Methadone vs Magnesium in Spinal Fusion: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Methadone vs Magnesium in Spinal Fusion (NCT01795495), a randomized phase 2 study. The primary outcome is Intra- and Post-operative Pain Relief.

2. Clinical Question

The study summary describes additional interests, including intraoperative anesthetic requirements and neurophysiologic monitoring measures. These aims provide context for the trial, but the posted primary outcome result concerns total hydromorphone use. The registry record does not report posted results for those other exploratory interests. Consequently, the available arm comparisons address the stated opioid-use measure and pain scores, rather than establishing how the full set of proposed intraoperative aims turned out.

3. Trial Design

The registry identifies this as a randomized, single-masked, parallel-group Phase 2 study. It was conducted at Nationwide Children’s Hospital and is marked completed. The registry dates the study start to 2013-09 and primary completion to 2016-08. Enrollment is listed as 63.

Participants were assigned to one of three regimens: remifentanil alone, remifentanil plus methadone, or remifentanil plus magnesium. The posted primary-outcome results include 19 participants in the remifentanil arm, 22 in the methadone arm, and 19 in the magnesium arm. The posted pain-score results give the same arm-specific counts. The registry record does not explain why the outcome counts differ from the enrollment figure, or whether all enrolled participants contributed to every analysis.

Random assignment is intended to make treatment groups comparable on average, including on characteristics that are not measured. In a small trial, however, randomization does not guarantee that each group will be closely balanced, and the registry record does not post baseline characteristics with which to assess balance. Single masking means that some participants or study personnel were masked, but the record does not specify who was masked. Details of the allocation procedure, concealment, treatment adherence, and departures from assigned treatment are not reported in the registry record.

The arm descriptions identify remifentanil alone as current practice and the other arms as adjunct regimens. The study summary frames the comparison as an investigation of intraoperative medications and subsequent opioid requirements. It does not establish that the posted results address every proposed study aim. The trial’s original sample-size justification, planned statistical analysis, interim analyses, and detailed protocol are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

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 Intra- and Post-operative Pain Relief, measured over Intra-operative and 24 hours post-operatively.

The primary endpoint is the total amount of hydromorphone administered in the operating room, recovery room, and inpatient ward through 24 hours after surgery, expressed in mg/kg. The registry labels the outcome as a mean with standard deviation and gives the timeframe as intraoperative and 24 hours post-operatively. This is a measure of opioid use, not a direct measure of pain intensity, satisfaction, or opioid-related side effects.

Hydromorphone use is relevant to the study’s stated question because the trial examines whether adding methadone or magnesium to remifentanil is associated with differences in subsequent opioid requirements. The measure combines administrations across the listed care settings and follow-up period into a single total. That makes the endpoint a summary of opioid consumption over the perioperative interval described in the record. It does not, by itself, show when doses were needed, why they were given, or how individual patients experienced pain.

The registry reports arm means and standard deviations, along with comparisons against remifentanil alone. A mean describes the group’s average recorded amount; a standard deviation describes how much individual measurements varied around that average. The record does not provide additional information about the distribution of hydromorphone use, missing measurements, or whether any adjustment was made for other variables. Those details matter when considering how fully the group averages represent the experience of participants in the trial.

7. Results Posted in the Registry

• Remifentanil Plus Methadone: mean 0.26 versus 0.34 on control; difference -0.08 (95% CI -0.14 to -0.02), standardized effect d = -0.76; z-test p = 0.015.
• Remifentanil Plus Magnesium: mean 0.38 versus 0.34 on control; difference 0.04 (95% CI -0.03 to 0.11), standardized effect d = 0.38; z-test p = 0.241.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Post-operative Pain Scores

