CHAPTER 9
Pain
Nothing in medicine is so personal, so compelling, and so isolating as pain. The doctor can’t measure it, frequently has had no personal experience of what the patient is trying to describe, and as a result, generally tends to underestimate and under-treat it. Because the most effective pain medications are addictive, the physician prefers to err on the side of caution when treating a patient, even when the sick person is dying. As for the patient herself, her inability to communicate the grinding constancy of often nearly unbearable pain compounds her plight with a terrible sense of isolation.
Doctors hate problems they can’t solve. Rarely do we feel more helpless than when we can’t put an end to—or even mitigate—a patient’s pain; so we tend to minimize or even deny its existence. It’s one of our worst failings. Excellent data support the fact that even a fetus can feel pain, and the assumption that a newborn baby boy cannot feel the pain of circumcision (or that, because he is tiny and without language, his pain must be diminutive as well) has now been utterly disproved.
Physicians seem to have particular prejudices about women in this area too. It is well established that women report more severe levels and more frequent and longer-lasting bouts of pain in more areas of the body than do men. All too often doctors assume that women simply are more willing to report pain’s existence and to seek help for it; some researchers have lumped it in with what they call women’s “health- seeking behavior” or have attributed it to a nineteenth-century view that some women still have of themselves as frail and unhealthy. In fact, new data from research done on female subjects suggests that the awareness and experience of pain, as well as the response to pain- relieving medications, does actually differ between men and women. This is one of the most interesting and potentially useful observations in the new science of gender-specific medicine.
On the first day of medical school, I have often thought, every student ought to have to answer the question, “What is the meaning of human suffering?” Since the daily business of doctors involves mitigating the pain and discomfort of their patients, both physical and emotional, all doctors ought to have an answer to the question. Mine has been refined considerably since my internship, when I entered the wards of Bellevue Hospital for the first time, thinking to myself, “Now I will really see suffering! These are the most destitute and abandoned people in New York City.” Bellevue was a charity hospital, a patient’s last stop when all the other hospitals were filled. When we ran out of beds in times of crisis, we brought up cots from the basement, and in the bleakest days of winter our corridors were filled with desperately sick patients whom our crowded wards could no longer contain. The first lesson I learned as a physician was that these poorest, most deprived people were no more happy or unhappy than my own friends and family. Pain knows no social or cultural barriers, and despair—or contentment—seems to depend on the inner structure of the personality much more than on the circumstances in which my patients find themselves. On those Bellevue wards, though, I did learn about pain. In that chaotic atmosphere, I learned about how human beings accommodate loss and suffering, and how they metabolize even the bitter realization that they will not survive their illness. If suffering was too acute, I discovered, people simply succumbed. They died of it, or sank into despair. If a patient did survive, it often proved to be a remarkable stimulus for him to develop resources that he never would otherwise have had. Many died without protest, often quite courageously. Others, though, seemed constantly overwhelmed by much less serious threats, and some patients who were not critically ill simply could not be comforted.
The science of how animals, including humans, respond to painful (nociceptive) stimuli may help to explain the tremendous variability in how individuals perceive and react to pain. Doctors have been exploring this issue for many decades, albeit with sometimes primitive experiments. One physician reported in 1934 that a measured amount of pressure on the skull behind the ear produced marked pain in 60 to 70 percent of his patients, while the rest of them had little or no pain!1 Recent, more scientific studies have helped to explain these enormous differences between people. In the brain’s response to a painful stimulus, many more areas of the brain are activated than we might have expected, and the number and location of these activated areas vary a great deal from person to person, implying that learned behavior (which would naturally vary from person to person) might play an important role, in ways we aren’t even aware of, in our response to pain. It also makes research in this difficult area even more complex. Finally, an important study about pain and the central nervous system has made the point that when we receive a noxious stimulus, areas of the brain associated with action are activated—as though the brain were developing new resources to help cope with the challenge.
ARE WOMEN MORE SENSITIVE
TO PAIN THAN MEN?
Some researchers believe there are real differences in how men and women experience pain based on their sex-specific anatomy and the function of some of the organs involved, most notably the brain and the peripheral nervous system. Others are convinced that any gender- specific variation in the experience and reporting of pain is overwhelmingly due to culture and conditioning and depends on the way men and women are taught to express themselves and the personal qualities they are encouraged to develop. (Boy toddlers who skin a knee are told to get up, stop crying, and keep walking; girls have their tears brushed away, get a comforting hug, and may even be allowed to get back into the stroller!)
