Brief History of Development

Naltrexone was first synthesized in 1963 by Endo Laboratories, which was acquired by DuPont in 1969. Naltrexone was initially developed to treat addiction to opioids and was approved by the U.S. Food and Drug Administration (FDA) for the treatment of addiction to drugs such as heroin, morphine, and oxycodone in 1984. DuPont branded naltrexone as Trexan^® and promoted it for the treatment of opioid addiction.

Animal studies conducted in the 1980s established that naltrexone decreased alcohol consumption through its action at the opiate receptors. Human clinical trials followed that confirmed that naltrexone, when used in combination with psychosocial therapy, could reduce cravings for alcohol and decrease relapse rates to alcohol use (O'Malley et al., 1992; Volpicelli, Alterman, Hayashida, & O'Brien, 1992; Volpicelli, Watson, King, Sherman, & O'Brien, 1995).

With FDA approval of naltrexone to treat AUDs in 1994, DuPont renamed the drug ReVia^®. ReVia and a generic version of naltrexone are now manufactured by Barr Pharmaceuticals. Mallinckrodt also manufactures naltrexone under the brand name Depade^®.

Pharmacology

Drinking alcohol enhances endogenous opioid activity. Several researchers who conducted animal studies observed that, under certain conditions, administration of small doses of morphine (an opioid agonist) increased consumption of alcohol in rats (Czirr, Hubbell, Milano, Frank, & Reid, 1987; Reid, Czirr, Bensinger, Hubbel, & Volanth, 1987; Reid, Delconte, Nichols, Bilsky, & Hubbell, 1991). Some researchers also reported that administration of opioid antagonists, including naloxone (which is similar to naltrexone), decreased alcohol consumption (Hubbell et al., 1986; Reid et al., 1991). It can be concluded that the rewarding effects of alcohol are mediated at least partly through the opiate system. Two teams of researchers, Woodson and Holman and Benjamin and colleagues (as cited in Spanagel & Zieglgansberger, 1997), reported that these rewarding effects are reduced when opioid antagonists block opiate receptor occupancy, thereby decreasing the amount of the neurotransmitter dopamine released from the nucleus accumbens. According to Spanagel and colleagues (as cited in Spanagel & Zieglgansberger, 1997), the mesolimbic dopamine reward system is important in initiating and maintaining the use of many substances of abuse, including alcohol, and may mediate both the positive effects of alcohol and the development of craving.

Oral naltrexone is rapidly and nearly totally absorbed in the gastrointestinal tract and is metabolized almost exclusively by the liver to the primary active metabolite, 6-β-naltrexol. Peak naltrexone plasma concentrations are reached within 1 hour of dosing. The long-acting properties of naltrexone are due primarily to 6-β-naltrexol, which has an elimination half-life of 13 hours. Naltrexone achieves therapeutic effectiveness rapidly following the initiation of oral dosing.

Efficacy

A meta-analysis (Bouza, Magro, Muñoz, & Amate, 2004) of 19 controlled clinical trials of naltrexone for treatment of AUDs (most of which were randomized and single or double blind) found that, compared with using placebo, short-term treatment (less than or equal to 12 weeks) with naltrexone significantly improved relapse rates during active treatment and a medication-free followup period. Short-term naltrexone treatment was also linked with a lower percentage of drinking days, fewer drinks per drinking day, longer times to relapse, more days of abstinence, and lower total alcohol consumption during treatment. Naltrexone may afford people with AUDs a measure of control that can prevent a slip from becoming a full-blown relapse. A European meta-analysis (Roozen et al., 2006) corroborated the positive findings of the Bouza and other studies.

A more thorough discussion of oral naltrexone efficacy studies is in the TIP's online literature review (http://www.kap.samhsa.gov).

Safety

Naltrexone has a low incidence of common adverse events. Naltrexone's FDA-approved label includes a black-box warning regarding hepatotoxicity, although these reversible effects tend to be associated with much higher doses than those used in routine clinical practice (e.g., 300 mg/day or more) and tend to occur only after a patient is on these high doses for extended periods.

