Modeling the Influence of the A118G Polymorphism in the OPRM1 Gene and of Noxious Stimulation on the Synergistic Relation between Propofol and Remifentanil

Abstract

Background:The presence of the A118G single nucleotide polymorphism in the OPRM1 gene as well as noxious stimulation might affect the requirements of remifentanil for patients undergoing ultrasonographic endoscopy under sedation-analgesia with propofol and remifentanil. Bispectral index (BIS) was used as a surrogate measure of effect. Methods:A total of 207 patients were screened for A118G and randomly received different combinations of propofol and remifentanil, changed depending on the nausea response to endoscopy tube introduction. Nonlinear mixed effects modelling was used to establish the relation between propofol and remifentanil with respect to BIS and to investigate the influence of A118G or noxious stimulation. The value of k e0 for propofol and remifentanil was estimated to avoid the hysteresis between predicted effect site concentration (Ce) and BIS. Results: Data from 176 patients were analysed. Eleven were recessive homozygous for A118G (OPRM = 1). A total of 165 patients were either dominant homozygous or heterozygous and considered normal (OPRM = 0). The estimated values of k e0 for propofol and remifentanil were 0.122 and 0.148 min −1 . Propofol and remifentanil were synergistic with respect to the BIS (α = 1.85). EC 50 estimate for propofol was 3.86 µg/ml and for remifentanil 19.6 ng/ml in normal patients and 326 ng/ml in OPRM = 1 patients. BIS increases around 4% for the same effect site concentrations with noxious stimulation. Conclusions: Predicted effect site concentration of remifentanil ranging 1-5 ng/ml synergistically potentiates the effects

Modeling Respiratory Depression Induced by Remifentanil and Propofol during Sedation and Analgesia Using a Continuous Noninvasive Measurement of pCO2

“…All participants gave written, informed consent before being enrolled in the project. The data were a subset of a larger study in which the influence of the A118G SNP genotype on opioid requirements during sedation for endoscopy was investigated (Borrat et al, 2013). Study methods are described in brief, and have been reported in detail previously (Borrat et al, 2013).…”

“…A model has previously been reported for the effects of propofol and remifentanil on bispectral index (BIS) in patients undergoing endoscopy under sedation and analgesia (Borrat et al, 2013). In that study, the effect of noxious stimulation on BIS was quantified, and the influence of the A118G single nucleotide polymorphism (SNP) of the OPRM1 gene (which encodes the m-opioid receptor) on remifentanil potency was investigated.…”

Impact of A118G Polymorphism on the Mu Opioid Receptor Function in Pain

“…In opposition, several reports failed to find the same correlations [35,[40][41][42]. On the other hand the G allele has been related to lower sedative effect by the synergic interaction between two opioid derived drugs, propofol and remifentanilfadil, used as anesthetics in surgeries [43].…”

Comparison of the qCON and qNOX indices for the assessment of unconsciousness level and noxious stimulation response during surgery

“…In this way, since the qNOX showed higher fall times than qCON, it can be assumed that qNOX is more accurate for detecting the effects in EEG induced by opioid analgesic drugs. The plasma-effect site equilibration for BIS has been recently calculated to be approximately 5.6 min [34]. However, there is evidence to suggest that BIS values do not reflect all components of anaesthesia [38] , since opioids do not produce the basic anaesthesia-related EEG pattern.…”

“…The present work shows consistent results with all these studies, obtaining a fall of the qCON under 65 between 2 and 4 min after drug induction. Even though, it would be interesting to estimate the value of k e0 optimized for qCON as it was done for BIS elsewhere [34].…”