Fentanyl Administered Intraorally for Rapid Treatment of Orthopedic Pain: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Fentanyl Administered Intraorally for Rapid Treatment of Orthopedic Pain (NCT00685295), a randomized phase 1, phase 2 study. The primary outcome is Time to Analgesia.

2. Clinical Question

3. Trial Design

The registry identifies this as a randomized, parallel-group trial with triple masking and a Phase 1 and Phase 2 designation. It records the study as completed, with Massachusetts General Hospital as sponsor. The registered enrollment is 60. The recorded study start is 2008-08 and primary completion is 2009-02. These details characterize the registered design and timing; they do not establish which people were masked or how randomization was implemented.

The two arms compare treatment regimens rather than a single drug against an inactive control. Arm 1 / Fentora received a placebo oral or swallowed pill alongside a rapidly dissolving transbuccal fentanyl tablet. Arm 2 / Percocet/Prevacid received oral or swallowed oxycodone/APAP alongside a rapidly dissolving transbuccal lansoprazole tablet. The record describes the comparator as active. Differences in the observed outcomes therefore relate to the regimens as assigned, not necessarily to fentanyl alone considered independently of all other treatment components.

The trial's parallel structure means that each arm represents a separate group assigned to one regimen. Randomization is intended, in general, to reduce systematic differences between groups at assignment. Masking is intended, in general, to reduce the influence of expectations on care, outcome assessment, or reporting. The registry does not specify the masking roles, sequence generation, allocation concealment, or procedures used to maintain masking, so those implementation details are not reported in the registry record.

The primary outcome was measured over 60 minutes. The secondary outcome concerned occurrence of untoward opioid side effects and used a 120 minutes timeframe. The registry also lists three outcome measures, while posted analyses are not reported. The record gives arm-level outcome summaries and does not identify a primary analysis population, handling of participants with incomplete outcome data, or protocol deviations. Accordingly, the design description should be read as the registry's overview, not as a complete account of trial conduct.

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 Time to Analgesia, measured over 60 minutes.

The primary endpoint is time to analgesia, defined in the registry as the time it took for subjects to achieve a pain-score reduction of 2 units on a 0 to 10 scale. The outcome is measured in minutes, with a 60 minutes timeframe. This definition combines a threshold for change in pain score with the time needed to reach that threshold. It differs from an endpoint that asks only for a pain score at one fixed assessment time: it focuses on when the specified reduction is achieved.

The registry reports the outcome as a median with an inter-quartile range. In general, the median describes the middle of an ordered set of observations, while the inter-quartile range describes the central half of the observations. These summaries are useful when an outcome such as time may have an uneven or skewed distribution, because the median is less influenced by unusually long or short times than the mean. They do not, by themselves, show every participant's time or quantify the uncertainty in the difference between treatment arms.

The endpoint is clinically interpretable because it ties the timing measure to a specified amount of pain-score reduction. However, the record does not report how time was assigned for participants who did not achieve that reduction within the assessment window, whether observations were censored, or how missing pain assessments were handled. Those details matter when interpreting a time-based outcome. The registered definition alone does not resolve them.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a median and inter-quartile range for the primary time outcome. The secondary outcome is a participant count, with an unadjusted risk-difference estimate and confidence interval also reported. The registry does not report a formal analysis for the primary comparison. General explanations below describe how these statistical quantities are usually interpreted; they do not establish which methods were used by the trial analysts.

What does a median describe?

In general, the median is the central observation when values are arranged from smallest to largest. It is a measure of location, not an average in the arithmetic sense. For a time outcome, it answers a question about the middle of the observed times. It does not tell whether every participant had a time close to the median, or how the observations are distributed in the tails.

The inter-quartile range gives the interval from the lower quartile to the upper quartile and describes the central half of the observations. It is a measure of spread. For the primary endpoint, the registry reports medians of 10.0 minutes and 35.0 minutes, with inter-quartile ranges of 5.0 to 15.0 minutes and 20.0 to 40.0 minutes. These intervals describe observed distributions; they are not confidence intervals for the medians or for a difference between arms. Overlap or separation of inter-quartile ranges is not, by itself, a formal hypothesis test.

Why can time outcomes need special care?

In general, a time-to-event outcome can include participants who have not experienced the defined event by the end of observation. Statistical methods for such data may account for differing observation times and censoring. The registry's primary outcome description specifies a 60 minutes timeframe, but does not report whether the analysis treated any observations as censored, how participants without the threshold reduction were represented, or which model was applied. It would be inappropriate to infer a survival-analysis method or assume a particular handling of unobserved event times.

Time distributions can also be asymmetric. In general, a small number of long times can pull an arithmetic mean upward, which is one reason medians and inter-quartile ranges are often used for skewed data. This is a general statistical rationale, not a statement that the trial's distribution was formally tested for skewness. The registry does not report a distributional assessment or a rationale for choosing the summary measure.

How should the secondary risk difference be read?

