Metabolites of Tramadol in the Postoperative Surgical Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Metabolites of Tramadol in the Postoperative Surgical Patients (NCT04004481), a registered phase not stated study. The primary outcome is Serum Concentration of Tramadol and Tramadol Metabolites With Respect to Metabolic Phenotype.

2. Clinical Question

The study also set out to record analgesic effects and adverse effects. The registry names pain assessments using the Numeric Rating Scale and Critical Care Pain Observation Tool, nausea and vomiting, respiratory depression, and length of ICU stay as secondary outcomes. These measures could describe pain, tolerability, and care duration alongside the concentration measurements, but outcome results for them are not reported in the registry record. The record does not state how metabolic phenotype was determined or which clinical factors were considered in comparisons. Accordingly, the stated question is about observed drug concentrations and their relationship to phenotype, not a randomized comparison of tramadol with another treatment.

3. Trial Design

This is an observational study of postoperative tramadol use, with an enrollment of 50. The registry status is completed. The recorded start date is 2019-01-25 and the primary completion date is 2020-02-28. Osijek University Hospital is listed as the sponsor. The record describes adult patients undergoing major open abdominal surgery for cancer and says tramadol was to be used for postoperative analgesia in the ICU.

Plasma concentrations of tramadol and its metabolites were scheduled for measurement at six time points: 1, 2, and 4 hours after the first 100 mg intravenous dose, and immediately before the second, third, and fifth doses. The stated overall timeframe is up to 24 hours. The primary outcome is serum concentration, reported as a median with an inter-quartile range, in mcg/L. The record describes concentration measurements for tramadol, O-desmethyltramadol, and N-desmethyltramadol.

The registry characterizes the study as observational, and allocation is not stated. There is no randomized treatment allocation described, and the record explicitly cautions that the arms are not a like-for-like control comparison. Although the primary outcome refers to metabolic phenotype, the record does not give phenotype definitions, group assignment procedures, or a detailed analysis plan. The usual care context and complete dosing schedule are also not reported in the registry record. These omissions limit how specifically the design can be reconstructed from the registration.

Analgesia and adverse effects were also to be recorded. Named secondary measures include pain scores, nausea and vomiting, respiratory depression, and ICU stay. The registry record reports no analyses. Thus, the design and measurement schedule are described, but the posted record does not provide a complete account of how the observations were analyzed.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Serum Concentration of Tramadol and Tramadol Metabolites With Respect to Metabolic Phenotype, measured over 1, 2, and 4 hours after first dose and immediately before 2nd, 3rd, and 5th dose, up to 24 hours.

The primary endpoint is serum concentration of tramadol and its metabolites in relation to metabolic phenotype. The compounds named are tramadol itself, O-desmethyltramadol (ODT), and N-desmethyltramadol (NDT). Concentrations are specified in mcg/L, with the summary measure given as the median and the spread described by the inter-quartile range.

Sampling is scheduled 1, 2, and 4 hours after the first dose of 100 mg tramadol i.v., then immediately before the second, third, and fifth dose. The record says this amounts to six measurements of tramadol and its metabolites, within a timeframe of up to 24 hours. The measurements are intended to characterize concentrations over the early postoperative dosing period and to examine how those concentrations relate to metabolic phenotype.

As a general statistical matter, the median describes the middle of a distribution, while the inter-quartile range describes the spread of its central portion. These summaries can be useful when concentration data are skewed or include unusually high or low values. They do not, by themselves, show the precision of a comparison between phenotype groups; that would require the group-specific results and an analysis of the differences. The actual concentration summaries, phenotype-specific estimates, and uncertainty measures are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record gives some information about what was measured and how the primary outcome was to be summarized, but it does not report a detailed statistical analysis plan. This distinction matters: an outcome definition and a summary measure describe the planned data, while a statistical analysis plan would explain how comparisons, uncertainty, repeated measurements, and incomplete observations were to be handled. Such details are not reported in the registry record.

What does the median and inter-quartile range describe?

As a general statistical explanation, the median is the value at the center of an ordered set of observations. The inter-quartile range describes the interval covering the central half of the observations. These summaries are often used for measurements that are not symmetrically distributed, because the median is less affected by extreme observations than the arithmetic mean. For drug concentrations, this can be a useful descriptive approach when values vary substantially across participants.

These summaries are descriptive, not a complete comparison method. A difference between group medians, if reported, would not alone show how uncertain that difference is or whether it could plausibly reflect sampling variation. Confidence intervals and a stated inferential method can add information about precision. Neither group-specific concentration summaries nor inferential results are reported in the registry record.

Why are the scheduled measurements relevant?

Concentrations are scheduled at 1, 2, and 4 hours after the first 100 mg i.v. dose, and immediately before the second, third, and fifth dose, within a timeframe of up to 24 hours. Repeated sampling can describe how concentrations vary over time within the postoperative period. Because measurements from the same participant are related, a statistical comparison across time points would generally need to account for that dependence rather than treating every measurement as an unrelated observation. This is a general consideration; the registry does not report whether a repeated-measures model or another method was used.

