The Puzzle of Gender and Pain
The work of science and medicine can be compared to putting together a jigsaw puzzle, laying out and connecting bits of information to ultimately reveal a clear picture. Sometimes the pieces are few, the images are distinct, and the resolution is simple. But at other times the number of pieces before us is vast, incomplete, and mixed with a jumble of pieces to other puzzles, and we have little sense, or perhaps even a false sense, of the picture we are trying to assemble. Such is the case with the intersection of pain and gender -- two of the most central paradigms in all living creatures.
A meeting entitled "Gender and Pain: A Focus on How Pain Impacts Women Differently Than Men" was held April 7-8, 1998 near the National Institutes of Health (NIH) and drew 200 researchers and clinicians. The meeting had a long gestation. In 1996, "Harold Varmus invited a couple of us, the director of the Neurology Institute and myself, to serve as a catalyst to stimulate all of the NIH activities that share an interest in pain," explained Harold C. Slavkin, DDS, Director of the National Institute of Dental Research (NIDR). In January 1997, Maryanne Ruda, PhD, a researcher in the Pain and Neurosensory Mechanisms Branch of the NIDR, organized a trans-NIH intramural pain research interest group to facilitate interaction around the subject. The conference was a parallel outreach to extramural NIH-sponsored researchers and others. "This conference is attempting to draw attention to the fact that recent studies have identified sex and gender differences between women and men in terms of responses to pain," said conference chair Ruda in her opening remarks. It looked for a cross-fertilization of thought among medical specialties where pain is a common element.
Just 20 to 25 years ago research into sexually related topics was "greeted with more giggles than anything else. Studying it wasn't that easy. One had to be almost 'holier than thou' in order to be taken seriously," said Allan Basbaum, PhD, Vice-Chair of the Department of Anatomy at the University of California, San Francisco. He called the meeting a "justification for 25 years of hard work."
The interdisciplinary program sifted through pieces of this puzzle of gender and pain, jumping from one pocket of knowledge to another, across broad swaths of the unknown, from the molecular to the sociocultural and back again in the next hour. The effect was both disorienting and exhilarating. It evoked fresh perspectives of the matrix the participants are trying to decipher and stimulated more questions that they hope to explore.
"Sex is Mother Nature's biggest experiment," said Karen J. Berkley, PhD, of the Program in Neuroscience at Florida State University. "It affects absolutely every aspect of our lives, ranging from genetic, to molecular, to physiological, to cellular, to psychological, to sociocultural issues. And at every different level, from metabolism to structural differences, including the brain." Berkley defined the traditional view of pain as a response to a stimulus. Then she offered a variation. Perhaps what "the nervous system is doing is creating a pain situation, not as an immediate response to a stimulus, but rather as a means to doing something to increase the likelihood of the individual remaining healthy." If that is the case, then women's generally lower pain threshold and their willingness to acknowledge pain may in fact be a protective mechanism that contributes to their health. "If you think about this as a means to an end, what this signifies is not that women are bigger complainers, or that women use healthcare way too much -- it is actually a positive situation." The first aspect of dealing with a problem is to recognize it. "At some levels, what women are doing is recognizing a problem earlier, which gives them more of a means to deal with it. So with greater vulnerability comes greater strength," and a longer life expectancy.
Berkley sketched out some of the physiological differences between the sexes with regard to pain. There is a "huge difference in the serotonin labeling with the spinal cords of males and females, suggesting that serotonic influences on the processing of information would be greater in males than females. The second aspect has to do with chronobiology. We all know that over a lifetime there is puberty and senescence that happens in both males and females. There is also a time of day difference that happens in males and females. But females have extra chronobiological factors, the episodic such as pregnancy and the extreme such as menopausal changes, as well as the cyclical changes of the menstrual cycle."
