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The effects of tramadol on static and dynamic pupillometry in healthy subjects-the relationship between pharmacodynamics, pharmacokinetics and CYP2D6 metaboliser status.

Fliegert F, Kurth B, Gohler K.

Department of Human Pharmacology, Research & Development, Grunenthal GmbH, 52099, Aachen, Germany, Frank.Fliegert@grunenthal.de.

OBJECTIVES: 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.

PMID: 15906019 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15906019&query_hl=2

Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol.

Laugesen S, Enggaard TP, Pedersen RS, Sindrup SH, Brosen K.

Institute of Public Health, Clinical Pharmacology, University of Southern Denmark.

OBJECTIVE: Tramadol hydrochloride (INN, tramadol) exerts its antinociceptive action through a monoaminergic effect mediated by the parent compound and an opioid effect mediated mainly by the O-demethylated metabolite (+)-M1. O-demethylation is catalyzed by cytochrome P450 (CYP) 2D6. Paroxetine is a very potent inhibitor of CYP2D6. The objective of this study was to investigate the influence of paroxetine pretreatment on the biotransformation and the hypoalgesic effect of tramadol. METHODS: With and without paroxetine pretreatment (20 mg daily for 3 consecutive days), the formation of M1 and the analgesic effect of 150 mg of tramadol were studied in 16 healthy extensive metabolizers of sparteine in a randomized, double-blind, placebo-controlled, 4-way crossover study by use of experimental pain models. RESULTS: With paroxetine pretreatment, the area under the plasma concentration-time curve (AUC) of (+)- and (-)-tramadol was increased (37% [P = .001] and 32% [P = .002], respectively), and the corresponding AUCs of(+)- and (-)-M1 were decreased (67% [P = .0004] and 40% [P = .0008], respectively). (+)-M1 and (-)-M1 could be determined in all subjects throughout the study period regardless of paroxetine pretreatment. The sums of differences between postmedication and premedication values of pain measures differed between the placebo/tramadol and the placebo/placebo combination, with median values as follows: pressure pain tolerance threshold, 390 kPa (95% confidence interval [CI], 211 to 637 kPa) versus -84 kPa (95% CI, - 492 to -32 kPa) (P = .001); single sural nerve stimulation pain tolerance threshold, 25.8 mA (95% CI, 15.3 to 29.8 mA) versus 9.0 mA (95% CI, 1.5 to 14.8 mA) (P = .005); pain summation threshold, 10.7 mA (95% CI, 5.2 to 17.6 mA) versus 5.0 mA (95% CI, 2.8 to 11.2 mA) (P = .066); cold pressor pain, -4.2 cm x s (95% CI, -6.8 to -1.9 cm x s) versus -0.4 cm x s (-1.4 to 1.4 cm x s) (P = .002); and discomfort, -4.7 cm (95% CI, -10.6 to -2.8 cm) versus 0.5 cm (-0.1 to 1.4 cm) (P = .002). The sums of differences of the paroxetine/tramadol combination also differed from placebo/tramadol for some of the measures, with median values as follows: cold pressor pain, -2.2 cm x s (95% CI, -3.7 to -0.4 cm x s) (P = .036, compared with placebo/tramadol); and discomfort, -2.0 cm (95% CI, -5.6 to -1.2 cm) (P = .056). For the other measures, the hypoalgesic effect was retained on the paroxetine/tramadol combination, with median values as follows: pressure pain tolerance threshold, 389 kPa (95% CI, 141 to 715 kPa) (P = .278, compared with placebo/tramadol); single sural nerve stimulation pain tolerance threshold, 12.5 mA (95% CI, 6.2 to 28.3 mA) (P = .278); and pain summation threshold, 8.2 mA (95% CI, 4.4 to 14.6 mA) (P = .179). Paroxetine in combination with placebo showed no analgesic effect. CONCLUSIONS: It is concluded that paroxetine at a dosage of 20 mg once daily for 3 consecutive days significantly inhibits the metabolism of tramadol to its active metabolite M1 and reduces but does not abolish the hypoalgesic effect of tramadol in human experimental pain models, particularly in opioid-sensitive tests.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15903129&query_hl=2