2 Dose Neuraxial Morphine for Prevention of PDPH: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for 2 Dose Neuraxial Morphine for Prevention of PDPH (NCT02473276), a randomized phase 4 study. The primary outcome is Number of Participants With Postdural Puncture Headache.

2. Clinical Question

The trial addresses a complication described in the registry background: headache after accidental dural puncture during labor neuraxial analgesia. The background notes that an epidural blood patch is the gold standard for treating this headache and can itself be associated with complications. It also describes a small prior study as having found a beneficial effect of epidural morphine on headache incidence. Those statements provide the rationale for the current study; they are not results from this trial.

The trial enrolled 44 participants. Its primary outcome is the number with headache at the specified assessment time, rather than headache severity as the primary measure. Severity was rated using a verbal rating scale from 0 to 10, but the registry record does not report severity results. The secondary outcome concerns the number of participants needing an epidural blood patch.

3. Trial Design

This was a phase 4, randomized, quadruple-masked, parallel-group trial sponsored by Columbia University. The registry lists a start date of 2015-09, primary completion in 2020-01, and a completed status. Enrollment was 44. The registry record does not report the randomization procedure, allocation concealment method, or the identities of the parties included in quadruple masking.

Four groups are listed. The EPID PFM group received preservative-free morphine through an epidural catheter, and the EPID SAL group received saline through an epidural catheter. The IT PFM and IT SAL groups received morphine and saline, respectively, through an intrathecal catheter. The protocol descriptions specify a second dose 16 to 24 hours after the first. For the epidural morphine group, the recorded first dose is 3 mg (6 ml), followed by 3 ml of saline. For the intrathecal morphine group, the recorded dose is 200 micrograms (mcg) (0.4 ml), followed by a 2 ml saline flush. The saline groups received saline through the corresponding catheter route.

The primary outcome was assessed 48 hours after accidental dural puncture. It was determined by a face-to-face questionnaire, and the description also mentions rating headache severity on a verbal rating scale from 0 to 10. The secondary outcome was the number of participants needing an epidural blood patch. Although two outcome measures are listed, the registry record reports no outcome analyses. It does not report the planned statistical model, testing procedures, or a sample-size justification.

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 Number of Participants With Postdural Puncture Headache, measured over 48 hours after accidental dural puncture.

The primary endpoint is the number of participants with postdural puncture headache 48 hours after accidental dural puncture. It is a binary participant-level outcome: each participant either met the registry’s headache outcome definition at that assessment or did not. The registry describes ascertainment through a face-to-face questionnaire and says headache severity was rated on a verbal scale from 0 to 10. The posted primary results are counts of participants with headache, not severity scores.

This endpoint is relevant to the trial’s stated prevention question because it records whether headache was present at a defined time after the dural puncture. A fixed assessment time makes the outcome’s timing explicit, but it also means the posted endpoint does not by itself describe headache onset, duration, later symptoms, or severity results. Those other details are not reported in the registry record.

The posted counts are 3 participants in EPID PFM (8 listed), 4 in EPID SAL (10 listed), 8 in IT PFM (11 listed), and 10 in IT SAL (15 listed). The registry record does not report an inferential comparison, confidence interval, or analysis of the severity scale. The secondary outcome is the number needing an epidural blood patch; its results are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods determine how observed group outcomes are compared, how uncertainty is quantified, and which participants and outcomes enter an analysis. The registry record gives the randomized parallel-group design and the endpoint counts, but it does not report the trial’s statistical analysis plan. The following concepts explain what would ordinarily be relevant to interpreting this kind of outcome; they are general explanations, not claims about analyses performed in this trial.

What kind of outcome is recorded?

The primary endpoint is binary at the participant level: the outcome is whether a participant had postdural puncture headache at 48 hours. A binary endpoint is commonly summarized by the number with the event and the number assessed in each group. The posted results give those counts for the four listed groups. Counts should be interpreted with their denominators because groups can contain different numbers of participants. A comparative analysis may express the contrast in different ways, such as a difference in event risks or a relative measure, but the registry record reports no such estimate.

What would an uncertainty estimate add?

A confidence interval is a range of values generated by a statistical method to represent uncertainty around an estimated effect. It helps readers judge how compatible the data are with a range of possible effects, rather than relying only on a single estimate. A confidence interval for a group contrast is not reported in the registry record. Without an estimate and its interval, the precision of any treatment comparison cannot be evaluated from the posted results. The event counts alone do not show whether a difference is statistically distinguishable from chance variation.

Why do the four groups require care?

