Learn why some people develop chronic pain and others do not, and some methods that may help to mitigate it.

When Kim Mulholland was training for her first triathlon in the summer of 2021, she realized something wasn't right. Always fit, the now 54-year-old had attended Arizona State University on a full athletic scholarship for gymnastics and worked as a trauma yoga specialist near her home in Clyde, NC, so she was very in tune with her body. “I noticed that I kept tripping over my left foot like I was going to face-plant,” she says. “When I was riding my bike, I wouldn't necessarily notice where that foot was, or it would turn in a direction I hadn't intended.”

Doctors first theorized she had back problems or tarsal tunnel syndrome in her ankle, but after she experienced three focal seizures (jerking movements) in her left foot over one weekend, she underwent an MRI. The scan revealed a large meningioma, a benign tumor in the membranes surrounding the brain, that had grown to the size of a potato and invaded the entire right side of her brain, which was inflamed and swollen.

“I needed an emergency craniotomy [surgical removal of part of the skull to access the brain], and the neurosurgeon warned there was a possibility due to the size of the tumor that I could be paralyzed on my left side afterward and unable to speak,” Mulholland says. While she did wake up after the surgery unable to move her leg from the knee down, most of the paralysis began to resolve after 24 hours. But what remains to this day, after almost a year and a half of physical therapy, is weakness, constant pain, and spasticity in her leg.

“I can't move my left toes at all, my left ankle is limited in mobility and strength, and my left hip feels like it's being pulled by a rubber band all the time,” she says. “The pain is the hardest part. My foot goes from feeling ice-cold to burning hot. It also feels like I'm walking on rocks anytime I stand. Any material that touches my foot seems abrasive, like sandpaper. It's as if I always have two thick rubber bands wrapped tightly around my left foot with weights on them, and those symptoms never go away.”

A Confounding Problem

Mulholland's experience with chronic pain is distressingly common. According to a report from the U.S. Centers for Disease Control and Prevention (CDC), at least one in five American adults live with chronic pain, and for nearly a third of them, the chronic pain frequently limits their life or work activities.

People like Mulholland, who have survived a brain tumor or other injury to the brain (such as a stroke), may experience a condition known as central pain syndrome, caused by damage to the pain-conducting pathways in the central nervous system. For others, chronic pain can be linked to trauma or an overuse injury, migraine or stress headaches, multiple sclerosis, neuropathy, fibromyalgia, or arthritis. In many cases, these pain syndromes overlap. And low back pain that lasts for an extended period can develop into a more brain-centric pain syndrome.

“Often, people who live with chronic pain experience what we call central sensitization,” says Nathaniel M. Schuster, MD, associate clinic director at the UC San Diego Center for Pain Medicine. “When you sustain a tissue injury, for example, the pain signals are conducted by the peripheral nerve from the injured area through the central nervous system along the spinal cord up to the brain. Some people then experience a ‘peripheral sensitization,’ a strengthening of the connection between the nerves, where the nerves become hypersensitized. In essence, the nervous system learns to be more sensitive to pain.”

Researchers are trying to figure out why some people develop central sensitization or chronic pain after an injury or illness while others do not. “This is a huge area of pain research and one that we know the least about, unfortunately,” says Gregory Corder, MD, assistant professor of psychiatry at the University of Pennsylvania. In his lab, Dr. Corder studies how the brain generates the perception of pain.

“Pain is deeply personal and individual, but it does seem that people who are predisposed to certain types of psychiatric disorders, such as depression and anxiety, are at higher risk of transitioning from acute to chronic pain,” he says. “Things like lifestyle—how sedentary you are versus how active you are—as well as your nutrition and sleep health also appear to be factors in whether or not you develop chronic pain.”

Genetic causes and inherited factors can predispose people to develop chronic pain as well. A major area of Dr. Corder's research focuses on the mu opioid receptor, a type of protein involved in how we perceive and respond to pain. “The body's natural painkillers—like endorphins—which are released in times of stress, pain, or injury, bind to those same receptors,” he explains. “If there are changes in this receptor gene, it can't signal or function properly, so the body lacks an ability to regulate pain. This is one example, among others, of a potential genetic cause of chronic pain.”

