The opioid epidemic has devastated communities across the United States, claiming the lives of over half a million people since 1999. Of those deaths, approximately three-quarters are men, according to the National Institutes of Health. This gender disparity in opioid misuse and overdose rates is well documented, but the underlying reasons for why men are disproportionately affected have remained unclear. However, new research conducted by scientists at Washington University School of Medicine in St. Louis is providing novel insights into the biological factors that may contribute to this disparity. Their findings, published in the journal Neuron, suggest that hormonal differences between men and women may play a key role in the way each gender responds to opioids, potentially offering new avenues for addressing the opioid crisis.
The research, which was conducted on rats, examined how sex hormones influence opioid-seeking behavior in the context of chronic pain. The study revealed a significant difference between male and female rats in their response to fentanyl, a powerful opioid. When both male and female rats with chronic pain were given the opportunity to self-administer fentanyl, the males gradually increased their doses over time, while the females kept their opioid intake constant. This behavioral difference was found to be driven by sex hormones, specifically estrogen. When male rats were treated with estrogen, they exhibited behavior more akin to the female rats, maintaining a steady level of fentanyl intake. These findings suggest that hormonal differences could underlie the gender gap in opioid misuse and may explain why men are more prone to developing opioid use disorders.
Jessica Higginbotham, Ph.D., a postdoctoral researcher at Washington University and the lead author of the study, emphasized the role of sex hormones in opioid addiction. According to Higginbotham, the findings point to the possibility that men may be inherently predisposed to misuse opioids in the context of chronic pain due to the hormonal balance in their bodies. Although the study focused specifically on estrogen, Higginbotham believes that the balance of all sex hormones—rather than estrogen alone—likely contributes to the gender differences observed in opioid misuse. “Men and women have the same sex hormones, just in different amounts,” she explained. “Our data suggest that females have a more protective hormonal balance than males, and if that balance shifts, the risk of developing opioid use disorder could change as well.”
Opioid misuse is often driven by the desire for pain relief, but men are more likely than women to overdose on opioids, even though they experience less chronic pain overall. This discrepancy has puzzled scientists, who hypothesize that other factors—such as differences in the brain’s reward systems—may contribute to the higher overdose rates among men. Previous research by Higginbotham’s colleague, Jose Moron-Concepcion, Ph.D., and others in his lab, found that chronic pain affects dopamine levels in the brain. Dopamine is a neurotransmitter that plays a key role in pleasure, reward, and motivation. When opioids are taken, they block pain signals and trigger the release of dopamine, creating a feeling of euphoria. The brain’s reward centers are therefore influenced by both the pain-relieving effects of the drugs and the pleasurable sensations they produce.
In order to investigate how pain affects opioid-seeking behavior in a sex-specific way, Higginbotham and Moron-Concepcion studied rats with chronic pain in their paws. The researchers measured how quickly the rats would withdraw their paws when they were touched, as a way of quantifying their pain levels. They found that there was no significant difference between male and female rats in terms of pain intensity or the amount of pain relief provided by fentanyl. However, the key difference came in the rats’ behavior over the course of the study. While both male and female rats were given the same opportunity to self-administer fentanyl, the male rats gradually increased their doses over time, whereas the female rats maintained a consistent level of opioid intake.
This behavioral difference was linked to dopamine release in the brain. The researchers found that male rats in chronic pain experienced an increasing dopamine response to fentanyl over the course of the study. In other words, the pain made the pleasurable effects of the drug feel even better for the males, driving them to take more of the opioid. In contrast, female rats did not experience this heightened dopamine response, regardless of whether they were in pain. This suggests that the combination of chronic pain and the brain’s reward system may be a key factor driving opioid misuse in men.
The researchers hypothesized that sex hormones could be influencing these dopamine responses. To test this, they removed the ovaries of female rats, which are the primary source of sex hormones such as estrogen, progesterone, and small amounts of testosterone. After the ovaries were removed, the female rats began to exhibit opioid-seeking behavior more similar to that of the males, increasing their fentanyl intake and showing a larger dopamine response. In contrast, when male rats were given estrogen, their dopamine responses and opioid-seeking behavior became more like that of the female rats, with a steady level of fentanyl intake. These results suggest that estrogen may play a protective role in regulating opioid use and could help explain why women, especially those who are post-menopausal, have lower rates of opioid misuse compared to men.
Higginbotham pointed out that these findings could have important implications for understanding opioid use disorder, particularly in the context of chronic pain. She suggested that a better understanding of how sex hormones influence opioid misuse could help guide new treatment strategies. “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,” she said. “This could involve not just estrogen, but potentially other hormones such as testosterone and progesterone.” Researchers are already considering the possibility of developing hormone-based therapies that could help regulate opioid use and reduce the risk of addiction.
One of the most significant aspects of this research is its potential to inform public health strategies aimed at reducing the opioid crisis. While opioid addiction has been widely recognized as a complex, multifaceted issue, the role of sex hormones in opioid misuse could offer a new lens through which to understand and address the problem. As the researchers noted, the balance of sex hormones in the body is a powerful force that may influence how individuals experience pain and respond to opioids. By identifying the hormonal factors that contribute to opioid misuse, it may be possible to develop more effective interventions for men and women alike.
Moreover, the findings could also shed light on the broader issue of gender differences in addiction. While men are more likely to engage in risky behavior and overdose on opioids, women are more likely to experience long-term opioid dependence and to develop opioid use disorders as a result of chronic pain. The new research suggests that the interaction between hormones, pain, and the brain’s reward system is complex and may be key to understanding these gender differences. By exploring the role of sex hormones in addiction, researchers may be able to develop more targeted, personalized treatments that take into account the unique biological and hormonal factors influencing opioid misuse.
More information: Estradiol protects against pain-facilitated fentanyl use via suppression of opioid-evoked dopamine activity in males, Neuron (2025). DOI: 10.1016/j.neuron.2025.02.013. www.cell.com/neuron/fulltext/S0896-6273(25)00131-X