But perhaps the Italians being studied simply expressed more pain because their culture permits greater expressiveness, and since expressing pain can ease it, perhaps they actually suffered less. Indeed, a recent study by British researchers asked volunteers to hold their hands in painfully icy water; one group was allowed to continually swear aloud with a curse word of their choice, and the other had to repeat a non-swear mantra. The people who were allowed to swear were able to keep their hands in the water longer, and they perceived it as less painful. The testers theorized that the swearing induced a fight-or-flight response (release of stress hormones), which reduced fear of pain and therefore pain perception.
A benchmark 1972 Stanford University study, led by Dr. Kenneth M. Woodrow, of more than forty thousand patients belonging to a large HMO found that age, sex, and race do modify pain tolerance. Older men’s pain tolerance was two-thirds to three-fourths of that of younger men’s. In women, the decline was less pronounced, however, and even the oldest men had a higher pain tolerance on average than the youngest women. Pain tolerance, in general, varied less among women than men. Whites showed more pain tolerance than blacks, and blacks showed more tolerance than Asian Americans. Another study found Hispanics to be more sensitive to pain than non-Hispanic whites.
The Woodrow study made no claims as to whether the differences in pain toleration between ethnic groups are culturally or biologically determined. But the more that subjective differences in pain sensitivity are studied, the more frequently they appear to have a biological basis. Although the data is complicated and debated, numerous studies suggest (irritatingly) that nature may indeed be sexist and females simply have lower pain tolerance than males. Perhaps as an adaptive response to males as warriors and hunters sustaining more acute injuries than females, there seem to be differences in male and female pain-modulatory systems, with males enjoying more robust pain modulation. Female hormones are a potential mediator of the sex difference in pain sensitivity. Certain phases of the menstrual cycle are associated with a lower pain threshold.
There are interesting differences in male and female opioid receptors. (The differences are also present in male and female rats.) There are three types of opioid receptors, most notably mu and kappa; most opioid drugs such as morphine target mu receptors. Few drugs that target kappa receptors have been developed, because early trials found them ineffective. The research, however, was conducted largely on men, and it turns out that women are more responsive to kappa-receptor drugs. One study of a rarely prescribed kappa-receptor analgesic (nalbuphine) on postoperative pain in men and women who had their wisdom teeth removed found that the drug had opposite effects on the two sexes, ameliorating female pain and exacerbating male pain. Studies of mice suggest that the sex differences in the analgesic effect of kappa opioids could be traced to one gene, known as melanocortin-1 receptor, or MC1R.
The common mu-receptor analgesics, by contrast, are less effective in women than in men (and less effective in female rats than in male rats). A 2003 study by Dr. M. Soledad Cepeda and Dr. Daniel Carr of postsurgical pain following general anesthesia found that “women have more intense pain and require 30% more morphine [on a per-weight basis] to achieve a similar degree of analgesia compared with men.” The study advises that “clinicians should anticipate the differences in opioid requirement to avoid under-treatment of pain in women.” So although women are less likely to be prescribed opioids, they actually require more. There is also some limited evidence that women respond differently to nonsteroidal anti-inflammatory drugs (NSAIDs): although the drugs act equally on inflammation in both genders, men receive more analgesic benefit from the drugs than women do (a finding that may provide clues to why women suffer more from chronic inflammatory conditions).
Even the far-fetched Victorian notion that hair color affects pain sensitivity turns out to have a grain of truth in regard to fair-skinned redheads. A certain type of opioid pain medication that acts on kappa receptors (pentazocine) was found to work dramatically better for red-haired women; it turned out that the same gene MC1R that accounts for women’s responsiveness to kappa opioids is also responsible for red hair and fair skin pigmentation. Interestingly, common opioids work less well in redheads. Redheaded women need an average of about 20 percent more general anesthesia than dark-haired women. They also derive less analgesia from novocaine and are more likely to avoid going to the dentist.
Puzzlingly, studies prior to Dr. Woodrow’s agreed with the Victorian notion that the old are less pain sensitive than the young. But those studies employed thermal pain (heat or cold stimuli applied to the skin), whereas the Woodrow study employed mechanical pressure on the Achilles tendon (which produces a deep pain). Aging, it turns out, has contradictory effects on pain: sensitivity to cutaneous pain decreases, while sensitivity to deep pain increases (which is more clinically relevant because it more closely resembles the pain produced by disease processes and injuries than does a superficial stimulus). This finding may be of great value in developing analgesia for elderly populations.
Although Galen believed that fat, phlegmatic types had diminished pain sensitivity, the contrary seems to be true. Unsurprisingly, obesity creates pain-causing conditions, such as greater rates of degenerative arthritis, because of the extra weight that joints must support. (Degenerative arthritis, also known as osteoarthritis or wear-and-tear arthritis, involves a deterioration of the cartilage that cushions the bones at joints, which results in pain, stiffness, and inflammation.) But do the obese also suffer from lower pain toleration? Do painful stimuli actually hurt them more?