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Remifentanil Plus Methadone: mean 5.10 versus 4.60 on control; difference 0.50 (95% CI -0.74 to 1.74), standardized effect d = 0.25; z-test p = 0.430.
  • Remifentanil Plus Magnesium: mean 5.10 versus 4.60 on control; difference 0.50 (95% CI -0.63 to 1.63), standardized effect d = 0.28; z-test p = 0.384.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Remifentanil Plus Methadone and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Remifentanil Plus Magnesium and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists postoperative pain scores as a secondary outcome. Across the arms, the posted means are close in numerical terms, and both adjunct comparisons have reported intervals that include zero. The pattern does not mirror the primary hydromorphone comparison in a simple way: the primary mean is lower in the methadone arm than in the remifentanil-alone arm, whereas the pain-score mean is higher in both adjunct arms. These measures are distinct and need not move together, because recorded medication use and reported pain intensity capture different aspects of postoperative care.

The pain-score comparisons are unadjusted and their intervals allow a range of possible differences. The registry does not state the scale range, whether higher scores represent greater pain, or a threshold for a meaningful change. Thus, the numeric direction can be described, but its practical interpretation is constrained by missing scale information. No registry-reported analyses are listed for the secondary outcome.

Secondary results generally carry less confirmatory weight when they are not identified as the primary endpoint, when multiple outcomes or comparisons are examined, or when the analysis plan is unavailable. Repeated testing can increase the chance of seeing an apparently notable result by chance if no multiplicity strategy is used. The registry record does not report whether a multiplicity adjustment was planned or applied. The pain-score comparisons should therefore be treated as exploratory context for the primary opioid-use result, not as independent confirmation or contradiction of it.

The posted secondary outcome is limited to pain scores. Although the study summary describes other interests, the registry record does not provide results for every proposed intraoperative measure. The overall secondary evidence is consequently incomplete, and it cannot resolve questions about anesthetic requirements or neurophysiologic monitoring.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Post-operative Pain Scores

9. Statistical Interpretation

10. Statistical Methods Explained

Arm-level results and between-arm comparisons answer related but different questions. A group mean summarizes the observed average outcome in that arm. A mean difference compares two such averages, using remifentanil alone as the reference group. For the primary endpoint, the reported methadone mean difference is -0.08 mg/kg and the magnesium mean difference is 0.04 mg/kg. A negative contrast indicates a lower group mean in the adjunct arm than in the reference arm; a positive contrast indicates a higher group mean.

What does a standard deviation describe?

A standard deviation describes variation among individual measurements around the arm mean. It is not the uncertainty interval for the mean and is not a range containing every participant’s result. The primary outcome’s standard deviations are 0.11, 0.1, and 0.1 mg/kg across the remifentanil, methadone, and magnesium arms. A standard deviation can help readers understand how variable the endpoint was within groups, while the confidence interval for a comparison addresses uncertainty in the estimated difference between group means.

How should a confidence interval be read?

A confidence interval gives a range of values compatible with the observed data under the statistical method used. It indicates the precision of an estimate: a narrower interval conveys greater precision than a wider one, all else being equal. The registry record does not state the confidence level or give a detailed method for constructing the posted comparison intervals, so those details should not be assumed. An interval that includes zero is compatible with no mean difference as well as with differences in either direction within its span. An interval that excludes zero indicates that zero is outside the range of values in that reported interval, but does not by itself establish clinical importance.

What do the p-values add?

A p-value measures how unusual data at least as discrepant as those observed would be under a specified null model, assuming that model and its conditions hold. It is not the probability that the null hypothesis is true, nor does it measure the size or importance of an effect. The reported p-values are unadjusted: the registry record does not report a correction for the multiple comparisons or outcomes. The methadone primary comparison has p = 0.015, and the magnesium primary comparison has p = 0.241. These values should be read together with the corresponding effect estimates and intervals, not as stand-alone conclusions.

Why do the posted comparisons have limits?

The registry contains arm means, standard deviations, and participant counts, but it does not list registry-reported analyses. The comparisons are therefore unadjusted recalculations from the posted summary statistics. Summary-statistic calculations cannot account for participant-level features, covariate adjustment, or analysis choices that are not represented in those summaries. The registry record does not report whether the original study analysis used different methods or whether an analysis plan specified a particular approach.

