Acute Pain Study Following Bunionectomy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Acute Pain Study Following Bunionectomy (NCT01333722), a randomized phase 2 study. The primary outcome is Sum of Pain Intensity Difference (SPID) Using the Pain Intensity Visual Analog Scale (VAS).

2. Clinical Question

The comparison concerns the average reported primary outcome over a short, defined period after the first dose. It does not by itself describe pain at later times, outcomes after the study period, or how individual participants responded. The registry record identifies safety as part of the study purpose, but the posted safety counts are limited to adverse-event categories and do not provide a detailed account of event type or timing.

3. Trial Design

This was a randomized, double-masked, parallel-group phase 2 study comparing hydrocodone/acetaminophen extended release with placebo. The registry record reports enrollment of 100 participants. The posted arm summaries include 51 participants in the hydrocodone/acetaminophen extended-release group and 49 in the placebo group. These are the observed group sizes in the endpoint results; the original allocation target and the rationale for the planned enrollment are not reported in the registry record.

The study addressed moderate to severe pain following bunionectomy. Each arm description specifies 1 oral tablet every 12 hours, with the active arm receiving hydrocodone/acetaminophen extended release and the comparator arm receiving placebo. The record identifies the trial as completed. It reports the study start as 2011-04 and primary completion as 2011-06.

For the primary outcome, the analysis population is described as all randomized participants who received at least 1 dose of study drug. The registry record does not report the number of randomized participants who did not receive a dose, or explain whether any randomized participants were excluded from the posted endpoint summaries. It also does not report details of the randomization procedure, concealment, masking assessment, or the statistical model used to obtain the least-squares means.

The primary endpoint covered the period from the first study-drug administration to 12 hours following that administration. Secondary outcomes listed in the record include total pain relief, pain relief and pain-intensity difference, and time to perceptible and meaningful pain relief. The record does not describe a longer follow-up period in the primary endpoint information.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All randomized participants who received at least 1 dose of study drug.

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 Sum of Pain Intensity Difference (SPID) Using the Pain Intensity Visual Analog Scale (VAS), measured over From time of first study drug administration to 12 hours following first study drug administration.

The primary endpoint was the Sum of Pain Intensity Difference (SPID) using a pain-intensity visual analogue scale (VAS). Participants rated pain on a 100 mm scale, where 0 meant no pain and 100 meant the worst pain imaginable. The SPID VAS score covered 0 to 12 hours following the initial study-drug dose and represented cumulative pain-intensity difference during treatment. Higher mean SPID VAS scores indicated greater improvement from baseline.

In general, a cumulative measure combines information over a period rather than describing pain at just one assessment. The registry record says the area under the curve was estimated using the linear trapezoidal rule. In general, this approach uses the measured values across time points to approximate the accumulated difference over the interval. This can express the overall pattern during the specified period, while still depending on the measurements collected and the method used to combine them.

The posted arm summaries are least-squares means, with standard errors reported as the dispersion measure. The registry record does not explain the adjustment variables or model used to produce those means. The endpoint is therefore best understood as a summary of the average cumulative pain-intensity difference during the first 12 hours, not as a direct estimate of the experience of every participant or a measure of pain beyond that interval.

7. Results Posted in the Registry

• Hydrocodone/Acetaminophen Extended Release: mean 259.00 versus 39.40 on control; difference 219.60 (95% CI 114.79 to 324.41), standardized effect d = 0.82; z-test p = <0.001.

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.

TOTPAR (Total Pain Relief)

• 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 errors.
• Result:
  • Hydrocodone/Acetaminophen Extended Release: mean 15.40 versus 5.30 on control; difference 10.10 (95% CI 5.30 to 14.90), standardized effect d = 0.83; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Hydrocodone/Acetaminophen Extended Release than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

SPRID (Pain Relief and Pain Intensity Difference)

• 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 errors.
• Result:
  • Hydrocodone/Acetaminophen Extended Release: mean 23.40 versus 7.20 on control; difference 16.20 (95% CI 8.54 to 23.86), standardized effect d = 0.83; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Hydrocodone/Acetaminophen Extended Release than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The posted secondary comparisons follow the same overall direction as the primary comparison: the least-squares mean is higher in the hydrocodone/acetaminophen extended-release group than in the placebo group for the secondary outcomes with numerical results. These include total pain relief and the combined pain-relief and pain-intensity-difference measure over the first 12 hours. The record also lists time to perceptible and meaningful pain relief as a secondary outcome, but a numerical estimate for that outcome is not reported in the registry record.

In general, agreement in direction across related outcomes can provide context for the primary endpoint. It does not make the outcomes independent confirmations: pain relief, pain intensity, and cumulative pain measures may capture overlapping aspects of the same experience. The secondary findings therefore complement the primary result rather than replace it or establish a separate conclusion about a different time period.

