Pain is an important defense mechanism to protect the body and promote healing. However, chronic pain can be debilitating. In the United States, 20 to 50 million adults experience chronic pain, and it is one of the most common reasons adults seek medical care. Additionally, it has been linked to restrictions in mobility and daily activities, dependence on opioids, anxiety and depression, and poor perceived health or reduced quality-of-life.

“Chronic pain can limit a person’s daily activities and is associated with reduced work productivity, anxiety and depression, suicide, and overall reduced quality of life,” said Huan Yang, PhD, associate professor at the Institute of Bioelectronic Medicine at the Feinstein Institutes. “Beyond potentially addictive opioids, chronic pain sufferers struggle to find relief.”

Recently, a new study published by scientists at The Feinstein Institutes for Medical Research in Bioelectronic Medicine examined the reduction in inflammation and pain that occurs when high-frequency stimulation (HFES) is applied transcutaneously. HFES therapy — like the device, TrueRelief that received FDA clearance in 2021 for acute, chronic, and post-operative pain — has been shown to reduce discomfort. Understanding the molecular reasons behind how to device works, however, has been a mystery until now.

In the study, researchers showed that in preclinical mice models HFES inhibits neuroinflammatory mediator release by sensory neurons, called nociceptors, to reduce pain.

“For your body to feel pain, neurons release molecules that kickstart the body’s immune response causing inflammation and pain,” said Sangeeta Chavan, PhD, professor at the Institute of Bioelectronic Medicine at the Feinstein Institutes. “High-frequency stimulation therapies have shown to be effective in reducing pain, but the ‘how’ it works remained in question. This study reveals a previously unidentified mechanism for the pain-modulating effect of HFES, which seems to reset sensory neurons by stopping the release of neuroinflammatory molecules, resulting in less inflammation and pain.”

The researchers used optogenetics — light to control the activity of neurons — in conjunction with pharmacologic and injury-related activation of nociceptors to measure the release of calcitonin gene related peptide (CGRP), substance P and high mobility group box 1 (HMGB1), which are pro-inflammatory molecules.

In a 2021 study published in Proceedings of the National Academy of Sciences of the United States of America, Chavan and Yang showed that HMGB1, the molecule that nerves release to produce inflammation in the body, could lead to a new strategy in the development of pharmaceutical and bioelectronic therapies. It was this observation, according to the researchers, that was advanced in the study utilizing HFES to target HMGB1 released by nerves.

“Until now, assessment of pain has been largely subjective. We now have a quantitative biomarker that correlates directly with pain symptoms and allows us to develop more effective treatments,” added Timir Datta, PhD, assistant professor at the Institute of Bioelectronic Medicine at the Feinstein Institutes. “This inflammatory biomarker released by neurons gives us new insight into the role of neuroinflammation in chronic pain.”

Results in the Bioelectronic Medicine study showed that HFES lessens neuroinflammatory mediator release by activated sensory neurons. This suggests, according to the researchers, that HFES could be used as a preventative therapy for patients at high-risk of chronic pain. The study notes that further research is necessary to better understand the effect HFES has on reducing pain and inflammation, including the potential for it to be used as an alternative to opioids. Additionally, more complete evaluations on the timing — including how long and how frequently, ideal waveform, and determination placement of electrodes will advance HFES as viable choice for chronic pain.

“The discovery that neurons produce molecules that cause inflammation represents a major advance,” said Kevin J. Tracey, MD, president and CEO of the Feinstein Institutes, Karches Family Distinguished Chair in Medical Research and senior author on the paper. “Now this exciting new work shows it is possible to stop inflammation by targeting these neurons with bioelectronic devices.”