During the estrous cycle, Berkley said, "the nucleus' processing of information shifts dramatically. What we see are huge shifts in use of molecules, in structural synaptology, in the processing of information, and in behavior. What is important is the increased variability of the female." This happens throughout the nervous system -- it is not limited to systems tied to reproduction. They are types of changes one will not see in males.
"This variability is an important feature of sexual difference," noted Berkley. "What this affects is every aspect of female biology and sociocultural aspects of life, ranging from effects on metabolism of various agents in the body to the activity of neuroactive substances. Some of this is related to hormones; it is related to the effects of estrogen and progesterone and their cyclical effects within the nervous system of females that differ from the more steady effects in males." Berkley noted that gender differences tend to disappear "when severe disease conditions really take hold." But while the effect of disease may appear similar, treatment may well be gender specific "because of the kinds of interactions between hormones and neuroactive molecules in the nervous system that have a relationship to pain."
"We may end up seeing males being diagnosed one way and females being diagnosed another, or females treated with one kind of pain reliever and males with another," Berkley said. "It won't be that absolute, but we will be able to use the factor of sexual difference as a way of individually designing treatments that are better for people of both sexes."
Linda LeResche, PhD, Professor of Oral Medicine at the University of Washington, reviewed the epidemiology of pain. "It suggests to us that studying pain across the life cycle is essential because those factors may vary with age." She cited data from Norway showing that back and shoulder pain were consistently higher for women than for men, and increased with age in the study group.
Another large cohort study indicated that women experience more abdominal pain (excluding menstrual pain) than do men, said LeResche, "but the prevalence appears to decrease with age in both sexes." It is unclear how much of this can be attributed to socialization, the expectations of a stoic older generation raised during the Depression, and how much is physiological in nature.
"The most significant risk factor for the onset of a new pain condition is the number of previous pain conditions," LeResche said. A body under attack by disease often experiences a cascading of secondary effects and symptoms that build on each other and may be experienced as painful. But it may also be true that the experience of admitting pain makes one more willing to admit to subsequent pain.
Berkley dismissed the distinction. "I don't know the difference between physiological and just reporting. There is almost no way that you can separate those questions. If we could change the language we would be doing ourselves a great service because the distinction between physical versus mental or theological versus sociocultural disappears. Willingness to respond is part and parcel of the physiology of existence."
We know that the hormone estrogen regulates a woman's monthly fertility cycle during the period from puberty to menopause. But research is uncovering ways that estrogen affects other body functions, even before birth. "During ontogeny, hormones secreted by the fetal gonads determine how the brain develops," said Jill B. Becker, PhD, a researcher at the University of Michigan, Ann Arbor.
The very wiring of the brain's circuitry "is subtly influenced by the process of sexual differentiation" in the developing fetus, said Bruce McEwen, PhD, a neuroendocrinologist at Rockefeller University. "The bottom line is that hormones and hormone receptors often work in collaboration with other DNA-binding proteins regulating neural activity, neural transmitter activation, and second messenger systems."
Male and female brains each have nearly the same number of receptors for estrogen and the male hormone androgen, McEwen explained. "And yet there are numerous examples where giving estrogen to a male does not do the same thing to his brain as does giving it to a female. And giving androgens to a female brain does not do the same thing as does giving it to a male."
Focusing on the hippocampus region of the brain in rats, McEwen found that "estrogens reversibly modulate the formation, and progesterone the destruction, of synapses during the estrous cycle of a female rat." He drew a parallel to limited data showing that "women who are severely estrogen deficient following surgical menopause or suppression of estrogens to treat uterine fibroids actually show deficits in hippocampal-dependent verbal memory." Estrogen replacement therapy "is associated with improvements in episodic and declarative memory known to depend on the hippocampus."
McEwen cited work of Christina Williams that has identified sex differences in strategies used by rats to solve a maze. Males "do much better" than females, but they all eventually reach the same end. Females who are given estradiol do as well as males, while males who are castrated do as poorly as females.