The trial has two administration routes, with morphine and saline groups for each route. A statistical analysis would need to specify the comparisons of interest. For example, a route-specific comparison would contrast morphine with saline within a route; a different analysis could examine route differences or an interaction between route and assigned drug. These address distinct questions. The registry record does not report which comparisons were planned or conducted, and it reports no analysis results. It would therefore be inappropriate to infer a particular contrast from the group arrangement alone.

What does randomization contribute?

In general, random assignment aims to make treatment groups comparable with respect to both measured and unmeasured characteristics, on average. It supports causal comparisons when the assignment is implemented as planned and participants are analyzed appropriately. Randomization does not guarantee that small groups will be closely balanced on every characteristic. The registry identifies the trial as randomized but does not report the sequence-generation or concealment methods, baseline characteristics, adherence, or analysis population. Those details are relevant when assessing how well the design supports interpretation.

What is the role of the planning illustration?

Sample-size planning asks how many participants would be needed under specified assumptions to detect an effect of a chosen size with a chosen level of statistical power. The assumptions recorded for the planning illustration refer to a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. Such figures are planning illustrations, not observed power and not the trial’s actual enrollment rationale. The registry record does not report the trial’s own sample-size justification. In addition, the recorded binary comparison is marked as missing or not estimable, so a comparative effect cannot be read from the registry record as a basis for interpreting the illustration.

Why can sparse data be difficult?

When outcomes are recorded in small groups, estimates can be imprecise, and some statistical methods may rely on approximations that work less well with sparse data. General methods for binary outcomes include exact approaches and regression models, but the suitable choice depends on the prespecified question and data structure. No method is identified in the registry record. Over-dispersion is a general concern when observed variability exceeds what a model assumes; it is not a reported feature of these results, and the registry does not provide information to assess it.

The registry lists zero outcome analyses. It also does not report p-values, confidence intervals, adjusted estimates, or a statistical model for the primary outcome. The posted arm counts can be described, but they should not be recast as a sponsor analysis or an independently calculated treatment effect. The registry record does not report an analysis from which to draw a comparative statistical conclusion.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("EPID PFM", "EPID SAL", "IT PFM", "IT SAL")
n      <- c(8, 10, 11, 15)
events <- c(3, 4, 8, 10)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  EPID PFM  8  3  37.5  8.5  75.5  13.7  69.4  13.7  70.1
ARM  EPID SAL  10  4  40.0  12.2  73.8  16.8  68.7  16.7  69.2
ARM  IT PFM  11  8  72.7  39.0  94.0  43.4  90.3  42.8  90.1
ARM  IT SAL  15  10  66.7  38.4  88.2  41.7  84.8  41.3  84.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures: the primary outcome of participants with postdural puncture headache at 48 hours and the secondary outcome of participants needing an epidural blood patch. It does not report a multiplicity strategy. In general, multiplicity arises when several outcomes, treatment contrasts, or time points are tested; testing more questions can increase the chance of a nominally significant result occurring by chance. A prespecified approach may define which outcome is primary and how other tests are interpreted. The record identifies a primary endpoint but does not report further multiplicity procedures or the planned hierarchy of comparisons.

Missing-data handling is not reported in the registry record. The primary outcome counts have arm-specific denominators, but the record does not describe whether any randomized participants lacked a 48-hour assessment, how missing assessments were handled, or whether an imputation method was used. It also does not report participant flow or reasons for exclusion. These details matter because an analysis based only on participants with observed outcomes can differ from an analysis that includes all randomized participants under a defined missing-data strategy.

The analysis populations are not reported in the registry record. It is therefore unclear whether the posted counts represent all randomized participants, participants who received assigned treatment, or another defined population. Adherence and protocol deviations are also not described. These omissions limit assessment of the relationship between randomization and the presented outcome counts.

12. 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

The safety listing reports serious adverse events in 0 participants in each group: EPID PFM had 8 at risk, EPID SAL had 10, IT PFM had 11, and IT SAL had 15. Deaths are also listed as 0 in every group. These are the registry’s posted serious-event and death counts; they do not establish that no unrecorded events occurred or that the groups have equivalent safety.

The listing also reports other adverse events in 3 participants in EPID PFM, 4 in EPID SAL, 8 in IT PFM, and 10 in IT SAL, using the same respective numbers at risk. The registry record does not provide event terms for these other adverse events. The serious adverse event term list is empty, so no specific serious-event types are reported.

Safety counts are descriptive. The registry record does not report a statistical comparison of adverse events, their timing, severity, or relationship to treatment. Group sizes are small, and zero recorded serious events should not be interpreted as proof that serious events cannot occur. The safety listing also does not explain whether events were actively solicited or how they were classified.

