After 36 agonizing years with sickle cell disease, Tesha Samuels is in complete remission — free, at least for now, of one of the most painful disorders known to medicine. Yet Samuels’s body still hurts almost every day.

The question that perplexes her doctors at the National Institutes of Health is why, after her blood disorder has been vanquished, she is still in pain.

Perhaps her newly healed red blood cells are not yet bringing enough oxygen to her tissues. Perhaps the emotional toll of a lifetime of constant pain has left her prepared to feel little else. Or perhaps the pain signals that have flooded her brain for more than three decades have permanently rewired some circuits, leaving her unusually sensitive to even the slightest irritation.

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There is evidence for all these theories, and more. But the truth is that no one really knows why pain persists in some people.

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More than 5,000 years after the Sumerians discovered they could quell aches with gum from poppies, medical science is still uncertain about who will develop chronic pain, how to prevent it and what to do when it occurs. The reasons the same insult to the body can leave one person with short-term discomfort and another with permanent misery have eluded researchers.

“Chronic pain is incredibly complex,” said Benjamin Kligler, national director of the Integrative Health Coordinating Center at the Veterans Health Administration. “It is interwoven with all kinds of psychological, emotional and spiritual dimensions, as well as the physical. Honestly, the profession of medicine doesn’t have a terribly good understanding, overall, of that kind of complexity.”

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Now — prompted by the opioid epidemic — NIH, university researchers, Veterans Affairs and drug companies, among others, are reexamining chronic pain, hoping to develop new approaches to predicting and preventing an ancient malady that afflicts 50 million adults in the United States.

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Finding these answers could not be more urgent. The medical blunder of casually prescribing opioids for acute and chronic pain is partly to blame for the addiction crisis that has taken more than 400,000 lives over the past 20 years. Even with a sharp downturn in narcotic prescribing over the past seven years, Americans still consume 33 percent more opioids per capita than Germans, the second-greatest users, according to the U.N. International Narcotics Control Board.

New discoveries could transform the treatment of long-term pain, allowing doctors, psychologists, physical therapists and others to intervene before pain becomes chronic, or provide alternatives to drugs when it does.

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Breakthroughs also could help head off a growing backlash among chronic pain patients and their doctors, who are terrified that medicine’s turn from powerful painkillers is cutting people off from the only thing that eases their suffering.

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“Our message is we need better medicine,” said Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke. “The methods we have now are just not effective.”

A major effort to put the clues together will begin Tuesday, when pain experts from around the nation meet at NIH for two days. They will review a list of predictors of chronic pain culled from the trove of research and winnow them to about 40 considered the most likely to be involved. Then the Acute to Chronic Pain Signatures project will award $40 million to researchers who will study 3,600 patients over 2½ years, a quick timeline as medical research goes.

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The goal is to develop a matrix of biological, psychological and social factors that might predict who is likely to develop chronic pain, and provide it to clinicians.

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“I think it’s pretty clear that we’re going to find some [markers],” said Linda Porter, director of NIH’s Office of Pain Policy, co-director of the effort. “But finding one that’s a solid signature — that’s our reach.

“The ultimate goal is to figure out treatment strategies that are preventive,” she said.

Hard to measure

Chronic pain is considered a “biopsychosocial disorder.” Genes, brain structures, the severity of injuries and nerve inflammation can all be involved. But so can psychological factors: People with depression are more susceptible to chronic pain. People who “catastrophize” an injury or illness are more often in chronic pain than people who dismiss or accept one. Childhood trauma has been associated with chronic pain in adulthood, as has social isolation.

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Chronic pain — low back pain, headaches, arthritis, neuropathy and many other forms of it — costs American society $635 billion annually, according to the National Academy of Medicine. Taken together, the many varieties of chronic pain make up the most common and disabling health problem in the world.

