This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Heritability of Opioid Effects: A Twin Study (NCT00672438), a randomized na study. The primary outcome is Heat Pain Threshold.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00672438 |
| Phase | NA |
| Condition | Pain |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | Double |
| Enrollment | 242 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Martin Angst |
| Results posted | Yes |
2. Clinical Question
Population
The study concerns participants in a twin study of pain sensitivity and responses to opioid therapy. The primary endpoint specifies that all participants were included for analysis. The registry record does not report further eligibility details or the number of participants who were twins of each type.
Intervention
Participants received an intravenous alfentanil infusion. The study's stated aim was to examine individual differences in pain sensitivity and pain relief in response to opioid therapy, including the extent to which those differences might be inherited or associated with environmental factors.
Comparator
The comparator was an intravenous infusion of normal saline, described as a saline placebo infusion. The registry record identifies the study as randomized, double-blind and crossover, but does not report the sequence of infusions or further details of how masking was implemented.
Primary question
The primary endpoint was heat pain threshold, measured in degrees centigrade. The posted medians were 49.6 for the Alfentanil Infusion and 48.6 for the Saline Infusion. These are endpoint summaries; the registry record does not report a statistical test or an analysis estimating the within-participant contrast.
The central scientific question was not only whether pain thresholds differed during the two infusions. The stated aim was to investigate how much variability between people in pain sensitivity and opioid-related pain relief might be inherited or instead associated with environmental factors. Such knowledge was described as relevant to guiding future studies of those individual differences.
The posted primary endpoint is heat pain threshold, rather than a direct measure of the proportion of pain relief attributable to treatment. The record also lists outcomes related to sedation, nausea, pruritis and drug liking or disliking. The primary endpoint summaries alone therefore do not answer every question posed by the study's broader rationale.
3. Trial Design
The registry describes a randomized, double-blind, crossover study with enrollment of 242. It lists Alfentanil and Saline placebo infusion as the interventions, and describes intravenous infusions for both. The study is marked completed. Its listed start was 2008-05 and its primary completion was 2010-06.
A crossover design generally means that a participant receives more than one study condition, allowing outcomes under those conditions to be compared within the same person. This can be useful when participants differ substantially from one another at baseline. However, the registry record does not report the infusion sequence, the time between infusions, or details of any washout period. It also does not describe whether period or sequence effects were included in the analysis.
Randomization and double masking are listed design features. The record does not report how the randomization sequence was generated or concealed, who was masked, or how masking was maintained. Those details should not be inferred from the design labels alone.
The study title and summary identify the work as a twin study and state its interest in inherited and environmental influences on pain sensitivity and opioid response. The registry record does not report the twin recruitment or pairing details, nor a statistical model for estimating heritability. The primary endpoint timeframe states that participants underwent pain testing at training before study procedures, at baseline and during each infusion.
The enrollment figure is 242, while the posted primary endpoint lists 228 participants for each infusion. The record says all participants were included for analysis, but does not explain the relationship between enrollment and the endpoint counts. It does not report a participant-flow account or reasons that any enrolled participants may be absent from the endpoint summaries.
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.
Before assignment: Participants were required to fast overnight except for clear liquids that were allowed up to 2 hours before starting the drug infusion. Subjects were also required to have at least 6 hours of night-time sleep before a study session. Some participants withdrew prior to study participation.
Infusion 1
| Stage | Alfentanil Infusion Prior to Saline Placebo Infusion | Saline Placebo Infusion Prior to Alfentanil Infusion |
|---|---|---|
| STARTED | 119 | 118 |
| COMPLETED | 119 | 118 |
| NOT COMPLETED | 0 | 0 |
Washout
| Stage | Alfentanil Infusion Prior to Saline Placebo Infusion | Saline Placebo Infusion Prior to Alfentanil Infusion |
|---|---|---|
| STARTED | 119 | 118 |
| COMPLETED | 119 | 118 |
| NOT COMPLETED | 0 | 0 |
Infusion 2
| Stage | Alfentanil Infusion Prior to Saline Placebo Infusion | Saline Placebo Infusion Prior to Alfentanil Infusion |
|---|---|---|
| STARTED | 119 | 118 |
| COMPLETED | 119 | 118 |
| NOT COMPLETED | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: All participants were included for analysis.
