Transdermal Nicotine and Melatonin Patches for Postoperative Pain Relief: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Transdermal Nicotine and Melatonin Patches for Postoperative Pain Relief (NCT02747628), a randomized phase 4 study. The primary outcome is A Mean Difference of Total Analgesic (Pethidine) Consumption..

2. Clinical Question

3. Trial Design

The registry describes a completed, randomized, parallel-group, Phase 4 trial sponsored by Ain Shams University. It records enrollment of 60 and lists three groups: placebo, transdermal nicotine, and transdermal melatonin. Each group description gives n=20. The study concerned postoperative pain relief after elective laparoscopic cholecystectomy under general anesthesia.

The intervention descriptions say that patches were placed 2 hours before surgery. The nicotine patch was described as 15 mg/16 h, and the melatonin patch as 7 mg/8h. Participants in the comparator group received a placebo patch. The registry identifies allocation as randomized and masking as triple. However, its brief summary describes the study as double-blind. The registry record therefore contains different descriptions of masking; further detail about who was masked is not reported in the registry record.

The primary outcome was total pethidine consumption, measured in milligrams over 12 hours after surgery. The brief summary also describes assessments of pain, sedation, hemodynamic variables, arterial oxygen saturation, side effects, satisfaction, intraoperative bleeding, and plasma cortisol. It gives postoperative assessment times of 30 minutes, 1, 2, 6, and 12 hours for several measures. The registry does not post secondary outcome results in the record.

The record lists a start date of 2013-04, primary completion of 2015-07, and status as completed. Further details about recruitment procedures, sites, protocol deviations, or the trial’s original statistical design assumptions are not reported in the registry record.

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 A Mean Difference of Total Analgesic (Pethidine) Consumption., measured over [Time Frame: The total pethidine requirements (mg) 12 hours postop].

The primary endpoint is the mean total amount of pethidine, in milligrams, required during the 12 hours after surgery. Pethidine is an analgesic, so its total consumption is a measure of analgesic use during the defined postoperative period. The registry’s outcome title describes a mean difference in total analgesic consumption, and the outcome is classified as a continuous measure.

Comparing group means provides a direct summary of average consumption in each randomized group. The mean difference expresses how far the active-treatment group’s average was from the placebo group’s average, in the original measurement units. A negative difference in these comparisons means that the active group’s posted mean was lower than the placebo group’s mean; it does not by itself establish the clinical importance of that difference.

The endpoint captures consumption over a fixed postoperative interval, not pain intensity at a single assessment time and not analgesic use beyond that interval. The brief summary mentions repeated pain assessments, but the primary endpoint is the total pethidine requirement. Details such as how consumption was handled for participants with incomplete observation or whether other analgesics contributed to the endpoint are not reported in the registry record.

7. Results Posted in the Registry

• TDN Group, (n=20): mean 55.50 versus 122.15 on control; difference -66.65 (95% CI -69.94 to -63.36), standardized effect d = -12.54; z-test p = <0.001.
• TDM Group, (n=20): mean 59.70 versus 122.15 on control; difference -62.45 (95% CI -65.85 to -59.05), standardized effect d = -11.37; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean difference express?

For a continuous outcome, a mean is the arithmetic average of the measured values in a group. The comparison reported for each active-treatment group is a difference between that group’s mean and the placebo group’s mean. Because all means use milligrams, the difference remains in milligrams and can be interpreted on the scale of the original endpoint. A negative estimate indicates a lower active-group mean than the comparator mean. In this trial, the posted means are 122.2 mg for placebo, 55.5 mg for nicotine, and 59.7 mg for melatonin.

A mean difference is a summary of group averages, not a statement that every participant had a value equal to that average or experienced the same difference. The standard deviation conveys how spread out individual measurements were within a group. The registry lists standard deviations for each group, but does not provide participant-level outcome data.

How should the unadjusted comparisons be understood?