For the secondary binary outcome, a risk difference expresses the difference between the proportions experiencing the event in two groups. In general, a risk difference of zero corresponds to equal observed proportions, while positive and negative values indicate different directions according to the order used for the contrast. The registry's unadjusted risk-difference estimate is 0.033, with a confidence interval from -0.031 to 0.098 and p = 0.313. The interval includes zero, so the estimate is compatible with no difference as well as with effects in either direction under the calculation used. This does not prove that the underlying risks are equal.

A confidence interval is, in general, a range produced by a statistical procedure intended to reflect uncertainty in an estimate. Its interpretation depends on the method and assumptions used. A wide interval indicates limited precision; it can include values that would represent meaningfully different effects. With sparse event counts, estimates of a binary outcome can be especially uncertain. The interval is not a guarantee that the true effect lies within its limits, nor is it the range of individual participant outcomes.

The displayed secondary comparison is identified as unadjusted. In general, an unadjusted comparison contrasts the observed groups without accounting for covariates or other variables in a model. It can be useful as a straightforward description, but it may not match an adjusted analysis specified by the investigators. The registry does not report an adjusted analysis for this endpoint.

What does a p-value contribute?

In general, a p-value describes how unusual data at least as incompatible with a specified null model would be, assuming that model and the test's assumptions hold. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The secondary p-value is unadjusted; no adjustment for multiple outcomes or testing is reported. No primary-outcome p-value is reported in the registry record.

Random allocation, in general, supports comparisons by reducing the chance that systematic baseline differences determine which group receives each regimen. It does not guarantee balance in a particular trial, and the registry does not report baseline characteristics or the method used to generate and conceal allocation. Likewise, masking can reduce some sources of bias, but the record does not identify who was masked or document whether masking was maintained. These design labels should not be mistaken for evidence that every potential bias was eliminated.

10. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a statistical analysis plan, a prespecified hierarchy of endpoints, or a method for controlling multiplicity. Multiplicity arises when several outcomes, timepoints, subgroups, or statistical comparisons are examined. In general, conducting many tests without adjustment can increase the chance of obtaining at least one apparently unusual result by chance. An adjustment or a prespecified testing hierarchy can address that concern, but the registry does not say whether either approach was used.

There is a named primary endpoint and a listed secondary outcome. That distinction identifies the outcome designated as primary in the record, but it does not reveal how the investigators planned to handle multiple analyses or whether additional comparisons were considered. The registry lists three outcome measures, while only one secondary outcome is represented in the posted secondary results. The status of any unposted outcome measures and reasons for their absence are not reported in the registry record.

The registry does not report missing-data counts or methods, an analysis population, exclusions after randomization, or the handling of participants who did not reach the primary pain-reduction threshold during the assessment window. It is therefore not possible to determine from the record whether the summaries use all randomized participants, participants who received treatment, or only participants with evaluable outcome data. These are important distinctions because exclusions or missing observations can alter the composition of the groups being compared.

The registry also does not report whether an intention-to-treat approach, a per-protocol approach, or another population definition was used. In general, intention-to-treat analysis aims to compare participants according to their randomized assignment, while other analysis populations may apply additional conditions. These approaches answer related but not identical questions. The design label of randomized does not, by itself, identify the analysis population used for the posted results.

Without a documented plan, it is not possible to assess whether the analyses followed prespecified decisions or whether analytic choices were made after outcomes were observed. This is a limitation of the registry reporting, not evidence that the trial did or did not follow a particular procedure. The posted results can be interpreted descriptively, but the missing analysis details limit conclusions about the intended confirmatory testing framework.

11. 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 0% reporting threshold.

The registry's adverse-event summary reports zero serious adverse events among the 30 participants at risk in Arm 1 / Fentora and zero among the 30 participants at risk in Arm 2 / Percocet/Prevacid. It also reports zero other adverse events in each group. These figures describe the counts recorded for the adverse-event categories in the registry. They do not establish that no event of any kind occurred outside the reported categories or observation procedures.

The deaths field is not populated for either group, so deaths are not reported in the registry record. A missing value should not be read as a count of zero. The separate secondary outcome, occurrence of untoward opioid side effects, has its own stated 120 minutes timeframe and should not be conflated with the broader adverse-event summary.

In general, an absence of recorded serious events in a trial does not demonstrate that a regimen has no serious risks. A trial's ability to characterize uncommon harms depends on its size, duration, follow-up, and event ascertainment. The registry does not provide detailed definitions, surveillance procedures, or longer-term safety follow-up in the record. These data are therefore a limited account of recorded events, not a comprehensive safety assessment.

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

The primary summaries show that the median time to the registry-defined pain reduction was 10.0 minutes in the fentanyl arm and 35.0 minutes in the comparator arm. The central ranges also fall at earlier times in the fentanyl arm. This describes the observed pattern in the registered trial results. It does not establish that every participant experienced a faster response, that the between-arm difference is statistically significant, or that the result applies to settings and populations beyond those represented in the trial.

The registry does not report an inferential comparison for the primary endpoint. There is no posted primary confidence interval or p-value with which to characterize uncertainty in the contrast. The results therefore support a descriptive statement about the reported medians and ranges, but not a complete account of the precision of a treatment-effect estimate. The observed summaries should not be converted into an unreported statistical conclusion.

