You might be tempted to think—as many scientists themselves thought until fairly recently—that it’s pretty much of a crapshoot which people in pain, after similar diseases or surgeries, would wind up in intense, even chronic pain, and which would sail through. All anybody really knew was that people were different. As Norwegian researchers put it in a 2009 paper, “Among people with the same condition, pain ratings typically cover the entire scale from ‘no pain’ to ‘the worst pain imaginable.’”1
But why? Why, for instance, do only one in 10 people over 50 who get shingles—that painful problem caused by the same virus that causes chickenpox—go on to develop an even longer lasting pain syndrome called postherpetic neuralgia?2, 3, 4 Why doesn’t everybody get it?
Millions of people have diabetes, too. But only 60 to 70 percent develop a kind of nerve damage called neuropathy, usually tingling or numbness. And only 13 percent of these go on to develop persistent painful neuropathy.5 Why don’t they all wind up with this debilitating pain?
It’s possible, of course, to explain some individual differences in the experience of chronic pain as psychological. After all, emotions, especially the tendency to “catastrophize,” can make pain worse (see Chapter 6). Gender plays a huge role, too (see Chapter 4). So do other factors, including stress. In fact, pain researchers have recently shown that there is an extremely complex interrelationship among genes, gender, and stress.
That said, scientists now know that genes—those 25,000 regions in our DNA that we all inherit from our parents—are especially crucial. In fact, unraveling the role that genes play in how susceptible a person is to pain is, in some ways, the most exciting scientific frontier in pain research. Indeed, the central question of chronic pain research has moved from “What causes chronic pain?” to “Of all the things that cause chronic pain, how come they usually don’t?” as McGill University pain geneticist Jeffrey Mogil puts it.6
Scientists now think that genes control perhaps 50 percent of susceptibility to chronic pain. (Genetic susceptibility, by the way, means the likelihood that you’ll get a chronic pain condition like, say, osteoarthritis; genetic sensitivity means how much it hurts if you do have a chronic pain condition.) “Across a number of different kinds of pain, genes seem to be at least half the driver of how much pain you experience,” says pain geneticist Clifford Woolf of Children’s Hospital in Boston. “Genes give us an amazing and powerful tool to begin to understand how pain is generated.”7
For one thing, the more that scientists can figure out which genes contribute to chronic pain susceptibility, the more new drug targets there are. That’s important because the standard drugs now used for chronic pain—opioids—are only partially effective and carry significant side effects. For another, the more scientists understand the genes that underlie individual differences in chronic pain susceptibility, the more researchers can “personalize” medications—that is, they can look at an individual’s genome (all the DNA in a person’s body) and figure out which drugs are most likely to help. For instance, an estimated 7 to 10 percent of Caucasians are born with a nonfunctioning gene that normally makes an enzyme that converts codeine (inactive) to morphine (active).8 If I were one of those people and a doctor gave me codeine, I would not get the pain relief that a person with the gene would get and, sadly, I would get some of the side effects.
There’s yet another reason why it’s important to find pain genes. Given how often people are told that the pain is all in their heads, the more scientists can prove—by tracing pain susceptibility and sensitivity to the genes we are born with—that pain has a biological basis, the more respect people in chronic pain will get, and the better doctors will treat them.
* * *
As a child, Pam Costa, now a 48-year-old wife, mother, and psychologist in Tacoma, Washington, thought it was normal to walk to her elementary school in the gutter. After all, the gutter usually had nice, cool water in it, which soothed the burning pain in her feet. Sometimes, if no other option were available, she’d stick her feet in the toilet to cool them off. “I couldn’t understand why the other kids didn’t have to do the same thing,” she told me. “It was very perplexing. I thought that everybody’s feet burned all the time and other people were just stronger than I was.”9
Burning pain was certainly normal in her family—30 other people in her extended family had it. Three of her cousins committed suicide because of unrelenting pain, and one died from an apparently accidental overdose of pain relievers. “My mother grew up coming home from school and soaking her feet in ice along with her five cousins,” she recalled. “All the kids would sit around the bathtub with their feet in it.” Pam Costa herself has needed daily opiate drugs for nearly 30 years, and even so, her pain is barely controlled.
