“It was an emergency situation,” she says. The horse Sally was riding was barreling straight towards another, younger horse, and the only way to stop him was to pull back on one rein, hard. She felt a pop in her wrist. Heat shot up her arm, excruciating pain fast on its heels.
That was four years ago. No one knows quite what happened to her wrist that day, but whatever it was has left her with constant pain that stretches from her fingertips to her neck, and sometimes creeps into her ribs. On the really bad days, even a hug is unbearably painful.
Sally is my youngest sister, and she is one of an unlucky fraction of people for whom an injury catapults their nervous system into a state of chronic pain. The injury itself heals, but like an insidious memory, the pain lingers. We don’t know why. “The whole issue of the transition from acute pain to chronic pain—why some individuals develop that chronic pain and many don’t—is a major, major question,” says Allan Basbaum, a professor at the University of California, San Francisco. Genetics may play a role. So can the severity of the original injury.
But what we do know is that once that pain has gotten a foothold, doctors and patients don’t have very many choices. “The irony is that morphine, the 2,000-year-old drug, still remains the number-one weapon against pain,” says Yves De Koninck, a professor of neuroscience at Université Laval in Canada.
And it’s not a weapon that anyone enjoys using. Opioids like morphine and oxycodone are famously addictive, and the numbers of people who abuse them are climbing. Painkiller overdoses now kill more people than cocaine and heroin combined. And while opioids are invaluable for acute pain, they’re less effective for persistent, chronic pain. In fact—in a particularly cruel irony—long-term opioid treatment can actually make pain worse. Non-opioid pain medications exist, but they don’t work for the majority of patients, and even then they are only partly effective.
Chronic pain is like “a maladaptive memory.”
Opioids work so well for acute pain because they bind to the receptors the body has designed for its own painkillers—molecules like endorphins and dynorphins that blunt the pain response. Finding good alternatives to opioids for treating chronic pain will mean finding different neurological mechanisms to target—mechanisms that explain not just why people hurt, but why some people hurt for so long.
De Koninck has found such a mechanism. One of the keys to understanding chronic pain, he believes, is to pay attention to the similarities between long-lasting pain and another, very familiar, neurological process that makes some connections stick around longer than others: memory.
Chronic pain is like “a maladaptive memory,” Basbaum explains. Both constitute patterns etched in your brain and nervous system that quicken the connections between “snake” and “poison” or between “bump” and “ouch.” Evidence has been piling up that chronic pain and memory share some of the same cellular mechanisms—and now, De Koninck’s work has shown that a neurochemical trick used to erase memory may be able to turn off chronic pain, too.
An Unmet Need
The number of people struggling with chronic pain has been hotly debated, and the fact that chronic pain is broadly defined and difficult to quantify doesn’t help. But even conservative estimates suggest that about 20% of the population have had at least one episode of serious, chronic pain. In the United States alone, that’s more than 60 million people. “It’s a major unmet need,” De Koninck says.
Pain is physically and psychologically debilitating in way that few other conditions are. “In fact, it’s often the most debilitating component of many diseases,” De Koninck notes. And it sharply circumscribes the lives of people who suffer from it. People can find a way to live with the other challenges of painful conditions like arthritis, cancer, even paralysis, he says, but “if you actually ask the patient, their number-one concern, and the one thing that they want us to cure, is the pain.”
When pain pathways are functioning properly, they play a protective role.
When chronic pain gets severe, many patients withdraw, sometimes even from their families. Sally says that she’s constantly nervous, afraid to accept invitations or do things that she loves—like riding horses—in case it makes her arm even worse. The ride that day, Sally says, “changed my life.” For some patients, chronic pain can lead to serious mental health problems—it’s strongly correlated with depression and suicide risk.
When pain pathways are functioning properly, they play a protective role. They are a relay of chemical and electrical signals that move from nerve endings to our brains. Pain teaches us to avoid things that are sharp, prickly, or hot. It’s the way our nervous system has adapted to living in a hazardous world. People who can’t feel any pain typically don’t live very long.
Our skin is packed with millions of specialized nerve endings, programmed to detect dangerous conditions like heat or pressure. When one of these pathways is activated, the neuron sends an electrical current shooting up its long, thin axon towards the spinal cord. When it reaches the end of the neuron, that electrical signal prompts the release of chemicals called neurotransmitters into the synapse, or the gap between the first neuron and the next. The neurotransmitters dock in receptors on the next neuron, triggering pores to open in the cell’s membrane. Charged particles rush in through these open pores, creating a new electrical current that carries the signal farther up the nervous system.
The first handoff occurs in a region of the spinal cord known as the dorsal horn, a column of grey matter that looks, in cross-section, like a butterfly. From this first relay point, the signal travels to the thalamus, one of the brain’s switchboards, and eventually to the cerebral cortex, where the signal is processed and decoded.
After an injury, it’s normal for the damage sensors near the trauma site to be touchy for a little while. During that time, your nervous system is encouraging you to protect the damaged tissue while it’s healing. But sometimes that extra sensitivity, called “hyperalgesia,” sticks around long after it’s useful. Hyperalgesia is often a major component of chronic pain, and it means that people with chronic pain have to be unceasingly alert. For example, Sally says, before she hurt her arm, hot coffee sloshing onto her hand might have hurt for a few seconds. Now, a careless moment like that means days of burning pain.
