27 Can pupillometry be used for CYP2D6 phenotyping in children treated with tramadol?

Introduction Following the contraindication of codeine use in children, an increase in the use of tramadol has been observed in pain management protocols. However, tramadol PK/PD are also influenced by CYP2D6 activity. Genotyping and phenotyping are available to assess CYP2D6 activity and guide tramadol dosing. In adults, a correlation between pupillary response and tramadol pharmacokinetics has been demonstrated. Our objective was to evaluate pupillometry as a phenotyping method to determine CYP2D6 activity in children treated with tramadol. Method We included children receiving their first dose of tramadol (2 mg/kg) in the emergency department (ED) of the Geneva Children's hospital as part of their routine care. Children with concomitant treatment with inhibitors of CYP2D6 and inhibitors/inducers of CYP3A and/or with drug with a known impact on pupillary diameter (PD) were excluded. Standard CYP2D6 phenotyping was performed by measuring blood dextrorphan/dextromethorphan metabolic ratio (DOR/DEM MR) and genotyping. Tramadol and its active metabolite, M1, concentrations were measured by LC-MS/MS. Static and dynamic pupillometry were performed with a hand-held pupillometer at the time of tramadol administration and once to twice per hour, during the ED stay . We studied the correlation between M1 concentration, DOR/DEM MR and difference in static and dynamic pupil measurements between T0 and T150. Results Of the 41 children included (mean age 11 years), 37 had interpretable pupillometric measurements. An effect of the tramadol administration on the static pupil diameter (PD) as well as the pupillary light reflex were observed with 83.8% of children showing a decrease in PD (p = 0.002) and 78.4% showing a decrease in reflex amplitude (p= 0.011) at T150 compared to T0, respectively. No other correlation could be identified. Conclusion As expected, tramadol affects pupillary parameters. However, under the real-life conditions of our study, we could not identify any correlation between pupillometry measurements and CYP2D6 activity due to probable confounding factors such as light intensity, pain intensity and stress. Our study confirmed that the pupillometer is safe and well tolerated by children and easy to use by caregivers. Further studies with a higher level of standardization, especially controlled and stable light conditions, are needed to test its use as a reliable phenotyping method.