I couldn’t help but notice, as I took my screeching neck and smoldering frustration to doctor after doctor, that most of the fellow sufferers in the waiting rooms were female. This was something of a surprise since I, like many people, male and female, had subscribed to the notion that women are less sensitive than men when it comes to pain. If men had to give birth, so the mythology goes, the human race would disappear because no man could stand the pain.
But this prevalent belief is wrong. The disparity in men’s and women’s pain—especially in clinical situations but also, albeit more controversially, in experimental pain labs—is one of the more puzzling observations in medicine. Scientists are just beginning to realize, for instance, how significant an effect sex has at even the most basic biological level, the expression—activation—of genes, including the genes that control responses to intense, potentially pain-inducing stimulation.
In fruit flies, for instance, researchers from North Carolina State University have shown that males and females are different in the expression of a whopping 90 percent of all their genes.
In other words, for almost all genes in the fly’s genome, sex plays a significant role in how active a particular gene is, how much it is “turned on” and how much of a role it plays in the animal’s physiology and behavior.1 Finding such sex differences in gene expression is exciting because it may point to important sex-related differences in pain processing biology, according to geneticist Inna Belfer of the University of Pittsburgh.2
In humans, the big picture is clear. Women are both more likely to get painful conditions that can afflict both sexes and to report greater pain than men with the same condition, according to studies over the last 15 years.3 (Although we’re focused on chronic pain here, women also have more acute pain than men even after the same surgeries, such as wisdom tooth extraction, gall bladder removal, hernia repair, and hip and knee surgery.4, 5)
The fact that chronic pain is higher in women has been consistently observed, but it is not well understood.6 In 2008, when researchers looked at the prevalence in 10 developed and seven developing countries, a sample that included 85,052 people, they discovered that the prevalence of any chronic pain condition was 45 percent among women, versus 31 percent among men.7
In a 2009 review, a different team of researchers similarly found that worldwide, women experience more irritable bowel syndrome, fibromyalgia, headaches (especially migraines), neuropathic pain (from damage to the nervous system itself), osteoarthritis, jaw problems like temporomandibular joint disorder (TMD), and musculoskeletal and back pain.8
A type of neuropathic pain called complex regional pain syndrome (CRPS) that can start with a minor injury to a limb also seems to stalk women.9, 10 Women are 3.4 times more likely to get CRPS than men, according to a 2007 study by Dutch researchers who examined patient records from 600,000 patients.11 A United Kingdom study on neuropathic pain came to fairly similar conclusions.12
Fibromyalgia, too, seems mainly to affect women. A few studies have failed to find significant sex differences in the prevalence of fibromyalgia (also called widespread pain), but many others have found such differences, including studies from Sweden, the Netherlands, the United Kingdom, Israel, and the United States.13
With osteoarthritis, the wear-and-tear joint disease of later life, both the prevalence and the severity are greater in women.14, 15, 16 TMD is also far more common in women,17 as are other types of facial pain, according to studies in Finland, Germany, Sweden, Turkey, the United States, Nigeria, and Brazil.18 The same is true for irritable bowel syndrome (IBS), a condition that causes abdominal pain and abnormal bowel movements. IBS is 3.2 times more common in women than men.19 (Except, curiously enough, in India and a few other places around the world where the ratio is inverted.20)
And, of course, headaches. With headaches in general and migraines in particular, women are much more likely to be afflicted. Over the course of a given year, the prevalence of migraine ranges from 3 to 33 percent in women, but from 1 to 16 percent in men. This pattern holds true in studies around the world.21
Overall, in other words, chronic pain tends to be a more severe and more complex problem for women.22 In a massive 2012 study—the biggest of its kind—Stanford University researchers studying 11,000 patients confirmed this. They found that women reported more pain with disorders in the musculoskeletal, circulatory, respiratory, and digestive systems. For the first time, the Stanford researchers also found significant sex differences with acute sinusitis and neck pain.23
So, we know there are sex differences in pain. But why? And are there evolutionary reasons behind it? One theory, explained to me by University of North Carolina pain researcher William Maixner, is that females may have evolved sensory mechanisms that allow for greater acuity across sense organs in general.24 Females are more sensitive to changes in smell, temperature, visual cues, and other stimuli that may signal danger. The fact that they are more attuned to pain makes some sense. Harold J. Bursztajn, a psychiatrist at Harvard Medical School, also suggested that a woman’s ability to feel and be more sensitive to a child’s pain may come with the price tag of higher sensitivity when feeling her own.25
But only recently have pain researchers begun to study the exact genetic, physiological, hormonal, and psychosocial factors that underlie sex differences. And that’s largely because pain researchers have been hampered by one—rather shocking—fact: Most—in fact, 79 percent—of basic pain research in mice and rats is still done using males.26
Many pain researchers, McGill’s Mogil among them, contend that this has been a catastrophe, and that the old rationale alleging that menstrual cycles make females too complicated to study is utterly bogus. This bias toward studying male rodents, he argues, is simply a product of inertia.