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

The results establish what the registry record counts: participants with headache at 48 hours in each of four randomized groups. They do not establish a comparative treatment effect. No statistical comparison, effect estimate, confidence interval, or p-value is reported for the primary endpoint. The counts should therefore be read as descriptive observations rather than evidence that one intervention is superior, equivalent, or inferior to another.

The arm structure allows distinct questions about morphine versus saline by route, as well as questions about route. But the registry record does not report which comparisons were prespecified or whether any were conducted. The presence of four groups does not itself supply those answers. Nor does the number of participants with headache alone show how precisely a contrast has been estimated.

The endpoint is limited to headache status at 48 hours. The record mentions a severity rating scale but does not report severity results, and it does not report later headache outcomes. It lists need for an epidural blood patch as a secondary outcome, but results for that outcome are not reported in the registry record. The data therefore do not describe the full course of symptoms or the frequency of that secondary outcome.

Likewise, completed status indicates that the trial is listed as completed, not that every planned analysis or result is present in the registry. The record does not report participant flow, analysis populations, missing-data procedures, or the statistical plan. These omissions limit what can be concluded from the posted counts. The trial’s rationale and prior-study context explain why the question was studied, but they do not replace results from a comparative analysis of this trial.

14. Why This Trial Matters Statistically

This trial is statistically notable because it combines a binary outcome with four treatment groups and two neuraxial routes. That structure makes the definition of the target contrast important. A morphine-versus-saline comparison within a route is not the same question as comparing routes or assessing whether the treatment contrast varies by route. Clear specification of the primary contrast and analysis is essential for interpreting a multi-arm randomized design.

The primary endpoint is assessed at a defined time after accidental dural puncture, which makes the timing of the outcome explicit. At the same time, the registry record presents counts without a comparative estimate or uncertainty interval. This illustrates the distinction between reporting outcome data and reporting an analysis that quantifies treatment differences and their precision. Descriptive counts are useful, but they cannot on their own resolve the trial’s comparative question.

The listed arm sizes are modest, and the endpoint counts differ across groups. In general, limited group sizes can make estimates uncertain and may make conclusions sensitive to a small number of outcomes. This is a reason to attend to confidence intervals and the analysis method rather than relying on a visual or informal reading of the counts. No such inferential results are reported in the registry record.

The registry also illustrates why transparency about analysis populations, missing data, multiplicity, and sample-size planning matters. These details help readers understand which participants and questions support a reported conclusion. Here, the posted information identifies the design and outcome counts but leaves those analysis details unreported. The statistical importance of the record is therefore as much about the limits of the available comparison as about the trial’s clinical question.

15. 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 primary limitation for interpreting the trial statistically is the absence of a reported comparative analysis. Although the registry provides arm-level headache counts, it does not report an effect estimate, confidence interval, p-value, or statistical model. No conclusion about the size or precision of a treatment contrast can be drawn from the registry results alone.

The record also does not describe participant flow, missing endpoint assessments, exclusions, or analysis populations. Without those details, it is not possible to determine how the posted denominators relate to the randomized population or how incomplete follow-up, if any, was handled. Baseline characteristics, adherence, and protocol deviations are likewise not reported in the registry record.

The endpoint is limited to headache at 48 hours. Although severity measurement is mentioned in the outcome description, severity results are not reported. Results for the listed secondary outcome, need for an epidural blood patch, are also not reported in the registry record. The posted outcomes therefore do not provide a broader picture of symptom course or secondary outcome frequency.

The registry does not report the randomization procedure, allocation concealment, masking details, prespecified comparisons, multiplicity plan, or statistical analysis plan. It also does not report the trial’s own sample-size justification. These gaps limit assessment of design implementation and the intended interpretation of the four-arm comparisons. The registry’s completed status does not resolve these reporting limitations.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: 2 Dose Neuraxial Morphine for Prevention of PDPH — NCT02473276.
• Registry record last updated 2025-02-05; status last verified 2025-01.
• Results first posted 2025-02-05.
• 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.

19. Record Summary

NCT02473276 is a completed phase 4 randomized, quadruple-masked, parallel-group trial sponsored by Columbia University, with enrollment of 44. It evaluates two doses of neuraxial preservative-free morphine, given by epidural or intrathecal route, against saline administered by the corresponding route after accidental dural puncture.

The primary outcome is the number of participants with postdural puncture headache 48 hours after the dural puncture. The registry lists counts of 3 in EPID PFM, 4 in EPID SAL, 8 in IT PFM, and 10 in IT SAL, with group sizes of 8, 10, 11, and 15, respectively. The secondary outcome is need for an epidural blood patch. The registry record does not report a comparative analysis, secondary outcome results, or details of missing-data handling and analysis populations.