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 Signs and Symptoms of Opioid-associated Iatrogenic Withdrawal in Critically Ill Adults (NCT03435614), a registered phase not stated study. The primary outcome is Description of Signs and Symptoms of OIWS in Patients Who Scored Positive for Withdrawal Syndrome (OIWS) According to Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Criteria.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03435614 |
| Phase | Phase not stated |
| Condition | Substance Withdrawal Syndrome |
| Allocation | Not Stated |
| Design model | Not Stated |
| Masking | Not Stated |
| Enrollment | 29 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Marc M. Perreault |
| Results posted | Yes |
2. Clinical Question
Population
Mechanically ventilated critically ill adults receiving regular opioids for more than 72 hours. The registry lists an enrollment of 29 and describes following participants during opioid reduction and after transfer out of the intensive care unit under the stated follow-up limits.
Intervention
Opioids are the listed intervention, but this is not a trial of an assigned opioid regimen. The study description says participants receiving regular opioids were prospectively followed as opioid doses were weaned.
Comparator
The primary outcome description distinguishes patients with and without opioid-associated withdrawal syndrome. The record does not describe randomized allocation or a like-for-like control comparison; allocation is not stated.
Primary question
Among patients classified as experiencing opioid-associated withdrawal syndrome by DSM-5 criteria, what percentage of daily assessments included each specified sign or symptom, and how did those assessment percentages compare with patients without the syndrome?
The clinical motivation in the registry is that prolonged opioid administration may be used to facilitate ventilator support and maintain comfort, while rapid weaning has been associated with withdrawal symptoms in critically ill patients. The record describes limited information about these symptoms in adults and the need to recognize them as a basis for developing an assessment tool. This study therefore addresses symptom description and recognition rather than the comparative effectiveness of assigned treatments. It was registered as a prospective follow-up of one described group, not as a randomized treatment comparison.
3. Trial Design
The registry describes a prospective observational follow-up of mechanically ventilated critically ill adults receiving regular opioids for more than 72 hours. Participants were to be followed for withdrawal symptoms as opioids were weaned. The listed intervention is opioids, but the record does not describe a randomized allocation or an experimentally assigned opioid regimen. It identifies one group, titled Critically Ill Patients, and gives an enrollment of 29.
The study is marked completed. Its recorded start date is 2018-02-26, and its primary completion date is 2018-09-30. The listed sponsor is Marc M. Perreault. The condition is Substance Withdrawal Syndrome. These registry entries describe the study record and do not establish how completely participants were followed or whether every planned assessment was available.
The primary outcome covers assessments from the first day of opioid dose reduction until transfer out of the intensive care unit or a maximum of 14 days, including one further assessment after intensive care transfer. Assessments were performed once daily. For participants experiencing withdrawal, the registry says symptom data are limited to the assessment on the day they experienced the syndrome. This restriction is important when interpreting the outcome: the description does not represent repeated symptom observations across all follow-up days for that group.
The record lists change in serum cortisol level as a secondary outcome and identifies 2 outcome measures. It records 1 analysis, but a statistical method, analysis population, and numerical primary-outcome results are not reported in the registry record. The registry also notes that this is not a randomized comparison and that the arms are not a like-for-like control comparison.
