Metabolites of Tramadol in the Postoperative Surgical Patients

NCT ID: NCT04004481

Last Updated: 2021-07-09

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

50 participants

Study Classification

OBSERVATIONAL

Study Start Date

2019-01-25

Study Completion Date

2020-03-13

Brief Summary

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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

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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.

Conditions

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Abdominal Surgery Respiratory Failure Renal Failure Liver Dysfunction Multiorgan Failure

Study Design

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Observational Model Type

COHORT

Study Time Perspective

PROSPECTIVE

Study Groups

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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.

Postoperative analgesia using tramadol

Intervention Type DRUG

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

Interventions

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Postoperative analgesia using tramadol

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

Intervention Type DRUG

Other Intervention Names

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Morphine for rescue analgesia

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Maximum Eligible Age

90 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Josip Juraj Strossmayer University of Osijek

OTHER

Sponsor Role collaborator

Osijek University Hospital

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Nenad Neskovic, MD

Role: PRINCIPAL_INVESTIGATOR

Osijek University Hospital

Locations

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University Hospital Osijek

Osijek, , Croatia

Site Status

Countries

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Croatia

References

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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.

Reference Type BACKGROUND
PMID: 28470112 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 26602992 (View on PubMed)

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

Reference Type BACKGROUND
PMID: 15509185 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 26947771 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 24640604 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 17361124 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 15731591 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 22867045 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 28800982 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 27833752 (View on PubMed)

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.

Reference Type DERIVED
PMID: 33935773 (View on PubMed)

Provided Documents

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Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

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OsijekUH

Identifier Type: -

Identifier Source: org_study_id

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