A different kind of normal prevails for Ashlyn Blocker, now a teenager in Patterson, Georgia. Since birth, she has been unable to feel any pain at all, which might seem like a blessing, though it’s not. Among other things, it means she and her parents have to monitor her body daily for injuries and infections that might otherwise go undetected.10
Strange as it may seem, both Ashlyn Blocker and Pam Costa have mutations in the same gene, a gene called SCN9A. Both mutations are exceedingly rare, but of high interest to researchers because of what they can teach us about the mechanics of pain. (A gene mutation is a permanent change in the DNA sequence of a gene; mutations can involve whole stretches of DNA or just a single building block. Gene mutations can be acquired from a parent or acquired during a person’s lifetime, although the latter kind of acquisition is very rare.)
By chance, Ashlyn inherited a recessive mutation in the SCN9A gene from each of her parents, John, a telephone technician, and Tara, who has a degree in physical education. John and Tara each have one normal, dominant copy of the gene, as well as an aberrant copy. That one “good” gene is enough to allow them to process pain normally. Their other two children are also normal. But with two copies of the “bad” gene, Ashlyn can’t process pain signals.
In its normal, healthy form, the SCN9A gene helps the body make “voltage-gated sodium channels” called Nav1.7 channels, little openings in nerve cells through which charged particles called ions flow in and out. So far, scientists have discovered 10 sodium channels. Sodium channels exist in large numbers only on excitable cells—nerve cells, muscle cells, and specialized muscle cells in the heart.
The job of sodium channels is to transmit messages along a nerve. When a nerve cell receives a signal such as contact with a nasty acid, that signal is converted into an action potential, which, like an electric current flowing through a copper wire, travels along the long axons of nerve cells. This is triggered when sodium from outside the cell rushes in through the sodium channels and briefly changes the electrical charge of the cell—a process called depolarization. The end result is the firing of the nerve, which causes the pain signal to be passed up from the periphery through the spinal cord to the brain, where pain is finally felt, kind of like the body making a telephone call to the brain.
Because of her mutation, Ashlyn’s sodium channels do not conduct sodium ions properly and so do not pass on pain signals. In technical jargon, this is called a loss-of-function mutation. (Mutations in the gene for this sodium channel also can cause loss of smell.11) But this wasn’t obvious at first. Nobody noticed that, even as a baby, Ashlyn could feel no pain, remembers her mother.12 All they could see was that she seemed happy, cheery, and easygoing. But when she was six months old, her left eye became inflamed. Antibiotics didn’t help, so the family pediatrician suggested a visit to an ophthalmologist. That visit revealed a massive corneal abrasion.
I can personally attest that a corneal abrasion hurts like crazy—but not for Ashlyn. She “was happily interacting and giggling,” her mother Tara recalls. Suspicious, the ophthalmologist referred the family to a geneticist. As they waited for that appointment, Tara and John began noticing other strange things. While Ashlyn was teething, she bit all the skin off the tip of her finger and would bite her lips and tongue bloody. “We think she could feel something,” Tara says. But whatever the sensation was, it wasn’t pain.
The geneticist didn’t know what specific gene might be at fault, but it was clear that Ashlyn’s insensitivity to pain was genetic, permanent, and dangerous. When she was three, Ashlyn burned her hand seriously, but didn’t even cry. Tara found her in the backyard simply staring at her red, blistered hand. Another time, during a family camping trip, Ashlyn broke her ankle. “She came back with dirt and grass on one side of her body,” Tara says. “But when we asked her what happened, she said, ‘I don’t know.’” It took two days for the ankle to swell enough for her parents to realize it might be broken. Impressively, even though she can’t feel pain herself, Ashlyn has learned to be sympathetic when she knows someone else is in pain. “She understands the concept,” Tara says.
