title: The effects of tramadol on static and dynamic pupillometry in healthy subjects--the relationship between pharmacodynamics, pharmacokinetics and CYP2D6 metaboliser status.
abstract: OBJECTIVE
  The main objective of the present study was to provide information on whether static and dynamic pupillometry can be used for pharmacodynamic profiling, particularly when investigating opioid-like drugs, such as tramadol.
  
  
  METHODS
  Healthy subjects (n = 26) participated in this randomised, double-blind, placebo-controlled, crossover Phase 1 study. Of these, 20 extensive metabolisers (EMs) with respect to polymorphic isoenzyme cytochrome P450 2D6 (CYP2D6) received up to 150 mg of tramadol-HCl and placebo. The 6 poor metabolisers (PMs) with respect to CYP2D6 received 100 mg tramadol-HCl and placebo.
  
  
  RESULTS
  In EMs, serum concentrations of the enantiomers of tramadol and of O-demethylated metabolite (M1) increased with increasing doses. Comparing the 100-mg dose between EMs and PMs, the latter exhibited higher serum concentrations of both enantiomers of tramadol. Serum concentrations of (+)-M1 remained below the lower limit of quantification, and that of (-)-M1 were lower than those in EMs. In EMs, doses from 100 mg tramadol-HCl on induced a significant (P<0.05) miosis as compared with placebo. The maximum mean differences from placebo after dosing with 50, 100 and 150 mg tramadol-HCL were -0.5, -0.8 and -1.1 mm, respectively, indicating a dose-dependent character of the changes. Dynamic pupillometry revealed significant (P<0.05) effects for the amplitude, latency and duration of reaction. The amplitude and velocity of constriction were decreased only at the highest dose; whereas, the changes of the amplitude reached statistical significance (P<0.05). Both the latency and reaction duration behaved in a dose-dependent manner. For the latency, significant changes compared with placebo (P<0.05) were found at the 150-mg dose level, while the reaction duration was already significantly (P<0.05) decreased from the 100-mg dose on. The velocity of redilatation did not respond at all. In PMs, no effect on the initial pupil diameter was found. Although the statistical analysis failed to demonstrate any significant change from placebo for the dynamic pupillometry, the effect-time profiles of EMs and PMs were comparable. For both metaboliser groups, a decrease of amplitude, velocity of constriction and reaction duration as well as an increase of latency was observed. In principle, the direction and magnitude of changes were comparable between EMs and PMs. Most important was the finding that the time course of effects was completely different between both groups of metabolisers. In EMs, effects slowly reached a maximum between 4 h and 10 h after dosing and diminished until 24 h; whereas, in PMs, both maximum effects and the return to baseline occurred much earlier, at approximately 3 h and 8 h, respectively.
  
  
  CONCLUSIONS
  The EMs and PMs of CYP2D6 treated with tramadol behaved differently in static and dynamic pupillometry. The reason for this could largely be explained with the aid of the metaboliser status and the pharmacokinetic properties of tramadol. In EMs, the pupillometric response was mainly driven by the (+)-M1, which comprises the mu action component of tramadol; whereas, in PMs, the non-mu component appears to play an important role. Thus, pupillometry was found to be useful in pharmacodynamic profiling and provides a good correlation with the pharmacokinetics.
authors.affiliation: Department of Human Pharmacology, Research & Development, Grünenthal GmbH, 52099 Aachen, Germany. Frank.Fliegert@grunenthal.de
authors.forename: Frank
authors.initials: F
authors.lastname: Fliegert
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kurth
authors.forename: Karin
authors.initials: K
authors.lastname: Göhler
mesh_terms: D000701:Analgesics, Opioid / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D014644:Genetic Variation; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D011680:Pupil / Q000187:drug effects*; D013997:Time Factors; D014147:Tramadol / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6