Preventing the transition from acute pain to chronic pain is key, says Gary Franklin, MD, FAAN, a research professor in neurology and environmental sciences at the University of Washington in Seattle. “Developing chronic pain after three months is essentially the same as developing a disability.”

In a landmark study conducted in the early 2000s, Dr. Franklin and colleagues studied nearly 4,000 people with either low back pain or carpal tunnel syndrome, tracking them over a year from their acute injury to assess what factors might predict who became disabled with chronic pain and who did not.

“We found that the physical elements of pain are influenced by psychological factors—thoughts, emotions, and behaviors—as well as social circumstances,” he says. He and his group developed a short questionnaire for people recovering from an injury that asks how much they expect pain to interfere with their ability to work and whether they're concerned about work exacerbating the pain. “If someone takes this questionnaire shortly after an injury, it's highly predictive of what will happen later and whether the pain will become chronic,” says Dr. Franklin.

People who believe pain will prevent them from returning to work or that work will make it worse—a phenomenon known as “catastrophizing”—are more likely to develop chronic pain, he says, adding: “Evidence shows that cognitive behavioral therapy can help overcome those barriers to recovery.”

Pain medications themselves sometimes make pain worse. Studies comparing people's pain sensitivity before and after opioid therapy, as well as the pain sensitivity of people who have taken opioids for a long time, found that exposure to opioids increased sensitivity to pain and made preexisting pain worse. The higher the opioid dose, the higher the sensitivity to pain, according to the studies. “Known as opioid-induced hyperalgesia, it's unclear how common it is,” says Dr. Schuster.

Medication Overuse Headaches

Overusing headache medication can contribute to episodic migraine becoming chronic. Jennifer Nierenberg Metzger, 52, an attorney in Montclair, NJ, had been “prone to headaches” from childhood—even taking a suitcase full of Advil to summer camp—but during her first pregnancy in 2006, the migraines became more frequent, as many as 25 a month. Her pain intensified after a doctor gave her prescriptions for sumatriptan (Imitrex) and Fioricet—a combination of acetaminophen, a barbiturate called butalbital, and caffeine—and suggested she medicate liberally and frequently.

“At one point I was taking Imitrex almost daily and Fioricet at least twice a week, and my headaches started getting worse both in severity and frequency,” she says. “I couldn't get out of the cycle. Every time I went back to the doctor, I kept getting more and different medications.”

When she moved to New Jersey from Massachusetts in 2008, her new neurologist explained the phenomenon of medication overuse headaches—recurring migraines caused by long-term use of headache medication—and prescribed a three-week medication detox. “It was probably the most hellacious three weeks of my life,” she says. “Since then, I'm very judicious about the medications I take. I don't want to say medication overuse headaches are more intense than a bad migraine, but they're close and they don't go away.”

As of 2017, the U.S. Food and Drug Administration has required that certain over-the-counter medications, including naproxen (Aleve), come with a warning that if used 10 or more days a month, headaches may worsen. Research suggests that taking certain pain relievers—including opioids, triptans, and nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and aspirin—so frequently can alter the brain's serotonin system and lead to increased pain sensitivity.

It Takes a Village

“Medication alone is not the answer,” says Dr. Schuster. “Pain management is individualized to the patient and may involve a combination of cognitive behavioral therapy (CBT), physical therapy, mindfulness meditation, and progressive muscle relaxation, as well as possibly neuromodulation tools such as spinal cord and peripheral nerve stimulators.”