The reported secondary comparisons have unadjusted p-values of <0.001. Unadjusted results do not account for the fact that more than one outcome is being examined. In general, considering multiple tests increases the chance of obtaining at least one small p-value even when the null hypotheses hold. The registry record does not report a multiplicity strategy, a hierarchy for interpreting endpoints, or adjusted p-values. For that reason, these secondary results carry less weight for confirmatory interpretation than a prespecified primary result, and they should be viewed as supportive descriptive evidence rather than stand-alone proof.

The record does not report detailed analysis methods for the secondary outcomes, including whether they used the same model and analysis population as the primary endpoint. Their direction can be noted, but differences in endpoint construction and unknown modeling details limit comparisons of the numerical scales across outcomes. The secondary measures should not be compared as if a point on one scale were equivalent to a point on another.

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

• TOTPAR (Total Pain Relief)
• SPRID (Pain Relief and Pain Intensity Difference)
• Time to Perceptible and Meaningful Pain Relief

9. Statistical Interpretation

10. Statistical Methods Explained

The main descriptive results are least-squares means, and their reported dispersion is the standard error. In general, a least-squares mean is a model-based estimate of a group mean. It can account for terms included in the statistical model, whereas a simple arithmetic mean uses the observed values directly. The registry record does not identify the model terms or adjustments used for these estimates. It is therefore not possible to determine from the record which covariates, if any, contributed to the reported least-squares means.

In general, a standard error describes the estimated sampling variability of an estimate, rather than the spread of individual participant outcomes. Smaller standard errors tend to correspond to greater precision, although precision also depends on the estimator and analysis assumptions. The registry record reports standard errors of 37.52 for the hydrocodone/acetaminophen extended-release group and 38.1 for placebo for the primary outcome. These values should not be confused with standard deviations or with the range of participant scores.

The primary contrast is expressed as a mean difference between the active group and placebo. The posted estimate is 219.6, with the active group as the higher-mean group. In general, a difference on the original outcome scale can be interpreted in the units of that outcome, subject to how the outcome is defined. Here, the measure is a cumulative pain-intensity difference score; it is not a direct VAS reading at a single time point. The registry record reports the contrast and its interval but does not provide a detailed inferential-method description.

The reported p-value is unadjusted and is <0.001. In general, a p-value evaluates how compatible the observed data are with a specified null hypothesis, under a statistical model and its assumptions. It is not the probability that the null hypothesis is true, and it does not quantify the probability that the result occurred by chance. The record does not report the test used, its assumptions, or an adjustment of this p-value for the number of outcomes considered.

The confidence interval for the primary mean difference extends from 114.8 to 324.4. In general, an interval gives a range of values compatible with the estimate and its uncertainty under the method used. It is not a guarantee that the true value lies in the reported range, and its interpretation depends on the confidence level and the procedure used to calculate it. The confidence level and interval method are not reported in the registry record. Accordingly, the interval can be described as posted, but its construction cannot be independently reconstructed from the record.

The registry record says that SPID was calculated from the area under the curve using the linear trapezoidal rule. In general, this method approximates the area between consecutive measurements by treating the change between them as linear. The accumulated area represents pain-intensity difference over the defined time interval. The record does not list the individual assessment times or the formula for baseline adjustment, beyond describing the score as cumulative pain-intensity difference and stating that higher scores indicate greater improvement from baseline.

The posted secondary results use the same broad reporting pattern: least-squares means, standard errors, and active-versus-placebo comparisons. In general, seeing a similar direction across outcomes can make the overall pattern easier to assess, but those outcomes may be related rather than independent. The registry record does not report a prespecified hierarchy among the primary and secondary outcomes or a multiplicity adjustment. Thus, secondary p-values should not be interpreted as if each were the only test conducted.

There are no reported analysis records listed in the registry record. That does not erase the posted group summaries and comparisons, but it limits the statistical detail available for evaluating them. The record does not report whether the primary analysis was adjusted, how protocol deviations were handled, or whether sensitivity analyses were conducted. It also does not report an interim-analysis plan. Those aspects cannot be filled in from the numeric estimates alone.

General statistical interpretation depends on the endpoint definition, analysis population, comparison, and uncertainty measure together. For this study, the population is described as randomized participants who received at least 1 dose; the endpoint accumulates pain-intensity difference through 12 hours; and the posted comparison is a difference in least-squares means. Reading these elements together prevents treating the score as a single-time pain rating, the standard error as participant variability, or the p-value as a measure of clinical importance.

