Biological differences between men and women impact perception of pain and choice of medication

From Wired Magazine – Women’s Pain Is Different From Men’s—the Drugs Could Be Too

Men and Women can’t feel each other’s pain. Literally. We have different biological pathways for chronic pain, which means pain-relieving drugs that work for one sex might fail in the other half of the population.

So why don’t we have pain medicines designed just for men or women? The reason is simple: Because no one has looked for them. Drug development begins with studies on rats and mice, and until three years ago, almost all that research used only male animals. As a result, women in particular may be left with unnecessary pain—but men might be too.

Now a study in the journal Brain reveals differences in the sensory nerves that enter the spinal cords of men and women with neuropathic pain, which is persistent shooting or burning pain. The first such study in humans, it provides the most compelling evidence yet that we need different drugs for men and women.

“There’s a huge amount of suffering that’s happening that we could solve,” says Ted Price, professor of neuroscience at the University of Texas, Dallas, and an author of the Brain article. “As a field, it would be awesome to start having some success stories.”

Modern-day pain control is notoriously dismal. Our go-to medicines—opioids and anti-inflammatories—are just new versions of opium and willow bark, substances we’ve used for thousands of years. Although they are remarkably effective in relieving the sudden pain of a broken bone or pulled tooth, they don’t work as well for people with persistent pain that lasts three months or longer.

Some 50 million people struggle with pain most days or every day, and chronic pain is the leading cause of long-term disability in the United States. Women are more likely than men to have a chronic pain condition, such as arthritis, fibromyalgia, or migraines.

Meanwhile, pain medications are killing us. About 17,000 people die each year from prescribed opioids as clinicians write almost 200 million opioid prescriptions, or more than one for every two American adults.

The failure to include sex differences in the search for better pain relief stems in part from flawed but deep-seated beliefs. “[Medical researchers] made the assumption that men and women were absolutely identical in every respect, except their reproductive biology,” says Marianne Legato, a cardiologist who began sounding an alarm in the 1980s about differences in heart attack symptoms among women. She went on to pioneer a new field of gender-specific medicine.

The physiology of pain is just one of many ways that men and women differ, she says. But she isn’t surprised that no sex-specific medicines have emerged. The medical community—including pharmaceutical companies—didn’t appreciate the variation between men and women, including in their metabolisms, immune systems, and gene expression.

“If there were differences in how their drugs worked between men and women, they didn’t want to hear about it,” she says.

… Tailoring new medicines to men or women would be revolutionary, particularly considering that it took many years for women (and female animals) to get included in pain research at all.

Fearful of potential birth defects, in 1977 the FDA cautioned against including women of childbearing age in clinical trials, which meant women used drugs solely designed for men. By 1993, the thinking had changed, and Congress passed a law requiring the inclusion of women in clinical trials funded by the National Institutes of Health. Although clinical trials now include both men and women, they often don’t report results by sex.

https://www.wired.com/story/womens-pain-is-different-from-mens-the-drugs-could-be-too/

Why the sexes don’t feel pain in the same way

Why the sexes don’t feel pain the same way –  After decades of assuming that pain processing is equivalent in all sexes, scientists are finding that different biological pathways can produce an ‘ouch!’. Amber Dance, Nature, 3/27/2019

Robert Sorge was studying pain in mice in 2009, but he was the one who ended up with a headache.

At McGill University in Montreal, Canada, Sorge was investigating how animals develop an extreme sensitivity to touch. To test for this response, Sorge poked the paws of mice using fine hairs, ones that wouldn’t ordinarily bother them. The males behaved as the scientific literature said they would: they yanked their paws back from even the finest of threads.

But females remained stoic to Sorge’s gentle pokes and prods1. “It just didn’t work in the females,” recalls Sorge, now a behaviourist at the University of Alabama at Birmingham. “We couldn’t figure out why.” Sorge and his adviser at McGill University, pain researcher Jeffrey Mogil, would go on to determine that this kind of pain hypersensitivity results from remarkably different pathways in male and female mice, with distinct immune-cell types contributing to discomfort2.

Sorge and Mogil would never have made their discovery if they had followed the conventions of most pain researchers. By including male and female mice, they were going against the crowd. At the time, many pain scientists worried that females’ hormone cycles would complicate results. Others stuck with males because, well, that’s how things were done.

Today, inspired in part by Sorge and Mogil’s work and spurred on by funders, pain researchers are opening their eyes to the spectrum of responses across sexes. Results are starting to trickle out, and it’s clear that certain pain pathways vary considerably, with immune cells and hormones having key roles in differing responses.

This push is part of a broader movement to consider sex as an important variable in biomedical research, to ensure that studies cover the range of possibilities rather than gleaning results from a single population.

