Preoperative IV Versus Oral Acetaminophen: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Preoperative IV Versus Oral Acetaminophen (NCT03468920), a randomized phase 4 study. The primary outcome is Patient Reported Pain.

2. Clinical Question

The question concerns the route of preoperative acetaminophen administration. The described regimens also include placebo pill or IV solution components, so the comparison is between the assigned regimens rather than a comparison of acetaminophen with no acetaminophen. The primary outcome is a pain score from 0 (no pain) to 10 (worst pain).

The registry record describes a study intended to examine whether outcomes differ by administration route. Its posted primary results are group means and a mean difference with a confidence interval. Those results describe the observed scores and the uncertainty around the between-group estimate; they do not by themselves establish that the regimens are equivalent, or that any difference is clinically important. A threshold for clinical importance is not reported in the registry record.

3. Trial Design

This completed phase 4 trial is registered as NCT03468920 and is sponsored by TriHealth Inc. The record describes randomized allocation, quadruple masking, and a parallel design. Enrollment was 120. The registry lists the study start as 2018-04-01 and primary completion as 2019-02-14.

The two arms each include 60 participants in the posted primary outcome results. The IV group was assigned IV Acetaminophen 1000mg in 100mL NS once and a PO placebo pill preoperatively. The oral group was assigned IV normal saline 100mL once and Acetaminophen 1000 mg PO once preoperatively. These descriptions indicate that the comparison included both the assigned active route and the corresponding placebo component.

Random allocation is intended to create groups that are comparable on average, while masking is intended to limit influences from knowing the assigned regimen. The registry record does not specify which individuals were masked or how masking was maintained. Further details about the randomization procedure, allocation concealment, adherence, or departures from assigned treatment are not reported in the registry record.

The record lists postoperative pain as the condition and patient-reported pain as the primary outcome. It also lists secondary outcomes concerning opioid administration in PACU, postoperative nausea and vomiting, length of stay, and patient satisfaction. The posted results include three of those secondary outcomes; a patient satisfaction result is not reported in the registry record. The record does not report the trial's original sample-size justification or the protocol's analysis plan.

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 Patient Reported Pain, measured over through study visit, less than 24 hours.

The primary endpoint is patient-reported pain, measured as a score on a scale from 0 (no pain) to 10 (worst pain). The registry describes the outcome as a mean with a standard deviation and gives the timeframe as through the study visit, less than 24 hours. This is a continuous measure: each participant contributes a score, and the group mean describes the average reported pain in that arm.

Pain is used as the primary outcome because it directly captures the patient-reported experience that the trial set out to compare across administration routes. The scale's direction is important for interpretation: a higher score corresponds to worse pain, while a lower score corresponds to less pain. The mean difference therefore summarizes the contrast in average scores, not the experience of every participant.

A mean can make group-level comparison straightforward, but it does not show the full distribution of individual scores. The registry record does not report additional details about when within the stated timeframe scores were collected, how multiple scores were handled, or what difference would be considered clinically important. Those omissions limit interpretation of the endpoint beyond the reported scale, summary statistics, and timeframe.

7. Results Posted in the Registry

• Arm 2: PO Acetaminophen Group: mean 4.37 versus 4.12 on control; difference 0.25 (95% CI -0.88 to 1.38), standardized effect d = 0.08; z-test p = 0.665.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Number of Participants Who Received Opioid Administration in PACU

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Arm 2: PO Acetaminophen Group: 56.7% (34/60) versus 51.7% (31/60) on control; risk difference 5.0 percentage points (95% CI -12.8 to 22.8), risk ratio 1.10 (0.79–1.53); unadjusted two-proportion z-test p = 0.583.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Arm 2: PO Acetaminophen Group and the control. The interval gives the range of effects that remain compatible with the data.