McEwen reminded the audience that estrogen influences dopamine and serotonin, both of which are involved with mood disorder. Differences in nerve synapses and serotonin receptors have also been found in male and female spinal cords. All of these differences affect the way our bodies make connections and process information. Women's greater sensitivity to pain may be dependent on some or all of these factors.
This line of research is likely to have importance in understanding and hopefully treating a variety of maladies, ranging from pain management to cognitive function, Alzheimer's disease, epilepsy, and depression.
William Isenberg, MD, evaluated gender and pain in rats by subjecting them to a pressure test at the University of California, San Francisco. He found that injecting opposite sex hormones in males and females for five days would reverse their thresholds of pain to reflect the gender of the hormone injected. When the hormones washed out, the patterns returned to their normal state. "We feel that sex steroid hormones work in a bidirectional fashion to modulate neuron function and report to the central nervous system about pain," he concluded.
Refining the work, Isenberg reduced the dose of hormone and administered it in only one paw, while injecting the other paw with the same peanut oil carrier, only lacking hormone. In males, estrogen exhibited a localized effect in about 40 minutes. It reversed the sensitivity to pressure in one paw to a "female" level, while the placebo paw remained "male."
This gender bending of rat paws has some profound implications. According to Isenberg, one is that it indicates regional level "receptors for hormones that are active in the peripheral nerves to moderate neuron function." Not all pain is processed in the brain; there is some local autonomy in the nervous systems. That opens up the possibility of using non-morphine-based pain blockers at a localized level. Those types of drugs are likely to be safer, with fewer side effects.
"Vaginal/cervical stimulation blocks responses to noxious stimulation," said Barry Komisaruk, PhD, in his joint presentation with Beverly Whipple, PhD, both professors at Rutgers University, New Brunswick, New Jersey. This conclusion has been demonstrated across species. His experiments with white rats showed how the electromyogram-measured pain of pinching the foot was completely blocked by stimulating the cervix. It was the same effect observed by severing the spinal cord. In further experiments he found that even while cervical stimulation inhibited noxious stimulation, it did not inhibit the more gentle stimulation of touch.
Whipple sought verbal confirmation of this last point from women and they concurred. Her experiments also found that the character of stimulation influenced the character of response. "The elevation of pain detection threshold increased by a mean of 47 percent when the stimulus was applied as pressure to the anterior vaginal wall. When the stimulus was applied in a pleasurable manner, the pain threshold went up by 84 percent" over the resting state. Women who experienced orgasm showed an elevated pain threshold of 106.7 percent. She suggested that these conditions might also be reproduced during labor to ease pain.
Whipple put together two disparate facts. One is that rats injected with the active ingredient of pepper do not experience an elevation of pain threshold. The agent seems to somehow block or at least reduce natural analgesia. The second observation was that Mexican women seem to experience more pain during labor. The latter she initially attributed to cultural factors: "They were more comfortable expressing their pain." However, Whipple later was able to classify these women into three groups according to their dietary consumption of chili peppers. Measuring their self-stimulation of the vagina, she found that those who consumed the most peppers did not express a significant elevation in pain threshold. Clearly it seems in the self-interest of women to cease, or at least reduce, their consumption of chili peppers during pregnancy to allow for the maximum expression of the natural analgesia associated with childbirth.
Komisaruk experimented with rats and found that cutting the pairs of pelvic or hypogastric nerves significantly reduces the analgesic effect of cervical stimulation. "Cutting both pairs has a stronger effect but doesn't abolish it completely." So how were these supposedly nerve dead regions communicating? Komisaruk and Whipple's recent study examined women with severe spinal cord injury and complete loss of feeling in the lower extremities, who nonetheless claimed to experience genital sensation. Using the same vaginal self- stimulation procedure, Whipple was surprised to find that pain detection thresholds increased 91.6 percent in this group. But there was no significant increase in tactile thresholds.