Many studies have shown that the obese report more pain in laboratory pain-toleration studies. But does this reflect a difference in their bodies’ innate pain sensitivity? A 2006 Ohio State University study attempted to answer that question by measuring the muscular response to electrical stimulation of a nerve in the legs of patients suffering from osteoarthritis of the knee. The obese patients reported no more pain than non-obese people (and rated their pain in a similar fashion in questionnaires). But their ankles demonstrated a greater muscular pain reflex. When all the volunteers were given a pain-toleration training session that included a progressive muscle relaxation exercise, both groups reported less pain and showed diminished pain responsiveness. But the obese continued to show greater pain sensitivity.
The view that children were not sensitive to pain continued to hold sway through the first half of the twentieth century. Many in the medical profession held that infants felt no pain at all and that young children were simply not developed enough to suffer. Until the late 1970s (this is not a typo), most surgeries in the United States and around the world were performed on infants with little or inadequate anesthesia (although they were paralyzed with a neuromuscular blocker) because general anesthesia was believed to introduce unnecessary risk. Pain medication was also withheld from infants and young children during recovery from surgery, cancer, and even severe burns.
Even after the practice was recognized as harmful, anesthesiologists and hospitals resisted change. As late as 1987, an editorial in The New England Journal of Medicine still found it necessary to argue that the evidence was “so overwhelming that physicians can no longer act as if all infants were indifferent to pain.” Finally, a study conclusively demonstrated that babies who were operated on without anesthesia were more likely to die! By contrast, those given anesthesia recovered more quickly from surgery and suffered fewer complications.
Although pain generates less lasting emotional reaction in infants and young children than in older children and adults (hence children can emit bloodcurdling screams of pain at one moment and then laugh the next), physiologically, young children are much more adversely affected by pain because the nervous pathways that conduct pain develop earlier than the brain’s ability to modulate pain. While the ancient Assyrians were concerned enough about pain to asphyxiate their baby boys to the point of unconsciousness before circumcision, many infants today continue to be ci
rcumcised without anesthesia, even though the practice has been shown to have long-lasting detrimental effects.
A doctor who worked for the French pain-treatment charity Douleurs Sans Frontières (Pain Without Borders), found that physicians in Africa had to be trained to recognize pain. A pediatrician at a good hospital in Mozambique, for example, assured the French doctor that none of his patients had pain. He took him to the children’s ward to prove it. “You see,” he said, “none of the children are crying or fussing. They are lying quietly in their beds.” The French doctor had to explain that it is natural for children to cry and move about and that not crying can be a sign of terrible pain. Daniel Carr recalled a paper submitted to Pain, a professional journal he edits, in which a Chinese physician argued that children in China recovering from abdominal surgery were not given—and did not ask for—pain medication and concluded that Western children are wimps.
The Victorians were also right that race affects pain sensitivity—but in the opposite way from what they believed. African Americans are more hampered by chronic pain; they report suffering greater pain severity and disability in connection with a variety of pain-causing conditions. Moreover, this phenomenon holds true over a wide variety of age-groups and populations, including young children.
Part of the reason is now thought to lie in ethnic differences in pain-modulation systems. Although it has been extensively documented that African Americans have lower pain tolerance than whites in laboratory studies, the relevance of the finding has been unclear. Most of the studies relied on healthy volunteers, often college students. Acute pain and chronic pain are known to involve different physiological mechanisms: the nervous system of a healthy person may differ profoundly from that of someone with chronic pain. Moreover, the psychological experience of suffering from chronic pain is utterly unlike that of the test of acute pain in a lab, where subjects are explicitly reassured that they will not be hurt (and ethical guidelines require that tests be discontinued prior to tissue damage, even if the subject does not request it).
A 2001 study led by Dr. Robert R. Edwards of Johns Hopkins School of Medicine tested pain tolerance in a chronic pain population of blacks and whites. His team tested 337 patients with a painful arm tourniquet procedure. African Americans showed dramatically less arm pain tolerance (whites tolerated the pain for an average of nearly nine minutes, and African Americans lasted five) and their increased sensitivity was found to correlate with their reports of higher levels of chronic pain as well as greater pain-related disability.
Why? Another study found that a subgroup of African Americans had significantly lower beta-endorphin levels in response to stress, which would lessen the ability to modulate pain. An alternative explanation may involve differences between black and white Americans in their central nervous systems in relation to cardiovascular and hormonal responses to stress. Pain causes the release of the stress hormone adrenaline (epinephrine), which has a variety of effects, increasing heart rate and blood pressure and intensifying the experience of pain; African Americans have been shown to have greater vascular and hormonal responses to stress than do whites, which might create more pain. Moreover, African Americans suffer from greater levels of daily stress, which may lead to greater levels of daily pain. A 2005 study at the University of North Carolina at Chapel Hill found changes in African Americans in pain-regulatory mechanisms involving blood pressure and the stress hormones cortisol and noradrenaline.
