The Area of Secondary Hyperalgesia following Heat Stimulation in Healthy Male Volunteers: Inter- and Intra-Individual Variance and Reproducibility

Abstract

Introduction: Clinical pain models can be applied when investigating basic physiologic pain responses in healthy volunteers. Several pain models exist; however, only few have been adequately validated. Our primary aim with this prospective study was to investigate the intra- and inter-individual variation in secondary hyperalgesia elicited by brief thermal sensitization (45°C for 3 min) in healthy volunteers.

Material and methods: Fifty healthy volunteers were included. Areas of secondary hyperalgesia following brief thermal sensitization were investigated by 2 observers on 4 experimental days, with a minimum interval of 7 days. Additionally, heat pain detection threshold and pain during thermal stimulation (45°C for 1 min.), and the psychological tests Pain Catastrophizing Scale and Hospital Anxiety and Depression Score were applied.

Results: For areas of secondary hyperalgesia, an intra-observer intra-person correlation of 0.85, 95% CI [0.78, 0.90], an intra-observer inter-person correlation of 0.03, 95% CI [0.00, 0.16], and a coefficient of variation of 0.17, 95% CI [0.14, 0.21] was demonstrated. Four percent of the study population had areas of secondary hyperalgesia both below the 1st and above the 3rd quartile considering all included participants. Heat pain detection threshold predicted area of secondary hyperalgesia with an adjusted R2 of 0.20 (P = 0.0006).

Conclusions: We have demonstrated a low intra-individual, and a high inter-individual variation in thermally induced secondary hyperalgesia. We conclude that brief thermal sensitization produce secondary hyperalgesia with a high level of reproducibility, which can be applied to investigate different phenotypes related to secondary hyperalgesia in healthy volunteers.

Trial registration: clinicaltrials.gov NCT02166164.

Conflict of interest statement

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

Figures

Fig 1. Flowchart of included study participants.

Fig 2. Sequence of clinical pain stimulation.

Sequence of clinical pain stimulation. Sequence of p-TS and HPDT depends on randomization. Abbreviations: BTS, brief thermal sensitization; p-TS, pain during 1 min. thermal stimulation; HPDT, heat pain detection threshold; min, minutes.

Fig 3. Areas of secondary hyperalgesia following BTS.

Areas of secondary hyperalgesia on the 4 experimental days following brief thermal sensitization. Medians and interquartile ranges are displayed. Values higher than 1.5 times of upper quartile or lower quartile are designated as outliers and marked with °. Abbreviations: Cm, centimeter; BTS, Brief thermal sensitization.

Fig 4. Heat pain detection threshold.

Heat pain detection threshold on the 4 experimental days. Medians and interquartile ranges are displayed. Values higher than 1.5 times of upper quartile or lower quartile are designated as outliers and marked with °.

Fig 5. maximum VAS during p-TS.

Maximum visual analogue score during 1 min. thermal stimulation on the 4 experimental days. Medians and interquartile ranges are displayed. Values higher than 1.5 times of upper quartile or lower quartile are designated as outliers and marked with °. Abbreviations: VAS, Visual analogue score; p-TS, Pain during 1 min. thermal stimulation.

Fig 6. VAS-AUC during p-TS.

Visual analogue score during 1 min. thermal stimulation on the 4 experimental days. Medians and interquartile ranges are displayed. Values higher than 1.5 times of upper quartile or lower quartile are designated as outliers and marked with °. Abbreviations: VAS, Visual analogue score; p-TS, Pain during 1 min. thermal stimulation; AUC, Area under the curve.