The comparison is between two regimens: transbuccal fentanyl with a placebo oral or swallowed pill, and oral or swallowed oxycodone/APAP with transbuccal lansoprazole. The result cannot isolate the effect of one component from the full regimen comparison. The record does not report additional co-interventions, rescue treatment, adherence, or protocol details that might clarify how the assigned regimens were delivered in practice.

The secondary side-effect assessment is not evidence that the regimens have equivalent safety. Its event information is sparse and the estimate is unadjusted. A lack of a statistically clear difference on one secondary measure does not rule out differences in other adverse events, later events, or outcomes that were not reported. Similarly, zero recorded serious adverse events in the registry summary does not prove the absence of risk.

In general, a trial result is most informative when its endpoint, analysis population, follow-up, and inferential methods are clear. Here, the endpoint definition and arm-level summaries are available, but important analysis details are not reported in the registry record. The result is best read as a small randomized comparison with a descriptive primary pattern and incomplete information for judging its statistical precision and broader applicability.

13. Why This Trial Matters Statistically

This trial illustrates why the form of an outcome summary matters. Time to a defined change in pain score is not simply a score recorded at one timepoint. Reporting a median and inter-quartile range communicates where the center of the observed times lies and how broadly the central observations are distributed. It also makes clear what the summary cannot show: individual trajectories, the full shape of the distribution, or uncertainty in the contrast between arms.

The registry's two regimens include several active and placebo components. Statistical interpretation must therefore follow the randomized comparison that was actually registered rather than attributing the whole observed pattern to one drug in isolation. The clinical question is framed around transbuccal fentanyl, but the comparison is between complete treatment assignments, including the oral and transbuccal components listed for both arms.

The record also demonstrates the difference between descriptive evidence and inferential evidence. The posted medians and inter-quartile ranges describe the observed primary outcome. Without a reported primary comparison and its uncertainty, readers cannot assess the precision of the between-arm result from the registry record alone. The secondary comparison provides an unadjusted estimate, but sparse events and unreported multiplicity procedures limit its evidential weight.

Finally, randomized and masked design labels do not replace reporting on conduct and analysis. Details about allocation, who was masked, missing outcomes, analysis populations, and prespecified methods are necessary to evaluate how robustly a trial's design was carried through to its results. This case is a useful reminder that the registry's outcome summaries can be informative while still leaving important statistical questions unresolved.

14. 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.

Several limitations are specific to the information recorded for this trial. The primary outcome is summarized by arm, but the registry does not report a between-arm test, confidence interval, or analysis method for the time outcome. That omission prevents a direct assessment of the statistical precision of the apparent difference in medians. The reported inter-quartile ranges describe the middle of each group's observations and cannot substitute for an uncertainty interval around a contrast.

The registry does not explain how participants who failed to achieve the defined pain reduction within 60 minutes were handled. It also does not describe missing pain assessments, censoring, or the number of participants included in the primary summaries. This leaves uncertainty about how the time outcome was constructed for all participants assigned to each arm.

The comparison includes different treatment components and routes in the two arms. Consequently, any contrast pertains to the assigned regimens as a whole, rather than the isolated effect of fentanyl versus oxycodone/APAP. The record does not describe other care or rescue medication, which further limits interpretation of the treatment context.

Although the trial is identified as randomized and triple-masked, the registry does not specify the randomization procedure, allocation concealment, masking roles, or maintenance of masking. It also does not report baseline characteristics or a detailed analysis population. These omissions make it difficult to assess comparability at baseline and the influence of post-randomization exclusions or missing data.

The secondary event assessment is limited by sparse counts and an unadjusted comparison. The registry does not report a multiplicity strategy or a full analysis plan. Safety information is similarly bounded by the categories and timeframes recorded: deaths are not reported, and follow-up or event-ascertainment details are not available in the registry record. These limitations concern what can be concluded from the registered information; they do not establish that unreported procedures were absent.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Fentanyl Administered Intraorally for Rapid Treatment of Orthopedic Pain — NCT00685295.
• Registry record last updated 2017-02-09; status last verified 2016-12.
• Results first posted 2017-02-09.
• 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.

18. Record Summary

The registry record identifies a completed, randomized, triple-masked, parallel-group Phase 1 and Phase 2 trial sponsored by Massachusetts General Hospital. Registered enrollment is 60, with study start recorded as 2008-08 and primary completion as 2009-02. The study concerns orthopedic pain associated with pain, fracture, or sprain in an emergency-department context.

The primary endpoint is time to a 2-unit reduction in pain score on a 0 to 10 scale during 60 minutes. Arm-level medians and inter-quartile ranges are posted, but a primary inferential analysis is not reported in the registry record. The secondary endpoint concerns untoward opioid side effects during 120 minutes and includes an unadjusted comparison. The registry does not report a detailed statistical plan, analysis populations, missing-data methods, or multiplicity procedures.

The record also reports zero serious and zero other adverse events in each group; deaths are not reported. The results provide descriptive evidence about the registered comparison, while important details needed to assess precision, analysis conduct, and the scope of safety follow-up are not reported.