Naltrexone


Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol use or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been found effective in the treatment of other addictions and may be used for them off-label. 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 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.
Naltrexone was first made in 1965 and was approved for medical use in the United States in 1984. Naltrexone, as naltrexone/bupropion, is also used to treat obesity. It is on the World Health Organization's 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. Naltrexone has been shown to decrease the quantity and frequency of ethanol consumption by reducing the dopamine release from the brain after consuming alcohol. It does not appear to change the percentage of people drinking. Its overall benefit has been described as "modest".
Acamprosate may work better than naltrexone for eliminating alcohol abuse, while naltrexone may decrease the desire for alcohol to a greater extent.
A method pioneered by scientist John David Sinclair 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 review of eight naltrexone trials concluded, "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 is an opioid antagonist, blocking the effects of heroin and other opioids, and decreases heroin use compared to a placebo. Unlike methadone and buprenorphine, it is not a controlled medication. It may decrease cravings for opioids after a number of weeks, and decreases the risk of overdose, at least during the time period that naltrexone is still active, though concern about risk of overdose for those stopping treatment remains. It is given once per month and has better adherence and effect for opioid use than the oral formulation.
A drawback of injectable naltrexone is that it requires patients with opioid use disorder and current physiological dependence to be fully withdrawn before it is initiated to avoid a precipitated opioid withdrawal that may be quite severe. In contrast, initiation of buprenorphine only requires delay of the first dose until the patient begins to manifest at least mild opioid 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 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 opioid use disorder is limited by the low retention in treatment. Naltrexone taken orally remains an ideal treatment for a small number of people with opioid use, 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, naltrexone is not useful for quitting smoking. Naltrexone has also been under investigation for reducing behavioral addictions such as gambling, NSSID, and kleptomania, as well as compulsive sexual behaviors in both offenders and non-offenders. 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, naltrexone may reduce pain and help to address neurological symptoms. Some patients report that LDN helps reduce their symptoms of ME/CFS, multiple sclerosis, fibromyalgia, or autoimmune diseases. Although its mechanism of action is unclear, some have speculated that it may act as an anti-inflammatory. LDN is 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. Vivitrol, a naltrexone formulation for depot injection containing 380 mg of the medication per vial, is also available. Additionally, naltrexone subcutaneous implants that are surgically implanted 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.

Contraindications

Naltrexone should not be used by persons with acute hepatitis or liver failure, or those with recent opioid use.

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:
Naltrexone should not be started until several 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 normal and 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:
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:
Persisting affective distress related to naltrexone may account for individuals taking the drug who drop out of treatment.
Naltrexone has been reported to reduce feelings of social connection. The μ-opioid receptor has been found to play a major role in social reward in animals and the μ-opioid receptor knockout mouse is an animal model of autism. Studies on whether naltrexone can decrease the pleasurable effects of listening to music are conflicting. Besides humans, naltrexone has been found to produce aversive effects in rodents as assessed by conditioned place aversion.