Metabolites of Tramadol in the Postoperative Surgical Patients

Respiratory Failure Clinical Trial

— METRAS  

Official title:

Metabolites of Tramadol in the Postoperative Surgical Patients Admitted in the ICU

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04004481
• Other study ID #: OsijekUH
• Status: Completed
• Start date: January 25, 2019
• Est. completion date: March 13, 2020

Study information

• Verified date: June 2021
• Source: Osijek University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: March 13, 2020
• Est. primary completion date: February 28, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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

Related Conditions & MeSH terms

• Abdominal Surgery
• Liver Diseases
• Liver Dysfunction
• Multiorgan Failure
• Multiple Organ Failure
• Renal Failure
• Respiratory Failure
• Respiratory Insufficiency

Intervention

Drug:
• Postoperative analgesia using tramadol
Tramadol 100 mg will be given to the patients in the postoperative period.

Locations

Country	Name	City	State
Croatia	University Hospital Osijek	Osijek

Sponsors (2)

Lead Sponsor	Collaborator
Osijek University Hospital	Josip Juraj Strossmayer University of Osijek

Country where clinical trial is conducted

Croatia, 

References & Publications (10)

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. — View Citation

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. — View Citation

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. — View Citation

Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Analgesic Effect of Tramadol Measured by Numeric Rating Scale (NRS)	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.	Before each dose of tramadol and 30 minutes after tramadol dose, up to 24 hours
Secondary	Analgesic Effect of Tramadol Measured by Critical Care Pain Observation Tool (CPOT)	In unconsciousness patents, the analgesic effect of tramadol will be tested by Critical Care Pain Observation Tool (CPOT). Highest score on a scale is 8 (worst pain) and lowest is 0 (no pain). The CPOT value of less than 2 will be considered as adequate analgesia.	Pain was assessed before and 30 minutes after each tramadol dose, up to 24 hours.
Secondary	Number of Participants With Nausea and Vomiting After Tramadol	Nausea and/or vomiting during treatment with tramadol in ICU will be recorded.	Nausea and vomiting was assessed during first 30 minutes after tramadol administration
Secondary	Number of Patients With Respiratory Depression After Tramadol	Respiratory depression after tramadol is considered to be any drop in saturation below 90% or drop in respiratory rate below 10/min.	Respiratory depression was observed up to 30 minutes after tramadol administration
Secondary	Length of ICU Stay	Length of stay in ICU will be recorded and correlated with standard laboratory values and tramadol and metabolites concentration.	Up to 6 months