Administration of Ketamine to Prevent the Post-operative Pain: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Administration of Ketamine to Prevent the Post-operative Pain (NCT00210210), a randomized phase 3 study. The primary outcome is Morphine Consumption (First 48 Post-operative Hours).

2. Clinical Question

3. Trial Design

The registry classifies this as a phase 3, randomized, double-masked, parallel-group trial. Randomized allocation means that participants were assigned to the ketamine or reference arm by a random process, as classified in the registry. In general, randomization is intended to reduce systematic differences between groups at the start of a trial; it does not guarantee that the groups will be identical in every characteristic. The record does not describe the randomization procedure or how the allocation sequence was generated.

Double masking indicates that the registry classifies the trial as masked at two levels. The record does not specify which people were masked, how masking was maintained, or whether the masking was assessed. The parallel model means the arms are separate groups receiving their assigned regimens during the trial rather than participants crossing between regimens. The registry lists ketamine and saline solution as drug interventions.

The ketamine regimen was added to a reference protocol at both anesthetic induction and maintenance. The recorded induction dose was 0.15 mg/kg, and the maintenance dose was 2 mg/kg/min. The reference arm received induction and anesthetic maintenance without ketamine. Details of the reference protocol, the conduct of anesthesia, and the timing of outcome assessment beyond the stated 48-hour window are not reported in the registry record.

The study is marked completed. The recorded start date is 2004-01-31, and the primary completion date is 2005-07-31. Enrollment was 230. The primary outcome records morphine use in the first 48 postoperative hours. The registry also lists postoperative pain as a secondary outcome. It does not give further detail on the secondary outcome's definition or its analysis. The outcome counts are 109 participants in the ketamine arm and 104 in the reference arm; the registry does not explain the relationship between those outcome denominators and the enrollment figure.

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:

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 Morphine Consumption (First 48 Post-operative Hours), measured over within 48 hours following surgery.

The primary endpoint is the number of participants who had at least one consumption of morphine within 48 hours following surgery. It is recorded as a participant count, so each participant is classified according to whether morphine was consumed at least once during the stated period. The endpoint does not capture the total amount of morphine, the number of doses, the timing of use, or pain intensity.

Morphine consumption was selected as an indicator relevant to the trial's stated analgesic question. The registry's summary describes postoperative pain after breast cancer surgery and proposes evaluating ketamine's analgesic effect in association with general anesthesia. In general, an endpoint is useful when it turns a clinical question into a defined outcome that can be compared across randomized groups. A binary endpoint such as this one permits comparison of the proportion of participants with any recorded use, while losing detail about the amount or pattern of use.

The registry gives the timeframe as within 48 hours following surgery. In the ketamine arm, 79 of 109 participants were recorded as having at least one morphine consumption; in the reference arm, the corresponding count was 77 of 104. These are participant counts for the stated window. The registry does not report a more detailed endpoint definition, such as how consumption was documented, or how participants with incomplete observation during the window were handled.

7. Results Posted in the Registry

• Ketamine Arm: 72.5% (79/109) versus 74.0% (77/104) on control; risk difference -1.6 percentage points (95% CI -13.4 to 10.3), risk ratio 0.98 (0.83–1.15); unadjusted two-proportion z-test p = 0.797.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is binary: a participant either had at least one morphine consumption within 48 hours following surgery or did not. The posted counts are 79 of 109 in the ketamine arm and 77 of 104 in the reference arm. A comparison of these groups can be expressed on several scales. Each scale answers the same broad question about group differences but expresses that difference differently. The registry record does not report a full analysis plan or the procedure used for the trial's original analysis.

What does a risk difference express?

In general, a risk difference subtracts one group's event proportion from the other group's event proportion. It is an absolute measure on the probability scale. The reported risk difference is -0.016, and its 95% confidence interval is -0.135 to 0.103. The negative estimate indicates a lower observed proportion in the ketamine arm under the comparison's orientation. The interval crosses 0, the value corresponding to no difference in proportions. Because its endpoints extend to either side of 0, the estimate is not precise enough to determine the direction of the underlying difference from these data alone.

How do risk ratios and odds ratios differ?

