Could sex hormones explain the difference in opioid use and misuse between genders?
Since 1999, the American opioid epidemic has killed more than half a million people, and according to the National Institutes of Health, three quarters of those casualties were men.
A new study from Washington University School of Medicine in St. Louis suggests that the reason for the gender disparity may be biological.
The research team found that male rats with chronic pain in their paws gave themselves ever increasing doses of fentanyl over time, while female rats with the same chronic pain kept their intake constant.
Researchers believe the difference in behavior is related to sex hormones. They found that when male rats were given the hormone estrogen, they maintained a steady rate of opioid intake.
“These data suggest that men may be inherently predisposed to misuse opioids in the context of pain because of their balance of sex hormones,” said lead author Jessica Higginbotham, PhD, a postdoctoral researcher in the lab of Jose Moron-Concepcion, PhD.
Published March 10 in the journal Neuron, these findings reveal that hormones play a pivotal role in how men and women respond to, use and abuse opioids.
By better understanding the relationship between hormones and chronic pain, experts are hopeful they can uncover new approaches and possible solutions for the growing opioid crisis.
Fentanyl is the leading cause of death for Americans between 18 and 45.
In 2023, the DEA seized a record-breaking 386 million deadly fentanyl doses across the US — enough to kill every American.
A record number of high school teens across the US were killed by fentanyl in 2022, primarily by fentanyl poisonings from counterfeit pills.
Experts note that people in mass misuse opioids for pain relief. Though statistically men are less likely to suffer from chronic pain, they are more likely to overdose on opioids than women.
The research team posits that something other than — or in addition to — chronic pain puts men at higher risk for substance abuse disorder.
“Men and women have the same sex hormones, just in different amounts, and our data suggest that females have a more protective balance than males. But if that balance changes, the risk of developing opioid use disorder could change, too,” said Higginbotham.
Fentanyl acts on the brain in two ways; it blocks the transmission of pain signals and releases dopamine from the brain’s reward center, triggering a euphoric feeling.
Researchers measured the lab rats’ pain response by measuring how quickly they withdrew their paws when touched. They found no difference between the amount of pain experienced by male and female rats or in how much pain relief a dose of fentanyl delivered.
Still, throughout the three-week study, the male rats returned for more and more fentanyl while the females did not.
Researchers uncovered a key gender difference in the amount of dopamine released after each fentanyl dose. The female rats produced the same amount of dopamine regardless of their pain level. Conversely, males in pain generated an ever-increasing dopamine response to the fentanyl doses.
“We had thought that maybe the males developed a tolerance to fentanyl and needed increasing amounts to relieve the pain, but that wasn’t it,” said Jose Moron-Concepcion, PhD, the Henry Elliot Mallinckrodt Professor of Anesthesiology at WashU Medicine and the paper’s senior author.
“The males were taking more and more fentanyl to feel that ever-increasing high. In males, but not females, the pain condition itself affected the reward centers of the brain and drove them to take more drugs.”
Further research indicated that sex hormones were directly responsible for the variation in dopamine responses.
In females, the ovaries are the primary producers of sex hormones like estrogen, progesterone, and even small amounts of testosterone.
Researchers found that female rats whose ovaries were removed reacted to fentanyl like males did, with increased dopamine responses and opioid-seeking behavior. In contrast, male rats treated with estrogen exhibited behaviors similar to those of females.
The team notes that these findings may help explain why menopausal women, who experience a drop in estrogen levels, have higher rates of opioid abuse than their younger, female counterparts.
“What we can do now is start thinking about how to find the right balance of hormones to prevent opioid use disorder in people with chronic pain,” Moron-Concepcion said.
“We haven’t yet looked at the role of other sex hormones such as testosterone or progesterone. Is there a perfect combination of hormones that can reverse the effects of pain on opioid use? That’s something we’d like to find out.”
Last month, the House of Representatives approved a bill to classify fentanyl among the most dangerous drugs — opening the door to traffickers facing mandatory minimum sentences for disseminating the highly addictive and deadly chemical.
The Halt All Lethal Trafficking of (HALT) Fentanyl Act passed by a 312-108 vote, with 98 Democrats joining 214 Republicans to vote “aye.”
The legislation permanently reclassifies most fentanyl as a Schedule I drug, meaning it has no accepted medical use and a high potential for abuse. The bill would not impact the Schedule II status of legal fentanyl that has Food and Drug Administration approval for medical use.