The registry record includes two comparisons against placebo: nicotine versus placebo and melatonin versus placebo. Their recalculated mean differences are -66.65 mg and -62.45 mg, respectively, and both have p < 0.001. These are unadjusted comparisons, meaning no multiplicity correction is reflected in the reported p-values. They are based on the posted summary statistics rather than a reported adjusted model. The record lists no analysis entries, and a detailed analysis plan is not reported in the registry record.

In general, a p-value is a measure of how surprising data at least as incompatible with a specified null hypothesis would be if that hypothesis and the test assumptions held. It is not the probability that a treatment effect is absent, nor a measure of the effect’s practical importance. A small p-value does not address possible bias, missing outcome data, or limits on applying results beyond the study population.

Why do spread and precision both matter?

Standard deviations describe variability among observations. The uncertainty around a mean difference depends on both the variability and the amount of information in each group. In general, more variability makes a group contrast less precise, while more observations can improve precision. These concepts are related but distinct: a small standard deviation is not itself a confidence interval, and a narrow interval does not establish that a result is clinically important.

The posted comparisons include intervals for each estimated mean difference. The nicotine-versus-placebo interval runs from -69.94 to -63.36, and the melatonin-versus-placebo interval runs from -65.85 to -59.05. They describe the range of values compatible with the data under the calculation’s assumptions. The registry does not provide enough information to assess alternative modeling choices or the effect of departures from those assumptions.

What can randomization and masking contribute?

Random allocation is intended to make treatment groups comparable, on average, with respect to factors known and unknown at assignment. It does not guarantee exact balance, particularly in a trial with the group sizes recorded here, and the registry does not post a baseline table to assess balance. Masking can reduce the influence of treatment expectations on care or assessment. The registry identifies triple masking, while the brief summary calls the trial double-blind; the identities of the masked parties and the reason for these differing descriptions are not reported in the registry record.

In general, a parallel-group design assigns participants to a group and compares outcomes across groups. The record identifies this as a randomized parallel trial with placebo, nicotine, and melatonin arms. Details of allocation concealment, implementation, adherence, and protocol deviations are not reported in the registry record, so their effects cannot be assessed from the posted information.

What does the endpoint’s time frame imply?

The primary measure is total pethidine consumption over 12 hours after surgery. A total over a fixed period summarizes use across that period, rather than isolating pain or consumption at one particular assessment. The brief summary describes repeated postoperative assessments at 30 minutes, 1, 2, 6, and 12 hours for several measures. The registry does not report how those repeated measurements were analyzed for the primary endpoint, nor does it post secondary outcome analyses. The primary result should therefore be interpreted as a comparison of the reported total-consumption means over the stated interval, not as a time-course analysis.

10. Confidence Intervals and Precision

The comparison intervals quantify statistical uncertainty around the estimated mean differences, conditional on the calculation and its assumptions. For nicotine versus placebo, the estimated difference is -66.65 mg, with an interval from -69.94 to -63.36. For melatonin versus placebo, it is -62.45 mg, with an interval from -65.85 to -59.05. Both intervals lie below zero, consistent with lower observed means in the active groups in these unadjusted comparisons.

The interval’s endpoints are not the lowest and highest individual outcomes. They concern the estimated difference between group means. A narrower interval generally indicates greater precision than a wider one, but precision is not the same as clinical importance or freedom from bias. The registry record does not state the confidence level associated with these intervals, so it is not identified.

Interpretation also depends on the analysis assumptions and data completeness. The registry record does not report missing outcome counts, an analysis population, or a detailed statistical model. It also does not report a threshold for a clinically important difference. As a result, the intervals quantify uncertainty in the recalculated comparisons but do not resolve these other questions. The findings are specific to the recorded population, treatment schedules, comparator, and 12-hour postoperative outcome.

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 sample-size figures are planning illustrations based on the observed effect, not the trial’s original design calculation. The assumptions listed for them are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The illustrations consider detecting 100%, 75%, and 50% of the observed effect. For these continuous outcomes, the entries are participants per arm, not total events. The record’s planning output reports 1 participant per arm for 80% power and 1 participant per arm for 90% power at each listed effect fraction.