Many factors mitigate the experience of pain and make real certainty about what is specifically the result of biological sex very difficult. For example,
• Women have different strategies to alleviate pain: they use more pain-relieving medicine and more adjunctive therapies like relaxation techniques, aromatherapy, massage, and visualization.
• In scientific experiments, when men and women are tested under controlled conditions with the same unpleasant stimulus, cultural conditioning seems to affect the results more than hardwiring. For men, but not women, the place the stimulus is delivered is important: men react more intensely if the lower abdomen near the genitals is stimulated. The gender and the attractiveness of the experimenter affects men’s responses but not those of women: men report less pain when the observing scientist is female, while women show no difference when the investigator is male or female! The personal traits of the subject (level of anxiety, reliance on and development of personal control, and the like) also affect the data.
• Other biological issues that have nothing to do with gender confound the data. Nutritional status (particularly the intake of sugar and fat) and the presence of other diseases, for example, also influence a person’s response to painful stimuli.
For whatever reasons, women tend to report pain with milder stimulation than men; they have a better ability to describe it, they tolerate it less well, and they feel it longer, more intensely, and in more areas of the body than do men. Some studies show that women experience more discomfort and pain from pressure and electrical stimulation than men, while thermal stimulation (heat or cold) and the pain that comes from cutting off the blood supply to a body part (ischemic pain) show fewer sex-specific differences in the response. But many of these experiments yield contradictory results, perhaps because they rarely take into account the fact that pain sensitivity in humans and even in animals varies with age, pregnancy, the menstrual cycle, and the use of exogenous hormones like oral contraceptives. Finally, there are sex-specific differences in the absorption and metabolism of pain-killing medications and anesthetics.
GENES AND PAIN
Some variability in the experience of pain is unquestionably genetic. Consider the remarkable story of the Human Pincushion, a carnival performer with a unique insensitivity to pain, although he could feel all other kinds of stimuli.2 He had a defect in a specific gene, NTRK1 (not surprisingly called the Congenital Insensitivity to Pain gene). At least three different kinds of mutation in that same gene have now been identified, which produce a variety of defects:
• Over 40 people have now been studied who lack a specific receptor in their nervous system that makes them unable to complete the circuits necessary for registering pain.
• One hundred and two people from four related Australian families have a defect in the nerve fibers that receive sensations from the outside world (sensory fibers). All incoming messages in the affected people are muted, especially those that have to do with pain.
• Two sisters have been described who had a unique combination of a spontaneous and unprovoked loss of their fingers and toes and an inability to feel pain.
The defect in NTRK1 affects both men and women, but some of the genetic defects that result in pain modification are sex-specific:
• A male-specific mutation on chromosome 4 affects the time it takes for a rat to withdraw its tail after being placed on a hot plate; depending on the presence of the mutation, the time the animal tolerates the high temperature before removing his tail varies significantly.
• When mice are forced to swim for long periods of time, the brains of both males and females produce an anesthetizing chemical that helps them tolerate the ordeal. This phenomenon is called stress-induced analgesia (SIA). The chemical comes in two different general types: one is called nonopioid, because it is not like morphine (it is not neutralized by naloxone, which is an antagonist of morphine), and the other is opioid (because it is neutralized by naloxone). Nonopioid SIA is different in the two sexes, a pattern set early in development. Male mice mount a more robust nonopioid SIA than female mice. The female-specific system has a different hormonal basis: it is dependent on the mouse fetus not being exposed to testosterone during intrauterine development; it emerges only after puberty; it varies with reproductive status; and it persists after the equivalent of menopause. Genetic analysis showed that the gene controlling SIA in the female mouse (but not in the male) is probably located on a specific site on chromosome 8. Variations in the gene are related to the amount of nonopioid SIA that different female mice produce; some produce none at all. All this is to say that, judging from their levels of these chemicals, the experience of pain in these mice may be more intense in the females than in the males.
• Other experiments in rodents have revealed an interesting link between the ability to tolerate pain and sensitivity to morphine. In general, when sex differences exist, it is males who show a significantly greater ability to tolerate a painful stimulus. These same animals also show greater responsiveness to analgesia: morphine has a greater impact on relieving pain in these “doubly advantaged” males.
