Trial of Caldolor for Treatment of Pain in Post-Operative Adult Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trial of Caldolor for Treatment of Pain in Post-Operative Adult Patients (NCT00225732), a randomized phase 3 study. The primary outcome is Change in the Patient Demand for the Narcotic Analgesic, Morphine, Post Surgery.

2. Clinical Question

The clinical question concerns an opioid-use outcome rather than a direct rating of pain intensity. The registry’s brief summary frames the objective as determining whether Caldolor reduces the requirement for morphine after surgery. The posted primary measure is described as the change in morphine use within each treatment group; the result is reported as a least-squares mean for each arm. The registry record does not report a separate pain-intensity outcome among the posted outcome measures.

The posted comparison concerns the 800 mg intravenous ibuprofen group and placebo. It estimates the mean difference in the primary measure, with the ibuprofen group subtracted from the placebo group according to the reported values. The registry record does not report additional details about eligible surgical procedures, baseline opioid use, or other clinical characteristics that would further define the question’s scope.

3. Trial Design

This is a completed phase 3 clinical trial with randomized allocation and a parallel-group model. The registry record identifies the masking as quadruple. The official title describes a multi-center, randomized, double-blind, placebo-controlled trial, while the registry’s masking field uses the quadruple label. The enrolled sample is reported as 319.

The comparison was between intravenous ibuprofen and normal saline placebo. The posted outcome results identify a placebo group with 153 participants and an 800 mg intravenous ibuprofen group with 166 participants. The registry record’s brief summary describes treatment of hospitalized postoperative adults every 6 hours for 48 hours. Those treatment details describe the study objective in the summary; the record does not provide further administration or adherence details in the posted results.

The primary completion date is 2008-01, and the record lists the study status as completed. The primary outcome is a continuous measure: change in patient demand for morphine after surgery, in milligrams, with a 24 Hours timeframe. One primary outcome measure is posted, and no secondary outcomes are posted. The registry record does not report the original sample-size justification, allocation procedure details, or the statistical analysis plan. It also does not report the precise eligibility criteria, participating centers, or the number of participants included in the primary analysis.

The trial’s randomized, parallel design makes the treatment groups the basis for the posted comparison. However, the record does not describe whether the analysis retained participants in their randomized groups, how protocol deviations were handled, or whether the reported means were adjusted for baseline or other variables. Those aspects should not be inferred from the design labels alone.

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.

Before assignment: A total of 319 participants were randomized into two treatment groups. Randomized participants were additionally stratified by age and weight; three participants were randomized to incorrect stratification categories. All 319 participants received at least one dose of clinical trial material.

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 Change in the Patient Demand for the Narcotic Analgesic, Morphine, Post Surgery, measured over 24 Hours.

The primary endpoint is titled “Change in the Patient Demand for the Narcotic Analgesic, Morphine, Post Surgery.” It is measured in milligrams, over a 24 Hours timeframe, and the registry describes it as the change in the amount of morphine used by subjects in each treatment group during a 24-hour period after surgery. The measure is reported as a least-squares mean, with its dispersion given as a standard error.

Morphine use serves as an indicator of analgesic requirement in the study’s stated objective. A lower value in the ibuprofen arm than in the placebo arm would correspond to lower reported morphine use on this measure. The posted arm estimates are 57.0 for placebo and 48.7 for 800 mg intravenous ibuprofen. The reported mean difference is -8.3.

The record’s endpoint title uses the word “change,” but its description refers to the amount of morphine used during the postoperative period. It does not specify the reference value or baseline measurement used to define change, nor does it explain whether the outcome is cumulative use or another summary of demand. These details are not reported in the registry record. The outcome therefore needs to be interpreted according to the posted description and timeframe, without assuming a more detailed measurement procedure.

7. Results Posted in the Registry

• 800 mg Intravenous Ibuprofen: mean 48.70 versus 57.00 on control; difference -8.30 (95% CI -14.82 to -1.78), standardized effect d = -0.28; z-test p = 0.013.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: it is measured in milligrams and summarized with a mean. The registry labels the arm summaries as least-squares means and identifies their dispersion as standard error. A mean describes the central value of a measurement, while a standard error describes the precision of an estimated mean. It does not describe how widely individual observations vary. The record does not give the model details needed to explain how the least-squares means were adjusted or estimated.

