Individual biomarkers may change the way pain is reported and managed.

Pages 14-15

With Alexander Niculescu, MD, PhD, and Forest Tennant, MD, DrPH

The measurement of pain has long been reliant on subjective, self-report tools, but growing strides in biomarker research may soon tip the scales in a more accurate direction.

One of the most commonly used methods to assess pain is the numeric rating scale (NRS), which asks patients to rate their current pain on a scale from 0 (no pain) to 10 (worst pain possible).1 The NRS functions as a verbal substitute for the visual analog scale (VAS), which similarly requires patients to report their pain by marking a number along a line running from 0 to 10.2

The Problem with Current Pain Scales

“There is currently no objective laboratory test that can identify pain and measure how severe it is,” Alexander Niculescu, MD, PhD, professor of psychiatry within Indiana University’s School of Medicine in Indianapolis, told PPM. “That creates problems in terms of management because you cannot measure response to treatment in an objective fashion.”

Forest Tennant, MD, DrPH, editor emeritus of PPM, added, “Scales are excellent for determining if you have pain at the moment, but pain scales for chronic therapy are pretty hazardous to use.” The problem, Dr. Tennant continued, is that patients receiving long-term treatment may start to perceive their pain differently, and self-reported pain scores lose their validity.

Can Biomarkers for Pain Assessment Be Identified?

In a recent study,3 Dr. Niculescu and his colleagues at the Indiana University School of Medicine reported findings on pain biomarkers obtained from psychiatric patients observed longitudinally at the Indianapolis VA Medical Center. After collecting up to six blood samples per person from a large cohort of patients over the course of the past 10 years, they focused in on 28 patients (19 male, 9 female) who experienced a change in pain over time, moving between a low pain state (VAS scores between 0 and 2) and a high pain state (VAS scores between 6 and 10).

“The approach [was] to initially correlate subjective feelings and thoughts with changes in molecules in the blood,” said Dr. Niculescu. The team adhered to a within-subject design, identifying genes that were expressed differentially within each patient by comparing every blood sample taken from a patient in a high pain state with a sample taken from the same patient in a low pain state.

Dr. Niculescu emphasized the power of this within-subject design. “If you did a population study where you studied people in pain versus normal controls,” he said, “you’d need three orders of magnitude more people to be able to start finding a signal because of all the variability between people that is not related to pain.”

The researchers compared their genetic findings with existing literature on pain disorders from both animal model studies and human studies to prioritize which biomarkers to pursue. They zeroed in on 65 biomarkers that may serve as objective indicators of pain—some of which were expressed at amplified levels by people in high pain states and some of which were expressed at diminished levels. They then conducted two additional tests to validate their findings and assess their predictive power:

Validation : Samples from an independent cohort of 23 patients (13 male, 10 female) with severe clinical pain (VAS scores between 6 and 10, plus disorders impairing daily physical function) validated five of the 65 biomarker candidates. The top five biomarkers associated with pain were MFAP3, PIK3CD, SVEP1, TNFRSF11B, and ELAC2.

Prediction : Drawing blood from two more independent cohorts, Niculescu’s team used the 65 biomarkers they had identified to predict—with varying success—which patients would report being in high pain states (162 patients; 134 male, 28 female) and which would require future trips to the emergency room (189 patients; 170 male, 19 female). The biomarkers that served as the strongest predictors were MFAP3, GNG7, CNTN1, LY9, CCDC144B, and GBP1.

For specific diagnoses among patients of a particular sex, Dr. Niculescu’s study revealed that individual biomarkers often served as stronger predictors of pain than did a collective panel of all 65 biomarkers. For example, CCDC144B may be an especially useful predictor of pain in males with psychosis, while LY9 appears well-suited to predicting pain among males with depression and PTSD.

Therefore, depending on each patient’s status, clinicians may find certain biomarkers to be more reliable than others as objective measures of pain. Clinicians could one day apply these blood biomarkers to monitor changes in pain among patients with particular conditions.

Potential Limitations in Practice

It is important to note that all of the aforementioned patients included in this study came from the Indianapolis VA Medical Center; each sample consisted only of veterans, with a mean age in the low 50s. Dr. Niculescu stated that future research should aim to determine how generalizable these findings are to different populations. However, he remains optimistic that any potential multicenter studies will corroborate his results, as his samples included individuals suffering from a variety of pain disorders and taking a variety of medications.

He added that, “There’s room for refinement and improvement by doing additional, larger studies in particular types of pain disorders to find which of our biomarkers [would] work best for acute pain, chronic pain, neuropathic pain, [and] migraine.”

Agreed Dr. Tennant, “They’ve done an enormous job of picking out markers that really could be something in the future.” Moving forward, however, Dr. Tennant pointed out that this type of diagnostic tool needs to be practical for frontline providers; they need to connect with it and its application. “When it comes to laboratory testing,” he said, “if you make it very complex, clinicians are going to bypass it.”

What About Biomarkers in Pain Care?

Meanwhile, Dr. Niculescu has made headway in another direction, shifting focus from diagnosis to treatment. In the same study, his team included additional analyses of natural compounds and existing drugs that might be repurposed to target specific biomarkers. The natural compounds that showed the most promise were pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), and apigenin (a plant flavonoid), while drugs like SC-560 (an NSAID), haloperidol (an antipsychotic), and amoxapine (an antidepressant) are among those that already target many of the 65 biomarkers associated with pain.

A liquid biopsy for pain would help clinicians assess and monitor patients with chronic pain, while the biomarkers themselves may serve as therapeutic targets. Patients with any number of pain conditions could also potentially benefit from the application of objective biomarkers, which would relieve them from having to rely on their own subjective feelings. “They can follow how they’re responding to treatment by doing repeat lab tests, and it’s reassuring if the markers move in the right direction,” explained Dr. Niculescu. “That gives them hope that their pain condition will be treated.”

Last updated on: August 2, 2019

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