Buprenorphine Plus Baclofen to Increase Analgesia in Healthy Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Buprenorphine Plus Baclofen to Increase Analgesia in Healthy Volunteers (NCT04251819), a randomized phase 2, phase 3 study. The primary outcome is Pain Threshold.

2. Clinical Question

The clinical question has two parts: whether the study’s intervention groups can be compared on the specified heat-pain measure, and whether those observations support a claim about enhanced analgesia. The registry names pain threshold as the primary outcome and provides a mean and standard deviation for each arm. It does not post an analysis comparing the arms, an estimate of the between-arm effect, or an inferential result. The available outcome values therefore support a descriptive account of the recorded measurements, not a conclusion about a treatment effect.

3. Trial Design

The registry record describes a randomized, open-label, parallel-group study in healthy volunteers, listed as phase 2 and phase 3. The study began on 2021-01-21, has a primary completion date of 2024-06-15, and is recorded as terminated. Enrollment is listed as 19. The reason for termination and the timing or circumstances of that decision are not reported in the registry record.

Three arms are listed: placebo, Baclofen 5mg, and Baclofen 10mg. Each arm description specifies one dose at the participant’s second study appointment. The registry record does not describe the allocation procedure beyond stating that allocation was randomized. It does not report whether allocation was concealed, how randomization was generated, or whether the arms were intended to be equal in size. Masking is listed as none, so the study is described as unmasked.

The posted baseline outcome counts are 6 in the placebo arm, 8 in Baclofen 5mg, and 5 in Baclofen 10mg. These are the counts associated with the reported primary outcome values. The registry does not provide a detailed participant-flow account explaining screening, enrollment, withdrawals, or whether all enrolled participants contributed to each outcome.

The title and brief summary describe a question about baclofen enhancing buprenorphine analgesia. The listed intervention names and arm descriptions, however, identify placebo and baclofen doses; further details of any buprenorphine administration or treatment schedule are not reported in the registry record. This limits how specifically the treatment contrast can be characterized from the posted information. The registry lists four secondary outcomes and 14 outcome measures, but no statistical analyses are posted.

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 Pain Threshold, measured over Baseline.

The primary endpoint is pain threshold at baseline, summarized as a mean with standard deviation and measured in degrees Celsius. The record describes threshold as the intensity at which a stimulus is first perceived as painful. Heat is delivered by a computer-controlled thermal stimulation system using a 30 millimeter X 30 millimeter probe. Starting from 32 degrees Celsius, the probe temperature increases at .5 degrees Celsius/second until the participant presses a handheld button to indicate that the sensation first becomes painful.

A threshold measure translates a participant’s response to a standardized stimulus into a temperature at the point the stimulus is reported as painful. In general, this kind of continuous measure preserves more gradation than a simple yes-or-no outcome, while its interpretation depends on consistent stimulus delivery and participant response. The registry also mentions pain-rating scores from 0-100, but the named primary endpoint is pain threshold in degrees Celsius. Those are distinct descriptions and should not be treated as interchangeable measures.

The endpoint is recorded at baseline. That timing matters: baseline values characterize participants’ measurements at the stated time point, but they do not establish change after a dose. The registry record does not report a later primary-endpoint time point or a treatment-effect analysis for pain threshold.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted primary outcome is a continuous measurement summarized by its mean and standard deviation. This is a descriptive approach: the mean gives a measure of the center of the observed values, while the standard deviation describes their spread. Both summaries are reported separately for each arm. Neither one alone quantifies the difference between arms or the uncertainty in that difference.

What would an arm comparison estimate?

In general, a two-arm comparison for a continuous outcome estimates how far apart the groups are on the outcome scale, with uncertainty around that estimate. An unadjusted comparison uses the observed group summaries without accounting for other variables. An adjusted comparison may account for prespecified covariates, if an appropriate model and analysis plan are available. The registry record does not post an estimate of either type for this endpoint. It states that values are missing or not estimable for a two-arm comparison of the continuous endpoint, so no such recalculation is presented as a result.

How should uncertainty be understood?

In general, a confidence interval gives a range of values compatible with the data and the assumptions of the analysis. A narrow interval indicates greater precision than a wide interval, although an interval is not a guarantee that the true effect lies within it. The registry record does not report confidence intervals for the primary outcome or an interval for any between-arm effect. The standard deviations reported for each arm describe individual-level spread; they should not be read as confidence intervals or as a direct measure of the precision of a treatment comparison.

In general, a p-value measures how surprising data at least as inconsistent with a specified null hypothesis would be under the assumptions of a statistical model. It does not measure the probability that the null hypothesis is true, and it does not give the size or practical importance of an effect. No p-value or inferential test for the primary endpoint is posted. It would therefore be inappropriate to describe the observed means as statistically different or statistically equivalent.

