According to the results of a new study, biological factors may explain why men are more susceptible to opioid misuse and fatal overdoses compared to women. The study, carried out by researchers at the Washington University School of Medicine, showed that male rats with chronic pain administered increasing doses of fentanyl to themselves over time, while female rats with chronic pain kept their intake constant.

These results are similar to those observed in humans. The research also showed that this behavioral difference in fentanyl use seemed to be driven by sex hormones, since treating male rats with estrogen resulted in them maintaining a steady level of fentanyl 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. We focused on estrogen in this study, but I doubt the effect we saw is due to estrogen alone,” said Jessica Higginbotham, the study’s lead author, in her interview with the NY Post. “It is more likely to be the balance of all the sex hormones in the body that influences risk. 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.”

In addition, the study also revealed significant gender differences in the amount of brain transmitter dopamine released after the animals received a fentanyl dose. The female rat brains produced the same amount of dopamine regardless of their pain level. However, male rat brains generated an increasing dopamine response to the fentanyl doses. Finally, the research results revealed that female rats whose ovaries had been removed responded to fentanyl doses in the same way as males, with increasing amounts of dopamine released in their brains, as well as increases in opioid-seeking behaviour.

“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, the study’s senior author and Professor of Anesthesiology at the Washington University School of Medicine. “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.”

Previous research had already demonstrated that men are disproportionately affected by fentanyl-related overdose deaths compared to women. One study published in the Canadian Medical Association Journal (CMAJ) showed that between 2019 and 2021, more than 70% of opioid-related deaths in Canada occurred among males.

The researchers also suggested that their findings may help explain why women who have gone through menopause and experienced a drop in estrogen levels have higher rates of opioid abuse compared to younger women.

“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.”