"We hypothesized a genital sensory role for vagus nerves to account for this unexpected finding," said Komisaruk. They carry stimuli directly to the brain, bypassing the spinal cord. They severed the vagus nerve in rats and found that the effect of cervical stimulation disappeared. Their initial work with two women seems to support the theory. Positron emission tomography and magnetic resonance imaging examination of brain during genital stimulation has detected activity in the medulla oblongata, which is associated with the vagus nerve. Their research continues.
The knowledge base of gender and pain is astonishingly small and of recent origin. "Prior to 1995 I could only find 11 studies that talked about gender differences," said Christine A. Miakowski, RN, PhD, Chair of the Department of Physiological Nursing at the University of California, San Francisco.
The University of California at San Francisco has closely studied analgesia. Researchers there have found that the kappa-opioid analgesic pentazocine has a very significant dose-response profile in males and females, producing significantly greater analgesia in females. They replicated the pattern using nalbuphine and butorphanol. Miakowski said that both genders seem to have a good initial response to the drug, but after about one hour "the males began to experience pain." The effect had a significantly more prolonged duration in females. "This suggests that women respond differently to kappa-opioid drugs."
Further research with placebo and escalated doses of nalbuphine, not yet published, discovered that a 5-mg dose in males "is actually antianalgesic," Miakowski said. "This suggests a very complex dose-response relationship with the antagonist." Only at the 20-mg dose did nalbuphine produce significant analgesia in males. Females showed no antianalgesic effect and achieved significant analgesia with just 10 mg of the drug. The studies controlled for body weight.
Roger B. Fillingim's work at the University of Alabama, Birmingham, has looked at gender differences in thermal pain responses. "We found that family history of hypertension influences thermal pain threshold and tolerance in a sex-dependent manner," even if the subject does not have high blood pressure. "High plasma levels of estradiol also were associated with thermal pain sensitivity regardless of the menstrual cycle." In addition, females showed greater sensitivity to ischemic pain during the luteal (premenstrual) phase of the menstrual cycle.
Fillingim found that resting blood pressure tended to correlate with pain sensitivity: the higher the blood pressure, the lower the pain sensitivity. This effect was most apparent in men. Women exhibited a trend in the same direction, but the degree of significance was much less. When they corrected the data for higher average resting blood pressure in men, the magnitude of the difference was reduced but still remained.
Fillingim asked his subjects a question of their self-perceived ability to control pain. What he found was a significant correlation in females. "Those who thought they could handle the pain, well, they were right. They had higher tolerance." For males, the correlation was not significant. "If the pain of labor were not mitigated in some fashion, it would lead to a very stressful situation," said Alan Gintzler, PhD, Professor of Biology at the SUNY Health Science Center at Brooklyn. "The presence of intrinsic pregnancy-activated analgesic processes would seem to have been critical to the evolution of all species."
Gintzler's research over two decades has led him to conclude that "of the three major types of opioid receptors present, activation of both delta and kappa are required for the analgesia of pregnancy to be manifest." Blockade of either can nullify the analgesic effect.
Jack H. Mendelson, MD, a professor at Harvard Medical School, Boston, whose work focuses on substance abuse, provided a highly entertaining survey of turn-of-the-century advertising for consumer products containing opiates. Even then, people understood that ingredients such as laudanum were more effective for women, while cocaine was more popular with men, though they did not know the pharmacokinetics behind those choices.
Mendelson administered intravenous cocaine to both males and females while monitoring them with magnetic resonance imaging and other means. Men achieved the maximal cocaine concentration at 8 minutes, women in the luteal phase of the menstrual cycle at 6.7 minutes, and women in the follicular phase of the menstrual cycle at 4 minutes.
Mendelson found differences in the cerebral blood flow that might explain the differences. "What we think may be happening is that as a function of menstrual cycle phase differences in vascular constriction, induced by cocaine, the tmax of cocaine may concomitantly be altered." He hopes that "study of substance abuse can tell us more about analgesia."