• Pain-killing drugs have several kinds of receptors in the human brain. The two best known are called the μ-opioid receptor and the kappa or k-opioid receptor. Morphine, for example, reacts with μ-opioid receptors. In human studies, women seem more responsive to agents that interact with the k-opioid receptor than men: after oral surgery, pentazocine (Talwin), nalbuphine hydrochloride (Nubain), and butorphanol tartrate (Stadol) all worked better at relieving pain in women than in men. The superiority of these medicines in women was not influenced by the menstrual cycle (which means that hormones had nothing to do with the gender differences in response to these medications).
Genes affect the experience of pain in other ways. Some painful diseases only occur in one sex: only men get hemophilia, for example. Our bodies often process and use many drugs, including drugs that relieve pain, in sex-specific ways, which are importantly influenced by gonadal (sex) hormones.
DRUGS AND PAIN
The ways in which the body processes analgesic drugs and anesthetic agents affect how men and women respond to pain treatment. Differences in body composition can be a factor: men have more muscle mass and women more fat, but some drugs bind to fat cells, so the amount of body fat affects the duration of a drug’s action. Because a woman’s digestive system moves solids and liquids along more slowly than a man’s, moreover, any pain-killer she takes by mouth may have a more potent effect, since it has more time to be absorbed during its passage through the digestive tract. The rate at which we process drugs in our liver and the efficiency and speed with which our kidneys operate to clear medicines from our system also influence the impact of pain-relieving medication. How people metabolize drugs as a result of genetic inheritance can also be very important: for example, 7 to 10 percent of Caucasians can’t convert codeine to morphine because of a variation in the cytochrome P450 system in their nerves. Since the pain-relieving action of codeine depends on its conversion in the body to morphine, these patients get no pain relief from taking the drug—although they are still able to suffer its side effects!
ANATOMICAL DIFFERENCES
IN THE NERVOUS SYSTEM
Anatomical differences in the nervous systems of men and women may account for some important differences in pain perception. One sex may simply have more nerve fibers than the other in an area of tissue that receives a painful or unpleasant stimulus. Special nerve fibers, called C fibers, are activated by injury or illness; the impulses that result can produce changes that persist long after the stimulus is over. These fibers are abundant in the pelvic organs of women. As a result of vaginal and uterine vulnerability to painful consequences of intercourse, the birth of children, and menstrual cramps, scientists theorize, women are more likely to suffer pelvic trauma than are men. The C fibers “remember” these stimuli and not only produce a heightened awareness of pain in the affected organ they supply but carry impulses to other nerves in their travels up the spinal cord. This is thought to be the reason women experience more referred pain (pain felt in a place other than where it originated) than men, particularly in the muscles of the head and neck.
HORMONES AND PAIN
Hormones are key modulators of the experience of pain. They modify our ability to keep nerves in optimal working condition, and they regulate the production of nerve growth factor and a substance involved in our awareness of pain called P substance. Estrogen influences the size of the “field” of nerves that are activated in response to a painful stimulus. Estrogen binds to opioid receptors in the brain. Thus the number of receptors and their affinity for medications that reduce pain vary with the phase of the menstrual cycle. Progesterone desensitizes opioid receptors in the brain and produces hypersensitivity to thermal stimuli, as well as (in rats) diminishing the power of morphine to relieve pain. These phenomena help to explain why sensitivity to pain varies with the menstrual cycle; menstruating women (who have relatively less available estrogen) are often more sensitive to pain than at other times in the month.
The same areas of the brain that scientists have identified as important to reproductive behavior are also very important to the experience of pain, which may explain the apparent link between hormonal fluctuations and response to noxious stimuli. In fact, if a woman experiences pain at a time when certain hormones are more abundant, she may become permanently sensitized to the experience of pain and have hypersensitivity and/or develop chronic pain at the site of the original stimulus even after that stimulus is no longer present—much like the effect of C fibers, mentioned earlier. This phenomenon is evident in some patients after mastectomy. Instead of recovering uneventfully, about one in ten develops chronic pain in the underarm, the chest, and occasionally the shoulder. In some women the pain is excruciating. Many develop a “frozen shoulder” because movement makes the pain worse; they protect the affected arm to the point that they lose mobility in the joint. This phenomenon is more common in women who remember severe postoperative pain and whose memory of how terrible it was increases with time. Understandably, these women eventually became sadder and more anxious than other patients who did not have this syndrome.
