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1 Supplementary Online Content Disher T, Gullickson C, Singh B, et al. Pharmacological treatments for neonatal abstinence syndrome: a systematic review and network meta-analysis. JAMA Pediatr. Published online January 22, doi: /jamapediatrics eappendix 1. Review protocol eappendix 2. PRISMA-NMA checklist eappendix 3. Search results eappendix 4. Synthesis feasibility eappendix 5. Outcome data eappendix 6. League tables eappendix 7. Threshold plots This supplementary material has been provided by the authors to give readers additional information about their work.

2 Abbreviations Abbreviation Treatments dto_plac dto_clon morph clon par pheno dto_pheno pheno_sc pheno_lc chlor_sc chlor_lc pheno_load pheno_tit diaz meth morph_clon morph_pheno laud Drug exposures tob ssri meth bup heroin oxy opium coc amp poly benz illicit Description Diluted tincture of opium + placebo Diluted tincture of opium + clonidine Morphine Clonidine Paregoric Phenobarbital Diluted tincture of opium + phenobarbital Phenobarbital (short course) Phenobarbital (long course) Chlorpromazine (long course) Chlorpromazine (short course) Phenobarbital (loading dose) Phenobarbital (titre) Diazepam Methadone Morphine + clonidine Morphine + phenobarb Laudanum Tobacco Selective Seretonin Re-uptake Inhibitor Methadone Buprenorphine Heroin OxyContin Opium Cocaine Methamphetamine Poly substance Benzodiazepine Illicit drugs

3 Appendix 1 Review Protocol PROSPERO Protocol Pharmacological treatments for neonatal abstinence syndrome: a network meta-analysis Timothy Disher, Marsha Campbell-Yeo, Louis Beaubien, Balpreet Singh, Courtney Gullickson Citation Timothy Disher, Marsha Campbell-Yeo, Louis Beaubien, Balpreet Singh, Courtney Gullickson. Pharmacological treatments for neonatal abstinence syndrome: a network meta-analysis. PROSPERO 2017 CRD Available from: Review question Which pharmacological treatment for neonatal abstinence syndrome is associated with the shortest length of treatment and lowest risk for the need of additional adjuvant treatments? Searches The following databases were searched from inception: Ovid MEDLINE (Epub Ahead of Print, In- Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R)), Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science Core Collection. No restrictions will be placed on the search strategy. Where possible, we will translate and include articles published in languages other than English. Types of study to be included Parallel randomized controlled trials. Condition or domain being studied Neonatal abstinence syndrome (NAS) defines a constellation of symptoms arising in neonates who have been exposed to prenatal substance abuse (e.g. opiates, cocaine), or anti-depressants (e.g. SSRIs). Symptom onset typically occurs within 4-5 days, and includes jitteriness, high-pitched cry, diaphoresis, diarrhoea, and seizures. The American Academy of Pediatrics (AAP) guidelines state that infants with suspected NAS should be monitored closely, encouraged to breastfeed, and removed from overstimulating environments. When non-pharmacologic interventions alone are unable to control NAS symptoms, the AAP recommends that first-line pharmacological treatment of NAS should consists of treatment with opiates, typically morphine or methadone. Current practices in most hospitals require that infants receiving pharmacological treatment for NAS be treated in the neonatal intensive care unit (NICU). As NICU days are costly, there has been significant effort dedicated to identifying which treatment strategy is associated with the shortest length of stay. While recent research suggests that the largest differences in length of stay are likely to result from interventions such as rooming in or weaning protocols, there is RCT level evidence that suggests that choice of pharmacological treatment has a clinically meaningful impact. In recent years, there has been emerging attention paid to the avoiding exposure to pharmacological agents which may be neurotoxic. Pre-clinical, and observational research suggests that exposure to opiates in the neonatal period may result in poorer neurodevelopmental outcomes. Similarly, when treatment with opioid alone is insufficient, commonly added adjuvant drugs such as phenobarbital have been associated with poorer developmental outcomes in later life. Unfortunately, the complicated nature of addiction means that it is difficult, if not impossible, to conduct research intended to tease out the potentially harmful developmental effects of exposure to opiates and sedatives in early life. While attempts to follow neonates after have been made, their conclusions are inextricably confounded by their home environment. This limitation aside, the risk of potential harm has resulted in increasing attention paid to reducing exposure to opiates or sedatives. Recently published reviews have thus identified reduced exposure to opiates and sedatives as clinically relevant.

