Metabolites of Tramadol in the Postoperative Surgical Patients

Study Overview
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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.

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

Conditions
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Abdominal Surgery, Respiratory Failure, Renal Failure, Liver Dysfunction, Multiorgan Failure

Intervention / Treatment
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* Drug: Postoperative analgesia using tramadol


Participation Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Adult patients undergoing major open abdominal surgery<br>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<br>* Tramadol 100 mg will be given to the patients in the postoperative period.<br>* Other names: Morphine for rescue analgesia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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. | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tramadol, CYP2D6 polymorphism, analgesia, intensive care, organ failure