To each sex its pains

Menstrual cramps, man flu, migraine. Several types of pain are associated more with one gender than another. Three studies have just shown that men and women actually experience pain differently. A researcher from Université Laval participated in two of these projects.

Mathieu Perreault
The Press

Female and male pain

These two studies were published last March, one in the Journal of Neurosciencethe other in the review Brain. The first established that a molecule called “calcitonin gene-related peptide” (CGRP) appears to be involved in the transmission of pain signals in women, but not in men. The second studied two other neurotransmitters, called BDNF and KCC2, which play a role in the transmission of pain in men, but not in women.

“We find an important signal for pain in women, and [l’autre étude identifie] an important signal for pain in humans,” explains Yves De Koninck. This neuroscientist from Laval University is one of the authors of the CGRP study.

Michael Hildebrand of Carleton University, the lead author of the other study, explains that in men (but not women), a problem with the neurotransmitter BDNF (or brain-derived neurotrophic factor) leads to uncontrollable excitability of neurons, which is the source of pain. “It’s like losing a brake,” says the D^r Hildebrand. CGRP induces a similar hypersensitivity.

Change in gastrointestinal bacteria

The other study which recently established a difference in the experience of pain between the sexes comes from Ireland. “I am an expert in pain and the links between the brain and the gastrointestinal system,” says Siobhain O’Mahony, of University College Cork, who published her work in June in the journal Brain, Behavior, and Immunity.

“Our animal models are male-based, because there’s more consistency in the results,” says Siobhain O’Mahony.

“We now need to identify the bacteria involved, to perhaps propose a change in diet (linked to the menstrual cycle) to women who suffer from chronic pain”, underlines the researcher. The study was based on 31 healthy people, half of them women, who were tested for sensitivity to ankle pain.

Migraine medications

In recent years, drugs targeting CGRP have greatly improved the treatment of migraine. Given the total or relative absence of the mechanism involving CGRP in men, do these drugs only work for women? “Migraine is a particular entity,” explains Jack Puymirat, neurologist specializing in migraine at the CHU de Québec.

“First of all, 80% of the patients are women. Then, it seems that migraine pain is different from other pains. Tension headaches are very common in women with migraine, more so than in men. Anti-CGRPs work well for this problem, in both women and men. But neck pain, also more common in women with migraine, is not reduced by anti-CGRP. » The D^r De Koninck believes that the CGRP mechanism is less important in humans, rather than being absent altogether.

Sexism in clinical trials

These studies echo a 30-year effort to increase the proportion of women in clinical trials. “In the 1980s, we realized that clinical trials of drugs were mostly done on men,” says Natalie DiPietro Mager, a pharmacist at the University of Northern Ohio. She published in 2016 in the journal Pharmacy Practice a history of changes in this file.

“In particular, there were drugs that were withdrawn because of side effects for women, which had not been observed during clinical trials on men. The situation has improved, according to the D^D Di Pietro Mager. But Irving Zucker, a biologist from the University of Berkeley who has published for twenty years on the subject, believes that there are still too few analyzes differentiated by sex.

“There are very few women in phase 1 trials, which focus on the safety of new molecules,” says Mr. Zucker, who is of Montreal origin. Phase 1 effects are often done on paid volunteers, usually young men. A study published in 2020 in the journal Critical Public Health showed that women are often turned away as paid volunteers because of the risks of undetected pregnancy or pregnancy occurring soon after the phase 1 clinical trial.

Women underrepresented in cancer clinical trials

Women are underrepresented in clinical trials in two-thirds of medical specialties, a 2021 Stanford University study published in the journal JAMA Network Open. Cancer was one such area of ​​underrepresentation.

The D^D Vikki Ho sent to The Press a study from the famous Mayo Clinic in Minnesota, which shows that for five types of cancer, women constituted only 41% of patients in clinical trials in 2013, even though they had 53% of the prevalence. The gap was particularly wide for lung cancer (39% and 55%) and melanoma (35% and 51%), according to the study published in 2018 in the journal Care Delivery. A Canadian study published last year in the JAMA Oncology had similar results, showing that there was no improvement over the years.

A Canadian Story

Canada has played an important role in studies of sex differences in medical research. In 2015, a study from the University of Toronto “opened the ball rolling, raising the question: what is different between the sexes? “, explains the D.^r From Koninck. “It was really at this time that we talked more about the importance of having animal studies with females, in general in medical research. »

This 2015 study, published in Nature Neuroscience, showed that KCC2 neurotransmitters did not appear to play a role in pain hypersensitivity in female mice. The importance of this neurotransmitter had been established in Nature in 2005 by the D^r De Koninck and by Mike Salter of Toronto’s Sick Kids Hospital.

Non-binarity

The notion of sex often gives way to that of gender. Should we still do analyzes according to birth sex? “I think it’s very important, but it will take more targeting of other minorities, including gender identities and non-binaries,” says Dr.^D Di Pietro Mager.

For its part, the D^D Ho points out that one way to arrive at analyzes focusing on sexual or gender minorities would be to combine several studies into a meta-analysis. “If we do analyzes for men and women, the statistical power is already halved,” says Dr.^D Ho. By encouraging the collection of data for different minorities, one could possibly combine 5 or 10 studies to see if there are different results for these minorities. »