Hitting pain’s off switch
Figuring out why some pain becomes agonizing and chronic
Stacey Morris remembers being roused in the emergency room one summer night in 2008. “I took too many pills,” she told the hospital staff. “I don’t know what I took.”
Morris, whose name is changed for this article to protect her privacy, was kept overnight on a psychiatric hold because the doctors thought she may have attempted suicide. But that wasn’t the case, she insists.
Morris said she had accidentally overdosed on her prescribed medications for chronic pain, sent to the ER by a combination of gabapentin, Ambien and a small glass of wine. She was nearly a statistic, illustrative of a disturbing trend: More than 6,600 American women died of prescription painkiller overdose in 2010 — more than five times as many as in 1999. In 2016, women died from prescription opioid overdose at a rate of 4.3 per 100,000.
Six months before Morris’ overdose, surgeons removed a spattering of calcium deposits from her right shoulder. A relentless ache flared up in their place. After seven prescriptions, countless medical appointments and that fateful trip to the ER, her pain was finally diagnosed as complex regional pain syndrome, or CRPS — a condition in which pain festers in a limb long after an injury, causing swelling, discoloration and changes in sensation.
Pain specialist Vivianne Tawfik, MD, PhD, diagnosed Morris with the syndrome and has treated her at Stanford Hospital for the past five years. Tawfik’s work helping patients like Morris manage their pain is increasingly important: More than 8 percent of American adults report being in severe pain every day, and pain medications rank as the second-most dispensed prescription.
Overall, an estimated 1 in 3 American adults suffer from chronic pain, meaning it has persisted for longer than three months. Morris’ pain syndrome is a relatively rare form of chronic pain, with about 55,000 newly diagnosed cases each year. The pain subsides for some and persists for years in others.
Tawfik aims to help her chronic pain patients with a variety of treatments, including physical therapy, sessions in pain psychology, pain-relieving drugs and procedures such as nerve block injections.
But many of Tawfik’s patients tick straight through that list and remain wracked with pain. They tote around packed pillboxes; swallow their empty promises of freedom from pain; and are left exhausted, foggy and constipated, rather than relieved. The stakes are even higher for women between the ages of 45 and 54, who have the highest risk of dying from a prescription painkiller overdose.
At the heart of the issue is a question that has plagued medicine for many years: Why does some pain dissipate after an injury has healed, while other pain hangs around long after the fact? If pain physicians knew that, they could prevent the onset of chronic pain, rather than trying to numb patients once it takes hold.
Tawfik, an assistant professor of anesthesiology, perioperative and pain medicine at Stanford School of Medicine, hopes to someday figure that out. In addition to caring for patients, she is studying the transition from normal, short-term pain to chronic pain, with mice as her subjects.
Studies offer hope for relief
Neuroscientists have known that cells called microglia amplify pain signals on their way to the brain. If this boost persists after the painful injury has healed, it may lead to chronic pain. If this is the case, Tawfik hopes she might be able to alter the activity of microglia, tone down the incoming pain signals and turn off that prolonged pain.
Tawfik’s challenge will be moving her research from mice to humans. Pain researchers have been under fire — often friendly fire — as some scientists increasingly argue that pain experiments in mice have little relevance in human disease. While pain signals move through mice and humans similarly, it’s not possible to re-create the suite of emotional, psychological and physical aspects of human pain in a rodent.
Still, animal studies are irreplaceable pieces in the pain research jigsaw, Tawfik said. For patients like Morris, these studies offer some hope for relief. In the 10 years since Morris’ shoulder surgery, her pain remains a moving target and a given in her daily existence. It has migrated to her left shoulder, and she compares the sensation to the pounding throb you feel after being hit with a hammer. It weighs down her body and mind like an invisible sandbag.
“I keep trying to find ways to be optimistic — that’s the hard part,” Morris said. “I don’t want to think that I won’t get better.”
Tawfik is striving to improve upon pain studies of old and to achieve results in a field infamous for its shortcomings. Her largest ongoing study hints at a remedy for chronic pain.
The seed of Tawfik’s current research took root in the early 1990s. Before then, scientists assumed that neurons — the excitable messenger cells of the nervous system — were wholly responsible for relaying pain signals through the body.
Neurons send electrical signals down an output cable, known as an axon, which releases chemical messages to neighboring cells. Neurons are surrounded by cells that lack axons, called glia. Glia means “glue” in Greek, and glia were once thought to bind neurons together, providing them with insulation and structural support.
Turning up the volume on pain
But as technologies were developed to better study glia, scientists found evidence that the cells are more than just brain stucco. Many neuroscientists dismissed the idea at first, but now years of extensive research have provided too much evidence to ignore.
Linda Watkins, PhD, a behavioral neuroscientist at the University of Colorado Boulder, was among those pioneering scientists who got glia into today’s textbooks. Her early studies of influenza-related pain helped define the broader role for glia. “It turns out that all the symptoms of the flu are created by glia,” she said. “And pain is part of that.” Though they have no axon or other direct line of communication with the brain or spinal cord, glia appear to contribute to that pain signal.
“You can think of them as turning up the volume on pain,” Watkins said. “If they become activated, they start spewing out substances that make pain neurons go wild.”
For example, substances called proinflammatory cytokines call immune cells to assemble at an injury site and ignite inflammation to fight infection. Such chemicals make neurons more sensitive to incoming pain signals, influencing how intense pain feels down the line. After “turning up” pain for a certain length of time, glia can become prone to faster, stronger and longer activation, said Watkins.