4 Participants/population Inclusion: Neonates exposed to illicit substances in utero requiring pharmacological treatment for symptoms of NAS, cared for in an intensive care unit. Exclusion: Iatrogenic NAS, treatment on a normal neonate floor (e.g. rooming in). Intervention(s), exposure(s) Pharmacological treatments for NAS typically take the form of opiate replacement or sedative agents. Examples of opiate replacement therapies include diluted tincture of opium, morphine, methadone, and buprenorphine. Examples of commonly used sedatives include phenobarbital, diazepam, and clonidine. Comparator(s)/control We will consider studies comparing any active treatments. Primary outcome(s) Length of treatment: Total days of pharmacological treatment required. Length of stay: Days of care measured from admission to intensive care unit to discharge. Secondary outcome(s) Adverse events. Need for adjuvant. Data extraction (selection and coding) Abstract and title screen, full-text screening, and data extraction, will be conducted independently by two reviewers using Covidence. Risk of bias (quality) assessment Critical appraisal will be conducted using the Cochrane risk of bias tool for randomized controlled trials. All studies will be assessed by two reviewers. Conflicts will be solved through consensus or, if necessary, resolved by a third reviewer. Risk of bias will not be used to judge trials for inclusion in planned synthesis. Strategy for data synthesis Relevant clinical and study design characteristics will be compared between eligible trials in order to assess acceptability to synthesis. These will include infant gestational age, birthweight, and prenatal drug exposure. Pairwise and network meta-analysis will be conducted using WinBugs. Results of continuous scales will be expressed in mean difference and accompanied with their 95% credible intervals (CrI). Adverse events will be expressed as odds ratios (ORs). In order to provide a coherent probabilistic ranking of treatments, surface under the cumulative ranking (SUCRA) curves will be developed. Heterogeneity will be assessed through the standard deviation of the random effect distribution, using previously established benchmarks which identify values of 0.1 to 0.49 as reasonable, as moderate, and greater than 1 as potentially indicative of serious heterogeneity. Assessment of inconsistency within the network (e.g. agreement between direct and indirect evidence) will be assessed by comparing the deviance information criteria (DIC) between a consistency and inconsistency model. Lower DIC indicates better fit, with differences of 3-5 indicating better fit. Skewed data: When results were reported as median and IQR, we will assess whether the assumption of symmetry is supported. In the absence of signs of skewness, we will use score as reported, treat medians as the mean and impute the standard deviation using method outlined by the Agency for Healthcare Research and Quality (AHRQ). Sensitivity analyses will be conducted excluding these trials. Analysis of subgroups or subsets None planned. Contact details for further information

5 Timothy Disher Organisational affiliation of the review Dalhousie University Review team members and their organisational affiliations Mr Timothy Disher. Dalhousie University Dr Marsha Campbell-Yeo. Dalhousie University/IWK Health Centre Dr Louis Beaubien. Dalhousie University/IWK Health Centre Dr Balpreet Singh. Dalhousie University/IWK Health Centre Ms Courtney Gullickson. Dalhousie University Anticipated or actual start date 09 January 2017 Anticipated completion date 30 June 2017 Funding sources/sponsors None Conflicts of interest None known Language English Country Canada Stage of review Review_Ongoing Subject index terms status Subject indexing assigned by CRD Subject index terms Female; Humans; Infant, Newborn; Neonatal Abstinence Syndrome; Network Meta-Analysis; Pregnancy; Pregnancy Complications Date of registration in PROSPERO 13 June 2017 Date of publication of this version 13 June 2017 Details of any existing review of the same topic by the same authors Stage of review at time of this submission Stage Started Completed Preliminary searches Yes Yes Piloting of the study selection process Yes Yes Formal screening of search results against eligibility criteria Yes Yes Data extraction Yes No

6 Risk of bias (quality) assessment Yes No Data analysis No No Deviations from protocol Deviation Analysis restricted to trials published 2000 or later Reason Consultation with clinical experts revealed large shift in clinical practice and no use of drugs identified in earlier trials (e.g. diazepam).

7 Appendix 2 PRISMA-NMA Checklist PRISMA-NMA Checklist Section/Topic TITLE Item # Checklist Item Title 1 Identify the report as a systematic review incorporating a network meta-analysis (or related form of meta-analysis). Reported on Page # p. 1 ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: Background: main objectives Methods: data sources; study eligibility criteria, participants, and interventions; study appraisal; and synthesis methods, such as network meta-analysis. Results: number of studies and participants identified; summary estimates with corresponding confidence/credible intervals; treatment rankings may also be discussed. Authors may choose to summarize pairwise comparisons against a chosen treatment included in their analyses for brevity. Discussion/Conclusions: limitations; conclusions and implications of findings. Other: primary source of funding; systematic review registration number with registry name. p. 5 INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known, including mention of why a network meta-analysis has been conducted. Objectives 4 Provide an explicit statement of questions being addressed, with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). p. 5 p. 6 METHODS Protocol and registration 5 Indicate whether a review protocol exists and if and where it can be accessed (e.g., Web address); and, if available, provide registration information, including registration number. Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. Clearly describe eligible treatments included in the treatment network, and note whether any have been clustered or merged into the same node (with justification). p. 6 p. 6