Number of Participants Who Experienced Postoperative Nausea and Vomiting

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Arm 2: PO Acetaminophen Group: 10.0% (6/60) versus 13.3% (8/60) on control; risk difference -3.3 percentage points (95% CI -14.8 to 8.1), risk ratio 0.75 (0.28–2.03); unadjusted two-proportion z-test p = 0.570.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Arm 2: PO Acetaminophen Group and the control. The interval gives the range of effects that remain compatible with the data.

Length of Stay

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Arm 2: PO Acetaminophen Group: mean 92.88 versus 88.25 on control; difference 4.63 (95% CI -5.51 to 14.77), standardized effect d = 0.16; z-test p = 0.371.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Arm 2: PO Acetaminophen Group and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes cover different aspects of postoperative care: opioid administration in PACU, postoperative nausea and vomiting, length of stay, and patient satisfaction. Their measures are not interchangeable. The first outcomes are counts of participants with an event, length of stay is a continuous measure in minutes, and the record lists patient satisfaction without posting its result.

Across the secondary outcomes with posted results, the estimates do not show a uniformly consistent direction. The risk difference for opioid administration is positive, the risk difference for nausea and vomiting is negative, and the mean difference for length of stay is positive. Each corresponding confidence interval includes the value for no difference. This pattern is compatible with sampling variation and does not establish a coherent set of between-group differences.

These outcomes complement the primary pain result by describing other short-term postoperative measures, but they do not replace it. Their findings do not materially sharpen the interpretation of the primary comparison: the pain estimate itself remains uncertain, and the secondary estimates are also imprecise. Patient satisfaction cannot contribute to this cross-outcome assessment because its result is not reported in the registry record.

Unadjusted secondary results carry less weight as confirmatory evidence when many outcomes are examined, because chance findings become more likely across multiple comparisons. The registry lists four secondary outcomes, while its posted results include three and report no analyses in the analysis listing. A multiplicity strategy is not reported in the registry record. Accordingly, the secondary estimates are best treated as descriptive and hypothesis-generating, rather than as independently decisive evidence about the administration route.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Number of Participants Who Received Opioid Administration in PACU
• Number of Participants Who Experienced Postoperative Nausea and Vomiting
• Length of Stay
• Patient Satisfaction

9. Statistical Interpretation

10. Statistical Methods Explained

The primary comparison is between two independent parallel groups. The outcome is a continuous pain score, and the registry reports each group's mean and standard deviation. A mean describes the group's average score; a standard deviation describes how dispersed individual scores are around that average. These summaries answer different questions: the mean concerns the typical level at group level, while the standard deviation concerns variation among participants.

The mean difference compares the group averages. For the primary result, the contrast is oral minus IV, so a positive estimate means the posted mean was higher in the oral group. Because higher scores indicate worse pain, the sign can be translated into direction without changing the estimate. The mean difference is 0.25 points. The estimate is an unadjusted comparison based on the posted group summaries, not an adjusted estimate from a model described by the sponsor.

A confidence interval describes uncertainty around an estimate under the assumptions of the method used to construct it. It gives a range of values that are reasonably compatible with the observed data and method; it is not a guarantee that the true value lies within that particular interval. For the primary outcome, the 95% interval extends from -0.881 to 1.381. Because this range includes zero, the posted data are compatible with no average difference as well as with differences in either direction. The registry record does not state a clinically important threshold against which to judge the interval.

The p-value describes how unusual data at least as incompatible with a no-difference hypothesis would be, assuming that hypothesis and the test's assumptions. It is not the probability that the null hypothesis is true, nor a measure of the size or clinical importance of an effect. The primary unadjusted p-value is 0.665. A p-value should be interpreted alongside the estimate and its interval, rather than as a standalone verdict.

For binary secondary outcomes, a risk is the proportion of participants with the outcome in an arm. A risk difference subtracts the control-arm risk from the comparison-arm risk, so zero represents equal risks. The posted risk differences use the IV group as the reference and the oral group as the comparison. A positive risk difference indicates a larger observed proportion in the oral group; a negative one indicates a smaller observed proportion. Confidence intervals around these differences express uncertainty, and intervals including zero do not isolate a direction of difference.