During the middle of the menstrual cycle, when progesterone levels are high, women’s brains have reduced activation patterns in response to painful stimuli. Progesterone, which is also at high levels when a woman is nursing a baby, is a sedating and anesthetizing hormone. In fact, the chemical structure of some anesthetics (alphaxolone, for example) is very much like that of progesterone. This sedating aspect is one way the body prepares a woman for bearing a child and nursing a newborn. Testosterone, for its part, mutes men’s experience of pain, which is one of the reasons that as men age and testosterone levels decrease, they become more sensitive to painful stimuli. (Testosterone’s dampening effect on pain perception is probably a coping maneuver to minimize the pain of physical combat for men that has evolved over millennia.)
Sometimes, for reasons scientists aren’t entirely sure of, hormones seem to exacerbate pain rather than mute it. A recent study showed that women who use birth control pills are more likely to have pain in the temporomandibular joint (TMJ, the joint connecting the jaw to the skull) than women who do not use them. In postmenopausal women, estrogen and, to a lesser extent, progesterone use significantly increases the risk for TMJ syndrome. The important point here is that exogenous hormones modulate the experience of pain, and women should know this when they agree to use birth control pills or HRT.
THE BRAIN AND PAIN
The brain’s organized system to receive, modulate, and react to painful stimuli is complex: essentially, it consists of four interactive components. The first receives the stimulus and transmits it to the brain, where the second integrates the activity of the parts of the brain that identify the nature of the stimulus, assess its importance, and generate an appropriate emotional response to it. The third component then telegraphs a message to the systems in the body that are under automatic or involuntary control, like breathing and digestion (which is why pain changes heart rate and blood pressure). Finally, the fourth component provides feedback about changes in those systems to the brain, so that those changes can be modified or stabilized.
The central networks of these components may be importantly modified by hormones: in adult female rats, the portion of the brain called the locus coeruleus, which is concerned with arousal and pain modulation, is bigger and has more cells than in male rats. If a female rat receives testosterone on the first day of her life, this difference never develops.
Male rats are more sensitive to morphine than female rats, who seem to have their own “built-in” nonopioid pain-killer, which is related at least in part to estrogen production. Female rats secrete more of these chemicals during the birth of pups than at other times, which may make delivery less painful for them.
There may be important gender differences in the sites of the brain that are involved with the perception of and physiological response to pain. For example, MRI imaging has shown that in both men and women, if the bowels are distended to the point of being painful, the same areas of the brain are activated. But when men and women with irritable bowel syndrome are given the same stimulus, different areas of the brain are activated between the two sexes. Why is the pain from IBS encoded differently for women than for men? What does this mean for pain control or for the treatment of IBS? Scientists still don’t know the answers.
OTHER GENDER DIFFERENCES IN
THE BODY’S RESPONSE TO PAIN
Men’s and women’s responses to pain also differ physiologically. For example, men in pain are more likely to experience a rise in blood pressure, whereas women in pain experience an accelerated heart rate more than do men. In cases of severe pain (produced in one study by occluding blood supply to the arm), women’s blood pressure rises only a little or not at all, and as pain is increased, their blood pressure falls. But in men blood pressure rises as soon as pain is experienced, and it continues to do so as the pain increases. These findings suggest not simply a physiological but an emotional and/or behavioral component to pain response. This is very useful information for the gender-specific treatment of pain. In the recovery room after surgery, anesthesiologists traditionally gauge the amount of pain that needs treatment by monitoring the patient for an increase in blood pressure rather than heart rate. While this is a good index of discomfort in men, it is not as useful for monitoring postoperative pain in women.
Males who are stressed by intellectual challenges, like a school examination, secrete more adrenaline and Cortisol (the stress hormones) than do females. In men, moreover, these hormones also seem to evoke feelings of accomplishment and triumph. Women in the same situation, however, produce less stress hormones and report more feelings of failure and anxiety. The stress response begins in the brain and works through the pituitary gland to stimulate the adrenal glands to produce these stress hormones, a process called activation of the hypothalamic-pituitary axis. R. B. Fillingim and William Maixner at the University of North Carolina in Chapel Hill have a very interesting idea of why noxious stimuli activate this axis in men more than in women; they hypothesize that the difference is an important result of evolutionary selection, because activating the axis brings practically all levels of the reproductive process to a halt.3 They point out that stress- induced analgesia (pain relief) is much less effective in females after ovulation, suggesting that this cyclic suppression of the activation of the axis preserves fertility.
