Mark Johnson
Madison Evans was 16 when she first felt sharp pain in her lower pelvis, pain that radiated through her back and grew so severe that some days she could not get out of bed.
Instead of asking the Severna Park, Maryland, adolescent to assess her pain, pediatricians told her “you’ll grow out of it.” She suffered for nearly 15 years until a doctor finally grasped the intensity of her discomfort and diagnosed endometriosis, a chronic condition that affects 1 in 10 women of childbearing age.
Researchers are now trying to find something the doctors who treated Evans lacked: objective indicators of pain that will enable physicians to quantify it as they do heart rate and blood pressure. The wave of research into these indicators, known as biomarkers, carries implications for the nearly 1 in 4 Americans who live with chronic pain. It may also give voice to infants and others who are unable to tell doctors what they feel.
Measuring pain, one of the most fundamental tasks in medicine, remains one of the least precise, a shortcoming that helped fuel the nation’s opioid crisis. In an era of genomic medicine and artificial intelligence, doctors still ask patients to rate their anguish from 0 to 10 or, in the case of very young children, with cartoon faces, ranging from smiley to frowny.
Studies have shown that these efforts are undermined by biases that have led the medical community to consistently underestimate the suffering of women and minorities, especially Black Americans.
Scientists hope to identify biomarkers among the proteins, hormones and metabolites that have been linked to pain. One researcher has been developing a way to measure the pain sensations transmitted by nerve fibers in the body.
Doctors said the ability to measure distress using these markers would improve the accuracy of diagnoses and help determine how effective medications are in providing relief.
An accurate objective measure could also wind up saving the health-care system money, said Julia Finkel, an anesthesiologist at Children’s National Hospital in Washington, who is hoping to develop the first device to determine both the type and intensity of pain.
“You get it right the first time instead of this empirical, trial-and-error approach,” Finkel said. “The current standard of care is that we ask the patient a bunch of questions; laboratory data is drawn. They get back to you next week. Then that next visit, which is the following month, based on what we saw in the labs, then we’ll escalate the dose, or decrease the dose or change the drug.”
In 2010, the National Academy of Sciences put the annual cost of chronic pain at between $560 billion and $635 billion - up to $300 billion of that in direct health-care costs and up to $110 billion in missed time at work.
Finding an objective measure of pain could also topple the barrier of doubt that sometimes stands between doctors and their patients, a problem Gissel Moralescasco ran into when she was 8. A doctor had asked her to rate the pain that spread from her stomach through her entire body on a scale of 0 to 10, with 10 being the most severe. “Ten,” she said, without hesitation.
“Are you sure?” the doctor asked. “Ten is really bad.”
Two months later, a different doctor spent almost a day examining Moralescasco and running through tests before diagnosing the D.C. resident with lupus.
“Wow,” the doctor told her. “Now I understand.”
Although pain is sometimes called the fifth vital sign after temperature, pulse, respiration and blood pressure, its complexity often goes unappreciated.
“When patients are told that the pain is all in their head, the implication is that it’s imagined, but the irony is that [is] sort of right,” said Adam Kepecs, a professor of neuroscience and psychiatry at Washington University in St. Louis.
“The pain only exists in your brain. It’s neural activity, which is why it’s invisible and uniquely personal. But it’s still real.”
Kepecs and Whitney Ross, Evans’s doctor in St. Louis, have a $3.4 million federal grant to develop a blood test that can measure pain in women with endometriosis, a condition that stems from the growth of tissue similar to the lining of the uterus but in the pelvic area outside the uterus.
“By comparing blood samples from the same individual at different times, when they experience high pain versus no pain, we can identify molecules specifically linked to pain,” Kepecs said.
At Children’s National Hospital, Finkel has an $8 million grant from the same federal program funding Kepecs’s project. In about two months, she plans to start clinical trials of the tool she has dubbed the Nociometer. The name is a nod to the term nociception, the detection of pain.
The Nociometer stimulates the patient’s three main sensory and pain nerve fibers - found in skin, muscles, joints and some organs - without actually causing pain. Instead, the device sends a tiny electrical current through a probe, usually attached to the patient’s finger or toe. The three fibers each transmit a different kind of sensation: temperature and slow-burning pain; sharp, localized pain; and touch and pressure.