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.
Population: Baseline data collected for all enrolled participants.
| Characteristic | Unit | Alfentanil Infusion Prior to Saline Placebo Infusion | Saline Placebo Infusion Prior to Alfentanil Infusion | Total |
|---|---|---|---|---|
| Participants analysed | 122 | 120 | 242 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 122 | 120 | 242 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 |
| Gender: Female | Participants | 76 | 74 | 150 |
| Gender: Male | Participants | 46 | 46 | 92 |
| Region of Enrollment: United States | participants | 122 | 120 | 242 |
6. Primary Endpoint
The registry lists the primary outcome as Heat Pain Threshold, measured over Participants underwent the pain testing measures at training prior to study procedures, at baseline and during each of the infusions..
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | Inter-Quartile Range |
| Unit | degrees centigrade |
| Endpoint classification | not reduced to a single comparison |
Heat pain threshold is the temperature at which a participant first reports pain during a controlled heat stimulus. In this study, heat was applied to the skin at the volar forearm using a thermal sensory analyzer. The thermode temperature rose from a comfortable starting temperature at a measured rate. Participants pressed a handheld button when the stimulus became painful, at which point the thermode temperature was reduced.
The endpoint is reported in degrees centigrade. It provides a standardized way to record the point at which a controlled heat stimulus is perceived as painful. In this study, measurements were scheduled at training before study procedures, at baseline and during each infusion. Repeated assessment across study conditions is consistent with the crossover design and makes it possible to describe pain thresholds under each infusion condition.
The registry identifies the endpoint summary as a median with an inter-quartile range. A median describes the middle of an ordered set of observations. An inter-quartile range describes the spread of the central portion of those observations and is less affected by extreme values than a standard deviation. The IQR values themselves are not reported in the posted arm summaries.
The record reports medians of 49.6 for Alfentanil Infusion and 48.6 for Saline Infusion. The bounds listed alongside those values are 48.3 to 50.4 and 47.1 to 49.3, respectively. The registry record does not identify the statistical meaning or confidence level of these bounds, so they should not be interpreted as a particular type of interval without further documentation.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted primary endpoint summaries describe heat pain threshold under the two infusion conditions. The reported median is 49.6 degrees centigrade for Alfentanil Infusion and 48.6 degrees centigrade for Saline Infusion. The bounds reported alongside the medians are 48.3 to 50.4 and 47.1 to 49.3, respectively. These are descriptive summaries; the registry record does not report a primary comparison estimate, a p-value or a confidence interval for the difference between conditions.
The endpoint is identified as a median with an inter-quartile range, but the IQR values are not reported in the arm summaries. Without those spread measures, the reader cannot assess the distribution of individual heat pain thresholds from the posted summaries alone. The bounds accompanying each median do not have a stated interpretation in the record and should not be treated as a substitute for the missing IQR or as a confirmed confidence interval.
Because the study is described as a crossover, an important inferential question is how each participant's outcome changed between infusions. The registry record reports one participant count and one median for each infusion, but does not report paired differences, a paired model, or another method for accounting for the within-participant structure. The two posted medians cannot establish the distribution of individual changes or the uncertainty around a paired comparison.
The primary endpoint summaries do not directly estimate heritability. The study's stated rationale concerns inherited and environmental contributions to differences between people, but the registry record does not report a heritability estimate or the model used to estimate one. Nor do the primary endpoint summaries quantify pain relief as a separate outcome. The record's broader scientific aim should therefore be distinguished from the limited set of primary endpoint summaries posted.
