It’s official! Men and women experience and manage pain differently

New study reveals that men rely on opioid-based systems to relieve pain, while women may use unknown pathways, prompting the development of gender-specific pain treatments.

Study: Autoregulatory analgesia in men but not women is mediated by endogenous opioids. Image credit: Prostock-studio / Shutterstock

In a recent study published in the journal PNAS Nexusresearchers in the United States used a rigorously designed double-blind, counterbalanced study design involving two separate clinical trials with 98 participants (51 women) to confirm that men and women experience pain differently and to unravel the mechanisms that underpin these differences. Naloxone (opioid antagonist, case) versus saline (placebo, control) were tested for their analgesic properties under noxious heat and meditation conditions.

Study findings revealed that meditation significantly reduced noxious pain in both male and female control cohorts. In the female cohort, naloxone administration did not significantly alter pain responses, but the same was not observed in the male cohort, highlighting that females may not rely on the self-regulating analgesia mechanism used by male bodies to manage pain. Together, these findings suggest the need for additional research aimed at uncovering women’s pain management mechanisms and gender-specific considerations when designing pain management interventions in the future.

Background

It is a medically established fact that compared to their male counterparts, female patients are disproportionately affected by chronic pain. This results in women being routinely prescribed stronger opioids at more frequent rates of consumption. Opioids are “feel good” compounds that bind to pleasure receptors in the brain, replacing pain with pleasurable sensations. They are produced naturally in response to pain in a process called ‘endogenous opioid involvement’.

Unfortunately, for reasons that are not fully understood, female patients are often observed to respond poorly (low treatment efficacy) to routine opioids, resulting in long-term pain severity and increased morbidity. Worryingly, women often respond by escalating pain medication doses, resulting in the development of unhealthy drug dependencies without adequate therapeutic relief. While recent evidence suggests that females (rodent and human) may use alternative non-opioid-based mechanisms of pain regulation, the historical absence of female inclusion in pain research has ensured that conventional pain interventions remain agnostic the gender.

“The identification of sex-related differences in the endogenous opioid system during acute pain relief has been largely overlooked,” the researchers noted. Differences between pain-free and chronic pain populations in opioid receptor availability further complicate this.

About the Study

The present study aimed to address existing gender-specific knowledge gaps in pain management by leveraging data from two randomized clinical trials (NCT03419858; NCT04034004) with closely aligned study methodologies designed to investigate the roles of opioids and meditation in pain relief from pain between the sexes. Both studies included adult (ages 18–65) participants divided into “healthy” (study 1; n = 39) and “chronic low back pain (cLBP; n = 59)” (study 2). Participants were classified as “cases” (meditation + naloxone) and controls (sham mediation + saline placebo).

The total participant cohort included 98 patients (47 men, 51 women), with those with prior meditation experience, blood test-confirmed opioid use, pregnancies, or back surgery within the previous year excluded from the experimental procedures. The study intervention involved subjects being trained in meditation in four 20-minute sessions conducted remotely. Controls were led to believe they were in the meditation cohort and assigned equivalent meditation durations as cases, but without guidance or supervision.

For pain ratings, pain was simulated using noxious (but harmless) heat (49 °C) applied to the participants’ right calves. Drug interventions included intravenous naloxone (high dose – 0.15 mg/kg in 25 mL saline) in cases and placebo (25 mL saline) in controls. An 11-point VAS scale was used to measure participants’ pain responses. Statistical testing of the study hypothesis was performed using analysis of variance (ANOVA) models.

Study Findings

Summary participant statistics revealed that females had a mean age of 37.6, males had a mean age of 39.4, and 78 participants were of white race/ethnicity. Experimental findings highlight that meditation significantly reduced pain sensations in both men and women. However, the addition of naloxone reduced the analgesic effects of meditation in men, while leaving women’s pain responses largely unchanged. Naloxone is an opioid antagonist, blocking the effects of endogenous opioids at their receptors. This finding suggests that male bodies use endogenous opioids to manage endogenous pain, whereas females may rely on alternative but unknown mechanisms to achieve similar pain relief.

Comparisons between patients without pain and patients with cLBP revealed that the beneficial effects of meditation were significantly higher in the latter cohort. Interestingly, these benefits were statistically indistinguishable between men and women, highlighting the utility of meditation as a chronic pain intervention.

conclusions

The present study provides compelling evidence for sex-related differences in endogenous pain management mechanisms. While men routinely use endogenous opioids for pain relief, the same is not true for women. Consequently, women’s bodies respond significantly worse to opioid-based clinical interventions compared to men’s. These findings highlight the need for gender-specific pain treatments, especially given that most conventional pain interventions are optimized for men and involve biological pathways with low efficacy in women.

“Dependence develops because people start taking more opioids when their initial dose stops working,” said Fadel Zeidan, Ph.D., professor of anesthesiology and Empathy and Compassion Research Endowed Professor at the Empathy and Compassion Institute at UC San Diego Sanford. “Although speculative, our findings suggest that one reason women are more likely to become addicted to opioids is that they are biologically less responsive to them and need more to experience any pain relief.”

These findings underscore the importance of continued research into opioid-free pain relief strategies, particularly for women.