Men and Women Don’t Just Feel Pain Differently—They Produce It Differently, Study Finds

There are many fascinating differences between male and female bodies—from outer anatomy to inner workings. A new study has found that pain production might also differ between the sexes, which could help us rethink—or even improve—how we treat pain.

Researchers from the University of Arizona Health Sciences Center found specific sex differences in nociceptors, the nerve cells that produce pain signals in response to damage or injury. The study included looking at tissue samples from animals and humans, which showed that pain-producing cells responded differently based on sex.

Pain is a common human experience, but data suggests that people in female bodies experience pain conditions at a higher rate. But their pain isn’t necessarily being diagnosed and treated adequately, leading to chronic, life-changing illness.

“It is absolutely true that the majority of the world’s pain patients are women—and we don’t really understand why,” Frank Porreca, PhDresearch director of the Comprehensive Center for Pain & Addiction at the University of Arizona Health Sciences Center and senior author of the study, told Verywell. “Our research could have significance in this.”

Building on the new research could lead to better treatments that address sex-specific pain differences. Here’s more about what the researchers learned about these differences.

How to Body Produces Pain

We have many types of sensory nerves—some detect light, others detect sound, and some detect touch. These sensory nerves activate in response to generally harmless stimuli. But we also have nociceptorswhich are specialized sensory cells. When activated by injury or damage, they send a signal to the brain via the spinal cord.

“Nociceptors are the first step in the chain that leads to pain perception,” said Porreca. “You can think of it as sort of an alarm sensor. The nociceptor is there to tell us when there’s something that is capable of producing damage to our bodies.”

Nociceptors “only respond to these high-intensity stimuli that can produce your perception of pain,” said Porreca, adding that this is important “because you obviously don’t want the alarm to be going off all the time. You only want it to be going off at the moment you need to do something.”

However, under some circumstances, the nociceptor activation threshold can be lowered. If that happens, then something that wouldn’t normally produce pain will.

“Think about going out for a hike and getting a sunburn, a mild inflammation,” said Porreca. “Now, what you realize is the T-shirt rubbing on the back of your neck is producing pain.” The fabric of the shirt would not normally produce discomfort, but the damage to your skin from the sunburn has lowered the threshold for nociceptor activation.

Specific substances in the body, such as prostaglandins (a group of lipid compounds with hormone-like effects), can also lower nociceptive thresholds. In response to an injury, prostaglandins produce an inflammatory response to generate healing by the immune system.

“If we block the actions of prostaglandins with drugs like ibuprofen, that produces pain relief in many circumstances,” said Porreca.

But popular pain treatments aren’t always helpful for everyone. And researchers think one reason may have to do with the sex differences in how pain is produced.

How Women and Men Produce Pain Differently

For the study, Porreca’s team used tissue samples from male and female mice, nonhuman primates, and humans to measure the excitability of nociceptors. The level of excitability usually correlates to the perception of pain, according to Porreca.

The researchers found that different mechanisms lower the threshold for activation of nociceptors in females and males. To experiment with changing the threshold of nociceptor excitability, they used two substances. One was prolactin, a hormone produced by the pituitary gland. The second was orexin B, a neuropeptide made in the brain that helps control wakefulness.

In the current study, the researchers found that prolactin lowered the threshold for nociceptor activation in female cells but did not lower it in male cells. They also found that orexin B lowered the activation threshold in male cells but not in female cells.

The researchers also experimented with blocking prolactin and orexin signaling. They found that blocking prolactin reduced nociceptor activation in female tissue samples but had no effect on male tissue samples. Likewise, blocking orexin B reduced the nociceptor activation in male tissue samples but did not affect female tissue samples.

“What that really means is that if the mechanism that is driving the activity or the ability of nociceptors to be activated is different in men and women—or males and females—then we can target those mechanisms to specifically treat pain only in men or only in women,” said Porreca.

Jagdish Khubchandani, PhDa professor of public health at New Mexico State University, told Verywell that the new study “helps build the biological evidence base for inclusion of various groups in clinical research on chronic and disabling problems like pain disorders.” Khubchandani, who was not involved in the research, added that “the evidence is strong as it was replicated from animals to humans.”

Could the Research Improve Treatment for Women’s Pain?

About half of chronic pain conditions, such as rheumatoid arthritis (RA), fibromyalgia, and migraine, are more prevalent in females. However, most pain medications and treatments do not account for sex differences. While the recent study did not address the differences in pain prevalence, the concepts may lead to better pain treatments for specific conditions where biological sex might be a factor.

“Perhaps the mechanisms that drive and produce migraine in women may be different from the mechanisms that produce migraine in men. Therefore, the therapies could be different for men and women,” said Porreca.

Most research on pain in humans has not analyzed or reported sex differences, according to the International Association for the Study of Pain. A recent review of research from 2012 to 2021 found that less than 20% of the studies on humans analyzed or separated sex-specific differences.

In light of the gap, the new study “provides further evidence on why there should be a tailored approach to research, conducting trials, and therapeutic developments,” said Khubchandani. “Specifically, pain disorders are a leading cause of disability, widely prevalent, and clearly affect a person based on their [sex].”

Porreca added that the knowledge of differences in pain production could help inform clinical trials for treatments of pain mechanisms. However, researchers first must determine if the mechanism they are trying to address is relevant to just males or females or both.

“There are plenty of examples that we can go back and think about and say, ‘Well, we concluded that that potential new therapy was inactive, but maybe the proportion of men and women in the trial were different,’” said Porreca.

The research team also recently released findings on a prolactin antibody, as prolactin may be involved in many pain disorders in females.

“If we sequester prolactin with an antibody, perhaps the antibody could be very useful in normalizing the thresholds for activation of nociceptors in women. That’s what we’d like to do,” said Porreca. At the same time, the team is looking at the orexin receptor to try to devise a way it could be targeted for the treatment of pain in men.

Additionally, Porreca said that many other substances might be involved in the production of pain that are sex-specific—and the team wants to discover and research them. However, studying these topics will take time.

“While this study hints at how [sex] might play a role in the way pain is treated, it also underscores the fact that we are only seeing one potential part of a larger puzzle,” Leia Rispoli, MDa double-board-certified interventional pain management specialist and physiatrist at DISC Sports & Spine Center, told Verywell.

Rispoli, who was not involved in the study, added that “we do not yet have a full grasp of how or why people may experience more pain than others, or maybe why certain patients with no obvious reasons for pain may still be experiencing pain at a high level. Hopefully, more studies like this will help give us that full picture.”