Abstract
Importance:
Infants with neonatal opioid withdrawal syndrome (NOWS) who receive pharmacologic treatment are traditionally managed with a scheduled opioid taper. An alternate approach, symptom-based dosing, may better align treatment with withdrawal severity.
Objective:
Compare time from birth to medical readiness for discharge for infants with moderate-to-severe withdrawal managed with either a symptom-based dosing or scheduled opioid taper approach.
Design/Setting/Participants:
In this cluster crossover randomized clinical trial with run-in period, twenty-three US hospitals cared for infants using the Eat, Sleep, Console approach (ESC) or Finnegan-based care (15 ESC, 8 Finnegan) and their preferred primary opioid. Opioid dosing was guided by study approved site-specific algorithms. Infants with NOWS ≥36 weeks’ gestation and at risk for pharmacologic treatment were enrolled between 3/25/2024-4/9/2025 with last 3 month assessment 7/15/2025.
Intervention:
Sites were randomized to one of two sequences 1) symptom-based dosing followed by scheduled opioid taper or 2) scheduled opioid taper followed by symptom-based dosing.
Main Outcome/Measure:
Time from birth to medical readiness for discharge
Results:
Of the 626 enrolled infants (mean gestational age, 38 weeks, 49% male), 383 were cared for with ESC (primary outcome cohort). The mean time to medical readiness for discharge was significantly shorter in the symptom-based dosing compared to the scheduled opioid taper group (9.18 vs. 11.61 days; adjusted mean ratio (aMR) 0.79, 95%CI 0.65–0.96). There was no difference in the risk for initiation of pharmacologic treatment (0.4 vs. 0.41; adjusted risk ratio 0.99, 95%CI 0.77–1.27) or length of stay (10.9 vs.12.1 days; aMR 0.9, 95%CI 0.72–1.13) between groups. For infants in the symptom-based group, 35% (95%CI 25–45%) required scheduled opioid dosing due to withdrawal severity that was not controlled with intermittent dosing. In the Finnegan cohort (n=243; planned secondary outcome) there were no significant differences in time to medical readiness for discharge (16 vs.17.6 days; aMR 0.91;95%CI:0.72,1.15) or length of stay (17.4 vs.19.4 days; aMR 0.9;95%CI:0.69,1.16). The inpatient composite safety outcome occurred rarely (in the ESC cohort, 3/188 in the symptom-based dosing vs 2/195 in the scheduled taper groups).
Conclusions:
Symptom-based dosing decreased time to medical readiness for discharge when compared to a scheduled opioid taper approach among infants managed with ESC.
Introduction
As the opioid epidemic persists, opioid use during pregnancy remains a substantial public health concern. In the United States (US), one infant is diagnosed with neonatal opioid withdrawal syndrome (NOWS) approximately every 27 minutes.1 Acute withdrawal typically occurs during the first week after birth and is assessed and managed with either the Eat, Sleep, Console approach (ESC)2,3 or Finnegan-based care.4 Among other aspects of care, the Finnegan-based approach focuses on a detailed scoring of the signs of withdrawal, whereas ESC emphasizes the functional well-being (eating, sleeping, and consolability) of the infant. While both care models are currently used in clinical practice, results from a recent multicenter randomized clinical trial demonstrated a substantial decrease in the length of hospital stay and receipt of pharmacologic treatment when infants were managed with the ESC, supporting the use of this approach.3,5,6
Nonpharmacologic care is the first-line of treatment for infants with NOWS.3,7 However, if infants do not adequately respond to these interventions, pharmacologic treatment is indicated. The two most frequently used approaches for the pharmacologic treatment of NOWS are the traditional scheduled opioid taper approach and a newer symptom-based dosing approach. With the scheduled taper approach, low dose opioids are initiated for infants meeting a severity threshold and escalated until the signs of withdrawal improve. Opioid dosing is then slowly weaned as withdrawal severity is monitored. With the symptom-based dosing approach, pharmacologic treatment is provided using a single opioid dose when a specified withdrawal threshold is met. Monitoring of withdrawal severity is continued, and additional opioid doses are administered only if the infant’s withdrawal severity remains above or escalates back to this treatment threshold. With consistent application, symptom-based dosing may decrease postnatal opioid exposure and truncate the duration of hospitalization for infants whose withdrawal is adequately controlled with intermittent opioid dosing.
To date, there are limited data to support the use of one dosing approach over the other. Retrospective studies and quality improvement initiatives from single centers and small regional collaboratives have evaluated symptom-based dosing, but only a limited number of these initiatives have assessed adoption of symptom-based dosing independent of other changes in clinical practice.8–14 Symptom-based dosing has been associated with improvement in hospital-based outcomes without an increase in the rate of hospital readmission. While these findings are promising, the efficacy, safety, and generalizability of a symptom-based dosing approach has yet to be rigorously studied.
To address this knowledge gap, we developed the Optimizing Pharmacologic Treatment for Neonatal Opioid Withdrawal Syndrome (OPTimize NOW): A Symptom-Based Dosing Approach study (NCT05980260). This trial was conducted by the National Institutes of Health Helping to End Addiction Long-Term (HEAL) Evaluation of Limited Pharmacotherapies for Neonatal Opioid Withdrawal Syndrome (HELP for NOWS) Consortium to evaluate the safety, efficacy, and generalizability of a symptom-based dosing approach compared to a traditional scheduled opioid taper approach for infants with NOWS assessed as at risk for pharmacologic treatment.
Methods
Trial Design and Oversight
This multicenter stratified cluster randomized clinical trial with one cluster (Finnegan) subordinate to the other (ESC) was conducted at 23 US sites in the HELP for NOWS Consortium between 3/25/2024 and 4/9/2025 (last 3-month assessment on 7/15/2025). Advarra served as the single Institutional Review Board (sIRB) with reliance agreements for all sites. The study was conducted with waiver of informed consent, as approved by the sIRB in accordance with the Code of Federal Regulations (45CFR 46.116).15 CONSORT reporting guidelines were followed. An independent data safety monitoring board, appointed by the Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, provided oversight for this trial.