“Multidisciplinary approaches to pain, whether it's chronic due to an injury or from a neurologic condition, are always better,” agrees Dr. Franklin. Those approaches may include medication, exercise, physical therapy, psychological counseling, massage, mindfulness, and biofeedback. Pain reprocessing therapy (PRT)—which uses techniques drawn from pain neuroscience education, CBT, and mindfulness-based stress reduction to help patients reframe chronic pain as a brain-generated false alarm—showed promising results in a randomized controlled trial published in JAMA Psychiatry in 2022.

Dr. Franklin recommends the progressive goal attainment program (PGAP)—developed by Michael Sullivan, PhD, professor of psychology, medicine, and neurology at McGill University in Montreal—to reduce disability associated with pain, depression, posttraumatic stress disorder, cancer, and other chronic health conditions. PGAP helps people get back to their usual activities through exercise and CBT, “two of the most effective treatments for preventing and treating chronic pain,” Dr. Franklin says.

Managing pain requires a team including doctors, physical therapists, and psychologists or social workers, says Dr. Schuster. “Patients who believe in themselves and want to partner with that team very often do better than those seeking doctors who are going to cure them,” he says.

“Make sure you have investigated the possible underlying causes as well,” says Jennifer W. McVige, MD, director of the Concussion Center at the Dent Neurologic Institute in Amherst, NY, and a specialist in adult and pediatric headache. She's had patients with peripheral neuropathy whose pain eased significantly when their vitamin B12 deficiency was discovered and treated. “Go back to basics: Are your iron levels okay? Is your liver function okay? Once you've ensured that everything has been appropriately evaluated, managing chronic pain becomes a mind-body proposition.”

Understanding your pain is hugely empowering, says Dr. McVige. “It's tempting to want to take a pill to make it all go away, but that's not how pain management works. Sometimes you have to do multiple things simultaneously to make yourself well, including taking care of your mental health and nurturing a strong support system. It's okay to invest time in being kind to yourself.”

Multidisciplinary Treatment Approach

Over the past 17 years, Jennifer Nierenberg Metzger has tried almost every migraine treatment available, from acupuncture, Botox, biofeedback, and massage to newer preventive treatments such as the injectable drug fremanezumab (Ajovy) and the electrical nerve stimulation device Cefaly, both of which helped her.

Before the COVID-19 pandemic, Kevin Tock considered himself moderately healthy. He was overweight and experienced migraine attacks, but he otherwise felt pretty good for someone in his late fifties. Then he contracted COVID-19 in November 2020 and missed 31 days of work as he recovered at home. Now 60, the Fort Myers, FL, resident is back at work maintaining an irrigation system at a golf course, but he's far from fully recovered. Sometimes when he wakes up his arms and legs feel like they're still asleep. His head is often stuffy and heavy, and every now and then he gets an inexplicable ringing in his ears. And he's perpetually exhausted. If he didn't need the money, he wouldn't have returned to work. Most days, he comes home and goes straight to bed at 7 pm. A new problem is especially alarming: short-term memory loss.

“Everybody tells me, ‘Well, you're 60 now,’ but you don't go from remembering 90 percent of everything to not remembering the majority of things,” Tock says. “At work, when someone tells me to do something, I have to write it down or type it into my phone. If I don't, I'll do something else and totally forget.”

Tock says his ongoing symptoms are puzzling to him and to the doctors he's seen, who have not been particularly helpful or empathetic. “When you have all these weird symptoms,” he says, “and you go to a specialist and he looks at you like you're a nut case, it's the worst thing.”

At the outset of the pandemic, health experts said most people who got infected would experience mild illness and recover in about two weeks. But a year and a half later, it has become apparent that some people—including some who were not severely ill initially—experience the disease very differently. Survivors of COVID-19 have been sharing stories on social media, and with their doctors, of never-ending symptoms. The term “long COVID” came into use to describe what they were going through. Experts now refer to it by a new term: post-acute sequelae of SARS-CoV-2 infection, or PASC.