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For hundreds of years, healers looked to the location and extent of injuries, disease and surgery for the clues that might explain chronic pain, generally defined as pain that lasts more than three months, or beyond the time of normal tissue healing. (Some experts think it should be six months.)

But that approach proved unreliable.

For one thing, pain is subjective and difficult to measure. A stimulus that is unbearably painful to one person may be tolerable to another and a mere annoyance to a third.

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The causes of some kinds of pain — such as low back pain, which affects 13 percent of the U.S. population — vary widely.

And the peripheral nervous system, which carries pain signals from the source, can be involved in chronic pain — along with, or instead of, the spinal cord and brain. In the brain, many regions are involved in registering and soothing pain signals.

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Attention, fatigue, distraction and mood also influence perception of pain. So do emotions such as fear and anger.

For some people, pain — evolution’s warning to protect ourselves from harm — becomes the problem itself.

“We think of pain as a symptom. But in those patients, the pain is the disease,” said Clifford J. Woolf, director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital and a neurology professor at Harvard Medical School.

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Technology that has become widely available this century — functional magnetic resonance imaging (fMRI) machines and other devices like them — has enabled scientists to see inside the brain, in real time, while people are in pain.

What they discovered has convinced many that the key to chronic pain is found in the organ that receives the signals, and whose makeup is altered slightly every time an electrical impulse arrives on the neuronal highway.

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“We said, ‘Why don’t we bring in some patients and look inside their brains?’ ” said A. Vania Apkarian, a professor of physiology, anesthesiology and physical medicine and rehabilitation at Northwestern University’s Feinberg School of Medicine. “And as soon as we did that, we found all kinds of differences between healthy pain patients and chronic pain patients.”

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The brain is so malleable that every interaction — including reading these words — alters its makeup in some tiny way. Imagine then, if circuits in some people’s brains remain transformed long after their bodies have healed and pain signals are gone.

“Our brains are like muscles,” said Eleni Frangos, a postdoctoral fellow who is working with Samuels, the sickle cell patient, at the National Center for Complementary and Integrative Health, part of NIH. “If you exercise them, they change. If you don’t exercise them, they still change.”

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Samuels, who lives in Brandywine, Md., believes she has been in pain since the day she was born. As an infant, she couldn’t be comforted. No one understood why, until she was diagnosed when she was 2 with sickle cell disease, which distorts red blood cells and prevents them from carrying sufficient oxygen to organs and tissues.

She nearly died during a medical crisis at age 7 and suffered a minor stroke at 13. To prevent another, she had blood transfusions nearly every month for years.

After adolescence, her pain became worse — and chronic.

“It’s a constant ache, deep down in the bones and in the muscles,” said Samuels, 37, a legal instrument examiner for the D.C. Department of Corrections. “The ache is so deep that it almost feels like it’s unreachable.” By age 10, Samuels said, she was taking heavy doses of morphine and Dilaudid before she got out of bed to go to school.

Like many sickle cell patients, her chronic aches were punctuated every few months by attacks of excruciating pain that sent her racing to an emergency room.

“I wouldn’t wish how I feel on my worst enemy,” she said. “But what I would say for people who have to live with pain every single day is, it’s a humbling experience. It’s humbling because you realize how life . . . is so precious.”

Eighteen months ago, Samuels became one of a handful of people whose sickle cell disease was wiped out by a new gene therapy pioneered at NIH — a medical miracle of its own. But as the months went by, Samuels remained in pain while others did not. Researchers realized that the group would make excellent subjects for testing theories on the causes of chronic pain.

In an NIH clinic and in M. Catherine Bushnell’s laboratory, where Frangos works, Samuels has gone through test after test to narrow down the possibilities. Pointed instruments were touched to her skin — first one, then two, to determine how well she could distinguish among them. Her hand was thrust in ice water. Pressure was applied to her thumbnail.

In June, Samuels lay in an fMRI scanner as a technician touched a small heated plate, called a thermode, at 119 degrees to precise spots on her leg at 10-second intervals. A second round of tests was performed at 115 degrees.

