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| Name | Class |
|---|---|
| Josip Juraj Strossmayer University of Osijek | OTHER |
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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Postoperative analgesia using tramadol | Drug | Tramadol 100 mg will be given to the patients in the postoperative period. |
|
| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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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.
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| Name | Affiliation | Role |
|---|---|---|
| Nenad Neskovic, MD | Osijek University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Osijek | Osijek | 31000 | Croatia |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28470112 | Background | 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. | |
| 26602992 | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Adult Patients Undergoing Major Open Abdominal Surgery | Observational study. In the patients undergoing major open abdominal surgery 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 and in regards to systemic inflammation and preoperative cholinesterase activity. Postoperative analgesia using tramadol: Tramadol 100 mg will be given to the patients in the postoperative period. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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: Tramadol 100 mg will be given to the patients in the postoperative period. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Median | Inter-Quartile Range | mcg/L | 1, 2, and 4 hours after first dose and immediately before 2nd, 3rd, and 5th dose, up to 24 hours |
|
24 hours
Postoperative nausea and/or vomiting
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | PONV in EM | We monitored the incidence of PONV with respect to metabolic phenotype. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| PONV | Gastrointestinal disorders | Non-systematic Assessment | Postoperative nausea and/or vomiting |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Nenad Neskovic | University hospital Osijek | +385996787250 | nneskov@gmail.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 25, 2019 | Jun 16, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D012131 | Respiratory Insufficiency |
| D051437 | Renal Insufficiency |
| D008107 | Liver Diseases |
| D009102 | Multiple Organ Failure |
| D000377 | Agnosia |
| ID | Term |
|---|---|
| D012120 | Respiration Disorders |
| D012140 | Respiratory Tract Diseases |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
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| ID | Term |
|---|---|
| D009020 | Morphine |
| ID | Term |
|---|---|
| D009022 | Morphine Derivatives |
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
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CYP2D6 polymorphism will be done from DNA isolated from white cells.
|
| 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 |
| 15509185 | Background | Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. doi: 10.2165/00003088-200443130-00004. |
| 26947771 | 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. |
| 24640604 | 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. |
| 17361124 | 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. |
| 15731591 | 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. |
| 22867045 | 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. |
| 28800982 | 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. |
| 27833752 | 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. |
| 33935773 | Derived | 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. |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Body mass index | Median | Inter-Quartile Range | kg/m^2 |
|
| ASA status | ASA I: A normal healthy patient; ASA II: A patient with mild systemic disease; ASA III: A patient with severe systemic disease; ASA IV: A patient with severe systemic disease that is a constant threat to life; ASA V: A moribund patient who is not expected to survive without the operation. | Count of Participants | Participants |
|
| CYP2D6 polymorphism | Count of Participants | Participants |
|
| Metabolic phenotype | Metabolic phenotype was determined according to the CYP2D6 diplotype polymorphism. | Count of Participants | Participants |
|
Median ODT concentration in 6 measurements point in postoperative 24 hours in PM
| OG002 | ODT Concentration in Intermediate Metabolizers (IM) | Median ODT concentration in 6 measurements point in postoperative 24 hours in IM |
| OG003 | ODT Concentration in Extensive Metabolizers (EM) | Median ODT concentration in 6 measurements point in postoperative 24 hours in EM |
| OG004 | ODT Concentration in Ultrafast Metabolizers (UM) | Median ODT concentration in 6 measurements point in postoperative 24 hours in UM |
| OG005 | NDT Concentration in Poor Metabolizers (PM) | Median NDT concentration in 6 measurements point in postoperative 24 hours in PM |
| OG006 | NDT Concentration in Intermediate Metabolizers (IM) | Median NDT concentration in 6 measurements point in postoperative 24 hours in IM |
| OG007 | NDT Concentration in Extensive Metabolizers (EM) | Median NDT concentration in 6 measurements point in postoperative 24 hours in EM |
| OG008 | NDT Concentration in Ultrafast Metabolizers (UM) | Median NDT concentration in 6 measurements point in postoperative 24 hours in UM |
|
|
| 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. | Pain was assessed by the NRS scale in patients who were awake. | Posted | Median | Inter-Quartile Range | score on scale | 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. | All unconscious patients had low CPOT values and were therefore not suitable for statistical analysis. | Posted | Median | Inter-Quartile Range | score on a scale | 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. | Posted | Count of Participants | Participants | 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. | Posted | Count of Participants | Participants | 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. | Posted | Median | Inter-Quartile Range | days | Up to 6 months |
|
|
|
| 0 |
| 22 |
| 0 |
| 22 |
| 12 |
| 22 |
| EG001 | PONV in IM | We monitored the incidence of PONV with respect to metabolic phenotype. | 0 | 22 | 0 | 22 | 4 | 22 |
|
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| D052776 |
| Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D004066 | Digestive System Diseases |
| D012769 | Shock |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D010468 | Perceptual Disorders |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D006571 |
| Heterocyclic Compounds |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |
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| 4th pain assessment |
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| 5th pain assessment |
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| 2nd assessment point |
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| 3rd assessment point |
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| 4th assessment point |
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| 5th assessment point |
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