Evaluation of Pupillometry for CYP2D6 Phenotyping in Children Treated with Tramadol

Abstract

Following the contraindication of codeine use in children, increasing use of tramadol has been observed in pain management protocols. However, tramadol's pharmacokinetics (PK) and pharmacodynamics are influenced by cytochrome P450 (CYP)2D6 activity, similarly to codeine. Previous studies in adults have demonstrated a correlation between pupillary response and tramadol PK. Our objective was to evaluate pupillometry as a phenotyping method to assess CYP2D6 activity in children treated with tramadol. We included 41 children (mean age 11 years) receiving a first dose of tramadol (2 mg/kg) in the emergency room (ER) as part of their routine care. CYP2D6 phenotyping and genotyping were performed. The concentrations of tramadol and its active metabolite, M1, were measured, and static and dynamic pupillometry was conducted using a handheld pupillometer at the time of tramadol administration and during the ER stay. Pupillometric measurements were obtained for 37 children. Tramadol affected pupillary parameters, with a decrease in pupil diameter in 83.8% of children (p = 0.002) (mean decrease 14.1 ± 16.7%) and a decrease in reflex amplitude constriction in 78.4% (p = 0.011) (mean decrease 17.7 ± 34.5%) at T150 compared to T0. We were unable to identify a correlation between pupillometry measurements and CYP2D6 activity. Likely confounding factors include light intensity, pain, and stress, making the procedure less feasible in paediatric emergency settings.

Keywords: CYP2D6; children; genotyping; pharmacogenomics; phenotyping; tramadol.

Figure 1

Study flowcharts for primary (a) and secondary (b) outcomes.

Figure 2

Distribution of dextrorphan-to-dextromethorphan metabolic ratio (DOR/DEM MR) for each predicted phenotype (a) and each assigned activity score (AS) based on the genotype (b), according to Caudle et al. [62]. DOR/DEM, dextrorphan to dextromethorphan; MR, metabolic ratio; PM, poor metaboliser; IM, intermediate metaboliser; NM, normal metaboliser; UM, ultrarapid metaboliser. Boxes indicate the interquartile ranges; dots represent observations, and crosses denote mean values.

Figure 2

Distribution of dextrorphan-to-dextromethorphan metabolic ratio (DOR/DEM MR) for each predicted phenotype (a) and each assigned activity score (AS) based on the genotype (b), according to Caudle et al. [62]. DOR/DEM, dextrorphan to dextromethorphan; MR, metabolic ratio; PM, poor metaboliser; IM, intermediate metaboliser; NM, normal metaboliser; UM, ultrarapid metaboliser. Boxes indicate the interquartile ranges; dots represent observations, and crosses denote mean values.

Figure 3

Distribution of O-desmethyltramadol (M1)/tramadol metabolic ratio (MR) for each predicted phenotype (a) and each assigned activity score (AS) based on the genotype (b), according to Caudle et al. [62]. M1, O-desmethyltramadol; MR, metabolic ratio; PM, poor metaboliser; IM, intermediate metaboliser; NM, normal metaboliser; UM, ultrarapid metaboliser. Boxes indicate the interquartile ranges; dots represent observations, and crosses denote mean values.