No statistical analyses are posted in the registry record. It does not report a test of the primary endpoint, an adjusted estimate, an analysis population beyond the statement that all participants were included, or a plan for handling repeated measurements. Without those details, the summaries do not establish whether the observed difference is statistically distinguishable from chance under a specified analysis. They also do not show how precisely any treatment contrast was estimated.
The registry lists 242 enrolled participants and 228 participants for each infusion in the primary endpoint summaries. It does not explain that difference or provide a detailed account of missing endpoint data. Consequently, the reader cannot assess from the record whether missingness was related to participant characteristics, study condition or observed pain threshold. The reported numbers remain useful as descriptive results, but their scope is limited by the absence of analysis and data-completeness details.
These observations should be read as registry summaries, not as a complete report of the study's statistical findings. They describe the reported medians and accompanying bounds, but do not support a conclusion about the magnitude or statistical certainty of a paired treatment effect, nor about genetic and environmental contributions to individual differences.
9. Statistical Methods Explained
Several design and analysis concepts help clarify what the posted results can and cannot establish. The registry labels this trial randomized, double-blind and crossover. These labels describe intended features of the design, but do not by themselves specify the statistical model, how the treatment sequence was assigned, or how the crossover data were analyzed. Those details are not reported in the registry record.
What does a crossover design contribute?
In a crossover study, participants receive multiple conditions, and outcomes can be compared within participants. A within-participant comparison can account for stable differences between people, such as a generally higher or lower pain threshold. This is potentially relevant to a study focused on differences between individuals. But a valid analysis also needs to consider the structure of repeated observations and possible effects of treatment order or study period. The registry record does not report whether or how such factors were addressed.
The posted counts of 228 for each infusion do not reveal whether the same participants contributed both observations or whether all planned measurements were available. The crossover label and endpoint counts are not enough to reconstruct individual paired data. Without a reported paired analysis or participant-level results, a reader cannot determine how the comparison was calculated.
Why report a median?
A median is the midpoint of an ordered set of measurements. Unlike a mean, it is not pulled as strongly by very high or very low observations. A median can be a useful summary when a distribution is skewed or contains unusual values. The primary endpoint is explicitly described using a median and an inter-quartile range, but the IQR values are not present in the arm summaries.
The inter-quartile range summarizes the spread of the central half of a distribution. It helps readers understand variability among participants, rather than only the central value. The record's stated dispersion measure is the IQR, but no numeric IQR is reported for either infusion. This limits the distributional information available from the primary endpoint summaries.
What do the bounds mean?
The posted results list bounds of 48.3 to 50.4 alongside the Alfentanil Infusion median and 47.1 to 49.3 alongside the Saline Infusion median. An interval can represent different quantities, including uncertainty around an estimate or a range of observed values. The registry record does not identify what these bounds represent or state a confidence level. It would therefore be inappropriate to describe them as confidence intervals or use them to make a formal inference about the difference between infusions.
In general, a confidence interval expresses uncertainty about an estimated quantity under a specified statistical method. Its interpretation depends on both the quantity being estimated and the method used. Because the registry record does not provide the interval definition or a treatment contrast, the bounds should be read only as bounds listed with the arm summaries.
What information is needed for an inferential comparison?
A formal comparison would need to state the estimand, meaning the precise quantity the analysis aims to estimate. For a crossover study, that might involve a within-participant contrast, but the registry record does not identify the estimand or say how the primary comparison was defined. It also does not report a test statistic, p-value, confidence interval for a contrast, or model specification.
The record lists no posted analyses. It therefore does not show whether the analysis used a paired method, adjusted for baseline measurements, modeled repeated measurements, or accounted for the crossover sequence. These are not minor reporting details: the method determines how the participant-level observations contribute to the estimate and how uncertainty is quantified. No particular approach should be assumed.
What do the planning assumptions describe?
The record describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between arms and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. These are planning assumptions, not evidence that the trial was designed using those assumptions. The registry record does not report the trial's own sample-size justification. Planning sample sizes, when presented, are illustrations and should not be interpreted as observed power or as a replacement for the trial's actual analysis.