Patients and Participating Sites
To enhance study generalizability, we selected geographically and demographically diverse sites that included academic and community hospitals (eFigure 1). Sites cared for a varying number of infants with opioid withdrawal in several different hospital care settings (i.e., neonatal intensive care units (open bay and single room), newborn nurseries, and pediatric floors). To reflect current clinical practice while acknowledging the increased use of ESC, we included hospitals that used either ESC or Finnegan-based care for the management of NOWS but powered the primary analysis on the ESC cohort.
We enrolled infants who were ≥36 weeks’ gestation at birth, had documented opioid exposure during the second and/or third trimester of pregnancy, were assessed for opioid withdrawal at a participating study site and were determined to be at risk for pharmacologic treatment (i.e., at least 1 Finnegan score ≥8 or at least 1 “yes” for difficulty with eating, sleeping, or consoling on ESC assessment). Complete eligibility criteria have been previously published.15 All outcomes are reported separately for the ESC and Finnegan cohorts.
Randomization
Sites were randomized in a 1:1 allocation to one of two sequences: 1) the symptom-based dosing approach (five months) followed by a scheduled opioid taper approach (five months); or 2) a scheduled opioid taper approach (five months) followed by the symptom-based dosing approach (five months). Each sequence began with a five-week run-in period and had a three-week washout prior to transitioning dosing approaches. Randomization was stratified by the assessment approach used at sites (i.e., ESC or Finnegan). Randomization included 16 ESC and 8 Finnegan sites.
Intervention
During the scheduled opioid taper approach pharmacologic management was per the site’s routine scheduled taper algorithm including the threshold used for initiation of pharmacologic treatment (using either the ESC or Finnegan-based assessments), the strategy for weaning, and monitoring for worsening signs of withdrawal prior to hospital discharge. Site-specific algorithms were reviewed by the study team and assessed as being within currently accepted practice.
During the symptom-based dosing approach (Figure 1) the same site-specific treatment thresholds were used however, rather than initiating scheduled dosing when this threshold was met, infants were given a single opioid dose, and withdrawal severity was monitored. The dosage provided for this as-needed dose was the same as the initiation dose used by the site for their scheduled opioid taper. Subsequently, infants did not receive additional opioid doses unless their signs of withdrawal again met the site threshold (either remaining at or escalated back to) for pharmacologic treatment. Each time the threshold for treatment was met, an as-needed dose was given as long as the infant had not already received three opioid doses in the preceding 24-hour period or two consecutive short-interval doses (morphine dosed every 2 hours, buprenorphine every 3 hours, or methadone every 4 hours). If the infant had already received 3 opioid doses in the preceding 24 hours, or two consecutive short-interval doses, the infant’s withdrawal severity warranted scheduled dosing. In these cases, the site’s scheduled opioid taper was initiated starting with the first escalation dose on the treatment algorithm and this scheduled opioid taper was followed for the duration of treatment.
Figure 1: Trial Intervention Groups.
This figure details the dosing intervention groups for the OPTimize NOW Trial
Throughout this trial, sites used a consistent assessment method (ESC or Finnegan) and their preferred primary opioid (morphine, buprenorphine, or methadone) for pharmacologic treatment. Opioid dosing was guided by study-approved site-specific algorithms. All sites administered primary opioid and secondary medication (phenobarbital and clonidine) doses that were within ranges commonly used in clinical practice and agreed upon by the protocol team as detailed in the trial protocol.15
Outcomes
The primary outcome was time from birth to medical readiness for discharge among infants cared for with the ESC care approach (ESC cohort). Infants were considered to be medically ready for discharge at the time they were discharged by a medical provider or when they met the study criteria for medical readiness (i.e., at least 96 hours of age and 48 hours from their last dose of opioid medication), whichever occurred first. This definition of medical readiness for discharge was informed by our previous work3 and the American Academy of Pediatrics 2020 published standards.7
Secondary outcomes included receipt of pharmacologic treatment and length of hospital stay for all infants. Among infants who received pharmacologic treatment, time to medical readiness for discharge, number of primary opioid doses, days of primary opioid administration, length of opioid treatment and receipt of secondary medications were evaluated. An important secondary outcome specific to the symptom-based dosing group was the proportion of infants who required initiation of scheduled opioid dosing due to persistently elevated signs of withdrawal despite intermittent dosing. Similarly in the scheduled opioid taper group, the proportion of infants who required discontinuation of opioids due to oversedation was assessed. Time to medical readiness for discharge in the Finnegan cohort was also a secondary study outcome.
Safety outcomes were assessed for all enrolled infants and for those who received pharmacologic treatment. Safety outcomes included a composite inpatient safety outcome (seizures or weight loss >15% from birthweight), an outpatient composite safety outcome (acute/urgent care or emergency room visits or hospital readmissions) assessed at 3 months of age, and a composite critical safety outcome (nonaccidental trauma or death) which was measured at hospital discharge and at 3 months of age. Outcomes after hospital discharge were assessed through a review of electronic medical records and through a search of public records (e.g. news reports, obituaries, and registries).3
Statistical Considerations
The sample size was calculated with data from the INFORM NOW: INFORMing NOWS Research through Retrospective Data Collection study, a multicenter chart review study designed to inform clinical trial development in the HELP for NOWS Consortium, using the approach of Hemming.16 This resulted in a sample size of 320 infants to detect a 21% difference in the time to medical readiness for discharge between the intervention groups with >80% power, using a two-sided Type I error of 0.05.
All efficacy outcomes were analyzed separately for the ESC and Finnegan cohorts using an intention-to-treat approach according to the site’s randomly allocated dosing sequence. Safety outcomes were also analyzed separately using an as-treated approach. Maternal and infant characteristics were summarized for each dosing group with frequencies and percentages for categorical variables and means (standard deviation) or medians (interquartile range) for continuous variables, and were compared using Pearson’s chi-squared tests, Fisher’s exact tests, or Wilcoxon two-sample tests, as appropriate.
