Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol use and opioid use disorders by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been found to be effective for the treatment of other addictions and may be used for them off-label. The combination naltrexone/bupropion is used to treat obesity.
Naltrexone is an opioid antagonist and works by blocking the effects of opioids, including both opioid drugs as well as opioids naturally produced in the brain. It is taken orally or by injection into a muscle. Effects begin within 30 minutes, though a decreased desire for opioids may take a few weeks to occur.
Side effects may include trouble sleeping, anxiety, nausea, and headaches. In those still on opioids, opioid withdrawal may occur. Use is not recommended in people with liver failure. It is unclear if use is safe during pregnancy.
Naltrexone was first made in 1965 and was approved for medical use in the United States in 1984. It is on the WHO Model List of Essential Medicines. In 2021, it was the 254th most commonly prescribed medication in the United States, with more than 1million prescriptions.
Medical uses
Alcohol use disorder Naltrexone has been best studied as a treatment for alcoholism, or alcohol use disorder (AUD). Naltrexone has been shown to decrease the quantity and frequency of alcohol consumption by reducing the release of dopamine, a neurotransmitter associated with the euphoria that often accompanies alcohol use. Studies comparing naltrexone to a placebo have shown a small but statistically significant decrease in relapse likelihood. Its overall benefit has been described as "modest". Acamprosate may be more effective for AUD management overall, while naltrexone may decrease the desire for alcohol to a greater extent.
A method pioneered by scientist John David Sinclair (dubbed commercially the "") in the 1980s advocates "pharmacological extinction" of problem drinking behavior by administering naltrexone alongside controlled alcohol consumption. In effect, he argues that naltrexone-induced opioid antagonism sufficiently disrupts reflexive reward mechanisms inherent in the consumption of alcohol and, given enough repetition, will dissociate positive associations formerly made with the consumption of alcohol. A 2001 review of eight studies of naltrexone treatment in the setting of AUD concluded that, "although all found benefits from naltrexone with the coping therapy, none of them found any significant benefit of naltrexone over placebo when combined with support for abstinence."
Opioid use disorder Long-acting injectable naltrexone, sold under the brand name Vivitrol, is an opioid antagonist, blocking the effects of heroin and other opioids, and decreases heroin use compared to placebo in the context of opioid use disorder (OUD). Unlike methadone and buprenorphine, it is not a controlled medication. It may reduce opioid cravings after several weeks and lower the risk of opioid overdose—at least while naltrexone remains active—but concerns about overdose risk for those who stop treatment continue. Injection naltrexone is administered once monthly and has demonstrated greater consistency in patient adherence and efficacy, as measured by opiate-negative urine samples, in comparison to placebo for OUD.
A drawback of injectable naltrexone is that it requires patients with OUD and ongoing physical dependence to be fully detoxified before initiation to prevent severe opioid withdrawal. In contrast, initiation of buprenorphine only requires delaying the first dose until the patient begins to manifest at least mild withdrawal symptoms. Among patients able to successfully initiate injectable naltrexone, long-term remission rates were similar to those seen in clinical buprenorphine/naloxone administration.
The consequence of relapse when weighing the best course of treatment for opiate use disorder remains a concern. Methadone and buprenorphine administration maintain greater drug tolerance while naltrexone allows tolerance to fade, leading to higher instances of an overdose in people who relapse and thus higher mortality. World Health Organization guidelines state that most patients should be advised to use opioid agonists (e.g., methadone or buprenorphine) rather than opioid antagonists like naltrexone, citing evidence of superiority in reducing mortality and retaining patients in care.
A 2011 review found insufficient evidence to determine the effect of naltrexone taken orally on opioid dependence. While some do well with this formulation, it must be taken daily, and a person whose cravings become overwhelming can obtain opioid intoxication simply by skipping a dose. Due to this issue, the usefulness of oral naltrexone in OUD is limited by the low retention in treatment. Naltrexone taken orally remains an ideal treatment for a small number of people with OUD, usually those with a stable social situation and motivation. With additional contingency management support, naltrexone may be effective in a broader population.
Others Unlike varenicline (brand name Chantix), naltrexone is not useful for smoking cessation. Naltrexone has also been under investigation for reducing behavioral addictions such as gambling, non-suicidal self-injury disorder, and kleptomania, as well as compulsive sexual behaviors in both offenders and non-offenders (e.g., compulsive porn viewing and masturbation). The results were promising. In one study, the majority of sexual offenders reported a strong reduction in sexual urges and fantasies, which reverted to baseline once the medication was discontinued. Case reports have also shown cessation of gambling and other compulsive behaviors, for as long as the medication was taken.
When taken at much smaller doses, a regimen known as low-dose naltrexone (LDN), naltrexone may reduce pain and help to address symptoms of conditions other than those related to addiction. Reports have been published on the usefulness of LDN in the settings of ME/CFS, multiple sclerosis, fibromyalgia, and autoimmune diseases. Although its mechanism of action is unclear, some have speculated that it may act as an anti-inflammatory. As of October 2022, LDN was also being considered as a potential treatment for long COVID.