For a study with a crossover structure, interpretation of any planning calculation also depends on the assumed variability and correlation of repeated observations. The listed general assumptions do not provide those details. The registry record does not report whether the planning illustration reflects the actual crossover design or the statistical method used for the posted summaries.
Finally, the study's stated purpose includes separating inherited from environmental influences. That goal requires a suitable model for the twin data and the relevant outcome structure. The registry record does not report such a model or a heritability estimate. The infusion medians describe the primary endpoint by condition, but they are not themselves estimates of genetic or environmental contributions.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 14 outcome measures and reports secondary outcomes related to sedation, average and maximum nausea, average and maximum pruritis, average and maximum drug liking, and maximum drug disliking. The record does not describe a hierarchy of endpoints, identify which comparisons were confirmatory, or report a plan for controlling the risk of false-positive findings across multiple outcomes. No multiplicity adjustment is reported. Because no analyses are posted, the record also does not show how many statistical tests were performed or which results, if any, were selected for reporting.
Multiplicity matters when several outcomes or comparisons are examined. As the number of statistical tests grows, the chance of at least one apparently notable result can increase if each test is interpreted in isolation. Methods for addressing that issue depend on the scientific questions and analysis plan. The registry record does not report a plan, so no specific approach should be assumed.
For missing data, the primary endpoint states that all participants were included for analysis. The registry lists enrollment of 242 and endpoint counts of 228 for each infusion, but does not explain the difference or give reasons for unavailable measurements. It does not report imputation, sensitivity analyses, or assumptions about missingness. The effect of missing observations on the summaries therefore cannot be evaluated from the record.
The analysis population is not described beyond the statement that all participants were included for analysis. The record does not specify whether this means all enrolled participants, all randomized participants, participants with at least one measurement, or participants with complete crossover measurements. It also does not report exclusions or protocol deviations. These omissions limit assessment of how closely the posted results represent the enrolled study population.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Alfentanil | 0 | 228 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Alfentanil | 0 of 228 |
For the Alfentanil group, the registry reports 228 participants at risk for serious adverse events and 0 affected. It also reports 228 at risk for other adverse events and 0 affected. No deaths are listed, and no top serious-event terms are listed. These are the safety figures recorded for the group; they do not establish that no event occurred outside the registry's reporting definitions or observation procedures.
A zero count means that the registry record reports no affected participants in that category for the stated group. It does not prove that the underlying risk is absent. The record does not provide further details about the safety observation period, event-collection procedures, or how events were classified. It also does not provide a corresponding safety group in the posted serious-adverse-event summary for saline.
The listed secondary outcomes include sedation, nausea, pruritis and drug liking or disliking. These outcomes are distinct from the serious and other adverse-event counts. The registry record does not provide numerical results for those outcomes in the posted safety summary, so their values should not be inferred from the zero adverse-event counts.
12. What the Result Does, and Does Not, Mean
The posted results show a median heat pain threshold of 49.6 degrees centigrade for Alfentanil Infusion and 48.6 degrees centigrade for Saline Infusion. The record also lists bounds of 48.3 to 50.4 and 47.1 to 49.3 alongside those medians. These figures describe the endpoint summaries, but the record does not state what the bounds represent.
The result does not, on its own, establish the statistical significance or precision of a difference between infusion conditions. No test, p-value, confidence interval for a contrast or paired analysis is reported. The IQR values are not reported either, so the spread of participants' threshold measurements cannot be assessed from the designated dispersion measure.
The study's title and summary describe a twin study intended to examine inherited and environmental contributions to differences in pain sensitivity and opioid response. The posted primary endpoint summaries do not quantify heritability or identify the source of individual differences. The registry record does not report a genetic or environmental model, or an estimate from such a model.
Nor should the primary endpoint be treated as a complete measure of pain relief or of all participant experiences during an infusion. The registry lists additional outcomes, including sedation, nausea, pruritis and drug liking or disliking, but numerical results for these outcomes are not included in the posted summary used for this interpretation.