“Sex matters,” concluded the prestigious Institute of Medicine in a 2001 report. “Sex, that is, being male or female, is an important basic human variable that should be considered when designing and analyzing studies in all areas and at all levels of biomedical and health-related research.”27
But many researchers still don’t take that to heart. While the National Institutes of Health now requires routine inclusion of both sexes in human studies, much animal research “continues to eschew females,” says University of Florida pain researcher Roger Fillingim. Given that pain is mainly a female problem, this means research that excludes females is incomplete at best and invalid at worst.28, 29
To me, the implication is obvious: If researchers want to insist on studying just one sex, why not study only females?
It’s not just clinical pain conditions that reveal the unequal burden of suffering. Sex differences have also shown up in lab experiments in which people voluntarily let scientists test their responses to potentially painful stimulation—with informed consent—though recent research suggests these differences may not be as significant as once thought.
I volunteered for some pain experiments at McGill University in Montreal, spurred partly by sheer curiosity and partly, I must confess, by the hope of proving objectively how tough I was (and therefore, despite my first doctor’s lack of empathy, how tough I had been during my most intense bouts with neck pain).
So I asked neuroscientist Catherine Bushnell, then at McGill, to assess me using some of the pain testing routinely done in her lab. She agreed. Her assistant sat me down, explained what would happen, then cheerfully applied varying amounts of thermal stimulation to my inner arm. I was supposed to say when the sensation went from just plain heat to pain, as she kept track of the rising temperatures and how long it took me to cry “uncle.”
In a separate test, she had me immerse my right hand in icy water for as long as I could stand it. I winced and grimaced—cold water really hurts!—but was delighted to learn from both tests that I had a higher than average pain threshold.
I felt like taking these results to that young physiatrist in a hospital outside of Boston who seemed not to believe me and had implied that my pain was all in my head. I wanted to say, “See? I really do have pain and I really am tough. Now do you believe me?”
* * *
Pain researchers are discovering fascinating things from lab experiments, but before we begin our discussion of them, a word of caution. It turns out that the gender of the experimenter—not just the gender of the subject—has an interesting effect on how men and women volunteers report their pain sensitivity—a reflection, no doubt, of the powerful role cultural expectations have on pain expression. In an interview, Karen Berkley, a Florida State University neuroscientist, explained to me that women are brought up to have permission to—and, in fact, are expected to—recognize problems more quickly and efficiently than men. Women are more sensitive to danger, and they will more quickly recognize a threat.30
In the pain lab, when the experimenter is a woman, men tend to report less pain (machismo in action!). Curiously, women’s reports of pain do not seem to be influenced as much by the gender of the experimenter, at least according to research conducted more than 20 years ago by scientists at the State University of New York.31
More recently, British researchers confirmed the same thing.32 They took two groups of male college students and two groups of females. A female experimenter tested one group of males and a male experimenter tested the other; the female students were tested similarly, one group by a man, the other by a woman. In all cases, the experimenters were dressed to emphasize their gender roles.