Finally, in 2006, when Ashlyn was seven, the Blockers found out which gene was defective. British researchers at the University of Cambridge discovered that a particular mutation in the SCN9A gene keeps people from feeling pain.13 Once the results from that study were published, Ashlyn’s doctor, rheumatologist Roland Staud at the University of Florida, checked her stored DNA and found that she had that very mutation.14 That fit with earlier stories of people with congenital pain insensitivity, including a 1932 report of carnival performer dubbed “The Human Pincushion.” In their 2006 report, the British researchers also noted a similar story—a 10-year-old Pakistani street performer who, feeling no pain, would jab knives through his arms and walk on burning coals. (He died at age 13 from injuries he suffered jumping off a roof.) The research team subsequently tracked down six people with the same genetic mutation from three related families in Pakistan.
As for Ashlyn, as long as she marries a man with two normal SCN9A genes, she won’t pass on pain insensitivity to her children. Which made me remark to Tara, half-joking, “At least when she is in labor, Ashlyn won’t feel pain.” To which Tara replied, “But how will she know when to go to the hospital?”
Instead of a loss-of-function mutation in the SCN9A gene, like Ashlyn has, Pamela Costa has the opposite—a gain-of-function mutation, which means that instead of not working at all, her sodium channels work overtime, ramping up pain signals day and night, every day of her life. (There are other gain-of-function mutations in SCN9A that cause more subtle changes in sodium channels.15, 16, 17) Pam’s mutation causes erythromelalgia, also known as “burning man syndrome” or “burning feet syndrome,” which affects several hundred people worldwide. Coping with erythromelalgia is almost impossible to describe in words, though Pam tries: “Imagine being born with this and never having an escape from it. That’s what’s so disheartening.”18
As with Ashlyn Blocker, it was not obvious right away when Pam was born that she carried the terrible gain-of-function mutation. To Pam’s mother, who has a milder form of the problem, red, painful feet were simply a fact of life. Pam’s maternal grandfather had had the same thing, as did his siblings and many of her cousins. When Pam was a baby, she did scream all the time, but her parents and grandparents attributed it to colic. They didn’t know what to make of the fact that she refused to keep booties or covers on her feet, either. By fourth grade, when her gym teachers made all the kids run around a track, Pam would collapse in agony after 50 feet. The teachers thought she was a behavioral problem, even though she was trembling and crying in pain. “It felt like my feet were on fire,” she says.
It was not until she was 11 that doctors at the Mayo Clinic in Minnesota and other doctors in Birmingham, Alabama, where most members of her extended family live, were able to put together a pedigree, tracking this dominant gene throughout the extended family tree. Knowing that she would pass the gene on to her children, Pam and her husband adopted a child.
Remarkably, Pam has, despite severe pain, managed to work at two university teaching positions. She can’t walk far or exercise aerobically because becoming hot makes the pain worse. But she does yoga and lifts weights three times a week at her physical therapist’s office, after which the therapist wraps her in cool gel packs to ease the pain enough so she can drive the eight blocks home. “I push through it because I want my heart and bones to be healthy,” she says. She hates taking opioid drugs— she takes a type that lasts for 12 hours and does not produce a “high.” The drugs have wreaked havoc on her colon, as opioids often do. To control constant constipation, she has to do, in essence, a partial colonoscopy prep to clean herself out every day. The few times she has tried to get off opiates, she developed such excruciating pain that her blood pressure soared to a dangerous 250 over 140 mm Hg. (Normal is 120 over 80.)
The only time in her life that she had no pain was when she emerged from surgery to remove her appendix. When she woke up in the recovery room, the anesthesia drugs were still working. “Oh, my God,” she remembers saying. “My feet don’t hurt. It’s incredible not to be in pain.”
