METRAS: Metabolites of Tramadol in the Postoperative Surgical Patients

• Sponsor: Osijek University Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT04004481
• Collaborator: Josip Juraj Strossmayer University of Osijek (Other)
• Enrollment: 50
• Location: 1
• Actual Duration (Months): 13.6
• Patients Per Site Per Month: 3.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Abdominal Surgery; Respiratory Failure; Renal Failure; Liver Dysfunction; Multiorgan Failure	Drug: Postoperative analgesia using tramadol

Detailed 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.

Study Design

• Study Type: Observational
• Actual Enrollment: 50 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Metabolites of Tramadol in the Postoperative Surgical Patients Admitted in the ICU
• Actual Study Start Date: Jan 25, 2019
• Actual Primary Completion Date: Feb 28, 2020
• Actual Study Completion Date: Mar 13, 2020

Arms and Interventions

Arm	Intervention/Treatment
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; Tramadol 100 mg will be given to the patients in the postoperative period.; Other Names: Morphine for rescue analgesia

Outcome Measures

Primary Outcome Measures

1. Serum Concentration of Tramadol and Tramadol Metabolites With Respect to Metabolic Phenotype [1, 2, and 4 hours after first dose and immediately before 2nd, 3rd, and 5th dose, up to 24 hours]

   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.

Secondary Outcome Measures

1. 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]

   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.

2. 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.]

   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.

3. Number of Participants With Nausea and Vomiting After Tramadol [Nausea and vomiting was assessed during first 30 minutes after tramadol administration]

   Nausea and/or vomiting during treatment with tramadol in ICU will be recorded.

4. Number of Patients With Respiratory Depression After Tramadol [Respiratory depression was observed up to 30 minutes after tramadol administration]

   Respiratory depression after tramadol is considered to be any drop in saturation below 90% or drop in respiratory rate below 10/min.

5. Length of ICU Stay [Up to 6 months]

   Length of stay in ICU will be recorded and correlated with standard laboratory values and tramadol and metabolites concentration.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospital Osijek	Osijek		Croatia	31000

Sponsors and Collaborators

• Osijek University Hospital
• Josip Juraj Strossmayer University of Osijek

Investigators

• Principal Investigator: Nenad Neskovic, MD, Osijek University Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 25, 2019

More Information

Publications

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

• Responsible Party: Osijek University Hospital
• ClinicalTrials.gov Identifier: NCT04004481
• Other Study ID Numbers: OsijekUH
• First Posted: Jul 2, 2019
• Last Update Posted: Jul 9, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Osijek University Hospital: Tramadol; CYP2D6 polymorphism; analgesia; intensive care; organ failure
• Additional relevant MeSH terms: Liver Diseases; Respiratory Insufficiency; Multiple Organ Failure; Morphine; Tramadol

Study Results

Participant Flow

Arm/Group Title	Adult Patients Undergoing Major Open Abdominal Surgery
Arm/Group Description	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.
Period Title: Overall Study
STARTED	50
COMPLETED	47
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Adult Patients Undergoing Major Open Abdominal Surgery
Arm/Group Description	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.
Overall Participants	47
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	67
Sex: Female, Male (Count of Participants)
Female	17 36.2%
Male	30 63.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	47 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Body mass index (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	26.1
ASA status (Count of Participants)
ASA II	11 23.4%
ASA III	27 57.4%
ASA IV	8 17%
ASA V	1 2.1%
CYP2D6 polymorphism (Count of Participants)
*1/*4	16 34%
*1/*1	22 46.8%
*1/*4xN	3 6.4%
*4/*4	2 4.3%
*1/*3	2 4.3%
*1/*1xN	1 2.1%
Metabolic phenotype (Count of Participants)
Poor	2 4.3%
Intermediate	22 46.8%
Extensive	22 46.8%
Ultrafast	1 2.1%

