Naltrexone in Treatment of Drug Dependence | Research & Encyclopedia Articles

Naltrexone (brand names Trexan^R, Revia^R [U.S.], Nalorex^R [France, U.K.]) is a synthetic antagonist of opiate (morphine-like) drugs, which blocks their actions without itself having any opiate effects. Naltrexone differs from most other pure opiate antagonists in having a relatively long duration of action (at least 24 hours) and being effective when taken by mouth. These characteristics have led to its clinical use as a long-term or maintenance treatment for OPIATE and OPIOID dependence after detoxification. Naltrexone is also being studied experimentally as a possible treatment for cigarette smoking and eating disorders, and was approved in 1995 for treatment of alcoholism.

The use of opiate ANTAGONISTS as treatment for opiate dependence was first proposed by William Martin and Abraham Wikler and their colleagues at the U.S. Addiction Research Center in the early 1960s. They hypothesized that chronic administration of an opiate antagonist, by blocking the pleasurable or rewarding effects of opiate drugs, would lead to the extinction of drug-seeking and drug-taking behavior—since the addict would no longer receive any pleasurable effects from takingan opiate. With abstinence from opiates, PHYSICAL DEPENDENCE and any chronic withdrawal syndrome would dissipate, removing important factors that cause craving for opiates. They suggested that antagonist treatment would have several advantages over treatment with an opioid such as METHADONE. Since antagonists do not produce any pleasurable effects, the addict would have little incentive to misuse the medication or divert it to illegal channels. Chronic use of an antagonist would not produce physical dependence, and an overdose of antagonist would not cause life-threatening opiate effects such as suppression of breathing. Use of the antagonist in nondetoxified opioid addicts, however, would cause an acute but not life-threatening withdrawal.

The earliest studies of opioid antagonists were not satisfactory, because of drawbacks in the then available antagonists. For example, NALOXONE was short-acting and not very effective when taken by mouth. Nalorphine and cyclazocine had some kappa-opioid effects (i.e., were not pure antagonists), which produced unpleasant side effects.

Further work was stimulated by the SPECIAL ACTION OFFICE FOR DRUG ABUSE PREVENTION created by President Richard M. Nixon in June 1971 as part of a "war on drugs." The 1972 funding legislation for this office called for research on "long-lasting, nonaddictive, blocking and antagonist drugs… for the treatment of heroin addiction." Eventually twenty-two studies with naltrexone (which had been synthesized by Blumberg and Dayton in 1965) were conducted at various treatment programs in the United States. These studies demonstrated the safety and effectiveness of naltrexone after detoxification as a long-term treatment for opiate dependence, leading to its marketing in North America and Europe. Its effectiveness, however, was defined in terms of blocking the effects of HEROIN, not in the success of changing the behavior of heroin users.

Naltrexone is usually used in conjunction with counseling and other rehabilitation services, as part of a structured and monitored treatment program. The best treatment results tend to occur in highly motivated, psychologically healthy addicts who are employed and well-functioning socially, especially when they face severe economic or legal consequences for failing treatment. For example, addicted health professionals whose treatment is required by their professional licensing boards and monitored as a condition of continued licensure will regularly take naltrexone for several years and remain abstinent from opiates. Some programs have reported five-year success rates as high as 95 percent. Most street addicts (e.g., those with unstable living situations who support their drug use by criminal activity) refuse to take naltrexone or, if started in treatment, quickly dropout. This is believed due to the lack of reward effect. Many such addicts prefer maintenance treatment with the synthetic opiate methadone and others find even methadone nonrewarding, so they relapse.

Fifty milligrams of naltrexone block the effects of 25 milligrams of heroin for 24 hours, so the typical weekly naltrexone dose is 350 milligrams. The actual medication schedule is adjusted to the individual patient and may range from 50 milligrams every day to 150 milligrams every third day. Patients are put on the least frequent medication schedule possible to enhance patient cooperation and reduce the number of clinic visits. To further reduce medication scheduling, researchers are working on a depot form of naltrexone that can be injected once a month and which slowly releases the medication into the body.

Care must be taken to avoid administering naltrexone to individuals still physically dependent on opiates. In opiate-dependent individuals, an antagonist will precipitate an acute opiate withdrawal syndrome. While not life-threatening, this syndrome can be extremely uncomfortable, with symptoms such as abdominal cramps; diarrhea; muscle, joint, and bone pain; runny nose (rhinorrhea); and goose bumps (piloerection). To avoid this situation, naltrexone is not administered to patients until they have been free of opiate drugs for at least seven to ten days to allow dependence to wear off. To confirm the absence of dependence, patients may be challenged with the short-acting antagonist naloxone before starting on naltrexone. To shorten the required opiate-free period, some programs are experimenting with combined administration of naltrexone and CLONIDINE, a medication that reduces symptoms of opiate withdrawal.

Naltrexone was shown to reduce the rate of relapse of full-blown compulsive drinking by detoxified alcoholics, although it did not substantially increase the number who were totally abstinent. In one research study, naltrexone seemed to reduce craving for alcohol. In contrast with opioid addicts, alcoholics were more willing to take naltrexone.

Wikler's Pharmacologic Theory of Drug Addiction)

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