Wanted: pain differences (M/F)

17 February 2025

Maybe you suspected it already: men and women experience pain differently. But that’s not because one is more sensitive than the other. Research shows that pain signals in men and women are processed via different cells and with different signaling molecules. Do women indeed have a higher pain threshold? And who can put their pain 'on hold' for a while?

When a biological man transitions to a transwoman, they experience more pain, such as headaches or joint pain. Strikingly, this does not happen vice versa. Switching off particular immune cells in male mice makes their neuropathic pain disappear, but in female mice it still continues. These are a few examples of research showing that there are various biological differences between men and women when it comes to pain.

However, it’s not so simple that biology can fully explain the differences in pain experience; there are many more factors involved. 'Research teaches us that pain is very complex', says pain specialist Selina van der Wal. 'In addition to biological differences, there are all sorts of social, cultural, and psychological factors that play a role in the pain experience for both men and women.'

Calming agents

These factors are also part of our society and cause unconscious gender bias. Pain researcher Esmeralda Blaney Davidson: 'When people look at images of a man and a woman both experiencing the same pain and displaying identical facial expressions, they tend to assess the woman’s pain as less severe. Women with acute pain complaints at the emergency room are less likely to receive good painkillers and have to wait longer to see a doctor. General practitioners take women’s pain complaints less seriously. And men are more often prescribed painkillers, while women are given calming agents.'

Women’s pain is underestimated. And while many people think that women have a higher pain threshold, research shows the opposite is true: women experience pain more frequently and more intensely and score higher on pain scales with standardized pain stimuli.

Wound

The fact that men and women biologically differ in the processing of pain signals has only received significant attention in the last decade. These differences are partly due to the immune system. 'When you get a wound, immune cells spring into action. They send pain signals through the nerves to the brain', explains Blaney Davidson. 'Men and women have the same basic immune cell set, but different types of cells are likely involved in pain, and they work with different signaling molecules.'

For example, animal studies show that in males, pain processing happens via microglia, immune cells of the nervous system surrounding the nerves. If these cells are disabled, male mice no longer experience pain, while female mice’s pain persists. In female mice, this pain processing is dependent on a different type of cell, namely T-cells.

Grey matter

And apparently, both sexes in mice can switch this process if necessary: males without the male hormone testosterone shift to a pain response like in females, via T-cells, and experience more pain. Conversely, pain in female mice without T-cells, or in pregnant mice, depends on microglia, like in males.

There are also differences in the brain between men and women. Esmeralda explains: 'Pain is only perceived as pain once the signal from the nerves is processed in the brain. MRI scans show that women have a larger volume of gray matter in brain regions important for empathy. Studies show that empathy plays a larger role in women’s pain experience. When a woman sees someone else in pain, she feels less pain herself than a man does. We think she puts her own pain on hold for a moment.'

Hormones

Hormones also play a role in pain perception. These differences start to become noticeable from puberty. The male hormone testosterone is protective, while female estrogen can worsen pain. 'It’s noteworthy that it’s not so much high estrogen levels that increase pain, but rather fluctuations in those hormone levels that cause higher pain sensitivity', Blaney Davidson explains. Pain sensitivity is also linked to fluctuations in the menstrual cycle.

Research with transgender individuals has also shown hormonal effects. Biological men transitioning to women experience more pain due to female hormones. And animal studies show that female mice feel less pain when given testosterone. How hormones affect the pain system is not completely clear. It could happen in many ways, for example, hormones are known to influence the function of the immune system, which in turn could change the way the pain stimulus is processed.

In the trash?

In the past, pain medication was rarely tested on women. Even in animal research, only 8% of the mice were female. Blaney Davidson: 'Now that we know there are biological differences, researchers include both males and females. But I keep wondering whether perhaps medication that did not work for men might have been very efficient for pain in women but ended up in the trash because nobody bothered to investigate this.'

Van der Wal and Blaney Davidson are busy exploring the mechanisms behind these pain differences. When more is known about underlying mechanisms this will provide important clues as to which types of pain medication might work for both sexes. Therefore, Blaney Davidson recently conducted much research on osteoarthritis and arthritis in mice. She discovered the differences in the immune cells linked to pain in men and women.

Exercise

She also found that in female mice, early pain symptoms in osteoarthritis were linked to damage that developed later. This link was not found in males. Blaney Davidson wondered if this is also the case for humans and has started a study with general practitioner Floris van de Laar, where they are searching GPs' databases. They are now exploring the hypothesis that women that present themselves with pain might develop the diagnosis osteoarthritis later while this link would not be present in males. This forms a nice bridge between basic research and patient implications.

To gain more insight into pain differences, Van der Wal and Blaney Davidson had more than ten thousand people fill out a questionnaire. It showed that women who already experience moderate or severe pain score higher on pain sensitivity. The fact that the pain threshold changes is an important new insight. Furthermore, a higher BMI causes more pain, especially for women. And exercising works really well for pain. For men, this effect is quicker, but for women, more hours of exercise were needed for a positive effect on pain.

But the most important insight? 'Pain is more complicated than we thought', says Van der Wal. 'This study opened our eyes to look much more broadly at other factors that influence pain, rather than just biological sex. We need to further unravel these biological differences. An important insight is that a lot happens on an individual level, influencing how pain signals are interpreted in different ways. With pain, we must focus on the individual and the context, taking all circumstances into account in our care.'

 

Raising pain threshold

Stubbing your big toe on a day when you're in a great mood and getting good news will hurt less than stubbing the same toe when you’ve just had an argument with your partner. Pain is relative and can’t be measured objectively. Research shows that you can influence your own pain experience. What works positively? Looking at cheerful colors, laughing, maintaining a broad social network, exercising, and singing.

 

Image: Eric Scholten

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