Scientists began zeroing in on the kind of mutation Pam has in 2004, when a Chinese dermatologist discovered two families with an inherited form of erythromelalgia. He tracked the problem to a mutation in the SCN9A gene and wrote it up in a genetics journal.
A world away, Stephen Waxman, a neurologist at Yale University who had been studying the SCN9A gene for other reasons, read the Chinese paper and had one of those rare eureka! moments. “You had to pull us off the ceiling,” he remembers.19 “We had done all the work on the normal SCN9A gene. We had the gene literally sitting in our refrigerator!” The Chinese team had described exactly where in the DNA the troublesome mutation lay, so it was almost child’s play for Waxman’s team of 20-odd scientists to create the same mutation in their gene, put it into cells, and see what happened.
What happened blew their minds. The mutation caused pain nerves in the dorsal root ganglia to fire abnormally, becoming hyperactive. In other words, the mutation allowed sodium channels to become activated much more easily than normal and to stay turned on longer—a classic case of gain-of-function. It was as if the nervous system’s sensory nerves, like “telephone wires,” could now pick up static and amplify it in such a way that the brain felt that these painful signals were constantly present. Waxman’s team and others, including a Dutch group, have since discovered more than a dozen families around the world with this gain-of-function mutation.20 “These people feel like hot lava is being poured onto their bodies,” says Waxman. And, unlike Ashlyn’s situation, in which it takes two recessive genes to cause the problem, it takes only one copy of the gain-of-function mutation—because it’s a dominant gene—to wreak lifelong misery.
Which raises an obvious question: Can overactive sodium channels be tinkered with to relieve pain? One way would be to use the anesthetic drug lidocaine, which does indeed reduce pain by blocking sodium channels. Lidocaine—plus its oral form, mexiletine—does help a few people with sodium channel mutations.21 Another sodium channel blocker, carbamazepine, has also been shown to help a few people in a family with a gain-of-function mutation.22
But so far, most existing sodium-channel blocking drugs are nonspecific—that is, they block multiple sodium channels, not just the ones that cause pain, but “good” ones in our muscles, heart, and brain as well.23, 24, 25, 26 “I suspect that I might be able to cure pain with lidocaine,” Waxman of Yale told me. But at least with traditional formulations, “the dose would be so high” that it would block lots of nerves. That could “cause heart arrhythmias and would affect the brain, too, making people confused or sleepy.” In fact, it could be lethal. Currently, a number of pharmaceutical companies are working on better versions. “There is a lot of work going on with Nav1.7 specific blockers. We hope that, in the not-too-distant future, there will be a new class of highly effective pain medications with few, if any, CNS [central nervous system] side effects,” says Waxman.27
Back in 1999, McGill’s Jeffrey Mogil picked 11 common laboratory mouse strains and ran all the mice through 12 common pain tests. He found that susceptibility to pain is quite heritable—it often runs in families—and ranges from 30 to 76 percent.28, 29
Obviously, that means that other factors—including psychological and environmental—also play significant roles in pain sensitivity. But the mouse results encouraged human pain geneticists to delve more deeply into the heritability question with that time-honored research technique: studying identical twins. Identical twins have the same genes but often manifest disease differently because of different environmental exposures and experiences.
In 2004, British researchers looked at 1,064 women, including 181 identical twin pairs and 351 fraternal twin pairs, and concluded that low back and neck pain were significantly heritable. For low back pain, there was a 52 to 68 percent chance that if one identical twin had the problem, the other did, too. For neck pain, the figure was 35 to 58 percent.30
Three years later, another British team looked at twins to study experimental, as opposed to clinical, pain.31 They recruited 51 pairs of identical twins, as well as 47 pairs of fraternal twins, all of them women. They brought the women into the lab and put them through many of the same tests that Mogil had used in mice: heat pain thresholds, responses to dilute hydrochloric acid, and the like. Just as in the mouse studies, the researchers found sensitivity to pain was 22 to 55 percent heritable.