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
| Stage | Iatrogenic Withdrawal Syndrome (IWS) Positive | Iatrogenic Withdrawal Syndrome (IWS) Negative |
|---|---|---|
| STARTED | 6 | 23 |
| COMPLETED | 6 | 23 |
| NOT COMPLETED | 0 | 0 |
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: 1128 patients screened; 59 eligible as per entry criteria; 29 enrolled and included in the analysis
| Characteristic | Unit | Opioid Iatrogenic WIthdrawal Syndrome (OIWS) Positive Patients | Opioid Iatrogenic Withdrawal Syndrome (OIWS) Negative Patients | Total |
|---|---|---|---|---|
| Participants analysed | 6 | 23 | 29 | |
| Age, Continuous | years | 70 (62.0 to 77.3) | 64 (44.0 to 74.0) | 65 (47.5 to 75.0) |
| Sex: Female, Male: Female | Participants | 2 | 6 | 8 |
| Sex: Female, Male: Male | Participants | 4 | 17 | 21 |
| Race/Ethnicity, Customized: Caucasian | Participants | 6 | 17 | 23 |
| Race/Ethnicity, Customized: Hispanic | Participants | 0 | 2 | 2 |
| Race/Ethnicity, Customized: Black | Participants | 0 | 2 | 2 |
| Race/Ethnicity, Customized: MIddle Eastern | Participants | 0 | 2 | 2 |
| Serum Creatinine at ICU admission (umol/L) | umol/L | 124 (78 to 307) | 136 (71 to 223) | 132 (74 to 222) |
| Reason for ICU admission (ICD-10): Diseases of the circulatory system | Participants | 1 | 6 | 7 |
| Reason for ICU admission (ICD-10): External causes of morbidity and mortality (trauma) | Participants | 1 | 5 | 6 |
| Reason for ICU admission (ICD-10): Infectious and parasitic diseases | Participants | 0 | 5 | 5 |
| Reason for ICU admission (ICD-10): Diseases of the digestive system | Participants | 3 | 2 | 5 |
| Reason for ICU admission (ICD-10): Diseases of the respiratory system | Participants | 0 | 4 | 4 |
| Reason for ICU admission (ICD-10): Other | Participants | 1 | 1 | 2 |
| Length of ICU stay | Days | 16.5 (9.5 to 38.0) | 16 (9.0 to 34.0) | 16.0 (9.0 to 35.0) |
| Duration of mechanical ventilation | Days | 9.0 (7.3 to 37.3) | 9.0 (5.0 to 26.0) | 9.0 (5.5 to 27.0) |
| Co-morbidities: Hypertension | participants | 3 | 12 | 15 |
| Co-morbidities: Coronary artery disease | participants | 2 | 11 | 13 |
| Co-morbidities: Diabetes | participants | 1 | 8 | 9 |
| Co-morbidities: Chronic kidney disease | participants | 1 | 5 | 6 |
| Co-morbidities: Chronic obstructive pulmonary disease | participants | 2 | 4 | 6 |
| Co-morbidities: Other | participants | 3 | 9 | 12 |
| As needed use of opioids prior to ICU admission | Participants | 0 | 1 | 1 |
| Use of benzodiazepines prior to ICU admission | Participants | 2 | 5 | 7 |
6. Primary Endpoint
The registry lists the primary outcome as Description of Signs and Symptoms of OIWS in Patients Who Scored Positive for Withdrawal Syndrome (OIWS) According to Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Criteria, measured over From first day of opioid dose reduction until transfer out of Intensive care unit (ICU) or a maximum of 14 days, including one further assessment post-ICU transfer.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | percentage of assessments |
| Endpoint classification | not reduced to a single comparison |
The primary outcome describes the percentage of daily assessments associated with each of seven specified signs or symptoms among patients with and without opioid-associated withdrawal syndrome. The symptoms are restlessness, agitation, anxiety, hallucinations, insomnia or sleep disturbance, mydriasis, and systolic blood pressure above 140 mmHg. The registry defines restlessness as a Richmond Agitation-Sedation Scale score of 1, agitation as a score greater than 1, sleep disturbance as less than 4 hours of continuous sleep, and mydriasis as pupil diameter greater than 2 mm. Assessments were made once daily during the stated follow-up period.
This outcome uses assessments, rather than simply counting whether each participant ever experienced a symptom. An assessment percentage describes how often a sign or symptom was recorded among the relevant assessments; it is not, by itself, the percentage of participants who experienced that symptom. The registry says that, for the group experiencing withdrawal, symptom data are limited to the assessment on the day withdrawal occurred. That restriction affects how the groups’ assessment percentages should be understood and compared.
The listed signs and symptoms were selected because the registry describes an absolute difference greater than 15% between groups as clinically significant. This is the stated selection rationale, not evidence that every symptom met the threshold in the observed results. The actual outcome values are not reported in the registry record. The endpoint is relevant to describing a symptom pattern that may inform assessment-tool development, but it does not itself validate a bedside tool.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry identifies the primary outcome and explains how it was defined, but numerical values for the symptom assessment percentages are not reported in the registry record. Consequently, the posted results do not establish which signs or symptoms were most frequent, whether assessment percentages differed between the groups, or how precisely any difference was estimated. No confidence intervals or primary-outcome test results are reported in the registry record.
The outcome is framed as a percentage of assessments. That is distinct from a percentage of people: one participant may contribute more than one daily assessment, and the same participant’s assessments may be related to one another. The record does not state how the assessment percentages were calculated, how the denominators were defined, or whether repeated observations were handled with a statistical model. These omissions limit interpretation of any group comparison, even if descriptive values are displayed elsewhere in the posted results.