In general, a risk ratio compares event proportions by division, while an odds ratio compares the odds of an event between groups. Both are relative measures and have 1 as the value representing no group contrast. The reported risk ratio is 0.979, with a 95% confidence interval from 0.832 to 1.151. The reported odds ratio is 0.923, with a 95% confidence interval from 0.503 to 1.695. Each interval includes 1. These relative measures are not interchangeable with the risk difference: they use different scales and can give different impressions of the same data, particularly when an outcome is common.

What does the confidence interval add?

In general, a confidence interval describes the range of estimates reasonably compatible with the observed data under the method's assumptions. It communicates uncertainty around an estimate, rather than only displaying one point estimate. A confidence interval is not a guarantee that the true effect lies within the particular reported bounds, nor is it a direct probability statement about the effect. For the risk difference, the interval from -0.135 to 0.103 includes no difference and effects on both sides of it. The risk-ratio and odds-ratio intervals likewise include their respective no-contrast values.

What does the p-value say?

The posted unadjusted p-value is 0.797. In general, a p-value is calculated under a null model, often one that specifies no group difference, and describes how compatible the observed data are with that model relative to the chosen test. It does not tell whether the null model is true, quantify the probability that a result occurred by chance, or measure clinical relevance. A larger p-value is not proof of equivalence. Establishing equivalence would require a defined equivalence margin and an analysis designed for that question; such a margin is not reported in the registry record.

Why can the outcome scale matter?

The endpoint is a count of participants with any morphine consumption, not a continuous measure of dose. This makes the outcome straightforward to interpret as whether any use occurred during the stated interval, but it collapses distinct patterns of consumption into the same category. In general, two groups could have similar proportions with any use while differing in the amount consumed among participants who used morphine. The posted endpoint does not answer that dose question. It also does not characterize the timing or reasons for use.

What can be inferred from the posted comparison?

The reported statistics quantify the contrast based on the outcome counts, and the unadjusted p-value and confidence intervals express different aspects of the comparison. The point estimates are near the no-contrast values, but precision is limited by the breadth of the intervals. The registry reports zero posted analyses. The analysis population, handling of missing observations, adjustment variables, test specification, and any sponsor analysis details are not reported in the registry record. The posted result should therefore be read as a comparison of the recorded counts, not as a complete description of the trial's analysis strategy.

In general, an unadjusted comparison uses the group outcome data without adjustment for other variables. Whether an adjusted analysis was planned or performed is not reported in the registry record. Random allocation supports a between-group comparison, but the details of implementation and analysis still matter when assessing how well an estimate answers the study question. No additional model assumptions or subgroup analyses should be inferred from the reported summary statistics.

10. Confidence Intervals and Precision

Precision concerns how narrowly the data locate the estimated group difference. The risk difference is -0.016, with a 95% confidence interval from -0.135 to 0.103. This interval includes 0, the value for no difference, and reaches both negative and positive values. The estimate therefore does not pin down whether the underlying difference favors either arm, nor does it tightly identify its size.

The relative measures also have intervals that include no contrast. The risk ratio is 0.979, with a 95% confidence interval from 0.832 to 1.151. The odds ratio is 0.923, with a 95% confidence interval from 0.503 to 1.695. Their breadth indicates uncertainty on the relative scales as well. These intervals should be interpreted on their own scales: 0 is the no-difference value for a risk difference, whereas 1 is the no-contrast value for a risk ratio or odds ratio.

In general, a confidence interval reflects both the estimated effect and the amount of information in the data, together with the method used to construct it. A narrow interval indicates more precision than a wide one, but even a narrow interval does not establish clinical importance by itself. The registry record does not report a prespecified threshold for a clinically important difference, so the clinical meaning of particular values within the intervals cannot be determined from the record alone.

The counts give the observed endpoint frequencies, while the intervals express uncertainty about the group contrast. They should be read together. The point estimate alone can make the comparison appear settled, while the interval shows that other effect sizes remain compatible with the data. Conversely, an interval that includes no difference does not prove that the true effect is exactly zero.

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 computed from the observed effect, not a report of the trial's own design calculation. The 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 in turn to 100%, 75%, or 50% of the observed effect. The registry record does not report the original sample-size justification or its design assumptions.

The 80% power column gives the number of participants per arm that the illustration estimates would be needed for an 80% chance of detecting the specified effect under those assumptions, if that effect and the other assumptions were correct. The 90% power column gives the corresponding planning number for a 90% chance. These are planning concepts, not statements about what happened in the trial. The illustration is not observed power.

