All sorts of strategies have been offered up as ways to stem the nation's opioid crisis, from new drug warning labels to new laws aimed at making it hard for patients to get multiple prescriptions for the powerful — and powerfully addictive — drugs.
But opioid overdoses continue at a tragic pace; each day, they claim the lives of about 78 Americans. The crisis is fueled in part when people suffering from chronic pain turn to opioids in an effort to curb their often debilitating discomfort.
Scientists have been working to develop painkilling medications that work as effectively as opioids without carrying the risk of addiction. Unfortunately, these efforts have met with little success. But ironically, new research on a rare genetic condition known as chronic insensitivity to pain, or CIP, could soon lead to the development of such drugs.
No Pain May Bring Big Gain
Just a few hundred people around the world suffer from CIP. One is Steven Pete, a 36-year-old drug dependency counselor in Kelso, Washington. Like others with the disorder, Pete is impervious to pain of all kinds. Cut a finger? Touch a hot stove? Pete doesn’t feel a thing.
Pete was diagnosed with CIP when he was just a few months old. “I was teething, and I ended up chewing a good portion of the tip of my tongue off,” he recalls. “My parents rushed me to a pediatrician, and he held a lighter to the bottom of my foot. I didn’t show any response, and he was like, ‘Yeah, I’m pretty certain this is what he’s got.’”
As a child, Pete broke bones more times than he can remember, often when he tried dangerous stunts to impress his peers. His left knee is now so badly damaged that he faces the prospect of having his left leg amputated.
“CIP is such a rare condition, partly because very few individuals who have it reach adulthood,” says Dr. Ingo Kurth, who studies the condition at the Institute of Human Genetics in Aachen, Germany. “Many end up killing themselves because they don’t understand what constitutes a harmful situation.”
For the better part of three decades, Pete had little idea of the precise defect in his DNA that caused him to have CIP. But in 2012, he was contacted by a small biotech company in Canada. Xenon Pharmaceuticals was using Facebook to track down people with CIP in order to sequence their DNA through saliva samples. Pete obliged, and he — like many others with CIP — was found to have a mutation in a particular gene known as SCNP9A.
The finding suggests that it may be possible to develop painkillers that work not by mimicking the body's natural pain-killing endorphins — as opioids do — but by blocking the transmission of pain signals within the body.
The Race Is On
Pain is a complex neurological process mediated by long nerve fibers that extend from the spinal cord throughout our bodies to the tips of our fingers and toes. The ends of these fibers are studded with protein molecules that sense acidity, pressure, and temperature. If activated, they generate a tiny electrical current that triggers the sensation of pain. (Opioid drugs interrupt this process by attaching directly to receptors in the brain, stimulating the reward and pleasure systems and causing the brain to ignore pain signals.)
But as a result of the SCNP9A mutation, Pete and many others with CIP lack one of these all-important proteins, Nav1.7. That finding suggests that it might be possible to develop molecules that can “switch off" the pain signals in chronic pain sufferers, who, of course, have the protein. Such molecules might be able to curb pain quickly and effectively — and, since they don't act directly in the brain, without the risk of addiction.
“The Nav1.7 discovery has enabled us to design novel drugs for a range of pain syndromes from inflammatory pain to lower back pain, osteoarthritis, and neuropathic pain such as pain from diabetic neuropathy,” says Dr. Robin Sherrington, a Xenon neuroscientist who was involved in the SCNP9A discovery.
She said the research has been facilitated in part by recent advances in gene sequencing. “In the past, we haven’t been able to use DNA sequencing in this way as it’s been too expensive,” she says. “But with sequencing becoming cheaper, we have the opportunity to identify the cause of these rare disorders in a way that we haven’t had before."
Xenon, working in partnership with big pharmaceutical and biotech firms Teva and Genentech, now has three Nav1.7-inhibiting drugs in clinical trials, with the hope that they will be commercially available within the next few years. One is being developed as a treatment for pain associated with shingles, the often extremely painful infection of the nerves caused by the same virus that causes chickenpox. The two others are being developed for pain associated with cancer and diabetic neuropathy.
Xenon, Teva, and Genentech aren’t alone in the quest to develop a new breed of safer painkilling drugs. Merck, Amgen, Lilly, Vertex, and Biogen are also among the companies involved in the race to develop Nav1.7-inhibiting medications.
The hope for Nav1.7 inhibitors is that they will be able to control pain more effectively than non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin and ibuprofen while avoiding the risk of addiction that make opioids so perilous for long-time use.
“This has the potential to give us a whole new family of analgesics which did not exist a couple of years ago,” says Dr. Geoff Woods, a pain researcher at the Institute for Medical Research in Cambridge, United Kingdom. “These new medications are potentially capable of switching off pain before it is even perceived by the central nervous system.”
What Next for Painkillers — and Pete?
The Nav1.7 discovery may not be the only potential breakthrough to come from studying the DNA of people with CIP. Ongoing research by scientists at Xenon and elsewhere is pinpointing new gene mutations that may point the way to additional ways to switch off pain.
Woods is studying PDRM12, another gene involved in switching neurons on and off. Targeting this gene may lead to a new treatment for individuals with fibromyalgia. “We’re hoping to find a way to activate PRDM12 so that it switches the pain neurons from an overactive state back to a normal state,” he says. “We think this could provide a painkiller with very few side effects.”
Pete long ago came to terms with his own condition. But finally being able to understand its molecular underpinnings — and foreseeing the day when it could bring drugs capable of helping millions of people around the world — has been extremely gratifying.
“It’s pretty awesome,” he says. “When you spend your entire life in a hospital room, especially as a child, you see a lot of people in pain, up, close and personal. And especially children in pain. So knowing that just going through a small amount of testing could make such a major life-altering impact on so many people’s lives is a pretty amazing feeling."