Oral Naltrexone At a Glance
Chemical name: Naltrexone hydrochloride (morphinan-6-one, 17-[cyclopropylmethyl]-4,5-epoxy-3,14-dihydroxy-[5α]).
Trade names: ReVia®; Depade®.
U.S. distributor: Barr Pharmaceuticals, Inc., Pomona, NY; Mallinckrodt, Inc., St. Louis, MO.
U.S. Food and Drug Administration approval to treat alcohol dependence: 1994.
Dosage/How taken: Tablet by mouth once daily.
How supplied: Bottles of 30 or 100 50 mg tablets (ReVia); bottles of 30 or 100 25, 50, and 100 mg tablets (Depade).
Storage: Keep out of reach of children; keep tightly closed in original container; store in a cool, dry place, away from excess heat and moisture (not in the bathroom or near a sink); discard when outdated or no longer needed.
What Is Oral Naltrexone?
Naltrexone hydrochloride is a relatively pure and long-lasting opioid antagonist. Oral naltrexone has been used to treat opioid dependence for many years and has been approved to treat alcohol use disorders (AUDs) since 1994. Naltrexone reduces both the rewarding effects of alcohol and craving for it.
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; ; ).
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 (; ; ). 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 ), 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 ), 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.
Why Use Oral Naltrexone?
Naltrexone appears to be effective for attenuating craving in people who are alcohol dependent (Monti et al., 1999, 2001). By blocking craving, naltrexone may enhance the ability of patients to abstain from drinking. By blocking the pleasure from alcohol, naltrexone also may reduce the amount of heavy drinking in those who do drink.
Efficacy
A meta-analysis () 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.
Oral Naltrexone Black-Box Warning
Naltrexone has the capacity to cause hepatocellular injury when given in excessive doses.
Naltrexone is contraindicated in acute hepatitis or liver failure, and its use in patients with active liver disease must be carefully considered in light of its hepatotoxic effects.
The margin of separation between the apparently safe dose of naltrexone and the dose causing hepatic injury appears to be only fivefold or less. Naltrexone does not appear to be a hepatotoxin at the recommended doses.
Patients should be warned of the risk of hepatic injury and advised to stop the use of naltrexone and seek medical attention if they experience symptoms of acute hepatitis.
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.
How Is Oral Naltrexone Used?
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.
Exhibit 4-1 Oral Naltrexone Dosages
| Initial dosage for most patients | 50 mg/day in a single tablet |
| Initial dosage for patients at risk of adverse events (e.g., women, younger patients, those with shorter abstinence) | 12.5 mg/day (quarter tablet) or 25 mg/day (half tablet) for 1 week, taken with food (2 weeks, if necessary); gradually increase to 50 mg/day |
| Average maintenance dosage | 50 mg/day |
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 () 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.
Exhibit 4-2 Oral Naltrexone Side Effects
| Most Common | Less Common |
|---|---|
| Nausea Vomiting Headache Dizziness Fatigue Nervousness Anxiety Somnolence | Diarrhea, constipation, stomach pains, cramps Chest pain, joint/muscle pain Rash Difficulty sleeping Excessive thirst, loss of appetite Sweating Increased tears Mild depression Delayed ejacul*tion |
Exhibit 4-3 Naltrexone Contraindications
| Patient Condition or Circ*mstance | Treatment Recommendation |
|---|---|
| Current illicit opioid use (as indicated by self-report or a positive urine screen) or buprenorphine (Suboxone® or Subutex®) or methadone maintenance therapy for the treatment of opioid dependence; currently undergoing opioid withdrawal | Do not prescribe oral naltrexone; consider an alternative medication |
| Acute hepatitis or liver failure | Do not prescribe oral naltrexone |
| Anticipated need for opioid analgesics within the next 7 days | Do not prescribe oral naltrexone |
| History of sensitivity to naltrexone, to structurally similar compounds (e.g., naloxone or nalmefene), or to any inactive ingredients in the tablet | Do not prescribe oral 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 (). 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.
Exhibit 4-4 Naltrexone Cautions
| Patient Condition or Circ*mstance | Treatment Recommendation |
|---|---|
| Active liver disease | Monitor liver function frequently |
| Moderate to severe renal impairment | Use with careful monitoring (naltrexone is eliminated through the kidneys) |
| Pregnant and nursing women | Do not prescribe during pregnancy and nursing unless potential benefits outweigh risks (oral naltrexone is FDA pregnancy category C; it is unknown whether oral naltrexone is excreted in human milk) |
| Women of childbearing age | Caution patients that effects on fetus are unknown and encourage use of an effective birth control method |
| Serum aminotransferase levels greater than 5 times the upper limit of normal | Generally avoid, unless potential benefits outweigh risks |
| Chronic pain syndromes; acute or recurring need for opioid analgesics | Have patients abstain from naltrexone for at least 3 days (conservatively, 7 days) before initiating opioid analgesics |
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 4-5 Adverse Reactions to Naltrexone and Their Management
| Adverse Reaction | Management |
|---|---|
| Nausea | Suggest that the patient take naltrexone with complex carbohydrates (e.g., bread) rather than on an empty stomach Suggest that the patient take naltrexone with a tablespoon of simethicone (e.g., Gas-X® and Mylicon®) or bismuth subsalicylate (e.g., Pepto-Bismol®) Reduce dose or cease for 3 or 4 days and reinitiate at lower dose |
| Liver toxicity | Discontinue naltrexone |
| Precipitated opioid withdrawal | Discontinue further doses of naltrexone Provide supportive treatments (i.e., hydration and antispasmodic and antidiarrheal medications) until opioid withdrawal symptoms resolve Provide α-2-agonists such as clonidine to mitigate some withdrawal symptoms; watch for enhanced side effects of clonidine, including dizziness, hypotension, fatigue, and headache |
| Naltrexone overdose | Treat symptomatically under close supervision Contact poison control for most recent information |
Exhibit 4-6 Signs and Symptoms of Liver Disease
| Abdominal pains that last more than a few days Light-colored bowel movements Dark, tea-colored urine Yellowing of the eyes or skin | Fatigue Fever Nausea Weakness |
Exhibit 4-7 lists interactions between naltrexone and other drugs.