The endpoint description says there will be six measurements of the parent drug and its metabolites. It does not provide the actual sampling values or say how measurements that were missed, delayed, or unusable were handled. The reasons for any missing concentration observations and the methods for addressing them are not reported in the registry record.

What can be inferred from an observational comparison?

In general, observational comparisons describe patterns among people who were not assigned to groups by random allocation. If phenotype groups differ in other characteristics that also relate to drug concentrations, an unadjusted comparison may combine those influences with the relationship of interest. Adjustment can sometimes address measured differences, but it cannot automatically eliminate unmeasured confounding. The registry does not report whether groups were adjusted for clinical characteristics, how phenotype groups were formed, or which covariates were considered.

The registration states that allocation is not stated and warns that the arms are not a like-for-like control comparison. The primary endpoint refers to metabolic phenotype, but the definitions of the phenotypes and the procedures used to classify participants are not reported in the registry record. Therefore, a reader cannot determine from the record how the intended comparison was constructed or whether the groups were comparable in other respects.

What do confidence intervals contribute?

As a general concept, a confidence interval gives a range of values compatible with the data under a specified statistical model and procedure. It communicates precision as well as the estimate itself. A narrow interval indicates greater statistical precision than a wide interval, while an interval spanning a range of materially different values leaves more uncertainty. A confidence interval does not resolve bias from study design, measurement, or confounding. The registry does not report confidence intervals for the primary outcome.

The posted outcome summary specifies medians and inter-quartile ranges, but no test, model, or interval-estimation method is stated. The record also lists zero analyses. The statistical procedure used to compare phenotypes, if any, and the handling of multiple sampling times are not reported in the registry record. No p-values or adjusted estimates for the primary endpoint are reported.

What does the sample-size planning language mean?

The planning illustration is described as based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect. For time-to-event planning, the illustration uses a total number of events; for other outcomes, it uses participants per arm. These are planning illustrations, not observed power and not evidence that the study was designed around those assumptions. The actual planning values and the original sample-size justification are not reported in the registry record. The registry does not state that this illustration was the trial's own design rationale.

In general, a power-based sample-size calculation is conditional on assumptions about the effect of interest, variability, allocation, and analysis. A calculation based on an observed effect is a retrospective planning exercise and should not be read as showing that the study had a particular probability of detecting an effect. No numerical planning estimates are included in the record details, and none can be used to assess the precision of the missing concentration results.

10. Multiplicity, Missing Data and Analysis Populations

The primary endpoint involves three named compounds measured at six scheduled time points, with the primary question framed in relation to metabolic phenotype. This creates several possible summaries or comparisons. As a general statistical matter, examining multiple outcomes, time points, or group contrasts can increase the chance of apparently notable findings arising by chance if many tests are conducted. A prespecified analysis plan can clarify which comparisons are primary and whether any adjustment or hierarchy is used.

The registry record does not report a multiplicity strategy, a hierarchy among the concentration comparisons, or the specific hypothesis tests. It lists six outcome measures overall and names secondary outcomes covering pain, nausea and vomiting, respiratory depression, and ICU stay. The registry does not state how the primary and secondary outcomes would be distinguished in the analysis, whether all planned outcomes were analyzed, or whether any outcomes were added or omitted after study conduct.

Missing-data methods are also not reported in the registry record. The scheduled concentration measurements imply repeated observations, but the record does not say how incomplete sampling, withdrawals, or measurements outside the stated timing windows were handled. The numbers with usable measurements at each time point and the reasons for missing observations are not reported. Without that information, it is difficult to assess whether the posted summaries—if available—would represent all enrolled participants or a subset with complete measurements.

The analysis population is not described. The record does not state whether analyses included all enrolled participants, only participants with particular phenotype classifications, or a defined subset with concentration samples. It also does not report exclusions from analysis. Since the registry lists zero analyses and no primary or secondary outcome results, the handling of multiplicity, missing observations, and analysis populations cannot be evaluated from the posted record.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists two groups titled “PONV in EM” and “PONV in IM.” Each group has 22 participants listed as at risk. For serious adverse events, 0 participants are listed as affected in each group, and deaths are listed for 0 participants in each. The other adverse event counts are 12 in the first group and 4 in the second. These are counts, not rates, and no comparison test or uncertainty estimate is reported.

The labels EM and IM are not defined in the registry record, and the relationship between these group listings and the metabolic phenotype categories is not explained. The registry does not report detailed event definitions, observation windows, severity criteria, or how events were collected. Although the group titles refer to PONV, the record does not provide enough detail to interpret the other-adverse-event counts as a complete account of nausea and vomiting or of all safety events.

Zero listed serious events or deaths should be read narrowly as the values recorded for these group entries. They do not establish that no such events occurred outside the recorded scope, and they do not settle the safety profile. The record’s safety counts also do not replace the unreported concentration and secondary-outcome analyses.

12. What the Result Does, and Does Not, Mean

The record describes a completed observational study with an enrollment of 50 and a defined pharmacokinetic question in postoperative ICU patients after major open abdominal surgery for cancer. It specifies measurements of tramadol, ODT, and NDT at six points after dosing and identifies medians and inter-quartile ranges as the primary summaries. This is enough to understand the intended measurements and their clinical setting.