What does the mean difference represent?

The posted contrast is a mean difference comparing 800 mg intravenous ibuprofen with placebo. Its estimate is -8.3. The arm means are 48.7 for ibuprofen and 57.0 for placebo, so the negative direction corresponds to a lower estimated mean in the ibuprofen arm. This is a difference in the outcome’s units, milligrams. It is not a percentage reduction, and no such percentage is needed to interpret the posted contrast.

A difference between group means summarizes the comparison but does not show every participant’s response or the distribution of individual outcomes. The registry record does not report participant-level data, a standard deviation for the endpoint, or a distributional plot from which those features could be assessed. The standard errors of the least-squares means should therefore not be read as the range of individual morphine use.

What does the confidence interval add?

A confidence interval expresses uncertainty around an estimated contrast using a procedure with a stated coverage property under its assumptions. The reported interval for the mean difference runs from -14.82 to -1.785. It gives a range of values compatible with the estimate under that procedure, rather than a guarantee that the true value lies within those particular endpoints. Because the interval does not cross zero, the reported uncertainty range is on the side corresponding to lower morphine use in the ibuprofen group. The registry record does not report all details of the interval calculation.

How should the p-value be read?

The unadjusted p-value is 0.013. In general, a p-value measures the compatibility of the observed result with a specified null model, assuming the model and analysis conditions hold. It does not measure the probability that the null hypothesis is true, and it does not quantify clinical importance. “Unadjusted” means the reported value is not presented as corrected for multiplicity. The registry record does not report a plan for handling multiple tests or identify a family of tests for which adjustment would apply.

Why can over-dispersion matter?

General statistical context: over-dispersion occurs when outcome variability is greater than a statistical model assumes. If the model understates variability, standard errors may be too small and confidence intervals too narrow; if it accounts for variability appropriately, uncertainty estimates can be more reliable. This is a general consideration for analyses, not a claim that over-dispersion occurred in this trial. The registry record does not report a diagnostic assessment of model fit or over-dispersion.

What can be concluded about the analysis?

The registry identifies the outcome summary and reports the arm estimates, comparison, confidence interval, and unadjusted p-value. It does not report the model specification, covariate adjustment, handling of missing outcomes, or analysis population. It also lists no posted analyses. The absence of posted analysis details limits independent assessment of how the reported contrast was produced; it does not show that no analysis was conducted. A randomized design is important context, but it does not substitute for reporting the analysis methods used for the posted estimate.

10. Confidence Intervals and Precision

The mean-difference estimate is -8.3 milligrams, with a reported confidence interval from -14.82 to -1.785. The interval expresses uncertainty around the estimated contrast and includes values representing different magnitudes of a mean difference. Its limits are both negative, consistent with lower estimated morphine use in the ibuprofen group under the reported comparison direction. The interval does not imply that every participant used less morphine, nor does it describe the spread of individual outcomes.

The arm means are reported with standard errors of 2.4 for placebo and 2.3 for 800 mg intravenous ibuprofen. Standard errors concern precision of estimated means; they are not standard deviations. The record does not report individual-level variability for the primary outcome, so the standard errors should not be used to infer the distribution of patient values.

The unadjusted p-value is 0.013. It is consistent with the confidence interval’s position, but it is not a measure of the size or clinical importance of the difference. The registry record does not describe the method used to calculate the interval or whether the estimate includes adjustment for covariates. The comparison is therefore most transparently interpreted as the posted statistical result, with its uncertainty, rather than as a fully specified model-based analysis.

Precision is also distinct from generalizability. The interval addresses uncertainty in the estimated comparison under its assumptions; it does not establish that the same estimate applies to every postoperative population or setting. The record does not provide enough detail about operations, eligibility, or analysis populations to assess such transportability.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total events. They are illustrations based on fractions of the observed effect, using a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. For 100% of the observed effect, the planning figures are 201 participants per arm for 80% power and 269 participants per arm for 90% power. For 75% of the observed effect, they are 357 participants per arm for 80% power and 478 participants per arm for 90% power. For 50% of the observed effect, they are 802 participants per arm for 80% power and 1,074 participants per arm for 90% power.