What does randomization contribute?

In general, random allocation is used to make assigned groups comparable on average with respect to measured and unmeasured characteristics. It does not ensure that small groups will have identical baseline characteristics, and it does not replace a clearly defined analysis. The registry identifies the study as randomized, but details of sequence generation, allocation concealment, and the planned statistical analysis are not reported in the registry record. The study is also listed as having no masking. That design feature can matter for outcomes involving participant reports, because expectations or knowledge of assignment may influence responses; the record does not quantify whether that occurred.

How do the planning illustrations differ from observed results?

In general, sample-size planning asks how many participants would be needed to detect a specified effect under stated assumptions. The planning illustrations associated with the registry results are described as using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. They are not the trial’s own design justification, and their assumptions do not establish that the trial had a particular probability of detecting an effect. Such planning values are not observed power and should not be interpreted as a result of the trial.

Planning for equal allocation between two arms also differs from the three-arm structure described in the registry. The illustrations are theoretical planning scenarios, not evidence that the actual allocation, enrollment, or analysis followed those assumptions. The registry does not report the original sample-size justification or the planned effect size. No numerical planning result is used as an observed trial finding.

Why can small samples limit precision?

In general, smaller groups tend to yield less precise estimates than larger groups, all else being equal. The observed standard deviation and the number of observations both contribute to the uncertainty of a mean or contrast. A limited number of observations can also make estimates sensitive to individual values. The posted arm counts are small, but the registry does not provide confidence intervals or a model-based analysis that would quantify the resulting uncertainty for the treatment contrasts.

The registry has no posted analysis results for the primary endpoint, and no recalculated inferential result is available for the continuous comparison. The appropriate statistical reading is therefore descriptive: the means, standard deviations, and counts characterize the posted baseline data. They do not establish a treatment effect, a lack of effect, or equivalence between groups.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Placebo", "Baclofen 5mg", "Baclofen 10mg")
n   <- c(6, 8, 5)
m   <- c(44.62, 45.11, 43.56)
sp  <- c(2.13, 3.04, 3.77)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Placebo  6  44.620  2.130  42.385  46.855
CARM  Baclofen 5mg  8  45.110  3.040  42.568  47.652
CARM  Baclofen 10mg  5  43.560  3.770  38.879  48.241

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 14 outcome measures and four secondary outcomes: the Opioid Symptom Checklist, the 26-item Visual Analog Scale (VAS), the Drug Effects Questionnaire-5, and the 26-item Visual Analog Scale for “Subjective Drug Effects.” No analyses are posted for these outcomes or for the primary endpoint. The registry record does not report a multiplicity strategy, such as a prespecified hierarchy or adjustment for testing several outcomes. Without analysis results and a stated strategy, the risk of selective emphasis across multiple outcomes cannot be assessed from the registry information.

The record does not report how missing outcome values were handled, whether any imputation was used, or how incomplete observations were included in an analysis. It also does not report a primary analysis population, such as an intention-to-treat or per-protocol population. The posted primary-outcome counts therefore indicate how many observations accompany the reported arm summaries, but do not explain why other enrolled participants may not appear in those summaries.

Participant flow, reasons for missingness, and the timing of any withdrawals are not reported in the registry record. These details matter because missingness can affect both the number of observations and the interpretation of a group comparison. No conclusion about whether missing data could have biased an estimate is possible without information on the missingness pattern, handling decisions, and the underlying analysis.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: emergency department visit (16.7%).

The registry lists serious adverse events for one participant among 6 in the placebo group, none among 8 in the Baclofen 5mg group, and none among 5 in the Baclofen 10mg group. It lists no deaths in any arm. The serious-event term identified is Emergency Department Visit, with a reported value of 16.7%. These figures are event descriptions from the registry, not comparative safety estimates.

Other adverse events are listed for one participant in the placebo group and none in either baclofen group. The registry does not provide additional detail about event timing, severity beyond the serious-event classification, duration, relatedness to study treatment, or follow-up completeness. The posted group counts are small, so a count of zero means no event was recorded in that arm in these results; it does not establish that the underlying risk is zero.

In general, safety comparisons require attention to the number of people observed, duration of observation, definitions of events, and how events were collected. The registry record does not provide a statistical comparison or enough detail to estimate a precise difference in risk. These data should therefore be read as a limited account of recorded events, not as evidence that one arm is safer than another.

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

The posted results establish that the registry contains baseline pain-threshold summaries for three randomized arms, along with limited adverse-event counts. The means and standard deviations describe the values recorded for participants in each arm. The counts show how many observations contributed to those particular summaries. They are useful for understanding what was recorded, but they do not answer the central treatment question on their own.

