Megan Hodge's first episode of severe pain struck when she was in her mid-20s. Hodge and her husband were preparing to visit family for Thanksgiving. Despite dealing with various chronic health issues, Hodge had a good workout that morning and felt she was finally gaining control over her health. As she reached into her closet to grab a sweater, her back suddenly gave out. The pain was so intense that she felt light-headed and feared she might vomit.
Over the years, Hodge experienced more frequent and severe episodes of back pain. Simple movements like grabbing a towel from the linen closet, picking up a toy off the floor, or even sneezing could trigger the pain. In 2021, Hodge had a particularly bad flare-up. None of the strategies she had previously used to manage her pain seemed to work. She was afraid to move and felt utterly hopeless. 'I just could not regain footing, metaphorically and physically,' she says. 'I truly felt frozen in my chronic pain and chronic health journey.'
Hodge is not alone. In the United States, chronic pain affects tens of millions of people—about 1 in 5 adults and nearly 1 in 3 people aged 65 and older. 'The amount of suffering from arthritis and aging that I've seen in my pain clinic is overwhelming,' says Antje Barreveld, an anesthesiologist at Mass General Brigham's Newton-Wellesley Hospital in Massachusetts. Moreover, the primary therapy for severe acute and chronic pain—prescription opioids—has contributed to an epidemic that kills tens of thousands of people each year. 'We need better alternatives,' she says.
Researchers have intensified their efforts to find new pain treatments that are less addictive than opioids. 'The pain field has made very rapid and tremendous progress in the last decade,' says D.P. Mohapatra, a former pain scientist who now oversees research at the National Institute of Neurological Disorders and Stroke in Bethesda, Md. There is hope that this research will soon lead to new therapies. Vertex Pharmaceuticals is currently seeking regulatory approval for a new drug, suzetrigine, which shows promise in clinical trials. If approved, possibly in early 2025, it would introduce the first entirely new class of pain therapies in decades. Though initially approved for acute pain, there is hope that the new drug could also help with chronic pain.
There is a growing recognition that treating chronic pain requires more than just medication. 'We have a culture where people really turned to medications,' Barreveld says. 'But there's so much more to pain management than the pills we prescribe.' Pain researchers are exploring non-pharmacological treatments, including devices that deliver pain-relieving stimulation and psychological strategies to help people manage their pain. The field is developing ways to enhance existing therapies and identify the most effective combinations, as well as determining which patients might benefit most from which strategies.
Pain is the body's warning system designed to protect us. It makes you pull your hand away from a hot pan or limp after twisting an ankle. Pain-sensing nerves in the body's periphery, called nociceptors, identify potential threats—changes in temperature or pressure—and send electrical alerts to the brain. The brain processes these signals and adjusts the intensity of the pain. Daniel Clauw, a pain researcher at the University of Michigan Medical School in Ann Arbor, compares the body's pain system to an electric guitar. The peripheral nerves are the strings, and the brain is the amplifier. You can increase the volume by plucking the strings harder or turning up the amplifier. If the brain perceives a real threat, it might enhance the pain.
In most cases, the body desensitizes and recovers, and the pain subsides. However, with chronic pain, the pain continues long after the initial trigger. In some cases, there is a clear physiological explanation and solution. In others, neither the problem nor the solution is clear. About 20 percent of U.S. adults experience chronic pain, defined as pain on most days or every day during the previous three months. Nearly 7 percent have high-impact chronic pain, which severely limits daily life or work activities.
We have medicines to treat pain, but they don't work for everyone. For mild to moderate pain, doctors often recommend nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin or ibuprofen, for both acute and chronic pain. Antidepressants like duloxetine and anticonvulsants like gabapentin also offer some relief for people with chronic pain. Doctors still turn to opioids, but these medicines often provide only modest, short-term improvements. A 2020 report by the U.S. Agency for Healthcare Research and Quality found little evidence for any long-term benefits of prescription opioid treatment. Clauw believes opioids may even worsen many types of chronic pain.
