Gender Differences Found in Effects of Pain Medication

March 14, 2000
News Office: Jennifer O'Brien (415) 502-6397

Researchers led by UCSF Medical Center physicians are reporting that an experimental pain drug known as a kappa-opioid brings pain relief to female rats but not males, a finding that adds weight to a recent UCSF clinical finding and highlights the need to evaluate drugs by gender, researchers say.

Traditionally, kappa-opioids have been dismissed as ineffective analgesics in humans, although the drugs have shown mixed results in animal studies, depending on how they were administered.

The new study, published in the March issue of Pain, may help to resolve the controversy about the drug's effectiveness, researchers say, and underscores a weakness in traditional drug screening: Until the early 1990s, most drugs, including kappa-opioids, were primarily evaluated in men.

"The problem of gender differences, particularly in response to opioid drugs, is extremely important and widely under-appreciated," says Dr. Howard Fields, a neurologist at UCSF Medical Center and senior author of the study. Fields is a leading expert on the brain mechanisms of pain and is a pain-treatment specialist, a professor of neurology, a member of the Keck Center for Integrative Neuroscience and director of the UCSF Wheeler Center for the Neurobiology of Addiction.

"There may be classes of drugs that are particularly effective in women that don't have the side effects of currently available potent drugs," says Fields. "Kappas are an example, but it may be true for a lot of drugs and we just don't know it because we haven't looked. Drug companies might be throwing away a perfectly good drug because it doesn't work in males."

The specific finding is important because morphine, a class of opioid and the painkiller most often used for severe pain, has limitations -- over time, people can develop tolerance to the drug and/or become dependent on it. As a result, researchers are intent on identifying an alternative class of opioids that lack the drug's limitations.

"A lot of people don't want to go on morphine because it is addictive," Field said. "What if kappa agonists were non-addicting in females but were potent analgesics?"

The idea that males and females respond differently to opioids is not new, but until recently the difference was believed to be limited to potency, with clinical studies showing that women require less morphine for post-operative pain than men.

Fields' finding -- that specific brain regions in male and female rats have opposite reactions to kappa-opioids -- suggests that the difference may be more fundamental, supporting clinical studies at UCSF that indicate kappa-opioids are more effective in women for clinically significant pain.

The original clinical study, led by UCSF's Dr. Jon Levine, showed that, in women, a drug made up of a diluted concentration of kappa-opioid had no effect, while a drug made up of a higher dose of the drug combination had a strong and lasting analgesic effect. In contrast, in men, the low dose actually increased pain; as the dose was increased, the heightened pain disappeared and a weak, short-lived analgesic effect set in.

The clinical finding was serendipitous. "The drug had been known for more than two decades and had simply been considered a bad analgesic," Levine said. The discovery demonstrates a clear biological difference in the way women and men respond to kappa-opioids.

"If it weren't for the people data, I'd say, 'who knows, a rat's a rat and our finding may have nothing to do with people,'" Fields said, "but taken together the findings have importance."

Fields' study pushes the investigation into the region of the brain where opioids bring about their analgesic effect, and puts researchers on track for determining the targets or mechanisms accounting for the contrasting responses.

The study also confirms the role of kappa-opioid in the contrasting analgesic responses. While Levine's team was restricted to using clinically available drugs that could have other effects, the Fields lab was able to use a drug that acted only at the kappa-opioid receptor.

The Fields investigators focused their study on a neural circuit in the brain that extends from a collection of pain-sensing neurons known as the ventrolateral periaqueductal gray (v1PAG) downward to another set, known as the rostral ventromedial medulla (RVM), and finally to a set in the spinal cord. This so-called "descending pathway" is the principal circuit through which opioids relieve pain in the body.

Co-authors of the Fields study were Sheralee A. Tershner, formerly a post-doctoral fellow in the Fields lab and currently of the Department of Psychology, Western New England College, and Jennifer Mitchell, formerly a graduate student in the Fields lab.

The study was funded by the National Institute on Drug Abuse.