2rd Post Series Part 3 Male - female pain

[johnsmith]

In the 28th March 2019 edition of Nature science journal pages 448 to 450 there is an article titled "The Pain Gap" by Amber Dance.

nature.com/articles/d41586-...

This article discusses the issue that the causes of pain in the female is different than that in the male. This is the first time that I have come across this issue. Up to to the point of reading the article I made the assumption that it was the same in both female and male genders. I cannot comment on the science. However, I thought that this was worth bringing to Painconcern so that those who are interested can undertake further investigation. I provided internet references so that those who want can give the appropriate to their doctors.

Pain responses seem to change throughout life, around the time hormone levels rise or fall. Studies looking only at biological sex have found that, at puberty the rates of pain conditions rise more in girls than in boys. And as people age, age some hit the menopause, hormonal levels change again, and sex differences in chronic pain rates begin to disappear. Pregnancy changes pain responses, too

I will present information from the article with internet references.

In 2009 Robert Sorge at McGill University Canada was investigating how mice develop an extreme sensitivity to touch. Sorge found that male mice responded the way the literature said they would. The female mice did not respond at all. Up to this time all the research had been done on male mice and none on female mice. Further investigation found that pain from hypersensitivity in male and female mice was due to different pathways, with distinct immune-cell types contributing to discomfort. The results from further research has made it clear that there is a spectrum of responses across the sexes. Results of investigations are showing that certain pain pathways vary considerably, with immune cells and hormones having key roles in differing responses.

"...some 20% of people worldwide experience chronic pain - and the majority are women. Today [sic March 2019] the pharmaceutical market offers the same pain drugs to everyone. But if the roots of pain are different, some drugs might work better in some people than in others.

Moreover, people might require different pain medications when hormone levels fluctuate though life. And a person's sex doesn't always fit clearly into the categories of male and female: it is determined by a spectrum of characteristics, including genetics, anatomical development and hormone levels, each of which might affect a person's needs in pain therapy. The picture is a long way from complete, ...."

Sorge R. E. et al. J Neurosci 31, 15450-15454 (2011).

jneurosci.org/content/31/43...

A bacterial molecule called lipopolysaccharide was injected into the spines of mice. This drew the attention of microglia, the nervous system's resident immune cells only in male mice and not in female mice. This led to inflammation only in male mice.

"...They injured the animals' sciatic nerves which run from the lower back down each leg. This led to a form of chronic pain that happens when the body's pain detecting system is damaged or malfunctioning. It caused both male and female mice to become extra sensitive to touch.

Yet even this case there were differences. Microglia seemed to have a prominent role in the pain of males, but not in that of female mice.[Sorge R. E. et al. Nature Neurosci 18, 1081-1083 (2015).]"

ncbi.nlm.nih.gov/pmc/articl...

"Sorge and a team of collaborators from three institutions found that, no matter how they blocked microglia, this eliminated the pain hypersensitivity in males alone.

It's not that females were immune to pain. They were just as bothered by nerve injury as the males were, but they weren't using microglia to become hypersensitive to touch."

"...Sorge tried the same nerve injury in female mice lacking T cells. They still became hypersensitive to the fine hairs [sic type of sensitivity test], but the mechanism now seemed to occur through microglia. In females lacking T cells, blocking the activity of microglia prevented this pain response [sic sciatic nerve damage], just as it did in males. And when the researchers transferred T cells back to female mice that was lacking them, the animals stopped using microglia in nerve-injury pain...

...The results showed that even though everybody's pain might look similar from the outside, scientists can't assume it's the same on the inside." This has implications in the treatment of people with chronic pain by medical doctors. Many a person with chronic pain where a treatment has not worked has been dismissed as its in the head. The patient had no defense to this accusation. The implications is that treatment maybe has not worked for a variety of reasons to do with physical reasons not yet examined for.

Research in in the 2011 and 2015 papers indicated that pain mechanism pathways depended on the hormone testosterone level. Male mice with low testosterone level had a mechanism similar to that of female mice. Female mice given testosterone had a mechanism similar to that of male mice.

"...neuropharmacologist Ted Price, at the University of Texas at Dallas, and his collaborators have found preliminary evidence, published this month [sic North, R.Y et al Brain https//doi.org/10.1093/brain/awz063 (2019). academic.oup.com/brain/adva...], of differences in how immune cells contribute to pain in people.

They're working with nerve tissue removed from individuals with cancer, whose tumours had invaded their spines. In nerves excised from men experiencing pain, Price's team found signs of inflammation caused by an immune cell called a macrophage. These cells serve a similar function to microglia. In women who were in pain, however, the more important players seemed to be nerve cells themselves and a short stretch of protein building blocks (called a peptide) that stimulates nerve growth. The results suggest parallels between human and rodent sex differences, says Price."