Study design adjusted analyses were performed for each outcome using a generalized linear mixed-effects model with a negative binomial (for count outcomes) or Poisson distribution (for binary outcomes). Each model included fixed effects for the dosing approach and study period, as well as a random effect for site. Small sample corrections using robust standard errors accounted for the small number of sites.17,18 An interaction term between dosing approach and study period was also added to determine if the effect of dosing approach varied by study period. Models of count outcomes were used to estimate the study design adjusted means (95% confidence intervals [CIs]), in each dosing approach, as well as adjusted mean ratios (95% CI) and mean differences (95% CI) between the two dosing approaches. Models of binary outcomes were used to estimate the study design adjusted risks (95% CIs) in each dosing approach, as well as adjusted risk differences (95% CIs) between the two dosing approaches. To estimate adjusted mean and risk differences and the variances thereof, 1000 bootstrap samples were used with replacement within sites.
Covariate adjusted analyses were conducted to determine the impact of prespecified baseline characteristics on the effect size for each outcome by adding the following fixed effects to the study design adjusted models: adequate prenatal care19, use of medication for opioid use disorder (MOUD) during pregnancy,20 concurrent non-opioid psychotropic substance use during pregnancy,19 infant sex,21 and birth weight.22 In addition, a prespecified sensitivity analysis was performed for the primary outcome that excluded infants transferred prior to discharge as outlined in the statistical analysis plan. A number needed-to-treat was calculated to highlight the clinical relevance of study findings.
A prospectively planned interim efficacy analysis was performed when approximately 50% of enrolled infants had met the primary outcome, resulting in a two-sided significance level of 0.045 for the final analysis to ensure an overall Type I error rate of 0.05 (see supplemental materials). Secondary outcomes were not adjusted for multiple comparisons. All analyses were completed using SAS version 9.4 (SAS Institute, Cary, NC).
Results
Patients
Of the 626 enrolled infants, 383 were cared for with ESC (ESC cohort) and included in the primary analysis and 243 were cared for with Finnegan-based care (Finnegan cohort) and included in secondary analyses (Figure 2). The ESC cohort was composed of 189 infants in the symptom-based dosing group and 194 infants in the scheduled opioid taper group. The Finnegan cohort included 119 infants in the symptom-based dosing group and 124 infants in the scheduled opioid taper group. Maternal and infant characteristics for the ESC and Finnegan cohorts were similar between intervention groups with the exception of tobacco exposure in the Finnegan cohort (Table 1).
Figure 2: Recruitment, Randomization, and Follow-up Assessment for the Optimize NOW Trial.
a Failed inclusion criteria: No antenatal exposure identified (n=4, [4 & 0]), Did not meet the study definition of at risk for pharmacologic treatment (n=11, [6 & 5]), and gestational age at birth less than 36 weeks (n=27, [19 & 8]).
b Met Exclusion criteria: Major birth defects (n=8, [6 & 2]), neonatal encephalopathy (n=2, [2 & 0]), postnatal opioid exposure prior to NOWS treatment (n=9, [3 & 6]), Receipt of respiratory support at 48 hours (n=60, [42 & 18]), Outborn and received pharmacologic treatment at transferring hospital (n=15, [2 & 13]). Multiple exclusion criteria (n=6, [5 &1]).
c The critical safety outcome (non-accidental trauma and death) was assessed through media review for all infants. Data for the outpatient safety outcome (Acute/urgent care or emergency room visits and hospital readmissions) was not recorded for 153 infants. These infants were evenly distributed between dosing groups in the ESC cohort [symptom-based dosing 50 (26%), scheduled opioid taper 49 (25%)] and Finnegan cohort [27 (23%), scheduled opioid taper 27 (22%)]. If data were not recorded, the study assumption was that the event did not occur.
Table 1:
Baseline Characteristics for the ESC and Finnegan Cohorts
| Hospital Characteristicsa | ESC Cohort | Finnegan Cohort | ||
|---|---|---|---|---|
| Type of Site | ||||
| Academic | 12/15 (80%) | 6/8 (75%) | ||
| Non-academic | 3/15 (20%) | 2/8 (25%) | ||
| Volume of infants contributed to study | ||||
| High (30+ infants) | 5/15 (33%) | 3/8 (38%) | ||
| Medium (20–29 infants) | 6/15 (40%) | 2/8 (25%) | ||
| Low (<20 infants) | 4/15 (27%) | 3/8 (38%) | ||
| Level of NICU | ||||
| Level 4 | 5/15 (33%) | 2/8 (25%) | ||
| Level 3 | 10/15 (67%) | 6/8 (75%) | ||
