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January 24, 2012
Do Women Feel Pain More Intensely Than Men?

Researchers have long debated that men and women use separate mechanisms in the brain to achieve pain relief. The reality of who can really stand more pain has been one of the more interesting battles of the sexes, spanning generations. According to Stanford University School of Medicine investigators, women report more intense pain than men in virtually every disease category.

When compared to men, women have less brain activity in areas that process fear and more activity in areas involved in preparing and planning movements to avoid the impending pain.

The researchers mined a huge collection of electronic medical records to establish the broad gender difference to a high level of statistical significance.

Their study, published online in the Journal of Pain shows the value of EMR data mining for research purposes. Using a novel database designed especially for research, the Stanford scientists examined more than 160,000 pain scores reported for more than 72,000 adult patients. From these, they extracted cases where disease-associated pain was first reported, and then stratified these findings by disease and gender.

"None of these data were initially collected for research, but this study shows that we can use it in that capacity," said Atul Butte, MD, PhD, the study's senior author.

Moreover, research shows that men and women also respond differently to pain medications and an increasing number of studies suggest that the fundamental biology of pain and pain relief differs between the sexes.

In fact, accumulating evidence implies that the days of sex-specific pain killers developed by pharmaceutical profiteers--perhaps pink and blue pills--may not be too far off.

New research by Jeffrey S. Mogil, professor of psychology at McGill University in Montreal, Canada, suggests that men and women use separate mechanisms in the brain to achieve pain relief.

By studying genetically modified mice, Mogil and colleagues have discovered that kappa-opioids, the same pain relievers UCSF researchers found were more effective in women, work through different pathways in female and male mice.

These scientists have identified the exact gene that controls for this sex difference in mice and are currently working on identifying the human gene equivalent.

Mogil's research suggests that men and women are wired differently for pain relief. Finding the genetic cause for this difference may lead to the development of a completely new class of pain relievers.

Another research team from London and Japan led by Professor Qasim Aziz, of the Wingate Institute for Neurogastroenterology, Queen Mary University of London, studied brain activity and reactions of 16 men and 16 women in the anticipation and processing of pain.

Prof Aziz said 'The fact that during pain our female subjects showed more activation of the emotion processing areas in the brain could suggest a mechanism whereby females may attribute more emotional importance to painful stimuli which may influence how they perceive, report and respond to pain in comparison to males.

The perception of pain is influenced by a number of factors, according to Dr. Roger B. Fillingim of the University of Florida, Gainesville.

``Pain is not what travels along the nerves,'' he said. ``Pain is our own personal experience.''

He noted that women are two to three times more likely to have migraine headaches than men are, and women are six times more likely to have fibromyalgia--a syndrome characterized by chronic pain in the muscles.

But although women experience more pain, physicians appear to be more willing to treat pain in men, he said. For example, in a study in which physicians were asked to describe a treatment plan based on clinical vignettes, physicians ''prescribed higher doses of hydrocodone for males than for females with back pain.'' Hydrocodone is a derivative of the pain-killing drug, codeine.

Fillingim suggests that at least some of the gender differences may be due to fluctuation in hormones. Younger women ``report greater pain sensitivity during the premenstrual period.'' Moreover, he said that women who have clinical premenstrual syndrome (PMS) ``are more sensitive to pain'' than women who don't experience PMS.

The medical literature contains numerous reports indicating that women report more pain than men for one or another particular disease, noted Atul Butte, a professor of systems medicine in pediatrics. "We're certainly not the first to find differences in pain among men and women. But we focused on pain intensity, whereas most previous studies have looked at prevalence: the percentage of men vs. women with a particular clinical problem who are in pain. To the best of our knowledge, this is the first-ever systematic use of data from electronic medical records to examine pain on this large a scale, or across such a broad range of diseases."

Butte's team selected only adult records and looked for gender-related differences in pain intensity as reported on 1-to-10 scales, in which a zero stands for "no pain" and 10 for "worst imaginable." Their search algorithm combed through de-identified EMR data for more than 72,000 patients, and came up with more than 160,000 instances, ranging across some 250 different disease categories, in which a pain score had been reported.

"If someone's reporting that they're in pain, they're probably going to be given medication, which might reduce any subsequently measured pain score," said Butte. To get pain estimates that weren't as confounded by subsequent pain-relief medications or procedures, his group analyzed only the first pain-intensity score reported by a patient per encounter with a hospital-associated health professional.

The search identified 47 separate diagnostic categories for which there were more than 40 pain reports for each gender. The sample included more than 11,000 individual adult patients, of which 56 percent were women and 51 percent of them white. The researchers were able to further analyze these 47 categories by condensing them into 16 disease clusters: "musculoskeletal and connective tissue" (in which the biggest gender differences in reported pain intensity were observed), "circulatory" and so forth.

"We saw higher pain scores for female patients practically across the board," said Butte. Those reported differences were not only statistically significant, but also clinically significant. "In many cases, the reported difference approached a full point on the 1-to-10 scale. How big is that? A pain-score improvement of one point is what clinical researchers view as indicating that a pain medication is working."

While the overall results tended to confirm previous clinical findings -- for example, that female fibromyalgia or migraine patients report more pain than their male counterparts -- the search also unearthed previously unreported gender differences in pain intensity for particular diseases, for example acute sinusitis and "cervical spine disorders," more commonly known as neck pain.

The study's results come with a few caveats. First, the investigators made the assumption that patients' pain hadn't already been treated -- for example, that they hadn't already self-medicated with over-the-counter painkillers -- by the time they showed up in the emergency room, doctor's office or neighborhood health clinic (or, equivalently, that the men and women were equally likely to have done so).

Other possible confounders include the setting in which pain was reported, Butte said. "Will an 18-year-old male report the same pain intensity with or without his mom present, or in the presence of a male vs. a female nurse? We can't be sure." But the sheer size of the study probably washes these concerns out at least to some extent, he said.

The third caveat is perhaps the most controversial. "It's still not clear if women actually feel more pain than men do," said Butte. "But they're certainly reporting more pain than men do. We don't know why. But it's not just a few diseases here and there, it's a bunch of them -- in fact, it may well turn out to be all of them. No matter what the disease, women appear to report more-intense levels of pain than men do."

To get to the bottom of this, Butte's team plans to search EMRs to see if they can find some objective measurement -- an already commonly measured blood-test variable, for instance -- that correlates highly with reported pain. "We want to find a biomarker for pain," he said.


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