As an opioid antagonist, naltrexone competitively displaces opioid medications from their binding sites, precipitating withdrawal. Healthcare providers must ensure that patients have been fully withdrawn from all opioids before considering therapy with naltrexone.

Initiating Treatment With Oral Naltrexone

FDA labeling recommends that treatment with naltrexone not begin until signs and symptoms of acute alcohol withdrawal have subsided. At least 3 days of abstinence are usually recommended, with as many as 7 days if possible. Patients may experience fewer medication side effects (particularly nausea) if they are abstinent from alcohol when they begin treatment with naltrexone. However, it is safe for patients to begin taking naltrexone during medically supervised withdrawal or if they are actively drinking.

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

• Conduct a medical evaluation that includes a physical exam, psychosocial assessment, and laboratory testing, including toxicological screening and liver function testing to establish suitability for medication and to establish a baseline for comparison
• Discuss the risks of naltrexone use during pregnancy and advise women of childbearing age to use birth control while taking naltrexone
• Ensure that patients are not regular users of opioids (illicit drugs, opioid maintenance medications, or opioid pain medications) to avoid precipitating withdrawal
• Strongly caution patients of the unpleasant physical effects of opioid withdrawal that will result if patients are not completely detoxified from opioids.

Dosage

Exhibit 4-1 summarizes dosage information for oral naltrexone. Naltrexone's duration of action (which is greater than 24 hours) allows a variety of flexible dosing schedules. Although 50 mg of naltrexone is currently the FDA recommended daily dose for treating AUDs, evidence from an open-label, small-scale trial suggested that higher doses (up to 150 mg/day) may be effective in reducing alcohol consumption in patients with complicated conditions (Oslin et al., 1999). Recent results from the large, multisite Combining Medications and Behavioral Interventions (COMBINE) study suggest that 100 mg naltrexone in combination with a brief medical management intervention is efficacious and well tolerated in patients dependent on alcohol (Anton et al., 2006). Mean adherence (the ratio of pills taken from returned blistercard pack counts to those prescribed throughout 16 weeks of treatment) for this higher naltrexone dose was more than 85 percent, and only 12 percent of patients required a dose reduction.

Side Effects, Contraindications, and Cautions

An attractive feature of naltrexone for treating patients who are alcohol dependent is that, like disulfiram and acamprosate, the medication has virtually no abuse potential and patients do not develop tolerance for its efficacy. Side effects are generally mild and often diminish over time (Exhibit 4-2), although less common reactions and some potentially serious reactions have been reported (Exhibit 4-3). Nausea is one of the most frequently reported side effects. One study (O'Malley, Krishnan-Sarin, Farren, & O'Connor, 2000) suggests that women may be particularly susceptible to this side effect, which the authors argue supports the use of risk-minimizing strategies, such as gradual dosing starting with a lower dose, requiring abstinence for a specific amount of time before starting naltrexone, and providing support and supervision to help patients cope with nausea until it subsides. However, in clinical studies side effects were rarely cited by patients as reasons for discontinuing treatment with naltrexone.

Data on safety and effectiveness with adolescents are limited. The results of a recent small, open-label pilot study suggest that naltrexone is well tolerated in adolescents seeking treatment and may reduce alcohol consumption and craving (Deas, May, Randall, Johnson, & Anton, 2005). However, additional work is needed before widespread naltrexone use in this population can be recommended.

Exhibit 4-4 lists situations in which use of naltrexone may require careful consideration or monitoring. Naltrexone is considered FDA pregnancy category C, meaning its effects on the fetus are unknown. Women of childbearing age should be informed of this and counseled to use effective birth control when sexually active. Some clinicians may choose to obtain a pregnancy test before starting naltrexone and whenever pregnancy is suspected. If a patient becomes pregnant while using naltrexone, the clinician and patient should decide whether to continue the medication, given the potential risks and benefits.

