Metabolites of Tramadol in the Postoperative Surgical Patients

NCT04004481 | Completed Results

• 1 other identifier: OsijekUH
• Study Type: observational
• Target: 50
• Locations: 1 country
• Sites: 1

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.

Conditions

Abdominal Surgery; Respiratory Failure; Renal Failure; Liver Dysfunction; Multiorgan Failure

Keywords

Tramadol; CYP2D6 polymorphism; analgesia; intensive care; organ failure

Outcome Measures

Primary Outcomes (1)

• Serum Concentration of Tramadol and Tramadol Metabolites With Respect to Metabolic Phenotype

  The plasma concentrations of tramadol, O-desmethyltramadol (ODT) and N-desmethyltramadol (NDT) 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.

  1, 2, and 4 hours after first dose and immediately before 2nd, 3rd, and 5th dose, up to 24 hours

Secondary Outcomes (5)

• Analgesic Effect of Tramadol Measured by Numeric Rating Scale (NRS)

  Before each dose of tramadol and 30 minutes after tramadol dose, up to 24 hours

• Analgesic Effect of Tramadol Measured by Critical Care Pain Observation Tool (CPOT)

  Pain was assessed before and 30 minutes after each tramadol dose, up to 24 hours.

• Number of Participants With Nausea and Vomiting After Tramadol

  Nausea and vomiting was assessed during first 30 minutes after tramadol administration

• Number of Patients With Respiratory Depression After Tramadol

  Respiratory depression was observed up to 30 minutes after tramadol administration

• Length of ICU Stay

  Up to 6 months

Study Arms (1)

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

Interventions

Postoperative analgesia using tramadol DRUG

Tramadol 100 mg will be given to the patients in the postoperative period.

Also known as: Morphine for rescue analgesia

Adult patients undergoing major open abdominal surgery

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Osijek University Hospital: lead
• Josip Juraj Strossmayer University of Osijek: collaborator

Study Sites (1)

University Hospital Osijek

Osijek, 31000, Croatia

Location

Related Publications (11)

• 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.

  PMID: 28470112 BACKGROUND

• 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.

  PMID: 26602992 BACKGROUND

• Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. doi: 10.2165/00003088-200443130-00004.

  PMID: 15509185 BACKGROUND

• 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.

  PMID: 26947771 BACKGROUND

• 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.

  PMID: 24640604 BACKGROUND

• 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. doi: 10.1038/sj.clpt.6100152. Epub 2007 Mar 14.

  PMID: 17361124 BACKGROUND

• 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. doi: 10.1097/00000542-200503000-00011.

  PMID: 15731591 BACKGROUND

• 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.

  PMID: 22867045 BACKGROUND

• 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.

  PMID: 28800982 BACKGROUND

• 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. doi: 10.1186/s40560-016-0192-x. eCollection 2016.

  PMID: 27833752 BACKGROUND

• 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.

  PMID: 33935773 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

CYP2D6 polymorphism will be done from DNA isolated from white cells.

MeSH Terms

Conditions

Respiratory Insufficiency; Renal Insufficiency; Liver Diseases; Multiple Organ Failure; Agnosia

Interventions

Morphine

Condition Hierarchy (Ancestors)

Respiration Disorders; Respiratory Tract Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Digestive System Diseases; Shock; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Perceptual Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Results Point of Contact

• Title: Nenad Neskovic
• Organization: University hospital Osijek

nneskov@gmail.com

+385996787250

Study Officials

• Nenad Neskovic, MD

  Osijek University Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 25, 2019
• First Posted: July 2, 2019
• Study Start: January 25, 2019
• Primary Completion: February 28, 2020
• Study Completion: March 13, 2020
• Last Updated: July 9, 2021
• Results First Posted: July 9, 2021

Record last verified: 2021-06

Locations

CR (1)