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Center for Substance Abuse Treatment. Incorporating Alcohol Pharmacotherapies Into Medical Practice. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2009. (Treatment Improvement Protocol (TIP) Series, No. 49.)

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Incorporating Alcohol Pharmacotherapies Into Medical Practice.

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Chapter 5—Extended-Release Injectable Naltrexone

Extended-Release Injectable Naltrexone At a Glance

Chemical name: Naltrexone for extended-release injectable suspension.

Trade name: Vivitrol®.

U.S. distributor: Alkermes, Inc., Cambridge, MA (manufacturer); Cephalon, Inc., Frazer, PA (distributor).

U.S. Food and Drug Administration approval to treat alcohol dependence: 2006.

Dosage/How taken: 380 mg intramuscular injection once every 4 weeks.

How supplied: Single-use cartons, containing one 380 mg vial of Vivitrol microspheres, one vial containing 4 mL (to deliver 3.4 mL) diluent for the suspension of Vivitrol, one 5 mL prepackaged syringe, one 20-gauge ½-inch needle, and two 20-gauge 1½-inch needles.

Storage: Store entire dose pack in refrigerator (2–8° C, 36–46° F); store unrefrigerated Vivitrol at temperatures not exceeding 25° C (77° F) for no more than 7 days before administration; do not freeze.

What Is Extended-Release Injectable Naltrexone?

Extended-release injectable naltrexone is a microsphere formulation of the opioid antagonist (blocker) medication naltrexone. It is administered by intramuscular (IM) gluteal injection once a month. The extended-release injectable form helps address patient noncompliance, which can limit the effectiveness of oral naltrexone (Volpicelli et al., 1997).

Brief History of Development

Interest existed in developing an injectable, long-acting naltrexone formulation for many years. Various long-acting naltrexone formulations were studied, but there was particular interest in the polylactide (Nuwayser, DeRoo, Balskovich, & Tsuk, 1990) and polylactide glycolide (PLG) polymer (Sharon & Wise, 1981). These polymers are prepared from naturally occurring sugar acids (lactic acid and glycolic acid), are known to be safe, and are used widely in human and veterinary medicine (e.g., in absorbable sutures and biodegradable orthopedic screws). The U.S. Food and Drug Administration (FDA) approved Alkermes' PLG polymer formulation of extended-release injectable naltrexone for treating alcohol dependence in April 2006.


Some behavioral effects of alcohol are caused by alcohol acting to release endogenous opioid neurotransmitters (e.g., endorphins, enkephalins, dynorphins) that bind to opiate receptors in the brain. Opioid antagonists, such as naltrexone, bind to opiate receptors and block the action of both opioid medications and opiate neurotransmitters.

The injectable naltrexone plasma concentration peaks approximately 2 hours after IM injection followed by a second peak approximately 2 to 3 days later. Beginning approximately 7 days after dosing, plasma concentrations slowly decline, maintaining a therapeutic naltrexone blood level over 4 weeks and avoiding daily peaks and troughs that occur with oral naltrexone. Steady state is reached at the end of the dosing interval following the first injection.

Unlike oral naltrexone, injectable naltrexone does not undergo first-pass metabolism in the liver. As a consequence, the total monthly dose of naltrexone administered is considerably less for extended-released (380 mg) compared with oral naltrexone (1,500 mg). Therefore, the peak concentration of the drug to which the liver is exposed is substantially less for injectable naltrexone than for oral naltrexone. Because naltrexone-induced hepatotoxicity is dose dependent, injectable naltrexone would be expected to show less hepatotoxicity than the oral form; however, a direct comparison of relative hepatotoxicity of the two medications has not yet been performed.

Why Use Extended-Release Injectable Naltrexone?


Findings on the efficacy of naltrexone in general to treat alcohol use disorders (AUDs) are briefly discussed in Chapter 4. More detailed information is included in the TIP's online annotated bibliography and literature review at http://www.kap.samhsa.gov. Garbutt and colleagues (2005) conducted a 6-month, randomized clinical trial of injectable naltrexone to assess its tolerability and efficacy. A group of patients receiving IM injection of 380 mg of injectable naltrexone (along with psychosocial support) had a 25-percent decrease in the event rate of heavy drinking days compared with those receiving placebo. Patients receiving a lower dose (190 mg) of injectable naltrexone also had a significant decrease (17 percent) in the event rate of heavy drinking days compared with those receiving placebo.