For continuous outcomes, a mean-based comparison is most directly informative when the mean is a suitable summary and the analysis assumptions are reasonable. Strong skew, outliers, or unequal variability can affect how well a simple mean comparison represents the data. The record does not post distributions, diagnostic checks, or individual measurements, so these features cannot be evaluated from the arm summaries alone. This is a general limitation of interpreting aggregate continuous-outcome results, not a claim that any particular assumption failed in this trial.

What is the relevance of over-dispersion?

Over-dispersion is a general concern when observed variability is greater than a model assumes. If a method underestimates variability, its uncertainty estimates can be too narrow and its statistical evidence can appear stronger than warranted. For a continuous mean comparison, distributional shape and outliers may also influence standard errors and interval estimates. The posted summary statistics do not permit a direct assessment of these characteristics, and the registry record does not report diagnostics or a model addressing them. No conclusion about over-dispersion in this trial can be drawn from the registry information.

The sample-size illustrations use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. They vary the effect to detect as a stated fraction of the observed effect. These are planning calculations based on the observed comparison, not details of the trial’s original design process. The original sample-size assumptions and justification are not reported in the registry record. The illustrations do not demonstrate that the completed trial had a particular probability of detecting an effect.

Finally, statistical methods rely on how outcomes and participants are handled. Missing data, analysis populations, protocol deviations, and repeated testing can affect estimates or their interpretation. The registry record does not describe the handling of missing outcome values, define an intention-to-treat or per-protocol population, or report multiplicity adjustment. These are absences in the registry information, not evidence that a specific method was or was not used outside the record.

11. Confidence Intervals and Precision

The primary methadone comparison estimates a mean difference of -0.08 mg/kg, with a reported interval from -0.145 to -0.015. The interval is entirely below zero, so the values represented by its endpoints correspond to lower mean hydromorphone use in the methadone arm relative to remifentanil alone. The interval still spans differences of varying sizes, and the registry record gives no clinical threshold for judging their importance. Its statistical direction should not be confused with proof of a particular practical benefit.

For magnesium, the estimated mean difference is 0.04 mg/kg, with an interval from -0.027 to 0.107. Because this range extends across zero, it is compatible with a lower, similar, or higher mean than in the remifentanil-alone group. This does not establish equivalence or absence of a difference: an interval can include zero while also allowing differences that may matter. The precision is limited by the group sizes and outcome variability, and the registry record does not define an equivalence margin.

The posted pain-score intervals are also wide relative to their point estimates: -0.743 to 1.743 for methadone versus remifentanil alone, and -0.627 to 1.627 for magnesium versus remifentanil alone. Both include zero. These ranges indicate uncertainty about the size and direction of the mean differences. The pain-score scale’s range and a meaningful-change threshold are not reported in the registry record, which further limits interpretation of the size of these estimates.

Intervals are most useful when read alongside the point estimate, the observed arm variation, and the outcome’s clinical meaning. They do not show where every participant’s value fell, and they do not remove the limitations of unadjusted comparisons or unreported analysis details. The confidence level and interval-construction method are not reported in the registry record.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning entries are participants per arm for 80% power and participants per arm for 90% power, rather than total event counts. The record describes the calculation assumptions as a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The figures are planning illustrations based on the observed data, not the trial’s own original design assumptions, which are not reported in the registry record.

In plain terms, the 80% power column gives the estimated number of participants in each arm for a planning scenario with an 80% chance of detecting the specified effect under the calculation assumptions, if that effect and the assumptions were correct. The 90% power column uses a higher target chance of detection and therefore generally calls for more participants. These are not guarantees: actual performance depends on the true effect, variability, analysis method, and other features of the eventual study.