It is not enough to establish what the study found. The actual concentration values by compound, time point, and phenotype are not reported in the registry record. No confidence intervals, p-values, or other inferential analyses are reported for the primary endpoint. Therefore, the magnitude and precision of any association between metabolic phenotype and concentration cannot be assessed.

The observational design also limits causal interpretation. The record does not state random allocation and warns that the arms are not a like-for-like control comparison. Even if group-specific concentrations were available, differences could reflect other characteristics of the groups as well as phenotype. Definitions of phenotype, adjustment for potential confounders, and the analysis population are not reported in the registry record.

Named secondary outcomes include analgesia, nausea and vomiting, respiratory depression, and length of ICU stay. Their outcome results are not reported in the registry record. The safety entries list zero serious adverse events and zero deaths in each of two groups, alongside other adverse event counts, but the group labels and collection context are not sufficiently explained to support a broad safety conclusion.

Overall, the registration establishes the study's intent and some design details, but the posted information does not provide the results needed to judge the observed pharmacokinetic patterns or their precision. It also does not establish a comparative treatment effect or provide a basis for clinical recommendations.

13. Why This Trial Matters Statistically

This study's statistical question involves the relationship between metabolic phenotype and concentrations of a parent drug and two metabolites, measured repeatedly during the postoperative period. That structure raises issues common to clinical pharmacology studies: distributions may be skewed, observations from the same participant are related, and comparisons across several compounds and time points need clear definition. The registry's use of medians and inter-quartile ranges indicates a descriptive approach suited to summarizing distributions, but the analysis details and results are not reported.

The observational setting is also statistically important. Phenotype is not described as randomly assigned, and allocation is not stated. Consequently, group comparisons—if made—would describe associations and could be affected by differences between participants. A clear account of phenotype classification and adjustment for relevant factors would help readers evaluate those comparisons, but these details are not reported in the registry record.

The study illustrates why registration alone is not a substitute for a results report. The record specifies an enrollment of 50, sampling times, the concentration units, and the primary summary measure. Yet without the actual group summaries, uncertainty estimates, and analysis methods, readers cannot judge the size or precision of the observed concentration patterns. Listing secondary outcome names similarly does not show what was observed for pain, adverse effects, or ICU stay.

Planning illustrations also need careful interpretation. The registry describes a planning framework based on an observed effect, but such calculations are not observed power and do not establish that a study was originally designed with those assumptions. Statistical interpretation depends on the estimates and methods used, not solely on the existence of a planned sample or a completed status. This record therefore offers a useful description of the intended measurements while leaving the central empirical question unanswered in its posted results.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The most important limitation of the registry record is the absence of reported results for the primary concentration endpoint. It specifies the analytes, units, summary measure, and sampling schedule, but does not report concentration distributions by time or metabolic phenotype. Without those results, neither the direction nor the magnitude of any observed pattern can be assessed. Precision estimates and inferential analyses are also not reported.

Details needed to interpret the phenotype comparison are missing. The record does not define metabolic phenotypes, describe how participants were classified, or explain the comparison groups. The registry cautions that the arms are not a like-for-like control comparison, and allocation is not stated. It does not report adjustment for clinical factors or other potential confounders.

Although six concentration measurements are planned within up to 24 hours, the record does not describe handling of incomplete sampling, delayed measurements, or unusable specimens. The number of participants contributing measurements at each time point and the analysis population are not reported. The statistical method for accounting for repeated observations is also not reported.

Secondary outcomes are named but their results are absent. The safety listings provide counts, yet group labels, event definitions, and collection details are not sufficiently explained. Finally, the registry does not report a detailed analysis plan, a multiplicity strategy, or the study's original sample-size justification. These omissions constrain assessment of both the pharmacokinetic question and the broader clinical outcomes.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Metabolites of Tramadol in the Postoperative Surgical Patients — NCT04004481.
• Registry record last updated 2021-07-09; status last verified 2021-06.
• Results first posted 2021-07-09.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT04004481, titled “Metabolites of Tramadol in the Postoperative Surgical Patients,” is registered as a completed observational study sponsored by Osijek University Hospital. The recorded enrollment is 50; the study start date is 2019-01-25 and the primary completion date is 2020-02-28. It concerns postoperative tramadol use in adult patients undergoing major open abdominal surgery for cancer.

The primary outcome is serum concentration of tramadol, ODT, and NDT, summarized by median and inter-quartile range in mcg/L. Measurements were scheduled at 1, 2, and 4 hours after the first 100 mg i.v. dose and immediately before the second, third, and fifth dose, up to 24 hours. Named secondary outcomes cover pain, nausea and vomiting, respiratory depression, and ICU stay.

The registry record does not report primary concentration results or statistical analyses. It also does not report phenotype definitions, missing-data methods, or a detailed analysis plan. Safety listings include zero serious adverse events and zero deaths in each of two groups, with other adverse event counts also recorded.