The men tested by a woman showed higher thresholds for pain—in other words, they seemed to be tougher—than those tested by a man. For the female students, ratings of pain were the same whether the experimenter was a man or woman. And lest you still doubt how much men care about how tough they appear, catch this. After University of Florida researchers told men in one experiment that women had tolerated the procedure better, the men then scored the highest pain tolerance of all.33
But the most intriguing—and controversial—findings from pain labs focus on the question of whether women in experimental pain situations truly have lower pain thresholds and lower pain tolerance than men. Observed differences have often been small, and are group averages, much like a height distribution. Just as, on average, most men are taller than most women, some women are taller than some men. It’s the same at the extremes of pain sensitivity—some females are less sensitive to potentially painful stimulation than some men.
Historically, women have often been shown to be more sensitive to experimental pain stimuli than men—with lower pain thresholds (they report pain at lower levels of stimulus intensity) and lower tolerance (they can’t bear intense painful stimulation as long).
It turns out in more recent studies, though, that the type of pain stimulus—heat, cold, mechanical pressure, electrical stimulation, ischemic pain (from tourniquets cutting off blood supply), and other methods—matters greatly. In a 2012 systematic review of 10 years’ worth of pain lab data (122 scientific papers) on sex differences in healthy people (not people with pain), Canadian researchers found that men and women have comparable thresholds for cold and ischemic pain, but that women have lower pain thresholds for pressure than men.34 As for tolerance, there is strong evidence, the Canadian team found, that women tolerate less heat and cold pain than men, but that tolerance for ischemic pain is comparable in men and women.
Previous research had shown that pain induced by mechanical pressure produces big sex differences in sensitivity,35 and that electrical stimulation is more painful for women, too.36 With thermal pain, women had also been found to be more sensitive to heat pain than men in 23 studies. The same holds true for pain induced by cold—in 22 studies reviewed, women proved more sensitive to pain.37
But overall, the experimental pain picture is muddy. Even 10 years’ worth of lab data, the Canadian team concluded, have not produced a clear and consistent picture of sex differences in human studies, which prompts the question of how useful experimental pain studies are in understanding the clear, significant sex differences in clinical pain.
There is an important twist to this—it’s what scientists call temporal summation of pain, adding up one’s cumulative experience of pain. In the lab, this is measured by the gradual increase in a person’s pain ratings as brief, potentially painful stimuli are delivered to the skin every three seconds or so.38, 39 Women show higher pain summation scores, though, again, studies are mixed and some of the higher levels of temporal summation in women may be explainable by anxiety.40
This is a crucial idea, notes neuroscientist Joel Greenspan of the University of Maryland. The fact that women’s brains tend to accumulate pain sensations more than men’s is likely to be one reason why women are more susceptible to chronic pain—pain that adds up over time.41
And it’s not just what men and women say about their pain when they’re being tested in pain labs that highlights sex differences, but what their brain scans show, too. With heat pain as the painful stimulus, positron emission tomography (PET) scans show that women exhibit more pain sensitivity than men at the same level of thermal stimulation of the inner arm (122 degrees Fahrenheit).42
In a different PET scan study that used rectal distention as the potentially painful stimulus, UCLA researchers looked at 23 women and 19 men with irritable bowel syndrome (abdominal pain and abnormal bowel movements).43 To be sure, some pain processing regions “lit up” similarly in men and women. But women’s brains showed more activation in the limbic system, which processes emotions, while men’s showed more activation in cognitive, or analytic, regions.
Harvard Medical School researchers have documented similar findings. With migraines, they found, women’s brains react differently than men’s, especially in the emotional reaction to the pain.44 This difference fits with the idea that women often express pain in more emotional terms—and may indeed have stronger emotional responses to pain.