There are hints that some women might have a genetic predisposition to chronic pain. A suite of RNA molecules have been found to be elevated in women who develop chronic neck, shoulder or back pain after motor-vehicle accident. Many of these RNA molecules are encoded by genes on the X chromosome, of which there are two copies in women. Linnstaedt has said: "It will enable us to develop new therapeutics that can either be used specifically in women or at higher doses in women.

"In a study published online in November 2018, Price and his team reported that a diabetes drug called metformin reduces microglial population surrounding sensory neurons in the spinal cord. They also showed that the drug blocks pain sensitivity from nerve damage only in male mice [sic Inyang, K. E. et al Pharmacol. Res 139 1-16 ncbi.nlm.nih.gov/pubmed/303... (2019)]. 'It doesn't do anything in the females; in fact, it got a little bit worse,' says Price, ..."

"...Higher doses do help females receiving one of the oldest pain drugs in the pharmacy: morphine. Women and female rodents both usually require higher doses of morphine to achieve the same pain relief as men and male rodents says Anne Murphy, a neuroscientist at Georgia State University in Atlanta."

Murphy's team reported in 2017 [sic Doyle, H. H., Eidson, L. N. Sinkiewicz, D. M, & Murphy,A. Z. Neurosci 37 3202-3214 ncbi.nlm.nih.gov/pubmed/282... (2007)] Morphine "dulls pain by blocking neurons in a brain called the periaqueductal grey, or PAG. But the drug can also activate microglia there, counteracting morphine's pain-relieving effects."

"...There's at least one drug already on the market that scientists have reason to think might work differently across sexes. In 2018, the US Food and Drug Administration approved migraine treatments based on antibodies against CGRP a peptide found in the nervous system that is involved in these kinds of headache. Migraines affect three times as many women as men.

In an as-yet-unpublished study of mice and rats led by Price and Dussor applied CGRP to the thick membrane surrounding the brain. In females, the peptide created a response that looked like a migraine: the animals grimaced and their faces were hypersensitive to touch. In males: 'Nothing,' says Dussor. Modern anti-CGRP medicines might work better in women than in men, he adds - but the drug's clinical trials didn't check for such effects.

That's typical of many drug trials. They usually include men and women, but the members of each often aren't high enough to suss out differences."

"...Mogil thinks that pain pathways will be determined by hormone levels. He predicts that people with more than a certain threshold of testosterone will have pain mechanisms associated with males, and those whose testosterone falls below that level will experience pain through mechanisms common in females.

Pain responses also seem to change throughout life, around the time hormone levels rise or fall. Studies looking only at biological sex have found that, at puberty the rates of pain conditions rise more in girls than in boys. And as people age, age some hit the menopause, hormonal levels change again, and sex differences in chronic pain rates begin to disappear. Pregnancy changes pain responses, too, Mogil's group reported in 2017 that, early in pregnancy mice swing from a typically female, microglia-independent mechanism of pain sensitization to a more male-associated one that involves microglia. By late pregnancy, the animals don't seem to feel chronic pain at all [sic Rosen, S, F. et al J. Neurosci 37 9819-9827 jneurosci.org/content/jneur... (2017)]."

I have been reading healthunlocked forum entries for about six to seven years. Throughout this time I have seen no comments on responses to medication based on gender. The "Nature " article, I have severely paraphrased in order to provide material to present to a medical consultant when discussing pain issues. The issue of gender, age and pain response clearly needs consideration. It is not my field of expertise and study. However, I do welcome critical responses and further inquiries. I may not be able to answer the queries, but I can try and make further inquiries.

[cyberbarn]

As a researcher (not a clinical) studying representations of pain, the article is a very good one and I urge people to read it for themselves (it isn't that John didn't do a good job of summarising, he did!).

The one thing I would say is that humans are not large mice or rats that have lost their fur and tails. There are many animal experiments that have translated across to humans, but many that don't. So if results are based on animal studies only, it is important not to jump to conclusions hoping that it also pertains to humans.

Equally, it is now fully recognised that the male and female of all species can react differently and that women were poorly served by the research on men only, which as the article says is no longer allowed to happen. However, the problem can arise, especially in pain, where the biases result in clinicians assuming that the differences are psychosocial (those weak old women in pain, it is only because they are lonely) rather than physical. Hence many women who express pain are sent off to social prescribing or psychiatrists.

[edythe in reply to cyberbarn]

Thanks to you both for drawing attention to the article and for the further clarification - most helpful!

[waylay in reply to cyberbarn]

Fascinating! I'm in perimenopause at the moment... Yay?