EXAMINING A PATIENT IN PAIN USUALLY STARTS WITH A SIMPLE QUESTION: Where does it hurt? But it’s the next question—how much does it hurt?—that proves more troublesome. As much as clinicians might want a precise measure, they currently must rely on patients accurately rating their own discomfort, usually on a single dimensional scale from zero (no pain) to 10 (the worst pain imaginable).

The level of a patient’s pain is useful information, but the subjective method of measuring it poses problems. Infants and the mentally incapacitated may not able to verbalize their pain. Other patients may willfully exaggerate how much it hurts, a problem that has come into focus for the role it may play in the overprescription of painkillers. In April, the organization Physicians for Responsible Opioid Prescribing issued a statement concerning current protocols that rely on subjective patient measures of pain—those that cause doctors to write too many prescriptions for opioid medications, potent analgesics that are widely abused, and which were linked to roughly 19,000 overdose deaths in this country in 2014, according to the Centers for Disease Control and Prevention.

But what if doctors had a tool that gave them a readout of how badly you were hurting? The push to develop so-called pain biomarkers—a physical measure of patients’ pain—has intensified over the past decade, and received a boost in 2013, when The New England Journal of Medicine published a report by University of Colorado, Boulder cognitive neuroscientist Tor Wager and colleagues. Using functional magnetic resonance imaging (fMRI), Wager and his team studied the brains of healthy subjects while the skin on their inner forearms was stung with a hot probe. They detected a unique, consistent “neurologic signature” of activity in the thalamus and other brain regions that identified with 93% accuracy when the subjects felt pain. When subjects received an opioid analgesic, remifentanil, that signal was greatly diminished.

Neurologist and Neurobiologist David Borsook of Boston Children’s Hospital is another pioneer in the use of fMRI to study the brains of patients with chronic pain, and his teams are exploring other measurement tools that show promise, including near-infrared spectroscopy. Finding pain biomarkers, he says, may pave the way to building more tailored approaches to treatment. Physicians might learn patients’ likelihood of responding to a given pain medication. “In addition, recent brain imaging data has begun to inform us on how the brain changes when a patient is given opioids for pain, and future studies may enable science to objectively define who might be at risk for developing dependence,” says Borsook.

In another effort to measure patients’ pain, pediatric gastroenterologist Jeannie Huang of the University of California, San Diego School of Medicine and Rady Children’s Hospital teamed up with computer engineers to create a video-recording system that can recognize and interpret facial expressions. Cameras were trained on the faces of children and teens who had recently undergone appendectomies; by detecting facial changes such as narrowing eyes and grimaces, the system generated pain scores for each patient. The scores closely matched the patients’ self-reported pain levels, Huang reported in a 2015 study published in Pediatrics. In fact, when it came to judging a patient’s pain, she adds, “our machine did better than the nurses.”

There has also been progress on gauging pain at a molecular level. In a 2015 pilot study published in the Journal of Pain Research, an analysis of cerebrospinal fluid from 11 patients with severe neuropathic pain found high levels of a protein called angiotensinogen, which plays a vital role in the renin-angiotensin system, which helps regulate blood pressure. Recent animal research suggests that RAS may also play a part in producing pain, notes Emmanuel Bäckryd, lead author of the study and chief of the pain unit at the Pain and Rehabilitation Centre in Östergötland, Sweden. While the research is in its infancy, it suggests that RAS proteins might serve as biomarkers and potential targets for pain relievers, says Bäckryd.

Not all pain experts believe that physical discomfort or misery can be measured. Pain is an unpleasant experience associated with tissue damage, notes anesthesiologist Gregory Terman of the University of Washington School of Medicine, immediate past president of the American Pain Society. “In general, it’s difficult to objectify an experience,” says Terman. “It’s like asking, ‘What is an objective measure of hate or love or boredom?’ ”

Yet Bäckryd believes that identifying biomarkers for pain will likely not only allow doctors to target therapies more safely and effectively, but also aid in developing new pain medicines. “We are trying to measure the biology that lies behind the experience,” says Bäckryd. That, he says, will call for big thinking and a steady research push.