8 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. Geometry of the network Risk of bias within individual studies Summary measures Planned methods of analysis Assessment of Inconsistency Risk of bias across studies Additional analyses S1 Describe methods used to explore the geometry of the treatment network under study and potential biases related to it. This should include how the evidence base has been graphically summarized for presentation, and what characteristics were compiled and used to describe the evidence base to readers. 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. 13 State the principal summary measures (e.g., risk ratio, difference in means). Also describe the use of additional summary measures assessed, such as treatment rankings and surface under the cumulative ranking curve (SUCRA) values, as well as modified approaches used to present summary findings from meta-analyses. 14 Describe the methods of handling data and combining results of studies for each network meta-analysis. This should include, but not be limited to: Handling of multi-arm trials; Selection of variance structure; Selection of prior distributions in Bayesian analyses; and Assessment of model fit. S2 Describe the statistical methods used to evaluate the agreement of direct and indirect evidence in the treatment network(s) studied. Describe efforts taken to address its presence when found. 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). 16 Describe methods of additional analyses if done, indicating which were pre-specified. This may include, but not be limited to, the following: Sensitivity or subgroup analyses; Meta-regression analyses; Alternative formulations of the treatment network; and Use of alternative prior distributions for Bayesian p. 6 etable 2.1 p. 6 p. 6 p. 6-7 p. 7 p. 7 p. 7 p. 7 p. 7-8 p. 8 p. 8

9 analyses (if applicable). RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. Presentation of network structure Summary of network geometry Study characteristics Risk of bias within studies Results of individual studies Synthesis of results Exploration for inconsistency Risk of bias across studies Results of additional analyses S3 Provide a network graph of the included studies to enable visualization of the geometry of the treatment network. S4 Provide a brief overview of characteristics of the treatment network. This may include commentary on the abundance of trials and randomized patients for the different interventions and pairwise comparisons in the network, gaps of evidence in the treatment network, and potential biases reflected by the network structure. 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. 19 Present data on risk of bias of each study and, if available, any outcome level assessment. 20 For all outcomes considered (benefits or harms), present, for each study: 1) simple summary data for each intervention group, and 2) effect estimates and confidence intervals. Modified approaches may be needed to deal with information from larger networks. 21 Present results of each meta-analysis done, including confidence/credible intervals. In larger networks, authors may focus on comparisons versus a particular comparator (e.g. placebo or standard care), with full findings presented in an appendix. League tables and forest plots may be considered to summarize pairwise comparisons. If additional summary measures were explored (such as treatment rankings), these should also be presented. S5 Describe results from investigations of inconsistency. This may include such information as measures of model fit to compare consistency and inconsistency models, P values from statistical tests, or summary of inconsistency estimates from different parts of the treatment network. 22 Present results of any assessment of risk of bias across studies for the evidence base being studied. 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression analyses, alternative network geometries studied, alternative choice of prior distributions for Bayesian analyses, and so forth). p. 9 Figure 1 p. 9 p. 9, Table 1, and etable efigure 3.1 efigure Figures 2-3, efigures and p p p. 9 NA

10 DISCUSSION Summary of evidence 24 Summarize the main findings, including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy-makers). Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review level (e.g., incomplete retrieval of identified research, reporting bias). Comment on the validity of the assumptions, such as transitivity and consistency. Comment on any concerns regarding network geometry (e.g., avoidance of certain comparisons). Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. p p p. 17 FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. This should also include information regarding whether funding has been received from manufacturers of treatments in the network and/or whether some of the authors are content experts with professional conflicts of interest that could affect use of treatments in the network. p. 1

11 Appendix 3 Search Results MEDLINE Search Strategy Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R), 1946-present 1. Neonatal Abstinence Syndrome/ 2. Substance Withdrawal Syndrome/ 3. exp Infant, Newborn/ 4. (baby or babies or newborn? or new-born? or infant? or infancy or neonatal or neo-natal or neonate? or neo-nate?).tw or and 5 7. ((baby or babies or newborn? or new-born? or infant? or infancy or neonatal or neo-natal or neonate? or neo-nate?) adj2 (abstinence or withdrawal? or addict* or opioid? or opiate? or narcotic? or substance)).tw or 6 or 7 9. exp Chloral Hydrate/ 10. chloral hydrate.tw. 11. Opium/ 12. ((tincture adj2 opium) or DTO).tw. 13. exp Phenobarbital/ 14. (phenobarbital or phenobarbitone or phenylethylbarbituric).tw. 15. Morphine/ 16. (morphine or morphia).tw. 17. exp Methadone/ 18. methadone.tw. 19. exp Buprenorphine/ 20. buprenorphine.tw. 21. Clonidine/ 22. clonidine.tw. 23. Opiate Substitution Treatment/ 24. ((opiate or opioid) adj (substitution or replacement)).tw or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or and 25