Of course, it’s not just increased activity in certain brain regions that show responsiveness to pain, but decreased responsiveness—deactivation—in other areas that document what’s going on in pain. In another study that used rectal distention as a pain stimulus, women showed evidence of deactivation in some brain areas, suggesting that they may actually get used to a certain amount of pelvic pain, perhaps because they are exposed so often to pain from menstrual cramps, endometriosis, pelvic inflammatory disease, and childbirth.45
While women are more likely to seek treatment for pain, they may be less likely to receive adequate treatment for it, though again, this is somewhat controversial. There is a “fairly extensive literature suggesting that physicians treat women and minorities less aggressively for their pain,” noted researchers from the Albany Medical Center in a 2003 paper.46 But the authors themselves did not find such a pattern. In fact, they found that, overall, comparable doses of opioids were selected for men and women, as well as for blacks and whites. And a 1995 study from Stanford University found that women sometimes get even more aggressive pain treatment than men. Women in the emergency room who came in with headache, neck pain, or back pain were perceived by providers as having more pain and got more powerful pain-relieving drugs.47
But, those studies aside, there is a lot of evidence pointing the other way—toward undertreatment of women.48 One reason women may be undertreated is that when women talk about their pain, they use more emotional language and thus are often perceived by healthcare providers as exaggerating. Indeed, psychiatrists have developed standardized criteria to assess the way men and women portray their pain. According to these criteria, women are often deemed histrionic—that is, dramatic and emotional.49 But a bigger reason is probably that doctors learn so little about pain in medical school that they may be just plain ignorant, or even shy, about some types of pain in women.
For example, consider Tarlov cysts. These are little sacs in the lower back that become filled with cerebrospinal fluid. The sacs then press painfully on nerve roots, causing pain in the genital and buttocks area. The cysts are overwhelmingly a female problem. Roughly 90 percent of cases occur in women, estimates Massachusetts General Hospital neuroscientist Anne Louise Oaklander. “Many women just do not reveal, even to their physicians, symptoms affecting their genitalia or anus, and this is the last thing that most spine surgeons want to discuss, either,” she says. It all adds up to barriers for women seeking treatment.50
Undertreatment of pain in women should not be such a surprise, given the undertreatment of a number of medical conditions in women. With heart attacks, for instance, Canadian researchers reviewed the charts of 142 men and 81 women with comparable symptoms and risk factors and found that men were more likely to be given lipid-lowering drugs, get angiograms (to detect potentially clogged blood vessels), and to have coronary artery bypass surgery.51 Women are also much less likely than men to be admitted to intensive care units, to get certain procedures (such as being put on respirators) once they get there, and to die after a critical illness, according to a large study involving nearly 25,000 critically ill patients in Canada.52 And after heart surgery? A controversial 2007 Rhode Island study tracked the medications given to 30 men and 30 women who had just had coronary artery bypass surgery. The researchers were astonished to find that men got pain medications, while women got sedatives.53
Indeed, women’s pain symptoms are often minimized. In one clever study, researchers from Georgetown University videotaped professional actors portraying people with chest pain. The researchers showed the videos to more than 700 primary care physicians and gave them data about each hypothetical patient. The doctors were much less likely to believe that the women had heart disease.54 Similarly, when European researchers looked at the records of 3,779 heart patients, 42 percent of them women, they found that women were not worked up as thoroughly.55 It was the same story in a Mayo Clinic study of 2,271 men and women who went to the emergency room with chest pain.56
Granted, chest pain is a tricky type of pain to evaluate, in part because women having heart attacks often exhibit different symptoms from men. But less complicated medical problems, like the knee pain of osteoarthritis, exhibit the same pattern. Women are three times less likely to get the hip or knee replacement that they need, and often don’t get the surgery in a timely manner, says Mary I. O’Connor, a former Olympic rower who now heads the orthopedic surgery department at the Mayo Clinic in Jacksonville, Florida. “And when they do have the surgery, they often do not do quite as well as men. We call it the ‘never catch up’ syndrome.”57
“A woman usually waits longer” to have surgery, says O’Connor, in contrast to a man, who usually seeks surgery before his pain becomes extreme. The surgery itself is equally beneficial for both sexes, but because a woman has typically had more advanced disease by the time she undergoes surgery, the result often “is not quite as good.”58 Even though women wait too long before having surgery, there may also be an “unconscious bias” at work that may make doctors less likely to recommend surgery to a woman with moderate knee arthritis, O’Connor thinks.