11. Confidence Intervals and Precision

The primary mean difference was 219.6, and its posted confidence interval extends from 114.8 to 324.4. This interval describes uncertainty around the estimated contrast under the method used. Its endpoints are both above 0, so the reported interval does not include no difference. The record does not report the confidence level or the procedure used to construct the interval; those details should not be assumed.

In general, a narrower confidence interval indicates greater precision than a wider interval for the same estimand and method. Precision is not the same as validity: an estimate can be precise while still depending on choices about the analysis, measurement, or study population. The registry record reports standard errors of 37.52 and 38.1 for the two primary endpoint group means, but does not report the model specification that produced the least-squares means or the interval.

The interval also helps distinguish the estimated magnitude from a binary significance label. The posted estimate is 219.6, while the interval shows a range of values compatible with the analysis rather than a single known effect. It does not show the spread of individual participants’ outcomes or imply that every participant experienced a change of that size. The registry record does not report a clinical-importance threshold for this score, so the interval cannot be classified against such a threshold.

For context, the group sizes in the primary result were 51 and 49. The record does not include participant-level outcome data, assessment-level completeness, or missing-data methods, so it is not possible to assess how those features affected precision. The reported interval should therefore be read as the precision of the posted comparison, not as a complete account of every source of uncertainty.

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 participants per arm, not total events. They are illustrations based on the observed effect in this study, rather than the trial’s original enrollment calculation. The registry record’s stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set at the stated fraction of the observed effect. The original design assumptions and sample-size justification are not reported in the registry record.

For each planning scenario, the 80% power column means the illustrated number of participants per arm for an 80% chance of detecting the specified effect under those assumptions, if the assumed effect and statistical model apply. The 90% power column gives the corresponding illustration for a 90% chance. These are planning concepts, not guarantees about a future study, and the registry record does not establish that its actual design used these assumptions.

The rows use 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. The number of participants per arm rises as the assumed effect becomes smaller: detecting a smaller difference generally requires more information, and often a larger sample, to achieve the same target power under otherwise similar assumptions. The displayed curve should be read as a visual companion to that relationship, not as evidence that any particular sample size was planned or achieved.

These figures are not observed power. They are planning illustrations that use the effect estimated from the posted results, so they should not be taken as an independent assessment of the design or as a substitute for the trial’s unreported original sample-size rationale.

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 = 219.600; pooled standard deviation σ = 267.337.
2. n = 2 × (1.96 + 0.842)² × 267.337² / 219.600² = 23.3, rounded up to 24 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 <- 219.6                      # observed difference in means
sigma <- 267.336641708539                     # 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(1333722)
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 = 24 (80% power), 32 (90% power)
 75% of observed effect: n per arm = 42 (80% power), 56 (90% power)
 50% of observed effect: n per arm = 94 (80% power), 125 (90% power)
power.t.test: 24.3 
Simulated power at n = 24 per arm: 0.794 (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 record identifies one primary endpoint and lists secondary outcomes, but does not report a multiplicity-control plan. It does not state whether the secondary outcomes were tested in a hierarchy, whether any adjustment was applied, or what role secondary results were intended to play in confirmatory interpretation. The reported p-values are unadjusted. In general, when several hypotheses are tested, unadjusted p-values do not account for the greater opportunity for a small p-value across the collection of tests.

Missing-data methods are not reported in the registry record. The record does not state how incomplete pain assessments were handled, whether participants with partial follow-up contributed to the endpoint, or whether any imputation or sensitivity analysis was used. This absence of method information does not show that data were missing; it means the record does not describe whether missingness occurred or how it was addressed.

The primary population is defined as all randomized participants who received at least 1 dose of study drug. This definition makes receipt of at least one dose part of the analysis population. The record does not report the number randomized who did not receive a dose, nor does it explain whether an all-randomized analysis was also conducted. It also does not provide a detailed account of exclusions, protocol deviations, or adherence to the assigned intervention.

The registry record lists no analysis records and does not describe the statistical model, test, interim analyses, or sensitivity analyses. Consequently, the posted summaries can be interpreted as reported, but the analysis process cannot be fully evaluated. The record does not report whether the analysis plan was finalized before outcome data were examined. These unknowns matter when assessing how firmly the estimates and unadjusted p-values support broader conclusions.

15. 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 non-serious adverse event terms

The posted serious adverse-event counts are 0 affected participants among 51 at risk in the hydrocodone/acetaminophen extended-release group and 0 among 49 at risk in the placebo group. This means the registry record reports no participants with a serious adverse event in either group during the reported safety accounting. The record does not provide a breakdown of serious adverse-event terms.

For other adverse events, 28 participants are reported as affected in the active-treatment group and 14 in the placebo group. These are counts, not estimates of comparative risk adjusted for exposure or follow-up. The registry record does not provide event timing, severity detail, recurrence, or a statistical comparison for these counts. Deaths are not reported in the registry record. The safety figures should therefore be read as a limited summary of the posted categories, not as a complete characterization of safety.