Length of stay is another continuous outcome, reported as a mean in minutes with a standard deviation. Its mean difference uses the same basic interpretation as the pain contrast, but its units are minutes rather than pain-score points. The scale and meaning of an estimate depend on the outcome being measured, so estimates across pain, binary events, and length of stay should not be directly compared by magnitude.

General statistical context: unadjusted estimates compare observed group summaries without accounting for additional covariates. Randomization supports a causal comparison when the trial is properly conducted and analyzed, but the registry record does not describe adjusted analyses or detailed analysis populations. Masking and randomization are design features, not substitutes for reporting how data were handled or how estimates were calculated.

Why dispersion matters

General statistical context: a mean difference is estimated with greater uncertainty when individual scores vary widely relative to the group sizes. The standard deviations reported for pain indicate that participants' scores were not all concentrated at the group means. The interval is a more useful guide to precision than the point estimate alone because it reflects both observed variation and the amount of information in the groups.

Over-dispersion is a concern for count outcomes when their variability exceeds what an assumed statistical model expects. General statistical context: ignoring over-dispersion can make uncertainty appear too small. The posted binary outcomes are counts of participants with events, not a count-rate model; the registry record does not report a separate dispersion assessment or model-based adjustment. No such assessment should be inferred from the unadjusted risk differences.

What the registry does not specify

The registry record does not report the original statistical analysis plan, any prespecified covariate adjustment, missing-data methods, or the population used for each analysis. It also does not report whether any interim analyses were planned or conducted, how multiplicity was handled, or whether outcome distributions were assessed. The summaries can be interpreted as posted, but those unreported details cannot be reconstructed from the aggregate results.

The trial's own sample-size rationale is not reported in the registry record. The planning illustrations associated with the posted effect are a separate calculation and should not be mistaken for the design assumptions used when the trial was planned. The interpretations of the reported p-values and intervals are consequently limited to the unadjusted comparisons and information available in the registry record.

11. Confidence Intervals and Precision

Precision concerns how tightly the data constrain the possible values of an effect. The primary mean difference is 0.25 points, while its 95% confidence interval runs from -0.881 to 1.381. The interval includes zero and extends on both sides, so the observed point estimate should not be treated as a precise determination of the direction or size of a difference in mean pain.

The interval also conveys more than the unadjusted p-value alone. It shows that the posted data are compatible with a range of effects, rather than pinpointing an exact value. Whether any portion of that range would matter to patients cannot be determined from the registry record because a threshold for clinical importance is not reported.

The same caution applies to the secondary comparisons. The confidence intervals for opioid administration in PACU, postoperative nausea and vomiting, and length of stay each include the no-difference value. Those intervals do not establish that the groups have identical outcomes; they show that the posted estimates remain uncertain. The registry does not report a patient satisfaction estimate or interval.

Confidence intervals are calculated under statistical assumptions. The registry record posts the estimates and intervals but does not give enough methodological detail to assess all assumptions or reproduce the sponsor's analyses. The displayed precision should therefore be understood as the precision represented by the posted summaries, not as a guarantee that all sources of uncertainty have been captured.

12. 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 illustrations based on fractions of the observed effect, not the trial's original design calculation. For these pain, binary-event, and length-of-stay outcomes, the figures are participants per arm, rather than total events. The assumptions listed for the illustrations are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect.

The 80% power column represents a planning scenario in which a study of the stated size would have an 80% chance of detecting the specified effect under the calculation's assumptions, if that effect were present. The 90% power column uses a higher target chance of detection and therefore generally requires more participants for the same assumed effect. These percentages describe design targets, not the probability that the observed result is correct.

Rows planning for 100%, 75%, or 50% of the observed effect show how the required sample size changes as the assumed difference gets smaller. A smaller effect is harder to distinguish from random variation, so more participants are needed to achieve the same target power. The planning numbers should be read as conditional illustrations: they depend on treating the observed effect as a starting point and on the stated statistical assumptions.