For the planning scenario using 100% of the observed effect, the figures are 12,614 participants per arm for 80% power and 16,885 per arm for 90% power. At 75% of the observed effect, they are 22,320 per arm for 80% power and 29,880 per arm for 90% power. At 50% of the observed effect, they are 49,985 per arm for 80% power and 66,915 per arm for 90% power. The pattern illustrates a general principle: smaller effects are harder to distinguish from no effect, so more participants are needed to detect them with the same planned power. The curve represents that relationship under the stated illustration assumptions; it is not a record of trial outcomes or evidence about the trial's actual 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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.740; treatment proportion p₁ = 0.725; average p̄ = 0.733.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6260 = 1.2268.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6259 = 0.5267.
4. n = (1.2268 + 0.5267)² / (-0.0156)² = 12,613.1, rounded up to 12,614 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
p0 <- 0.740384615384615                          # control proportion
p1 <- 0.724770642201835                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(210210)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 12,614 (80% power), 16,885 (90% power)
 75% of observed effect: n per arm = 22,320 (80% power), 29,880 (90% power)
 50% of observed effect: n per arm = 49,985 (80% power), 66,915 (90% power)
power.prop.test: 12613.1 
Simulated power at n = 12,614 per arm: 0.799 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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 lists morphine consumption within 48 hours following surgery as the primary outcome and postoperative pain as a secondary outcome. It records 2 outcome measures and 1 posted secondary outcome. The multiplicity strategy, including whether any adjustment was planned for testing more than one outcome, is not reported in the registry record. The registry also does not state whether any secondary outcome was prespecified as confirmatory or exploratory.

Multiplicity is a general statistical concern when several hypotheses are tested: as the number of tests increases, the chance of at least one apparently notable result can increase if no adjustment or other strategy is used. Whether this concern applies to a particular analysis depends on the planned questions and how results are interpreted. The record does not provide enough detail to determine the full set of tests performed or the approach used to control or describe multiplicity. The posted unadjusted p-value should not be interpreted as evidence that multiplicity was or was not addressed elsewhere.

The registry reports zero posted analyses. The analysis population used for the primary comparison is not reported in the registry record. It is also not reported whether the analysis followed intention-to-treat, per-protocol, or another population definition. The record does not describe exclusions, crossovers, protocol deviations, or whether every randomized participant had complete outcome ascertainment.

Missing-data procedures are not reported in the registry record. In particular, the record does not describe the amount or pattern of missing outcome data, any imputation, or how participants without a recorded outcome were handled. Interim analyses, stopping rules, covariate adjustment, and subgroup analyses are also not reported. These omissions limit assessment of how the posted comparison relates to the planned analysis, but they do not alter the meaning of the counts that are recorded.

14. 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

For serious adverse events, the registry reports 0 affected participants among 109 at risk in the ketamine arm and 0 among 104 at risk in the reference arm. Deaths are recorded as 0 in each arm. These figures describe the posted serious-event and death counts for the groups at risk; they do not establish that no event of any kind occurred or that the groups have identical safety profiles.

The record also lists 20 participants affected by other adverse events in the ketamine arm and 14 in the reference arm. Those are separate from the serious adverse-event counts. The registry does not provide the terms for serious adverse events, and the specific other adverse-event categories and their severity are not described in the record. The number of affected participants does not indicate how many events each participant experienced.

In general, zero recorded events in a group is a count, not proof that the underlying risk is zero. Safety interpretation depends on the observation period, event definitions, completeness of reporting, and the size of the groups. Further details about event ascertainment and follow-up are not reported in the registry record.

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

The posted result describes morphine consumption within 48 hours after surgery in the two randomized arms. The observed counts were 79 of 109 participants in the ketamine arm and 77 of 104 in the reference arm. The estimated risk difference was -0.016, and its 95% confidence interval, -0.135 to 0.103, includes no difference and values in either direction. The posted unadjusted p-value was 0.797. Taken together, these statistics show an uncertain estimate rather than a precise answer about the direction or size of a group difference.

The result does not establish that ketamine reduced morphine use, nor does it establish that ketamine had no effect. A non-significant comparison is not the same as proof of equivalence or absence of an effect. Such conclusions require a design and analysis suited to those claims, including a prespecified margin where relevant; the registry does not report such a margin.

