Research Suggests Chronic Pain Should be Treated Differently in Men and Women

By Pat Anson, PNN Editor

Why are women more likely than men to suffer from fibromyalgia, osteoarthritis, irritable bowel syndrome, and other chronic pain conditions?  

Various theories have been proposed over the years, such as gender bias in healthcare, the lingering effects of childhood trauma, and women “catastrophizing” about their pain more than men.

Now there’s a new theory, which could radically change how men and women are treated for pain.

In a groundbreaking study published in the journal BRAIN, researchers at University of Arizona Health Sciences identified two substances – prolactin and orexin B – that appear to make mice, monkeys and humans more sensitized to pain. Prolactin is a hormone that promotes breast development and lactation in females; while orexin B is a neurotransmitter that helps keep us awake and stimulates appetite.

Both males and females have prolactin and orexin, but females have much higher levels of prolaction and males have more orexin.  In addition to promoting lactation and wakefulness, both substances also appear to play a role in regulating nociceptors, specialized nerve cells near the spinal cord that produce pain when they are activated by a disease or injury.

“Until now, the assumption has been that the driving mechanisms that produce pain are the same in men and women,” says Frank Porreca, PhD, research director of the Comprehensive Center for Pain & Addiction at UA Health Sciences. “What we found is that the basic, underlying mechanisms that result in the perception of pain are different in male and female mice, in male and female nonhuman primates, and in male and female humans.”

Porreca and his colleagues made their discovery while researching the relationship between chronic pain and sleep.  Using tissue samples from male and female mice, rhesus monkeys and humans, they found that prolactin only sensitizes nociceptors in females, regardless of species, while orexin B only sensitizes the nociceptors of males.

The research team then tried blocking prolactin and orexin B signaling, and found that blocking prolactin reduced nociceptor activation only in female cells, while blocking orexin B only affected the nerve cells of males. In effect, they found that there are distinctive “male” and “female” nociceptors.  

“The nociceptor is actually different in men and women, different in male and female rodents, and different in male and female non human primates. That’s a remarkable concept, because what it's really telling us is that the things that promote nociceptive sensitization in a man or a woman could be totally different,” Porreca told PNN. “These are two mechanisms that we identified, but there are likely to be many, many more that have yet to be identified.”

Once such mechanism could be calcitonin gene-related peptides (CGRPs), a protein that binds to nerve receptors in the brain and trigger migraine pain. In a recent study, Porreca suggested that sexual differences may be the reason why migraine drugs that block CGRPs are effective in treating migraine pain in women, but are far less effective in men.  

Until these differences are more fully understood, Porreca says clinical trials should be designed to have an equal number of men and women. That way differences between the sexes could be more easily recognized and applied in clinical practice.

For example, therapies that block prolactin may be an effective way to treat fibromyalgia in women, while drugs that block orexin B might be a better way to treat certain pain conditions in men.

“We have an opportunity to develop therapies that could be more effective in treating pain in a man or in a woman than the generalized kinds of therapies that we use now,” said Porreca. ‘I think it's critically important that these pain syndromes really be taken very seriously. And that we find better ways of treating female pain and also male pain.” 

Genetics May Explain Why Women Are More Likely to Have Chronic Pain

By Pat Anson, PNN Editor

It’s no secret that women are far more likely than men to experience fibromyalgia, migraine, osteoarthritis and other chronic pain conditions. Why that is has been linked to everything from gender bias in healthcare to childhood trauma to women “catastrophizing” about their pain.  

A new study published by UK researchers in PLOS Genetics suggests that part of the reason is genetic differences between men and women.

In the largest genetic study of its kind, researchers at the University of Glasgow looked for genetic variants associated with chronic pain in over 209,000 women and 178,000 men who donated their medical and genetic data to the UK Biobank.

The researchers also investigated whether the activity of those genes was turned up or down in tissues commonly involved with chronic pain.

They found that 37 genes in men and 30 genes in women were active in the dorsal root ganglion, a cluster of nerves in the spinal cord that transmit pain signals from the body to the brain.

The findings support previous work by the same research team, which found that chronic pain originates to a large extent in the brain, and to a lesser degree in parts of the body where people “feel” pain. The study also suggests genetic differences between men and women may affect the immune system and how the two sexes respond to medication.

“Overall, our findings indicate the existence of potential sex differences in chronic pain at multiple levels… and the results support theories of strong nervous system and immune involvement in chronic pain in both sexes,” wrote lead author Keira Johnston of the University of Glasgow. "Our study highlights the importance of considering sex as a biological variable and showed subtle but interesting sex differences in the genetics of chronic pain."

