When it comes to chronic pain, there are few effective treatments available to patients, in large part because there is still so much that researchers don’t understand about it. Among the biggest mysteries: how—and when—does pain become chronic?
To help answer those questions, pain researchers met in 2017 with the Interagency Pain Research Coordinating Committee, a part of the US National Institutes of Health (NIH), to set a course for the Federal Pain Research Strategy. The strategy formulates a long-term plan to address chronic pain and find new treatments. Of the five working groups convened for this purpose, one focused on understanding the transition from acute to chronic pain.
The group’s aim was to reconcile recent findings about the transition and chart a path for future research that will lead to better treatments. The researchers who are a part of this effort published a comment summarizing their recommendations for the Federal Pain Research Strategy May 15 in the journal Nature Reviews Neuroscience (subscription required).
In the comment, they lay out two main goals: to develop new pain therapies, including non-opioid drugs and non-drug interventions aimed at both acute and chronic pain, and to target the body’s own healing processes to reduce or potentially reverse chronic pain.
Chronic pain is different
Ted Price is a pain researcher at the University of Texas at Dallas and the group’s co-chair together with Robert Dworkin from the University of Rochester. One thing experts all agree on, says Price, is that chronic pain is not simply acute pain that lasts for a long time. Instead, it’s a pathological condition that affects the brain and nerves. As a result, medications that work for acute pain are often not effective against chronic pain.
“The concept of simply calling it ‘chronic pain’ after six months is not useful, and it has probably been detrimental to effectively treating patients,” says Price.
Researchers also agree on risk factors that render some people more vulnerable to developing chronic pain, although how the factors convey risk remains murky. For example, some genetic differences increase susceptibility to chronic pain, as do social and environmental factors such as poverty and abuse.
The past decade of research has made clear that chronic pain involves neuroplasticity—that is, changes in the way nerve cells look under a microscope, their electrical activity, and how they communicate with one another. Animal studies have identified many different forms of neuroplasticity occurring during chronic pain, and brain imaging studies show that the brain’s structure and function change over time in people with chronic pain. Immune cells also appear to play a key role in chronic pain. On top of all this, the way that chronic pain develops probably differs in males and females and may differ depending upon age as well.
Drugs beyond opioids
For Price, developing new, non-opioid pain relievers is the biggest priority. “It’s absolutely the most critical thing for the field,” he says. While that has long been a goal—even a “holy grail”—for pain researchers, few new drugs have made it to market over the past 20 years. That may be changing, though, as drugs in development for a long time finally make their way through clinical trials to approval by the US Food and Drug Administration (FDA).
“Migraine had a drug approved recently,” Price says, referring to an antibody aimed at blocking a protein associated with headaches (see RELIEF related feature article). Other non-opioid drugs directed at a protein called nerve growth factor are now being tested in people with osteoarthritis (see RELIEF related feature article.) “I think they are going to get approved, and if they do, that will be a huge deal for a huge population of patients.”
Price is also optimistic about drugs that affect Nav1.7, a protein found in pain-sensing neurons that could potentially be manipulated with a drug to quell the electrical activity of nerve cells that contribute to chronic pain (see RELIEF related feature article and podcast).
The researchers also want to see new drugs developed in response to more recent discoveries. What has prevented the successful creation of new drugs, in part, is the wide gap between academic researchers making scientific discoveries about how pain works, and those who are developing drugs that are safe and effective in humans—mostly pharmaceutical companies, which also need to make a profit.
“What might make the difference now,” Price said, “is funding or other resources from pharmaceutical companies to help move new drugs from the lab to the market. There seems to be a tailwind now on public-private partnerships to make these ideas move forward.”
That might entail taking ideas developed in academia and having medicinal chemists and others at companies work out the details of how to use those ideas to produce an effective drug—something that many academic researchers are not equipped to do.
Those public-private partnerships are at the center of a new funding initiative recently announced by the NIH for pain and addiction research, called HEAL, for Helping to End Addiction Long-term (see RELIEF related feature article).
Even as they work to discover new pain drugs, researchers are also investigating how non-drug therapies can best help people with chronic pain.
“Non-pharmacological treatments are the way to go,” says Kathleen Sluka, an author of the comment and a pain researcher at the University of Iowa. “Using them gives people control of their own destiny, it teaches people skills they can use to help manage their pain, and it gets around the issues we have now with opioids,” she says.
“There is a lot out there,” Sluka says, with respect to non-drug therapies such as cognitive-behavioral therapy (CBT), physical therapy, and yoga, “but these treatments are not well utilized.” More research is needed on how to best implement them to help patients, but the most effective treatment plans will be tailored to each individual.
“Someone with high anxiety might get a behavioral intervention like CBT. Someone with a sedentary lifestyle and poor motor function might be better treated with an exercise program. Understanding the mechanisms behind chronic pain can give us a more targeted approach,” Sluka says.
And, she adds, “if we use non-pharmacological treatments first to treat, for example, someone with acute back pain, and change their behaviors, we may be able to prevent chronic pain from developing.”
Non-drug treatments ease pain in unknown ways, but they may do so through the brain’s innate capability to dampen pain and to heal itself.
“Whether it’s pain inhibition by endogenous opioids,” the brain’s own morphine-like molecules, “or a healing mechanism in the immune system, a lot of non-pharmacological interventions change those processes,” Sluka says.
Annemieke Kavelaars, a member of the working group and a researcher at the University of Texas MD Anderson Cancer Center, suspects that regardless of how pain starts initially, immune healing mechanisms might be the key to resolving it.
“The body uses a very active process to resolve pain,” Kavelaars says. “And studies show it’s actually the immune system that makes it go away.”
The immune system can function in two directions, Kavelaars says. One “arm” of the system consists of pro-inflammatory, activating cells, which may help maintain or even initiate chronic pain. And then there is a healing, anti-inflammatory, suppressive arm, which Kavelaars suspects is required to heal and resolve pain.
“Maybe patients who develop chronic pain are overactive in that activating arm, or maybe they’re deficient in the suppressive arm, so pain that should go away, doesn’t,” Kavelaars says.
If there were a way to jumpstart the healing immune cells, “that might be a way to attack the whole condition—not just the bodily sensation of pain, but the whole constellation of other symptoms that comes with it,” Kavelaars says, referring to chronic pain’s psychological and emotional toll. She and others continue to study how the immune system can heal chronic pain, and how treatments might be aimed at immune cells to speed healing, perhaps one day even preventing pain from becoming chronic.
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.