Recent research suggests that men and women rely on different biological systems for pain relief, which could explain why the most powerful medications are often less effective in women, who have more chronic pain than men.
In a study evaluating meditation for chronic lower back pain, the researchers at University of California San Diego School of Medicine discovered that men and women utilise different biological systems to relieve pain.
While men relieve pain by releasing endogenous opioids, the body’s natural painkillers, women rely instead on other, non-opioid based pathways.
Synthetic opioid drugs, like morphine and fentanyl, are the most powerful class of painkilling drugs available. But women are known to respond poorly to opioid therapies, which use synthetic opioid molecules to bind to the same receptors as naturally-occurring endogenous opioids.
This aspect of opioid drugs helps explain why they are so powerful as painkillers, but also why they carry a significant risk of dependence and addiction.
“Dependence develops because people start taking more opioids when their original dosage stops working,” said Fadel Zeidan, professor of anaesthesiology and Endowed Professor in Empathy and Compassion Research at UC San Diego Sanford Institute for Empathy and Compassion.
“Although speculative, our findings suggest that maybe one reason that females are more likely to become addicted to opioids is that they’re biologically less responsive to them and need to take more to experience any pain relief.”
The study combined data from two clinical trials involving a total of 98 participants, including both healthy individuals and those diagnosed with chronic lower back pain.
Participants underwent a meditation training programme, then practised meditation while receiving either placebo or a high-dose of naloxone, a drug that stops both synthetic and endogenous opioids from working.
At the same time, they experienced a very painful but harmless heat stimulus to the back of the leg. The researchers measured and compared how much pain relief was experienced from meditation when the opioid system was blocked versus when it was intact.
The study, published in PNAS Nexus, found:
• Blocking the opioid system with naloxone inhibited meditation-based pain relief in men, suggesting they rely on endogenous opioids to reduce pain.
• Naloxone increased meditation-based pain relief in women, suggesting they rely on non-opioid mechanisms to reduce pain.
• In both men and women, people with chronic pain experienced more pain relief from meditation than healthy participants.
“These results underscore the need for more sex-specific pain therapies, because many of the treatments we use don’t work nearly as well for women as they do for men,” said Zeidan.
The researchers said by tailoring pain treatment to an individual’s sex, it might be possible to improve patient outcomes and reduce the reliance on and misuse of opioids.
“There are obvious disparities in how pain is managed between men and women, but we haven’t seen a clear biological difference in the use of their endogenous systems before now,” added Zeidan. “This study provides the first clear evidence that sex-based differences in pain processing are real and need to be taken more seriously when developing and prescribing treatment.”
Study details
Self-regulated analgesia in males but not females is mediated by endogenous opioids
Jon Dean, Mikaila Reyes, Valeria Oliva, Fadel Zeidan et al.
Published in PNAS Nexus on 14 October 2024
Abstract
Background
Converging lines of preclinical and clinical research indicate that females, in stark contrast to males, display an increased prevalence of chronic pain. Females also demonstrate weaker analgesic efficacy in response to opioid therapies when compared with males. These sex-specific differences may be driven by dimorphic endogenous opioidergic responses. In rodent models, analgesia exhibited in males but not females was reversed by inhibiting endogenous opioidergic reception. In humans, the sex-specific endogenous system(s) supporting the direct attenuation of evoked pain has not been identified.
Methods
To determine if opioidergic-blockade reverses self-regulated analgesia in males as compared to females, the present study combined two operationally analogous clinical trials (n=98; 51 females; 47 males). In a double-blinded, counterbalanced study involving healthy (n=39) and chronic low-back pain (n=59) populations, a high-dose naloxone (μ-, κ-, δ-opioid antagonist) vs. placebo-saline crossover design (15mg/kg bolus + 0.1mg/kg/hour) tested the hypothesis that endogenous opioids mediate analgesia in males but not females. An 11-point visual analogue scale (0=no pain; 10=worst pain imaginable) evaluated pain ratings after noxious heat stimulation (49°C; calf). After baseline pain testing, participants were randomised to a validated four-session mindfulness-meditation or sham-mindfulness meditation training intervention. Participants practiced their respective meditation during noxious heat, intravenous high-dose naloxone and placebo-saline, respectively.
Results
In males and females, meditation significantly lowered evoked pain during saline infusion. Intravenous naloxone inhibited analgesia in males, but pain-relief was well-preserved in females.
Conclusions
The present findings indicate that endogenous opioids mediate self-regulated analgesia in human males but not females and underscore the need to establish sex-specific pain therapeutics.
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