Gender Bias

While genetic differences may partially explain why women are more likely to feel pain than men, gender biases may explain why they are treated differently, according to another study recently published in the Journal of Pain.

Researchers at the University of Miami found that when volunteers observed male and female patients expressing the same amount of pain, they had a tendency to view female patients' pain as less intense and more likely to benefit from psychotherapy.

The study consisted of two experiments in which adult volunteers were asked to view videos of men and women who suffered from shoulder pain. The videos came from a database of real patients experiencing different degrees of pain, and included their self-reported pain levels when moving their shoulders in a series of exercises.

The volunteer observers were asked to gauge the amount of pain they thought the patients in the videos experienced. They were also asked how much pain medication and psychotherapy they would prescribe to each patient, and which of the treatments they thought would be more effective.

The study found that female patients were perceived to be in less pain than the male patients — even when they reported and exhibited the same pain levels. Researchers believe those perceptions were partially explained by gender-based stereotypes.

"If the stereotype is to think women are more expressive than men, perhaps 'overly' expressive, then the tendency will be to discount women's pain behaviors," said co-author Elizabeth Losin, PhD, assistant professor of psychology at the University of Miami.

"The flip side of this stereotype is that men are perceived to be stoic, so when a man makes an intense pain facial expression, you think, 'Oh my, he must be dying!' The result of this gender stereotype about pain expression is that each unit of increased pain expression from a man is thought to represent a higher increase in his pain experience than that same increase in pain expression by a woman."

The volunteer observers were also more likely to choose psychotherapy as a treatment than pain medication for the female patients.

Interestingly, the gender of the observers did not influence pain estimation. Both men and women interpreted women's pain to be less intense.

"I think one critical piece of information that could be conveyed in medical curricula is that people, even those with medical training in other studies, have been found to have consistent demographic biases in how they assess the pain of male and female patients and that these biases impact treatment decisions," said Losin.

"Critically, our results demonstrate that these gender biases are not necessarily accurate. Women are not necessarily more expressive than men, and thus their pain expression should not be discounted."

Sex Bias Persists in Pain Research

By Pat Anson, PNN Editor

It’s long been known that women are more likely than men to have chronic pain conditions such as fibromyalgia, rheumatoid arthritis, irritable bowel syndrome (IBS) and migraine. Women are also more likely to feel more severe, recurring and longer lasting pain.

Why then are women less likely to receive pain treatment? And why are some treatments less effective for women?

One obvious reason is that men and women have different biology and process pain differently. Another is a “blind spot” in pain research, which is more focused on studying males than females, according to a new review published in the journal Nature Reviews Neuroscience.

"The pain literature is biased such that, because of the overwhelming use of male animals in experiments, we are increasingly learning about the biology of pain in males. And wrongly concluding that this is the biology of pain. It's only the biology of pain in males," says author Jeffrey Mogil, PhD, a Professor of Psychology and Anesthesia at McGill University in Montreal.

Mogil reviewed over 1,000 research articles published in the journal Pain between 2015 and 2019, and found a distinct change in the sex of laboratory animals used in research. In 2015, for example, 80 percent of the studies only used male rodents. By 2019, half of studies were male-only.

SOURCE: Nature Reviews Neuroscience.

The trend towards using both male and female animals may sound like a promising change in research design. But when Mogil looked more closely at sex differences in pain literature, he found clear evidence that a male bias still exists in pain research.

"The very ideas we come up with for experiments, are based on experiments in males and therefore they work in males and not in females,” says Mogil.

Even in studies that included both male and female rodents, Mogil found that the research was often geared toward the males’ response. In experiments that “worked out” -- meaning the scientific hypothesis being tested was found to be true -- over 72% of the male rodents had a positive response, while only about 28% of the female rodents did. That strongly suggests the research was biased even before the experiments began.

"If there were no bias in the literature and there were a number of papers where the experiment worked in one sex and not the other, it should work in females just as often as in males,” explained Mogil. “Why has this happened? Because the hypothesis that that experiment tested out was generated based on prior data from experiments on only males. So, of course, it only worked in males."

The bias in research can have lasting effects on pain treatment and may help explain why some analgesic medications are more effective when taken by men.

"This research suggests that lots of what's in the pipeline right now, if it works in anyone at all, will largely be men. Whereas the clear majority of chronic pain patients have been and continue to be women," Mogil said.

Steps have been taken to reduce bias in pain research. If they want to get government funding, researchers in the United States, Canada and several European countries are now required to evaluate both sexes in their research. Mogil is optimistic those policies will eventually make a difference, but it may take awhile to undo decades of research that focused primarily on male animals.

