When the pain comes, Alina Delp retreats to air conditioning as soon as possible. What begins to feel like a mild sunburn will, if left unattended, turn into a raging, burning pain.
“It’s this turbulent, violent sensation that feels electric and stinging,” Delp says, describing the pain at its worst. “I’ve run out of the building screaming like a lunatic before because it’s been so bad.”
Delp has erythromelalgia, a rare condition in which a person’s body (typically the feet and the hands, though Delp experiences pain all over) reacts to mild warmth as though it is on fire. Mild exertion, even just standing, will set it off for Delp, which meant quitting her job of 15 years as a flight attendant. Two years of countless doctors’ appointments finally got her a diagnosis in 2012, but current medications are unable to relieve pain in most patients.
“I’m pretty much a prisoner in my own home,” she says. Her house in Tacoma, Washington, is kept at a chilly 58 degrees Fahrenheit, thanks to some special duct work that her husband, coincidentally in the heating and cooling business, was able to arrange. Delp spends most of her time reading, watching TV, or working on her computer to maintain an online erythromelalgia support group that she co-founded.
But, this horrific condition has handed pain researchers their most promising drug target in years. In 2004, a study of an inherited version of erythromelalgia pinpointed a mutation in a gene that directs the making of a sodium channel, called Nav1.7; sodium channels are proteins that help control the electrical excitability of neurons.
“The channel sets the sensitivity of pain-signaling neurons, and when you have those Nav1.7 mutations, the neurons fire when they shouldn’t,” says Stephen Waxman of Yale University School of Medicine, New Haven, US, and the Veterans Affairs Medical Center, West Haven, Connecticut. Waxman was the first to study the effects of Nav1.7 mutations in neurons.
Delp doesn’t know if she has this type of mutation, but medicines that calm the channel may still give her relief. Multiple clinical trials are underway to test Nav1.7 channel blockers, not only in inherited erythromelalgia, but in more common conditions, like sciatica and trigeminal neuralgia, which both involve intense shooting pain in different parts of the body.
“This is an example where a rare genetic disease may teach us important lessons that are relevant to larger populations,” Waxman says.
Now, more researchers are reaching for genetics to understand the roots of chronic pain. With new techniques that allow comprehensive examinations of the 3 billion DNA letters making up a human genome, researchers are banding together to understand genetic contributors to conditions such as migraine, back pain, mouth and face pain, and neuropathic pain, which arises after nerve injury. Though still early days, the endeavor promises to find new therapeutic targets, as well as take steps toward a personalized medicine approach, in which a person’s genetic makeup would inform his or her diagnosis, prognosis, and treatment. This approach is also expected to illuminate new players in the biology of pain that could never have been guessed at before.
“Genetics is an amazing technique because it allows you to pull rabbits out of your hat,” says Jeff Mogil, who studies pain genetics at McGill University in Montreal, Canada. “You can find genes and proteins that are relevant to pain without having any prior information about them at all.”
That supply of genetic rabbits, however, seems endless.
“If you believe, like I do, that there are probably hundreds, or even thousands of pain genes, of which we’ve found around 30, then that means we really haven’t gotten very far at all,” Mogil says. “It may take quite a long time to figure out enough of the genes to actually change clinical practice in any reasonable way.”
Acute pain is a helpful feature of human biology: it alerts us to trouble in our bodies, such as a broken bone or infection. Once the injury is taken care of, the pain subsides.
But for quite a few people, the pain continues, becoming a chronic condition in its own right because of changes in the nervous system. These persistent pain conditions can arise with no immediate, discernible cause, as with erythromelalgia or fibromyalgia, for instance. Others take hold after nerve injuries, such as the phantom limb pain felt by amputees or the pain experienced by those with diabetic neuropathy.
Yet, chronic pain is under-recognized as an urgent health problem. Nearly 20% of adult Europeans have been estimated to suffer from some kind of moderate to severe chronic pain, and a recent analysis from the National Institutes of Health (NIH) found that 125 million American adults reported at least some pain in the 3 months before they were surveyed, with about 50 million of them reporting daily chronic pain or severe pain. And yet, funding for pain research is less than 1% of the NIH budget, even though more suffer from chronic pain than from cancer, heart disease, and diabetes combined.
“Chronic pain continues to be seen as a symptom of a disease, where if you fix the disease the pain will go away,” says Marshall Devor, a pain researcher at Hebrew University, Jerusalem, Israel. “Certainly for neuropathic pain that’s wrong, but even if it weren’t wrong, I don’t see any time soon that we’re going to cure all diseases.”