The enrollment and endpoint counts also require caution. Enrollment is reported as 242, while the primary endpoint summaries list 228 participants for each infusion. The registry record does not explain the counts or describe missing data. The summaries therefore cannot show whether participants with unavailable observations differed from those included in the endpoint results.
Overall, the registry record offers descriptive endpoint and safety counts but not a full statistical account. It is not possible to infer an unreported analysis plan, a treatment effect estimate, or a heritability result from these summaries.
13. Why This Trial Matters Statistically
This study is statistically notable because its scientific purpose concerns differences between people, while its randomized crossover design can also support comparisons within people. Those are related but distinct questions. A within-participant comparison addresses how an individual's measurement varies across study conditions; a heritability analysis asks how variation between people relates to inherited and environmental factors. The registry record states the broader goal but does not report an analysis that connects the posted endpoint summaries to that goal.
The record also illustrates why a central summary is not enough to characterize a result. The medians provide a description of the middle of the endpoint distribution under each infusion, but the stated IQR values are absent. The bounds that accompany the medians are not defined. Without a reported contrast and an identified measure of uncertainty, readers cannot assess the precision of the comparison in the usual inferential sense.
Repeated measurements make the analysis structure important. In a crossover study, observations from the same participant are related. An analysis that recognizes that relationship may differ from one that treats the infusion summaries as independent groups. The record does not report which method was used, so the design label cannot substitute for an analysis description.
Finally, the registry makes clear that the question motivating a study can be broader than the outcome results posted. The stated rationale includes inherited and environmental influences, while the available primary summaries concern heat pain threshold by infusion. Keeping those levels of evidence separate helps prevent descriptive treatment-condition summaries from being mistaken for a genetic finding or a complete answer to the study's scientific aim.
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.
The registry record leaves important design and analysis details unreported. It does not describe the twin recruitment structure, the infusion sequence, the interval between infusions or whether period and sequence effects were assessed. It identifies the study as randomized and double-blind but does not explain randomization procedures, allocation concealment or how masking was maintained.
For the primary endpoint, the record gives medians and accompanying bounds but does not define those bounds. Although the endpoint specifies an inter-quartile range as the dispersion measure, numeric IQR values are not reported. There is no posted contrast estimate, inferential test, p-value or confidence interval for a treatment comparison. The analysis method for repeated measurements is not reported.
The registry lists 242 enrolled participants and 228 participants for each infusion in the primary endpoint results, without a participant-flow explanation or a missing-data account. The statement that all participants were included for analysis does not clarify the analysis population or explain how unavailable measurements were handled. No sensitivity analysis for missing data is reported.
The broader aim was to examine inherited and environmental contributions to individual differences, but the registry record does not report a heritability model or estimate. The secondary outcomes are listed, but numerical results for them are not included in the posted results. The record does not report a multiplicity strategy, the trial's sample-size justification or a detailed statistical analysis plan. These limitations restrict interpretation to the descriptive endpoint and safety figures that are recorded.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Heritability of Opioid Effects: A Twin Study — NCT00672438.
- Registry record last updated 2017-01-06; status last verified 2017-01.
- Results first posted 2016-07-21.
- 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.
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18. Record Summary
NCT00672438, titled Heritability of Opioid Effects: A Twin Study, is listed as a completed randomized, double-blind crossover study with enrollment of 242. Alfentanil infusion was compared with saline infusion. The primary endpoint was heat pain threshold in degrees centigrade, measured at training before study procedures, at baseline and during each infusion.
The posted medians were 49.6 for Alfentanil Infusion and 48.6 for Saline Infusion. Each arm summary lists 228 participants. The record reports 0 affected participants among 228 at risk for serious adverse events and 0 among 228 at risk for other adverse events in the Alfentanil group.
The registry record does not report a statistical comparison of the primary endpoint, the meaning of the bounds accompanying the medians, numeric IQR values, or a heritability analysis. It also does not explain the difference between enrollment and the endpoint counts or describe missing-data methods.