“Performing biomedical experiments in both sexes is not only the ethically correct thing to do but also the scientifically correct thing to do, especially if we wish to reverse the particularly unimpressive track record of clinical trial success in the past few decades,” Mogil wrote.

‘Catastrophizing’ Doesn’t Mean Pain Is All in Your Head

(Editor’s Note: Last month we published a story about pain “catastrophizing,” and how a new study showed that women who have negative or emotional responses to pain are more likely than men to be prescribed opioid medication. Several readers were offended by the study, as well as our story, feeling they belittled women and their ability to handle pain.

The two co-authors of the study, which was published in the journal Anesthesiology, kindly agreed to address some of these concerns and further explain their research.)

By Yasamin Sharifzadeh and Beth Darnall, PhD, Guest Columnists

Thank you for taking the time to share your thoughts and ideas about our recently published paper on opioid prescription and pain catastrophizing. We would like to address a few concerns brought up and to clarify some of the statements made in our publication.

First and foremost, our study analyzed pain catastrophizing, which has a different and more nuanced definition than terms such as complaining or worrying, that are commonly used to describe it.

Pain catastrophizing is measured via a 13 question survey, with specific subsets used to assess varying aspects of the way we emotionally approach pain. This term is not meant to downplay or discredit pain or its associated emotions. In fact, we use it to better understand the many manifestations of pain.

But for some people, the term “catastrophizing” is offensive. We hear those negative responses, but in clinic, when the term is described, many patients will say:  “I do that!  That is totally me.”  So while not everyone is offended by the term, some people are. It’s important to know that catastrophizing does not mean that pain is all in your head, or your fault, or that you did anything wrong.

Our nervous systems are hardwired to respond to pain with alarm. It is actually an acquired skill to learn to disengage one’s attention to pain and develop strategies that counteract this agitation in the nervous system. Otherwise, it can set us up to have greater distress and pain. This is true for everyone, but for some people the alarm in the nervous system rings louder. 

We sometimes use “negative mindset” as a way to describe difficulties in disengaging from attention to pain or focusing on worsening pain or worst-case scenarios. The science is clear on how our thoughts, attention, and emotions impact pain and pain treatment response.

Whatever the term used to describe this specific form of pain-related distress, it is highly predictive of response to various pain treatments. For this reason, it is important that we identify it and treat it. Not addressing these issues would be neglectful, given the degree to which one’s mindset can undermine treatment response and contribute to suffering.

Men and Women Catastrophize

We also wish to clarify some of the findings of the study. We found that men and women, in a general sample of chronic pain patients, had similar levels of pain catastrophizing. In other words, men and women do not significantly differ in their pain-related emotions. Also, consistent with previous peer-reviewed work, we found that women reported higher than average pain levels.

We took our robust analysis a few steps further to show that in women, pain-related emotions played a bigger role in the likelihood of having an opioid prescription than it did in men. Again, this is not saying that pain catastrophizing played no role in opioid prescribing for men -- just that it had a higher effect in women despite equal levels of pain catastrophizing between the sexes.

Overall, we view our study as a stepping-stone towards an improved understanding of both the physical and emotional manifestations of pain.

Pain catastrophizing is a unique term that describes just one of many ways that we can look at pain-related emotional distress, and it is not meant to discount pain in any way. Rather, it validates the importance of treating pain comprehensively in order to attain better results.

We hope that this study helps people with pain look at pain from many angles and work with their physician to find the solution that works best for them.

Yasamin Sharifzadeh is lead author of the study. She is a second year medical student at Virginia Commonwealth University.

Beth Darnall, PhD, is senior author of the study.  She is a clinical associate professor at Stanford University School of Medicine and author of 3 books:    "Less Pain, Fewer Pills," "The Opioid-Free Pain Relief Kit," and a forthcoming book entitled “Psychological Treatment for Chronic Pain.”

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

Women Who ‘Catastrophize’ More Likely to Get Opioids

By Pat Anson, Editor

Women who complain or focus negatively on their pain – a psychological condition known as catastrophizing -- not only feel chronic pain more intensely, they are more likely than men to be prescribed opioids for the same condition, according to a new study.

"Our research underscores how psychological factors such as negative thoughts or emotions have the capacity to influence how we experience pain and the likelihood that someone will be taking prescribed opioids," said Beth Darnall, PhD, a clinical associate professor at Stanford University School of Medicine and senior author of the study published in the journal Anesthesiology.

"The findings suggest that pain intensity and catastrophizing contribute to different patterns of opioid prescribing for male and female patients, highlighting a potential need for examination and intervention in future studies."