Patient Management

Exhibit 4-5 lists adverse reactions and their management. Patients should call their physician if they experience any signs or symptoms of liver disease. Exhibit 4-6 lists symptoms of liver disease.

Exhibit 4-7 lists interactions between naltrexone and other drugs.

The consensus panel recommends that liver function tests (i.e., ALT, AST, gamma glutamyltransferase, bilirubin) be performed before naltrexone treatment begins and at intervals thereafter. In healthy patients without liver disease, typical intervals can be 1, 3, and 6 months, then yearly thereafter. Liver function tests should be performed more frequently if baseline liver function test results are high, there is a history of hepatic disease, a potential hepatotoxic medication is also prescribed, or the patient is taking doses higher than 50 mg/day. Naltrexone should be used cautiously in patients whose serum aminotransferase results are greater than five times the upper limit of normal.

A careful drug use history and urine toxicological screening should be used to confirm abstinence from opioids, including prescribed pain medications, and a lack of opioid dependence before initiating treatment. A comprehensive urine test should be used to measure methadone and other opioids. However, urine testing can be subject to error because typical urine screening tests may not cover all opioids and samples can be tampered with to affect the results.

Patient Education

In addition to the general patient education guidelines discussed in Chapter 6, education about naltrexone should precede its use. Patients should be informed of the following:

• The effects of naltrexone on the fetus are unknown, so women who are pregnant or think they may be pregnant should inform their physician.
• The symptoms of protracted alcohol withdrawal (e.g., sleep disturbance) may overlap with side effects of naltrexone; patients should be reassured that symptoms typically improve with time.
• Naltrexone blocks the effects of opioids in prescription drugs such as pain relievers (e.g., morphine, oxycodone) and antidiarrheal and antitussive medications. Physicians should inform patients about other options for pain relief.
• Administering opioids to overcome naltrexone's blockade of the opiate receptors increases the risk of overdose, respiratory arrest, coma, and death.
• After taking naltrexone for some time and then stopping it, patients may be more sensitive to lower doses of opioids and thus risk overdose if they take opioids.
• Patients should continue to take naltrexone if they slip and return to drinking because it may help limit the severity of relapse.
• Participation in psychosocial interventions (e.g., cognitive-behavioral or other specialized treatment) and 12-Step or other mutual-help groups can increase the effectiveness of therapy with naltrexone.
• Patients should carry a medical alert card that indicates they are taking naltrexone and lists the physician or institution to contact in an emergency.

Patients Who Are Motivated or Monitored

A study by Volpicelli and colleagues (1997) concluded that patient compliance with naltrexone dosing is associated with treatment retention and positive treatment outcomes. As a result, it is important that either the patient be highly motivated for treatment or a medication monitoring plan be used to encourage naltrexone use if the patient is not highly motivated. To maximize compliance, physicians should observe dosing or encourage a family member or significant other to monitor medication use, especially at the beginning of treatment with naltrexone. Strategies such as incentives and feedback on medication compliance have been incorporated into treatment planning to enhance compliance. After the patient's motivation has increased and he or she feels better and stronger, medication monitoring may no longer be needed.

Patients Who Are Abstinent From Opioids

Naltrexone is an opioid antagonist; patients who are using opioids, being maintained on opioid replacement therapy, or anticipating surgery or dental work that will require opioid analgesics are not good candidates for treatment with naltrexone. Naltrexone's opioid antagonist properties may make it a particularly good treatment option for individuals with a history of opioid abuse/dependence who are seeking treatment for AUDs because naltrexone will reduce the reinforcing effects of and curb cravings for both opioids and alcohol.

Patients With Intense Alcohol Craving

Patients with intense alcohol cravings during treatment may experience greater medication benefit than patients with low levels of alcohol craving (Monterosso et al., 2001). Also, patients with more somatic complaints may have better outcomes when treated with naltrexone compared with patients with less physical distress. Both human laboratory studies and clinical trials have suggested that patients with a family history of alcohol dependence may benefit more from naltrexone treatment than patients without a family history of alcohol dependence (Monterosso et al., 2001; Rubio et al., 2005).