Developing new therapies to treat chronic pain has been challenging. A diagnosis doesn't always reveal the underlying mechanism. Is lower back pain caused by a compressed nerve or an amplifier problem? A treatment addressing one may not work for the other. Objective evidence that a medication alleviates pain is hard to come by. There are no biomarkers, lab values, or imaging results that can reliably measure pain. 'You ask your patient to rate their pain from 0, no pain, to 10, the worst pain they can imagine. That's a very noisy metric,' says Stephen Waxman, a neurologist and pain researcher at the Yale School of Medicine. It depends on stress levels, sleep, mood, pain resilience, and many other factors. Plus, 'the placebo response is somewhere between large and immense.'
The quest for new pain medicines has been fraught with failures. Promising compounds have fizzled during development, including in late-stage trials. In 2021, Pfizer and Eli Lilly halted development of a promising antibody for arthritis and chronic back pain after regulators raised safety concerns. Vertex's new pain compound, suzetrigine, could be the first to deliver in a heated race to target specific sodium ion channels found on pain-sensing nerve cells. When these channels open, sodium enters the cell, decreasing the voltage between the cell's interior and exterior. Eventually, the voltage reaches a threshold, and the nerve sends an electrical impulse to the next nerve.
Scientists started seriously pursuing these channels in the late 1990s, and the pace of research accelerated in the mid-2000s after researchers identified families with a defect in a gene that codes for a particular sodium channel called Nav1.7. The defect cut pain off at the source. Earlier this year, Vertex reported that suzetrigine, which blocks a related channel called Nav1.8, curbed pain better than a placebo in people who had just had tummy tuck surgery or bunion removal. However, in people who underwent bunion removal surgery, it didn't work any better than the opioid hydrocodone combined with acetaminophen. In tummy tuck patients, the opioid combination better alleviated pain.
Pain medications that block sodium channels already exist, such as the anticonvulsant carbamazepine. However, these compounds target a variety of sodium channels, not just those involved in pain. Blocking these channels causes side effects that limit the maximum dose. That's why drugs like lidocaine and novocaine, which also block sodium channels, are injected locally. 'If you put them in the form of a pill, they block all of the sodium channels, including those in the heart and in the brain. So you get double vision, loss of balance, confusion, sleepiness,' Waxman says.
Though the effect of suzetrigine is 'modest,' Waxman says, it's a proof of principle: Targeting sodium channels specific to pain-sensing neurons works. The hope is that the next generation of these compounds could be much better. In December, Vertex reported that the drug seems to alleviate pain in people with diabetic peripheral neuropathy, a kind of pain stemming from nerve damage typically in the hands and feet. This is an early step in extending suzetrigine's potential use from acute to chronic pain.
New genetic discoveries may lead to more targets. Waxman has been studying people with a genetic condition called 'man on fire' syndrome. Some people with this condition have overactive Nav1.7 channels that typically lead them to experience intense pain, but a subset of these individuals experience far milder pain than expected. He and his colleagues discovered that the individuals who experience milder pain harbor mutations in a gene that controls the activity of a family of potassium channels that stabilize neurons so they don't fire. Waxman's team is now working with a biotech company to develop a potential drug that would increase the activity of these channels in people who don't have the mutations.
Treating pain isn't just about pills. In some cases, surgical procedures or injections can help relieve pain. Physical therapy can strengthen and stretch muscles and ligaments to curb pain. Neuromodulation therapies deliver electrical pulses directly to nerves to alleviate pain. Some, like spinal stimulation, are invasive. Others rely on electrodes placed on the skin. A team led by researchers at the University of Wisconsin–Madison has developed a minimally invasive technique. The team created an injectable electrode to create a pathway from the skin's surface to nerves deep in the body's tissue. This 'injectrode,' currently being tested in people, enters the body as a flexible polymer-coated metal coil that can deliver electrical stimulation from a device outside the body to nerves deep in the tissues.
