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出境医 / 临床实验 / Metabolites of Tramadol in the Postoperative Surgical Patients (METRAS)

Metabolites of Tramadol in the Postoperative Surgical Patients (METRAS)

Study Description
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 24 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 24 hours side effect of tramadol, such as nausea, vomiting and new respiratory depression will be recorded.

Study Design
Layout table for study information
Study Type : Observational
Actual Enrollment : 50 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
Actual Primary Completion Date : February 28, 2020
Actual Study Completion Date : March 13, 2020
Arms and Interventions
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
Outcome Measures
Primary Outcome Measures :
  1. Serum concentration of tramadol and tramadol metabolites [ Time Frame: 24 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: 24 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: 24 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: 24 hours ]
    Nausea and vomiting during treatment with tramadol in ICU will be recorded.

  4. Incidence of onset of respiratory depression after tramadol [ Time Frame: 24 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.

Eligibility Criteria
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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
Contacts and Locations

Locations
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Croatia
University Hospital Osijek
Osijek, Croatia, 31000
Sponsors and Collaborators
Osijek University Hospital
Josip Juraj Strossmayer University of Osijek
Investigators
Layout table for investigator information
Principal Investigator: Nenad Neskovic, MD Osijek University Hospital
Tracking Information
First Submitted Date June 25, 2019
First Posted Date July 2, 2019
Last Update Posted Date March 17, 2020
Actual Study Start Date January 25, 2019
Actual Primary Completion Date February 28, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: December 19, 2019) 		Serum concentration of tramadol and tramadol metabolites [ Time Frame: 24 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.
Original Primary Outcome Measures
 (submitted: June 29, 2019) 		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.
Change History
Current Secondary Outcome Measures
 (submitted: December 19, 2019)
  • Analgesic effect of tramadol measured by Numeric Rating Scale (NRS) [ Time Frame: 24 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.
  • Analgesic effect of tramadol measured by Critical Care Pain Observation Tool (CPOT) [ Time Frame: 24 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.
  • Incidence of nausea and vomiting after tramadol [ Time Frame: 24 hours ]
    Nausea and vomiting during treatment with tramadol in ICU will be recorded.
  • Incidence of onset of respiratory depression after tramadol [ Time Frame: 24 hours ]
    Respiratory depression after tramadol is considered to be any drop in saturation below 90% or drop in respiratory rate below 10/min.
  • 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.
Original Secondary Outcome Measures
 (submitted: June 29, 2019)
  • 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.
  • 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.
  • Incidence of nausea and vomiting after tramadol [ Time Frame: 32 hours ]
    Nausea and vomiting during treatment with tramadol in ICU will be recorded.
  • 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.
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Metabolites of Tramadol in the Postoperative Surgical Patients
Official Title Metabolites of Tramadol in the Postoperative Surgical Patients Admitted in the ICU
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.
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 24 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 24 hours side effect of tramadol, such as nausea, vomiting and new respiratory depression will be recorded.
Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
CYP2D6 polymorphism will be done from DNA isolated from white cells.
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.
Condition
  • Abdominal Surgery
  • Respiratory Failure
  • Renal Failure
  • Liver Dysfunction
  • Multiorgan Failure
Intervention Drug: Postoperative analgesia using tramadol
Tramadol 100 mg will be given to the patients in the postoperative period.
Other Name: Morphine for rescue analgesia
Study Groups/Cohorts 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.
Intervention: Drug: Postoperative analgesia using tramadol
Publications *
  • Yang Y, Botton MR, Scott ER, Scott SA. Sequencing the CYP2D6 gene: from variant allele discovery to clinical pharmacogenetic testing. Pharmacogenomics. 2017 May;18(7):673-685. doi: 10.2217/pgs-2017-0033. Epub 2017 May 4. Review.
  • Qiao W, Yang Y, Sebra R, Mendiratta G, Gaedigk A, Desnick RJ, Scott SA. Long-Read Single Molecule Real-Time Full Gene Sequencing of Cytochrome P450-2D6. Hum Mutat. 2016 Mar;37(3):315-23. doi: 10.1002/humu.22936. Epub 2015 Dec 18.
  • Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. Review.
  • de Moraes NV, Lauretti GR, Coelho EB, Godoy AL, Neves DV, Lanchote VL. Impact of fraction unbound, CYP3A, and CYP2D6 in vivo activities, and other potential covariates to the clearance of tramadol enantiomers in patients with neuropathic pain. Fundam Clin Pharmacol. 2016 Apr;30(2):153-61. doi: 10.1111/fcp.12168. Epub 2015 Dec 11.
  • Xu J, Zhang XC, Lv XQ, Xu YY, Wang GX, Jiang B, Cai L, Cai XJ. Effect of the cytochrome P450 2D6*10 genotype on the pharmacokinetics of tramadol in post-operative patients. Pharmazie. 2014 Feb;69(2):138-41.
  • Stamer UM, Musshoff F, Kobilay M, Madea B, Hoeft A, Stuber F. Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther. 2007 Jul;82(1):41-7. Epub 2007 Mar 14.
  • Candiotti KA, Birnbach DJ, Lubarsky DA, Nhuch F, Kamat A, Koch WH, Nikoloff M, Wu L, Andrews D. The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology. 2005 Mar;102(3):543-9.
  • Bosilkovska M, Walder B, Besson M, Daali Y, Desmeules J. Analgesics in patients with hepatic impairment: pharmacology and clinical implications. Drugs. 2012 Aug 20;72(12):1645-69. doi: 10.2165/11635500-000000000-00000.
  • Rijkenberg S, Stilma W, Bosman RJ, van der Meer NJ, van der Voort PHJ. Pain Measurement in Mechanically Ventilated Patients After Cardiac Surgery: Comparison of the Behavioral Pain Scale (BPS) and the Critical-Care Pain Observation Tool (CPOT). J Cardiothorac Vasc Anesth. 2017 Aug;31(4):1227-1234. doi: 10.1053/j.jvca.2017.03.013. Epub 2017 Mar 15.
  • Severgnini P, Pelosi P, Contino E, Serafinelli E, Novario R, Chiaranda M. Accuracy of Critical Care Pain Observation Tool and Behavioral Pain Scale to assess pain in critically ill conscious and unconscious patients: prospective, observational study. J Intensive Care. 2016 Nov 7;4:68. eCollection 2016.
  • Neskovic N, Mandic D, Marczi S, Skiljic S, Kristek G, Vinkovic H, Mraovic B, Debeljak Z, Kvolik S. Different Pharmacokinetics of Tramadol, O-Demethyltramadol and N-Demethyltramadol in Postoperative Surgical Patients From Those Observed in Medical Patients. Front Pharmacol. 2021 Apr 15;12:656748. doi: 10.3389/fphar.2021.656748. eCollection 2021.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: March 14, 2020) 		50
Original Estimated Enrollment
 (submitted: June 29, 2019) 		60
Actual Study Completion Date March 13, 2020
Actual Primary Completion Date February 28, 2020   (Final data collection date for primary outcome measure)
Eligibility 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
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Croatia
Removed Location Countries  
 
Administrative Information
NCT Number NCT04004481
Other Study ID Numbers OsijekUH
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement
Plan to Share IPD: Undecided
Responsible Party Osijek University Hospital
Study Sponsor Osijek University Hospital
Collaborators Josip Juraj Strossmayer University of Osijek
Investigators
Principal Investigator: Nenad Neskovic, MD Osijek University Hospital
PRS Account Osijek University Hospital
Verification Date June 2019

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