Jeffrey Mogil, PhD, University of Illinois, believes that most of the gender differences with respect to pain are "quantitative differences, matters of degree rather than of essence. But his research has led him to believe that there also is the suggestion of qualitative sex differences in pain, where males and females achieve the same ends, but they do so using completely separate mechanisms."
Mogil turned to mice, looking for a genetic link to pain sensitivity. Sociocultural influence would presumably be eliminated, he claimed, "since male mice are probably not trying to act macho in front of me and female mice are probably not trying to act coy." Any differences that he found were likely to be genetic in origin.
Mogil used quantitative trait locus (QTL) mapping "to look for statistical association between a particular region of a particular chromosome and variability of a particular trait." The technique does not identify an exact gene but a region of perhaps a thousand genes where there is a 95 percent correlation.
"What we think we have found here is a male-specific QTL, a region of chromosomes, that is relevant to baseline thermal sensitivity in male but not female mice," Mogil said. That region on chromosome 4 includes "the OPRD gene which codes for the delta-opioid receptor."
This became Mogil's "candidate gene to mediate this phenomenon." He ran a hot plate latency experiment with a variety of strains of laboratory mice and found reactions that "suggest that delta-receptor mechanisms, which are polymorphic, different from strain to strain, have a role to play in setting basal thermosensitivity in male but not female mice."
Next, Mogil moved on to pain inhibition, the stress-induced analgesia that underlies much of pain modulation in the brain. The experiment was cold waterforced swimming in mice, and the QTL perimeters were for nonopioids. He had already demonstrated that male rodents possess a nonopioid endogenous analgesic mechanism involving activation of N-methyl-D-aspartate (NMDA) receptors, while female rodents display equipotent analgesia that is nonopioid and non-NMDAergic.
"However," Mogil noted, "the fact that female mice had as much analgesia as the male mice, even in the presence of an opioid and a NMDA blockade, suggests that they must have their own female-specific analgesia mechanism." The work has been confirmed and extended by others.
"The expression of this female-dependent mechanism does not change throughout the estrous cycle," Mogil said. "And it turns out that as long as a mouse has enough estrogen, which females always have and males never have, they express the female system." Removing the ovaries stops the expression, while estrogen replacement therapy restores it. "So in this particular case, estrogen appears to be not so much a modulator of a common system but rather a switching device that activates one system and in its absence allows expression of another system."
Mogil ran a parallel QTL mapping of female mouse strains and located a region on chromosome 8 that results in three times the level of stress-induced analgesia with its presence than in its absence. Unfortunately "there is no good candidate gene in the region" to explain the effect. "But when we do figure out what this gene is, it will shed light on the identity of the female-specific system."
Mogil constructed morphine response curves of males and females in eleven different mouse strains. Generally males of a species are more sensitive than females. In this study three strains reflected that, seven showed no significant difference, and one reversed the pattern, with females being significantly more sensitive to morphine analgesia than males. Thus the ability to find quantitative sex differences in analgesic responses may well depend on the strain of mouse used. And failure to replicate an experiment may well be tied to changing a variable by using a different strain of mice from the original experiment.
Mogil believes that his work in mice carries over into humans. "Keep in mind that we are talking about pain here. And pain is very, very old" in an evolutionary sense. Many of its central loci are in the oldest part of the brain stem, not the more recently evolved areas of reasoning. He foresees the possibility of eventually developing "an entirely different class of pharmaceuticals for use in males versus females, which utilizes these systems."
Pain in children is "very plastic and very complex," said Patricia McGrath, PhD, Professor of Pediatrics at the University of Western Ontario. "Although it may begin as tissue damage, the final pain the child feels also depends on environmental and internal factors." As a rule, the younger a child is, the more overtly the child expresses distress when in pain. "We find that the pain intensity decreases as children age," and they experience a diversity of pain on which to construct their own scale of values. Thus people who have experienced a major accident or major surgery tend to acknowledge a larger gradation of pain.
"Girls rate certain types of pain as more painful than boys, and seem predisposed or vulnerable to having certain kinds of recurrent or chronic pain condition," McGrath said. The approach of puberty seems to bring increased recurring headaches and stomachaches in females.
"If people don't know what is happening is painful and don't express it in some way, it may mean that they don't get good pain control," fears McGrath. She believes that "parents need to help children understand something that most children learn on their own: that pain does have a positive, protective signal. You can deal with the reason for this pain and go on and resume normal activities."
Francis Keefe, PhD, works with patients with osteoarthritis at Ohio University. Osteoarthritis affects 40 percent of middle-aged adults and 70 percent of older adults. Any two individuals with the same degree of disease severity will report quite different levels of pain severity. "One may report excruciating pain and be confined to a wheelchair, while another may report little or no pain and be out walking the golf course every day," he marveled.
Keefe wondered why, so he asked his patients to keep a daily diary noting their level of pain and how they coped. They mailed it in at the end of each day. "Women reported 40 percent more pain. They were much more prone to use emotional focused coping strategies to help them deal with the pain." These coping skills seemed to help them get beyond the pain and have much less spillover effect into the next day. Men tended to carry the sense of pain over time.
"Men have a lesson to learn here, particularly in the utility of active coping approaches," said Keefe. "It could well be that increasing the frequency of coping, particularly the strategies that have to do with the regulation of emotions, might have some benefits for men."
Dennis Turk, PhD, teaches anesthesia and pain at the University of Washington School of Medicine. His survey of 428 patients coming to a pain center revealed no significant differences between men and women in terms of prior treatment. Women were more likely to be taking antidepressant medication, but that reflected rates of antidepressant use in the regional population.
Turk ran a full battery of physical and psychological tests on the groups and found that the overall responses were virtually identical in every category. He concluded, "Individual differences within sexes seem greater than differences between men and women." However, he cautioned, "Treatment-seeking patients may be quite different from people who may have similar symptoms but don't seek treatment."
"Many of these studies will only be done one time," said Marietta Anthony of the Food and Drug Administration (FDA). She pled for "the best possible quality data" or "we will miss a unique opportunity" to learn important information. Among the problems she noted were ones as simple as dates being recorded in as many as 20 different ways, and the lack of standardization of nomenclature for drugs, some with literally dozens of different names. "So we have to spend a tremendous amount of time cleaning the data, at least as much time doing that as analyzing the data."
"About 30 percent [of data submitted] do not have gender even recorded," Anthony said. And those studies that do record it often fail to perform analysis by sex. That can be tremendously important. She spoke of the pharmacokinetics of one particular beta-blocker where women accumulated the drug "in much higher presentations than men." For some reason women were not able to clear the drug as quickly. Lowering the dose did not achieve the same effect, "so the drug was not having the same clinical benefit in women. They found out that women had more receptors and therefore needed more of the drug to get the same clinical outcome."
Data submitted to the FDA for drug approval should include gender, age by date of birth, and the size of the patient in terms of height and weight. "This gets to the issue of the difference between gender and sex," Anthony said. "Sometimes we will see a difference in drug disposition and we don't know if it is related to the fact that the person is a woman, or to the body weight and metabolism, which can be corrected by dosing."
The ideal data set would include cultural factors such as diet. Anthony used the example of "large consumption of barbecued food [that] will dramatically alter the way that people metabolize drugs." This type of information is useful in trying to tease out whether the observed effect is genotypic or influenced by other factors.
Anthony also urged the recording and analysis of data such as whether a women is pre- or postmenopausal, where she is in the menstrual cycle, or if hormone replacement therapy is being used.
However, despite all the urging for uniform and inclusive data, the FDA has shown little inclination to use its regulatory authority to set standards for the uniform submission of data.
This article was provided by International Association of Physicians in AIDS Care. It is a part of the publication Journal of the International Association of Physicians in AIDS Care.