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.)
FDA approved a REMS for naltrexone to ensure that the benefits 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 ().
Uses for Naltrexone
Used 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 who were formerly physically dependent on opiates and who have successfully undergone detoxification1 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
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
Management of alcohol dependence in conjunction with a behavior modification program1 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
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 Dosage and Administration
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
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
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
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.)
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
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
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
Available for oral administration as naltrexone hydrochloride; dosage expressed in terms of the salt.1
Available for IM administration as naltrexone.247
Induction of Therapy for Opiate CessationOral
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
Maintenance Therapy for Opiate CessationOral
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
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
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
The following regimen of naltrexone, given in conjunction with clonidine to attenuate withdrawal manifestations, has been studied.38
Day of Detoxification Therapy
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
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
Administered only as needed to reduce signs and symptoms of withdrawal38
10 mg 3 times daily38
Administered only as needed to reduce signs and symptoms of withdrawal38
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
Dosage adjustment not needed in patients with mild to moderate (Child-Pugh class A or B) hepatic impairment.247
Dosage adjustment not needed in patients with mild renal impairment (Clcr of 50–80 mL/minute).247
Cautions for Naltrexone
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
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
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
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
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
Individuals with Bleeding Disorders
Use IM preparation with caution in individuals with thrombocytopenia or a coagulation disorder (e.g., hemophilia).247
Common Adverse Effects
Interactions for Naltrexone
Specific Drugs and Laboratory Tests
Drug or Test
Both drugs are potentially hepatotoxic1
Manufacturers recommend concomitant use only if the potential benefits justify the possible risks1
Avoid use of opiate-containing preparations during naltrexone therapy when alternative nonopiate therapy is available1
Tests, urinary opiates
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
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
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 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
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
Plasma Protein Binding
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 84 100 101 102 103 104 105 106 107 109 112 113 115 116 117 118 other minor metabolites are formed.1 2 62 67 72 84 100 101 102 103 105 107 108 111 114 117 118
Because oral but not IM administration of naltrexone results in substantial first-pass hepatic metabolism, 6-β-naltrexol concentrations following IM administration are substantially lower than concentrations achieved following oral administration.247 251 252
Following IM administration, pharmacokinetics not altered in patients with mild renal impairment (Clcr of 50–80 mL/minute).247
After mixing with diluent, use immediately.247
In patients who have received single or repeated large doses of 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
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
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 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
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 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
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 By competitively binding to opiate receptors, naltrexone 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
Advice to Patients
Importance of patient reading the medication guide prior to initiating parenteral naltrexone therapy and before each injection of the drug.258 Importance of ensuring that patient understands risks.260
Importance of patients informing clinicians that they are taking naltrexone.1 247 258 Advise patients to carry a medical identification card that can alert clinicians to this fact in an emergency situation.1 247 258
Importance of contacting a clinician 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) occur.1 247 258 Discontinue oral naltrexone.1
Importance of not self-administering opiates (e.g., heroin) during naltrexone therapy, since self-administration of small doses of opiates in an attempt to overcome the antagonist activity of naltrexone will not result in any pharmacologic effect and large doses may result in serious consequences (e.g., coma, death).1 102 247 258
Advise patients receiving parenteral naltrexone to monitor the injection site and to contact 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 Advise patients to notify 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
Advise patients that they may need to be referred to a surgeon for worsening injection site reactions.257
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
For injectable suspension, extended-release, for IM use
Vivitrol (available as a dose pack containing naltrexone microspheres, diluent, needles)
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.
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