 102 124}

Suicide

Increased risk of suicide in substance abusers with or without depression;^{1 247} risk is not abated by naltrexone therapy.¹

Individuals with Bleeding Disorders

Use IM preparation with caution in individuals with thrombocytopenia or a coagulation disorder (e.g., hemophilia).²⁴⁷

Specific Populations

Pregnancy

Category C.^{1 102 247}

Not known whether naltrexone affects the duration of labor and delivery.^{1 102 247}

Lactation

Naltrexone and the active metabolite (6-β-naltrexol) are distributed into human milk.^{247 254} Discontinue nursing or the drug.²⁴⁷

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 102 121 247 248}

Hepatic Impairment

Contraindicated in patients with acute hepatitis or hepatic failure.^{1 102 247} (See Boxed Warning and see Hepatic Effects under Cautions.)

Use with caution in patients with hepatic impairment.¹ When administered orally, possible increased systemic exposure to the drug.¹

Renal Impairment

Use with caution in patients with moderate to severe renal impairment.^{1 247}

Common Adverse Effects

Treatment of opiate dependence: insomnia,¹ anxiety,¹ nervousness,¹ abdominal pain and cramps,¹ nausea,¹ vomiting,¹ fatigue,¹ joint and muscle pain,¹ headache.¹

Treatment of alcohol dependence: nausea,^{1 247} headache,^{1 247} dizziness,^{1 247} nervousness,¹ fatigue,¹ insomnia,^{1 247} vomiting,^{1 247} anxiety,^{1 247} somnolence,^{1 247} injection site reaction.^{247 257}

Interactions for Naltrexone

Specific Drugs and Laboratory Tests

Drug or Test	Interaction	Comments
Clonidine	Concomitant administration may reduce the duration of opiate withdrawal by decreasing opiate-induced postsynaptic supersensitivity38 168 230
Disulfiram	Both drugs are potentially hepatotoxic1	Manufacturers recommend concomitant use only if the potential benefits justify the possible risks1
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 pain1 102 247 Naltrexone can precipitate potentially severe opiate withdrawal1 102 247	Avoid use of opiate-containing preparations during naltrexone therapy when alternative nonopiate therapy is available1 Avoid use of naltrexone in patients receiving opiates or in nondetoxified patients physically dependent on opiates1 102 247
Phenothiazines (thioridazine)	Possible increased lethargy and somnolence1 220 221 222 237
Tests, urinary opiates	Possible interference with some enzymatic assays for opiates1 247 No interference reported with thin-layer (TLC), gas-liquid (GLC), or high-performance liquid (HPLC) chromatography assays for methadone or morphine1
Tests, urinary quinine	No interference reported with TLC, GLC, or HPLC methods1

Naltrexone Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely (about 96%) absorbed following oral administration,^{1 2 3 22 67 71 72 100 102 105} but undergoes extensive first-pass metabolism in the liver;^{1 2 3 33 62 71 102} only 5–40% reaches systemic circulation unchanged.^{1 2 67 71 72 74 102}

Peak plasma concentrations of naltrexone and the active metabolite (6-β-naltrexol) usually occur within 1 hour following oral administration.^{1 71 72}

Following IM administration of the extended-release injection, naltrexone is released slowly and gradually from the microspheres by diffusion and erosion as the polylactide co-glycolide polymer degrades.^{247 249 251 252} Peak plasma concentrations of naltrexone and the active metabolite (6-β-naltrexol) occur in about 2–3 days; ^{247 251 252} 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}

Following administration of a single IM dose of naltrexone 380 mg, total naltrexone exposure is three- 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}

Onset

Onset of opiate antagonism occurred 15–30 minutes following oral administration in a limited number of patients who had been receiving morphine chronically.²⁵

Decreases opiate craving within 3–5 weeks after start of oral naltrexone in individuals formerly dependent on opiates;^{42 66 158 160} reduction in opiate craving has occurred during the first week of therapy in some individuals, with further decreases occurring in subsequent weeks.^{102 182}

Duration

Duration of opiate antagonist activity appears to be dose dependent^{1 7 12 102} and is longer than that of equipotent doses of naloxone.^{5 7 22 25 33 72}

Special Populations

Changes in oral bioavailability appear to be related to severity of liver disease.¹ AUC increased 5- or 10-fold in patients with compensated or decompensated cirrhosis, respectively.¹

Following IM administration, plasma concentrations of naltrexone and 6-β-naltrexol 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

Extent

Widely distributed throughout the body;^{69 75} considerable interindividual variation in distribution parameters during the first 24 hours following a single oral dose.^{62 71 72}

Not known whether naltrexone and/or its metabolites cross the placenta.²¹⁷ Naltrexone and 6-β-naltrexol are distributed into human milk.^{247 254}

Plasma Protein Binding

Approximately 21–28%.^{1 2 76 77 102 247}

Elimination

Metabolism

Metabolized in the liver principally by reduction of the 6-keto group of naltrexone to an active metabolite, 6-β-naltrexol (6-β-hydroxynaltrexone); ^{1 2 33 62 67 72 84 100 101 102}