| Maternal and Infant Characteristics | Symptom-Based N=189 |
Scheduled Taper N=194 |
Symptom-Based N=119 |
Scheduled Taper N=124 |
| Maternal Characteristics | ||||
| Age (years), median (IQR) | 32 (29, 36) | 32 (29, 35) | 32 (28, 35) | 31 (29, 35) |
| Race, n (%)b | ||||
| Black | 24 (13) | 32 (16) | 18 (15) | 19 (15) |
| White | 148 (78) | 150 (77) | 93 (78) | 97 (78) |
| Otherc | 17 (9) | 12 (6) | 8 (7) | 8 (6) |
| Hispanic or Latino Ethnicity, n (%)b,d | 34/184 (18) | 35/188 (19) | 2/110 (2) | 8/119 (7) |
| Metropolitan, Rural-Urban Commuting Area Code (RUCA) status, n (%)e | 174 (92) | 175 (90) | 78 (66) | 86 (69) |
| Married, n (%)d | 22/179 (12) | 26/193 (13) | 21/110 (19) | 23/115 (20) |
| Public insurance, n (%) | 162 (86) | 169 (87) | 97 (82) | 91 (73) |
| Adequate prenatal care, n/N (%)d | 118/178 (66) | 119/185 (64) | 69/100 (69) | 71/108 (66) |
| Prescribed medications for treatment of opioid dependency, n/N (%)d | 151/187 (81) | 144/192 (75) | 96/115 (83) | 103/121 (85) |
| Buprenorphine | 58/151 (38) | 53/144 (37) | 39/96 (41) | 42/103 (41) |
| Methadone | 65/151 (43) | 55/144 (38) | 32/96 (33) | 24/103 (23) |
| Buprenorphine + naloxone | 28/151 (19) | 35/144 (24) | 25/96 (26) | 37/103 (36) |
| Otherf | 0/151 (0) | 1/144 (1) | 0/96 (0) | 0/103 (0) |
| Polysubstance use in the 2nd or 3rd trimester, n (%) | 140 (74) | 154 (79) | 96 (81) | 94 (76) |
| Number of substances used, median (IQR) | 1 (0, 2) | 1 (1, 2) | 1 (1, 2) | 1 (1, 2) |
| Nicotine exposure in the 2nd or 3rd trimester, n (%)g | 118 (62) | 123 (63) | 90 (76) | 79 (64) |
| Infant Characteristics | ||||
| Inborn, n (%) | 184 (97) | 187 (96) | 94 (79) | 96 (77) |
| Gestational age at delivery (weeks), mean (SD) | 38 (1) | 38 (1) | 38 (1) | 38 (1) |
| Sex, n (%) | ||||
| Male | 87 (46) | 98 (51) | 59 (50) | 62 (50) |
| Female | 102 (54) | 96 (49) | 60 (50) | 62 (50) |
| Birthweight (kg), mean (SD) | 3.0 (0.5) | 3.1 (0.5) | 3.0 (0.4) | 3.0 (0.5) |
| Head circumference at birth (cm), mean (SD) | 33.4 (1.7) | 33.4 (1.5) | 33.2 (1.6) | 33.5 (1.8) |
| Length at birth (cm), mean (SD) | 48.8 (2.8) | 48.9 (2.7) | 48.3 (2.5) | 48.2 (3.0) |
| Breastfed during initial hospitalization, n (%)d,h | 18/79 (23) | 19/81 (23) | 31/89 (35) | 24/80 (30) |
| Neonatal toxicology screening done, n (%) | 144 (76) | 148 (76) | 112 (94) | 110 (89) |
| Positive toxicologyd | 130/144 (90) | 132/148 (89) | 103/112 (92) | 105/110 (95) |
| Positive toxicology excluding opioidsd | 71/144 (49) | 80/148 (54) | 38/112 (34) | 49/110 (45) |
One ESC site withdrew after randomization and prior to enrollment
Maternal race and ethnicity obtained from the electronic medical record. Race and ethnicity were included as they have been associated with NOWS severity. The NIH definition of race and ethnicity was used to categorize these characteristics.
In ESC, includes American Indian or Alaskan Native (n=4), multiracial (n=6), and unknown (n=19). In Finnegan, includes Asian (n=1), Multi Race (n=4), Native Hawaiian or Other Pacific Islander (n=1), and Unknown (n=10)
Denominators are provided for variables with missing data. For analyses using these variables, missing data were grouped with “No” Responses
Metropolitan defined as RUCA code 1–3
Includes one infant who received both buprenorphine and methadone but duration prior to delivery was unclear
p<0.05 in the Finnegan cohort
Breastfeeding data were only collected in infants who were pharmacologically treated
Abbreviations: IQR, interquartile range; SD, standard deviation; cm, centimeter; kg, kilogram
Primary Outcome
The mean length of time to medical readiness for discharge was significantly shorter for infants who received the symptom-based dosing approach compared to those who received a scheduled opioid taper approach (9.18 vs. 11.61 days; adjusted mean ratio (aMR) 0.79 [95% CI: 0.65, 0.96], p=0.02) (Table 2). Results were similar when adjusted for baseline covariates. The effect size was similar when transferred infants were excluded from the model for the primary outcome, and for other planned sensitivity analyses (see supplemental materials).
Table 2:
Primary Outcome and Secondary Outcomes for Infants Assessed and Managed with ESC
| Outcomes | Study Design Adjusteda Analysis | Covariate Adjustedb Analysis | ||||||
|---|---|---|---|---|---|---|---|---|
| Symptom-Based Mean or Risk (95% CI) |
Scheduled Taper Mean or Risk (95% CI) |
Mean or Risk Ratio (95% CI) |
Mean or Risk Difference (95% CI) |
Symptom-Based Mean or Risk (95% CI) |
Scheduled Taper Mean or Risk (95% CI) |
Mean or Risk Ratio (95% CI) |
Mean or Risk Difference (95% CI) |
|
| Primary Outcome | ||||||||
| Time to Medically Readiness for Discharge (days)c | 9.18 (7.51, 11.23) |
11.61 (10.03, 13.43) |
0.79* (0.65, 0.96) |