That same year, Norwegian researchers also did a twin study of pain sensitivity, looking at 53 pairs of identical twins and 39 pairs of fraternal twins, both male and female. In their research, they added an extra test—sensitivity to an extreme cold stimulus.32 Intriguingly, the cold and heat pain stimuli produced different effects. With cold, there was a 60 percent chance that one twin would have the same response as the other; with heat, there was only a 26 percent chance. Puzzling, isn’t it? Among other things, the different results from hot and cold stimuli show how careful researchers—and drug makers—need to be in the pain tests they choose to study.
The Danes and Finns have also found significant heritability in pain susceptibility. A huge Danish study of 15,328 male and female twins found that inherited susceptibility explained 38 percent of lumbar (lower back) pain, 32 percent of thoracic (mid-back) pain, and 39 percent of neck pain.33 A Finnish twin study of 10,608 twins found that susceptibility to fibromyalgia was 51 percent inherited.34 Other studies have documented a strong hereditary link for migraines, menstrual cramps, back pain in general and sciatica specifically, as well as osteoarthritis.35 With osteoarthritis (OA), twin studies have shown that heredity probably accounts for 39 to 65 percent of the knee problems and 60 percent of hip problems—at least in women.36
To be sure, there are some caveats in all this, as with twin studies in general. If a disease were totally heritable in a simple way, you would expect that if one identical twin had it, the other would, too. But, as we’ve seen, it’s rarely that straightforward. With twin studies in general, notes Mogil, “heritability is like a glass of water. Is it half full or half empty?”37
Part of this variability is beginning to be explained by the emerging field of epigenetics, which refers to changes in proteins (histones) that are associated with DNA and help determine what genes are actually expressed. (Histones are the main components of a structure called chromatin, around which DNA wraps itself.) These epigenetic changes—such as the attachment of a chemical called a methyl group to DNA—can actually be passed down from one generation to another even though there is no change in the DNA itself. With pain, University of Texas researchers have shown that epigenetic changes that occur near a certain gene in response to inflammation or nerve injury can “lead to persistent pain by altering pain-modulating pathways.”38 The net result increases pain.39
This is all very sophisticated science, to be sure, but the basic idea is that a person’s “genotype”—his or her genes—is not the same as that person’s “phenotype.” The manifestation of something as complex as chronic pain can involve both susceptibility genes and epigenetic changes that—in response to a person’s environment and experience— can change whether those genes are expressed or not. In other words, a person’s environment can enhance or repress the genes he or she is born with. That’s part of the reason why identical twins with the same genes don’t always get sick with the same disease, including chronic pain.
While the SCN9A gene is obviously important, researchers are now busy deciphering dozens more pain susceptibility genes. Ultimately, the idea is to put together a “panel” of pain genes that could provide a genetic risk profile for each person. This way, for instance, doctors could identify before surgery which patients would be likely have intense pain afterward or to have acute postsurgical pain turn into chronic pain. Those people could have their pain treated more aggressively.
There are various ways to figure out which genes contribute to pain susceptibility.
One way is to “think backward.” Once it’s known which particular neurological mechanism transmits pain—such as a nerve receptor for heat or acid—scientists can look for the gene that makes that receptor. Another way to hunt for pain susceptibility and sensitivity genes is through “linkage analysis.” Scientists take two or more strains of mice, and run them through various tests of experimental pain. Some strains of mice turn out to be more sensitive to certain types of pain than others, while some strains are strikingly pain resistant. Scientists then look at the DNA—the whole genome—of the different strains and see where the genes differ. The implication is that the differences in genes may account for the differences in pain sensitivity.
In humans, scientists often do something similar, genome-wide association studies (GWAS). They start with two groups of people, one with a certain disease, like chronic pain, and the other without. They then compare the genomes of both groups in hopes of finding genes that have different forms (alleles) in the sick versus the healthy people. Again, at least in theory, the different genes might be responsible for the different “phenotypes,” that is, having chronic pain or not.
