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.

Pharmacology

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.

Efficacy

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.

Safety

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 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).

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.

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.

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.

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.