The FDA Center for Drug Evaluation and Research (CDER) analysis of the study data concluded that injectable naltrexone is effective only in those who were abstinent at baseline. CDER's analysis emphasized the proportion of patients who did not relapse to heavy drinking (FDA CDER, personal communication, 2008). O'Malley and colleagues (2007) conducted a secondary analysis of outcomes from the Garbutt study to determine whether patients with lead-in abstinence of 4 or more days also experienced particularly good treatment outcomes—a practical issue in U.S. detoxification settings, where detoxification commonly takes 4 days. They found that injectable naltrexone prolongs abstinence and reduces both the number of drinking days and the number of heavy drinking days in patients who are abstinent for as few as 4 days before starting treatment.

The online literature review provides more detailed information on these and other efficacy studies.

Enhanced Medication Compliance

A major benefit of using an extended-release formulation in the treatment of AUDs is decreased concern about compliance with daily administration, thus ensuring efficacy of naltrexone delivery and therapeutic effect. In a randomized, double-blind, clinical trial, there were no differences in drinking outcomes in 175 patients with alcohol dependence assigned to minimal psychosocial treatment and treated with either oral naltrexone or placebo (Chick et al., 2000). However, when only those subjects demonstrating greater than 80-percent medication compliance were included in the analysis, oral naltrexone was found to be effective.

The importance of medication compliance is further supported by a clinical trial that compared oral naltrexone with placebo in 97 individuals with alcohol dependence receiving weekly one-on-one counseling. Among individuals who were treatment compliant, those receiving oral naltrexone reported fewer episodes of heavy drinking (14 percent vs. 52 percent) and had fewer drinking days (2.8 percent vs. 11 percent) than those receiving placebo, whereas the drinking outcomes in the noncompliant individuals did not differ from individuals who received placebo (Volpicelli et al., 1997).


Injectable naltrexone appears to be well tolerated, with a side effects profile similar to that of oral naltrexone (with the exception of injection-site reactions). Like oral naltrexone, the injectable formulation carries a black-box warning regarding liver toxicity (see Chapter 4, Safety). However, because of its lack of first-pass metabolism, injectable naltrexone significantly reduces liver exposure to the drug, reducing the risk of potential liver toxicity.

How Is Extended-Release Injectable Naltrexone Used?

Treatment with injectable naltrexone should be part of a management program that provides patient education, addresses the psychological and social problems of patients, and encourages attendance at 12-Step or mutual-help meetings or other community support.

Before initiating treatment with injectable naltrexone, healthcare practitioners should do the following:

  • Conduct a physical examination
  • Determine liver function (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma glutamyltransferase [GGT], and bilirubin)
  • Obtain toxicological screening tests.

Naltrexone is an opioid antagonist, so individuals who are opioid dependent may experience opioid withdrawal. Treatment with injectable naltrexone should not be initiated unless the patient is opioid free for 7 to 10 days (or at least 14 days for patients who have been taking methadone for more than 3 to 4 weeks), as determined by medical history or toxicological screening.

Patients being maintained on buprenorphine (Suboxone® or Subutex®) or methadone for the treatment of opioid dependence cannot undergo treatment with naltrexone. Before administering injectable naltrexone, physicians should advise patients of the unpleasant physical effects of opioid withdrawal that will result if patients are not completely detoxified from opioids. Injectable naltrexone is available through specialty pharmacies.

How To Administer

Injectable naltrexone should be administered only by a medical professional (e.g., physician, nurse, physician assistant) who can administer IM (gluteal) injections. Injectable naltrexone comes in a kit that contains a vial of naltrexone as a dry powder that must be reconstituted with a liquid diluent immediately before use. The kits must be refrigerated during storage but should be brought to room temperature 30 to 60 minutes before the injection. The reconstituted microspheres in solution must be mixed vigorously to prevent clumping, which can clog a needle during injection. A syringe and two needles are provided—one for mixing the microspheres with the diluent and one for injecting the suspension into the upper outer quadrant of the gluteal muscle. The medication is administered every 4 weeks. If a dose is delayed or missed, the next injection should be administered as soon as possible. However, it is not recommended that medication be readministered earlier than 4 weeks or at a higher dose than 380 mg.

Proper IM injection technique is essential. Serious injection site reactions, sometimes requiring extensive surgical debridement, have been observed with Vivitrol. CDER reports that these severe reactions may be more common if the product is inadvertently administered subcutaneously, rather than intramuscularly (FDA CDER, personal communication, 2008).