These figures are not observed power. Observed power would not resolve the uncertainty in the posted estimates; the confidence intervals are the more informative guide to the range of effects compatible with the data. The registry record does not report the trial's own original sample-size justification, so these planning illustrations should not be interpreted as evidence about how the enrollment target was chosen.

13. 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 = 0.250; pooled standard deviation σ = 3.160.
2. n = 2 × (1.96 + 0.842)² × 3.160² / 0.250² = 2,507.6, rounded up to 2,508 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 <- 0.25                      # observed difference in means
sigma <- 3.15971042977042                     # 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(3468920)
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 = 2,508 (80% power), 3,357 (90% power)
 75% of observed effect: n per arm = 4,458 (80% power), 5,968 (90% power)
 50% of observed effect: n per arm = 10,031 (80% power), 13,428 (90% power)
power.t.test: 2508.5 
Simulated power at n = 2,508 per arm: 0.802 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists several outcomes: patient-reported pain as the primary endpoint, along with opioid administration in PACU, postoperative nausea and vomiting, length of stay, and patient satisfaction. Assessing several outcomes creates a multiplicity issue. General statistical context: when many hypotheses are tested, the chance of at least one apparently unusual result can increase even if there are no genuine effects. A prespecified strategy can define which results are confirmatory and how error across comparisons will be addressed.

A multiplicity adjustment or testing hierarchy is not reported in the registry record. The posted comparisons are described as unadjusted, and the registry record reports no analyses in its analysis listing. The secondary p-values should therefore not be read as multiplicity-controlled evidence. The primary p-value is also reported as unadjusted; whether its role was protected by a prespecified testing strategy is not reported in the registry record.

Important analysis details are also absent from the registry record. The analysis population is not reported, including whether results follow an intention-to-treat, per-protocol, or other approach. The record does not state how missing outcome data were handled, whether all randomized participants contributed to each endpoint, or how any protocol deviations were treated. Missing-data methods and the amount of missingness are not reported in the registry record.

The registry record does not report an interim analysis plan, a stopping rule, or the original statistical analysis plan. These omissions do not prove that such procedures were absent; they mean that their role cannot be assessed from the record. Interpretation should remain with the posted group results and unadjusted comparisons, without attributing to them unreported adjustment, population definitions, or missing-data procedures.

15. 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 0% reporting threshold.

The posted serious adverse event figures show 0 affected participants among 60 at risk in the IV acetaminophen group and 0 among 60 at risk in the oral acetaminophen group. The record also reports 0 deaths in each group. These counts describe the events recorded during the reported period; they are not estimates of all possible safety risks.

A zero count in a trial group does not establish that an event cannot occur. With a limited number of participants and the stated follow-up timeframe, uncommon events may not be observed. The registry record does not list serious adverse event terms and reports zero other adverse events in both groups among 60 at risk in each arm.

These figures should be read as registry-reported counts, not as a comprehensive safety comparison or proof of equal safety. The record does not provide further detail about event ascertainment, severity categories beyond the posted serious-event counts, or longer-term follow-up.

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

The registry record reports similar group averages for patient-reported pain, with an unadjusted mean difference of 0.25 points and a confidence interval that includes zero. The result does not clearly distinguish the average pain scores between the assigned regimens, but it also does not demonstrate equivalence. The interval permits differences in either direction, and no clinical-importance threshold is reported.

The result applies to the measured outcome, timeframe, participants, and regimens described in the registry record. It is not a comparison of acetaminophen with no treatment: both groups received acetaminophen by one route and a placebo component by the other. The findings concern the assigned preoperative regimens and the pain score reported through the study visit, less than 24 hours.

