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.

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Pharmacodynamic Effects of VX-150, a Highly Selective NaV1.8 Inhibitor, in Healthy Male Adults

“…Rather, the integral combination of evoked pain models is used to profile the analgesic effects and magnitude of observed effects for each compound specifically. This allows for benchmarking of tested drugs, as briefly touched upon in the Introduction, as discussed in more detail previously [ 19 , 26 ], and as discussed in the last paragraph of the Discussion.…”

“…Unadjusted multiple testing was performed to assess VX-150’s temporal effect (primary analysis, Table 2 ) and the size of its total analgesic effect ( Table 3 ). Although we acknowledge the increased risk of reporting erroneous inferences, the effect size analysis was performed as an add-on to allow for comparing the study results presented here with the results of other studies in which the same pain test battery was used [ 19 , 20 , 26 , 63 ]. This was deemed reasonable given the experimental nature of the study.…”

“…The sample size of 20 subjects was chosen on the basis of known variability in the cold pressor and capsaicin pharmacodynamic assessments [ 19 , 26 ] and was considered sufficient to meet the objectives of the study. For a one-sided significance level of 0.05, there was at least 80% power to detect a standard effect size of 0.6.…”

“…The effect size calculation was performed post hoc to compare the study results with results of previous studies that had used the same pain test battery at an exploratory level [ 19 , 20 , 26 ]. All statistical inferences and P values were also exploratory.…”

Sweet taste does not modulate pain perception in adult humans

“…Different models of pain and hyperalgesia are sensitive to modulation by specific classes of exogenous analgesics (e.g. opioids, NMDA receptor antagonists 37 , 38 ). The modality of pain sensation affected by sucrose or hedonic consumption is therefore likely to depend on the mechanism of endogenous analgesia.…”