RESUMEN
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.
RESUMEN
OBJECTIVE: The aim of the present study was to test the effects of vagus nerve stimulation (VNS) on the descending pain inhibition, quantified by the nociceptive flexor (RIII) reflex and the conditioned pain modulation (CPM) paradigm, and on supraspinal nociceptive responses, assessed by pain intensity and unpleasantness ratings and late somatosensory evoked potentials (SEPs), in healthy subjects. BACKGROUND: Non-invasive vagus nerve stimulation (nVNS) showed promising effects on headache and pain treatment. Underlying mechanisms are only incompletely understood but may include the activation of the descending pain inhibitory system and/or the modification of emotional responses to pain. METHODS: Twenty-seven adult, healthy, and pain-free subjects participated in this double-blind cross-over study conducted at a university research center. They received 4 minutes of cervical nVNS or sham stimulation in randomized order. RIII reflexes, pain ratings, and SEPs were assessed before, during, and 5, 15, 30, and 60 minutes after nVNS/sham stimulation, followed by CPM testing. The primary outcome was the nVNS effect on the RIII reflex size. Three subjects were excluded after the preparatory session (before randomization), 1 subject was excluded after outlier analysis, leaving 23 for analysis. RESULTS: RIII reflex areas were 917.1 ± 563.8 µV × ms (mean ± SD) before, 952.4 ± 467.4 µV × ms during and 929.2 ± 484.0 µV × ms immediately after nVNS and 858.4 ± 489.2 µV × ms before, 913.9 ± 539.7 µV × ms during and 862.4 ± 476.0 µV × ms after sham stimulation, revealing no differences between the immediate effects of nVNS and sham stimulation (F [3,66] = 0.67, P = .574). There also were no effects of nVNS over sham on RIII reflex areas up to 60 minutes after nVNS (F [1.7,37.4] = 1.29, P = .283). Similarly, there was no statistically significant effect of nVNS on pain intensity ratings and thresholds, RIII reflex thresholds, late SEP amplitudes, and the CPM effect, compared to sham. Pain unpleasantness ratings statistically significantly decreased from 4.4 ± 2.4 (NRS 0-10) to 4.1 ± 2.5 during nVNS compared to sham stimulation (F [1,22] = 8.74, P = .007), but there were no longer lasting effects (5-60 minutes after stimulation). CONCLUSIONS: The present study does not support an acute effect of nVNS on descending pain inhibition, pain intensity perception or supraspinal nociception in healthy adults. However, there was a small effect on pain unpleasantness during nVNS, suggesting that nVNS may preferentially act on affective, not somatosensory pain components.
