Trial Outcomes & Findings for Metabolites of Tramadol in the Postoperative Surgical Patients (NCT NCT04004481)
NCT ID: NCT04004481
Last Updated: 2021-07-09
Results Overview
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.
Recruitment status
COMPLETED
Target enrollment
50 participants
Primary outcome timeframe
1, 2, and 4 hours after first dose and immediately before 2nd, 3rd, and 5th dose, up to 24 hours
Results posted on
2021-07-09
Participant Flow
Participant milestones
| Measure |
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.
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|---|---|
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Overall Study
STARTED
|
50
|
|
Overall Study
COMPLETED
|
47
|
|
Overall Study
NOT COMPLETED
|
3
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Metabolites of Tramadol in the Postoperative Surgical Patients
Baseline characteristics by cohort
| Measure |
Adult Patients Undergoing Major Open Abdominal Surgery
n=47 Participants
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.
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|---|---|
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Age, Continuous
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67 years
n=5 Participants
|
|
Sex: Female, Male
Female
|
17 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
30 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
47 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
|
Body mass index
|
26.1 kg/m^2
n=5 Participants
|
|
ASA status
ASA II
|
11 Participants
n=5 Participants
|
|
ASA status
ASA III
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27 Participants
n=5 Participants
|
|
ASA status
ASA IV
|
8 Participants
n=5 Participants
|
|
ASA status
ASA V
|
1 Participants
n=5 Participants
|
|
CYP2D6 polymorphism
*1/*4
|
16 Participants
n=5 Participants
|
|
CYP2D6 polymorphism
*1/*1
|
22 Participants
n=5 Participants
|
|
CYP2D6 polymorphism
*1/*4xN
|
3 Participants
n=5 Participants
|
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CYP2D6 polymorphism
*4/*4
|
2 Participants
n=5 Participants
|
|
CYP2D6 polymorphism
*1/*3
|
2 Participants
n=5 Participants
|
|
CYP2D6 polymorphism
*1/*1xN
|
1 Participants
n=5 Participants
|
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Metabolic phenotype
Poor
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2 Participants
n=5 Participants
|
|
Metabolic phenotype
Intermediate
|
22 Participants
n=5 Participants
|
|
Metabolic phenotype
Extensive
|
22 Participants
n=5 Participants
|
|
Metabolic phenotype
Ultrafast
|
1 Participants
n=5 Participants
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PRIMARY outcome
Timeframe: 1, 2, and 4 hours after first dose and immediately before 2nd, 3rd, and 5th dose, up to 24 hoursThe 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.
Outcome measures
| Measure |
Tramadol Concentration
n=47 Participants
Median of tramadol concentration in 6 measurements point in postoperative 24 hours
|
ODT Concentration in Poor Metabolizers (PM)
n=2 Participants
Median ODT concentration in 6 measurements point in postoperative 24 hours in PM
|
ODT Concentration in Intermediate Metabolizers (IM)
n=22 Participants
Median ODT concentration in 6 measurements point in postoperative 24 hours in IM
|
ODT Concentration in Extensive Metabolizers (EM)
n=22 Participants
Median ODT concentration in 6 measurements point in postoperative 24 hours in EM