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

The primary result describes a difference in average cumulative pain-intensity difference over the first 12 hours after the initial dose. The active group had a higher posted least-squares mean than placebo, and the reported mean difference was positive with a confidence interval that did not include 0. The unadjusted p-value was <0.001. These statistics describe the posted comparison for this endpoint and analysis population.

They do not establish how each participant responded. A group mean can coexist with varied individual outcomes, and the registry record does not report the distribution of responses or the proportion of participants meeting a defined response threshold. It also does not provide a clinical-importance threshold for SPID VAS. Statistical evidence of a group difference should not be treated as a judgment about whether the difference matters to patients.

The result is specific to the population, intervention, comparator, endpoint, and time window described in the record: participants with pain following bunionectomy, hydrocodone/acetaminophen extended release versus placebo, and cumulative pain-intensity difference through 12 hours after the first dose. The result does not establish outcomes after that interval, for other procedures or populations, or for other dosing regimens. Such extrapolations are not assessed by these posted results.

The record includes secondary outcome summaries that generally point in the same direction, but their p-values are unadjusted and a multiplicity plan is not reported. The results also do not provide a complete account of missing data, analysis decisions, or detailed safety events. A careful interpretation therefore recognizes the clear direction of the reported primary contrast while keeping the limits of the registry information in view. No treatment recommendation follows from these statistics alone.

17. Why This Trial Matters Statistically

Statistically, this study illustrates the distinction between a single-time rating and an outcome accumulated across time. SPID VAS summarizes cumulative pain-intensity difference during the first 12 hours, and the registry record describes how the area under the curve was estimated. Interpreting the numerical result requires understanding that it is a cumulative score, not a direct VAS reading at one assessment.

The record also makes visible the importance of matching the estimate to its uncertainty. A mean difference and confidence interval convey magnitude and precision in a way that a p-value alone cannot. Here, the estimate is accompanied by an interval and standard errors, while the record does not report the confidence level or detailed model. That combination demonstrates why statistical interpretation should include both what is reported and which methodological details remain unknown.

The study further illustrates the difference between design information and retrospective planning illustrations. The sample-size figures use fractions of the observed effect under stated assumptions, while the original design rationale is not reported. These calculations can help explain how assumed effect size relates to required sample size, but they do not document the trial’s original planning process and are not observed power.

Finally, the primary and secondary outcomes raise an important issue of multiplicity. Related outcomes may offer a coherent descriptive pattern, but unadjusted secondary tests do not carry the same interpretive weight as a single prespecified primary comparison. The record’s missing details about multiplicity, missing data, and model specification show how registry summaries can support useful statistical reading while still leaving important aspects of analysis transparency unresolved.

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 describes a phase 2 study with 100 enrolled participants and endpoint group sizes of 51 and 49. This is a relatively limited record of a specific study population and setting; the results alone do not establish how well the findings apply outside pain following bunionectomy. Further participant characteristics are not reported in the registry record, so the composition of the analyzed population cannot be assessed from these summaries.

The primary endpoint covers only the first 12 hours following the first study-drug administration. The record does not provide a primary estimate for pain beyond that interval. The listed time-to-relief outcome does not have a numerical result reported in the registry record, limiting what can be said about that aspect of the study from the posted statistics.

Important statistical details are absent, including the model specification, confidence-interval method and level, missing-data handling, and multiplicity approach. The primary analysis population excludes randomized participants who did not receive at least 1 dose by definition, but the record does not give the number in that category or report another analysis population. This limits assessment of how those decisions relate to the posted estimates.

The safety summary reports counts for serious and other adverse events but gives no event-term detail or timing, and deaths are not reported in the registry record. The counts therefore do not provide a comprehensive account of the safety data. These limitations are specific to the information available for this study and should be kept separate from the direction and precision of the primary endpoint comparison.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Acute Pain Study Following Bunionectomy — NCT01333722.
• Registry record last updated 2014-04-08; status last verified 2014-03.
• Results first posted 2014-03-07.
• 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

The registry record describes a completed, randomized, double-masked, parallel-group phase 2 study of hydrocodone/acetaminophen extended release versus placebo for moderate to severe pain following bunionectomy. Enrollment was 100, and the primary endpoint population was randomized participants who received at least 1 dose.

The primary outcome was cumulative pain-intensity difference on the VAS through 12 hours after the first dose. The posted mean difference was 219.6, with a confidence interval from 114.8 to 324.4 and an unadjusted p-value of <0.001. The record reports secondary outcome summaries and limited adverse-event counts, while leaving important analysis, missing-data, multiplicity, and safety details not reported in the registry record.