Inter-Individual Differences Explain More Variance in Conditioned Pain Modulation Than Age, Sex and Conditioning Stimulus Intensity Combined

Abstract

Conditioned pain modulation (CPM) describes the reduction in pain evoked by a test stimulus (TS) when presented together with a heterotopic painful conditioning stimulus (CS). CPM has been proposed to reflect inter-individual differences in endogenous pain modulation, which may predict susceptibility for acute and chronic pain. Here, we aimed to estimate the relative variance in CPM explained by inter-individual differences compared to age, sex, and CS physical and pain intensity. We constructed linear and mixed effect models on pooled data from 171 participants of several studies, of which 97 had repeated measures. Cross-sectional analyses showed no significant effect of age, sex or CS intensity. Repeated measures analyses revealed a significant effect of CS physical intensity (p = 0.002) but not CS pain intensity (p = 0.159). Variance decomposition showed that inter-individual differences accounted for 24% to 34% of the variance in CPM while age, sex, and CS intensity together explained <3% to 12%. In conclusion, the variance in CPM explained by inter-individual differences largely exceeds that of commonly considered factors such as age, sex and CS intensity. This may explain why predictive capability of these factors has had conflicting results and suggests that future models investigating them should account for inter-individual differences.

Monoaminergic mediation of hyperalgesic and analgesic descending control of nociception in mice

“…Although usually not discussed in such terms, pain modulation observed on application of a CPM paradigm may in fact be facilitatory or inhibitory (or absent), and interindividual differences represent a large unsolved problem in the subfield. 22 Although there has been intense study of the role of conditioning stimulus intensity, with conflicting results, 22 test stimulus intensity has to the best of our knowledge never been systematically varied in a CPM study. It is conceivable that variability in baseline pain sensitivity may serve to alter the subjective intensity of the test stimulus within a CPM paradigm, leading to variability not only in the extent of CPM but also its direction.…”

“…1 While DNIC is consistently analgesic in our hands when measured in healthy anaesthetized animals, 2,3,47 application of a CPM paradigm to a healthy human population reveals considerable interindividual variability in its magnitude and direction (ie, pain inhibition or facilitation). 13,19,22,30,48…”

“…1 While DNIC is consistently analgesic in our hands when measured in healthy anaesthetized animals, 2,3,47 application of a CPM paradigm to a healthy human population reveals considerable interindividual variability in its magnitude and direction (ie, pain inhibition or facilitation). 13,19,22,30,48 We recently discovered that pain modulation is not always inhibitory (ie, analgesic) on the application of a DCN paradigm. Specifically, in both wakeful mice and rats, using a variety of "test" (ie, the noxious stimulus being modified) and conditioning stimuli, we observed that behavioral responses to noxious test stimuli of low intensity are exacerbated instead of inhibited by conditioning stimuli, such that hyperalgesia is produced rather than analgesia.…”

Diffuse noxious inhibitory controls and conditioned pain modulation: a shared neurobiology within the descending pain inhibitory system?

“…For mechanism-oriented studies, CPM paradigms would benefit from: (1) including a nonpainful control conditioning stimulus (SHAM) to disentangle real CPM effects from repeated-measures or antinociceptive SHAM effects, 26 (2) assessing parallel and sequential CPM effects to better understand the respective outcomes, and (3) monitoring cardiovascular changes, particularly when using the most frequently applied 50 conditioning stimulus, ie, a cold water bath, originally designed to assess cardiovascular reactivity. 46 Finally, CPM effects are mainly explained by interindividual differences other than age, sex, and conditioning stimulus intensity, 39 and their origin (eg, psychological or genetic) requires further investigation.…”

Inter-individual variability in mechanical pain sensation in patients with cervicogenic headache: an explorative study

“…A condition to be measured was a score of 0 on the 11-point NPRS for headache intensity on the test day. Suffering from pain at the test day would have complicated the interpretation of the PPT-measurements, given its variation within and between individuals 51,68 . Measuring PPTs bilaterally, and at remote sites of the painful www.nature.com/scientificreports/ source in a pain-free period, might uncover hidden potential features of pain modulation of the individual, which are not necessarily related to a current CeH episode.…”