Symptoms like this suggest that changes in the nervous system have migrated to the spinal cord. De Koninck believes that a major factor is the number of receptors on the signal-receiving neurons in the dorsal horn. If those neurons synthesize too many receptors, they’ll pick up too many neurotransmitter molecules. Then the neurons’ pores will flutter open to let charged particles in more often than they should, sending electrical signals shooting up to the brain at too high a frequency. The result is a pain signal that’s much stronger than it should be. De Koninck’s work gives us a new window into how it happens, and how to stop it.
Recall, Then Erase
The key lies in a study about memory that was published nearly 15 years ago. Long-term memories seem to depend on the synthesis of extra receptors, too, and scientists knew that blocking the synthesis of those receptors during a memorable event could keep memories from forming.
But what a group of researchers at New York University discovered was that there is a brief period when interrupting receptor synthesis can actually erase old memories. Memories are reinforced when they’re retrieved, but, paradoxically, during that process, even well-established memories have a brief window of vulnerability—like jewelry in a safe deposit box, memories are useless when they’re stored but accessible to thieves when they’re being used. A chemical called anisomycin blocks the production of receptors that neurons need to form memories. When the researchers injected anisomycin into rats’ brains right after triggering a particular memory, that memory didn’t just fail to get reinforced—it was erased altogether.
The right chemical injected at just the right place at just the right time could erase the physiological “memory” of pain.
Accumulating evidence that pain and memory use similar mechanisms led De Koninck to wonder if this same neurochemical trick could erase chronic hyperalgesia. De Koninck and his colleagues made mice hypersensitive to pain by injecting their paws with capsaicin, the chemical responsible for chili peppers’ fiery bite. Capsaicin activates the same pain sensors that respond to extreme heat and can turn on hyperalgesia without the tissue damage that an actual burn would cause. After their capsaicin injection, the mice’s paws were more sensitive to pressure for hours afterward.
Before that sensitivity had had a chance to wear off, the team gave the mice a second capsaicin injection—and this time, they added an injection of anisomycin. What happened after this second injection is “like magic,” De Koninck says. When the second injection initiated the same flurry of neurotransmitters and electrical signals that encoded the hyperalgesia the first time—the pain analogue of recalling a memory—anisomycin shut down the pain-amplifying mechanism by keeping the spinal cord neurons from making extra receptors. “It’s in the process of reorganizing itself,” De Koninck explains, “and there there’s that window of opportunity to actually shut it back down.” The mice lost seventy percent of their hypersensitivity to pain.
The theory that overdeveloped connections other than memories could be attenuated by retriggering them “is not a new idea,” Basbaum says, “but the fact is, there really has been very little evidence that it’s doable.” De Koninck’s results suggest that the right chemical injected at just the right place at just the right time, can erase the physiological “memory” of pain. Ted Price, a professor at the University of Texas-Dallas, says that this “ paves the road to disease modification instead of just palliatively treating people with these terrible drugs like opioids, which everybody, everybody in the field wants to get away from.”
For now, there are a few other types of treatment doctors can turn to besides opioids. Antidepressants help some people, as do certain antiseizure medications. A controversial technique called “transcutaneous electrical nerve stimulation” may work by making sure that there are plenty of receptors in the dorsal horn for the body’s natural opioid chemicals; a wearable device using this technology was just approved for over-the-counter sale by the FDA.
Treatments based on De Konick’s capsaicin-anisomycin model would constitute an entirely new category of drugs. “When you find a new mechanism,” De Koninck says, “boy, it opens a whole new array of things.” But finding the right combination of chemicals won’t be easy. Capsaicin patches are already sold over the counter at drugstores, but anisomycin is far too indiscriminate for clinical use. Brian Wainger, a physician and researcher at Massachusetts General Hospital, says, “It’s obviously going to be a long time for a discovery like this to work towards a clinical approach, but I think it sort of sets a framework for some options.”
“Options” is a word that seems to come up a lot among pain specialists. One of the reasons chronic pain is so difficult to treat is because “there’s a lot of different forms of chronic pain,” De Koninck says. “But the arsenal that we have so far to treat it is still quite meager.” And the weapons we do have are woefully inadequate.
Still, discovering that this retrigger-and-erase phenomenon works for hyperalgesia, as well as for memory, suggests that it may be useful in other parts of the nervous system. If that’s true, these kinds of treatments could help with pain syndromes more complicated than hyperalgesia—conditions that are so severe that even light touches become painful, or in cases where patients experience pain with no stimulus at all.
One big advantage of De Koninck’s strategy is that it isn’t just an incremental improvement, a way to make a slightly more effective or slightly less addictive analgesic. It’s a totally different angle on the problem. It targets the “chronic” part of chronic pain. “What the field I think really needs is options,” Price says. “And more importantly, patients need options.” For millions of people, and their doctors, a totally different angle is exactly what they’ve been looking for.
Photo credits: NIH, Suh-Young Jeong/NIH