12 PRISMA flow diagram

13 Appendix 4 Synthesis feasibility Treatment protocols Study Dose Treatment protocol summary Definition of Need for adjuvant Buprenorphine Kraft 2008 Kraft 2011 Dose: Freq: q8h Dose: Freq: q8h kraft 2017 Dose: Freq: q8h Increase protocol: rescue dose of 50% of previous dose followed by 20% increase for buprenorphine. Wean indication: 3 days of dose stabilization, weaning for scores less than 8 for buprenorphine Wean protocol: 10% daily with no more than one wean per day, cessation when dose was within 10% of initial dose. Discharge indication: 10% of initial dose Discharge on treatment: no Increase protocol: buprenorphine 25% increase, morphine 10% increase/day Wean indication: 3 days of dose stabilization, weaning for scores less than 8 Wean protocol: Weaned 10% daily with no more than one wean per day, cessation when dose was within 10% of initial dose. Discharge indication: 10% of initial dose Discharge on treatment: no Increase protocol: up titrate buprenorphine/placebo 25%, morphine placebo 20% Wean indication: Stability for two days + Sum of three scores < 18 Wean protocol: 10% once a day 0.039mg/kg/day for bup, 1mg/kg/day morph For buprenorphine if escalation was required beyond 0.06mg/kg/day, 1mg/kg/day for morphine Max dose reached (60ug/kg/d for buprenorphine, 1.2mg/kg/d morphine)

14 Chlorpromazine Kahn 1969 Clonidine Bada 2015 Diazepam Finnegan 1982 Finnegan 1984a Kaltenbac h 1986 Madden 1977 Dose: 2.8 Freq: q4h * 10 days Dose: 5 ug/kg/d Freq: q3 Discharge indication: 10% of initial dose Discharge on treatment: no Increase protocol: increase by 1/7 Wean indication: time/infant too drowsy Wean protocol: Weaned to 16 days (decrease by 1/7) Discharge indication: 16 days of treatment Discharge on treatment: no Increase protocol: increase by 25% every 24 hours up to a max of 12 ug/kg Wean indication: 48 hours of all scores <8 Wean protocol: decrease dose by 10% of the max dose every other day. If reescalation was needed the previous dose was administered and weaning was resumed after 48 hours Discharge indication: <1 ug/kg/d Discharge on treatment: yes after 3 consecutive successful weanings and at physician discretion NA physician discretion - Not reported - - Not reported - - Not reported - - Not reported - - Not reported - symptoms not controlled at highest dose of a specific drug - Not reported - - Not reported - not defined explicitly but Dose: 0.5mg-2.0mg Freq: q8h Increase protocol: increased to max of 8mg/day Wean indication: NA Wean protocol: NA likely 3 NASS scores >7? pediatrician's opinion

15 Diluted tincture of opium Langenfel d 2005 Agthe 2009 Dose: Freq: q4h Dose: 0.48 mg me/d Freq: q4 Discharge indication: NA Discharge on treatment: no Increase protocol: increase dose by 0.016mg/kg until 3 below 8 or mean score < 8 Wean indication: Stable for 72 hours Diluted tincture of opium + Clonidine Agthe 2009 Dose: dto = same as control, clonidine = 6 ug/kg/d Freq: NA Wean protocol: Decrease daily dose by 10%, if score = 8 keep dose for 24 hours, if >8 increase to last dose that controlled withdrawal symptoms Discharge indication: Not described, but scoring for 72 hours following disconcontinuation Discharge on treatment: no Increase protocol: 0.3/0.4/0.5 ml q4 then 0.5/0.7/0.9 ml q3 Wean indication: mean daily mfs <9 for at least 48 hours Wean protocol: dto deescalated by increments of 0.05mL per dose for each 24 hour period. If there were two consecutive mfs >= 12 during deescalation, the last previous dto dose that controlled symptoms was resumed. Discharge indication: NA Discharge on treatment: NA Increase protocol: 0.3/0.4/0.5 ml q4 then 0.5/0.7/0.9 ml q3 Wean indication: mean daily mfs <9 for at least 48 hours Wean protocol: dto deescalated by increments of 0.05mL per dose for NA 2 consecutive mfs >= 9 at the highest dose 2 consecutive mfs >= 9 at the highest dose

