One day as a child Billy Smith (not his real name), a resident of Newfoundland, could not take off his shoe. No amount of twisting or tugging would loosen its grip on his foot. The reason for his struggle eventually surfaced: a nail had pierced the sole and entered Smith’s flesh, tightly binding the two. Removing the nail freed the foot, but solving that problem only underscored a bigger one: Smith had not noticed.

Smith is among a tiny cluster of people, fewer than 30 in the world, who harbor a genetic quirk that renders them incapable of perceiving pain. “These humans are completely healthy, of normal intelligence, but don’t know what pain is,” says clinical geneticist C. Geoffrey Woods, who studied a group of such patients from northern Pakistan. They can sense touch, heat, vibration and their body’s position in space. Yet for them, root canals are painless, as are falls, fires and whacks on the head with a baseball bat. One woman with so-called congenital indifference to pain (CIP) delivered a baby without discomfort.

“The children have lots of bruises, cuts and scalds from exploring like kids do, but with no pain to restrict their activities,” Woods says. One Pakistani boy entertained others by sticking knives in his arms and leaping out of trees. Before Woods could see the child, he died jumping off a roof. The kids who survive are often deformed and disabled by self-mutilation or broken bones that they failed to notice or refused to rest. When Smith was three, he fractured a bone in his foot but kept walking on it as if nothing had happened.

Although such cases are exceptional, doctors and scientists have known for decades, if not centuries, that human beings at large differ greatly in how sensitive they are to pain. Much of the variation is apparently random. But gender matters. Women tend to hurt more than men do. Ethnicity can also interface with ache; some ethnic groups are more tolerant of discomfort than others are.

In the past few years, as technological advances have eased the deciphering of the human genome, researchers have begun unearthing the genetic roots of these differences. They are also pinpointing social, cultural and psychological factors that play parts in pain sensitivity. The multitude of influences on pain refutes the conventional conception of this sensation as an index of tissue damage. Thus, assessing patients’ vulnerability to anguish may be essential to accurately judging the severity of their condition. It is also critical to deciding how to treat their pain. Revealing the molecular causes of individual variation in pain perception is already helping to unravel the biology of agony and providing targets for novel pain medications.

Spectrum of Suffering
Physicians have long noticed wide disparities in the pain tolerance of the people they treat. Among patients with the same condition, pain ratings typically range from “no pain” to “the worst pain imaginable.” And although some disorders are more painful than others, the variation in distress among individuals with the same physical malady is far greater than the difference in the discomfort people feel, on average, from one condition to the next. “Two soldiers may be shot in the same nerve,” says Stephen G. Waxman, a neurologist at Yale University and the Veterans Administration Connecticut Health Care Center. “One has sensory loss but is otherwise okay; the other has intractable burning pain.”

Objective indicators of physical harm often correspond poorly to perceived pain. In one study the amount of inflammation in rheumatoid arthritis patients did not parallel the degree of suffering they reported. In people with osteoarthritis, the tissue damage shown on an x-ray often bears little relationship to the amount of discomfort a patient feels. Even when a scientist carefully controls the intensity of a painful procedure—say, a cold bath or compression of a limb—people significantly differ in how much they say it stings. (On the other hand, an individual’s evaluations of agony are surprisingly consistent. If you ask someone to hold an object that becomes increasingly hot to tell you when the pain starts, that moment will be the same—within 0.2 degree Celsius—every time you repeat the procedure, even a few years later.)

What a person says about pain does jibe with changes in the brain if not the body. In a 2003 investigation neurobiologist Robert C. Coghill of the Wake Forest University School of Medicine and his colleagues asked 17 adults to evaluate the pain they felt from a hot metal device touching their lower leg. At the same time, the researchers scanned the volunteers’ brains using functional magnetic resonance imaging. Pain-related regions of the brain were more active in the individuals who judged the twinge as more intense than they were in less sensitive subjects, Coghill and his colleagues found.

Verbal pain ratings also predict a person’s vulnerability to chronic pain. In 2007 neurobiologist William Maixner of the University of North Carolina at Chapel Hill and his colleagues tested healthy female volunteers for pain sensitivity and psychological functioning. The researchers then tracked them for three years to determine who would acquire temporomandibular joint disorder (TMJD), which causes persistent discomfort in the joints on either side of the ear where the upper and lower jaw meet. Sixteen of 243 women came down with classic TMJD, and the disorder was three times more likely if a woman was very sensitive to pain than if she was relatively insensitive, Maixner says. His team has also associated elevated sensitivity to painful stimuli with other persistent pain syndromes such as fibromyalgia.

