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Metabolites of Tramadol in the Postoperative Surgical Patients (METRAS)

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ClinicalTrials.gov Identifier: NCT04004481
Recruitment Status : Recruiting
First Posted : July 2, 2019
Last Update Posted : July 2, 2019
Sponsor:
Collaborator:
Josip Juraj Strossmayer University of Osijek
Information provided by (Responsible Party):
Osijek University Hospital

Brief Summary:
Tramadol is opioid analgesic widely used to treat moderate to severe pain. It is metabolized by cytochrome CYP2D6 into two major metabolites: pharmacologically active metabolite O-desmethyltramadol (M1) and inactive N-desmethyltramadol (M2), respectively. Tramadol kinetics in a population of patients undergoing major abdominal surgical procedures, and in patients with a greater or lesser degree of organic failure, is still not well researched. The investigators will measure plasma concentrations of tramadol and its metabolites after usual tramadol doses in ICU patients after major abdominal surgery. Also analgesic affect and side effect of tramadol will be recorded.

Condition or disease Intervention/treatment
Abdominal Surgery Respiratory Failure Renal Failure Liver Dysfunction Multiorgan Failure Drug: Postoperative analgesia using tramadol

Detailed Description:

The blood samples for the CYP2D6 gene polymorphism analysis will be taken from all patients included in the study. The patients will be categorized as slow (PM), normal (NM) or ultra-fast metabolizers (UM) of tramadol using analysis of the CYP2D6 phenotype. Standard laboratory findings including red blood cells, urea, creatinine, and cholinesterase will be done before surgery.

The patients will receive 500 mg of tramadol intravenously divided into 5 doses during the first 32 postoperative hours in the ICU. The plasma concentrations of tramadol, O-desmethyltramadol and N-desmethyltramadol will be measured 1, 2 and 4 hours after the first dose, and immediately before the 2nd, 3rd and 5th dose. There will therefore be 6 measurements of tramadol and its metabolites.

The analgesic effect of tramadol will be measured in awake patients with Numeric Rating Scale - NRS (0 - without pain, 10 - strong pain) 30 minutes before and 30 minutes after tramadol administration. The NRS value of 3 or less will be considered as adequate analgesia. In case of inadequate analgesia rescue analgesic (morphine) will be used according to the local protocol.

In unconscious patients the analgesic effect of tramadol will be tested by Critical Care Pain Observation Tool (CPOT). The CPOT value of less than 2 will be considered as adequate analgesia. In case of inadequate analgesia rescue analgesic (morphine) will be used according to the local protocol. During the first 32 hours side effect of tramadol, such as nausea, vomiting and new respiratory depression will be recorded.


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Study Type : Observational
Estimated Enrollment : 60 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Metabolites of Tramadol in the Postoperative Surgical Patients Admitted in the ICU
Actual Study Start Date : January 25, 2019
Estimated Primary Completion Date : February 28, 2020
Estimated Study Completion Date : April 30, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Tramadol

Group/Cohort Intervention/treatment
Adult patients undergoing major open abdominal surgery
Observational study. In the patients undergoing major open abdominal surgery for cancer tramadol will be used for postoperative analgesia. In the postoperative period parent compound and metabolites of tramadol will be measured. Postoperative analgesia and adverse effects will be registered and compared between CYP2D6 phenotypes observed.
Drug: Postoperative analgesia using tramadol
Tramadol 100 mg will be given to the patients in the postoperative period.
Other Name: Morphine for rescue analgesia




Primary Outcome Measures :
  1. Serum concentration of tramadol and tramadol metabolites [ Time Frame: 32 hours ]
    The plasma concentrations of tramadol (µg/L), O-desmethyltramadol (µg/L) and N-desmethyltramadol (µg/L) will be measured 1, 2 and 4 hours after the first dose of 100 mg tramadol i.v., and immediately before the 2nd, 3rd and 5th dose. There will therefore be 6 measurements of tramadol and its metabolites.


Secondary Outcome Measures :
  1. Analgesic effect of tramadol measured by Numeric Rating Scale (NRS) [ Time Frame: 32 hours ]
    The analgesic effect of tramadol will be measured in awake patients with Numeric Rating Scale (NRS, 0 - without pain, 10 - the worst pain) 30 minutes before and 30 minutes after tramadol administration. The NRS value of 3 or less will be considered as adequate analgesia. In case of inadequate analgesia morphine will be used according to the local protocol.

  2. Analgesic effect of tramadol measured by Critical Care Pain Observation Tool (CPOT) [ Time Frame: 32 hours ]
    In unconsciousness patents, the analgesic effect of tramadol will be tested by Critical Care Pain Observation Tool (CPOT). The CPOT value of less than 2 will be considered as adequate analgesia.

  3. Incidence of nausea and vomiting after tramadol [ Time Frame: 32 hours ]
    Nausea and vomiting during treatment with tramadol in ICU will be recorded.

  4. Incidence of onset of respiratory depression after tramadol [ Time Frame: 32 hours ]
    Respiratory depression after tramadol is considered to be any drop in saturation below 90% or drop in respiratory rate below 10/min.

  5. Length of ICU stay [ Time Frame: Up to 6 months ]
    Length of stay in ICU will be recorded and correlated with standard laboratory values and tramadol and metabolites concentration.


Biospecimen Retention:   Samples With DNA
CYP2D6 polymorphism will be done from DNA isolated from white cells.


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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
The patients undergoing major open abdominal cancer surgery in Osijek University Hospital who are admitted in the ICU after surgery, age between 18 and 90 years, BMI >18 and <35, who signed the informed consent will be included in the study.
Criteria

Inclusion Criteria:

  • patients after major abdominal surgery will be observed.
  • surgical interventions requiring a laparotomy and involving resection of the organs of the digestive system
  • postoperative ICU admission.

Exclusion Criteria:

  • allergic reaction to tramadol
  • patients under 18 years old
  • patient over 90 years old
  • BMI <18 and >35
  • laparoscopic surgery
  • chronic therapy with tramadol, cimetidine, paroxetine, pimozide, metoclopramide, amiodarone, olanzapine, chlorpromazine, fluphenazine, haloperidol, thioridazine, risperidone and clozapine

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04004481


Contacts
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Contact: Nenad Neskovic, MD +385996787250 nneskov@gmail.com
Contact: Slavica Kvolik, Prof +38531511502 slavica.kvolik@gmail.com

Locations
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Croatia
University Hospital Osijek Recruiting
Osijek, Croatia, 31000
Contact: Nenad Nešković, MD    +385996787250    nneskov@gmail.com   
Contact: Slavica Kvolik, PhD    +38598723925    slavica.kvolik@gmail.com   
Sponsors and Collaborators
Osijek University Hospital
Josip Juraj Strossmayer University of Osijek
Investigators
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Principal Investigator: Nenad Neskovic, MD Osijek University Hospital

Publications:

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Responsible Party: Osijek University Hospital
ClinicalTrials.gov Identifier: NCT04004481     History of Changes
Other Study ID Numbers: OsijekUH
First Posted: July 2, 2019    Key Record Dates
Last Update Posted: July 2, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Osijek University Hospital:
Tramadol
CYP2D6 polymorphism
analgesia
intensive care
organ failure
Additional relevant MeSH terms:
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Tramadol
Liver Diseases
Respiratory Insufficiency
Multiple Organ Failure
Respiration Disorders
Respiratory Tract Diseases
Digestive System Diseases
Shock
Pathologic Processes
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents