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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified February 2009 by University of Southern Denmark.
Recruitment status was  Active, not recruiting
Sponsor:
Information provided by:
University of Southern Denmark
ClinicalTrials.gov Identifier:
NCT00785603
First received: November 4, 2008
Last updated: February 12, 2009
Last verified: February 2009
  Purpose

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.


Condition Intervention Phase
Depression
Pain
Drug: Paroxetine
Drug: Paroxetin placebo
Drug: Tramadol
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Paroxetines Effect on Tramadols Metabolism and Pharmakodynamics: a Dose Response Study

Resource links provided by NLM:


Further study details as provided by University of Southern Denmark:

Primary Outcome 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • MR-ratio [ Time Frame: 8 hours ] [ Designated as safety issue: No ]

Enrollment: 12
Study Start Date: August 2008
Estimated Study Completion Date: February 2009
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Paroxetine
    tablets of 20 mg paroxetine
    Other Name: Paroxetin, copyfarm
    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
    Other Name: Nobligan
Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00785603

Sponsors and Collaborators
University of Southern Denmark
Investigators
Principal Investigator: Anette Green Nielsen, Stud. pharm Institut of Public Health
  More Information

No publications provided

Responsible Party: Kim Brøsen/ dr. med, Institut of Public Health
ClinicalTrials.gov Identifier: NCT00785603     History of Changes
Other Study ID Numbers: AKF-374
Study First Received: November 4, 2008
Last Updated: February 12, 2009
Health Authority: Denmark: The Regional Committee on Biomedical Research Ethics

Keywords provided by University of Southern Denmark:
Depression
pain
CYP2D6
interactions
Pupillometry
Tramadol
Paroxetine
MR-ratio

Additional relevant MeSH terms:
Depression
Depressive Disorder
Behavioral Symptoms
Mood Disorders
Mental Disorders
Tramadol
Paroxetine
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Serotonin Agents
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs

ClinicalTrials.gov processed this record on September 22, 2014