The nervous system’s dials for communicating chronic pain to the body work differently in male and female mice, according to a study published today in Nature Neuroscience. If this difference is also found in humans, it could lead to chronic pain treatments that are better tailored to the patient. But the most immediate impact might be in basic research — the earliest stages of work — since right now, the mice being used are almost exclusively male.

Chronic pain affects more than 100 million people in the US, which is more than heart disease, cancer, and diabetes combined. And many pain conditions occur more often in women than in men, according to the FDA. That’s why figuring out how male and female mice deal with pain — and whether they do so differently than humans — is so important. After all, most medical research — including pain research — starts with mice.

In the study, researchers focused on microglia, a type of immune cell that can be found in the brain and the spinal cord. These cells are known to play a role in the “volume knob” for pain, explains Jeffrey Mogil, a pain researcher at McGill University and a co-author of the study. The knob turns way up after an injury. A genetic study done in Mogil’s lab a few years ago had indicated that microglia weren’t as important in the pain circuit of female mice. So, the scientists decided to find out if interfering with the microglia would have the same effect in male and female mice.

Male mice had no pain, whereas female mice did

The researchers used mice that were suffering from a hypersensitivity to pain. The scientists gave them drugs that target the microglial cells in the spinal cord, in the hopes that this would prevent the animals from feeling pain. But only male mice responded to the drugs — the female mice still had an increased sensitivity to pain.

When the researchers repeated these experiments in mice under varying conditions, they saw the same results: male mice had no pain, whereas female mice did. “Whatever the manipulation is, in every case, blocking microglia or some part of the microglial system brings the pain sensitivity back to normal in male mice, and doesn’t do anything in female mice,” Mogil says.

Now looking at the human we see this: There is a growing body of literature that indicates women are more likely than men to be undertreated for their pain.

It appears that gender affects not only pain perception, pain coping, and pain reporting, but also pain-related behaviors, including use of healthcare and the social welfare system. It is also probable that men and women differ systematically in their responses to pain treatments, although further research is needed in this area.

For many common pain conditions, including migraine and tension-type headache, facial pain, and abdominal pain, population-based studies indicate higher prevalence rates in adult women than in adult men.

Despite the difficulties with human laboratory experiments on pain sensitivity, many investigators are willing to draw the inference from these studies that women are, in general, more sensitive to painful stimuli than men, and that this difference is biologically based.

Whatever the pain prevalence differences for men and women, most studies show that women seek healthcare for pain at a higher rate than men:

• • One study indicated that women are more likely to be given sedatives for their pain, while men are more likely to be given pain medication.

  • Faherty and Grier studied the administration of pain medication after abdominal surgery and found (after controlling for weight) that physicians prescribed less pain medication for women than for men ages 55 or older, and that nurses administered less pain medication to women than to men ages 25-54 years.

  • Beyer et al examined pain medication given to children and found that, after surgery, boys received significantly more codeine than girls, and girls were more likely than boys to be given acetaminophen.

  • In a 1994 study of 1,308 outpatients, Cleeland and colleagues found that women with metastatic cancer were significantly more likely than men with the same diagnosis to receive inadequate pain medications.

  • In a study of several hundred AIDS patients, Breitbart and colleagues found that, based on the WHO analgesic ladder guideline, women were significantly more likely than men to receive inadequate analgesic therapy.

  • A study by Weir and colleagues found that women are less likely than men to be referred to a specialty pain clinic, at least upon initial encounters with their physicians.

  • A study reviewing cancer care at seven outpatient clinics in California found that female cancer patients were prescribed half the pain medication as male patients with the same pain intensity scores.

  • Males outnumber females two to one in the burn population. This is related to male household and job roles, which increase the risk for burn injury. Furthermore, males more commonly engage in risk-taking behaviors involving chemicals, flammable materials, or electricity.So what do we see so for at this point:

• We feel pain more intensely than men, according to a new study of 11,000 men and women who were patients at the Stanford Hospital and Clinics.

• Researchers analyzed electronic medical records of patients’ reports of pain across a range of different diseases, and found a distinct gender-driven difference in how much discomfort patients say they felt. The study included 47 disorders — from cancer to back conditions and infectious diseases — and more than 161,000 patient-reported pain scores. The patients were all asked by nurses or other health personnel to rate their pain on an 11-point scale, with 0 representing “no pain” and 11 signifying the “worst pain imaginable”.

• Not surprisingly, most responses clustered around either the two extremes of very little pain or extreme pain or the middle score of 5. But overall, women were more likely to indicate higher pain levels than men, says lead author Dr. Atul Butte, chief of systems medicine in the department of pediatrics at Stanford University School of Medicine. And that was true across almost all of the different diseases. “That was the most surprising finding,” says Butte. “We completely wouldn’t have expected such a difference across almost all disorders, where women were reporting a whole pain point higher on the 0-to-10 scale than men.”

• Of course, self-reports can’t account for the fact that people may define tolerable and intolerable pain in vastly different ways, says Butte, but the fact that a gender difference emerged from such a large number of patients suggests that the effect is real.

• What accounts for the gender gap? Hormones may explain some of the difference — studies have shown that estrogen in women can help dampen the activity of pain receptors, helping them to tolerate higher levels of pain. That means, however, that they may become more sensitive to pain during low-estrogen parts of the menstrual cycle.

• There may also be explanations that have nothing to do with biology. Men, for example, may feel compelled by cultural stereotypes to be tough, and therefore report feeling less pain than they really do —especially when asked by the mostly female nursing staff.

Still, even if non-biological factors are influencing how much pain men and women report, Butte says the difference is worth noting. “The reasons may be biological or they may not be, but we should still be aware of the bias that patients have in reporting pain,” he says. He is hoping to continue the research by following up these results with surveys of patients’ ratings after they were treated for pain. That may help doctors to better address the real pain patients may be feeling.

Through the National Library of Medicine in 2022 (https://pubmed.ncbi.nlm.nih.gov/36038207/) They state; “Chronic pain affects 20% of adults and is one of the leading causes of disability worldwide. Women and girls are disproportionally affected by chronic pain. About half of chronic pain conditions are more common in women, with only 20% having a higher prevalence in men. There are also sex and gender differences in acute pain sensitivity. Pain is a subjective experience made up of sensory, cognitive, and emotional components. Consequently, there are multiple dimensions through which sex and gender can influence the pain experience. Historically, most preclinical pain research was conducted exclusively in male animals. However, recent studies that included females have revealed significant sex differences in the physiological mechanisms underlying pain, including sex specific involvement of different genes and proteins as well as distinct interactions between hormones and the immune system that influence the transmission of pain signals. Human neuroimaging has revealed sex and gender differences in the neural circuitry associated with pain, including sex specific brain alterations in chronic pain conditions. Clinical pain research suggests that gender can affect how an individual contextualizes and copes with pain. Gender may also influence the susceptibility to develop chronic pain. Sex and gender biases can impact how pain is perceived and treated clinically. Furthermore, the efficacy and side effects associated with different pain treatments can vary according to sex and gender. Therefore, preclinical and clinical research must include sex and gender analyses to understand basic mechanisms of pain and its relief, and to develop personalized pain treatment.”.