In plain terms, the 80% power column gives the planned number per arm for a hypothetical study designed to have an 80% chance of detecting the stated effect under the listed assumptions. The 90% column gives the number per arm for a hypothetical design with a 90% chance under those assumptions. These are planning illustrations, not observed power for the completed trial.

The assumed effect is a stated fraction of the effect observed in this trial. Smaller target effects require more participants to distinguish them from random variation with the same planned power and significance level. The figures do not report the original design assumptions for this trial; those assumptions are not reported in the registry record. They should not be interpreted as a reconstruction of the original enrollment plan or as a guarantee that a future study will achieve its planned power.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -8.300; pooled standard deviation σ = 29.659.
2. n = 2 × (1.96 + 0.842)² × 29.659² / -8.300² = 200.4, rounded up to 201 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -8.3                      # observed difference in means
sigma <- 29.6588201913353                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(225732)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 201 (80% power), 269 (90% power)
 75% of observed effect: n per arm = 357 (80% power), 478 (90% power)
 50% of observed effect: n per arm = 802 (80% power), 1,074 (90% power)
power.t.test: 201.4 
Simulated power at n = 201 per arm: 0.799 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry record posts one primary outcome measure and no secondary outcomes. It lists no posted analyses. This is not enough to establish that no other outcomes or analyses were collected or considered; it means they are not reported among the posted registry results. The record does not describe a prespecified hierarchy of outcomes or an analysis plan for multiple comparisons.

The reported p-value of 0.013 is unadjusted. When multiple hypotheses are tested, the chance of at least one false-positive result can rise, depending on the testing structure. General statistical methods address this in different ways, such as defining a primary testing family in advance or adjusting inference for multiple tests. The registry record does not report whether any such method was planned or used. As a result, the posted p-value should be read as unadjusted, without assuming a correction or an absence of other testing.

Missing-data handling is also not reported in the registry record. The outcome description and group results do not say how missing morphine-use measurements were treated, whether participants with incomplete records were excluded, or whether any imputation method was used. The record does not report whether the analysis was based on all randomized participants, only participants with observed outcome data, or another defined population.

The outcome summaries identify group sizes, but those counts alone do not establish the analysis population or the completeness of outcome measurement. Nor do they show whether exclusions occurred after randomization. These omissions limit assessment of possible bias from missing data, deviations from assigned treatment, or selective reporting. The randomized design is relevant, but transparent interpretation also depends on knowing which participants and measurements contributed to the estimates and how unavailable outcomes were handled.

14. Safety Results

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

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: ileus (1.8%), atelectasis (1.3%), oxygen saturation decreased (0.7%), peritoneal hemorrhage (0.7%), cholecystitis (0.7%).

The registry reports serious adverse events for 6 participants in the placebo group, with 153 at risk, and 12 participants in the 800 mg intravenous ibuprofen group, with 166 at risk. These are the posted group counts; they should be read as descriptive safety information rather than as a complete comparison of all possible harms. The record does not provide a statistical comparison or confidence intervals for these figures. Death counts are not reported in the registry record.

Other adverse events are reported for 149 participants in the placebo group, with 153 at risk, and 150 participants in the ibuprofen group, with 166 at risk. These counts are separate from the serious adverse event counts in the registry fields. The record does not give further detail about event severity, timing, duration, or whether an event was judged related to treatment.

The listed serious-event terms include Ileus at 1.8%, Atelectasis at 1.3%, Oxygen saturation decreased at 0.7%, Peritoneal Hemorrhage at 0.7%, Cholecystitis at 0.7%, and Abdominal Abscess at 0.6%. The record does not identify the treatment group for these term percentages in the posted list. They should not be assigned to either arm or interpreted as a comparative risk estimate.

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

The posted primary result is a lower least-squares mean for morphine use in the 800 mg intravenous ibuprofen group than in the placebo group: 48.7 compared with 57.0. The estimated mean difference is -8.3, with a confidence interval from -14.82 to -1.785 and an unadjusted p-value of 0.013. The interval is on the negative side of zero, but the estimate remains subject to the uncertainty and analysis limitations described in the registry record.

This result is about morphine use as described by the primary endpoint. It is not a direct estimate of pain intensity, patient satisfaction, recovery, or longer-term outcomes. The registry record’s objective links the intervention to postoperative pain treatment through reduced morphine requirement, but the posted primary measure does not itself establish how participants experienced pain. It also does not establish the clinical importance of the estimated difference.