GENDER AND PAINFUL DISEASES
Headache
In a comprehensive recent review of gender differences in chronic headache, Dawn A. Marcus at the University of Pittsburgh observes that the incidence of simple chronic headache was equal in both sexes, but women had worse headache-related emotional distress, and men had more headache-related disability (they were less able to work and function at daily tasks than women).4 A combination of depression and anxiety was identified in 75 percent of female sufferers but in only 25 percent of the men; 45 percent of all patients, regardless of gender, had anxiety. Dietary restrictions and regularization of eating patterns were more helpful to women than to men. Findings like these, that women’s pain may stem more often from depression and can be managed more easily with simple diet adjustments, will prove valuable in our attempts to develop gender-specific strategies for pain management.
Some kinds of pain seem quite specifically associated with the female sex. A certain type of susceptibility to migraine headaches that runs in families, for example, stems from a defect on the X chromosome, which may help to explain why migraines are more frequent in women than in men. Migraine headaches are definitely more frequent in women (15 to 17 percent of all females have them) than in men (3 to 6 percent). Interestingly, this difference does not develop until puberty; until then, boys and girls seem to be equally affected, although the incidence in boys is maximal at five years of age and in girls at twelve. The difference begins to decrease again when adults reach middle age and tends to disappear as people age further. Migraines are associated with depression, and some scientists believe that the increased incidence in women is related to the fact that depression in women is more common.
Hormones too are probably to blame. Migraines worsen in many women with the menstrual period, probably because estrogen levels decrease at that time. In fact, 14 percent of women sufferers have migraines only in connection with their menstrual periods. Interestingly, it seems to be the change in estrogen concentrations, more than the low levels, that triggers migraine. Before low levels of estrogen will cause a headache, women have to be exposed to it in high levels (estrogen priming). If estrogen levels are chronically low (as they are in the postmenopausal period), headaches disappear. High estrogen levels are associated with high levels of one of the chemicals in the brain, 5-hydroxy tryptamine (5-HT), which inhibits the pain of headaches; when estrogen levels fall, so does 5-HT and the result is a migraine. Because of the potentiating effect of estrogen on migraine, 40 percent of women who suffer from migraines and use birth control medication will have an increase in symptoms. This may persist for as long as a year after stopping oral contraceptives. Progesterone-only contraception, on the other hand, increases symptoms only about 3 percent in migraine sufferers, although it is associated with other (tension-type) headaches in 25 percent of women who use this method. Pregnancy, because it provides the mother with stable estrogen levels, usually helps headache; it is the cyclicity of estrogen levels that cause the problem. In postmenopausal women, the introduction of HRT may cause an increase in the severity and frequency of headaches; this is usually handled by using a constant estrogen dosage instead of cyclic therapy.
Menstrual migraines can be treated quite effectively with low-dose estrogen patches four days before and for the first three days of the menstrual period.
In contrast to migraine headaches, cluster headaches are more frequent (by 4 to 7.5 times) in men. These intensely painful headaches occur in groups or clusters; between a series of attacks, patients are peculiarly symptom free. These headaches too are thought to be a result of hormonal dysregulation—in this case, a relatively low concentration of testosterone, caused by an impaired ability to make testosterone in response to luteinizing hormone (LH). An excess of epidermal growth hormone is known to impair the response of the gonads to LH and is thought to be the reason for cluster headaches as well as the peculiar lionlike facial appearance, known as leonine facies, of men who have them.
Osteoarthritis
This wear-and-tear disease of the joints affects 40 percent of middle-age adults and 70 percent of those over sixty. The specific joints are not affected equally in men and women: females are twice as likely to have arthritic knees than are men, but arthritis of the hips is equal in the sexes.
Francis J. Keefe, a psychologist at Ohio University, studied sex differences in the pain men and women feel with osteoarthritis. He found that women show a unique approach to the discomfort: 40 percent more females than males complained about their pain, and they were also more proactive than men in talking to others about it, asking for help from friends and families, and seeking distractions and counseling. This resulted in less depression in women than in men after a day of particularly disturbing pain. When subjects were shown videotapes of their spouses performing ordinary tasks, women were also better than men at identifying pain in their spouses. (The increased sensitivity of wives was only to their own husbands, by the way; it didn’t extend to anyone else!) When Keefe studied the interactions of spouses with osteoarthritis when they were together, he found that the women tended to complain and give nonverbal clues about their discomfort (wincing, grimacing, and so on), whereas husbands encouraged their arthritic wives with humor as a supportive strategy.