Canadian researchers looked into this very question, asking 38 family physicians and 33 orthopedic surgeons to evaluate one “standardized,” or typical, male patient and one “standardized” female patient with moderate knee arthritis. That’s the degree of arthritis in which it’s a judgment call whether surgery is necessary or not.59 (Two orthopedic surgeons confirmed that the male and female patients had the same severity of disease.) The odds of a surgeon recommending knee replacement, the Canadian team found, were 22 times higher for the male patient than the female.
Women are undertreated for abdominal pain, too. In Philadelphia, emergency room doctors kept track of 981 men and women who arrived with acute abdominal pain. The men and women had similar pain scores, but women were significantly less likely to get any kind of pain medication and were 15 to 23 percent less likely than men to get opiates specifically. Women also had to wait longer before they got any kind of pain medicine—65 minutes, on average, compared to 49 for men.60
Women with cancer and AIDS have also historically been more likely than men to get inadequate pain treatment.61, 62
A fascinating Swedish study also revealed gender biases. Using a modified version of a national exam for young doctors, the Swedish researchers described hypothetical neck pain in patients. Some of the hypothetical patients were male and some female; all were described as bus drivers who were living in tense family situations. The interns were more likely to ask female patients psychosocial questions, and more likely to request lab tests in the males.63 Female interns were just as biased as males.
I hate to say it, but I believe it, based on my own experience.
If, as we’ve seen, women have more chronic pain conditions than men, the question then becomes, why? Why do women have more pain than men? There are several possible reasons.
One theory is that the chemical pathways that get activated inside nerve cells may be different in males and females. In studies with male rats, says neuroscientist Jon Levine of the University of California, San Francisco, the “secondary messengers” (chemicals that relay pain signals) are different in females and males. Male rats use three different secondary messengers; females use one.64 Women also have more nerve endings in their skin than men, which could partially explain why women may be more sensitive to potentially painful stimulation, according to research from Massachusetts General Hospital in Boston.65 Moreover, the nerve cells that convey information about intense stimulation are studded with receptors for sex hormones: testosterone and estrogen, in particular.
In fact, perhaps the most intriguing reason for sex differences in pain responsiveness may lie with these two hormones. But understanding this potential hormonal contribution has been nightmarishly tricky, as researchers have reported in a number of review papers since 1999.66
As young children, boys and girls show comparable patterns of pain until puberty. But once puberty hits, certain types of pain are strikingly more common in girls. Even when the prevalence of a pain problem is the same in both sexes, pain severity is often more intense in girls than boys.
Take migraines. Before puberty, boys and girls get roughly the same number. After puberty, the prevalence becomes 18 percent for women, and 6 or 7 percent for men.67, 68 A similar pattern holds for TMJ, now called temporomandibular joint disease (TMD): no sex differences before puberty, significant differences afterward—women get it twice as often as men.69 Indeed, as girls progress through puberty, chronic pain of various sorts—back pain, headaches, TMD, and stomach pain—worsens.70, 71
Overall, many researchers think that testosterone generally protects against pain, an idea illustrated dramatically in some rat studies. Newborn male rats that are castrated are unable to produce testosterone later, during puberty. The result? The animals become less sensitive to the pain-reducing effects of the opioid morphine.72 If newborn female rats are given testosterone, they get better pain relief from morphine. (A word of caution, though: It’s not clear how well pain findings in rats translate to people.)