−2.3 (−3.96, −0.62) |
9.2 (7.88, 10.75) |
11.41 (10.1, 12.89) |
0.81* (0.69, 0.94) |
−2.12 (−3.61, −0.57) |
| Secondary Outcomes | ||||||||
| Length of Stay (days)c | 10.91 (8.98, 13.27) |
12.09 (9.98, 14.63) |
0.9 (0.72, 1.13) |
−1.1 (−3.30, 1.26) |
10.85 (9.19, 12.81) |
12.01 (10.03, 14.37) |
0.9 (0.74, 1.1) |
−1.09 (−3.13, 0.95) |
| Receipt of Pharmacologic Treatmentd | 0.4 (0.3, 0.54) |
0.41 (0.33, 0.51) |
0.99 (0.77, 1.27) |
−0.01 (−0.10, 0.08) |
0.42 (0.31, 0.58) |
0.41 (0.32, 0.53) |
1.04 (0.86, 1.26) |
0.01 (−0.08, 0.10) |
| Secondary Outcomes in Pharmacologically Treated Infants | ||||||||
| Time to Medically Readiness for Discharge (days)c | 13.1 (9.72, 17.65) |
17.56 (14.14, 21.8) |
0.75* (0.61, 0.91) |
−4.54 (−6.79, −2.25) |
12.03 (9.25, 15.64) |
16.45 (13.27, 20.4) |
0.73* (0.6, 0.9) |
−4.55 (−6.57, −2.22) |
| Length of Stay (days)c | 18.62 (13.01, 26.64) |
19.47 (14.01, 27.07) |
0.96 (0.78, 1.17) |
−1.06 (−4.63, 2.93) |
15.34 (11, 21.39) |
16.96 (12.35, 23.29) |
0.9 (0.76, 1.08) |
−1.88 (−4.74, 1.12) |
| Number of Primary Opioid Treatment Daysc | 7.63 (4.21, 13.85) |
11.1 (7.19, 17.12) |
0.69 (0.44, 1.06) |
−3.49 (−5.84, −1.28) |
6.55 (3.69, 11.61) |
9.89 (6.26, 15.61) |
0.66 (0.43, 1.02) |
−3.44 (−5.47, −1.43) |
| Length of Primary Opioid Treatment (days)c | 8.05 (4.54, 14.28) |
11.43 (7.51, 17.41) |
0.7 (0.47, 1.05) |
−3.42 (−5.81, −1.12) |
6.9 (3.96, 12.02) |
10.16 (6.51, 15.87) |
0.68 (0.46, 1.01) |
−3.38 (−5.44, −1.34) |
| Number of Doses of Primary Opioidc | 29.55 (12.12, 72.02) |
45.49 (21.74, 95.16) |
0.65 (0.39, 1.09) |
−16.1 (−26.9, −6.29) |
21.7 (9.86, 47.77) |
35.29 (16.89, 73.74) |
0.61 (0.38, 1.01) |
−13.9 (−22.8, −5.48) |
| Receipt of Secondary Medicationsd | 0.11 (0.04, 0.31) |
0.25 (0.12, 0.49) |
0.46 (0.19, 1.09) |
−0.13 (−0.23, −0.03) |
0.1 (0.03, 0.35) |
0.22 (0.09, 0.53) |
0.46 (0.17, 1.19) |
−0.11 (−0.21, −0.02) |
Conducted in an intention to treat population. Adjusts for design effects only (study intervention and study period). There was no missing data for the outcomes presented.
Conducted in an intention to treat population. Adjusts for study design effects and baseline demographic characteristics that have been associated with NOWS severity (adequate prenatal care, MOUD use during pregnancy, number of psychotropic substances used during pregnancy, sex, birth weight, positive neonatal toxicity screen for psychotropic substances other than opioids (i.e., amphetamines/methamphetamines, barbiturates, benzodiazepines, cocaine, gabapentin, marijuana, medetomidine, methaqualone, phencyclidine, serotonin reuptake inhibitors, tianeptine, and xylazine). In pharmacologically treated infants we also adjusted for primary opioid medication.
Estimates for this outcome correspond to adjusted means in each study intervention, as well as adjusted mean ratios and adjusted mean differences between symptom-based dosing and scheduled opioid taper dosing.
Estimates for this binary outcome correspond to adjusted risks in each study intervention, as well as adjusted risk ratios and adjusted risk differences between symptom-based dosing and scheduled opioid taper dosing.
p values < .045 for primary outcome, p < .05 for all secondary outcomes
Abbreviations: CI, Confidence Interval
Secondary and Safety Outcomes
For the ESC cohort, the likelihood of initiating pharmacologic treatment and the length of hospital stay were not different between dosing strategies (Table 2). Among infants who received pharmacologic treatment in the ESC cohort, the mean time to medical readiness for discharge was also shorter in the symptom-based dosing group (13.1 vs 17.56 days; aMR 0.75 [95% CI 0.61,0.91]) when compared to the scheduled opioid taper group (Table 2). Additionally, 35% (95% CI 25%, 45%) of the pharmacologically treated infants in the symptom-based dosing group required scheduled opioid dosing due to persistently elevated signs of withdrawal, which equates to a number needed-to-treat of 1.5 (95% CI 1.3, 1.8) to prevent one infant from receiving scheduled opioids. There were no significant differences in the mean number of primary opioid doses administered between intervention groups, the number of opioid treatment days, the length of treatment or the receipt of secondary medications (Table 2). Only one infant in the scheduled opioid taper group required cessation of opioid treatment due to excessive sedation.
For the Finnegan cohort, there was no significant difference in any of the secondary outcomes, except for the risk of initiating pharmacologic treatment, which was higher in the symptom-based dosing group (0.76 vs 0.63; aRR 1.21 [95% CI 1.03, 1.42]). The effect size across most outcomes, while not significant, was similar to the ESC cohort (Table 3).