“In the meantime, to improve people’s quality of life by understanding pain a little bit is a very important thing,” he adds. “Genetics is one angle that has promise.”
However, geneticists shied away from pain at first, considering it too subjective for rigorous study. But Devor was drawn to the idea, noting that genes could explain why, after the same injury, one person suffers from chronic pain while another doesn’t. In 1980, Devor found that rats could be bred to exhibit enhanced pain responses after injury — essentially pegging genes to pain for the first time.
Nearly twenty years later, Mogil worked with Devor to find differences in pain sensitivity among different mouse breeds. Later experiments revealed a gene important for responses to a painkiller in mice, and the effect was confirmed in women, marking a first human pain genetics finding.
This is not to say that pain is purely genetically determined; rather, it arises from a complex mix of genes and environmental factors. Human twin studies estimate that genes carry about half the blame for a range of painful conditions. Going after a finite number of genes may be easier than studying countless environmental factors, including stress, diet, and life events.
“There are a lot of genes, but there are only 22,000 of them” in the human genome, Mogil says. “The number of environmental factors could be a lot bigger than that, and we may never identify them all.”
Leaving no genetic stone unturned
Human genetic studies initially required a “candidate gene” approach, in which researchers examined selected genes they had reason to believe were involved in pain.
But with the completion of the Human Genome Project in 2003, and the many tools that followed, geneticists acquired the ability to scan the entire genome comprehensively for genetic variations that might matter for pain.
“The candidate gene approach assumes you know the answer before you’ve done the experiment,” Devor says. “The real power of genome-wide approaches is being able to see the entire genetic landscape without bias.”
Genome-wide sequencing reads out all the DNA letters in order — an expensive, though rapidly more affordable prospect. In the meantime, many have turned to genome-wide association studies (GWAS) that examine about a million locations in the genome where humans commonly differ from each other by one DNA letter. These spots of variability, called single nucleotide polymorphisms (SNPs), may produce slight changes in our biology that together nudge us toward a disease.
Many common SNPs with mild effects may conspire to give a person a disease — in contrast to the rare but powerful mutations that underlie rare conditions like inherited erythromelalgia. While both common and rare genetic variations operate in pain, researchers expect that common SNPs will account for most common pain conditions. Statistically, however, detecting the numerous SNPs and the slight increases in disease risk they confer requires scanning the genomes of a very large number of people, comparing people with a painful condition to those without it. To overcome this problem, across the world, researchers have pooled once tightly-guarded DNA samples to complete GWAS of many traits and diseases, such as height, cardiovascular disease, and schizophrenia.
The pain field followed suit in 2010 with a migraine GWAS, based on DNA samples collected from over 13,000 people, which was carried out by researchers from 12 different countries (http://www.headachegenetics.org). Their latest, larger GWAS implicates 12 regions of the genome associated with increased risk for migraine, five of which were completely new to the field. A larger GWAS of about 150,000 people is anticipated in the next year, which could identify even more genetic suspects.
Smaller GWAS are also underway for other pain conditions, like face pain, phantom limb pain, and fibromyalgia. Yet for all the GWAS enthusiasm, the hard-won results may still not have anything to do with pain per se. Instead, the genetic variations identified by GWAS might only increase the chances of developing a condition, like arthritis, that leads to pain.
This means that GWAS findings are starting points, from which researchers face the substantial task of understanding exactly how the genetic signals relate to pain. Here at least, they can turn to established animal models to test the impact of each genetic variation on pain sensitivity.
“When something comes out of GWAS you hope you can connect it with pain physiology somehow,” Devor says.
The search for drug targets
Yet even when a gene is firmly linked to pain, it may or may not make a good drug target. Some genes may be too fundamental to a cell’s well being such that modulating them with a drug could be dangerous. This means pain researchers need to think about how networks of genes work together. Potential fixes may involve directly repairing the faulty part of the network, or modulating another gene product to compensate for the deficient part.
An example of this approach comes from GCH1, a gene that ramps up after nerve injury in rodents (see related RELIEF article here). GCH1 encodes a protein that sits at the top of a multi-step molecular pathway, which ultimately boosts neurotransmitter levels, driving a frenzy of pain-related signaling in neurons.
“There’s something quite important about this ongoing barrage of activity that is causing the neuropathic pain,” says Michael Costigan of Boston Children’s Hospital and Harvard Medical School, US, who helped discover GCH1’s role in pain in animals and humans.