Each row changes the assumed effect size. The full observed effect is used in one scenario, and smaller fractions of that effect are used in the other scenarios. Smaller effects are harder to distinguish from random variation, so the planning figures require more participants per arm. The resulting numbers are therefore illustrations of how design needs can change with the effect a future study aims to detect. They are not observed power for this completed trial, and they should not be read as evidence that the trial did or did not answer its question. The registry record does not report the sample-size justification used when the trial was designed.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -0.080; pooled standard deviation σ = 0.105.
2. n = 2 × (1.96 + 0.842)² × 0.105² / -0.080² = 26.9, rounded up to 27 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -0.08                      # observed difference in means
sigma <- 0.104734095543098                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(1795495)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 27 (80% power), 37 (90% power)
 75% of observed effect: n per arm = 48 (80% power), 65 (90% power)
 50% of observed effect: n per arm = 108 (80% power), 145 (90% power)
power.t.test: 27.9 
Simulated power at n = 27 per arm: 0.792 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The posted results involve more than one treatment comparison and include both a primary outcome and a secondary outcome. When many hypotheses are tested, the chance of at least one apparently unusual result can rise unless the analysis plan accounts for repeated testing. The registry record does not report a multiplicity strategy, such as which comparisons were designated confirmatory or whether p-values were adjusted. The displayed p-values are unadjusted, so they should not be treated as family-wise error-controlled evidence.

The registry record does not report how missing outcome values were handled, whether all randomized participants were included in each analysis, or which analysis population was used. The posted outcome counts are 19, 22, and 19 for the primary endpoint and the same counts for postoperative pain scores, while enrollment is listed as 63. These figures alone do not explain the difference, establish the reason for any non-contribution, or indicate whether data were missing. The record also does not describe imputation, exclusions, protocol deviations, or treatment adherence.

These omissions limit assessment of potential bias. For example, an analysis restricted to participants with recorded outcomes can differ from an analysis that includes all randomized participants if missingness is related to treatment or outcome. This is a general methodological concern; the registry information does not establish that such a problem occurred in this trial. Similarly, not having an analysis population specified in the record prevents a reader from determining whether the posted comparison follows an intention-to-treat approach.

The original statistical analysis plan, interim analysis procedures, and prespecified handling of multiple outcomes are not reported in the registry record. In the absence of those details, interpretation should distinguish the registry’s descriptive summaries and unadjusted recalculations from a fully documented prespecified analysis.

15. 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 reports zero serious adverse events in each listed arm. The numbers at risk for serious adverse events are 21 for remifentanil, 22 for remifentanil plus methadone, and 20 for remifentanil plus magnesium. It also reports zero other adverse events, with 20, 22, and 21 participants at risk in those arms, respectively.

These are counts recorded in the registry, not proof that no adverse events occurred outside the events captured or reported. The denominators differ between the serious and other adverse event summaries and do not match every posted outcome count, so the record does not support assuming a single common safety population. The registry does not provide descriptions of other adverse events, and deaths are not reported in the registry record.

With small groups, zero recorded events cannot precisely characterize the frequency of uncommon harms. The safety figures are descriptive for the participants counted and should be interpreted alongside the limited detail in the registry record. They do not establish a comparative safety profile between regimens.

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

The posted results describe average hydromorphone use and postoperative pain scores in three randomized groups. For the primary outcome, the methadone group had a lower observed mean than the remifentanil-alone group, and the unadjusted comparison interval excludes zero. The magnesium group’s mean was higher than the reference mean, but its interval includes zero. These are observations from this trial and its posted summaries; they do not establish the clinical importance of either difference.

The findings do not show that a regimen works or does not work. No threshold for a meaningful change in opioid use is reported, and the pain scale’s range and interpretation are not specified. The mean opioid amount is not itself a direct measure of pain, satisfaction, or side effects. A difference in average medication use should therefore not be translated into a claim about all participants’ experiences or broader clinical outcomes.

The randomized design supports a comparative question, but interpretation is constrained by the arm sizes, the lack of posted baseline information, and the absence of details about the original analysis plan, missing-data handling, and analysis populations. The reported comparisons are unadjusted recalculations from summary statistics, and the registry does not list sponsor analyses. No discrepancy is flagged, but this does not fill the gaps in the record’s methods description.