16 each 24 hour period. If there were two consecutive mfs >= 12 during deescalation, the last previous dto dose that controlled symptoms was resumed. Diluted tincture of opium + Phenobarbital Jackson 2004 Methadone Brown 2014 Dose: 8 mg/kg/d Freq: q4h Dose: finnegan <= 12: 0.2 mg/kg/d; > 12: 0.4 mg/kg/d Freq: q4h Discharge indication: NA Discharge on treatment: NA Increase protocol: NA Wean indication: scores <= 4 for 48 hours Wean protocol: reduce by 20%, if <=4 at next 24 hours reduce by 20% and so on. Discharge indication: keep for 36 hours of discontinuation before final discharge Discharge on treatment: NA Increase protocol: increased by 0.05 mg/kg/dose (0.2 mg/kg/d) to a max of 0.2 mg/kg/dose (0.8 mg/kg/d) Wean indication: scores <= 8 for 24-36h Wean protocol: decrease dose by 10% of stabilizing dose using a dated weaning schedule provided by the pharmacy. Intolerance of wean defined as 2 out of 3 sequential finnegan scores >= 9 in the 12h prior to next dose to be weaned. The wean was held at current level unless scores remained >= 9 for 12 h, at which point an extra dose of study drug was given. If withdrawal re-emerged, maintenance dose was increased to the previous dose. lipsitz > 4 after 24 hours failure to wean twice in a 4-day period. If rescue drug failed the infant was removed from the study and treated with standard protocol.

17 Discharge indication: after last dose minimum of 36 hours for observation of rebound withdrawal before discharge Discharge on treatment: NA Madden 1977 Dose: 0.25mg Freq: q6h Increase protocol: increased to a max of 3mg/day pediatrician's opinion Wean indication: NA Wean protocol: NA Discharge indication: NA Discharge on treatment: no Davis 2018 Dose: Finnegan Dose: fs 8-10: 0.3/mg/kg q4h 11-13: : 0.7 >= 17: 0.9 Freq: q8h Increase protocol: NA Wean indication: control of withdrawal Wean protocol: decreased by 10% every hours Discharge indication: 20% initial dose max dose reached Discharge on treatment: no

18 Morphine Bada 2015 Dose: 0.4 mg/kg/d Freq: q3 Increase protocol: increase by 25% every 24 hours up to a max of 1 No improvement at 1 mg/kg/d mg/kg/d Wean indication: 48 hours of all scores <8 Wean protocol: decrease dose by 10% of the max dose every other day. If reescalation was needed the previous dose was administered and weaning was resumed after 48 hours Discharge indication: morphine: <0.1 mg/kg/d Discharge on treatment: yes after 3 consecutive successful weanings and at physician discretion Brown 2014 Dose: finnegan <= 12: 0.2 mg/kg/d; > 12: 0.4 mg/kg/d Freq: q4h Increase protocol: increased by 0.05 mg/kg/dose (0.2 mg/kg/d) to a max of 0.2 mg/kg/dose (0.8 mg/kg/d) Wean indication: scores <= 8 for 24-36h failure to wean twice in a 4-day period. If rescue drug failed the infant was removed from the study and treated with standard protocol. Wean protocol: decrease dose by 10% of stabilizing dose using a dated weaning schedule provided by the pharmacy. Intolerance of wean defined as 2 out of 3 sequential finnegan scores >= 9 in the 12h prior to next dose to be weaned. The wean was held at current level unless scores remained >= 9 for 12 h, at which point an extra dose of study drug was given. If withdrawal re-emerged, maintenance dose was increased to the previous dose. Discharge indication: after last dose minimum of 36 hours for

19 observation of rebound withdrawal before discharge Discharge on treatment: NA Jackson 2004 Dose: 0.2 mg/kg/d Freq: q4h Increase protocol: NA Wean indication: scores <= 4 for 48 lipsitz > 4 after 24 hours hours Wean protocol: reduce by 20%, if <=4 at next 24 hours reduce by 20% and so on. Discharge indication: keep for 36 hours of discontinuation before final discharge Discharge on treatment: NA Kraft 2008 Dose: 0.4 Freq: q6h Increase protocol: rescue dose of 50% of previous dose followed by 0.039mg/kg/day for bup, 1mg/kg/day morph 20% increase for buprenorphine. Escalation of 10%/day for morphine and equivalent dose for rescue Wean indication: 3 days of dose stabilization, weaning for scores less than 8 for buprenorphine, 38 hours for morphine Wean protocol: Buprenorphine weaned 10% daily with no more than one wean per day, cessation when dose was within 10% of initial dose. For morphine, weaned by 10% per day until 0.15mg/kg/day Discharge indication: 10% of initial dose for buprenorphine, 0.15mg/kd/day for morphine Discharge on treatment: no Kraft 2011 Dose: 0.4 Freq: q6h Increase protocol: 10% increase/day Wean indication: 3 days of dose Escalation was required beyond 1mg/kg/day for morphine stabilization, weaning for scores less than 8