Exhibit 4-7 Drug Interactions With Oral Naltrexone
| Drug | Effect With Oral Naltrexone |
|---|---|
| Cough/cold medications | May decrease benefit if medication contains an opioid |
| Antidiarrheal medications | May block benefit if medication contains an opioid |
| Opioid analgesics | May require greater amount of analgesic than usual and may result in deeper and more prolonged respiratory depression than if the patient were not taking naltrexone |
| Thioridazine | May result in lethargy and somnolence |
| Yohimbine | May result in anxiety and increased pulse and blood pressure |
| Nonsteroidal anti-inflammatory drugs (NSAIDs) | May result in liver enzyme elevations (i.e., aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) in combination with regular use of very high doses of naltrexone (200–250 mg/day) (); this effect has not been observed in the recommended therapeutic dose range of naltrexone (50–100 mg) |
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.
Pain Management
As an opioid antagonist, naltrexone blocks the effect of opioid analgesics. Typical doses of narcotic analgesics (e.g., codeine, morphine, oxycodone, hydrocodone) may not be effective. Fortunately, many nonopioid analgesic medications (e.g., aspirin, NSAIDs) and procedures (e.g., regional nerve block) can still be used for analgesia.
When opioids must be used, it is possible to reverse the naltrexone blockade using higher than usual doses of opioids. However, because of the potential for opioid-induced respiratory depression, reversal of naltrexone blockade should be done only in medical settings with the provision for respiratory support.
Naltrexone does not block aspirin, acetaminophen, or NSAIDs, including ibuprofen and naproxen sodium. It does not block the effects of local anesthetics such as lidocaine or general (nonopioid) anesthetics. (If patients taking naltrexone require opioid pain medication, a rapidly acting opioid analgesic is recommended to minimize the duration of respiratory depression. Patients should be monitored closely.)
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.
Who Is Appropriate for Treatment With Oral Naltrexone?
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).
Treatment Duration and Discontinuing Oral Naltrexone
The FDA label states that naltrexone should be taken for up to 3 months to treat AUDs. Healthcare providers should tailor the length of treatment to individual patients. Naltrexone has been administered to patients who are alcohol dependent for 6 months to 1 year with no additional safety concerns (Balldin et al., 2003; O'Malley et al., 2003).
One controlled study (Hernandez-Avila et al., 2006; Kranzler et al., 2003) addressed targeted use of naltrexone during periods of risk for problem alcohol use. The findings and clinical experience support periodic or targeted dosing. Because of naltrexone's efficacy in reducing the rewarding effects of alcohol consumption () and reducing cravings for alcohol (O'Malley et al., 1992), patients who achieve abstinence may benefit from taking naltrexone at times when they are at higher risk of relapse, such as on vacations, on holidays, or during a personal tragedy.
Discontinuation of oral naltrexone is not associated with a withdrawal syndrome, and it is not necessary to taper the dose. Providers should remind patients that they should not take opioid medications for at least 3 days and that they may be more sensitive to the effects of opioid drugs (see Patient Education above).
Final Clinical Thoughts
Controlled clinical trials have demonstrated that naltrexone can be an effective medication for the treatment of patients who are alcohol dependent. Clinicians indicate that some patients report that naltrexone helps, and some report no difference with its use. These anecdotal reports provide intriguing suggestions that particular patient types or subgroups may be more likely than other groups to respond to naltrexone. A recent finding has suggested that a variant in a gene encoding for the mu opiate receptor (OPRM1) in the opiate neurotransmitter system may predict response to naltrexone treatment in people dependent on alcohol (Anton et al., 2008). When treated with naltrexone and a medical management intervention, 87.1 percent of persons carrying the less prevalent Asp40 variant had a good clinical outcome, compared with only 54.8 percent of individuals with the more common Asn40/Asn40 genotype (odds ratio, 5.75; confidence interval, 1.88–17.54); no difference between groups was observed in placebo treatment outcomes. This finding suggests that OPRM1 genotyping may be a useful procedure for improving identification of those patients most likely to benefit from naltrexone treatment for alcohol dependence. It also suggests that clinicians should not become discouraged if the first patients they prescribe naltrexone for do not find it beneficial. Naltrexone's efficacy is modest, but it is significantly better than placebo in most studies, and some patients benefit from naltrexone therapy.
Although attention is frequently drawn to the risks of hepatotoxicity with naltrexone, this rarely occurs, is typically reversible, and is more likely with very high doses used over a sustained period. It is unfortunate that such effects have become so closely associated with naltrexone, but the clinician would be prudent to monitor liver function.
Naltrexone—and all the medications described in this TIP—does not “cure” AUDs the way an antibiotic cures bacterial pneumonia. However, as a part of comprehensive treatment, it may increase the likelihood of sustained remission from problem alcohol use.