Yet another major approach to finding pain genes is to use a microarray (also called the gene chip method), which involves RNA, not DNA. (DNA is a long, double-stranded chain of molecules called nucleotide bases that is the master blueprint for our genes; DNA makes RNA, which is a single strand of nucleotides that carries the code for all the proteins in our cells.)
In the gene chip technique, scientists compare mice that are in pain with mice that are not. (There are multiple ways—including a mouse “grimace scale”—to tell whether a mouse is in pain.40) The scientists then sacrifice the mice and take samples from specific tissues such as the dorsal root ganglia, the first relay station for pain signals in the spinal cord, looking for RNA. Since different genes are active, or “turned on,” in animals with pain as opposed to those not in pain, finding the RNA produced by pain nerves is a step toward identifying the pain genes themselves.
Still another way to understand pain genes is to create special strains of mice in which a possible pain gene is “knocked out” (deleted altogether; these mice are then knockout mice) or “knocked down” (made somewhat less active; the mice are then knockdown mice). Then these mice are tested for their sensitivity to pain.
One of the world’s busiest pain genetics labs belongs to McGill’s Jeffrey Mogil. Mogil is a friendly, energetic, curly-haired man better known as “the mouse guy.” As we talk, he gestures toward his inner sanctum, the home, at any one time, to dozens of strains of mice. On the wall hangs a poster of a mouse genome, a colorful diagram showing every one of the 22,000 genes that a mouse is born with. (That’s roughly the same number of genes as a human.) As he guides me through the door, I am assaulted by that unmistakable odor—eau de mouse— common to many biological labs. Here, in their pristine little cages, live black mice, white mice, black-and-white mice, brown mice, and even “redheaded” mice, though these actually look sort of yellow. The mice are all carefully bred to create colonies of mice that are all genetically identical to one another, a process that takes 20 generations. The mice are labeled and studied for their susceptibility to pain and their responsiveness to pain-relieving medications.
Mogil keeps meticulous track of his own and other scientists’ searches for mouse pain genes, updating findings every week on his Pain Genes Database, where he lists the results of all published knockout mouse studies. At last count, researchers had found roughly 370 potential pain genes, with new ones being discovered almost daily. “I’ve got six or seven in my pocket right now,” Mogil told me. Still, it’s a daunting task. “We’re putting together a 1,000-piece puzzle. We are nowhere near putting it all together.”41
In addition to the sodium channel genes that play such a huge role in the lives of Ashlyn Blocker and Pamela Costa, scientists are exploring genes that control other ion channels, particularly channels for calcium and potassium. For instance, if just one tiny speck of DNA is changed in a potassium channel gene, people who inherit this mutation are at significantly higher risk for pain, as demonstrated by genetic studies of 1,359 patients.42 Indeed, an estimated 18 to 22 percent of the population inherits two copies of this mutation—one from each parent—and thus is at significantly higher pain risk. An additional 50 percent of people inherit one copy of the mutation and are at somewhat higher risk. People who inherit no copies of the mutation are the lucky ones—they are at lowest risk.
On the flip side, geneticists have found a mutation in a calcium channel gene that seems to protect against pain rather than raise the risk.43 This mutation appears to make people less sensitive to pain, at least to pain triggered by intense heat. People who inherit this gene mutation also appear to be less susceptible to chronic back pain. If scientists can find a way to mimic the proteins that this gene makes and use them as drugs, this could provide a novel approach to treatment, particularly for chronic back pain.
