DepressionPhase 4NCT00785603
Paroxetines Effect on Tramadols Metabolism and Pharmakodynamics: a Dose Response Study
A Phase 4 study testing Paroxetine and Tramadol in people with Depression and Pain, run by University of Southern Denmark.
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. Read more about this study
- Who is it for?
- Ages 18 to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Depression, Pain
- What is being tested?
- Paroxetine and Tramadol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12 participants
- Where
- No sites listed yet
- Study dates
- Aug 2008to Feb 2009
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Who cannot join
- 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
About this 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.
Read more
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.
Read the 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.
- Conditions
- Depression, Pain
- Being tested
- Paroxetine, Paroxetin placebo, Tramadol
- Keywords
- Depression, pain, CYP2D6, interactions, Pupillometry, Tramadol, Paroxetine, MR-ratio
- Medical subject headings
- Depression, Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ParoxetineDrug
Also called Paroxetin, copyfarm
tablets of 20 mg paroxetine
Paroxetin placeboDrug
capsules with lactulose to hide, whether the volunteer are receiving 0, 10, 20, 30 or 50 mg paroxetine
TramadolDrug
Also called Nobligan
Capsules of 50 mg tramadol
What is being measured
The primary outcome is the main question the study is designed to answer.
Primary endpoint Pupil measurements Min. diameter mm Reduktion % Latenstime s Maks. constriktions velocity mm/s constriktions velocity mm/s Dilatation velocity mm/s
Measured: 3 hours
Secondary outcomes (1)
MR-ratio
Measured: 8 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Nov 2008 (estimated)
- Study startAug 2008
- Primary completionAug 2008
- Study completionFeb 2009 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for DepressionStudies of the same condition, open and under way.
- More trials run by University of Southern DenmarkThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Southern Denmark
- Sponsor type
- University, hospital or other
- Investigators
- Anette Green Nielsen, Stud. pharm, Principal investigator, Institut of Public Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00785603
- Sponsor's protocol ID
- AKF-374
- Status last verified
- Feb 2009
- First submitted
- 4 Nov 2008
- Last updated
- 13 Feb 2009
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 13 Feb 2009. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Paroxetines Effect on Tramadols Metabolism and Pharmakodynamics: a Dose Response Study
- ClinicalTrials.gov ID
- NCT00785603
- Acronym / sponsor ID
- AKF-374
- Conditions
- Depression, Pain
- Keywords
- Depression, pain, CYP2D6, interactions, Pupillometry, Tramadol, Paroxetine, MR-ratio
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 12 participants (actual)
- Lead sponsor
- University of Southern DenmarkUniversity, hospital or other
- Study start
- Aug 2008
- Primary completion
- Aug 2008 (actual)
- Study completion
- Feb 2009 (estimated)
- First posted
- 5 Nov 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (4 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ParoxetineAlso: Paroxetin, copyfarmtablets of 20 mg paroxetine | Drug | – |
| Paroxetin placebocapsules with lactulose to hide, whether the volunteer are receiving 0, 10, 20, 30 or 50 mg paroxetine | Drug | – |
| TramadolAlso: NobliganCapsules of 50 mg tramadol | Drug | – |
Primary outcome
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
1 secondary outcome
MR-ratio
Time frame: 8 hours
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Feb 2009.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Anette Green Nielsen, Stud. pharm principal investigator
Institut of Public Health
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Paroxetine and Tramadol in people with Depression and Pain, run by University of Southern Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 13 Feb 2009. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Feb 2009.