The effects of tramadol on static and dynamic pupillometry in healthy subjects--the relationship between pharmacodynamics, pharmacokinetics and CYP2D6 metaboliser status (2004)

[Jatelka]

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Description:
Eur J Clin Pharmacol. 2005 Jun;61(4):257-66

Fliegert F, Kurth B, Göhler K.

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

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Reputation Comments on this post:

Proved useful, Thank you.

[delphinen]

Hope this clears why some people get really high on Tramadol after some hours and some people dont get high at all.

[radiometer]

Why is this so key with Tramadol? Is Tramadol a pro-drug?

[Paracelsus]

Yes, it is. This file contains a lot of information on its pharmacology.

[silentghost]

Is there any sure way to determine if one is EM or PM? Besides going to your doctor for a test.

[radiometer]

I'm pretty sure there are home tests one can purchase, presumably one takes a sample and sends it in to a lab.

Reputation Comments on this post:

ty for quick answer

[delphinen]

the best prove is try if you get high after 3 hours of 400mg of Tramadol, when the O-Desmethyl should be binding to your MU receptors thus giving you pleasure.

[silentghost]

Good point. The time of effects would hint at my enzyme's metabolism. Will try tonight.

Though SWIM can't handle 400mg all at once without nausea.

[Bajeda]

Originally Posted by delphinen

the best prove is try if you get high after 3 hours of 400mg of Tramadol, when the O-Desmethyl should be binding to your MU receptors thus giving you pleasure.

But you could be a rapid metaboliser also, plus I'm sure there is substantial variation in the rate of metabolism within the different classifications as well. Any exact figures like that are simply a mean value.

I think DXM would be a better litmus test, as poor metabolisers tend to experience the worst of the side effects. If DXM simply doesn't agree with your body at recreational doses, perhaps your are a poor metaboliser. I don't think any test you could do at home could conclusively identify you as one or the other.

[silentghost]

SWIM has very pleasant DXM experiences... Also his tramadol seems to kick in late and last a very long time, so he thinks he may be a decent metabolizer.

[delphinen]

Originally Posted by Bajeda

But you could be a rapid metaboliser also, plus I'm sure there is substantial variation in the rate of metabolism within the different classifications as well. Any exact figures like that are simply a mean value.

I think DXM would be a better litmus test, as poor metabolisers tend to experience the worst of the side effects. If DXM simply doesn't agree with your body at recreational doses, perhaps your are a poor metaboliser. I don't think any test you could do at home could conclusively identify you as one or the other.

True. SWIM gets very high on low doses of DXM too. SWIM gest to a second plateau with 300mg veery fast.