Migraine headaches, too, have a clear genetic susceptibility. Indeed, migraines, which afflict an estimated 20 percent of adults, have long been known to run in families. Numerous genes are involved in triggering migraines, says neurologist Michael Moskowitz of Massachusetts General Hospital in Boston.44 One type of migraine called familial hemiplegic migraine has been linked to problems in ion channels for both calcium and potassium.45 (A different gene variant on chromosome 8 has been linked to an even more common form of migraine.46)
But it’s not just genes for ion channels that pain geneticists are chasing. One of the most important of these is a gene called GCH1, which was found in 2006 by Clifford Woolf and others.47 This gene makes an enzyme that controls production of a molecule called BH4, which scientists joke could stand for “Big Hurt.”48, 49 People who have high levels of BH4 experience more pain, while people with less BH4 experience less. Encouragingly, it’s now possible to predict which people are likely to be more or less sensitive to pain by screening for only three single nucleotide polymorphisms (SNPs), which are tiny bits of DNA.50
Another “favorite” gene of pain geneticists is COMT.
“We all have the COMT gene,” medical geneticist Luda Diatchenko of the University of North Carolina told me.51 “But some people have a form of the gene with high activity, and some, the form with low activity. High activity is better. High COMT means low pain and low COMT means high pain.” The luckiest 40 percent of Caucasians, says Diatchenko, have the high-activity form and are relatively unsusceptible to pain. In fact, these folks are only half as likely as normal to develop the painful jaw condition called temporomandibular joint disease (TMD).
COMT works in part by making enzymes that get rid of stress hormones like norepinephrine, William Maixner, director of the Center for Neurosensory Disorders at the University of North Carolina, explained to me.52, 53 Since norepinephrine acts directly on nerves—thus boosting pain—getting rid of norepinephrine can reduce pain.
There’s already good news emerging from this research. A common blood pressure drug, propranolol, which blocks norepinephrine, blocks pain, too. Genetic testing for COMT can help identify which people are most likely to benefit from the drug.54, 55 There’s another key finding emerging from the COMT research. The hormone estrogen decreases COMT activity. Because lower COMT means more pain, this may partly explain why women, who have more estrogen, experience more pain than men, as we’ll see in the next chapter.
Other genes generating excitement are the PAP gene, which boosts the body’s production of a pain-relieving substance called adenosine, and another gene that, when deleted in mice, reduced chronic pain.56, 57
Less exciting, unfortunately, is the research on genes that control receptors for opioids (narcotics). There are three main opioid receptors—mu, delta, and kappa—each of which is produced by separate genes. The hope, still unfulfilled, is that studying mutations in opioid receptor genes might lead to better opioid drugs, including forms of the drugs that are less likely to lead to addiction.58 So far, the best studied is the gene that makes the mu-opioid receptor. At least three subtypes of mu receptors, and perhaps as many as 10, can be made as the gene gets chopped up and spliced in different ways by the body.59 But, so far at least, the effort to link specific variants of opioid receptor genes to differences in susceptibility to pain and responsiveness to opioid drugs has been disappointing. A recent meta-analysis,60 in which data from eight other studies were pooled, found no significant association between changes in an opioid receptor gene and the amount of opioid drugs needed to control pain.
Nonetheless, pain geneticists are optimistic. One of the most ambitious efforts to decipher pain genes is the $25 million Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) project, funded by the federal government, and based at the University of North Carolina.61, 62 The first part of the project is a prospective study in which 3,200 men and women, all healthy volunteers, have been tested in the lab for sensitivity to various kinds of experimental pain. They’ve also been put through psychological tests for anxiety and depression to see how those factors may influence development of pain. And they’ve had their blood drawn and saved for genetic testing. The idea is to follow them for five years and see who gets the notorious TMD.
The second part of the project involves people who already have the disease. It began with 200 TMD patients, with 1,000 more patients to be added over time. The idea is to compare the people with TMD with the 3,200 from the first part of the study who don’t yet have the disease in hopes of finding genes that confer risk for TMD. If the OPPERA project can live up to the dreams of its creators, it could become a model for unraveling the many ways in which genes influence susceptibility to pain.