Research suggests this prolonged glial activation might push short-term pain over the edge so that it becomes chronic. But no one knows exactly how. By studying glial cells found only in the brain and spinal cord, called microglia, Tawfik hopes to understand how these cells contribute to chronic pain and how to stop it.
Making do with mice
Pain is a complex interaction of physical, emotional and psychological factors, and scientists studying mice have yet to figure out how to ask a mouse how it’s feeling, emotionally. Researchers can only study painlike behavior and nociception — how the nervous system reacts to painful stimuli — in animals. For instance, a researcher may prod a mouse’s injured paw and note whether it pulls away and how quickly.
Compounding the problem, the vast majority of pain research has been done in male mice from the same genetic strain, even though chronic pain affects far more women than men.
Tawfik has tried to deal with these concerns by building an animal study that closely replicates what she sees in her patients, most of whom are women. Many of them first fracture a bone; then, after the cast comes off, the fracture pain lingers and develops into complex regional pain syndrome. Tawfik reproduces this scenario in her mouse experiments to study symptoms she sees in humans.
In her Stanford lab, Tawfik is using genetic engineering technology to disable different genes along the pain pathway in mice that are bred to lack an essential microglial protein. She also is experimenting with disabling this component with an injectable drug to investigate how different levels of microglial activation correspond to the intensity of pain symptoms.
The classic symptom of complex regional pain syndrome is long-lasting pain that is stronger than expected given the injury that triggered it. Other symptoms include muscle tremors and weakness, brittle nails, slow-growing hair, swelling, redness or unexplained warmth in the affected limb. Those with the syndrome may become hypersensitive: A minor cut or bruise might cause severe pain while normally painless sensations, such as feeling clothing against their skin, can become excruciating. For instance, when Morris walks on pebbles with bare feet, it can feel as if she’s walking on jagged shards of glass.
Tawfik studies these symptoms by observing whether her genetically altered mice are more sensitive to touch and heat after injury, or exhibit other symptoms that mimic those of her patients.
“If mice have some sort of injury, they tend to respond at a very low threshold,” she said. The same goes for the mice’s sensitivity to heat.
Tawfik also uses an imaging technology called positron emission tomography to scan the brains and spinal cords of her mice. She plans to use the same technology in human patients to take a snapshot of their own nervous systems. Tawfik uses the scanner to measure how active her mice’s microglia are before and after injury. She hopes the scans will tell her whether injuries cause microglia to become more active in her mice, and how that activation might be paralleled in humans.
Tawfik has run six groups of mice through her experiments. Time and time again, the same results have come back: Manipulating microglia, even temporarily or to a moderate degree, can completely change the trajectory of pain. By disabling or deleting 25 percent or more of a mouse’s microglia, Tawfik can block their abnormally strong pain response before it takes hold. When she allows the mice’s microglia to increase back to a normal level, they’re still fine. It seems Tawfik may be flipping pain’s off switch.
These are promising results, but the mechanisms that cause microglia to prolong pain remain a mystery. Tawfik wants to solve that so other scientists might develop medications to interfere with microglia and perhaps provide new treatments for chronic pain.
A pain-free tomorrow
Such drugs could give patients like Morris a new lease on life. From the outside, you’d never guess Morris was living with debilitating pain. Her fashionable outfits, sparkling nail polish and sleek, sandy hair seem incongruent with someone who’s had an accidental drug overdose. If you overheard her joking at a coffee counter, asking for a unicorn drawn in her cappuccino foam, you wouldn’t guess that years of relentless pain have left her clinically depressed.
“I can’t even clean the dishes in my sink. I can’t even put the toilet paper rolls in the bathroom, or make my bed in the morning, because I just don’t want to do anything,” she said, describing her worst days. “And that’s so unlike me.”
Morris said she has always had a “get-up-and-go” personality. She worked for years as a hospital marketing representative and raised two daughters who are now in college. She volunteers with local foster children at a Santa Cruz County nonprofit organization. In her free time, her ideal day would be filled with mountain biking, paddle boarding and canyoning, followed by beach volleyball at sunset. Tawfik notes that Morris remains extremely active — traveling, working and volunteering — in spite of her pain.
But none of this is possible without pain medications. Morris takes two tablets of the narcotic Vicodin two to three times a day, along with a nerve pain medication, Topamax, that makes her face twitch. That’s in addition to injections twice a month of a nerve blocker — a medication that numbs the nerves in her neck to prevent the pain in her arm. She recently upped her Cymbalta prescription to treat her depression and nerve pain. The medications put her in a fog, make her drowsy, sap her motivation and disrupt her digestion.
On bad days, the pain still keeps her from her favorite activities and from her work with foster children.
“How can I be there for them when I’m not there myself?” Morris said.
In March of 2018, Watkins helped usher into human trials a glia-targeting drug that aims to interrupt the signals that glial cells use to turn up pain in patients with arthritis. It’s already worked in rats, dogs and horses, and Watkins hopes it will prove effective in people.
“The end goal would be that a patient comes into clinic, they get a scan and we can see that their microglia are activated,” Tawfik said. “Then we can say, ‘You’re appropriate for treatment with this drug that modulates those cells.’”
Tawfik envisions a better future for her patients — one where she can offer them permanent escape from the pain that holds them hostage.