Pain is ‘dramatically’ different in men and women

Men and women don't experience pain the same way.

Give someone an electric shock; bind a tourniquet tighter and tighter around their leg; submerge their hand in icy water; prick them with a pin: Researchers have done it all, and they've found — across years and hundreds of studies — that the same stimuli provoke greater pain responses in women .

Women, in other words, are more sensitive to pain than men. They report feeling it more in just about every way: more intensely, more often, for a longer time. They grapple with more headaches, more painful gut conditions, more pain in their backs and pelvises and bones and, research suggests, virtually every other part of their bodies . Of the hundreds of millions of chronic pain patients around the world, they comprise roughly 70 percent.

And underlying those striking disparities, studies are finding, is a still more extensive web of differences connected to both gender and biological sex that help shape how pain manifests, and how badly it hurts.

Distinct types of cells appear to be involved in processing pain in each sex. Sex hormones have been shown to exacerbate or dampen it. Disparate stress levels, gender roles and even the ways men and women tend to think about their own pain all seem to influence how hard it hits. The list goes on — and likely keeps going on far beyond what research has so far uncovered.

Though studies have long pointed toward sex and gender differences in pain, until recently most researchers devoted little attention to them, if not dismissing them entirely.

That has at last started to change in the past decade, as new requirements from health agencies have driven a surge of new findings on the subject and, for the first time, brought it out of the narrow corner of the field where it was historically relegated.

But researchers may still just be scratching the surface of the disparities.

"We're not even remotely close to answering the question of how much is sex and how much is gender," says Jeffrey Mogil, a psychology professor at McGill University. "We only know a fraction of the biological sex differences. I mean, they're only starting to emerge now. And pain and gender is almost completely unstudied. There's only a handful of papers that have ever been done."

Major differences in biology

The sex differences researchers have found in pain biology, though they may only represent a "fraction" of all those that exist, are nonetheless extensive.

"The biological processing of pain, regardless of how much pain is produced, is dramatically sex dependent. Different genes are being used in both sexes, different proteins, different cell types, dramatically different biology in each case," summarizes Mogil, who has been studying the subject for decades.

Dozens of genes and proteins have now been linked to pain in one sex but not the other. As of early this year, studies had tied at least 49 to chronic pain processing only in male rodents and 35 only in female rodents, according to a fact sheet compiled by Mogil and other researchers for the International Association for the Study of Pain.

Some gene-level differences may contribute to disparities in pain tolerance. A variation in a gene that encodes one type of opioid receptor, for instance, has been connected to increased pain sensitivity in women , while variations in a gene that encodes another type have been linked to a higher threshold for thermal and muscle pressure pain in men.

Hormones, too, have been found to influence pain sensitivity. Estrogen appears to play a role in suppressing pain at high concentrations, while lower levels of estrogen or higher ones of progesterone typically seem to amplify it.

Prolactin, a hormone best known for its role in producing breast milk, increases "female-selective" sensitivity in the sensory receptors that initiate pain signals in the body, according to a study published earlier this year . The researchers found that a separate chemical messenger, orexin B, does the same in men and male mice.

Testosterone, meanwhile, seems to inhibit pain in both sexes. And research indicates it could be critical in determining which cells and pathways in the immune system are involved in transmitting pain, or developing chronic pain.

This is another aspect of pain processing that apparently varies markedly between sexes: A 2015 study led by McGill University researchers found that distinct types of immune cells act as key mediators of pain in male and female mice. Mounting evidence indicates those differences exist in both the central and peripheral immune systems, as well as in the brain.

Brain imaging studies have also identified "significant sex differences" in both the structure of chronic patients' brains and how they respond to pain.

These differences are a result of more than just biology, researchers note. Natalie Osborne, a postdoctoral research fellow who uses neuroimaging to study chronic pain, emphasizes that brain scans reflect not only research subjects' biological sex, but also the influence of gender and other aspects of their lives.

"I'm bringing individuals in and scanning them in the MRI," she says. "I'm not just scanning the biological differences, because this brain has also been socialized as one gender or another for years. So the differences that I see in the brain are a cumulative result of their XX, XY or whatever chromosomes, their hormone exposure over their life and how they were socialized."

Gender's role

Research is showing that pain itself is "multifactorial," says Diane Hoffmann, the director of the University of Maryland Law School's law and health care program and co-author of a widely cited 2001 study examining sex and gender disparities in pain and its treatment.