Using a handheld instrument, the doctor then examines the dilation of the patient’s pupil in response to the electrical current. The pupil is connected to the pain processing centers of the brain that receive information from the three nerve fiber types. Finkel’s Nociometer measures and compares the relative sensitivity of each type and uses the information to determine the kind of pain and its intensity.
The clinical trials will test the device’s accuracy in measuring pain associated with different conditions, including pediatric acute postoperative pain, lupus (an example of inflammatory pain) and carpal tunnel syndrome (an example of neuropathic pain, which arises from damage or dysfunction of the nervous system, rather than from damage to tissue).
Another study will evaluate people without pain, though “they’re hard to find,” Finkel said.
The Nociometer would not replace the self-reported pain scales that doctors use, but rather add clarity.
“Well, you said ‘I’m in pain.’ I don’t doubt that,” Finkel explained. “In order to be most effective, I need to know why; what are the underpinnings of why you feel this way. Different components impact one’s perception of pain. Depression can exacerbate it. Happiness can mitigate it.”
One problem with using pain scales alone is that they’re imprecise and vulnerable to manipulation. Craving medication, some patients overrate their pain; others, fearing they’ll be viewed as overly sensitive, downgrade their pain.
“You don’t want to leave people in terrible pain, but the problem we got into is that that seemed to translate into large amounts of opioids being prescribed,” said David Clark, a professor of anesthesiology, perioperative and pain medicine at Stanford Medicine, an academic medical center that is part of the university.
Clark said doctors try to go beyond the self-reported scales by asking specific questions: How does the pain interfere with the things you want to do? Can you work? Can you take care of your kids? Is the pain interfering with sleep?
Still, health-care professionals struggle with their biases, and with the significant challenge of determining pain in newborns and young children who cannot communicate.
“There is a huge need, really, for objective biomarkers to assess pain in these vulnerable populations,” said Neha Santucci, director of the chronic abdominal pain program at Cincinnati Children’s hospital.
Since infants cannot talk, Santucci said, “we go by more of their behavior. Crying is a sign of being in discomfort, but babies cry. Crying is their primary language. A baby crying does not necessarily mean pain. They might be crying because they’re hungry. They may be crying because they need a diaper change.”
Kevin Jackson, Finkel’s partner in the company AlgometRx, which will produce the Nociometer, said they hope the device will receive approvals and be ready for clinical use within about five years. Although the cost has not been decided, Jackson said it will probably be between $10,000 and $15,000.
“We do envision it being a ubiquitous tool,” he said.
The projects involving Finkel and Kepecs are among four aimed at developing ways to measure pain, all funded with grants from the Department of Health and Human Services’ Advanced Research Projects Agency for Health.
Another recipient, Tufts University biomedical engineering professor Sameer Sonkusale, is using a $3 million grant to develop a patch containing microneedles that is placed against the skin. The microneedles would take samples of interstitial fluid, the watery substance found between cells and tissues in the body.
Doctors would peel the patch off after 35 to 40 minutes and insert it into a reader that would search for molecules such as hormones, metabolites and cytokines (small proteins important in cell signaling), Sonkusale said. The patches, he said, should be ready for human testing within six months.
“The whole project rests on the premise that there’s no one biomarker of pain,” he said. “We are looking for a panel [of different biomarkers].”
The fourth project is led by Wei Gao, a professor of medical engineering at the California Institute of Technology, who received a $3 million grant to develop a “wearable” pain tool that would measure pain through proteins, hormones and metabolites found in sweat. It might be a ring or a device worn around the wrist like the Fitbit, which tracks a person’s fitness.
“A lot of biomarkers associated with pain can be identified in blood,” he said. “But taking a blood draw at home would not be practical.”
That’s why, Gao said, “we are looking at what’s in the sweat.”
The as-yet-unnamed device can actually induce sweat, even while the wearer is sleeping. Gao said it would consist of a disposable patch costing less than $1 that would collect the sweat and a reusable reader that costs between $10 and $20.
Evans, the woman with endometriosis, who now lives in St. Louis, said the ability to measure pain through methods like the blood test being developed for her condition will have profound implications for patients.
“I think if the blood test had existed 15 years ago,” she said, “I would have essentially gotten those 15 years of my life back.”