Coronary Artery Disease
Coronary artery disease is a very interesting illness for gender-specific medicine because so many features of it differ between the sexes (see Chapter 5); one of the most important is pain. The famous Framingham Heart Study, which began in 1948 and traced the natural history of CAD in the population of a small New England town, was the first study to point out differences between men’s and women’s experience of the disease. Doctors have long known that chest pain in women is much less well correlated with demonstrable disease of the coronary arteries when patients come to cardiac catheterization: 50 percent of women with chest pain show no disease in the large arteries supplying the heart, while the figure for men is only 17 percent. On the other hand, this does not mean the disease is less serious for women than men: more women than men have no pain at all with their heart attacks, these are called silent myocardial infarctions (SMIs). One in five women has a very unusual but consistent presentation: a constellation of pain in the upper abdomen or back, extreme shortness of breath, and profuse sweating.
The disconnect between severe chest pain and actual CAD is most marked in younger women; severe chest pain appeared in premenopausal women with high estrogen levels and in postmenopausal women on HRT. At this writing, The National Institutes of Health is completing a four-year study of the nature and cause of chest pain in women (the Women’s Ischemia Syndrome Evaluation, or WISE, study); results should be forthcoming soon and will help doctors identify and treat the cause of chest pain in women much more accurately. Most physicians who treat women for chest pain believe that in a substantial number of patients the pain is caused by spasm of the heart’s small muscular arteries. Such spasm can’t be visualized by cardiac catheterization, in which only the largest vessels at the surface of the heart are filled with dye and examined for dangerous deposits of plaque.
Recently David Sheps and his colleagues at East Tennessee University reported on their detailed investigation of what produces angina (chest pain brought on by emotion or exertion) in men and women.5 The subjects agreed to endure physical and emotional challenges on two different days and report their responses. Women’s complaints of chest pain were more frequent on a day when they experienced mental stress (public speaking) and on an ordinary day than on a day of physical stress (riding a stationary bicycle). Like the rats I’ve described earlier in this chapter, women turned out to have lower levels than men of beta-endorphins—the chemicals in the brain that soothe and comfort and that increase in response to pain.
Reproductive Organs
Both men and women experience chronic pain in the reproductive organs, but the medications that help men don’t work as well in women. Ursula Wesselmann at Johns Hopkins University School of Medicine compared 25 women with chronic noncancerous pelvic pain with 25 men with chronic nonmalignant testicular pain and gave each patient one of four different types of medication: an antidepressant, an anticonvulsant, an opioid, or a membrane-stabilizing agent.6 All of these medications worked better to relieve women’s pain—except for antidepressants, which worked better in men: 9 out of 11 men improved with antidepressant medication, compared with only 4 out of 25 women.
Other interesting data emerged from Wesselmann’s study:
• Women and men both found the pain hard to localize but severe enough at times to make them nauseated and sweaty.
• Both sexes found it hard to discuss pain in these areas with a doctor and as a result delayed seeking help for their discomfort.
• In women, the intensity of chronic pelvic pain may have no relationship to the physical source of the problem; the small site of endometriosis in the uterus, for example, can cause significant discomfort.
• Women have a 5 percent lifetime risk of chronic pelvic pain and a 20 percent lifetime risk of pelvic inflammatory disease; in both cases the pain can persist even when the acute infection has been cured.
• Men suffer chronic pain (that lasts more than three months) in their testes in their late thirties; in a third of these men, no disorder is apparent, but in the other two-thirds, bicycle accidents, vasectomies, infections, and tumors are triggering causes.
Fibromyalgia
One of the most poorly understood disorders that doctors face in practice is fibromyalgia (FM), which is what I call a “wastebasket illness.”19 Like chronic fatigue syndrome, it is not a flight of a patient’s imagination: it causes life-disrupting discomfort and is extraordinarily difficult to treat. Researchers know almost nothing about its cause or where the symptoms come from. Some important recent advances in our understanding of fibromyalgia, which occurs in nine times as many women as men, come from Laurence A. Bradley at the University of Alabama.7 He studied 66 women being treated in a fibromyalgia clinic. All had had more than three months of widespread body pain and had increased pain in response to pressure in at least eleven of the eighteen points that are considered characteristically sensitive in FM. Bradley documented several interesting facts:
• FM patients found a pressure stimulus of any given strength more painful than did healthy women.