|
ODT Concentration in Ultrafast Metabolizers (UM)
n=1 Participants
Median ODT concentration in 6 measurements point in postoperative 24 hours in UM
|
NDT Concentration in Poor Metabolizers (PM)
n=2 Participants
Median NDT concentration in 6 measurements point in postoperative 24 hours in PM
|
NDT Concentration in Intermediate Metabolizers (IM)
n=22 Participants
Median NDT concentration in 6 measurements point in postoperative 24 hours in IM
|
NDT Concentration in Extensive Metabolizers (EM)
n=22 Participants
Median NDT concentration in 6 measurements point in postoperative 24 hours in EM
|
NDT Concentration in Ultrafast Metabolizers (UM)
n=1 Participants
Median NDT concentration in 6 measurements point in postoperative 24 hours in UM
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|---|---|---|---|---|---|---|---|---|---|
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Serum Concentration of Tramadol and Tramadol Metabolites With Respect to Metabolic Phenotype
1st measurement
|
372.7 mcg/L
Interval 250.6 to 535.7
|
7.05 mcg/L
Interval 4.52 to 7.05
|
17.1 mcg/L
Interval 6.3 to 38.1
|
40.9 mcg/L
Interval 21.9 to 53.9
|
13.8 mcg/L
|
11.7 mcg/L
Interval 7.6 to 11.7
|
4.5 mcg/L
Interval 3.5 to 11.1
|
4.76 mcg/L
Interval 3.5 to 19.1
|
3.5 mcg/L
|
|
Serum Concentration of Tramadol and Tramadol Metabolites With Respect to Metabolic Phenotype
2nd measurement
|
270.6 mcg/L
Interval 201.6 to 447.9
|
7.6 mcg/L
Interval 4.5 to 7.6
|
15.7 mcg/L
Interval 7.3 to 39.6
|
46.7 mcg/L
Interval 23.6 to 64.3
|
19.4 mcg/L
|
15.3 mcg/L
Interval 9.2 to 15.3
|
6.1 mcg/L
Interval 3.9 to 12.2
|
5.2 mcg/L
Interval 3.5 to 22.0
|
3.5 mcg/L
|
|
Serum Concentration of Tramadol and Tramadol Metabolites With Respect to Metabolic Phenotype
3rd measurement
|
232.1 mcg/L
Interval 153.5 to 369.8
|
10 mcg/L
Interval 4.6 to 10.0
|
20.2 mcg/L
Interval 12.5 to 40.4
|
46.4 mcg/L
Interval 31.0 to 72.6
|
26 mcg/L
|
28.9 mcg/L
Interval 12.3 to 28.9
|
9.1 mcg/L
Interval 5.3 to 14.7
|
8.5 mcg/L
Interval 3.6 to 22.9
|
3.5 mcg/L
|
|
Serum Concentration of Tramadol and Tramadol Metabolites With Respect to Metabolic Phenotype
4th measurement
|
181.2 mcg/L
Interval 122.9 to 270.2
|
12.4 mcg/L
Interval 5.2 to 12.4
|
19.1 mcg/L
Interval 11.4 to 47.8
|
38.1 mcg/L
Interval 30.3 to 74.5
|
25.1 mcg/L
|
31.2 mcg/L
Interval 15.7 to 31.2
|
9.6 mcg/L
Interval 5.1 to 20.7
|
9.7 mcg/L
Interval 3.5 to 23.9
|
3.5 mcg/L
|
|
Serum Concentration of Tramadol and Tramadol Metabolites With Respect to Metabolic Phenotype
5th measurement
|
300.1 mcg/L
Interval 191.8 to 417.6
|
19.1 mcg/L
Interval 10.7 to 19.1
|
36.6 mcg/L
Interval 21.2 to 71.4
|
75.1 mcg/L
Interval 46.3 to 117.6
|
58.2 mcg/L
|
71.4 mcg/L
Interval 43.0 to 71.4
|
20.2 mcg/L
Interval 10.5 to 37.2
|
19 mcg/L
Interval 7.4 to 45.6
|
9.8 mcg/L
|
|
Serum Concentration of Tramadol and Tramadol Metabolites With Respect to Metabolic Phenotype
6th measurement
|
408.5 mcg/L
Interval 273.8 to 677.8
|
29.7 mcg/L
Interval 23.9 to 29.7
|
51.7 mcg/L
Interval 25.7 to 93.5
|
97.4 mcg/L
Interval 52.6 to 139.0
|
61.9 mcg/L
|
180.5 mcg/L
Interval 124.9 to 180.5
|
34.9 mcg/L
Interval 18.5 to 69.9
|
34.4 mcg/L
Interval 18.6 to 72.5
|
18.1 mcg/L
|
SECONDARY outcome
Timeframe: Before each dose of tramadol and 30 minutes after tramadol dose, up to 24 hoursPopulation: Pain was assessed by the NRS scale in patients who were awake.
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.