Previous studies have found that pain catastrophizing can have a powerful influence on a patient’s sensory perception, and may magnify the intensity of chronic pain by as much as 20 percent.

In their retrospective study, Darnall and her colleagues analyzed clinical data from nearly 1,800 adult chronic pain patients at a large outpatient pain treatment center. Most of the patients said they were prescribed at least one opioid medication.

For women, pain catastrophizing was strongly associated with having an opioid prescription, even when there were relatively low levels of pain. Pain intensity was a stronger predictor of opioid prescriptions in men.

"Our findings show that even relatively low levels of negative cognitive and emotional responses to pain may have a great impact on opioid prescribing in women," said lead author Yasamin Sharifzadeh, a medical student at Virginia Commonwealth University.

It was Sharifzadeh who first sought to study the relationship between pain catastrophizing and opioid prescriptions as a third-year undergraduate student at Stanford, where the research was conducted. She says more research is needed to understand sex differences in pain so clinicians can develop better treatments for both men and women.

“If physicians are aware of these gender-specific differences, they can tailor their treatment,” she said. “When treating chronic pain patients — especially women — they should analyze pain in its psychological aspect as well as its physical aspect.”

Previous studies have found that women are more likely to have chronic pain, be prescribed prescription pain relievers, be given higher doses, and to use them for longer periods. Women may also become dependent on medication more quickly than men, according to the CDC.

Why Women Feel Chronic Pain More Than Men

By Pat Anson, Editor

A new study may help explain why women are more likely to have chronic pain and are more sensitive to painful sensations than men.

It’s because their brains work differently.

In experiments on laboratory animals, researchers at Georgia State University found that immune cells in female rats are more active in regions of the brain involved in pain processing. Their study, published in the Journal of Neuroscience, found that when microglia cells in the brain were blocked, the female rats responded better to opioid pain medication and matched the levels of pain relief normally seen in males.

Women suffer from a higher incidence of chronic pain conditions such as fibromyalgia and osteoarthritis. And studies have found that they often have to take more morphine than men to get the same level of analgesia.

“Indeed, both clinical and preclinical studies report that females require almost twice as much morphine as males to produce comparable pain relief,” says Hillary Doyle, a graduate student in the Neuroscience Institute of Georgia State. “Our research team examined a potential explanation for this phenomenon, the sex differences in brain microglia.”

In healthy people, microglia cells survey the brain, looking for signs of infection or pathogens like bacteria. Morphine is perceived as a pathogen and activates the cells, causing the release of inflammatory chemicals such as cytokines. Researchers say this causes "a neuroinflammatory response that directly opposes the analgesic effects of morphine."

To test their theory, researchers gave male and female rats naloxone, a drug that reverses the effects of an opioid overdose, and found that it inhibits the microglia activation triggered by morphine.

“The results of the study have important implications for the treatment of pain, and suggests that microglia may be an important drug target to improve opioid pain relief in women,” said Dr. Anne Murphy, PhD, co-author of the study and associate professor in the Neuroscience Institute at Georgia State.

Murphy says her team’s finding may also help explain why women are significantly more likely to experience chronic pain conditions than men.

A recent study at UCLA and UC Irvine found that microglial cells in both female and male rats can be activated by chronic pain.  The researchers found that brain inflammation in rodents caused by chronic nerve pain led to accelerated growth of microglia. The cells triggered chemical signals in the brain that restricted the release of dopamine, a neurotransmitter that helps control the brain's reward and pleasure centers.

Few Differences in Fibromyalgia Between Men & Women

By Lana Barhum

Fibromyalgia is remarkably more common in women than it is in men, but when it comes to feeling its effects, there is little difference between the sexes, according to results of a new study published in the journal Pain Research and Management.

Fibromyalgia is a poorly understood disorder characterized by deep tissue pain, fatigue, depression and insomnia. As many as 90 percent of fibromyalgia cases are diagnosed in women.

The Al-Andalus Project consisted of 405 fibromyalgia patients and 247 non-fibromyalgia participants from southern Spain, the vast majority of them women. A significant limitation of the study is that only 73 men participated.

The researchers followed the groups for two years to see if gender-specific symptoms in the fibromyalgia patients existed. Participants were evaluated in several ways, including pain, lifestyle impact, fatigue, sleep issues, mental and emotional health, and cognitive performance.

In the fibromyalgia group, the men showed better working memory than women, whereas sleep latency (the length of time that it takes to go from full wakefulness to the lightest non-REM sleep state) was lower in the female participants. In the non-fibromyalgia group, the male participants showed higher pain thresholds in some areas, but not in others. 