Liza Fisher, 37, of Houston calls her constant cycle of COVID-19 symptoms the “coronavirus hamster wheel.” In summer 2020 she contracted the virus and was hospitalized for a week with COVID-19-related pneumonia. Fisher subsequently developed postural orthostatic tachycardia syndrome (POTS)—a disorder of the autonomic nervous system characterized by an abnormal increase in heart rate triggered when moving from lying down to standing—and started having full-body tremors that make it difficult for her to walk.

She now uses a wheelchair for most of the day and has not returned to her jobs as a flight attendant and yoga instructor. “I've turned into a person with a chronic illness,” says Fisher, but notes that both her “better moments” and “hours of functionality” have increased in recent months.

For Lesley Tessler, a 74-year-old retired speech therapist from Oakland, NJ, the lingering impact of a COVID-19 infection has been the worsening of symptoms of cerebellar ataxia. Diagnosed five years ago with the progressive condition, which affects balance and movement, Tessler worried when the pandemic hit that she'd be at high risk for complications if she got the virus. She and her husband wore masks and went out only to go to the grocery store and to Tessler's physical therapy appointments.

Despite their vigilance, they both got sick in April 2020. Tessler was hospitalized for a week, during which she received oxygen. Since then, she has noticed an exacerbation of her neurologic symptoms. “My balance is worse, and I'm constantly light-headed,” she says. “I drive only locally now; before COVID, I could drive anywhere.”

The most difficult symptom for Tessler has been fatigue. “I am tremendously short of breath all the time,” she says. “I do the simplest thing and I have to lie down.” She finds it uncanny how the coronavirus has affected her: “It seems like it knows where to go. It knows the vulnerable areas of every person, and whatever area is compromised, it goes straight there.”

On the days when all Tessler wants to do is lie on the couch, her husband encourages her to be more active. She takes a low-dose antidepressant and attends physical therapy a few times a week. “I keep my mind busy and positive because it is really easy to shut down and let it all go,” she says.

Long COVID can affect people in many ways, including neurologically and psychologically. In a survey of 3,762 people from 56 countries who'd had COVID-19, published in July in EClinicalMedicine, respondents reported a total of 203 symptoms, with each person experiencing on average more than 55 symptoms. The most frequently reported ones after six months were fatigue, post-exertional malaise, and cognitive dysfunction. But symptoms as wide-ranging as tremors, itchy skin, sexual dysfunction, heart palpitations, bladder control problems, shingles, hallucinations, memory loss, blurred vision, diarrhea, and tinnitus were reported. Most respondents still had symptoms seven months after first becoming ill.

The public health consequences of long COVID are profound enough that in December, Congress allotted the National Institutes of Health $1.15 billion over four years to fund research into PASC.

The exact number of people with PASC isn't known, but studies suggest it affects 10 to 30 percent of COVID-19 survivors, says Avindra Nath, MD, FAAN, clinical director of the National Institute of Neurological Disorders and Stroke in Bethesda, MD. PASC symptoms generally fall into three broad categories: dysautonomia (malfunctioning of the autonomic nervous system); cognitive impairment, which includes conditions such as brain fog, depression, and anxiety; and exercise intolerance and extreme fatigue.

A study published in Nature Medicine in March analyzing data from more than 4,100 people in the United States, the United Kingdom, and Sweden who tracked their COVID-19 symptoms on an app identified certain risk factors for long COVID: being female, being older, having five or more symptoms after the first week of being sick, having asthma, and experiencing symptoms severe enough to warrant possible hospitalization.

Unraveling a Mystery

Several hypotheses are circulating about how the coronavirus affects the body. One is that oxygen deprivation caused by the virus leads to lung and brain damage. Another is that the virus damages cells in the nervous system. And another, which Dr. Nath considers the most plausible, is that the virus causes indirect damage by triggering an intense immune response that confuses the body, making it attack healthy cells it thinks are foreign invaders.

“The theory of direct infection of the brain hasn't really panned out,” says Dr. Nath. “Some studies claim they've found virus in the brain, but they include only a few patients and the amount of virus in the brain is very small. Even if the theory is correct, it cannot explain the variety of symptoms we see.”

