Reproducibility of a battery of human evoked pain models to detect pharmacological effects of analgesic drugs

Abstract

Background: Although reproducibility is considered essential for any method used in scientific research, it is investigated only rarely; thus, strikingly little has been published regarding the reproducibility of evoked pain models involving human subjects. Here, we studied the reproducibility of a battery of evoked pain models for demonstrating the analgesic effects of two analgesic compounds.

Methods: A total of 81 healthy subjects participated in four studies involving a battery of evoked pain tests in which mechanical, thermal and electrical stimuli were used to measure pain detection and tolerance thresholds. Pharmacodynamic outcome variables were analysed using a mixed model analysis of variance, and a coefficient of variation was calculated by dividing the standard deviation by the least squares means.

Results: A total of 76 subjects completed the studies. After being administered pregabalin, the subjects' pain tolerance thresholds in the cold pressor and pressure stimulation tests were significantly increased compared to the placebo group. Moreover, the heat pain detection threshold in UVB-irradiated skin was significantly increased in subjects who were administered ibuprofen compared to the placebo group. Variation among all evoked pain tests ranged from 2.2% to 30.6%.

Conclusions: Four studies using a similar design showed reproducibility with respect to the included evoked pain models. The relatively high consistency and reproducibility of two analgesics at doses known to be effective in treating clinically relevant pain supports the validity of using this pain test battery to investigate the analgesic activity and determine the active dosage of putative analgesic compounds in early clinical development.

Significance: The consistency and reproducibility of measuring the profile of an analgesic at clinically relevant doses illustrates that this pain test battery is a valid tool for demonstrating the analgesic activity of a test compound and for determining the optimal active dose in early clinical drug development.

Figure 1

Star plot summarizing the effects of pregabalin (300 mg) on the indicated pain assessments in studies I through IV. The percentages shown for each assessment reflect the difference between pregabalin and placebo. Values marked with a circle are significantly different (p < 0.05) compared with placebo. PDT, pain detection threshold; PTT, pain tolerance threshold

Figure 2

Star plot summarizing the effects of ibuprofen (600 mg) on the indicated pain assessments in studies I, III, and IV. The percentages shown for each assessment reflect the difference between ibuprofen and placebo. Values marked with a circle are significantly different (p < 0.05) compared with placebo. PDT, pain detection threshold; PTT, pain tolerance threshold