Outcome Measures

1. Primary Outcome

Title	Serum Concentration of Tramadol and Tramadol Metabolites With Respect to Metabolic Phenotype
Description	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.
Time Frame	1, 2, and 4 hours after first dose and immediately before 2nd, 3rd, and 5th dose, up to 24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tramadol Concentration	ODT Concentration in Poor Metabolizers (PM)	ODT Concentration in Intermediate Metabolizers (IM)	ODT Concentration in Extensive Metabolizers (EM)	ODT Concentration in Ultrafast Metabolizers (UM)	NDT Concentration in Poor Metabolizers (PM)	NDT Concentration in Intermediate Metabolizers (IM)	NDT Concentration in Extensive Metabolizers (EM)	NDT Concentration in Ultrafast Metabolizers (UM)
Arm/Group Description	Median of tramadol concentration in 6 measurements point in postoperative 24 hours	Median ODT concentration in 6 measurements point in postoperative 24 hours in PM	Median ODT concentration in 6 measurements point in postoperative 24 hours in IM	Median ODT concentration in 6 measurements point in postoperative 24 hours in EM	Median ODT concentration in 6 measurements point in postoperative 24 hours in UM	Median NDT concentration in 6 measurements point in postoperative 24 hours in PM	Median NDT concentration in 6 measurements point in postoperative 24 hours in IM	Median NDT concentration in 6 measurements point in postoperative 24 hours in EM	Median NDT concentration in 6 measurements point in postoperative 24 hours in UM
Measure Participants	47	2	22	22	1	2	22	22	1
1st measurement	372.7	7.05	17.1	40.9	13.8	11.7	4.5	4.76	3.5
2nd measurement	270.6	7.6	15.7	46.7	19.4	15.3	6.1	5.2	3.5
3rd measurement	232.1	10	20.2	46.4	26	28.9	9.1	8.5	3.5
4th measurement	181.2	12.4	19.1	38.1	25.1	31.2	9.6	9.7	3.5
5th measurement	300.1	19.1	36.6	75.1	58.2	71.4	20.2	19	9.8
6th measurement	408.5	29.7	51.7	97.4	61.9	180.5	34.9	34.4	18.1

2. Secondary Outcome

Title	Analgesic Effect of Tramadol Measured by Numeric Rating Scale (NRS)
Description	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.
Time Frame	Before each dose of tramadol and 30 minutes after tramadol dose, up to 24 hours

Outcome Measure Data

Analysis Population Description

Pain was assessed by the NRS scale in patients who were awake.

Arm/Group Title	Median NRS Score Before Tramadol Administration	Median NRS Score After Tramadol Administration
Arm/Group Description	NRS score value in awake patients before tramadol administration in 5 measurement point	NRS score value in awake patients after tramadol administration in 5 measurement point
Measure Participants	45	44
1st pain assessment	7	5
2nd pain assessment	5	3
3rd pain assessment	3.5	2
4th pain assessment	4	2
5th pain assessment	3	2

3. Secondary Outcome

Title	Analgesic Effect of Tramadol Measured by Critical Care Pain Observation Tool (CPOT)
Description	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.
Time Frame	Pain was assessed before and 30 minutes after each tramadol dose, up to 24 hours.

Outcome Measure Data

Analysis Population Description

All unconscious patients had low CPOT values and were therefore not suitable for statistical analysis.

Arm/Group Title	Median CPOT Score Before Tramadol Administration	Median CPOT Score After Tramadol Administration
Arm/Group Description	CPOT score value in awake patients before tramadol administration in 5 measurement point	CPOT score value in awake patients after tramadol administration in 5 measurement point
Measure Participants	39	34
1st assessment point	0	0
2nd assessment point	0	0
3rd assessment point	0	0
4th assessment point	0	0
5th assessment point	0	0

4. Secondary Outcome

Title	Number of Participants With Nausea and Vomiting After Tramadol
Description	Nausea and/or vomiting during treatment with tramadol in ICU will be recorded.
Time Frame	Nausea and vomiting was assessed during first 30 minutes after tramadol administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PONV in EM	PONV in IM
Arm/Group Description	We monitored the incidence of PONV with respect to metabolic phenotype.	We monitored the incidence of PONV with respect to metabolic phenotype.
Measure Participants	22	22
Count of Participants [Participants]	12 25.5%	4 NaN

5. Secondary Outcome

Title	Number of Patients With Respiratory Depression After Tramadol
Description	Respiratory depression after tramadol is considered to be any drop in saturation below 90% or drop in respiratory rate below 10/min.
Time Frame	Respiratory depression was observed up to 30 minutes after tramadol administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Number of Patients With Postoperative Respiratory Depression
Arm/Group Description	We examined the occurrence of tramadol-induced respiratory depression in the first 24 hours
Measure Participants	47
Count of Participants [Participants]	0 0%

6. Secondary Outcome

Title	Length of ICU Stay
Description	Length of stay in ICU will be recorded and correlated with standard laboratory values and tramadol and metabolites concentration.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low Plasma Cholinesterase Activity	Normal Plasma Cholinesterase Activity
Arm/Group Description	Preoperative plasma cholinesterase activity < 4244 U/L	Preoperative plasma cholinesterase activity > 4244 U/L
Measure Participants	18	25
Median (Inter-Quartile Range) [days]	1.5	1

Adverse Events

Time Frame	24 hours
Adverse Event Reporting Description	Postoperative nausea and/or vomiting
Arm/Group Title	PONV in EM		PONV in IM
Arm/Group Description	We monitored the incidence of PONV with respect to metabolic phenotype.		We monitored the incidence of PONV with respect to metabolic phenotype.
All Cause Mortality
	PONV in EM		PONV in IM
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/22 (0%)
Serious Adverse Events
	PONV in EM		PONV in IM
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	PONV in EM		PONV in IM
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/22 (54.5%)		4/22 (18.2%)
Gastrointestinal disorders
PONV	12/22 (54.5%)	12	4/22 (18.2%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.