As adolescence progresses, boys actually develop more pain tolerance, perhaps partly because of the flood of testosterone, says Lonnie Zeltzer, a pediatric pain specialist at the University of California, Los Angeles.73
But if the role of testosterone in pain is relatively straightforward (more testosterone, less pain), the role of estrogen is anything but. Genetics research suggests that estrogen down-regulates—or reduces— the activity of one of the leading “pain genes,” called COMT. The job of the COMT gene is to chew up stress hormones like epinephrine. That means that if COMT activity is too low, the body can’t get rid of stress hormones as well. Since stress hormones act directly on nerves to rev up pain, the net result of estrogen acting on COMT is more pain, says William Maixner, director of the Center for Neurosensory Disorders at the University of North Carolina.74
And other research, too, supports the “estrogen is bad” theory. At the University of Maryland, neuroscientist Richard Traub studies hormones and pain in rats. He starts by testing female rodents’ sensitivity to pain, then takes out their ovaries (which make estrogen), and then tests them again. Without their ovaries, these females act more like males— that is, they’re less sensitive to pain.75 He then gives back estrogen to these animals. They soon go back to feeling pain, just as in the bad old days before their ovary surgery, says Traub.
You could think of menopause as the human version of this experiment. At menopause, women’s ovaries stop pumping out estrogen, almost as if the ovaries had been surgically removed. To combat the symptoms caused by this precipitous drop in estrogen, many menopausal women begin taking exogenous estrogen—that is, estrogen not made naturally in the body but taken as a drug.
If the general theory—that estrogen increases pain—is true, you would expect that taking exogenous estrogen (hormone replacement therapy) would make pain worse. But it turns out that the “estrogen is bad” theory is too simplistic. Sometimes exogenous estrogen makes pain worse, but sometimes it doesn’t. And sometimes it makes it better.
Several studies have shown that menopausal women who take hormone replacement therapy do have more back pain, and more pain from TMD as well, as the theory would predict. Linda LeResche, a pain researcher at the University of Washington, looked at the histories of more than 6,000 women over 40. She found that those who took hormone replacement therapy were 30 percent more likely to be referred for treatment of TMD.76 She found much the same pattern in a different study of more than 6,000 younger women—those taking birth control pills were 20 percent more likely to be referred for TMD treatment.77
Back pain, too, clearly seems to be associated with hormone replacement therapy.78, 79 The same goes for thermal pain. University of Alabama researchers found that women taking hormone replacement therapy were more sensitive to heat stimulation than women not taking the therapy and than men.80
But other studies show no link between hormone replacement therapy and pain in older women. And still others show that when post-menopausal women stop taking hormone replacement therapy, their pain goes up: just the opposite of what the theory would predict.81
Similarly, some women with a history of migraines begin getting the headaches anew within a couple of weeks of stopping estrogen therapy.82 And some pain conditions like trigeminal neuralgia that are more common in women typically don’t start until after menopause.83
And have you ever wondered what happens when transsexuals take hormones to enhance the sexual characteristics of their “new” sex? Anna Maria Aloisi, a physiologist at the University of Siena, wondered exactly that. In a preliminary study, she tracked male-to-female human transsexuals who take estrogen to enhance female sex characteristics, and found that approximately one-third develop chronic pain, especially headaches. She also looked at female-to-male transsexuals who take testosterone to enhance male characteristics, and found that their chronic pain goes down.84 All of which fits with the overall theory.
But no one is quite sure why these hormones have such effects. One theory is that testosterone dulls the excitatory pain pathways in the brain that would crank up pain, while estrogen may block the nervous system’s pathways for inhibiting responses to potentially painful stimuli.
What makes unraveling the estrogen–pain link even more complicated, of course, is that in premenopausal women, estrogen levels rise and fall dramatically over the course of each menstrual cycle, with many women experiencing striking fluctuations in pain responsiveness at different points in the cycle. Pain in a number of conditions—including irritable bowel syndrome, TMD, headache, and fibromyalgia—changes significantly over the cycle.
But not always in the direction one might expect. Some women feel more sensitive to pain during times in their cycles when estrogen is low.85 During pregnancy, when estrogen levels are high, some women experience fewer migraines and TMD pain, whereas after childbirth, when estrogen falls abruptly, the number of migraine attacks increase.