Outcome measures
| Measure |
Tramadol Concentration
n=45 Participants
Median of tramadol concentration in 6 measurements point in postoperative 24 hours
|
ODT Concentration in Poor Metabolizers (PM)
n=44 Participants
Median ODT concentration in 6 measurements point in postoperative 24 hours in PM
|
ODT Concentration in Intermediate Metabolizers (IM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in IM
|
ODT Concentration in Extensive Metabolizers (EM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in EM
|
ODT Concentration in Ultrafast Metabolizers (UM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in UM
|
NDT Concentration in Poor Metabolizers (PM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in PM
|
NDT Concentration in Intermediate Metabolizers (IM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in IM
|
NDT Concentration in Extensive Metabolizers (EM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in EM
|
NDT Concentration in Ultrafast Metabolizers (UM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in UM
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|---|---|---|---|---|---|---|---|---|---|
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Analgesic Effect of Tramadol Measured by Numeric Rating Scale (NRS)
1st pain assessment
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7 score on scale
Interval 3.0 to 9.0
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5 score on scale
Interval 3.5 to 6.0
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—
|
—
|
—
|
—
|
—
|
—
|
—
|
|
Analgesic Effect of Tramadol Measured by Numeric Rating Scale (NRS)
2nd pain assessment
|
5 score on scale
Interval 3.0 to 6.75
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3 score on scale
Interval 1.0 to 4.75
|
—
|
—
|
—
|
—
|
—
|
—
|
—
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|
Analgesic Effect of Tramadol Measured by Numeric Rating Scale (NRS)
3rd pain assessment
|
3.5 score on scale
Interval 2.25 to 5.0
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2 score on scale
Interval 1.0 to 3.0
|
—
|
—
|
—
|
—
|
—
|
—
|
—
|
|
Analgesic Effect of Tramadol Measured by Numeric Rating Scale (NRS)
4th pain assessment
|
4 score on scale
Interval 2.0 to 5.0
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2 score on scale
Interval 1.0 to 4.0
|
—
|
—
|
—
|
—
|
—
|
—
|
—
|
|
Analgesic Effect of Tramadol Measured by Numeric Rating Scale (NRS)
5th pain assessment
|
3 score on scale
Interval 2.0 to 5.0
|
2 score on scale
Interval 1.0 to 3.0
|
—
|
—
|
—
|
—
|
—
|
—
|
—
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SECONDARY outcome
Timeframe: Pain was assessed before and 30 minutes after each tramadol dose, up to 24 hours.Population: All unconscious patients had low CPOT values and were therefore not suitable for statistical analysis.
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.
Outcome measures
| Measure |
Tramadol Concentration
n=39 Participants
Median of tramadol concentration in 6 measurements point in postoperative 24 hours
|
ODT Concentration in Poor Metabolizers (PM)
n=34 Participants
Median ODT concentration in 6 measurements point in postoperative 24 hours in PM
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ODT Concentration in Intermediate Metabolizers (IM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in IM
|
ODT Concentration in Extensive Metabolizers (EM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in EM
|
ODT Concentration in Ultrafast Metabolizers (UM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in UM
|
NDT Concentration in Poor Metabolizers (PM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in PM
|
NDT Concentration in Intermediate Metabolizers (IM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in IM
|
NDT Concentration in Extensive Metabolizers (EM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in EM
|
NDT Concentration in Ultrafast Metabolizers (UM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in UM
|
|---|---|---|---|---|---|---|---|---|---|
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Analgesic Effect of Tramadol Measured by Critical Care Pain Observation Tool (CPOT)
1st assessment point
|
0 score on a scale
Interval 0.0 to 0.0
|
0 score on a scale
Interval 0.0 to 0.0
|
—
|
—
|
—
|
—
|
—
|
—
|
—
|
|
Analgesic Effect of Tramadol Measured by Critical Care Pain Observation Tool (CPOT)
2nd assessment point
|
0 score on a scale
Interval 0.0 to 0.0
|
0 score on a scale
Interval 0.0 to 0.0
|
—
|
—
|
—
|
—
|
—
|
—
|
—
|
|
Analgesic Effect of Tramadol Measured by Critical Care Pain Observation Tool (CPOT)
3rd assessment point
|
0 score on a scale
Interval 0.0 to 0.0
|
0 score on a scale
Interval 0.0 to 0.0
|
—
|
—
|
—
|
—
|
—
|
—
|
—
|
|
Analgesic Effect of Tramadol Measured by Critical Care Pain Observation Tool (CPOT)
4th assessment point
|
0 score on a scale
Interval 0.0 to 0.0
|
0 score on a scale
Interval 0.0 to 0.0
|
—
|
—
|
—
|
—
|
—
|
—
|
—
|
|
Analgesic Effect of Tramadol Measured by Critical Care Pain Observation Tool (CPOT)
5th assessment point
|
0 score on a scale
Interval 0.0 to 0.0
|
0 score on a scale
Interval 0.0 to 0.0
|
—
|
—
|
—
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Nausea and vomiting was assessed during first 30 minutes after tramadol administrationNausea and/or vomiting during treatment with tramadol in ICU will be recorded.
