- In 1994, the Food and Drug Administration approved naltrexone for the treatment of alcoholism.
- It has since proven to be highly effective for many in recovery, but it does not work for everyone.
- A recent study has found that individual metabolism may be a factor in naltrexone's effectiveness.
- Its effectiveness can, in turn, be partially determined by measuring blood levels for naltrexone and its major metabolite, 6-beta-naltrexol.
The 1994 approval of naltrexone by the federal Food and Drug Administration was a milestone in the treatment of alcoholism. Naltrexone is a medication that decreases the rewarding effects of drinking and reduces the craving for alcohol that often leads people to relapse. Yet despite its effectiveness for many recovering alcoholics, it does not work for everyone. A study in the September issue of Alcoholism: Clinical & Experimental Research has found that, first, naltrexone's effectiveness may be influenced by individual metabolism, and second, this may be detected by measuring blood levels for the medication's major metabolite, 6-beta-naltrexol.
"Determining blood levels may be useful for patients who are not helped by the standard naltrexone dose," explained Mary E. McCaul, associate professor at Johns Hopkins University School of Medicine and lead author of the study. "This study demonstrates the importance of adjusting naltrexone dosage to ensure than an adequate blood level of 6-beta-naltrexol is achieved. If an individual does not achieve a therapeutic effect at the standard naltrexone dose of 50 milligrams per day, he or she may want to discuss a dose increase with the prescribing physician."
McCaul explained that drugs can have agonist and/or antagonist properties. Agonists activate a receptor to achieve their effect. Antagonists block the receptor from being activated by another endogenous (produced within the organism) or exogenous (produced outside the organism) chemical, but do not produce any activity of their own. Naltrexone is an opioid antagonist. This means that naltrexone blocks the opioid receptor from being activated but does not cause any psychoactive effects for the person taking the medicine.
Naltrexone was first developed in the 1970s as a compound to block heroin and other opioid agonists from activating the receptors for opiates like heroin. In the mid-1980s, naltrexone was approved for the treatment of heroin addiction. In the late 1980s, researchers began to suspect that drinking alcohol was pleasurable because it released endogenous morphine-like molecules. Joseph R. Volpicelli, associate professor and senior scientist at the Treatment Research Center at the University of Pennsylvania, was one of those original researchers.
"The reward system in the brain involves several neurotransmitters," said Volpicelli, "one of which is the opioid neurotransmitter system." Activation of this system - by alcohol consumption, for example - is associated with pain relief, calming and euphoria. "When opioids are stimulated," he said, "that in turn causes an increase in the neurotransmitter called dopamine." Dopamine activity in the brain center called the nucleus accumbens is thought to be key to reward and experiencing the "high" of a variety of different drugs such as cocaine, amphetamines, and nicotine. "What happens is that the brain gets a 'taste' of having endorphins or dopamine released, and it wants more of it," Volpicelli continued. "So first use is like an appetizer for the brain, particularly for people who have a family history of alcoholism and may have a genetic susceptibility for becoming addicted to alcohol. Having a taste of these endogenous opioids is enough to make some people want more of them."
Preclinical research has shown that animals treated with an opioid antagonist such as naltrexone decrease voluntary consumption of alcohol in the laboratory. In human clinical trials, naltrexone decreases alcohol consumption, slows the onset of relapse, and reduces craving for alcohol in recently abstinent alcohol-dependent patients. Yet researchers couldn't quite determine why some alcoholics were helped and others were not, despite their equal commitment to quit drinking. McCaul's findings may help resolve this mystery.
"This paper is especially important on two fronts," said Volpicelli. "First, it begins to identify that, for at least blocking the pleasure associated with drinking, doses higher than 50 milligrams may be helpful for some people. There seems to be a huge individual variability in how naltrexone is metabolized, so those people who may be the more rapid metabolizers may benefit from higher doses of the medication." He explained that the usual 50-milligrams-per-day dose of naltrexone for treatment of alcoholism was based on the dosage formerly given to heroin addicts. "Furthermore," he said, "this study also shows us that we can and measure blood levels and know if this person needs a higher dose. We can now dose people specifically to get the best level of beta-naltrexol in their systems in order to have the best clinical effect."
McCaul is planning to continue her studies in this area. "Currently," she said, "we are using positron emission tomography to scan brain opioid receptors to determine the extent of opioid receptor blockade by naltrexone. This may vary among individual patients as a function of possible genetic differences, effects of chronic alcohol consumption, and differences in naltrexone blood levels. We expect that those patients with greater receptor blockade will experience greater alcoholism treatment effectiveness than patients with lower blockade. If so, this will help further elucidate the mechanisms of naltrexone's effectiveness in alcoholism treatment."
"McCaul's study as well as other studies showing how alcohol affects the brain are very important," said Volpicelli. "They provide more evidence that alcohol addiction is a medical disease, and medicines like naltrexone can be helpful in helping people recover."
Co-authors of the Alcoholism: Clinical & Experimental Research paper included: Gary S. Wand of the Johns Hopkins University School of Medicine; and Charles Rohde and Shing M. Lee of the Johns Hopkins University School of Public Health. The study was funded in part by the National Institute on Alcohol Abuse and Alcoholism, and the Johns Hopkins Bayview Medical Center General Clinical Research Center.