The posted secondary results similarly do not establish clear differences in the listed outcomes. Their unadjusted nature, uncertainty, and lack of reported multiplicity handling limit the weight they can carry. Patient satisfaction is named as an outcome, but its result is not reported in the registry record. The serious adverse event counts are zero in both arms, which describes the observed registry counts but does not rule out uncommon events.

The record alone does not support broad conclusions about other operations, settings, dosing schedules, patient groups, or longer-term outcomes. It does not report enough detail to evaluate the original analysis plan, missing data, or the analysis population. The appropriate statistical reading is therefore narrow: these are the posted results for this randomized comparison, with uncertainty that remains substantial relative to the estimated differences.

17. Why This Trial Matters Statistically

This trial illustrates an important distinction between a point estimate and the evidence supporting it. The primary estimate has a direction and numerical size, but the confidence interval indicates that the data do not determine that direction precisely. Reporting the estimate, interval, and p-value together helps prevent a single threshold from replacing a fuller reading of the result.

It also shows why a non-significant comparison should not be translated into proof of sameness. The interval includes no difference, but it also covers values on either side. Without a prespecified equivalence margin and an appropriate design and analysis, the absence of clear evidence for a difference is not evidence that the regimens are equivalent.

The registry's secondary outcomes add useful context about other postoperative measures, while also illustrating the difficulty of interpreting multiple unadjusted comparisons. Their varied directions and uncertainty do not form a strong confirmatory pattern. The missing patient satisfaction result and lack of a reported multiplicity strategy further limit an overall claim based on the full set of listed outcomes.

Finally, the record distinguishes observed results from planning assumptions. Illustrative sample-size calculations based on observed effects are not the trial's original design rationale and are not observed power. Keeping these concepts separate supports transparent interpretation, especially when the reported estimates are imprecise and important analysis details are not reported in the registry record.

18. 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 gives aggregate outcome summaries but limited detail on how outcomes were collected and analyzed. For pain, the scale and broad timeframe are stated, but the exact collection schedule and handling of repeated measurements are not reported in the registry record. Further participant characteristics, surgery types, and eligibility criteria are also not reported, limiting assessment of how broadly the results apply.

Although the trial is described as randomized and quadruple masked, the registry record does not explain the randomization method, allocation concealment, who was masked, or how masking was maintained. Adherence and departures from assigned treatment are not reported. These details matter when judging whether the observed groups and estimates reflect the intended comparison.

The record does not report an original sample-size justification, analysis plan, analysis population, missing-data approach, or interim-analysis plan. It also does not state how multiplicity was addressed. The posted aggregate results cannot answer these questions, and the absence of a reported detail should not be taken as proof that the procedure was not used.

Several outcome results are unadjusted, and the registry reports no analyses in its analysis listing. The patient satisfaction outcome is listed but its result is not reported. The short timeframe, through the study visit and less than 24 hours, also means the posted results do not describe longer-term outcomes. These limitations constrain interpretation beyond the immediate reported measures.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Preoperative IV Versus Oral Acetaminophen — NCT03468920.
• Registry record last updated 2019-05-14; status last verified 2019-05.
• Results first posted 2019-05-07.
• 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.

22. Record Summary

NCT03468920 is a completed randomized, quadruple-masked, parallel phase 4 trial sponsored by TriHealth Inc. It enrolled 120 surgical patients to compare preoperative IV acetaminophen with preoperative oral acetaminophen using placebo components in the other route.

The primary endpoint was patient-reported pain on a 0-to-10 scale through the study visit, less than 24 hours. The posted mean difference was 0.25 points for oral versus IV, with a 95% confidence interval from -0.881 to 1.381 and an unadjusted p-value of 0.665. The interval includes zero and leaves uncertainty about the direction and size of any difference.

Three secondary outcomes have posted results, all with unadjusted comparisons; patient satisfaction is listed but its result is not reported in the registry record. Serious adverse events and deaths were reported as zero in both groups. The record does not report the original sample-size rationale, analysis population, missing-data methods, or multiplicity strategy.