Outcome measures
| Measure |
Tramadol Concentration
n=22 Participants
Median of tramadol concentration in 6 measurements point in postoperative 24 hours
|
ODT Concentration in Poor Metabolizers (PM)
n=22 Participants
Median ODT concentration in 6 measurements point in postoperative 24 hours in PM
|
ODT Concentration in Intermediate Metabolizers (IM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in IM
|
ODT Concentration in Extensive Metabolizers (EM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in EM
|
ODT Concentration in Ultrafast Metabolizers (UM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in UM
|
NDT Concentration in Poor Metabolizers (PM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in PM
|
NDT Concentration in Intermediate Metabolizers (IM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in IM
|
NDT Concentration in Extensive Metabolizers (EM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in EM
|
NDT Concentration in Ultrafast Metabolizers (UM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in UM
|
|---|---|---|---|---|---|---|---|---|---|
|
Number of Participants With Nausea and Vomiting After Tramadol
|
12 Participants
|
4 Participants
|
—
|
—
|
—
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Respiratory depression was observed up to 30 minutes after tramadol administrationRespiratory depression after tramadol is considered to be any drop in saturation below 90% or drop in respiratory rate below 10/min.
Outcome measures
| Measure |
Tramadol Concentration
n=47 Participants
Median of tramadol concentration in 6 measurements point in postoperative 24 hours
|
ODT Concentration in Poor Metabolizers (PM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in PM
|
ODT Concentration in Intermediate Metabolizers (IM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in IM
|
ODT Concentration in Extensive Metabolizers (EM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in EM
|
ODT Concentration in Ultrafast Metabolizers (UM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in UM
|
NDT Concentration in Poor Metabolizers (PM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in PM
|
NDT Concentration in Intermediate Metabolizers (IM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in IM
|
NDT Concentration in Extensive Metabolizers (EM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in EM
|
NDT Concentration in Ultrafast Metabolizers (UM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in UM
|
|---|---|---|---|---|---|---|---|---|---|
|
Number of Patients With Respiratory Depression After Tramadol
|
0 Participants
|
—
|
—
|
—
|
—
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Up to 6 monthsLength of stay in ICU will be recorded and correlated with standard laboratory values and tramadol and metabolites concentration.
Outcome measures
| Measure |
Tramadol Concentration
n=18 Participants
Median of tramadol concentration in 6 measurements point in postoperative 24 hours
|
ODT Concentration in Poor Metabolizers (PM)
n=25 Participants
Median ODT concentration in 6 measurements point in postoperative 24 hours in PM
|
ODT Concentration in Intermediate Metabolizers (IM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in IM
|
ODT Concentration in Extensive Metabolizers (EM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in EM
|
ODT Concentration in Ultrafast Metabolizers (UM)
Median ODT concentration in 6 measurements point in postoperative 24 hours in UM
|
NDT Concentration in Poor Metabolizers (PM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in PM
|
NDT Concentration in Intermediate Metabolizers (IM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in IM
|
NDT Concentration in Extensive Metabolizers (EM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in EM
|
NDT Concentration in Ultrafast Metabolizers (UM)
Median NDT concentration in 6 measurements point in postoperative 24 hours in UM
|
|---|---|---|---|---|---|---|---|---|---|
|
Length of ICU Stay
|
1.5 days
Interval 1.0 to 6.0
|
1 days
Interval 1.0 to 1.0
|
—
|
—
|
—
|
—
|
—
|
—
|
—
|
Adverse Events
PONV in EM
Serious events: 0 serious events
Other events: 12 other events
Deaths: 0 deaths
PONV in IM
Serious events: 0 serious events
Other events: 4 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
PONV in EM
n=22 participants at risk
We monitored the incidence of PONV with respect to metabolic phenotype.
|
PONV in IM
n=22 participants at risk
We monitored the incidence of PONV with respect to metabolic phenotype.
|
|---|---|---|
|
Gastrointestinal disorders
PONV
|
54.5%
12/22 • Number of events 12 • 24 hours
Postoperative nausea and/or vomiting
|
18.2%
4/22 • Number of events 4 • 24 hours
Postoperative nausea and/or vomiting
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place