The results also do not settle the study summary’s other interests, including anesthetic requirements and neurophysiologic monitoring, because corresponding results are not reported in the registry record. The safety summary records zero serious and zero other adverse events in the listed risk groups, but limited counts and reporting detail cannot establish that a regimen is free of harm. Overall, the posted information supports a cautious description of the measured outcomes in the enrolled trial, not broad claims beyond them.

17. Why This Trial Matters Statistically

This trial illustrates why a treatment comparison is more than a comparison of group averages. The primary endpoint captures medication use across several care settings, while postoperative pain scores capture a different outcome. The observed pattern across these measures is not identical, emphasizing that related clinical measures can tell different parts of the story.

It also illustrates the importance of precision. A point estimate gives a concise description of the observed difference, but its interval shows the range of values compatible with the data under the calculation method. The methadone primary comparison and the magnesium primary comparison have different interval patterns, and neither interval alone establishes clinical importance. The trial’s arm sizes and the lack of a meaningful-change threshold are important context for reading the estimates.

The registry record further shows how much interpretation depends on reporting. Randomization and masking are identified, but details about who was masked, allocation methods, missing data, analysis populations, multiplicity, and the original sample-size rationale are not reported. Those omissions do not invalidate the descriptive results, but they limit independent assessment of the analysis and its safeguards.

Finally, the planning illustrations make clear that future sample-size needs depend on the effect a study aims to detect. They are not a retrospective measure of the completed trial’s success. Distinguishing design planning, observed outcomes, and statistical uncertainty is central to responsible interpretation of small clinical trials.

18. 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 posted primary endpoint combines hydromorphone administered in the operating room, recovery room, and inpatient ward through 24 hours after surgery. This total does not show the timing of administrations or distinguish the settings’ contributions. It is a measure of opioid use rather than direct pain intensity. The registry does not report a clinically meaningful threshold for the endpoint.

The results are based on modest arm counts, and the registry does not post baseline characteristics or individual-level data. It is therefore not possible to evaluate group balance from the posted summaries, investigate outliers or distributional shape, or assess how representative the means are of individual experiences. The pain-score scale range and direction are also not reported, limiting interpretation of those secondary values.

Several methods details are absent: who was masked, the allocation procedure, the original sample-size justification, the prespecified analysis, the handling of missing data, and the analysis population. The registry does not report whether multiplicity was addressed or whether interim analyses occurred. The comparisons are unadjusted recalculations from summary statistics, and registry-reported analyses are not listed. These gaps mean that the calculations cannot be matched against a fully documented sponsor analysis.

Safety reporting is also limited. The record gives zero counts for serious and other adverse events in the listed risk groups but provides little further detail; deaths are not reported in the registry record. The small groups and absence of event descriptions constrain conclusions about uncommon or comparative harms. Finally, results for other proposed study interests are not reported in the registry record, so the posted outcomes do not cover the full scope described in the study summary.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Methadone vs Magnesium in Spinal Fusion — NCT01795495.
• Registry record last updated 2018-02-08; status last verified 2018-02.
• Results first posted 2018-02-08.
• 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.

22. Record Summary

The registry record describes a completed, randomized, single-masked, parallel-group Phase 2 trial of remifentanil alone, remifentanil plus methadone, and remifentanil plus magnesium in people with idiopathic scoliosis undergoing posterior spinal fusion. Enrollment is listed as 63.

The primary outcome is total hydromorphone use through 24 hours after surgery, expressed in mg/kg. The posted means are 0.34 for remifentanil alone, 0.26 for methadone plus remifentanil, and 0.38 for magnesium plus remifentanil. The registry also posts postoperative pain scores as a secondary outcome. No registry-reported analyses are listed; the displayed comparisons are unadjusted recalculations from summary statistics.

The record reports zero serious and zero other adverse events in the listed risk groups. Important details about the original statistical plan, missing data, analysis populations, multiplicity, and sample-size justification are not reported in the registry record. The results are best read as limited descriptive and comparative evidence for the posted outcomes, with uncertainty and reporting gaps kept in view.