Given such complexity, a growing number of researchers now suspect that it’s not the absolute level of estrogen that is key for pain, but rapid changes in hormone levels. “It’s the change that produces the change,” according to pain research Fernando Cervero at McGill University.”86
One of the hottest questions tormenting pain scientists these days is why some opioid drugs—narcotics—work better in one sex than the other. No one doubts that the problem exists. It is clear that “there are sex differences in opioid analgesia,” say Roger Fillingim of the University of Florida and Robert Gear of the University of California, San Francisco. What’s unclear, they note, is “the direction and magnitude” of these differences.87, 88, 89
Part of the reason this is so hard to figure out is that answers vary depending on which pain assays, or tests, researchers use, whether they study rats or humans, whether they look at experimental pain in the lab or clinical pain in real patients, and whether the pain is acute or chronic. And, of course, which opioid drugs they are studying.90
What is clear, however, in both the rodent and human nervous systems, is that there are three major classes of opioid receptors: mu, delta, and kappa. These receptors are like magnets into which pain-relieving opioids fit. This lock-and-key setup is the same whether the opioids come from inside the body (endorphins) or are taken as drugs. Wherever the opioid comes from, a filled opioid receptor is a happy receptor—it acts quickly to reduce pain.
Morphine, the most commonly used opioid, binds to mu receptors, the largest of the three classes of receptors. Fentanyl, a drug that is 100 times more powerful than morphine, also binds to mu receptors. Codeine does not bind strongly to mu receptors, but after the body turns codeine into morphine, it binds just fine.
Other, less frequently used drugs, such as Talwin, Nubain, and Stadol, are different. They bind primarily to kappa receptors. This is important because response to kappa opioids varies depending on sex and may even be specific to certain pain situations, such as tooth extraction.91 (So far, there are no drugs designed to fit into delta receptors.)
All three receptors—mu, kappa, and delta—work roughly the same way. When the receptors are filled, they trigger a cascade of chemical events inside the nerve cell that ultimately block production of pain-boosting chemicals like substance P. The result? Decreased pain.92
At Georgia State University, neuroscientist Anne Z. Murphy is trying to unravel the mechanics of sex differences in response to opioids, especially with respect to chronic inflammatory pain. She focuses on an area of the brain called the periaqueductal gray (PAG), a processing center for morphine-type drugs.93 To produce that inflammatory pain in a rat, Murphy injects a rat’s paw with a solution called complete Freund’s adjuvant (FRA), an oil, with a smidgen of tuberculosis bacterium thrown in. This injection stimulates an immune (inflammatory) response. The animal’s paw quickly swells, and the rat starts “guarding” its now-hypersensitive paw. Murphy then gives the rats, male and female, morphine to stop the pain—with dramatic results.
Females require twice as much morphine as males to produce the same level of anesthesia.94, 95 So, if morphine works better in male rats than in females, why might that be? Perhaps, Murphy reasoned, the answer might lie in the mu receptors onto which morphine binds.
Knowing that morphine binds to mu receptors and that the PAG brain region is loaded with mu receptors, Murphy decided to look more closely at PAG regions in males and females. Using a sophisticated radioactive staining technique called autoradiography, Murphy counted the number of mu receptors in the PAG area of male and female rat brains. Lo and behold, there turned out to be twice as many mu receptors in male rats as in females. (So far, nobody has done a similar experiment in people.) Murphy thinks this might explain why morphine is twice as effective in male rats. It conceivably might explain the difference in people, too.
In 2003, anesthesiologist Daniel Carr at Tufts University Medical School in Boston found that, following surgery, women report more intense pain than men and need at least 30 percent more morphine.96
But other researchers have doubts about all this. It’s unlikely, says Robert Gear, a pain researcher at the University of California, San Francisco, that the sheer number of mu receptors is even close to the whole story. “Even if there is such a difference,” he says, “I don’t think it explains any sex differences in opioid analgesia.”97
And a 2010 systematic review and meta-analysis of 50 studies on sex and opioid efficacy threw cold water on the whole idea, suggesting that there is actually greater morphine efficacy in women.98 “Interestingly,” wrote the authors, a team from Leiden University in the Netherlands, “while animal studies show a tendency for opioids to act more efficaciously in males, human studies are less clear…. Our observations that women display greater opioid analgesia than men are completely opposite to what has been found in the rodent literature.”99
But it’s actually even more complicated than that. In pain experiments in the lab, for instance, mu opioids may indeed be more effective in women, the Dutch researchers found. But clinical studies—with real pain patients—are more ambiguous, with some studies showing more mu opioid efficacy in men, and others, more efficacy in women. Curiously, when patients themselves control their analgesia—by pushing a button to release a dose of drug intravenously—men consumed more opioids.100
Again, the interesting question is why. If women consume fewer opioids, is it because they are feeling less pain? Or because they experience more or worse side effects from opioids, including negative mood, nausea, and vomiting.101 In other words, women who control their own analgesia may deliberately underdose themselves to avoid the side effects.