20 kraft 2017 Dose: 0.4 Freq: q4h Langenfel d 2005 Nayeri 2015 Dose: Freq: q4h Dose: Based on finnegan score: 8-10: 0.6 mg/kg/day 11-13: 1.2 mg/kg/day 14-16: 1.6 mg/kg/day >=17: 2 mg/kg Freq: q4h Wean protocol: Weaned by 10% per day until 0.15mg/kg/day Discharge indication: 0.15mg/kd/day Discharge on treatment: no Increase protocol: up titrate buprenorphine/placebo 25%, morphine placebo 20% Wean indication: Stability for two days + Sum of three scores < 18 Wean protocol: 10% once a day Discharge indication: Buprenorphine within 10% of initial dose, morphine 0.025mg/kg q4h Discharge on treatment: no Increase protocol: increase dose by 0.016mg/kg until 3 below 8 or mean score < 8 Wean indication: Stable for 72 hours Wean protocol: Decrease daily dose by 10%, if score = 8 keep dose for 24 hours, if >8 increase to last dose that controlled withdrawal symptoms Discharge indication: Not described, but scoring for 72 hours following disconcontinuation Discharge on treatment: no Increase protocol: Based on finnegan score: 8-10: 0.6 mg/kg/day 11-13: 1.2 mg/kg/day 14-16: 1.6 mg/kg/day >=17: 2 mg/kg Max dose reached (1.2mg/kg/d morphine) NA physician discretion

21 Davis 2018 Dose: Finnegan Dose: fs 8-10: 0.3/mg/kg q4h 11-13: : 0.7 >= 17: 0.9 Freq: q4h Morphine + Clonidine Surran 2013 Dose: finnegan 8-10: morphine 0.32 mg/kg/d + phenobarbital 6 mg/kg/d 11-13: morphine 0.48 mg/kg/d + phenobabital 8 mg/kg/d 14-16: morphine 0.64 mg/kg/d + phenobarbital 10 mg/kg/d >= 17: morphine 0.8 mg/kg/d + phenobarbital 12 mg/kg/d Freq: NA Morphine + Phenobarbital Surran 2013 Dose: finnegan 8-10: morphine 0.32 mg/kg/d + Wean indication: score below 8 for 72h Wean protocol: reduce by 10%/day while scores below 8 Discharge indication: dose less than 0.1mg/kg/day for Discharge on treatment: no Increase protocol: Same as treatment Wean indication: control of withdrawal Wean protocol: decreased by 10% every hours Discharge indication: 20% initial dose Discharge on treatment: no Increase protocol: as per protocol Wean indication: all scores in 24h < 8 Wean protocol: morphine reduced once in 24 h by 10% of absolute dose. If symptoms recurred with two consecutive scores > 8 in 24h then dose was held, if greater than 10 then increased to last dose for 24h Discharge indication: morphine 0.12 mg/kg/d, clonidine discontinued and then monitored for 36-48h before discharge. Phenobarb weaned at home Discharge on treatment: yes if phenobarb Increase protocol: as per protocol Wean indication: all scores in 24h < 8 max dose reached NA NA

22 Paregoric Carin 1983 Finnegan 1984a Kaltenbac h 1986 Kandall 1983 Phenobarbital Carin 1983 phenobarbital 6 mg/kg/d 11-13: morphine 0.48 mg/kg/d + phenobabital 8 mg/kg/d 14-16: morphine 0.64 mg/kg/d + phenobarbital 10 mg/kg/d >= 17: morphine 0.8 mg/kg/d + phenobarbital 12 mg/kg/d Freq: NA Dose: 0.17 mg/kg/d me; 0.42 to 2.1 ml/kg Freq: NA Wean protocol: morphine reduced once in 24 h by 10% of absolute dose. If symptoms recurred with two consecutive scores > 8 in 24h then dose was held, if greater than 10 then increased to last dose for 24h Discharge indication: morphine 0.12 mg/kg/d. Phenobarb weaned at home Discharge on treatment: yes if phenobarb Increase protocol: paregoric: max = 0.84 mg/kg/d me Wean indication: score <= 4 for 2 days Wean protocol: decrease dose by 20%, subsequent decrements of 20% were made every other day Discharge indication: paregoric: 0.1 ml/kg; phenobarb: 1 mg/kg Discharge on treatment: NA - Not reported - - Not reported - symptoms not controlled at highest dose of a specific drug - Not reported - - Not reported - not defined explicitely but Dose: 1.6mL/day Freq: q3h Dose: 5 mg/kg/d Freq: NA Increase protocol: increase dose each day until score <6, increase paregoric by 0.05 ml Wean indication: <6 5 days Wean protocol: maintain dose for 5 days then reduce by 0.05mL/day Discharge indication: NA Discharge on treatment: no Increase protocol: NA NA likely 3 NASS scores >7? NA NA