The outcome is limited to whether a participant consumed morphine at least once in the stated postoperative interval. It does not show the quantity consumed, differences in pain intensity, the timing of use, or longer-term outcomes. Postoperative pain is listed as a secondary outcome, but its detailed results are not reported in the registry record. The posted primary outcome therefore cannot answer every question about analgesia or recovery.

The registry record also does not describe the analysis population, missing-data handling, or full statistical plan. These details matter when judging the reach of an estimate. The findings should be read as a comparison of the recorded endpoint counts in this trial, with the reported uncertainty, rather than as a universal conclusion for all surgical settings or patients.

16. Why This Trial Matters Statistically

This trial illustrates why an outcome definition should be kept close to its statistical interpretation. The primary endpoint is the presence of any morphine consumption within 48 hours, a clear binary event. That makes the group contrast interpretable as a difference in participants with any recorded use, but it cannot describe dose or the pattern of analgesic use. The clinical question and the statistical endpoint overlap, but they are not identical to every dimension of postoperative pain.

It also illustrates the value of reporting estimates alongside p-values. The risk difference, risk ratio, odds ratio, and their confidence intervals communicate the direction and uncertainty of the comparison on different scales. The point estimates are near their respective no-contrast values, while the intervals include those values and extend to alternatives. The unadjusted p-value alone would not convey the breadth or direction of the plausible contrasts.

The registry record identifies a randomized, double-masked, parallel-group phase 3 trial, but records no posted analyses and does not report the full statistical plan. That gap highlights the importance of access to analysis populations, missing-data procedures, multiplicity strategy, and prespecified effect measures when interpreting a clinical trial. Without those details, readers can interpret the posted outcome counts and comparison, but cannot reconstruct all aspects of the analysis or its relationship to a complete protocol.

Finally, the planning illustration emphasizes the connection between effect size and required information. Smaller target effects require more participants under the stated assumptions. This is a planning principle, not a retrospective measure of whether the trial was adequately powered. Distinguishing design calculations from observed results helps keep sample-size planning separate from inference about the trial's outcome.

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's outcome information is narrow: the primary endpoint records any morphine consumption within 48 hours, not total dose, number of doses, pain severity, or the timing of consumption. Although postoperative pain is listed as a secondary outcome, its detailed results are not reported in the registry record. The posted primary comparison therefore cannot characterize the full analgesic experience.

The relationship between the enrollment figure of 230 and the primary outcome denominators of 109 in the ketamine arm and 104 in the reference arm is not explained in the registry record. The record does not report the primary analysis population, participant flow, exclusions, or completeness of outcome collection. Missing-data handling and sensitivity analyses are also not reported, limiting assessment of how incomplete data might affect the comparison.

Details needed to evaluate trial conduct and analysis are absent from the registry record. These include the randomization procedure, which roles were masked, the reference anesthesia protocol, the full statistical plan, adjustment methods, multiplicity handling, interim analyses, and stopping rules. The registry reports zero posted analyses. The available comparison is therefore not a substitute for a full protocol or statistical analysis plan.

Safety reporting is also limited. Serious adverse-event counts and deaths are reported, along with counts for other adverse events, but event terms and further clinical details are not reported in the registry record. The posted counts alone do not describe event duration, severity beyond the serious classification, or the completeness of safety follow-up. These limitations qualify what can be inferred from this record without changing the reported outcome counts.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Administration of Ketamine to Prevent the Post-operative Pain — NCT00210210.
• Registry record last updated 2025-09-19; status last verified 2025-09.
• Results first posted 2025-09-08.
• 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

The registry record identifies NCT00210210 as a completed phase 3 randomized, double-masked, parallel-group trial sponsored by Institut Bergonié. It lists breast cancer and postoperative pain as conditions, with enrollment of 230. The recorded start date is 2004-01-31, and the primary completion date is 2005-07-31.

The ketamine arm received ketamine added to the reference anesthesia protocol at induction and maintenance; the reference arm received anesthesia without ketamine. The primary endpoint was at least one morphine consumption within 48 hours following surgery. Counts were 79 of 109 in the ketamine arm and 77 of 104 in the reference arm. The risk difference was -0.016, with a 95% confidence interval from -0.135 to 0.103, and the unadjusted p-value was 0.797.

Postoperative pain is listed as a secondary outcome. The record reports no serious adverse-event-affected participants and no deaths in either arm, while recording other adverse events in both arms. The detailed statistical plan, analysis population, and missing-data procedures are not reported in the registry record.