Table 3:
Secondary Outcomes for Infants in Finnegan Cohort
| Outcomes | Study Design Adjusteda Analysis | Covariate Adjustedb Analysis | ||||||
|---|---|---|---|---|---|---|---|---|
| Symptom-Based Mean or Risk (95% CI) |
Scheduled Taper Mean or Risk (95% CI) |
Mean or Risk Ratio (95% CI) |
Mean or Risk Difference (95% CI) |
Symptom Based Mean or Risk (95% CI) |
Scheduled Taper Mean or Risk (95% CI) |
Mean or Risk Ratio (95% CI) |
Mean or Risk Difference (95% CI) |
|
| Secondary Outcomes | ||||||||
| Time to Medically Readiness for Discharge (days)c | 15.99 (10.48, 24.4) |
17.56 (11.31, 27.25) |
0.91 (0.72,1.15) |
−1.56 (−4.65, 1.42) |
15.26 (10.01, 23.26) |
17.32 (11.22, 26.74) |
0.88 (0.67,1.16) |
−2.07 (−4.98, 0.93) |
| Length of Stay (days)c | 17.38 (11.64, 25.95) |
19.39 (11.86, 31.7) |
0.9 (0.69,1.16) |
−1.96 (−5.48, 1.70) |
16.46 (11.27, 24.05) |
19.38 (12.34, 30.45) |
0.85 (0.62,1.16) |
−2.75 (−5.95. 0.96) |
| Receipt of Pharmacologic Treatmentd | 0.76 (0.62, 0.94) |
0.63 (0.49, 0.82) |
1.21* (1.03,1.42) |
0.13 (0.01, 0.25) |
0.73 (0.64, 0.84) |
0.63 (0.48, 0.81) |
1.16* (1.01,1.34) |
0.1 (−0.02, 0.23) |
| Secondary Outcomes, Pharmacologically Treated Infants | ||||||||
| Time to Medically Readiness for Discharge (days)c | 17.94 (11.93, 26.99) |
22.95 (15.83, 33.27) |
0.78 (0.58,1.05) |
−5.03 (−8.25, −1.91) |
16.41 (12.25, 21.99) |
21.39 (15.92, 28.74) |
0.77 (0.56,1.05) |
−5 (−8.05, −1.93) |
| Length of Stay (days)c | 19.73 (13.63, 28.56) |
25.37 (16.61, 38.74) |
0.78 (0.59,1.03) |
−5.63 (−9.17, −2.14) |
18.17 (14.18, 23.27) |
23.89 (17.44, 32.72) |
0.76 (0.55,1.04) |
−5.61 (−9.17, −2.20) |
| Number of Primary Opioid Treatment Daysc | 13.45 (8.20, 22.07) |
18.24 (11.34, 29.35) |
0.74 (0.54,1.00) |
−4.78 (−7.99, −1.75) |
11.98 (8.88, 16.16) |
16.71 (11.9, 23.47) |
0.72 (0.51,1.01) |
−4.65 (−7.73, −1.75) |
| Length of Primary Opioid Treatment (days)c | 13.96 (8.71, 22.39) |
18.69 (11.67, 29.95) |
0.75 (0.55,1.02) |
−4.71 (−8.11, −1.59) |
12.42 (9.41, 16.39) |
17.09 (12.16, 24.03) |
0.73 (0.51,1.03) |
−4.6 (−7.80, −1.62) |
| Number of Doses of Primary Opioidc | 59.98 (22, 163.55) |
79.41 (27.99, 225.30) |
0.76 (0.48,1.19) |
−19.5 (−36.5, −4.87) |
49.72 (24.14, 102.42) |
67.51 (31.89, 142.93) |
0.74 (0.48,1.12) |
−17 (−31.5, −3.78) |
| Receipt of Secondary Medicationsd | 0.2 (0.08, 0.53) |
0.3 (0.1, 0.89) |
0.68 (0.46,1.01) |
−0.09 (−0.18, 0) |
0.18 (0.04, 0.83) |
0.27 (0.05, 1.32) |
0.67 (0.41, 1.1) |
−0.08 (−0.17, 0.01) |
Conducted in an intention to treat population for all outcomes. This analysis adjusts for design effects only (study intervention and the study period). There was no missing data for the outcomes presented.
Conducted in an intention to treat population. Adjusts for study design effects, for nicotine (unbalanced between the groups) and for baseline demographic characteristics that have been associated with NOWS severity (adequate prenatal care, MOUD use during pregnancy, number of psychotropic substances used during pregnancy, sex, birth weight, positive neonatal toxicity screen for psychotropic substances other than opioids (i.e., amphetamines/methamphetamines, barbiturates, benzodiazepines, cocaine, gabapentin, marijuana, medetomidine, methaqualone, phencyclidine, serotonin reuptake inhibitors, tianeptine, and xylazine). In pharmacologically treated infants we also adjusted for primary opioid medication.
Estimates for this outcome correspond to adjusted means in each study intervention, as well as adjusted mean ratios and adjusted mean differences between symptom-based dosing and scheduled opioid taper dosing.
Estimates for this binary outcome correspond to adjusted risks in each study intervention, as well as adjusted risk ratios and adjusted risk differences between symptom-based dosing and scheduled opioid taper dosing.
Abbreviations: CI; Confidence Interval
p <.05
Inpatient safety events were rare in all study groups. There were no significant differences in inpatient or outpatient safety outcomes between dosing groups for either the ESC or Finnegan cohorts (Table 4). Serious adverse events during the study were also rare (eTable 1).
Table 4:
Summary Safety Outcomes for Infants in the ESC and Finnegan Cohorts
| Safety Outcomesa | ESC Cohort | Finnegan Cohort | ||||
|---|---|---|---|---|---|---|
| Infants at Risk for Pharmacologic Treatmentb | Symptom-Based n=188 |
Scheduled Taper n=195 |
Risk Ratio (95% CI) |
Symptom-Based n=118 |
Scheduled Taper n=125 |
Risk Ratio (95% CI) |
| Inpatient | ||||||
| Composite Critical Safety Outcome (Nonaccidental trauma or death) | 0 (0%) | 0 (0%) | NA | 0 (0%) | 0 (0%) | NA |
| Composite Safety Outcome (Seizuresc or weight loss >15% from birthweight) | 3 (2%) | 2 (1%) | 1.54 (0.23,10.59) | 1 (1%) | 6 (5%) | 0.11 (0,2.6) |
| Outpatient | ||||||
| Composite Critical Safety Outcome (Nonaccidental trauma or deathd) | 0 (0%) | 3 (2%) | NA | 0 (0%) | 0 (0%) | NA |
| Composite Safety Outcome (Acute/urgent care or emergency room visit or hospital readmissions) | 31 (16%) | 46 (24%) | 0.7 (0.37,1.33) | 25 (21%) | 15 (12%) | 1.6 (0.49,5.19) |
| Pharmacologically Treated Infants | Symptom-Based n=78 |
Scheduled Taper n=82 |
Risk Ratio (95% CI) |
Symptom-Based n=88 |
Scheduled Taper n=81 |
Risk Ratio (95% CI) |
| Inpatient | ||||||
| Composite Critical Safety Outcome (Nonaccidental trauma or death) | 0 (0%) | 0 (0%) | NA | 0 (0%) | 0 (0%) | NA |
| Composite Safety Outcome (Seizuresc or weight loss >15% from birthweight) | 1 (1%) | 0 (0%) | NA | 0 (0%) | 3 (4%) | NA |
| Outpatient | ||||||
| Composite Critical Safety Outcome (Nonaccidental trauma or deathd) | 0 (0%) | 1 (1%) | NA | 0 (0%) | 0 (0%) | NA |
| Composite Safety Outcome (Acute/urgent care or emergency room visit or hospital readmissions) | 8 (10%) | 16 (20%) | 0.51 (0.25,1.05) | 20 (23%) | 9 (11%) | 1.92 (0.46,8.08) |
NA, Not applicable because events were rare and a risk ratio cannot be calculated when the denominator is zero.