As Samuels rated the level of pain by pushing buttons on a handheld device, the machine recorded images of her brain. Later, using software developed for the purpose, Frangos would be able to examine which parts of her brain lit up in response to pain. The team is comparing them with images of the brains of former sickle cell patients who aren’t in pain and of healthy volunteers to find differences.

More than two dozen structures in the brain are known to be involved in the perception of pain, and no two people react quite the same way. “Unfortunately, humans don’t come standard,” Frangos said.

Bushnell’s working theory is that the constant pain of sickle cell disease has permanently altered the circuitry somewhere in Samuels’s brain, inclining her toward chronic pain, even though she is in remission.

“My brain has just been feeling these pain signals for so long that it’s just accustomed to pain being there,” Samuels said.

Finding the source of Samuels’s pain is one challenge. Doing something about it is another.

“There’s not a lot of data on that, because there’s not a lot of people who’ve had pain for a long, long time and then suddenly get cured,” Bushnell said.

But what if nothing significant has changed in Samuels’s brain circuitry, and nature unfortunately set up her brain — and those of other people — to feel chronic pain?

That is Apkarian’s theory. He has put away the pointy instruments, ice water and thermodes because he doesn’t think he needs them. Apkarian has published research showing that he can accurately predict who is likely to experience chronic low back pain just by examining his or her brain images and connectivity. He also says he can tell who will respond well to interventions, including placebo.

“If we simply look at these people before they’re even exposed to placebo . . . in all of them their brain properties tell us beforehand who will respond to the sugar pill and how much they will respond to the sugar pill,” he said.

Woolf, in contrast, thinks that about half the explanation for someone’s likelihood to develop chronic pain is genetic. Not the work of one gene, unfortunately, but the complex interaction of many, he said. The rest can be explained by the many other factors that researchers are now considering — biological, psychological and social.

He envisions a day, not many years from now, when clinicians will encounter people in acute pain, or going into surgery, and first examine their genomes for clues to how likely they are to develop chronic pain. Then health-care providers will ask questions to assess their psyches and their social situations with the same goal.

By then, there may be drugs to prevent the onset of chronic pain. Or perhaps psychotherapy. Or a decision not to do surgery. All to avert chronic pain before it starts.

“If we could find a way of intervening, and preventing this consistent pain, then their need of opioids or heavy doses of analgesics will diminish,” he said.

“Instead of symptom management, we would be managing the disease.”

'Is this really me?'

In the past month, Samuels’s pain has diminished so substantially that she has stopped taking opioid painkillers. On some days, she feels no pain at all. When it does flare, she takes acetaminophen or ibuprofen. And that is enough.

Recently she jogged up an escalator at a Metro station for the first time she could remember. She wasn’t too tired. And she wasn’t in too much pain.

She played catch with her nieces and a nephew. For years, she had to decline.

“The fact that I was able to run after the ball, and bend down, and pick it up and throw it back and go real fast — I had to pinch myself and say, ‘Is this really me?’ ”

Her doctors have told her that her red blood cells are becoming more robust, carrying oxygen around her body better than ever before. Bushnell and Frangos are still peering into her brain, searching for hints that might offer hope to others. Perhaps, they say, her brain circuitry is adjusting yet again.

Samuels is allowing herself to think a bit more about the future. She has begun to consider returning to school to earn her college degree.

And she is trying to adjust to living without pain or drugs. It’s not as easy as she had imagined.

“Imagine having pain every single day at such an intensity, and then almost overnight you’re going through something where you’re not in as much pain,” she said. “So people look at it now like, ‘She’s fine.’ You know, mentally, I’m struggling, trying to figure out what’s my new normal. I have to find out what that normal is for me.

“I want people to understand, but they don’t understand,” she added. “So again, you feel alone because there’s only a select few that actually have been through what I’ve been through.”