– After 36 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 her 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.

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

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.”

Now 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.

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.

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. “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.”

Pain experts from around the nation recently met at the NIH, reviewing a list of predictors of chronic pain culled from the trove of research. IT will help guide the Acute to Chronic Pain Signatures project in awarding $40 million to researchers who will study 3,600 patients over 2½, a quick timeline as medical research goes.

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.

“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.

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. Childhood trauma has been associated with chronic pain in adulthood.

Chronic pain — low back pain, headaches, arthritis, neuropathy and many other forms of it — costs American society $635 billion annually, said 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.

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.

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.

The causes of some kinds of pain vary. 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 Woolf, director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital and a neurology professor at Harvard University’s medical school.

Technology that has become widely available this century — such as functional magnetic resonance imaging machines — has enabled scientists to see inside the brain while people are in pain. “We said, ‘Why don’t we bring in some patients and look inside their brains?’ ” said Vania Apkarian, a professor 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.”

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. Bushnell’s working theory is that the constant pain of sickle cell disease has altered the circuitry in Samuels’ brain.

But what if nothing significant has changed in Samuels’ brain circuitry, and nature set up her brain to feel chronic pain? That is Apkarian’s theory. He has published research showing that he can accurately predict who is likely to experience chronic low back pain just by examining brain images and connectivity.

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, but the interaction of many.

He envisions a day when clinicians will encounter people in acute pain, or going into surgery, and examine their genomes for clues to how likely they are to develop chronic pain. “Instead of symptom management,” he said. “we would be managing the disease.”