23 Fabris 1985 Kandall 1983 Madden 1977 Kahn 1969 Finnegan 1984a Wean indication: score <= 4 for 2 days Wean protocol: decrease dose by 20%, subsequent decrements of 20% were made every other day Discharge indication: phenobarb: 1 mg/kg Discharge on treatment: NA - Not reported - - Not reported - not specified Dose: 5 Freq: q8 Dose: 5 to 8 Freq: q8th then q24h Dose: 8.4 Freq: q4h * 10 days Dose: 20 mg/kg loading dose, then 5 mg/kg as well as Increase protocol: increase dose each day until score <6, increase phenobarb by 1 mg/kg/day Wean indication: <6 5 days Wean protocol: for paregoric: maintain dose for 5 days then reduce by 1mg/kg/day for phenobarbital Discharge indication: NA Discharge on treatment: no Increase protocol: increased to max of 8mg/kg/day Wean indication: NA Wean protocol: NA Discharge indication: NA Discharge on treatment: no Increase protocol: increase by 1/7 Wean indication: time/infant too drowsy Wean protocol: Short course groups drug was abruptly terminated, long course weaned to 16 days (decrease by 1/7) Discharge indication: short course 4 days, long course 16 days Discharge on treatment: no Increase protocol: not specified Wean indication: not specified Wean protocol: not specified NA pediatrician's opinion NA symptoms not controlled at highest dose of a specific drug

24 Finnegan 1984b Kaltenbac h 1986 Nayeri 2015 Kahn 1969 Finnegan 1984b Kaltenbac h 1986 some infants receiving a titration based approach Freq: not specified Dose: 20 mg/kg then maintenance dose to control symptoms Freq: not specified Dose: NA Freq: NA Dose: loading dose 20mg/kg then 5mg/kg q 8-12h if symptoms persisted until the entire loading dose = 40mg/kg. Maintenance dose based on loading dose: 20mg/kg = 5mg/kg/day 30mg/kg = 6mg/kg/day 40mg/kg = 8mg/kg/day Freq: q8-12h then q24h Dose: 8.4 Freq: q4h * 4 days Discharge indication: not specified Discharge on treatment: not specified Increase protocol: not specified Wean indication: not specified Wean protocol: not specified Discharge indication: not specified Discharge on treatment: not specified Increase protocol: NA Wean indication: NA Wean protocol: NA Discharge indication: NA Discharge on treatment: no Increase protocol: Based on finnegan score: 8-10: 0.6 mg/kg/day 11-13: 1.2 mg/kg/day 14-16: 1.6 mg/kg/day >=17: 2 mg/kg Wean indication: score below 8 for 72h Wean protocol: reduce by 10%/day while scores below 8 Discharge indication: Until completely discontinued Discharge on treatment: no Increase protocol: increase by 1/7 Wean indication: time/infant too drowsy Wean protocol: Drug was abruptly terminated after 4 days Discharge indication: 4 days Discharge on treatment: no not specified not defined explicitly but likely 3 NASS scores >7 physician discretion Dose: 6-12 mg/kg/d Freq: q8h - Not reported - not specified - Not reported - - Not reported - not defined explicitely but likely 3 NASS scores >7? NA

25

26 Adjuvant treatment info Study Adjuvant drug Adjuvant protocol Agthe 2009 discretion of the clinical care - Not reported - team Bada 2015 attending physician's discretion - Not reported - Brown 2014 clonazepam or phenobarbital Dose: with clonazepam used unless clonazepam: mg/kg/dose parents were concerned about (0.015 mg/kg/d) oversedation phenobarb: two loading doses of 10mg/kg 8h apart followed by 5mg/kg/d Freq: clonazepam: q8h; phenobarb: q12h Indication for increase: NA Indication for wean: opiate weaned Wean protocol: clonazepam: weaned over 72h followed by 36h observation; phenobarb: weaned as outpatient Adjuvant D/C: NA Carin 1983 NA NA Jackson 2004 chloral hydrate Dose: 15 mg/kg/d Freq: NA Indication for increase: score > 4 after 24 hours, third line treatment considered Indication for wean: scores <= 4 for 48 hours Wean protocol: stopped abruptly Adjuvant D/C: scores <= 4 for 48 hours Kahn 1969 NA NA Kaltenbach 1986 Phenobarbital for paregoric arm, - Not reported - Paregoric for phenobarbital, and paregoric or phenobarbital for diazepam Kandall 1983 NA NA Kraft 2011 phenobarbital Dose: 20mg.kg loading dose then 2.5mg/kg twice a day for at least 2 days Freq: q12h Indication for increase: NA I ndication for wean: NAS reliably <8 Wean protocol: daily dose reduced by 50% followed by complete cessation as tolerated