• FM patients’ cerebrospinal fluid contained more P substance (a chemical involved in transmitting the message of pain to the brain) than did that of healthy women.
• The areas of the brain critical to the experience of pain were different in FM patients than in healthy women.
• More FM patients had been diagnosed with psychiatric illnesses (anxiety disorder, depression, and the like) than healthy women.
Temporomandibular Disorder
Temporomandibular disorder (TMD) involves pain in the temporomandibular joint, which joins the lower jaw (the mandible) to the skull, and in the surrounding muscles. It affects seven times as many women as men. It is quite common, affecting as many as one in four young adult females, according to William Maixner at the University of North Carolina at Chapel Hill. Several aspects of the disease are reminiscent of the kinds of symptoms endured by FM patients:
• TMD patients feel painful stimuli anywhere in the body much more intensely than do healthy people. 8
• When healthy people have toothache, a tight tourniquet on the arm lessens or eliminates the tooth pain. (The painful impulses from the arm “jam the highway” to the brain so that impulses from the tooth are blocked.) But when Maixner tried this maneuver in patients with TMD, two-thirds of them had either no change or an increase in their tooth pain!
• FM and TMD may overlap, because 75 percent of FM patients have TMD, and the latter may actually be an early stage of fibromyalgia.
MEN AND WOMEN IN PAIN:
SHOULD DOCTORS TREAT THEM BOTH THE SAME WAY?
As we saw in Chapter 3, each medication has its own particular pharmacokinetics, which may vary according to an individual patient’s gender, genotype, and other factors. Premenopausal women, for example, do not absorb medications in a consistent way. During midcycle their gastric absorption of alcohol and aspirin is less efficient, and the intestinal transit time of any ingested substance slows down. This is also true during pregnancy and when women take hormonal supplements or birth control pills. Levels of proteins that bind a drug like lidocaine (an anesthetic given by injection) are generally lower in women than in men, and less of the drug is bound in a female patient taking birth control pills (which compete for binding with the lidocaine). The more a drug binds to carrier-proteins, the less effective it generally is.
Men and women metabolize drugs in significantly different ways (see Chapter 3) because of the sex-specific characteristics of the liver’s cytochrome P450 system, which purifies the blood. Birth control pills can intensify the effect of some pain medications by lengthening the time they remain in the body. Other medicines, like the sedative and anticonvulsant drug mephobarbital, are processed more quickly by younger men than by women and older men, as a function of younger men’s higher testosterone levels.
Males, as I’ve said, seem to be more sensitive than women to morphine. And for some reason, nonsteroidal anti-inflammatories (NSAIDs) like ibuprofen (Advil) are less likely to reduce pain in women than in men, although they reduce inflammation equally in both sexes. So the pain relief a woman experiences from an NSAID may be a consequence of its effect on inflammation more than the drug’s direct action on her pain.
Such data make it important for a physician to consider a woman’s age, weight, and body composition, as well as whether she is taking birth control pills, before prescribing pain medication or anesthesia for her. If her pain is recurrent and cyclic, a preemptive strike might be useful, starting pain medication in advance of the predicted discomfort or the time when the pain is expected to be worse. A fixed regimen might not be the most useful strategy, since many painful conditions worsen during the menstrual period. So pain medication might be increased automatically just before menses begin.
Medicines used during and after surgical procedures should be carefully chosen on the basis of the patient’s sex. Women experience more muscle discomfort and headache after surgery, which may well be related to a muscle relaxant used during surgery called succinyl choline; this drug is associated with more muscle pain in women than in men in the first days after recovery from surgery.
Finally, education and attitude may be among the most useful tools we have for pain management. Lamaze classes for women and their husbands on how to get through labor, for example, have proven very helpful. In general, women are more willing than men to verbalize their concerns and respond to communication and teaching from their health care providers. Doctors should make an extra effort to teach male patients about their treatment options, especially when it seems that situational changes (like finding suitable help) or adjunctive therapies (like meditation or massage) might help recovery or at least lessen the intensity of discomfort.
Throughout the pain-management process, physicians have to consider their own attitudes toward pain. Many doctors are more likely to discount women’s complaints than men’s, out of a conviction that women are simply less able to bear discomfort than men. These prejudices are hard to expunge. In fact, in my experience, most physicians avoid scrutinizing their own abilities to be objective and helpful to patients. One of the first—and last—chances that the health care system has to help doctors improve their interpersonal skills and correct harmful and destructive attitudes to patients is during their medical school training and immediately after graduation from medical school, when they are house officers on a hospital staff. In addition to the spoken instructions of older physicians, the example provided by supervising doctors as they deal with patients become very important in molding the sensitivity and empathy of young trainees.
