Opioid Receptor Antagonists: Naltrexone, Nalmefene, and Naloxone

For a more detailed discussion of this topic, see Opioid Receptor Antagonists: Naltrexone and Nalmefene, Sec. 31.25, p. 3177, in Comprehensive Textbook of Psychiatry, 9th Edition.

Naltrexone, an opioid antagonist, was synthesized in 1965 and proved to have a number of advantages over earlier opioid antagonists, including cyclazocine, nalorphine, and naloxone. Specifically, naltrexone had a relatively long half-life, was orally effective, was not associated with dysphoria, and could be administered once a day. Whereas earlier narcotic antagonists—principally naloxone—were used to reduce narcotic overdose, these characteristics of naltrexone made it suitable for use in preventing relapse to opiate use in detoxified opiate addicts. In 1984, naltrexone was approved for providing blockade of the effects of exogenously administered opiates in detoxified opiate addicts. Since then, naltrexone has been tried for the treatment of a wide range of psychiatric disorders, including, among others, eating disorders, autism, self-injurious behavior, cocaine dependence, gambling, and alcoholism. Naltrexone (ReVia; Depade) was approved for the treatment of alcohol dependence in 1994. A number of generic formulations are also available. An extended-release, once-a-month injectable suspension (Vivitrol) was also approved in 2006. Nalmefene (Revex) is indicated for the complete or partial reversal of opioid drug effects and in the management of known or suspected opioid overdose. An oral formulation of nalmefene is available in some countries but not in the United States.

Pharmacologic Actions

Oral opioid receptor antagonists are rapidly absorbed from the gastrointestinal (GI) tract, but because of first-pass hepatic metabolism, only 60% of a dose of naltrexone and 40 to 50% of a dose of nalmefene reach the systemic circulation unchanged. Peak concentrations of naltrexone and its active metabolite, 6-β-naltrexol, are achieved within 1 hour of ingestion. The half-life of naltrexone is 1 to 3 hours, and the half-life of 6-β-naltrexol is 13 hours. Peak concentrations of nalmefene are achieved in about 1 to 2 hours, and the half-life is 8 to 10 hours. Clinically, a single dose of naltrexone effectively blocks the rewarding effects of opioids for 72 hours. Traces of 6-β-naltrexol may linger for up to 125 hours after a single dose.

Naltrexone and nalmefene are competitive antagonists of opioid receptors. Understanding the pharmacology of opioid receptors can explain the difference in adverse effects caused by naltrexone and nalmefene. Opioid receptors in the body are typed pharmacologically as µ, κ, or δ. Whereas activation of the κ- and δ-receptors is thought to reinforce opioid and
alcohol consumption centrally, activation of µ-receptors is more closely associated with central and peripheral antiemetic effects. Because naltrexone is a relatively weak antagonist of κ- and δ-receptors and a potent µ-receptor antagonist, dosages of naltrexone that effectively reduce opioid and alcohol consumption also strongly block µ-receptors and therefore may cause nausea. Nalmefene, in contrast, is an equally potent antagonist of all three opioid receptor types, and dosages of nalmefene that effectively reduce opioid and alcohol consumption have no particularly increased effect on µ-receptors. Thus, nalmefene is associated clinically with few GI adverse effects.

Naloxone has the highest affinity for the µ receptor but is a competitive antagonist at the µ, κ, and δ receptors.

Whereas the effects of opioid receptor antagonists on opioid use are easily understood in terms of competitive inhibition of opioid receptors, the effects of opioid receptor antagonists on alcohol dependence are less straightforward and probably relate to the fact that the desire for and effects of alcohol consumption appear to be regulated by several neurotransmitter systems, both opioid and nonopioid.

Therapeutic Indications

The combination of a cognitive-behavioral program plus use of opioid receptor antagonists is more successful than either the cognitive–behavioral program or use of opioid receptor antagonists alone. Naltrexone is used as a screening test to ensure that the patient is opioid free before the induction of therapy with naltrexone (see naloxone challenge test on page 184).

Opioid Dependence

Patients in detoxification programs are usually weaned from potent opioid agonists such as heroin over a period of days to weeks, during which emergent adrenergic withdrawal effects are treated as needed with clonidine (Catapres). A serial protocol is sometimes used in which potent agonists are gradually replaced by weaker agonists followed by mixed agonist-antagonists and then finally by pure antagonists. For example, an abuser of the potent agonist heroin would switch first to the weaker agonist methadone (Dolophine), then to the partial agonist buprenorphine (Buprenex) or levomethadyl acetate (ORLAAM)—commonly called LAAM—and finally, after a 7- to 10-day washout period, to a pure antagonist, such as naltrexone or nalmefene. However, even with gradual detoxification, some persons continue to experience mild adverse effects or opioid withdrawal symptoms for the first several weeks of treatment with naltrexone.

As the opioid receptor agonist potency diminishes, so do the adverse consequences of discontinuing the drug. Thus, because there are no pharmacologic barriers to discontinuation of pure opioid receptor antagonists, the social environment and frequent cognitive-behavioral intervention become extremely important factors supporting continued opioid abstinence. Because of poorly tolerated adverse symptoms, most persons not simultaneously enrolled in a cognitive-behavioral program stop taking opioid receptor antagonists within 3 months. Compliance with administration of an opioid receptor antagonist regimen can also be increased with participation in a well-conceived voucher program.

Issues of medication compliance should be a central focus of treatment. If a person with a history of opioid addiction stops taking a pure opioid receptor antagonist, the person’s risk of relapse into opioid abuse is exceedingly high because reintroduction of a potent opioid agonist would yield a very rewarding subjective “high.” In contrast, compliant persons do not develop tolerance to the therapeutic benefits of naltrexone even if it is administered continuously for 1 year or longer. Individuals may undergo several relapses and remissions before achieving long-term abstinence.

Persons taking opioid receptor antagonists should also be warned that sufficiently high dosages of opioid agonists can overcome the receptor antagonism of naltrexone or nalmefene, which may lead to hazardous and unpredictable levels of receptor activation (see Precautions and Adverse Reactions).

Rapid Detoxification

Only gold members can continue reading. Log In or Register to continue