There is also an important asymmetry in the outcome description. In the group experiencing withdrawal, symptom data are limited to the assessment on the day the syndrome occurred. The record does not describe an equivalent event-day selection rule for those without withdrawal. The comparison should therefore be read as a comparison of the registry-defined assessments, not as a direct estimate of symptom burden across all follow-up time.
The registry describes patients with and without withdrawal syndrome but does not report randomized allocation, and it explicitly cautions that the arms are not a like-for-like control comparison. Group differences, if reported in other results, would be descriptive associations in this observational setting. The record does not establish that opioid reduction caused a symptom or that a symptom distinguished withdrawal independently of other clinical factors.
The stated greater-than-15% absolute difference was the registry’s threshold for selecting symptoms as clinically significant. It should not be confused with a statistical significance test, a confidence interval, or a threshold demonstrated by the results. The recorded outcome definitions identify what the study intended to describe; without the numerical outcome findings and their uncertainty, the magnitude and reliability of any pattern cannot be evaluated from the registry record.
The study’s stated motivation is to improve recognition of opioid-associated withdrawal in critically ill adults. The endpoint can contribute descriptive information toward that aim, but symptom description alone does not establish the performance of a screening or diagnostic instrument. The record does not report measures of diagnostic accuracy, a validated score, or evidence that the selected signs reliably classify individual patients.
9. Statistical Methods Explained
The registry describes prospective follow-up during opioid weaning, with one daily assessment over the specified follow-up period. It does not report the statistical methods used to analyze the primary outcome. The explanations below describe general statistical considerations relevant to an outcome expressed as a percentage of assessments; they are not claims about methods used in this study.
What does a percentage of assessments represent?
In general, an assessment-level percentage uses assessments as its observational units. Its interpretation depends on which assessments enter the numerator and denominator and on whether every participant contributes the same number of assessments. It is not automatically a participant-level prevalence. A participant-level prevalence would instead describe the proportion of people who experienced a symptom at least once, using people as the units of analysis. These quantities answer different questions and should not be treated as interchangeable.
The registry identifies the assessment frequency and the follow-up window, but does not report the actual denominator for each symptom or group, the number of completed assessments, or the handling of unavailable assessments. Those details are needed to reproduce an assessment percentage and understand how much information supports it. They are not reported in the registry record.
Why can repeated assessments matter?
In general, observations from the same person often share characteristics. A person’s assessment on one day may therefore be more similar to that person’s other assessments than to an assessment from another participant. Analyses that treat every assessment as independent can overstate the amount of independent information when this within-person dependence is present. Methods for repeated or clustered data can account for that dependence, but the registry does not state whether such methods were used.
The outcome description also imposes different observation rules for the withdrawal group: its symptom data are limited to the assessment on the day withdrawal occurred. In general, selecting observations according to an event time can change the set of assessments being compared. Interpretation depends on how the comparison group’s observations were selected and on whether the analysis accounts for the different observation structure. The registry record does not provide those analytic details.
What does the symptom-selection threshold mean?
The registry says that the listed symptoms were selected based on an absolute difference greater than 15% between groups, judged clinically significant. This describes the stated selection rationale. In general, a clinical-importance threshold and a statistical test address different questions. A threshold concerns the size of a difference considered meaningful for a specified purpose; a statistical test evaluates compatibility with a statistical model and its assumptions. Neither supplies the other’s information. The record does not report symptom-specific estimates or uncertainty measures with which to assess the observed differences.
Because the record presents several symptoms, interpreting a set of findings also raises the general issue of multiple comparisons. Examining several outcomes can increase the chance of at least one apparently unusual result when each is assessed separately. Whether and how to address that issue depends on the prespecified analysis plan and inferential goals. Such a plan and any multiplicity adjustment are not reported in the registry record. The symptom-selection statement alone does not establish that a formal multiplicity procedure was used.
How should uncertainty be read?
In general, a confidence interval gives a range of values compatible with the data under a specified statistical procedure. Its width reflects precision: a wider interval indicates less precision than a narrower interval, all else equal. An estimate without an interval can conceal substantial uncertainty, particularly when based on a limited number of participants or assessments. The registry record does not report confidence intervals for the primary symptom outcomes, so their precision cannot be assessed from the stated results.
A p-value, when used, describes how unusual data at least as inconsistent with a specified null model would be if that model and the test assumptions were correct. It does not measure the size or clinical importance of an effect, and it does not give the probability that the null hypothesis is true. The record does not report primary-outcome p-values or identify a test. No inferential conclusion should be imputed from the symptom-selection threshold.
