Paroxetines Effect on Tramadols Metabolism and Pharmakodynamics: a Dose Response Study

Depression Clinical Trial

Official title: Paroxetines Effect on Tramadols Metabolism and Pharmakodynamics: a Dose Response Study

Status Active, not recruiting

Clinical Trial Summary

The purpose of the study is to examine the connection between the dose of paroxetine and the effect of paroxetine on tramadols metabolism and thereby the effect of tramadol on the median pupil size.

In the study 12 healthy volunteers are going through 5 phases where they are suppose to consume a determined dose of tramadol and 5 various doses of paroxetine corresponding to the 5 phases. Fig 1.

phases 1 2 3 4 5 Dosis Tramadol mg 50 50 50 50 50 Dosis Paroxetine mg Placebo 10 20 30 50 Paroxetin / placebo 2 ½ placebo 2 placebo 1 ½ placebo 1 placebo tablets ½ paroxetine 1 paroxetine 1 ½ paroxetine 2 ½ paroxetine Fig. 1 summary of the 5 phases

There is a variation in the time where maximal plasma concentration is obtained in consumption of respectively tramadol (1 - 2 hours) and paroxetine (6 hours). For that reason there has to be at least 6 hours between the administration of paroxetine and tramadol.

The healthy volunteer brings the research medicine home and consumes it before bedtime the night before the day of the study. At eight o'clock next morning the healthy volunteer arrives to the first pupil measurement and consumption of tramadol. Tree hours later the next pupil measurement is carried through. The healthy volunteer accumulates his or her urine until 2 pm. As paroxetine is a irreversible inhibitor of the enzyme CYP2D6 there has to go at least 14 days before the next phase takes place. In that amount of time there can be recreated a new pool of enzyme.

Clinical Trial Description

The purpose of the study is to examine the connection between the dose of paroxetine and the effect of paroxetine on tramadols metabolism and thereby the effect of tramadol on the median pupil size.

Tramadol is being metabolized in the liver to O-desmethyltramadol (M1) catalysed by the enzyme P450 CYP2D6 and to N-desmethyltramadol (M2). Tramadol is a racemic mixture of the two enantiomers (+)-tramadol hydrochlorid and (-)-tramadol hydrochlorid and therefore there is formed two enantiomer metabolits, (+)-M1 and (-)-M1. The (+)-M1 has a much higher affinity fore the human opioid µ-receptor compared to (+)-tramadol, (-)-tramadol and (-)-M1.

Paroxetine is a very potent inhibitor of the enzyme CYP2D6 and when there is contemporary administration of paroxetine and tramadol the formation of the active metabolit (+)-M1 will be inhibited. The patient will experience a poorer analgesic effect of tramadol.

It is also the effect of (+)-M1 on the opioid µ-receptor than results in the contracted pupils and that is why it can be shown how potent paroxetine inhibits the enzyme CYP2D6 by measuring the median pupil size.

In the study 12 healthy volunteers are going through 5 phases where they are suppose to consume a determined dose of tramadol and 5 various doses of paroxetine corresponding to the 5 phases. Fig 1.

phases 1 2 3 4 5 Dosis Tramadol mg 50 50 50 50 50 Dosis Paroxetine mg Placebo 10 20 30 50 Paroxetin / placebo 2 ½ placebo 2 placebo 1 ½ placebo 1 placebo tablets ½ paroxetine 1 paroxetine 1 ½ paroxetine 2 ½ paroxetine Fig. 1 summary of the 5 phases

There is a variation in the time where maximal plasma concentration is obtained in consumption of respectively tramadol (1 - 2 hours) and paroxetine (6 hours). For that reason there has to be at least 6 hours between the administration of paroxetine and tramadol.

The healthy volunteer brings the research medicine home and consumes it before bedtime the night before the day of the study. At eight o'clock next morning the healthy volunteer arrives to the first pupil measurement and consumption of tramadol. Tree hours later the next pupil measurement is carried through. The healthy volunteer accumulates his or her urine until 2 pm. As paroxetine is a irreversible inhibitor of the enzyme CYP2D6 there has to go at least 14 days before the next phase takes place. In that amount of time there can be recreated a new pool of enzyme. ;

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Depression
• Pain

• NCT number: NCT00785603
• Study type: Interventional
• Source: University of Southern Denmark
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: August 2008
• Completion date: February 2009