Gender Bias
For a decade or longer, researchers have known that women are at greater risk than men for a number of chronic pain conditions, including rheumatoid arthritis, lupus and fibromyalgia. Women are also more sensitive to noxious stimuli: in laboratory experiments the average woman exhibits a lower pain threshold (the point at which she first feels pain) and less pain tolerance (the degree or duration of pain she can stand) than the average man.

Sex hormones may contribute to this gender difference. Estrogen, for example, can often increase pain, in part by acting at receptors that sit on pain nerves. During her menstrual cycle, a woman perceives more pain after ovulation when progesterone—and to a lesser extent, estrogen—levels are high, consistent with the idea that female hormones intensify pain. In addition, hormone replacement therapy increases pain sensitivity in women, whereas drugs that stymie estrogen’s actions provide long-term pain relief in certain situations. (In other circumstances, such as pregnancy, high levels of female hormones are accompanied by diminished pain perception; scientists do not fully understand why.)

Male and female brains seem to register discomfort differently. In 1999 Coghill’s team reported that women perceived the same painful stimulus as more intense than men did and showed more activity in brain regions involved in processing pain. This excess excitement may stem in part from a weaker network for blocking pain. In 2002 psychiatrist Jon-Kar Zubieta, now at the University of Maryland, and his colleagues gave 14 men and 14 women an excruciating injection of saline into their cheeks while scanning their brains, focusing on parts of a “descending” pain-thwarting pathway in which endorphins, the body’s natural painkillers, bind to mu opioid receptors to squelch the pain signal after acute injury [see “The Psychology of Pain,” by Howard L. Fields]. In the males this pain-curbing network was flooded with more endorphins and activity at mu opioid receptors than it was in females—a sign of a more powerful pain-control system.

Other evidence points to weaker pain inhibition in women. Intense or long-lasting pain applied to one part of the body, say, an arm, can suppress pain at another site, such as a tooth. The initial pain is thought to invoke the body’s descending pain suppression system. In 2003 neuroscientist Donald D. Price of the University of Florida College of Dentistry and his colleagues showed that this phenomenon was less pronounced in women: in men, dunking one hand into a painfully hot bath diminished the discomfort of a scorching object touching the other hand, but the women felt no such relief.

Emotional and social factors may also contribute to women’s enhanced pain sensitivity. For instance, women tend to engage in pain-related catastrophizing—that is, expecting that pain will be awful and unbearable—more than men do. On the other hand, men are typically less willing than women to admit to being in pain because men want to appear tough and strong.

But pain is not necessarily a sign of weakness. In fact, women’s tendency toward discomfort might be adaptive. Women are generally more attuned to bodily sensations than men are and have a greater capacity to sense all environmental stimuli, such as light, noise and odor, which may improve their ability to detect threats. Some scientists argue that evolutionary pressures may have promoted such a trait in women to enable them to better protect their offspring.

Not only are women more prone to pain, so are certain ethnicities. African-Americans display greater sensitivity to painful stimuli in the laboratory and report more negative emotional responses to pain than Caucasians do.

Cultural, social and psychological factors probably contribute to this disparity. In a study published in 2007 clinical psychologist Roger B. Fillingim, also at the University of Florida College of Dentistry, and his colleagues demonstrated that a person’s ethnic identity—that is, the degree to which a person relates to a minority group’s ancestry, language, physiology and culture—strongly affects his or her pain sensitivity. The researchers tested 63 African-Americans, 61 Hispanics and 82 non-Hispanic whites for their susceptibility to pain from a hot object touching their arm, very cold water surrounding a hand, and constriction of blood flow to an arm. Each person also filled out a questionnaire called the Multigroup Ethnic Identity Measure (MEIM).

The researchers found that the range of temperatures and the time that a person was willing to endure pain were lower for members of the two minority groups than they were for whites. And for the African-Americans and Hispanics, but not the whites, the stronger a participant’s ethnic identity as judged by the MEIM, the greater his or her sensitivity to any of the types of pain. “Within a minority group the greater your ethnic identity, the greater your pain sensitivity,” Fillingim concludes. Cultural factors related to ethnic identity such as religion, education or social expressiveness might bestow specific meanings on pain or suggest coping strategies, he posits. Such shared beliefs and practices may not only influence people’s outward expressions of pain; they may also sculpt the biological infrastructure that underlies the experience of pain.

Some of that physiology apparently differs between African-Americans and whites. In 2008 Fillingim and his colleagues tested the natural pain suppression elicited by a strong or prolonged sensation of pain in 29 African-Americans and 28 whites. They induced ischemic pain, depriving an arm muscle of oxygen, by squeezing the arm with a tourniquet; during that procedure, they electrically shocked each person’s ankle. The researchers found that ischemic pain produced greater reductions in electrical pain ratings in whites than it did in African-Americans, who may have a weaker inhibitory pathway. “This suggests that African-Americans are less effective at controlling pain than whites,” Fillingim says.