What is and is not documented about analysis?
The registry records one analysis, but does not describe its model, covariates, handling of repeated observations, or whether symptom comparisons were adjusted for other characteristics. It also does not report a sample-size justification or interim-analysis plan. These items are not reported in the registry record; their absence does not show that a particular method was or was not used outside the information recorded.
More generally, an observational symptom study can describe patterns in its enrolled participants, but comparisons between groups can be influenced by differences in who entered each group and by clinical circumstances related to both symptoms and withdrawal classification. Randomization is not reported, and the registry cautions that the groups are not a like-for-like control comparison. Statistical adjustment can address measured factors under suitable assumptions, but it cannot guarantee removal of unmeasured differences. The registry does not report whether adjustment was performed.
The study also lists change in serum cortisol level as a secondary outcome. The outcome name alone does not specify its measurement schedule, summary statistic, missing-data approach, or analysis method. Those details are not reported in the registry record. General statistical principles can clarify what the endpoints might represent, but cannot fill in unreported analysis decisions or results.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 2 outcome measures: the primary description of withdrawal signs and symptoms and the secondary outcome of change in serum cortisol level. The primary outcome itself includes several distinct symptoms. The record states that the symptom list was selected using an absolute between-group difference greater than 15% judged clinically significant, but it does not report a prespecified testing hierarchy, a multiplicity adjustment, or how any family of comparisons was defined. Those details are not reported in the registry record.
Multiplicity matters in general when several outcomes or comparisons are examined: interpreting each in isolation can make a chance finding among the set more likely. That general concern does not establish that the study’s findings are invalid, nor does the registry record show whether a correction was used. The actual symptom estimates and inferential results are not reported in the registry record, so the consequences of any multiplicity approach cannot be assessed.
The record does not report the number of missing daily assessments, reasons for missingness, or a method for handling missing outcome data. It also does not state whether participants who left follow-up or transferred out of intensive care contributed the planned further assessment. These omissions matter because observed assessment percentages can depend on which observations are available and how unavailable observations are treated.
No randomized analysis population, such as an intention-to-treat population, is described. This is a prospective observational study with a listed group of critically ill patients, and the record does not define an analysis population beyond its study description. The registry records 1 analysis but does not identify the included participants or assessments. The population used for each outcome is therefore not reported in the registry record.
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 |
|---|---|---|---|
| Critically Ill Patients | 0 | 29 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Critically Ill Patients | 0 of 29 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Critically Ill Patients | 0 of 29 |
For the listed Critically Ill Patients group, the registry reports 29 participants at risk for serious adverse events and 0 affected. It also reports 29 at risk for other adverse events and 0 affected, with 0 deaths. No serious-event terms are listed. These are the registry’s recorded counts for this group.
Zero reported events should be read as a count in the registry, not as proof that the underlying risk is absent. The figures do not quantify how precisely an event rate is known, and no confidence interval or additional safety analysis is reported in the registry record. The registry record also does not describe the adverse-event collection procedures, observation duration for safety, event definitions, or whether all expected safety information was available.
These safety counts are not a comparison between randomized treatment groups. The record describes one critically ill patient group and does not provide a like-for-like control comparison. The counts therefore cannot establish whether opioid use, opioid reduction, or another aspect of care caused or prevented an adverse event. They should be interpreted narrowly as the adverse-event figures entered for the listed group, alongside the limits of the registry’s reporting.
12. What the Result Does, and Does Not, Mean
The record documents a prospective study designed to describe signs and symptoms associated with opioid-related withdrawal in mechanically ventilated critically ill adults during opioid weaning. It gives operational definitions for the assessed signs and symptoms, identifies the daily assessment schedule, and states the follow-up limits. These details clarify the intended measurement and the clinical motivation: recognition of withdrawal symptoms as a basis for developing an assessment tool.
The numerical primary-outcome findings are not reported in the registry record. It is therefore not possible to use this record to say which symptoms were observed more often, how large any group differences were, or how precise those estimates were. The stated symptom-selection threshold is a rationale for choosing measures, not a substitute for the outcome values. The secondary outcome is named as change in serum cortisol level, but its numerical result is not reported in the registry record.
The study does not establish a causal treatment effect. It is described as prospective follow-up rather than randomized allocation, and the registry cautions that the arms are not a like-for-like control comparison. Any group contrast would need to be interpreted in light of the observational design and the specific assessment rules. The record also does not report a validated diagnostic tool or measures of diagnostic accuracy.