The 80% power column represents the number of participants per arm the planning calculation estimates would be needed to have an 80% chance of detecting the specified effect under its assumptions, if that effect were present. The 90% column uses a higher target chance of detection. Power is a design property under assumptions, not a guarantee about the outcome of a study. The trial’s own original sample-size assumptions and justification are not reported in the registry record.

The curve should be read as a planning relationship between the assumed effect and the required group size, rather than as evidence about what the trial achieved. Smaller effects need more participants to detect, other assumptions held constant. The printed output of 1 per arm is a consequence of this particular observed-effect-based illustration and should not be mistaken for a recommendation for future trials. This is not observed 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 = -66.650; pooled standard deviation σ = 5.313.
2. n = 2 × (1.96 + 0.842)² × 5.313² / -66.650² = 0.1, rounded up to 1 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 <- -66.65                      # observed difference in means
sigma <- 5.31344050498357                     # 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(2747628)
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 = 1 (80% power), 1 (90% power)
 75% of observed effect: n per arm = 1 (80% power), 1 (90% power)
 50% of observed effect: n per arm = 1 (80% power), 1 (90% power)
power.t.test: 1.6 
Simulated power at n = 1 per arm: NA (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 brief summary describes several outcome domains, including pain, sedation, hemodynamic variables, oxygen saturation, side effects, satisfaction, intraoperative bleeding, and plasma cortisol. It also gives repeated postoperative assessment times for several measures. The registry identifies total pethidine consumption over 12 hours as the primary outcome, but does not post secondary outcome results in the record.

When several outcomes, time points, or group contrasts are examined, the chance of finding at least one apparently notable result can increase. In general, multiplicity methods are used to address this issue when appropriate, but the registry record does not report whether an adjustment was planned or used. The posted p-values for the two comparisons are unadjusted. The record does not provide a complete statistical analysis plan, so it is not possible to determine which comparisons were prespecified or how any additional analyses were intended to be handled.

Information about missing data is also not reported in the registry record. The outcome summaries do not state whether all assigned participants contributed to the primary analysis, whether any values were missing, or how incomplete observations were treated. The analysis population—such as whether results were based on all randomized participants or another defined group—is not reported. No imputation method, sensitivity analysis, or handling rule for protocol deviations is described.

These omissions limit assessment of how robust the posted comparisons are to missing outcomes, exclusions, or multiple testing. They do not change the arithmetic meaning of the reported group means and recalculated contrasts, but they leave important aspects of the analysis process undocumented in the registry record.

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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: vomiting (20.0%).

The registry reports serious adverse events affecting 0 participants in the placebo group, 4 in the nicotine group, and 0 in the melatonin group. For other adverse events, the respective counts are 0, 8, and 0. The listed group denominators at risk are 20 for each group. These are counts of participants affected as reported in the registry; they are not measures of event severity beyond the registry’s serious-versus-other classification.

The registry’s listed serious-event term is vomiting, shown as 20.0%. It does not provide further event-level detail in the record, such as timing, recurrence, or the basis for classifying an event as serious. Death counts are not reported in the registry record.

Adverse-event counts should be read descriptively and in the context of the trial’s size and follow-up. They do not establish that a treatment caused an event or that an event did not occur outside the recorded period. The brief summary mentions monitoring for nausea, vomiting, pruritis, respiratory depression, and hemodynamic instability, but the registry does not provide results for each listed event type individually.

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

The posted results show lower mean total pethidine consumption in each active-patch group than in the placebo group during the 12-hour postoperative period. The unadjusted recalculated mean differences are -66.65 mg for nicotine versus placebo and -62.45 mg for melatonin versus placebo, with p < 0.001 for each comparison. Their intervals are reported alongside the estimates. These statistics describe the trial’s recorded group summaries and the uncertainty around the calculated contrasts.

They do not, by themselves, establish how important the differences are to patients or clinicians. The registry record does not report a threshold for a clinically important difference, and a statistical comparison cannot substitute for that context. The summaries also do not show individual responses, pain outcomes, or results for all outcomes mentioned in the brief summary.