The primary outcome is specified at baseline, and no post-intervention primary outcome or between-arm analysis is posted. The record therefore does not show a treatment-related change in pain threshold. It also does not provide a statistical estimate of whether baclofen enhanced buprenorphine analgesia. Absence of a reported analysis is not evidence that the groups were the same, just as descriptive differences in group means are not evidence that an intervention caused a difference.

The registry record also does not establish equivalence, non-inferiority, or a lack of effect. Those conclusions require a suitable design and analysis, with an estimate and uncertainty evaluated against a defined criterion. No such comparison or criterion is posted for this endpoint. The outcome summaries should not be used as a substitute for that missing inferential evidence.

Likewise, the small number of recorded adverse events does not establish safety or a comparative safety advantage. The event counts can be reported descriptively, but the registry does not provide the detail or analysis needed to make a precise comparison. The study is recorded as terminated, but the reason for termination is not reported in the registry record, so its status should not be taken as an explanation of the outcome data.

The most defensible reading is narrow: the posted record describes baseline heat pain threshold and adverse events in a small randomized study, while leaving the intervention-effect question unresolved in the registered results. Further interpretation would require outcome timing, analysis methods, missing-data information, and between-arm estimates that are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically instructive because a randomized design and numerical arm summaries can appear informative while still leaving the main causal question unanswered. Randomization is important for a valid comparison, but a treatment effect is learned from an appropriate outcome contrast, not from group-specific means alone. Here the primary endpoint is recorded at baseline, and the registry posts no inferential analysis for it.

The distinction between descriptive and inferential statistics is especially important when group counts are limited. A mean and standard deviation provide a compact description of observed data. They do not reveal how precise a between-arm effect would be, whether an observed contrast is compatible with chance variation, or whether the contrast is large enough to matter. Confidence intervals and a clearly specified comparison would be needed to address uncertainty, but they are not reported in the registry record.

The registry also illustrates why outcome reporting and analysis planning matter when a study lists multiple measures. Four secondary outcomes and 14 outcome measures appear in the record, while no analyses are posted. Without the analysis plan, multiplicity approach, missing-data methods, and defined analysis population, readers cannot evaluate how the results were selected or how robust any conclusion might be.

Finally, planning calculations and observed trial evidence answer different questions. Planning illustrations under stated assumptions do not establish that the enrolled study was adequately sized, nor do they give the probability that the observed result is true. Separating those concepts helps prevent an intended design scenario from being mistaken for an empirical result. The central statistical lesson is to distinguish study structure, outcome description, and evidence from a treatment comparison.

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 registry record leaves important design and reporting details unspecified. Although the study is listed as randomized and unmasked, the method of sequence generation and allocation concealment is not reported. The record does not provide a detailed protocol, analysis plan, or sample-size justification. The reason for the terminated status is also not reported, so the status alone cannot explain whether or how study conduct or reporting was affected.

The primary endpoint is listed at baseline, and no later primary-outcome result or treatment contrast is posted. This makes the available endpoint values unsuitable for answering whether an intervention changed heat pain threshold. Although the study title and summary refer to buprenorphine analgesia, the listed arm descriptions specify placebo or a baclofen dose at the second appointment; further details of buprenorphine administration are not reported in the registry record.

There are no posted statistical analyses, confidence intervals, or p-values. Handling of missing data, participant flow, analysis populations, outcome timing beyond the stated baseline, and multiplicity procedures are not reported. The primary-outcome group counts are limited, and the record does not show whether participants without posted values differed from those with values.

The safety information is also sparse: event counts are posted, but further event details and an inferential comparison are not. Taken together, these limitations constrain interpretation to the descriptive information in the registry; they do not justify claims about efficacy, absence of effect, or comparative safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Buprenorphine Plus Baclofen to Increase Analgesia in Healthy Volunteers — NCT04251819.
• Registry record last updated 2026-01-07; status last verified 2025-10.
• Results first posted 2026-01-07.
• 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

The registry describes a randomized, unmasked, parallel-group study of placebo and Baclofen 5mg or Baclofen 10mg in healthy volunteers. It is listed as phase 2 and phase 3, with enrollment of 19, and is recorded as terminated. The study question concerns whether baclofen enhances buprenorphine analgesia for acute pain.

The primary outcome is baseline heat pain threshold in degrees Celsius, summarized by arm as a mean and standard deviation. The record posts outcome counts of 6 for placebo, 8 for Baclofen 5mg, and 5 for Baclofen 10mg. No analyses are posted, and the registry does not provide a between-arm estimate for the primary endpoint. It also lists four secondary outcomes and 14 outcome measures.

One serious adverse event is listed in the placebo arm and none in the baclofen arms; no deaths are listed. The posted information supports a descriptive account of the recorded outcomes and events, but does not establish an intervention effect or a comparative safety result.