"You can't just look at the biological and physiological," says Hoffmann. "You have to look at that in combination with not just the psychological, but social and cultural impacts and how they affect a person's experience of pain as well."

Stress, for instance, has been found to exacerbate pain , and childhood trauma to increase the risk of developing chronic pain later in life. Depression and anxiety have also been shown to worsen both chronic and acute pain.

Women report suffering all four at notably higher rates than men .

Researchers have linked gender roles to disparities in pain tolerance as well. People who identify as more stereotypically masculine display a higher threshold for pain, a 2012 meta-analysis found, as do those who consider themselves less sensitive to pain than the typical man or woman. Women and men appear to employ different mechanisms to cope with pain, too: Studies have found that women do more catastrophizing , or dwelling on their pain and making it out to be much worse than it actually is. That practice is associated with greater pain severity.

Women are also more likely to seek help for pain than men are. But when they do, health care providers more often dismiss, psychologize and undertreat their pain, potentially worsening existing disparities.

Pain researchers stress that a lot of work still has to be done to pick apart the tangle of biological and sociocultural factors that play a part in men and women's disparate experiences of pain.

Many pain studies don't separate out data based on sex or gender, much less actively examine their potential influence, researchers point out. Vanishingly few incorporate any transgender or gender-diverse people. And only recently have a significant proportion begun to include female research subjects.

'' body of research

When Mogil started studying sex differences in pain in the early 1990s, there were "just a small number of people doing it," and other researchers were "resistant," he says.

"They would be like, 'Yeah, OK, you found one. You found two. But it's not really anything across the board,'" he recalls.

He began studying the subject because of a quirk of the lab he started working in. While most preclinical researchers bought male rodents to conduct their pain studies with, his lab bred its own mice to save money, which naturally provided both male and female research subjects.

And once female subjects are in the mix, he says, "the sex differences just stare people in the face."

For a long time, however, pain studies including female research subjects remained in the minority — despite increasing evidence that sex differences not only existed, but also posed major questions about findings based only on males.

Mogil and other researchers contended in their 2015 study on the disparate immune cells and pathways involved in mediating pain that "this sexual dimorphism suggests that male mice cannot be used as proxies for females in pain research."

Two years later, researchers from the University of California, Los Angeles reached a similar conclusion in their review of sex-based differences in the brains of chronic pain patients. "Given those differences," they wrote, "mixed-sex studies of chronic pain risk creating biased data or missing important information and single-sex studies have limited generalizability."

During the same time period, however, Mogil found that 80 percent of rodent studies published in 2015 in Pain, the leading journal in the field, included only male research subjects — roughly the same proportion as two decades earlier.

That has at last begun to shift in the intervening years, after the National Institutes of Health (NIH) and its Canadian counterpart began requiring preclinical studies to consider sex as a variable: Mogil found that by 2019 the share of studies including female rodents had climbed to 50 percent .

"And lo and behold," he says, "the number of reported sex differences started exploding."

That 50 percent figure is still far higher than the "essentially zero" it should be, Mogil notes, and male bias persists even in the research that incorporates female subjects. Human studies, meanwhile, dedicate even less attention to the role of sex and gender, even though clinical research with NIH funding has been legally required to include women for more than three decades.

"In animals, it seems well accepted that there are sex differences in pain physiology going from the cellular molecular level on up to the systems level," says Elizabeth Reynolds Losin, the director of Pennsylvania State University's Social and Cultural Neuroscience Lab. "In humans, I feel like it's still kind of a controversial idea that there could be sex differences in pain."

Even as doubts and unanswered questions continue to loom, however, Roger Fillingim, the director of the University of Florida's Pain Research and Intervention Center of Excellence, says he's been "very encouraged by the increased attention, the increased number of publications."

"If you look at research on sex, gender and pain over the last 30 years, it is a dramatically upward slope," he says, citing health agencies' requirements as the driving force for the rise. "There's a lot more attention to sex as a biological variable, to sex differences in pain, and now to the complexity and nuances of sex versus gender."

In the years to come, Fillingim predicts the growing focus on the topic could change not just the understanding of how pain is processed, but also the way it's treated.

"I think it's conceivable," he says, "that within my lifetime, we'll see specific treatments that are developed for women versus men."