Spectacular Mutations
Of course, individuals within a gender or ethnic group also vary in their sensitivity. Genes account for 22 to 60 percent of the variance, according to studies comparing the correspondence in this trait between fraternal twins, who share about half of their genes, with that between identical twins, who have virtually the same DNA.

In rare cases, such as those with a congenital indifference to pain, a single gene has a huge effect. Smith and others like him have a mutation in a gene for a tiny molecular gate, or channel, that sits on the endings of nerves that sense pain. The channel ordinarily serves as an amplifier of neural signals and appears to be necessary for all types of pain perception. In patients with the mutation, the channel does not work, knocking out pain perception. “This spectacular observation seals the case, at least in the extreme, that genetics can have profound effects on sensitivity to pain,” says Stanford University anesthesiologist David Clark.

Other mutations in the same channel protein make its gate flip open more readily and stay open too long, turning up the amplifier instead of knocking it out. This molecular mishap results in the flip side of Smith’s perilous indifference to pain: an existence infused with agony. Patients experience mild warmth as searing or scalding heat. They liken slipping on socks to pouring hot lava on their feet, Waxman says. One teenager’s pain gets so severe that he requires anesthesia in an intensive care unit [see “The Pain Gate,” by David Dobbs; Scientific American Mind, April/May 2007].

Subtler genetic tuning of this channel could underlie more ordinary variation in pain sensitivity. Woods has unpublished data fingering a relatively uncommon change in a single base pair that makes the channel more responsive and its bearers feel a moderate amount of additional pain, about the level that could be countered by codeine.

Inherited Ache
Common variants of genes for other proteins, including enzymes, appear to underlie a hardiness to hurt, or the opposite. The enzyme catecholamine-O-methyltransferase (COMT) breaks down the stress hormones adrenaline and noradrenaline (also known as epinephrine and norepinephrine) as well as dopamine, a brain chemical involved in reward and mood. If this enzyme is scarce or not working properly, stress hormone and dopamine levels rise, and that chemical bounty apparently intensifies pain. Fibromyalgia patients and people with facial pain have higher levels of these chemicals. People who are disposed to pain such as females or chronic pain patients also often have relatively sluggish COMT.

Lethargic COMT can result from an alteration in the gene for the enzyme, leading to a threefold to fourfold reduction in its function. In a study published in 2003 Zubieta and his colleagues found that people who had at least one genetic blueprint for the less active enzyme were more sensitive than those with only active COMT to pain from intramuscular injections of saline, requiring less saline to reach the same level of agony.

In recent years Maixner, geneticist Luda Diatchenko, also at the University of North Carolina, and their colleagues linked two other versions of the same gene, along with the one Zubieta studied, with distinct levels of pain sensitivity—low, average and high—as well as with vulnerability to chronic pain. (Zubieta evaluated the “average” version, for the enzyme with lower activity.) The researchers analyzed the gene in 202 healthy women, whom they also tested for sensitivity to 16 types of painful stimuli and followed for three years to determine which ones developed TMJD. Compared with the other versions of the gene, the variant conferring low pain sensitivity gives rise to vastly greater quantities of COMT and lowers a woman’s risk for TMJD more than twofold.

These COMT alternatives account for 11 percent of the variability in human pain perception, the largest contributor to pain sensitivity people have found so far, Diatchenko says. COMT type is a better predictor of the risk of developing a chronic pain condition than cholesterol level is for cardiovascular disease risk, Maixner adds.

The link between COMT and pain turns out to involve intermediaries called beta-adrenergic receptors that sit on pain-sensitive nerve endings. Adrenaline stimulates these receptors, whose activation (by drugs) can result in an agonizing arthritislike syndrome. Variation in the genes for these receptors, too, can shape pain perception. Maixner’s group has nabbed one version of the gene for the beta-adrenergic 2 receptor, which is especially responsive to epinephrine and thereby sensitizes a person to pain.

Diversity in pain sensitivity may also arise from different forms of the mu opioid receptor, which also influence responses to opioid drugs. Opioids such as morphine and the body’s endogenous painkillers exert their pain-suppressing effects by acting on this receptor. Responses of patients to opioid painkillers vary widely. The lowest effective dose may be five to 10 times higher for some patients than for others, and in 25 percent of patients morphine is ineffective or causes intolerable side effects.

In 2009 Diatchenko and her colleagues looked at the mu opioid receptor gene in 196 females who were also scored for their sensitivity to a battery of painful stimuli, including those that were hot, piercing and squeezing. After analyzing the gene at 25 places at which a chemical unit tends to vary between individuals—so-called single nucleotide polymorphisms (SNPs)—the researchers found one site associated with pain sensitivity. The rarer version of this SNP, carried by 6 percent of the population, seemed to make a person pain-prone and relatively unresponsive to opioid medication; its more common counterpart, on the other hand, conferred high pain tolerance and a good morphine response.

