No Global Brain Response to Noxious Stimuli in Patients With Chronic Pain

Researchers’ goal was to employ fMRI to identify differential brain responses to noxious stimuli in patients with chronic pain while adhering to best practices for neuroimaging meta-analyses.

A systematic review and meta-analysis failed to detect evidence for aberrant functional magnetic resonance imaging (fMRI) activity among individuals living with chronic pain compared with healthy controls. These findings were published in JAMA Network Open.

Researchers searched publication databases through May 28, 2019, for studies of fMRI and chronic pain. In 29 articles, the 37 experiments meeting inclusion criteria included 511 patients and 433 healthy controls.

The chronic pain conditions included in more than 1 study were migraine (n=7), irritable bowel syndrome (n=5), fibromyalgia (n=5), chronic back pain (n=4), and complex regional pain syndrome (n=2). During brain assessments, pain was mechanically (n=14), thermally (n=10), electrically (n=4), or chemically (n=1) induced. Pain was either fixed (n=11) or perceptual ratings were matched between controls and patients (n=18).

Convergent differences in response to painful stimuli were not observed between patients and controls (voxel height, P >.001; familywise error-corrected cluster, P <.05).

Among studies that used perceptual-matched pain ratings, no convergent differences were observed.

Among pain-specific brain regions, the sum of activation likelihood estimation (ALE) scores derived from calculating the estimated scores within the pain network compared with all spatial permutations, patients with chronic pain had an ALE estimate of greater than 25. The expected null distribution determined ALE scores greater than 20 to be well within the significant range (P <.001). This significant score indicated some evidence of pain-specific aberrant activity among patients with chronic pain within pain-specific brain regions.

These findings may have been biased by including only task-activated, blood-oxygen level-dependent responses to pain and disregarding functional connectivity, cerebral blood flow, variation between chronic and subacute pain, or response to spontaneous pain.

Although there was no evidence for differences in brain response to noxious stimuli among patients with chronic pain, these studies did suggest there may be differences in the pain network. However, these limited activation differences are unlikely to be robust or consistent.

Disclosure: Multiple authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.


Xu A, Larsen B, Henn A, et al. Brain responses to noxious stimuli in patients with chronic pain: a systematic review and meta-analysis. JAMA Netw Open. 2021;4(1):e2032236. doi:10.1001/jamanetworkopen.2020.32236