Official Title: “Paroxetines Effect on Tramadols Metabolism and Pharmakodynamics: a Dose Response Study”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Crossover Assignment, Pharmacodynamics Study

Study Primary Completion Date: August 2008

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.

Intervention(s) in this Clinical Trial

• Drug: Paroxetine
  • tablets of 20 mg paroxetine
• Drug: Paroxetin placebo
  • capsules with lactulose to hide, whether the volunteer are receiving 0, 10, 20, 30 or 50 mg paroxetine
• Drug: Tramadol
  • Capsules of 50 mg tramadol

Primary Measures

• Primary endpoint Pupil measurements Min. diameter mm Reduktion % Latenstime s Maks. constriktions velocity mm/s constriktions velocity mm/s Dilatation velocity mm/s
  • Time Frame: 3 hours
    Safety Issue?: No

Secondary Measures

• MR-ratio
  • Time Frame: 8 hours
    Safety Issue?: No

Inclusion Criteria:

• Healthy volunteers judged from the medical anamnesis and examination, inclusive a laboratory examination.
• Signed written approval and authorization, witch give relevant people (the GCP-unit, the the Danish Medicines Agency and the ethics committee of Southern Denmark) access to documents and data of interest to this study
• Age: 18 - 45 years
• Women must use one of the Danish Medicines Agency defined safe contraception. A negative pregnancy test has to ensure that the volunteers are not pregnant at the start of the study
• All the volunteers have to be phenotyped as CYP2D6 extensive metabolizer (EM) by a "tramadol test": the volunteer ingest 50 mg tramadol and all urine is collected fore 8 hours. By a HPLC method the metabolic ratio (MR) of (-)-M1/(+)-M1 is determined in the urine. Volunteers with a MR-ratio smaller than 2 is defined as CYP2D6 EM's

Exclusion Criteria:

• Any clinical significant observation at the medical- or laboratory examination
• Daily use of medicine or alcohol. Periodic use of medicine can be accepted after individual valuation by a doctor
• Allergy or intolerance to paroxetine or tramadol
• Former participation in a clinical study in the last 3 months

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 45 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: University of Southern Denmark

Overall Clinical Trial Officials and Contacts

Anette Green Nielsen, Stud. pharm Principal Investigator Institut of Public Health  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00785603

Study ID Number: AKF-374

ClinicalTrials.gov Identifier: NCT00785603

Health Authority: Denmark: The Regional Committee on Biomedical Research Ethics