The researchers found that some symptoms, including pain, in fibromyalgia men were worse than their non-fibromyalgia male peers. They believe the findings show that fibromyalgia might affect men more severely than women in tender point tenderness, mental health, and sleep latency, which contradicts earlier research on gender differences.

“Previous research has shown that fibromyalgia men present more severe limitations in physical functioning, social functioning, and health perception. However, we failed to find these differences between fibromyalgia women and men in the present study. Our results are consistent with other studies finding no gender differences in clinical key features in fibromyalgia," they wrote. 

It does still seem that the worst fibromyalgia symptoms, especially pain, affect females more severely than they do males, but the Al-Andalus researchers do not feel that is unique to fibromyalgia. 

"In the general population, women usually present greater pain sensitivity and lower pain threshold than men, which is in agreement with the results found in the nonfibromyalgia group of the present study," they wrote, noting that there is a difference in the way genders perceive and handle pain.

"It has been speculated that both peripheral and central nervous systems pathways might be involved in pain experiences; however, the mechanism underlying gender differences in pain remains misunderstood."

While the findings of the Al-Andalus Project do not support any significant gender differences in fibromyalgia and only offer some indication that fibromyalgia might affect men more severely with some symptoms, the researchers believe there’s a need to further understand why men and women perceive fibromyalgia pain and symptoms differently.

"Our results, then, suggest that fibromyalgia pain might be aggravated in men and, consequently, there might be gender-specific pain mechanisms in fibromyalgia," they said.

The Al-Andalus researchers believe further studies are needed that look at male and female fibromyalgia patients separately

“Given the low sample size of our sample, our findings should be interpreted as preliminary and future studies with a larger sample size of men might confirm or contrast the cut-off scores suggested in the present study," they wrote.

Lana Barhum lives and works in northeast Ohio. She is a freelance medical writer, patient advocate, legal assistant, and mother. Having lived with rheumatoid arthritis and fibromyalgia since 2008, Lana uses her experiences to share expert advice on living successfully with chronic illness. She has written for several online health communities, including Alliance Health, Upwell, Mango Health, and The Mighty.

 To learn more about Lana, visit her website.

Women More Likely to Get Addicted to Pain Meds

Pat Anson, Editor

Over half the women being treated for addiction at methadone clinics in Canada say their first experience with opioids was a pain medication prescribed by a doctor, according to a new study.

Researchers at McMaster University in Hamilton recruited over 500 men and women being treated for opioid dependence at 13 clinics in Ontario. The aim of the study, which is published online in the journal Biology of Sex Differences, was to identify any significant gender differences between men and women attending the clinics. Participants provided researchers with detailed information about their health and lifestyle, as well as urine tests to measure their use of illicit and legal drugs.

Compared to men, women were found to have more physical and psychological health problems, more childcare responsibilities, and were more likely to have a family history of psychiatric illness.

While over half the women (52%) and about a third (38%) of the men reported doctor-prescribed painkillers as their first contact with opioids, only 35% of participants said they suffered from chronic pain during the study period.

"It's not clear why women are disproportionately affected by opioid dependence originating from prescription painkillers - it could be because they're prescribed painkillers more often due to a lower pain threshold, or it might simply be because they're more likely than men to seek medical care,” said lead author Monica Bawor of McMaster University.

“Whatever the reasons, it's clear that this is a growing problem in Canada and in other countries, such as the U.S., and addiction treatment programmes need to adapt to the changing profile of opioid addiction."

Only about a third (36%) of the study participants were employed or had completed a high school education (28%).

Men were more likely than women to be employed, and were more likely to smoke cigarettes. Men were also more likely to report having smoked marijuana, although rates of marijuana use were relatively high among both men and women, Nearly half (47%) said they had used marijuana in the month prior to the study.

"Most of what we currently know about methadone treatment is based on studies that included few or no women at all. Our results show that men and women who are addicted to opioids have very different demographics and health needs, and we need to better reflect this in the treatment options that are available,” Bawor said.

"A rising number of women are seeking treatment for opioid addiction in Canada and other countries yet, in many cases, treatment is still geared towards a patient profile that is decades out of date - predominantly young, male injecting heroin, and with few family or employment responsibilities."

Compared to studies from the 1990s, the average age of patients being treated for opioid addiction is older (38 vs. 25 years of age), and patients also started using opioids at a later age (25 vs. 21 years). There was a 30% increase in the number of patients becoming addicted to opioids through doctor-prescribed painkillers.

The number of opioid painkiller prescriptions has doubled in Canada over the last two decades. According to the World Health Organization, Canada consumes more opioid painkillers per capita than any other country.