Healthy volunteers can be phenotyped using cutaneous sensitization pain models

Abstract

Background: Human experimental pain models leading to development of secondary hyperalgesia are used to estimate efficacy of analgesics and antihyperalgesics. The ability to develop an area of secondary hyperalgesia varies substantially between subjects, but little is known about the agreement following repeated measurements. The aim of this study was to determine if the areas of secondary hyperalgesia were consistently robust to be useful for phenotyping subjects, based on their pattern of sensitization by the heat pain models.

Methods: We performed post-hoc analyses of 10 completed healthy volunteer studies (n = 342 [409 repeated measurements]). Three different models were used to induce secondary hyperalgesia to monofilament stimulation: the heat/capsaicin sensitization (H/C), the brief thermal sensitization (BTS), and the burn injury (BI) models. Three studies included both the H/C and BTS models.

Results: Within-subject compared to between-subject variability was low, and there was substantial strength of agreement between repeated induction-sessions in most studies. The intraclass correlation coefficient (ICC) improved little with repeated testing beyond two sessions. There was good agreement in categorizing subjects into 'small area' (1(st) quartile [<25%]) and 'large area' (4(th) quartile [>75%]) responders: 56-76% of subjects consistently fell into same 'small-area' or 'large-area' category on two consecutive study days. There was moderate to substantial agreement between the areas of secondary hyperalgesia induced on the same day using the H/C (forearm) and BTS (thigh) models.

Conclusion: Secondary hyperalgesia induced by experimental heat pain models seem a consistent measure of sensitization in pharmacodynamic and physiological research. The analysis indicates that healthy volunteers can be phenotyped based on their pattern of sensitization by the heat [and heat plus capsaicin] pain models.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Basic scatterplots of area of secondary hyperalgesia (cm2), first vs. second measurement, in the heat/capsacin model (panel A, pooled data from eight studies [n = 189]), the brief thermal stimulation model (panel B, pooled data from four studies [n = 120]) and the burn injury model (panel C, data from one study [n = 100]).

The Spearman’s rank correlation coefficient (rho) and line of identity are indicated.

Figure 2. Bland-Altman plots illustrating the mean of measurement 1 and measurement 2 (x-axis) plotted against the difference between measurement 1 and measurement 2 (y-axis) for secondary hyperalgesia areas induced by the heat/capsacin model (panel A, pooled data from eight studies [n = 189]), the brief thermal stimulation model (panel B, pooled data from four studies [n = 120]) and the burn injury model (panel C, data from one study [n = 100]).

The solid vertical line (mean of difference) indicate bias between the methods and the dashed vertical lines indicate the upper and lower 95% confidence interval (CI [±1.96×SD = limits of agreement]).