But because of its prime position in the pathway, GCH1 doesn’t make a good drug target: clamping down on it would lead to side effects all over the body, Costigan says. Instead, suppressing a gene further down the pathway, called SPR, can rein in the pathological profusion of neurotransmitters while leaving open other neurotransmitter-producing pathways to allow cells to make what they need. SPR inhibitors have successfully quelled neuropathic pain and inflammation in animal models, and in January, pharmaceutical giant Merck made a $595 million deal with Quartet Medicine, a company developing SPR inhibitors, to bring them to clinical trials.
“It’s an example of using the genetics as a beginning, but ultimately the therapeutic insights are not necessarily tied exactly to the genetics,” says Costigan, who has founding shares in and consults for Quartet Medicine.
What makes a good drug target may also vary between people. A medicine that works for one person may not do much for another, given some quirk in an individual’s physiology. Many hope genetics will help resolve which treatment will work best via a blood test that detects the genetic variants a person carries. This personalized approach could shorten the current trial-and-error process many patients endure as they seek effective treatments.
But this prospect is still in the distance. The complexity in a single gene, which may give rise to several different versions of that gene, defies a simple genetic link to a person’s response to a treatment. Some genetic variants have been deemed too slight to matter, and even those with relatively robust effects, such as variants controlling drug metabolism, have not yet been embraced by hospitals.
For example, opioid drugs like codeine and tramadol are broken down by enzymes in the liver, which releases the active pain-killing ingredients. About 10-12% of people carry genetic variants in an enzyme, called CYP450, that make them poor drug metabolizers, leaving them insensitive to the typical dose. About 5% are ultrahigh metabolizers, who get instant pain relief, but who are also at serious risk of overdose.
The genetic test to find a person’s metabolizer status takes a few hours, yet hospitals continue to give opioid doses designed for middle-of-the-road metabolizers to everyone. For hospitals, the cost of dealing with occasional side effects from improper dosing does not yet outweigh the cost of testing every patient for their CYP450 type, says Frank Stüber of Bern University, Switzerland, who has studied CYP450 and tramadol.
“Although we’ve known about genetic effects on metabolism for years, it’s still just very gradually and slowing getting into the hospital world,” he adds.
Similarly, variants in a gene called COMT may flag those with musculoskeletal pain who could benefit from beta-blocker drugs like propranolol. A company called Proove Biosciences now sells a genetic test based on these results, but it is not used routinely in hospitals, says Luda Diatchenko of McGill University, Montreal, Canada, who was involved in the COMT studies.
Genetic fences and bridges
People may develop the same pain condition for different, often hidden reasons. The consequences of pain can amplify pain, too, which further clouds cause and effect.
“People with high psychological distress start to have high sensitivity to pain, and people with high sensitivity to pain start to have psychological distress,” says Diatchenko, who likens the pathway toward chronic pain to a spiral.
“Once people start on the spiral, it’s difficult to stop and it’s difficult to distinguish what was the original reason that got them there,” she says.
But identifying the original reason could help to identify subtypes of conditions, which may have different outcomes and treatments. One thought is that the reason may be written in the constellation of genetic variants a person has. Finding patterns in hundreds of thousands of SNPs, however, is not easy, but the search might be helped by diving more deeply into the observable features, or “phenotypes”, characteristic of a person’s pain. Amassing detailed phenotype data is time-consuming and expensive, but a multi-million dollar study called OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) has been doing this to understand who develops temporomandibular disorder, a painful condition afflicting the jaw.
Based on data about pain sensitivity and psychological factors, researchers have begun to discern patient subgroups, and combining genetic information with that data may pull out even more robust clusters of patients, says Diatchenko, an OPPERA investigator.
Others, like Devor, remain skeptical that genetics will help much in identifying subtle subtypes, citing the many commonalities between different neuropathic pain conditions. Indeed, a recent twin study points to common genetic roots among different chronic pain conditions, including chronic widespread pain, chronic pelvic pain, and irritable bowel disease. Other fields have also seen that genes do not always obey the diagnostic boundary fences set up by doctors.
If the same genes contribute to multiple pain conditions, how genes interact with other factors — both genetic and environmental — may explain how specific pain conditions arise. One example of this possibility comes from a three-way interaction between gene, sex, and stress discovered by Mogil and colleagues. Specifically, they reported that a gene variant boosted pain relief from a drug, but only in males — mouse and human — who were not under stress.
Bridging the gap between finding a pain gene and understanding its spectrum of effects will eventually lead to a fuller understanding of pain genetics, but this remains far off. Yet new treatments may come along the way, and Alina Delp is watching the clinical trials of Nav1.7 blockers closely. She remains optimistic no matter what. “If these drugs don’t work out, the findings may lead to something else,” she says.
Michele Solis is a science writer and former neuroscientist who lives in Seattle, Washington, US.