Editor’s note: The following is a summary of a talk from the 2018 Australian Pain Society 38th and New Zealand Pain Society Conjoint Annual Scientific Meeting. This year, the meeting took place from April 8-11 in Sydney, New South Wales, Australia.
Why are women more likely to suffer from chronic pain than men? This question was at the heart of a talk by Stephen McMahon at the 2018 Australian Pain Society 38th and New Zealand Pain Society Conjoint Annual Scientific Meeting. McMahon, a pain researcher at King’s College London, discussed current thinking on what remains a thorny question.
“The burden of pain falls significantly more heavily on women compared to men,” McMahon began his talk, “and if you accept that, it immediately gives rise to other questions about why that is, and whether it has any implications for treatment and research.”
Pain is more common in women than in men
McMahon first showed evidence from a self-report questionnaire study from 2009 involving more than 50,000 people. This study examined the prevalence of chronic pain—that is, how common it is—in men and women across the lifespan. The prevalence of chronic pain increased with age for both men and women. But, there was a steady increase in the difference in the number of men and women reporting chronic pain. This separation started in the late teens, and grew larger with age. Another study of sex differences in pain revealed that back pain, osteoarthritis, and migraine were all more common in women compared to men.
However, McMahon was quick to point out that these sex differences don’t apply to all conditions that feature pain. “For some autoimmune conditions, women are greatly more affected than men, but in other conditions, such as diabetes, it’s a much more balanced picture,” he said.
Similarly, in men vs. women, the disparities and changes in the prevalence of chronic pain across the lifespan sometimes vary, depending on the pain condition under consideration. For example, the prevalence of fibromyalgia increases with age, as does the discrepancy between how common this condition is in men vs. women. But, the prevalence of migraine peaks much earlier in women – between the ages of 20 and 30 – and then declines after menopause. McMahon said that this “gives a clue that for some painful conditions, there may be a clear hormonal drive, and that may represent a key difference between men and women in who suffers the most.”
A similar picture: sex differences in experimental pain
Many experimental studies in the lab set out to investigate potential differences in sensitivity to pain between men and women. Some of these studies did not find meaningful differences between the sexes. But when considering and analyzing all of these studies together, as a group—a type of investigation known as a meta-analysis—rather than looking just at individual studies, researchers found that women were consistently more sensitive to experimental pain compared to men.
However, the extent of the differences in experimental pain sensitivity between men and women varies according to the questions researchers ask, and how they measure pain. Measurements of pain can include the pain threshold (the point at which a stimulus such as heat or cold is first perceived as painful), pain tolerance (the most pain a person can tolerate), and pain unpleasantness (a rating of how unpleasant the stimulus is). Still, women consistently report greater sensitivity to different types of experimental pain, including cold pain, heat pain, pressure pain, and muscle pain, compared to men.
Looking to the building blocks of pain
So why are women more sensitive to pain than men? Given that pain is a complex phenomenon, involving different biological, psychological, and social factors, the question is difficult to answer.
McMahon said he is interested in taking a “bottom-up” perspective on this issue. That is, he wants to understand how the pain system works beginning at the level of peripheral nociceptors—the sensory neurons outside the brain and spinal cord responsible for detecting potentially harmful things in the environment such as extreme heat or dangerous chemicals. The next level to consider is the spinal cord, which receives and processes electrical signals from the nociceptors and ultimately relays those signals to the brain, which then interprets all the information it receives, culminating in an experience of pain.
There are countless suggestions for how sex differences in pain sensitivity arise. The bottom-up perspective could help researchers gain a more precise understanding of those differences.
Of great interest to McMahon is the possibility that “the fundamental building blocks of the pain signalling system—the way in which it transduces noxious stimuli—may be different in males and females.” Here he was referring to the manner in which the nociceptors relay sensory information from the body and into the spinal cord.
Over the last two years McMahon and his laboratory have run a number of experiments in animals to identify potential sex differences in these basic workings of the pain system. Many pain researchers set their sights on a piece of tissue from the back of a spinal nerve called the dorsal root ganglia (DRG). The DRG contains the so-called cell body (which contains the cell nucleus) of a nociceptor. The electrical signals produced by nociceptors are transmitted from the body to the DRG, which then relays those signals to the spinal cord.
In pain research, there is a push towards trying to understand what is happening at the level of an individual cell type. This means studying the nociceptors and examining the DRG, which will provide much more detailed information about how the pain system works.
No differences at the cellular level
One approach to studying an individual cell type such as a nociceptor is to look at its sequence of RNA. RNA is a molecule closely related to DNA and is a crucial player in gene expression—the process by which the genetic information stored in DNA directs the making of proteins, which carry out the various functions that cells perform.
When comparing the sequence of RNA in nerve cells from the DRG in pain-free male and female animals, McMahon and his team have found nearly no differences. Indeed, more than 99% of the RNA found in males was also found in females; only nine genes out of more than 25,000 showed differences in expression.
Almost all of the nine genes were linked to either the X or Y chromosome – the sex chromosomes that determine if we are male or female. That wasn’t much of a surprise, since McMahon and his team were indeed looking for differences between sexes. Interestingly, none of the nine genes were related to pain in any known way.
Repeating the above experiments using nerve cells from animals with experimental neuropathic pain (pain from nerve injury), the team again saw nearly no differences between males and females. These findings differed from previous animal studies reporting differences in individual genes in males vs. females with neuropathic pain.
Clearly there are differences between men and women in the prevalence of pain, and in the way they respond to experimental pain in the lab. But McMahon concluded that these differences are not due to changes in the building blocks of the pain system – the nociceptors themselves. Something else must explain the sex differences in pain, and this remains an active area of research in the pain field. Stay tuned…
Lincoln Tracy is a postdoctoral research fellow in the School of Public Health and Preventive Medicine at Monash University, Australia