Available forms
Naltrexone is available and most commonly used in the form of an oral tablet (50 mg). Vivitrol, a naltrexone formulation for depot injection containing 380 mg of the medication per vial, is also available." Additionally, naltrexone subcutaneous implants are available. While these are manufactured in Australia, they are not authorized for use within Australia (but only for export). By 2009, naltrexone implants showed superior efficacy in the treatment of heroin dependence when compared to the oral form.
Side effects The most common side effects reported with naltrexone are gastrointestinal complaints such as diarrhea and abdominal cramping. These adverse effects are analogous to the symptoms of opioid withdrawal, as the μ-opioid receptor blockade will increase gastrointestinal motility.
The side effects of naltrexone by incidence are as follows:
Greater than 10%: difficulty sleeping, anxiety, nervousness, abdominal pain/cramps, nausea and/or vomiting, low energy, joint/muscle pain, and headache. Less than 10%: loss of appetite, diarrhea, constipation, thirstiness, increased energy, feeling down, irritability, dizziness, skin rash, delayed ejaculation, erectile dysfunction, and chills. A variety of other adverse events have also been reported with less than 1% incidence.
Opioid withdrawal Naltrexone should not be started until several (typically 7–10) days of abstinence from opioids have been achieved. This is due to the risk of acute opioid withdrawal if naltrexone is taken, as naltrexone will displace most opioids from their receptors. The time of abstinence may be shorter than 7 days, depending on the half-life of the specific opioid taken. Some physicians use a naloxone challenge to determine whether an individual has any opioids remaining. The challenge involves giving a test dose of naloxone and monitoring for opioid withdrawal. If withdrawal occurs, naltrexone should not be started.
Adverse effects Whether naltrexone causes dysphoria, depression, anhedonia, or other aversive effects has been studied and reviewed. In early studies of opioid-abstinent individuals, acute and short-term administration of naltrexone was reported to produce a variety of aversive effects including fatigue, loss of energy, sleepiness, mild dysphoria, depression, lightheadedness, faintness, confusion, nausea, gastrointestinal disturbances, sweating, and occasional derealization. However, these studies were small, often uncontrolled, and used subjective means of assessing side effects. Most subsequent longer-term studies of naltrexone for indications like alcohol or opioid dependence have not reported dysphoria or depression with naltrexone in most individuals. According to one source:
Naltrexone itself produces little or no psychoactive effect in normal research volunteers even at high doses, which is remarkable given that the endogenous opioid system is important in normal hedonic functioning. Because endogenous opioids are involved in the brain reward system, it would be reasonable to hypothesize that naltrexone might produce anhedonic or dysphoric effects. Although some evidence from small, early trials suggested that patients with a history of opiate dependence might be susceptible to dysphoric effects in response to naltrexone (Crowley et al. 1985; Hollister et al. 1981), reports of such effects have been inconsistent. Most large clinical studies of recovering opioid-dependent individuals have not found naltrexone to have an adverse effect on mood (Greenstein et al. 1984; Malcolm et al. 1987; Miotto et al. 2002; Shufman et al. 1994). Some studies have actually found improvements in mood during the course of treatment with naltrexone (Miotto et al. 1997; Rawlins and Randall 1976).
Based on available evidence, naltrexone seems to have minimal untoward effects in the aforementioned areas, at least with long-term therapy. It has been suggested that differences in findings between acute and longer-term studies of naltrexone treatment might be related to altered function in the opioid system with chronic administration of naltrexone. For example, marked upregulation of opioid receptors and hyper-sensitivity to opioids have been observed with naltrexone in preclinical studies. Another possibility is that the central opioid system may have low endogenous functionality in most individuals, becoming active only in the presence of exogenously administered opioid receptor agonists or with stimulation by endogenous opioids induced by pain or stress. A third possibility is that normal individuals may experience different side effects with naltrexone than people with addictive disease such as alcohol or opioid dependence, who may have altered opioid tone or responsiveness. It is notable in this regard that most studies of naltrexone have been in people with substance dependence.
Naltrexone may also initially produce opioid withdrawal-like symptoms in a small subset of people not dependent on opioids:
The side-effect profile [of naltrexone], at least on the recommended dose of 50 mg per day, is generally benign, although 5 to 10 percent of detoxified opioid addicts experience immediate, intolerable levels of withdrawal-like effects including agitation, anxiety, insomnia, light-headedness, sweating, dysphoria, and nausea. Most patients on naltrexone experience few or no symptoms after the first 1 to 2 weeks of treatment; for a substantial minority (20 to 30 percent) protracted discomfort is experienced.
Persisting affective distress related to naltrexone may account for individuals taking the drug who drop out of treatment.