The pharmacological implications of genetic differences among ethnic groups is an emergent area of research, as drugs have traditionally been tested exclusively on Western populations. Research done on genetic samples from Tel Aviv University, for example, recently discovered that many Ethiopian Jews have a gene variation that makes them metabolize opioids and some other common drugs more quickly than other Jews, thereby putting them at risk for greater side effects.
Although the Victorians were wrong more often than they were right about the sequence of the links in their great chain—and Anarcha, the slave on whom J. Marion Sims honed his surgical techniques, may have been more sensitive to pain than he—the concept of a continuum of pain sensitivity turns out not to be entirely specious. But the social and moral implications of the metaphor of the chain and the algorithm employed in the calculus of suffering certainly were: while the difference in pain sensitivity between a fair maiden and a wild beast is significant, beasts nevertheless feel pain and suffer from it, and among humans, the differences are modest. With respect to pain, humans are more alike than different—and in need of treatment.
INDIVIDUAL PAIN SENSITIVITY
If certain groups are more likely to develop chronic pain, what about certain individuals? Most pain does not become chronic pain—why does some of it? Are some people genetically at risk for pain in the same way others are at risk for cancer or obesity? If so, how can we identify them and try to prevent the development of a chronic pain syndrome?
An article by Dr. Robert R. Edwards hypothesizes that individual differences in pain sensitivity and pain modulation place individuals at varying risks of suffering severe acute pain following an injury and also of suffering chronic pain. Although most studies focus on pain sensitivity, another important factor is how well an individual’s nervous system modulates pain. When repeated painful stimuli are administered close together in time, their effects become additive: each successive shock hurts more than the last as the nervous system becomes increasingly sensitive. But this effect is checked by the body’s own pain-modulatory capacities—the robustness of its descending analgesia (the brain’s ability to temporarily switch on pain-inhibiting mechanisms). In chronic pain patients, those capacities are reduced. In fibromyalgia patients, for example, the pain caused by successive noxious stimuli increases much more rapidly than in normal individuals. And while both high pain sensitivity and low pain-modulatory capacities increase an individual’s risk of developing acute and chronic pain, pain modulation seems to be the more significant factor.
Innate pain sensitivity not only makes the development of pain syndromes more likely, it also reduces the efficacy of opioid analgesics to ameliorate the syndromes (in mice as well as humans). Patients who suffer from postherpetic neuralgia (recurrent herpes that causes itchy, burning pain) also have low pain thresholds in areas of their bodies unaffected by the neuralgia, and they have been found to derive less analgesic relief from opioids than those with normal pain thresholds. Moreover, treatments that do not involve drugs (physical therapy, talk therapy, meditation, and so forth) have also been found to be less successful on pain-sensitive people.
Pain sensitivity may reflect the influence of countless factors, ranging from cultural training to personal history. Brain imaging has shown that the psychological tendency to “catastrophize”—to embroider pain with fear and anxiety—results in enhanced central nervous system activity and more pain and anxiety. Early exposure to pain has been shown to lower pain thresholds by damaging the undeveloped nervous system. Emotional trauma has also been shown to affect pain sensitivity: victims of childhood sexual abuse, for example, have higher rates of chronic pelvic pain as adults because the trauma seems to alter the way they process pelvic sensation.
There also appears to be an important—if largely unknown—genetic basis for variations in pain sensitivity. In addition to the opioid-receptor genes, there is promising research on a lesser-known gene that encodes an enzyme (catecholamine-O-methyltransferase, or COMT) that appears to modulate pain. A 2005 study published in Human Molecular Genetics identified three variants of the COMT gene associated with differing degrees of pain sensitivity in the laboratory, which turn out to be predictive of the chance of healthy women developing myogenous temporomandibular joint disorder (a common musculoskeletal condition involving pain and inflammation of the joint that connects the lower jaw to the skull, often called TMJ or TMD).
Another recent study concerned a gene called SCN9A that is involved in the functioning of nociceptive neurons. Severe mu
tations of SCN9A are known to produce both extreme pain syndromes (when they increase neuronal activity) or, in other cases, complete congenital analgesia (when they block it), but the new study showed that much smaller, more common mutations were predictive of pain scores among patients with osteoarthritis, sciatica pain, and phantom limb pain, and even affected the pain sensitivity of healthy women to a heat stimulus in a lab setting.
If individuals at high risk for chronic pain could be identified through genetic tests, many pain syndromes could be prevented through aggressive early intervention. For example, pain-sensitive individuals are more likely to experience severe pain during an initial outbreak of herpes zoster. And higher pain ratings, in turn, have been shown to be predictive of the development of postherpetic neuralgia many years later. Yet an immediate antiviral drug treatment for herpes zoster can prevent the development of the syndrome.
Knowledge of genetic vulnerability to chronic pain might influence choices about surgery. With certain surgeries, nerve-sparing techniques are available, although not always practiced. With other surgeries, such as plastic surgery, knowing the likelihood of chronic pain might make the risks outweigh the benefits. Greater pre- or postoperative analgesia might be employed, or more intense follow-up conducted.
The Pain Chronicles Page 18