Side Effects, Contraindications, and Cautions

Exhibit 5-1 lists the most common side effects experienced by patients treated with injectable naltrexone. As when using oral naltrexone, patients should contact their physician if they experience signs or symptoms of liver disease (see Exhibit 4-6).

Exhibit 5-1 Extended-Release Injectable Naltrexone Side Effects

Injection site reactions (sometimes severe)
Back pain
Upper abdominal pain
Decreased appetite

Injectable naltrexone carries the same contraindications as oral naltrexone (see Exhibit 4-3) plus those listed in Exhibit 5-2. There are no data on use of naltrexone in children or adolescents; treatment of these populations with naltrexone is not recommended.

Exhibit 5-2 Extended-Release Injectable Naltrexone Contraindications

Patient Condition or CircumstanceTreatment Recommendation
History of sensitivity to PLG, carboxymethylcellulose, or any components of the diluentDo not administer injectable naltrexone
Anticipated need for opioid analgesics within the next 30 daysDo not administer injectable naltrexone
Patient obesityDo not administer injectable naltrexone if patient's body mass precludes IM injection with the provided 1.5-inch needle
Inadvertent subcutaneous injection may cause a severe injection-site reaction

Injectable naltrexone should be used with many of the cautions applicable to oral naltrexone (see Exhibit 4-4) plus the cautions listed in Exhibit 5-3. Injectable naltrexone should be used cautiously with individuals with current or recent opioid dependence for two reasons. First, these individuals are at risk for overdose of opioids if they use large amounts of opioids to overcome naltrexone's opioid blockade (to feel the effects of the drugs). Second, naltrexone blockade can decrease tolerance for opioids, making a person more sensitive to their effects. If a person stops taking naltrexone, then takes what used to be a “normal” dose of opioids, overdose with respiratory depression can result.

Exhibit 5-3 Extended-Release Injectable Naltrexone Cautions

Patient Condition or CircumstanceTreatment Recommendation
Thrombocytopenia or coagulation disordersMonitor carefully for 24 hours after injection
Recent opioid dependenceExplain to the patient the risk of precipitated withdrawal if the patient has used opioids recently
Explain to the patient that the opioid-blocking effects last for at least 30 days and that the risks associated with a return to opioid use are significant

Patient Management

Possible adverse reactions are the same as those for oral naltrexone (see Exhibit 4-5). In addition, injection-site reactions are common adverse reactions to administration of injectable naltrexone. Some pain and tenderness at the injection site are common and are similar to those occurring after any IM injection. Usually, this pain resolves within several days. A small lump at the injection site frequently occurs and resolves over 2 to 4 weeks. However, patients should be instructed to seek immediate medical attention if skin at the injection site becomes painful, red, and swollen and does not improve within 1 week after the injection. As noted above, severe injection-site reactions are possible.

Patients taking injectable naltrexone also should be monitored for depression. The package label states:

In controlled clinical trials of Vivitrol, adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall, but were more common in patients treated with Vivitrol than in patients treated with placebo (1% vs. 0). In some cases, the suicidal thoughts or behavior occurred after study discontinuation, but were in the context of an episode of depression which began while the patient was on study drug. In the 24-week, placebo-controlled pivotal trial, adverse events involving depressed mood were reported by 10% of patients treated with Vivitrol 380 mg, as compared to 5% of patients treated with placebo injections.

Patients who take injectable naltrexone should undergo the same tests as those required for patients taking oral naltrexone (see Chapter 4, Patient Management).

Overdose should not be a concern for patients receiving injectable naltrexone because it is unlikely that patients will receive more than one IM injection per month.

Pain Management

As an opioid antagonist, injectable naltrexone blocks the effects of opioid analgesics. Pain management for patients taking naltrexone is discussed in Chapter 4. Pain management for patients using injectable naltrexone can be even more complicated because the medication is long acting. The package insert offers the following advice:

  • In an emergency situation in patients receiving Vivitrol, a suggested plan for pain management is regional analgesia, conscious sedation with a benzodiazepine, and use of non-opioid analgesics or general anesthesia.
  • In a situation requiring opioid analgesia, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged.
  • A rapidly acting opioid analgesic which minimizes the duration of respiratory depression is preferred. The amount of analgesic administered should be titrated to the needs of the patient. Non-receptor mediated actions may occur and should be expected (e.g., facial swelling, itching, generalized erythema, or bronchoconstriction), presumably due to histamine release.
  • Irrespective of the drug chosen to reverse Vivitrol blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation.