That has been a leading theory since 1999, when a team of California researchers reviewed 18 studies to see how much pain-relieving medication men and women used after surgical operations. They found that there were no sex differences in some studies, and that in others, women indeed used less medication.102 But most of the 18 studies did not actually assess pain—they looked only at medication use. So, again, women may have been underdosing themselves.
Morphine also seems to have a slower onset of action in women compared to men, which, in the short run, would make it appear to be less effective in women. Women also typically have more body fat than men, and since mu opioids become concentrated in body fat, this could mean lower blood levels, and hence less efficacy, in women. It’s a complex picture, to be sure.
Luckily, things are a bit clearer with opioids other than morphine, particularly with drugs such as Talwin, Nubain, and Stadol that work on kappa receptors. In general, these drugs work better in women. More than 20 years ago, Robert Gear and Jon Levine of the University of California, San Francisco demonstrated this in people having their wisdom teeth extracted.103, 104, 105 Since then, other studies from the same group have confirmed the greater effectiveness of kappa drugs in women.
There is, however, a strange twist to this: Kappa opioids seem to work especially well in women with red hair. In 2003, Jeffrey Mogil, the rodent geneticist at McGill University, and Roger Fillingim, a psychologist and human pain researcher at the University of Florida, joined forces to test a prediction of Mogil’s theory based on mouse studies: that red-headed women would respond especially well to Talwin (pentazocine). They used fancy genetic mapping and found that one particular gene called Mc1R (for melanocortin-1 receptor) was key.
Women (and mice) with red hair (actually, yellowish hair in mice) or very fair skin have two mutant copies of the Mc1R gene, essentially rendering it useless. (This is analogous to animal experiments in which researchers deliberately “knock out” certain genes to see what happens). The Mc1R gene is in the pain circuit that contains kappa opioid receptors. Somehow, Mogil thought, knocking out this gene seems to allow activation of the kappa opioid system, producing analgesia.106
As Mogil and Fillingim discovered, this is exactly what happens in red-headed women, who have two mutant Mc1R genes. They get “significantly greater analgesia” from pentazocine than all other groups.107 Indeed, pentazocine produces more analgesia in red-headed women than in non-red-headed women or men of any hair color. While many doctors don’t know about this, the good news is that at least some obstetricians do.
An even more important wrinkle is the observation that the efficacy of opioids in women can vary depending on where she is in her menstrual cycle. In her studies, Murphy has found that the degree to which female rats respond to morphine varies according to the menstrual (estrus) cycle. When estrogen is highest, she says, morphine is the least effective, perhaps because estrogen down-regulates, or reduces the number or availability of, mu receptors. When estrogen is low, morphine works better, possibly because of more mu receptors.
But, once again, the picture gets complicated. Researchers from the University of Michigan have found just the opposite: that when women are in the high-estrogen phases of their cycles, there is an increase in mu activity.108 And when the female rats were in low-estrogen periods of their cycles, there were reductions in mu receptor activity and more sensitivity to pain. This piece does fit with some—but not all—human data showing that women may be most sensitive to noxious stimulation when their estrogen is lowest, as just before their periods.
Basically, a straightforward theory to explain the data on sex and opioid efficacy remains “elusive,” as the Leiden researchers put it.109 Murphy, the Georgia neuroscientist, assesses the ridiculously complex interplay between sex and opioid response more bluntly: “It stinks, doesn’t it?”