Other genetic differences may also impinge on a person’s response to opiates. Certain human enzymes metabolize medications, and the results of their actions may be required to make the drugs effective and nontoxic. For example, a liver enzyme known as CYP2D6 converts codeine into morphine, the substance that relieves pain. In 7 to 10 percent of Caucasians, however, codeine does not work, because these individuals’ CYP2D6 enzyme cannot accomplish the conversion. On the other hand, 1 to 7 percent of whites have multiple copies of the same gene. These individuals break down codeine extremely quickly, making even low doses of the drug potentially toxic. In one 62-year-old man with this gene duplication, a small dose of codeine nearly killed him, according to a report from Geneva University Hospital in Switzerland.

The genes nabbed so far probably represent just a tiny fraction of the body’s Lilliputian conspirators in creating or modulating pain. “At the end of the day, there will be scores to hundreds of genes related to explaining individual differences in pain,” predicts behavioral geneticist Jeffrey S. Mogil of McGill University.

Tailoring Treatments
Careful assessment of a patient’s pain sensitivity could be invaluable for preventing and treating pain. Pain-sensitive patients are, for example, likely to experience a lot of discomfort after surgery and thus may require a higher-than-average dose of a painkiller. “Even in people who had identical surgeries, there can easily be a severalfold difference in the amount of pain reliever a person will need during recovery,” Clark says.

An awareness of such differences may also help doctors better assess the severity of a person’s illness. Low pain sensitivity might, for example, mask the true seriousness of a patient’s condition. In contrast, an unusually strong reaction to a painful event might exaggerate the degree of physical injury it caused.

Evaluating the pain tolerance of healthy patients may help doctors identify who is most vulnerable to developing persistent pain syndromes and thus who might want to forgo elective surgeries or take preventive analgesics after accidents or trauma. Genetic tests may further clarify a patient’s risk. “Combining a couple of these genes together could give us good predictive value for who is likely to develop several persistent pain syndromes,” Maixner says.

Testing people for variations in the mu opioid receptor or metabolic enzymes might further reveal who will respond well to opioids and at what dose and who might benefit from alternative therapies. Responses to future generations of analgesics might also depend on a patient’s genetic makeup. “It’s critical to understand the impact of genetics on the treatment of a patient,” Clark says.

Unearthing genes involved in pain perception, or lack thereof, can also pave the way toward new therapies. Pharmaceutical and biotech scientists, including those at Xenon Pharmaceuticals in British Columbia, are trying to discover and build molecules that silence the sodium channel that is out of order in congenital insensitivity to pain. “It looks very hopeful that people will have a new generation of painkillers” that target this molecule, Woods says.

Blocking beta-adrenergic receptors may help treat pain conditions stemming from either low COMT activity or high adrenaline levels, or both. In 2007 Maixner’s team found that inhibiting beta-adrenergic receptors in rats that had poor COMT function prevented the animals from showing signs of heightened pain sensitivity. In a study published in 2009 Maixner, along with neuroscientist Kathleen C. Light of the University of Utah and colleagues, found that propranolol, which treats high blood pressure by blocking beta-adrenergic receptors, decreased pain in 10 fibromyalgia and 10 TMJD patients as compared with a dummy medication.

Even without genetic tests, doctors may one day base their prognosis and treatments on a person’s gender, ethnicity and individual psychology. Some genetic differences seem to be more common among certain genders or races, in accordance with group differences in pain sensitivity. Unpublished work by Fillingim and his colleagues, for example, indicates that a form of the mu opioid receptor associated with stronger natural pain control is far less frequent in African-Americans than it is in whites.

The science of pain peculiarities also helps all of us to gain a better appreciation of pain in those around us. We cannot assume that another person’s pain is inconsequential even if the injury looks unimpressive or would not be painful to us. Indeed, the pain perceived, almost by definition, exaggerates or minimizes the damage inflicted, given that pain stems from biological quirks particular to the sensation itself, along with cultural, social and psychological influences.

Of course, extreme cases of pain indifference put the survival value of our aches in stark relief. Despite the unpleasantness of pain and the commercial quest for ever more powerful analgesics, humanity cannot afford to wipe out pain the way it might strive to end cancer or heart disease. “We might joke that we wish we felt no pain, but that would be terrible—and is terrible for those who can’t experience pain,” Clark says. Aside from their physical injuries, people like Smith must endure a dollop of emotional isolation resulting from their inability to experience a virtually universal sensation. They keep quiet about this void. When they fall, they pretend that it hurts, because they want to be normal.

Note: This article was originally printed with the title, "I Do Not Feel Your Pain."