Another area of interest is how the virus affects the arteries throughout the body and brain that are too small to see on an MRI, says Jonathan Rosand, MD, MSc, co-founder of the McCance Center for Brain Health at Massachusetts General Hospital in Boston. “I'm wondering if the clots in tiny blood vessels that have been found in some patients with COVID-19 will yield important discoveries about what actually is causing COVID-related brain dysfunction,” he says.

Another possibility is that the virus attacks through the olfactory bulb, says Gabriel de Erausquin, MD, PhD, MSc, endowed professor of neurology at the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio. A structure near the front underside of the brain, the olfactory bulb contains nerves that transmit information about smells to the brain. “It might be enough for the virus to be just in the olfactory bulb to trigger an abnormal molecular process in the brain,” he says.

While researchers investigate causes, doctors are doing what they can to help patients. Once they've ascertained that there is no underlying, unrelated disease, doctors prescribe medications and therapies to treat symptoms. “Even without knowing the pathophysiologic mechanism, physicians can still make a difference in the quality of life of their patients,” Dr. de Erausquin says.

The growing number of patients with PASC has prompted many medical centers to open post-COVID-19 clinics, staffed by health care providers in various specialties such as physical rehabilitation, pulmonary medicine, infectious disease, neurology, psychology, and social work. Survivor Corps, an online support group for people with long COVID, has a map on its website showing the locations of these clinics.

Most patients of the Center for Post-COVID Care at Mount Sinai in New York City didn't have severe cases of COVID-19 and were never hospitalized, says Allison P. Navis, MD, lead neurologist at the clinic. That is consistent with what's been documented in published research: Most people with long COVID surveyed in the EClinicalMedicine study, for instance, were not hospitalized.

The most common symptoms Dr. Navis sees are brain fog, headaches, sensory disturbances, dysautonomia, and intense fatigue. She treats brain fog by addressing factors that may contribute to it, like poor sleep, depression, or anxiety.

Targeting Symptoms

For patients who develop a tremor, Dr. Navis may prescribe drugs commonly used for essential tremor and seizures. Some long-haulers have also reported an internal vibration sensation—for which Dr. Navis has prescribed gabapentin, an anticonvulsant and painkiller. She says the cause of these symptoms is unclear, but it could be COVID-19's damage to nerves.

“We've yet to see one thing that provides relief for everything,” Dr. Navis says. “We target individual symptoms and see if we can eliminate or diminish them. One symptom can trigger others. Physical or mental exertion can lead to fatigue or headaches, for example.”

Dr. Navis used to order diagnostic imaging and autonomic function tests to try to trace the cause of patients' symptoms. But results often came back normal, so now she's more likely to skip the testing and go straight to treatment. And the management course is generally the same no matter what the tests show. 

“It's frustrating not getting answers, but that doesn't mean nothing's going on,” Dr. Navis says. “Either the tests aren't sensitive enough or we're not looking for the right things. As the research scales up, we're going to learn more, but it will take time.”

Long COVID is similar to other diseases known or thought to be caused by viruses, such as chronic fatigue syndrome, Middle Eastern respiratory syndrome, and severe acute respiratory syndrome, says Nicholas R. Mathenia, DO, director of general neurology at the Edward Neurosciences Institute in Naperville, IL. Another condition that can develop after viral infections, including COVID-19, is POTS, which Liza Fisher has experienced. Its symptoms are similar to those of long COVID: fatigue, light-headedness, brain fog, headaches, and an abnormally fast heartbeat when standing up.

“A significant number of people with lingering long COVID symptoms have a higher resting and standing heart rate due to some type of autonomic dysfunction,” says Svetlana Blitshteyn, MD, director and founder of the Dysautonomia Clinic and assistant professor of neurology at the Jacobs School of Medicine in Buffalo, NY.

The Healing Journey

Recovery from long COVID is gradual, and getting back to normal activities slowly is key, says Dr. Navis, who cautions against pushing too hard, which can aggravate symptoms. “Scheduling lots of breaks is important,” she says.