The findings concern female non-smokers aged 18–50 years, classified as ASA I or II, undergoing elective laparoscopic cholecystectomy under general anesthesia, with patches placed 2 hours before surgery and pethidine use assessed over 12 hours after surgery. The record does not establish whether similar results would apply to other populations, operations, treatment schedules, or longer follow-up.

The registry identifies randomized allocation, but contains differing descriptions of masking: triple in the design fields and double-blind in the brief summary. It also does not report details needed to assess missing observations, analysis populations, or multiplicity handling. The safest interpretation is therefore descriptive and bounded: the posted means and unadjusted comparisons indicate the observed differences in this trial, while important questions about clinical importance, analysis conduct, and generalizability remain unresolved by the registry record.

16. Why This Trial Matters Statistically

This trial illustrates why an effect estimate should be read together with its measurement scale, comparator, time frame, and uncertainty. The primary endpoint is a mean amount of pethidine in milligrams over a defined postoperative period. The mean differences retain that scale, making clear that the contrasts concern average analgesic consumption rather than a direct measurement of pain intensity.

It also demonstrates the distinction between a group summary and an individual outcome. The posted means and standard deviations describe averages and within-group spread, while the comparison intervals address uncertainty around estimated differences. Neither type of summary reveals every participant’s experience, and neither establishes clinical importance without a relevant threshold or context.

The record presents two active-versus-placebo comparisons, but its brief summary describes a wider set of outcomes and repeated assessments. Since multiplicity handling and secondary outcome analyses are not reported, the unadjusted p-values should be interpreted as results for those specific comparisons rather than as a complete account of all analyses that may have been considered.

Finally, the sample-size illustrations use the observed effect and stated planning assumptions, whereas the trial’s original design assumptions are not reported. Keeping those two purposes separate avoids treating a retrospective planning illustration as evidence of the design process or as a measure of the trial’s observed power. The registry’s differing masking descriptions and lack of detail on missing data also show why statistical interpretation depends on careful attention to what the record documents and what it leaves unspecified.

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 trial’s defined population is narrow: female non-smokers aged 18–50 years and classified as ASA I or II, undergoing elective laparoscopic cholecystectomy under general anesthesia. The results cannot automatically be extended to other populations, operations, or clinical settings. The registry reports group sizes of 20 and does not provide a baseline characteristics table in the record.

The primary endpoint covers total pethidine consumption over 12 hours after surgery. It does not describe later outcomes, and the registry record does not report how the total was handled if observations were incomplete. Although the brief summary lists other clinical assessments and adverse events, secondary results are not posted in the record.

The record identifies randomization and triple masking, while its brief summary calls the trial double-blind. It does not explain this difference or identify which parties were masked. Details of allocation concealment, adherence, protocol deviations, and analysis populations are also not reported in the registry record. These gaps limit evaluation of potential bias and the exact population represented by the outcome summaries.

The posted comparisons are unadjusted, and multiplicity handling is not reported despite multiple outcomes and assessment times being described. No clinical-importance threshold is reported. These limitations do not negate the stated group means, but they constrain how broadly or definitively the contrasts can be interpreted.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Transdermal Nicotine and Melatonin Patches for Postoperative Pain Relief — NCT02747628.
• Registry record last updated 2020-08-25; status last verified 2020-08.
• Results first posted 2020-08-20.
• 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 describes a completed randomized, parallel-group Phase 4 trial sponsored by Ain Shams University, with enrollment of 60. It compares placebo patches with transdermal nicotine and melatonin patches placed 2 hours before surgery in female non-smokers undergoing elective laparoscopic cholecystectomy.

The primary outcome is mean total pethidine consumption in milligrams over 12 hours after surgery. Posted group means were 122.2 mg for placebo, 55.5 mg for nicotine, and 59.7 mg for melatonin. Recalculated unadjusted comparisons against placebo were -66.65 mg for nicotine and -62.45 mg for melatonin, both with p < 0.001. The record does not report secondary outcome results, missing-data handling, analysis populations, or a clinical-importance threshold.