Safety events were rare throughout the study and were reported as >0 if there was 1 or more composite events. The only composite safety outcome for which there was an adequate population to conduct inferential statistics was the outpatient composite safety outcome and no significant differences were seen between treatment groups in both the at risk and pharmacologically treated study populations.
Analyses conducted in an As Treated Population. Number of infants not treated per protocol ESC cohort (symptom-based dosing 9 and scheduled opioid taper 9). Number of infants not treated per protocol in the Finnegan Cohort (symptom-based dosing 10 and scheduled opioid taper 3). Infants with missing data for the 3 month assessment were considered to not have the outcome. Missing data were evenly distributed between dosing groups in both cohorts.
No infants were reported to have seizures during their inpatient stay
One infant died after hospital discharge due to sudden unexplained infant death that was deemed to be unrelated to the study intervention
Discussion
Among infants with opioid withdrawal who were at risk for pharmacologic treatment and managed with ESC in this cluster crossover design randomized clinical trial, use of the symptom-based dosing approach led to a significantly shorter mean time to medical readiness for discharge when compared to a scheduled opioid taper approach.
Symptom-based dosing gives clinicians a framework to provide pharmacologic support when withdrawal thresholds are met, without committing infants to scheduled opioid dosing and a prolonged opioid taper when their withdrawal severity oscillates around the threshold for pharmacologic treatment. In this study, 65% of pharmacologically treated infants in the symptom-based dosing group were successfully treated without the use of scheduled opioid dosing. These results support the premise that opioid withdrawal follows a severity continuum to which pharmacologic treatment should be matched and provides the evidence to move beyond the “all or nothing“ approach inherent in the use of a scheduled opioid taper. In addition, the symptom-based dosing approach used in this study provides the means to readily identify and appropriately support infants who require scheduled opioids, thus minimizing the likelihood of undertreatment.
The study population was defined to include infants at risk for pharmacologic treatment rather than only infants who were actually treated to maintain comparability between groups and counteract the potential that the option to administer a single opioid dose in the symptom-based dosing group might lower a clinician’s prescribing threshold. This choice provided for assessment of withdrawal severity between groups and increased the likelihood that differences observed between dosing approaches were truly reflective of the intervention. However, we did not find a difference in the proportion of infants who were started on postnatal opioids between the intervention groups in the ESC cohort, which suggests that symptom-based dosing did not alter prescribing thresholds.
Inpatient safety events were rare in all study groups. There were no material differences in safety outcomes identified through three months of age between dosing approaches. Longer-term follow-up is needed to further inform the safety profile for symptom-based dosing.
This study did not have power to detect differences in outcomes between dosing approaches in the Finnegan cohort. Therefore, findings in this cohort were not unexpected. Although, similarities in the effect sizes for most outcomes in the Finnegan and ESC cohorts suggest that further study may be warranted.
Strengths and Limitations
Strengths of this study include the large study population, inclusion of study sites across geographically diverse regions, and the use of waiver of consent, all of which increase the generalizability of these results. In addition, the primary outcome of time to medical readiness for discharge avoids the impact of non-NOWS related factors on the duration of hospital stay and provides a more accurate reflection of healthcare utilization specifically due to opioid withdrawal.
Study limitations include first, assessment of post-discharge safety outcomes was limited by reliance on electronic medical records from the enrolling hospital, linked medical records when available, and media review. Although this strategy may not have captured all outcomes, it has been previously used,3 missing data were balanced between intervention groups, and this pragmatic approach allows for assessment of short-term outcomes under waiver of consent. Second, contamination between groups was a potential risk, but was tempered by limiting access to training materials for the symptom-based dosing approach until just prior to each site’s transition and inclusion of a washout period. Third, the results could have been affected by temporal trends, but the analysis adjusted for such trends. Fourth, all studies are limited by the quality of data abstracted from the medical record, this was addressed through the use of a data quality framework that has been shown to decrease abstraction error during the trial.23,24
Conclusions
In this randomized clinical trial, use of the symptom-based dosing approach decreased time until medical readiness for discharge and resulted in avoidance of scheduled opioid dosing for 65% of infants managed with ESC. For infants with NOWS who are managed with the ESC approach, symptom-based dosing should be considered an effective evidence-based approach for pharmacologic treatment.
Supplementary Material
Key Points.
Question:
Does pharmacologic treatment with a symptom-based dosing approach decrease time to medical readiness for discharge when compared to a scheduled opioid taper for infants managed with the Eat, Sleep, Console approach (ESC)?
Findings:
In this cluster crossover randomized clinical trial, including 383 infants managed with ESC, time to medical readiness for discharge was 2.3 days shorter for infants treated with symptom-based dosing when compared to a scheduled opioid taper. No difference was noted in safety outcomes through 3 months of age.
Meaning:
Symptom-based dosing decreased time to medical readiness for discharge for infants with opioid withdrawal managed with ESC.