The findings, as recorded, do not establish that any particular symptom can independently identify withdrawal, that a bedside instrument is reliable, or that a particular approach to opioid weaning is beneficial or harmful. Those questions require evidence beyond the endpoint description and safety counts available in the registry record. The most defensible reading is that the record captures a clinically motivated symptom-description study and its planned measurement framework, while leaving its primary numerical results and key analysis details unreported.
13. Why This Trial Matters Statistically
This study addresses a measurement problem in a clinical setting where symptoms may be difficult to identify: critically ill adults receiving prolonged opioids during mechanical ventilation and subsequent opioid reduction. The registry describes a need for better information about withdrawal symptoms in adults and presents recognition of those symptoms as a foundation for assessment-tool development. Statistically, that makes clear definitions and an appropriate unit of analysis especially important.
The primary outcome is expressed as a percentage of daily assessments, not simply a percentage of participants. This distinction can materially affect the question answered. Assessment-level summaries describe the frequency of recorded symptoms across observations; participant-level summaries describe how many people experienced a symptom. Repeated observations from the same person can also be correlated, so the analysis method matters when interpreting precision and group contrasts.
The registry’s note that withdrawal-group symptom information is limited to the day withdrawal occurred is another important feature. It highlights how the timing and selection of assessments shape the estimand: a comparison of specified assessments is not necessarily a comparison of overall symptom burden throughout follow-up. The outcome definitions and timing rules are therefore central to interpreting what a reported percentage would mean.
The record is also a reminder that a clinical-importance threshold and an inferential result are not interchangeable. The stated greater-than-15% threshold explains why symptoms were selected, but does not provide estimates, uncertainty, or evidence of diagnostic performance. Because the primary numerical findings and analysis details are not reported in the registry record, the study’s statistical contribution cannot be judged from the symptom definitions alone. The design and measurement framework are informative, while the registered record leaves the key quantitative conclusions unavailable.
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 most consequential limitation for interpreting the registry record is that numerical primary-outcome results are not reported in the registry record. The record describes the outcome and the symptom-selection rationale, but does not provide symptom-specific assessment percentages, group differences, or uncertainty estimates. The secondary outcome is named, but its numerical findings are not reported either.
The study is observational rather than a randomized comparison. Allocation is not stated, and the registry explicitly says the arms are not a like-for-like control comparison. Group contrasts therefore cannot be interpreted as causal effects of opioid reduction or any assigned intervention. The record does not report whether differences between groups were adjusted for clinical or demographic characteristics.
The assessment structure also constrains interpretation. Assessments were daily, while symptom data for participants experiencing withdrawal are limited to the day of withdrawal. The record does not explain how comparison-group assessments were selected or how repeated observations were analyzed. It does not report denominators by symptom and group, unavailable-assessment counts, missing-data methods, or the analysis population.
The symptom-selection criterion is described as an absolute difference greater than 15% judged clinically significant, but the record does not report a testing plan, multiplicity handling, or validation of the symptoms as diagnostic indicators. The registry’s motivation to support development of an assessment tool should not be mistaken for evidence that such a tool was developed or validated in this study. The recorded enrollment is 29, but the record does not provide enough outcome and analysis detail to assess precision or generalizability.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Signs and Symptoms of Opioid-associated Iatrogenic Withdrawal in Critically Ill Adults — NCT03435614.
- Registry record last updated 2025-01-01; status last verified 2024-12.
- Results first posted 2021-01-28.
- 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
NCT03435614 is a completed prospective observational study titled Signs and Symptoms of Opioid-associated Iatrogenic Withdrawal in Critically Ill Adults. It lists an enrollment of 29, a start date of 2018-02-26, and a primary completion date of 2018-09-30. The listed sponsor is Marc M. Perreault.
The study description follows mechanically ventilated critically ill adults receiving regular opioids for more than 72 hours as opioids are weaned. Its primary outcome concerns the percentage of daily assessments associated with specified withdrawal signs and symptoms, with symptom observations for participants experiencing withdrawal limited to the day withdrawal occurred. Change in serum cortisol level is listed as a secondary outcome.
The registry reports 0 serious adverse events, 0 other adverse events, and 0 deaths in the listed group. Numerical primary-outcome results, analysis methods, missing-data handling, and analysis-population details are not reported in the registry record. The registry notes that this is not a randomized comparison and that the arms are not a like-for-like control comparison.