Abstract
The purpose of the study was to investigate placebo and buprenorphine effects on event-related potentials (ERPs) in experimental pain and the potential benefit of population pharmacodynamic modelling in data analysis. Nineteen healthy volunteers received transdermal placebo and buprenorphine in a cross-over study. Drug plasma concentrations and ERPs after electrical stimulation at the median nerve with intensity adjusted to pain detection threshold were recorded until 144 hrs after administration. Placebo and concentration-effect models were fitted to data using non-linear mixed-effects modelling implemented in NONMEM (V7.2.0.). Pharmacodynamic models were developed to adequately describe both placebo and buprenorphine ERP data. Models predicted significant placebo effects, but did not predict significant effects related to buprenorphine concentration. Models revealed that ERPs varied both between subjects and between study occasions. ERPs were found to be reproducible within subjects and occasions as population variance was found to be eight times higher than the unexplained variances. Between-subject variance accounted for more than 75% of the population variance. In conclusion, pharmacodynamic modelling was successfully implemented to allow for placebo and variability correction in ERP of experimental pain. Improved outcome of ERP studies can be expected if variation between subjects and study occasions can be identified and described.
Highlights
The purpose of the study was to investigate placebo and buprenorphine effects on event-related potentials (ERPs) in experimental pain and the potential benefit of population pharmacodynamic modelling in data analysis
This allows for the description and explanation of the variability, such as between-subject variabilities (BSV) and between-occasion variabilities (BOV) that can be essential to the evaluation of effects [13]
Pharmacokinetic and pharmacodynamic modelling of psychophysical assessments and different experimental pain models for the study have been published in a complimentary paper [15], and an advanced quantification method of ERP has been published on data [16]
Summary
The purpose of the study was to investigate placebo and buprenorphine effects on event-related potentials (ERPs) in experimental pain and the potential benefit of population pharmacodynamic modelling in data analysis. Pharmacodynamic non-linear mixed-effects modelling is a technique that allows for mathematical descriptions of placebo effects and drug effects related to plasma concentration and is applicable to studies of pain and analgesics, both across the population and in the individual subjects [11,12]. This allows for the description and explanation of the variability, such as between-subject variabilities (BSV) and between-occasion variabilities (BOV) that can be essential to the evaluation of effects [13]. This was done using a na€ıve pooled data approach that did not take into account BSV, BOV or placebo effects
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