Acknowledgements:
Potential Conflicts of Interest
The authors reported no potential conflicts of interest with the exception of Dr. Scott Wexelblatt and Dr. Namasivayam Ambalavanan. Dr Scott Wexelblatt disclosed a financial relationship with Abbott Nutrition as a speaker and a financial relationship with Sanofi as a speaker. Dr. Ambalavanan disclosed membership on the DSMB for Oak Hill Bio, and his role as a Medical Advisor with Intellectual Property and Stock ownership in Alveolus Bio and ResBiotic LLC.
Funding/Support
The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the NIH Helping to End Addiction Long-term (HEAL) Initiative provided funding via cooperative agreements (U24 HD107621, UG1 HD107580, UG1 HD107616, UG1 HD107627, UG1 HD107628, UG1 HD107631, UG1 HD107649, UG1 HD107650, UG1 HD107653). NICHD staff had input into design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and/or approval of the manuscript; and decision to submit the manuscript for publication. While NICHD staff had input, the comments and views of the authors do not necessarily represent the views of NICHD, the National Institutes of Health, the Department of Health and Human Services, or the U.S. Government.
Study Acknowledgements
We extend our deepest gratitude to the infants and caregivers/parents who participated in this study, without whom, the study and resulting implications for the medical community would not have been possible.
We also extend our gratitude to the HELP for NOWS Patient and Community Engagement Committee who provided feedback on the study design and assisted in the development of community facing study materials.
We are indebted to our medical and nursing colleagues who agreed to take part in the study. The following investigators and research coordinators in addition to the those listed as authors participated in this study:
AtlantiCare Hospital – Crystal Bass; Elizabeth Hendricks.
Christiana Care Health Systems – David Paul, MD; Jennifer Chambers, BSN, RN, CCRC; Amy Mackley, MSN, CNS-BC, CCRC.
Cincinnati Children's Hospital Medical Center, University of Cincinnati Medical Center, Good Samaritan Hospital, and St Elizabeth Healthcare (UG1 HD107616) – Ward Rice, MD; Cathy Grisby, BSN CCRC; David Russell, JD; Lisa Tully, MA; Traci Beiersdorfer, BSN RN RNC-NIC; Carla King, BSN RN; Cynthia Reid, BSN RN.
Eunice Kennedy Shriver National Institute of Child Health and Human Development – Stephanie Wilson Archer, MA.
Golisano Children’s at University of Kentucky – Henrietta Bada, MD, MPH; Mina Hanna, MD, MSc; Amanda Wilburn, CCRP; Susan DeGraaff, CCRP, CPC-A; Beth McKinney-Whitlock, CCRP; Carrie Hobbs, RN, MSN, CCRP; Crystal Wilson, LPN.
Indiana University, Sidney & Lois Eskenazi Hospital (UG1 HD107653) Anna E. Thomas, MD; Hannah Rakow, BSN RN MBA-HM; Jessica Mendoza, BSN RN, Betsy Tudor, CCMA.
Kettering Health – Loren Nallu, MD; Mary Connolly, PhD, ACRP-CP; Allison Dymacek, MACPR, BSN, RN; Karen Herzing, RN.
University of Oklahoma Health Center– Natalie Goodman, BA; Erin Bohon, LPN; Aprill Shockley, BSN, RN.
RTI International (U24 HD107621) –Emily Smith, MPH; Jenny Auman, BS; Anna Mazur, BS; Shannon Barnes, MSN, CCRP; Brittany Thomas, BS; Eugene Turner, BS; James Pickett, BS; David Leblond, BS; Savannah Moore.
Thomas Jefferson University (UG1 HD107628) –Courtenay Fulmor, RN; Lisa Pullaro; Emily J. Murray, RN; Megan Lennon Kundrat, RN; Angela Pallotto, BSN, RN; Melette Pearson, RN.
University of Alabama at Birmingham Health System and Children’s of Alabama (UG1 HD107580) –Myriam Peralta-Carcelen, MD MPH; Waldemar A. Carlo, MD; Samuel Gentle, MD; Sandra Turner, BSN; Rachel Benz MSN RN; Sharon Owen, RN.
University of Arkansas for Medical Sciences (UG1 HD107650) –Vallon Williams, DNP APRN, AGNP-C; Allyson Cheathem, BSN RN CRS; Alperdis Keyes, BSN RN CRS.
University of Kansas Medical Center- Kristina Foster, RN, MS, APRN-BC, CCRP; Allison Scott, RN, CCRC.
University of Louisville, Norton Children’s Research Institute Affiliated with the University of Louisville School of Medicine (UG1 HD107649) –Madison Jessie, BSN RN; Sarah Morris, BSN RN CCRC; Jennifer Nason, BSN RN CCRC; Audrey Miller, BSN RN; Rachel Welch-Miles, BSN RN; Molly Hemmerle BSN RN.
University of Nebraska Medical Center - Betty Oberle, RN; Matt VanOrmer, PhD; Sarah Newman, NNP, APRN, DNP; Emilee Kendall, BS; Kym Abraham, RN.
University of New Mexico (UG1 HD107627) – Sofia Markee, MD; Nicole Yonke, MD; Jessie Maxwell, MD, MBA; Sandra Beauman, MSN RNC-NIC; Conra Lacy, RN; Ashley Palmer, BSN, RN; Elizabeth Kuan, BSN RN.
University of Pennsylvania and Children's Hospital of Philadelphia (UG1 HD107631) –Megan Dhawan, MSN CRNP; Mary Catherine Gambacorta, BSN RN; Jon Snyder, RN; Melanie Risch, BSN, RN; Hanna Rosewood, BA.
University of Rochester Medical Center, Golisano Children's Hospital – Ronnie Guillet, MD, PhD; Julie Riccio, MD; Melissa Moreland, MPH, Rachel Jones.
University of South Florida - Marcia Kneusel, RNC, CCRC; Courtney Casey.
University of Utah Medical Center – Robin K. Ohls, MD; Camille Fung, MD; Carrie A. Rau, RN, CCRC, BSN; Kathie Coleman, RN; Kandace M. McGrath, BS; Manndi C. Loertscher, BS CCRP.
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