There are also complementary and behavioral health therapies that can have a big impact on pain: acupuncture, meditation, yoga, massage, talk therapy, and more. Many of these seem to work, at least in part, by addressing the amplifier problem. 'The idea that your brain is actively creating pain, turning it up and down, facilitating spinal cord signaling of pain or dampening it, is really kind of a revelation over the past few decades,' says Tor Wager, a neuroscientist and psychologist at Dartmouth College. And it's an idea that's just beginning to percolate into mainstream medicine.
These therapies aren't new. Cognitive behavioral therapy, for example, has been used to treat pain for decades. But researchers are using the latest discoveries in pain science to refine these therapies to make them more accessible and effective. Wager has developed a version of cognitive behavioral therapy called pain reprocessing therapy. It aims to help patients understand that chronic pain is often a construct of the brain and not necessarily a warning that needs to be heeded. In a recent study of 151 people with chronic back pain, two-thirds of the people who received pain reprocessing therapy were pain-free or nearly so, compared with 20 percent in the placebo group and 10 percent who received their standard care. And the effect lasted at least a year.
Talk therapy requires a serious time commitment. But Beth Darnall, a psychologist and pain scientist at Stanford University, is working on more user-friendly strategies. She is the chief science adviser for AppliedVR, a company developing virtual reality tools to treat pain. The company's program for back pain, called RelieVRx, teaches pain-relief strategies such as mindfulness, deep breathing, and relaxation. The system also measures respiratory rate to provide participants with biofeedback. 'The world reflects back to them the changes that are occurring in their own body as they engage in a skill. And that's pretty unique to be able to do that from home,' Darnall says.
In a recent trial, researchers assigned roughly 1,000 people with chronic lower back pain to receive RelieVRx or a sham virtual reality treatment for two months. Both groups experienced a reduction in pain, but the RelieVRx group reported a slightly larger drop, on average. (The sham treatment's impact was attributed to the placebo effect.) While the list of potential pain-relief options keeps growing, there is also an understanding that no single therapy or combination of therapies will work for everyone. 'Pain is so complex and so diverse,' says Mohapatra, of the National Institute of Neurological Disorders and Stroke. 'We cannot make pain therapy as a one size fit for all.'
Many patients have to find solutions through trial and error, which means it might be months or years before they find any relief. 'Right now, we just fly blind,' Clauw says. What's needed is a way to identify which therapies might work for which patients. In 2019, the U.S. National Institutes of Health launched a study that aims to change that. The project, part of the NIH's massive Helping to End Addiction Long-term—or HEAL—Initiative, will aim to find biomarkers to help predict which therapies will work for the most common and debilitating chronic pain condition: lower back pain. 'It's applying a precision medicine approach to low back pain for the first time,' Clauw says.
In one study, researchers will assign about 1,000 participants to one of four pain-relief strategies: an online education program; a kind of cognitive behavioral therapy known as acceptance and commitment therapy; physical therapy; or the pain medication duloxetine. Each participant will undergo an assessment that includes blood work, imaging of the spine, and a physical exam. The hope is that these data can be used to create a model to predict which patient will benefit from which treatment—or more likely, treatments. A multitreatment approach is what finally gave Hodge some relief. At the Shirley Ryan AbilityLab Pain Management Center in Chicago, she received comprehensive care that included physical therapists, occupational therapists, pain psychologists, and physicians, all of whom collaborated and monitored her progress and well-being.
'That's not to say that I now live a life without any pain or without any flare-ups,' she says. 'It's not a cure-all.' But she does have a road map for how to deal with her pain, as well as the tools and mindset to better navigate future flare-ups. After Hodge graduated from the program, she wrote a letter to her care team about the impact of the skills she learned. 'I am no longer constantly on edge, waiting for the other shoe to drop,' she wrote. 'I finally feel safe in my body.'
