Since its 1994 approval by the federal Food and Drug Administration, naltrexone remains the sole prescription medication used to reduce drinking in alcoholics. Naltrexone is taken by mouth and quickly metabolized in the liver to a number of different compounds or metabolites that can be measured in blood or urine. Naltrexone’s major metabolite is called 6-beta naltrexol. A study in the October issue of Alcoholism: Clinical & Experimental Research examines if 6-beta naltrexol itself can reduce alcohol consumption.
"Although 6-beta naltrexol is a metabolite that can be measured in human plasma and urine after administering naltrexone," explained Margaret R. Rukstalis, assistant professor of psychiatry at the University of Pennsylvania-VA Treatment Research Center and lead author of the study, "it is not known if 6-beta-naltrexol is independently pharmacologically active in reducing alcohol consumption. Studies have shown that high plasma levels of 6-beta naltrexol are critical in preventing relapse to alcoholism. Yet human plasma levels of both naltrexone and 6-beta naltrexol are highly variable following standardized oral doses of naltrexone. This is probably related to individual differences in the ability of the liver to metabolize naltrexone." The variable metabolism of naltrexone in individuals may explain why the medication doesn’t work for everyone.
Treatments for alcohol dependence have helped scientists understand more about the biology of this brain disorder. First and foremost, as noted by Raymond Anton, professor of psychiatry and scientific director of the Alcohol Research Center at the Medical University of South Carolina, "alcohol works on cells in the brain. Alcohol alters the function of these cells immediately. While most people's cells return to normal once the alcohol is removed/metabolized, some people (those at risk for developing alcoholism) are likely to have their cells more permanently changed. If this occurs again and again during episodes of intoxication, the cells begin to depend on alcohol. This dependency is manifested in a change in chemical signalling between the cells."
The reward system in the brain involves several neurotransmitters, one of which is the opioid neurotransmitter system (see EurekAlert/A:C&ER September 2000). Activation of this system - by alcohol consumption, for example - is associated with pain relief, calming and euphoria. When opioids are stimulated, that 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, including alcohol.
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. Both naltrexone and 6-beta naltrexol are opioid antagonists. This means that they block the opioid receptor from being activated.
"Repeated alcohol exposure in some individuals," continued Anton, "may increase the cellular release of heroin/opiate-like chemicals called endorphins and enkephalins. This could lead to higher pleasure or a craving for alcohol. Drugs like naltrexone and 6-beta-naltrexol specifically block this effect of alcohol so that, in individuals that have this type of alcohol dependency, the drug counteracts the alcohol effect."
"Like naltrexone," agreed Rukstalis, "6-beta naltrexol blocks opioid receptors, but it is about one-tenth as effective in doing this. Since 6-beta naltrexol has not yet been administered to humans, it is difficult to know how the doses we used with rodents correspond to doses for humans. However, previous studies in humans have shown that plasma levels of 6-beta naltrexol following naltrexone administration were two to 10 times as high as naltrexone. Naltrexone is typically given in 50-mg tablets. The dose range of 6-beta naltrexol we tested was comparable to levels of 6-beta naltrexol found in humans following a 50-mg oral dose of naltrexone."
In the study, researchers compared the amount of alcohol drinking by rats given 6-beta naltrexol to the amount of alcohol drinking by rats given salt water. They found that alcohol drinking by the rats decreased as the doses of 6-beta naltrexol increased. "These results suggest that 6-beta naltrexol is a potential new medication to treat alcohol dependence," said Rukstalis.
Both Rukstalis and Anton are optimistic about the future possibilities of 6-beta naltrexol as a treatment for alcoholism.
"Naltrexone is so quickly metabolized by the liver that for many people," said Rukstalis, "there is much more 6-beta naltrexol in the blood than naltrexone. Currently, naltrexone is the only way to obtain 6-beta naltrexol. In the future, giving patients 6-beta naltrexol directly may lead to higher and more consistent therapeutic levels compared to the variable levels seen with naltrexone. Six-beta naltrexol may be easier to give and more effective than currently available medications that help prevent alcohol relapses in alcoholics."
"It is also clear that compliance with taking naltrexone is a crucial aspect of its efficacy," added Anton. "One of the benefits of 6 beta-naltrexol as an alternative to the parent compound naltrexone is that it is longer acting (has a longer metabolic half-life) than naltrexone. It is possible that it can be given less frequently or, if someone misses a dose, it can still provide some protection against ‘slip’ drinking. One nice thing about naltrexone, even now, is that it needs to be taken only once a day, which is very important for medication compliance, especially in an alcoholic population who may be ambivalent about taking medications to begin with. If 6 beta-naltrexol shows promise, it could potentially be given every other day, or maybe produced in a skin-patch or a long term (depot) injectable format."
However, Anton remains somewhat cautious. "Unfortunately, the opioid neurotransmitter system probably does not explain all of the types of alcohol dependency," he said. "Other people may have changes in other cells and transmitters that are not impacted upon by drugs like naltrexone and 6-beta-natrexol. Future research will begin subtyping alcoholics, perhaps by using a genetic approach, so that more specific medications can be used and more effectiveness predicted for a given individual."
Funding for this Addiction Science Made Easy project is provided by the Addiction Technology Transfer Center National Office, under the cooperative agreement from the Center for Substance Abuse Treatment of SAMHSA.
Articles were written based on the following published research:
Rukstalis, M.R., Stromberg, M.F., O’Brien, C.P., & Volpicellie, J.R. (2000, October). 6-B-naltrexol reduces alcohol consumption in rats. Alcoholism: Clinical and Experimental Research, 24(10), 1593-1596.