Naltrexone: Medical Uses, Available Forms, Contraindications, Side Effects and Mechanism of Action

It is an opioid antagonist that works by blocking the effects of opiates, both from inside and outside the body.

Naltrexone, which is sold under the brand names ReVia and Vivitrol, among others, is a drug primarily used to control dependence on alcohol or opiates.

An opioid dependent person should not receive naltrexone prior to detoxification.

It is taken by mouth or by injection into a muscle. Effects start in 30 minutes.

Side effects can include trouble sleeping, anxiety, nausea, and headaches. In those still taking opioids, opioid withdrawal may occur. It is not recommended for use in people with impaired liver function .

It is not clear if use is safe during pregnancy.

Naltrexone was first manufactured in 1965 and approved for medical use in the United States in 1984.

Medical uses

Alcoholism

Naltrexone has been best studied as a treatment for alcoholism.

Naltrexone has been shown to decrease the amount and frequency of alcohol consumption. The percentage of people who drink does not seem to change. Its overall benefit has been described as “modest.”

Acamprosate may work better than naltrexone in eliminating alcohol consumption, while naltrexone may decrease the desire for alcohol to a greater extent.

The Sinclair method is a method of using opiate antagonists such as naltrexone to treat alcoholism. The person takes the drug about an hour (and only after) before drinking to avoid side effects that arise from chronic use.

The opioid antagonist blocks the positive reinforcing effects of alcohol and enables the person to stop or reduce alcohol use.

Opioid use

Long-acting injectable naltrexone decreases heroin use more than placebo.

It has benefits over methadone and buprenorphine, as it is not a restricted drug. It can decrease opioid cravings after several weeks and lowers the risk of overdose.

It is administered once a month and has a better compliance than the oral formulation.

A 2011 review found insufficient evidence to determine the effect of oral naltrexone on opioid dependence.

Although some do well with this formulation, it must be taken daily, and a person whose cravings become overwhelming can get opioid intoxication simply by skipping a dose.

Due to this problem, the usefulness of oral naltrexone in opioid use disorders is limited by low retention in treatment.

Oral naltrexone remains an ideal treatment for a small number of people with opioid use, generally those with stable social status and motivation. With additional support for contingency management, naltrexone may be effective in a broader population.

Others

Naltrexone is not helpful for quitting smoking.

Available shapes

Naltrexone is available and most commonly used as an oral tablet (50 mg).

Also available is Vivitrol , a depot injection formulation of naltrexone that contains 380 mg of the drug per vial.

Additionally, subcutaneous naltrexone implants that are surgically implanted are available.

While these are made in Australia, they are not licensed for use within Australia, only for export. In 2009, naltrexone implants showed encouraging results.

Contraindications

Naltrexone should not be used by people with acute hepatitis or liver failure, or those with recent opioid use (usually 7 to 10 days).

Side effects

The most common side effects reported with naltrexone are gastrointestinal complaints such as diarrhea and abdominal cramps.

These adverse effects are analogous to opioid withdrawal symptoms, as mu receptor blockade will increase GI motility.

Naltrexone has been reported to cause liver damage (when administered at higher than recommended doses). It carries a boxed FDA warning for this rare side effect.

Because of these reports, some doctors may monitor liver function tests before starting naltrexone, and periodically thereafter.

Concerns about liver toxicity initially arose from a study of nonaddicted obese patients who received 300 mg of naltrexone.

Subsequent studies have suggested limited toxicity in other patient populations.

Naltrexone should not be started until several (usually 7-10) days of opioid withdrawal 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 withdrawal time may be shorter than 7 days, depending on the half-life of the specific opioid taken. Some doctors use a naloxone challenge to determine if an individual has any remaining opioids.

The challenge is to administer a test dose of naloxone and manage opioid withdrawal . If a withdrawal occurs, naltrexone should not be started.

Mechanism of action

Blocking opioid receptors is the basis of the action of naltrexone in the treatment of opioid dependence: it reversibly blocks or attenuates the effects of opiates.

Its mechanism of action in alcohol dependence is not fully understood, but as an opioid receptor antagonist it is likely due to modulation of the mesolimbic dopamine pathway (one of the primary centers for risk-reward analysis in the brain and a tertiary “pleasure center”), which is hypothesized to be a major reward center associated with addiction believed to activate all major drugs of abuse.

The mechanism of action may be antagonism to endogenous opioids such as tetrahydropapaveroline, whose production is increased in the presence of alcohol.

Pharmacokinetics

Naltrexone is metabolized in the liver primarily to 6β-naltrexol by the enzyme dihydrodiol dehydrogenase.

Other metabolites include 2-hydroxy-3-methoxy-6β-naltrexol and 2-hydroxy-3-methoxy-naltrexone. These are then metabolized by glucuronide conjugation. The plasma half-life of naltrexone and its metabolite 6β-naltrexol is approximately 4 hours and 13 hours, respectively.