Sex differences in pain responses

Current Opinion in Physiology, Volume 6, December 2018, Pages 75-81, by Robert E Sorge, Larissa J Strath

Sex differences have been reported in the experience of pain and in the prevalence of chronic pain conditions. However, recently work has uncovered biological differences in the utilization of immune cells and basic function of afferents that shed light on the underpinnings of these sex-dependent findings. In addition, work in healthy controls and chronic pain patients have highlighted biases in attribution of pain and assessment of pain intensity that further reinforce sex differences.

Together, the combination of biological differences, distinct psychological coping strategies and outside bias result in the maintenance of disparities in the experience of pain based on sex. Recognition of sex differences and the underlying mechanisms can only improve treatment and patient outcomes.

Does Gender Influence Pain Sensitivity?

Biology may play a role in nociception and analgesia, and researchers are examining the potential effects of social and psychologic factors. Neurology Reviews. 2017 May;25(5):16-19

Biologic differences may explain gender differences in pain sensitivity. Research during the past 20 years has suggested that microglia play an important role in nociception. Newer data, however, indicate that microglial involvement in pain may be specific to males. Because the majority of animal research had been performed in male rodents, this observation had not been made previously, said Dr. Mogil.

He and his colleagues injured male and female mice to induce mechanical allodynia. The mice exhibited the same amount of mechanical allodynia, regardless of gender. The investigators next administered minocycline, a glial inhibitor, to the mice. The intervention reversed the allodynia in male mice, but not in female mice. Using fluorocitrate or propentofylline in place of minocycline produces the same result, said Dr. Mogil. Research into the biologic basis for pain modulation in females is ongoing.

All Pain Is Not the Same

Psychologist Discusses Gender Differences in Chronic Pain, Translating Research in Women’s Health and Mental Health to Practice.

Women experience chronic pain longer, more intensely and more often than men, according to a psychologist who works with both men and women dealing with diseases and conditions that leave them suffering.

“Chronic pain affects a higher proportion of women than men around the world,” said Jennifer Kelly, PhD, of the Atlanta Center for Behavioral Medicine. “We need to encourage women to take a more active role in their treatment and reduce the stigma and embarrassment of this problem.”

Speaking Thursday at the 118th Annual Convention of the American Psychological Association, Kelly said the latest research offers interesting insights into how physicians and mental health providers can better treat women with chronic pain.

… The American Psychological Association, in Washington, D.C., is the largest scientific and professional organization representing psychology in the United States and is the world’s largest association of psychologists.

Women suffer needless pain because almost everything is designed for men

Why women are 50 percent more likely to be misdiagnosed after a heart attack and 17 percent more likely to die in a car crash. By Sigal Samuel, Apr 17, 2019, Vox

In medical lore, the term “Yentl syndrome” has come to describe what happens when women present to their doctors with symptoms that differ from men’s — they often get misdiagnosed, mistreated, or told the pain is all in their heads. This phenomenon can have lethal consequences.

Many, many women have had this experience when they go to the doctor. I had it myself, years ago. As a spate of articles about the phenomenon has come out in the past couple of years, more people have begun talking about a “gender pain gap.”

In a new book, Invisible Women: Data Bias in a World Designed for Men, the British journalist and feminist activist Caroline Criado Perez argues that this is part of a larger problem: the “gender data gap.”

Basically, the data our society collects is typically about men’s experience, not women’s. That data gets used to allocate research funding and make decisions about design. Because most things and spaces — from pain medications to cars, and from air-conditioned offices to city streets — have been designed by men with men as the default user, they often don’t work well for women.

Even when researchers do gather data from women as well as men in their studies, they often fail to sex-disaggregate it — to separate out the male and female data they’ve collected and analyze it for differences. That’s crucial, because a new pain medication that’s ineffective for men may work great for women, but you’d never know it if you mixed all their data together.

All this gives rise to a powerful possibility: What if we can reduce suffering for half the population, simply by ceasing to design everything as if it’ll only be used by men?

Criado Perez’s book discusses how biased design shows up pretty much everywhere, but the issues she identifies in the realm of health are the most striking because they’re the most dangerous.

I spoke to Criado Perez about why the medical system treats women’s pain differently, whether we need to design drugs specifically for women, and how she dealt with the gaslighting she experienced while working on the book. A transcript of our conversation, lightly edited for length and clarity, follows.

Not just in humans – gender differences are in other mammals

Sorge RE, Mapplebeck JC, Rosen S, et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci. 2015;18(8):1081-1083.

A large and rapidly increasing body of evidence indicates that microglia-to-neuron signaling is essential for chronic pain hypersensitivity. Using multiple approaches, we found that microglia are not required for mechanical pain hypersensitivity in female mice; female mice achieved similar levels of pain hypersensitivity using adaptive immune cells, likely T lymphocytes. This sexual dimorphism suggests that male mice cannot be used as proxies for females in pain research.