WHAT DOES THE NEW SCIENCE MEAN FOR YOU?
I am planning elective (nonemergency) surgery. Does it matter what phase of my menstrual cycle I’m in when I have the operation?
You might have not only less pain but a better response to medication in midcycle than just before or during your menstrual period. Ask your doctor to consider your monthly cycle in scheduling the procedure.
Every time I menstruate, I get a terrible headache. Why? Can I do anything about it?
Menstrual migraines are not a mystery: they occur because of the sudden drop in estrogen that precedes the beginning of menstruation. Often the temporary use of an estrogen patch just before and during the first few days of a menstrual cycle will help.
Which is likely to be more effective in relieving pain from my infected finger, Tylenol or Advil?
If you are a woman and your pain is caused by an infection, you are more likely to get relief from a nonsteroidal agent like aspirin or ibuprofen than from acetaminophen. Inflammation is a bigger component of a response to infection in women than in men, so a drug that specifically lessens inflammation is likely to be more helpful for pain relief.
My doctor told me I couldn’t be having a heart attack, because I was having back pain and not chest pain. Yet I was terribly short of breath, nauseated, and sweating profusely. In fact, testing in the ER proved I had a heart attack. Why was my pain in such an unusual place?
The place you experienced pain was not unusual for a woman: one out of five women with acute heart attack (myocardial infarction) has pain in the epigastrium (upper abdomen) and not under the breastbone, which is the classic site for discomfort in men. Sex-specific differences in the anatomy of the nervous system produce gender-specific variations in the sites of pain; often it can be relatively remote from the organ that’s injured. If you suspect you’re having a heart attack, insist that it be ruled out by proper testing before you agree to leave the emergency room!
I couldn’t convince my doctor to give me enough medicine for pain just after I had major abdominal surgery; he said he saw no indication to increase my dose over what he’d already given me. What criterion was he using to decide?
Probably it was the fact that your blood pressure didn’t rise when you began to feel more pain. In men, the level of pain is mirrored by a rise in blood pressure. For women patients, informed anesthesiologists follow the heart rate rather than the blood pressure to monitor the severity of pain.
Pain medication seems to wear off in my husband sooner than it does for me. Is he just a wimp?
Decidedly not: men and women process many pain-killers, anesthetics, and other medicines differently. Some drugs bind to fat cells, and women have more body fat than men. You might absorb more of the drug than your husband does because everything, including food, moves through women’s digestive tracts more slowly than through men’s. Some of the difference may be genetic: a small percentage of men can’t metabolize codeine properly, and so they get little or no pain relief from the medication.
The time in your menstrual cycle and whether you take oral contraceptives could also influence the efficacy of a pain-relieving drug: some hormones compete in the liver for the sites used to process medicines and make them available to the body If one pain-reliever works less well depending on your cycle, for example, let your doctor know so that she can choose another type of analgesic for you.
I’ve noticed a really painful ache in my jaw recently. What should I tell my doctor that might be relevant to why this is happening?
One thing you might want to mention is whether you are taking prescribed oral contraceptives: women who use them are more likely to have temporomandibular joint pain than those who don’t.
After an exhausting fight with my husband, I notice that he’s much less depressed than I am—I feel exhausted and anxious. Is this sociology (he simply doesn’t care as much if we’re getting along) or biology?
It could be both. Both sexes, when stressed, secrete the stress hormones adrenaline and Cortisol, but men secrete more than women. In men, these hormones are more likely to evoke feelings of triumph and success; for women, the effect is to lower self-esteem and increase anxiety.
When my husband had a tooth pulled yesterday, I offered him one of the pain-killers my dentist gave me when I had my own extraction. It worked fine in my case, but my husband didn’t get much relief. Is it because he’s bigger than lam and needs a bigger dose?
It depends on the medication. The brain has two kinds of receptors for analgesic drugs: the μ-opioid and the k-opioid. Women get a much better effect from drugs that interact with the latter. Several medicines dispensed by dentists work better in women; three of them are pentazocine (Talwin), nalbuphine (Nubain), and butorphanol (Stadol).