Patient Education

In addition to the general patient education guidelines discussed in Chapter 6, patient education specific to injectable naltrexone should precede use. Healthcare providers should ensure that patients understand the following:

  • Once naltrexone is injected, it is impossible to remove it from the body; if problems occur, the effects can last up to 30 days.
  • The onset of naltrexone's effects will probably occur within several hours although full effectiveness may not occur for 2 to 3 days following first injection. The duration of the effects appears to be 30 days.
  • Injectable naltrexone blocks the effects of opioids and opioidlike drugs (e.g., heroin, opioid analgesics, opioid-based antidiarrheals, and antitussives) for up to 30 days, which may complicate the treatment of pain if it occurs during this period. Patients should be assured that other options for analgesia exist.
  • Injectable naltrexone blocks low to moderate doses of opioids, but large doses of heroin or other opioids may lead to serious injury, coma, or death. For patients with a history of opioid use, the use of injectable naltrexone may lower tolerance for opioids, resulting in a greater sensitivity to lower doses of opioids after injectable naltrexone treatment is discontinued; this increased sensitivity could result in overdose and respiratory depression.
  • Injectable naltrexone is more likely to reduce drinking if it is used in conjunction with psychosocial interventions, such as specialized substance abuse treatment and community supports (e.g., counseling, 12-Step, or other mutual-help groups).
  • Patients should carry a safety ID card that indicates they are taking injectable naltrexone.

Who Is Appropriate for Treatment With Extended-Release Injectable Naltrexone?

This medication should be considered for individuals with alcohol dependence who have not responded to other pharmacological and behavioral treatments, in particular those who have problems with treatment adherence. The medication could be considered a first-line therapy for any patient who is alcohol dependent, interested in treatment, and not subject to the contraindications listed in Exhibit 4-3 and Exhibit 5-2. However, the monthly cost of injectable naltrexone is significantly higher than that of oral naltrexone and may not be a viable choice for many patients.

For optimal results with injectable naltrexone, candidates for treatment should meet several criteria:

  • They must be medically appropriate to receive naltrexone.
  • They should not be using opioids currently or have evidence of recent use.
  • They should not be anticipating surgery or have a condition, such as chronic pain, for which opioid analgesics may be required in the future.
  • They should not have severe liver or kidney disease, although naltrexone can be used cautiously in persons with mild to moderate hepatic impairment or mild renal insufficiency.
  • They should not have a condition, such as a bleeding disorder or obesity, that prevents them from receiving a deep IM injection.
  • They should have been abstinent for at least 4 days.
  • They should be motivated to maintain abstinence or to reduce their drinking.
  • They should be willing to participate in psychosocial substance abuse treatment such as counseling and support groups.

The consensus panel believes that the opioid antagonist properties of injectable naltrexone may make it a good treatment option for individuals who are seeking treatment for alcohol dependence and who are in recovery from co-occurring opioid use. However, no evidence for efficacy in this population is available, and injectable naltrexone has not been approved for the treatment of opioid dependence.

Treatment Duration and Discontinuing Extended-Release Injectable Naltrexone

Research has not yet clearly defined the optimal duration of treatment with injectable naltrexone. Healthcare providers may consider discontinuing injectable naltrexone once a patient has achieved stable abstinence from alcohol and has established a sound plan and support for ongoing recovery or if a patient is not compliant with the medication regimen. Like oral naltrexone, injectable naltrexone may be useful for short periods when a patient in stable recovery is at particular risk for relapse to problem alcohol use.

Patients discontinuing injectable naltrexone should be reminded that they should not take any opioid medications for at least 30 days from the date of their last injection. Patients also should be warned that after discontinuing treatment they may be more sensitive to the effects of opioid drugs (see Patient Education above).

Final Clinical Thoughts

Physicians may be concerned that the decreased frequency of required medical visits that comes with monthly medication will result in decreased use of medical and psychosocial services, making patients less likely to attend counseling, 12-Step, or mutual-help group meetings. Treatment with injectable naltrexone is new, but the experience of the consensus panel suggests that patients who return monthly for their injectable naltrexone continue to participate in treatment and to attend these groups.

Possible target patients include those who are unable to maintain medication adherence for some reason (e.g., poor memory) and those who would prefer not to have the burden of remembering to take medication daily.

Because injectable naltrexone is the newest form of a medication for the treatment of AUDs, the optimal situations for its use remain to be defined. However, it combines two attractive features: a medication for which there is substantial evidence for efficacy and a delivery system that eliminates daily medication compliance. As such, it represents an important addition to the list of medications for the treatment of alcohol dependence.


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