The result does not show that every participant in one group used less morphine than every participant in the other group. Group means conceal individual variation, and the record does not report the distribution of individual values. Nor does the comparison establish that the estimate applies to all surgeries, hospitals, or patient groups; relevant eligibility and setting details are not reported in the registry record.

Safety findings should be considered separately from the primary efficacy measure. The registry reports serious and other adverse-event counts, but does not provide a full comparative safety analysis, event attribution, or death counts. The posted result therefore describes a specific outcome and a limited set of reported safety information. It does not, by itself, settle the overall balance of treatment effects or support medical decisions for an individual.

16. Why This Trial Matters Statistically

This trial illustrates how a clinical question can be translated into a quantitative endpoint. The stated objective concerns postoperative pain treatment, while the primary measure is morphine use in milligrams. That makes the outcome concrete and countable, but it also means the result speaks most directly to analgesic use, not to every dimension of pain or recovery.

The report distinguishes an estimated group contrast from its uncertainty. A mean difference of -8.3 is accompanied by a confidence interval, while the arm means are presented with standard errors. These measures answer different questions: the difference describes the estimated contrast, the interval communicates uncertainty in that contrast, and the standard errors concern precision of the arm means. Keeping these quantities distinct is essential when reading continuous outcomes.

The trial also demonstrates why a p-value should not stand alone. The unadjusted p-value of 0.013 is one component of the reported inference, not a measure of clinical importance and not a substitute for the interval or endpoint definition. With the multiplicity plan and detailed analysis methods not reported in the registry record, readers have reason to keep the interpretation tied to the posted analysis rather than infer unreported safeguards.

Finally, planning calculations based on the observed effect are not equivalent to the trial’s original design rationale. Their assumptions are explicit, but they are illustrations rather than descriptions of the original sample-size process. Together, the outcome definition, uncertainty, analysis transparency, and safety reporting show why statistical interpretation depends on more than a single estimate or significance test.

17. 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 registry record leaves important clinical and methodological details unreported. It does not specify eligible procedures, detailed inclusion or exclusion criteria, baseline opioid use, or other participant characteristics. Those omissions make it difficult to judge which postoperative populations are most represented by the result or how comparable the two groups were on clinical features beyond randomization.

The endpoint is called a change in morphine demand, while the description refers to the amount of morphine used during a 24-hour postoperative period. The record does not explain the reference for the change, the precise method of measuring demand, or the handling of rescue medication. It also does not clarify whether the least-squares means were adjusted for baseline values or other covariates. The comparison can be described as posted, but its full construction cannot be independently assessed from the registry record.

There is no posted account of missing outcome data, analysis populations, protocol deviations, or treatment adherence. The record also does not report the original sample-size assumptions, multiplicity strategy, interim analyses, or detailed statistical plan. No interim analyses or other procedures should be inferred from the absence of these details.

The safety information is limited to the posted counts and selected serious-event terms. The record does not report event attribution, timing, or death counts, and the listed term percentages are not assigned to treatment groups. These limitations mean that neither the primary endpoint nor the adverse-event listing alone provides a comprehensive assessment of the treatment comparison.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Trial of Caldolor for Treatment of Pain in Post-Operative Adult Patients — NCT00225732.
• Registry record last updated 2016-06-22; status last verified 2016-05.
• Results first posted 2011-09-15.
• 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.

21. Record Summary

NCT00225732 is a completed phase 3 randomized parallel-group trial of intravenous ibuprofen versus normal saline placebo for postoperative pain in hospitalized adults. The record reports quadruple masking and enrollment of 319. The primary outcome is change in patient demand for morphine, measured in milligrams over 24 Hours and summarized as least-squares means with standard errors.

The posted arm means are 57.0 for placebo and 48.7 for 800 mg intravenous ibuprofen. The reported mean difference is -8.3, with a confidence interval from -14.82 to -1.785 and an unadjusted p-value of 0.013. The registry record posts no secondary outcomes or analyses. It reports serious and other adverse-event counts, but does not report death counts. Important details about the analysis population, missing data, multiplicity, and original design assumptions are not reported in the registry record.