Lifestyle changes are also recommended, says Janna L. Friedly, MD, director of the UW Post-COVID Rehabilitation and Recovery Clinic at Harborview Medical Center in Seattle. Patients with insomnia are advised to stop looking at their smartphones and television screens close to bedtime and to maintain a regular sleep schedule; they may be prescribed melatonin or other sleep aids as well.

"It takes longer than initially thought to recover from long COVID, but we're seeing a lot of improvement,” says Dr. Friedly, who contracted COVID-19 herself in April 2020 and had symptoms that lasted months.

Patients with cognitive problems should get adequate sleep, exercise, eat healthy foods, and reduce stress, says Lindsay McAlpine, MD, BSc, a neurologist in the NeuroCOVID Clinic at Yale New Haven Hospital in Connecticut. Doctors recommend seeing a psychiatrist for treatment of anxiety or depression. For patients who continue to have problems with concentration, Dr. McAlpine prescribes ADHD medications.

An ADHD drug has helped Liza Fisher, who is receiving care through the Post-COVID-19 Recovery Clinic at UT Health San Antonio. “For the first time, I was able to have a conversation with somebody and not sound off-the-wall,” she says. She hopes to be able to resume reading every night, as she used to do before getting sick. Fisher also takes beta-blockers and corticosteroids, and says they have reduced her tremors.

Research continues for a treatment that will change the course of PASC. Dr. Nath, for one, is undertaking a study to test treatment with a corticosteroid and intravenous immune globulin against a placebo to see how the combination affects recovery.

As patients wait for research to yield answers, they remain optimistic. Kevin Tock looks forward to an appointment at a post-COVID-19 clinic in Hollywood, FL. Liza Fisher is encouraged that she's now able to lift both feet while holding on to bars during rehabilitation training.

“Ride the roller coaster and take it for what it is,” she advises people with long COVID. “Let the bad moments be, knowing that the good moments always come after the bad.”

AAN Releases Updated COVID-19 Vaccine Position Statement

The American Academy of Neurology is releasing the following updated position statement on COVID-19 vaccination as the delta variant compels us to once again rethink how we keep ourselves, our communities, and our patients safe.

The American Academy of Neurology has responded to the world’s disruption and recovery from the COVID-19 pandemic by providing resources and awareness for neurology providers; engaging in efforts to mitigate the long-term health and financial impacts on patients; and publishing research as new data emerge. 

The AAN continues to focus on the health and safety of neurology providers, neurology care teams, and patients. We now know that the vaccines provide increased protection against severe illness, hospitalization, and death if breakthrough infections occur and that nearly all mortality as of July 2021 is among the unvaccinated population. 

To that end, on July 30, 2021, the AAN signed onto a joint statement calling for all health care employers to mandate employees be vaccinated against the SARS-CoV-2 virus. Unless there are medical reasons, unvaccinated patients should be encouraged by all members of the health care team to get vaccinated to prevent illness, death, long-term effects, and further spread of COVID-19. 

Children with neurologic diseases are among the most vulnerable of populations. For children to safely engage with their families and in their communities, vaccinations for children under the age of 12 are needed. The AAN supports continued efforts to expedite regulatory approvals and deployment of COVID-19 vaccinations for children under the age of 12 once clinical trial data support their use. In addition, it is imperative that those eligible become vaccinated to protect this vulnerable population.

While current evidence suggests the COVID-19 vaccines are still effective, booster vaccinations may be needed if immunity wanes over time or does not protect against a new developing variant. When booster vaccinations are approved and available, the AAN will advocate for immediate administration to all eligible recipients, including those with compromised immune systems and health care providers who risk contracting and spreading COVID-19 to vulnerable populations. 

The American Academy of Neurology is the world's largest association of neurologists and neuroscience professionals, with 36,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer's disease, stroke, migraine, multiple sclerosis, concussion, Parkinson's disease and epilepsy.