27 by scores. Generally 2 days following 50% dose reduction Adjuvant D/C: as tolerated Kraft 2008 phenobarbital Dose: administered to achieve serum concentration of mg/dl Freq: NA Indication for increase: NA Indication for wean: NA Wean protocol: NA Adjuvant D/C: NA Langenfeld 2005 NA NA Madden 1977 diazepam Dose: 0.5mg Freq: q8 Indication for increase: persistant symptoms Indication for wean: NA Wean protocol: NA Adjuvant D/C: NA Nayeri 2015 phenobarbital in morphine group - Not reported - and morphine in phenobarbital group Surran 2013 NA NA kraft 2017 phenobarbital Dose: 20mg/kg load then 5 mg/kf/d Freq: NA Indication for increase: NA Indication for wean: Opioid weaned to 50% of highest dose Wean protocol: 2.5mg/kg/d with d/c after three additional steps Adjuvant D/C: three weans after reduction to 2.5 mg/kg/d Finnegan 1984a not specified Dose: not specified Freq: not specified Indication for increase: not specified Indication for wean: not specified Wean protocol: not specified Adjuvant D/C: not specified Finnegan 1984b NA NA Davis 2018 Phenobarbital Dose: 20mg/kg load then 5 mg/kf/d; if uncontrolled extra 10mg/kg/dose q8-12h for max two more doses with maintenance dose increases to 6.5/8 mg/kg/d respectively.

28 Freq: once daily Indication for increase: See dosing Indication for wean: Start weaning 24h after study drug weaned Wean protocol: if in hospital: wean 20% of max dose q3days for scores <9. Adjuvant D/C: Yes, after two doses

29 Risk of bias by study

30 Length of treatment pairwise meta-analysis

31

32 Length of stay pairwise meta-analysis

33

34 Need for adjuvant effect plots

35

36 Adverse events effect plot

37 Appendix 5 Outcome data Length of treatment data Study Control mean Treatment Mean Control SD Treatment SD Control N Treament N Control drug Treatment drug Agthe DTO DTO + Clonidine Bada Morphine Clonidine Brown Morphine Methadone Jackson Morphine Phenobarbital 2004 Kraft Morphine Buprenorphine Kraft Morphine Buprenorphine Kraft Morphine Buprenorphine Langenfeld Morphine DTO 2005 Nayeri Morphine Phenobarbital (loading dose) Davis Morphine Methadone Length of stay data Study Control mean Treatment Mean Control SD Treatment SD Control N Treament N Control drug Treatment drug Bada Morphine Clonidine Kraft Morphine Buprenorphine Kraft Morphine Buprenorphine Kraft Morphine Buprenorphine Langenfeld Morphine DTO 2005 Nayeri Morphine Phenobarbital (loading dose)

38 Davis Morphine Methadone Need for adjuvant data Study Control events Treatment events Control N Treatment N Control drug Treatment drug Brown Morphine Methadone 2014 Jackson Morphine Phenobarbital Kraft Morphine Buprenorphine 2008 Kraft Morphine Buprenorphine 2011 Kraft Morphine Buprenorphine Nayeri Morphine Phenobarbital (loading dose) Davis Morphine Methadone

39 Appendix 6 League Tables League plot for length of treatment

40 Treatments are reported in order of SUCRA ranking using a fixed effects model. Comparisons should be read left to right with mean differences of less than 0 indicating the treatment in the column is favoured over the treatment in the row. Shaded cells indicate 95% Credible Intervals exclude zero. For example, Buprenorphine is estimated to have a ( to 12.19) reduction in length of treatment compared to clonidine. League plot for length of stay Treatments are reported in order of SUCRA ranking using a fixed effects model. Comparisons should be read left to right with mean differences of less than 0 indicating the treatment in the column is favoured over the treatment in the row. Shaded cells indicate 95% Credible Intervals exclude zero. For example, Buprenorphine is estimated to have a ( to 3.53) reduction in length of treatment compared to clonidine.

41 League plot for treatment failure Treatments are reported in order of SUCRA ranking using a fixed effects model. Comparisons should be read left to right with odds ratios of less than one indicating the treatment in the column is favoured over the treatment in the row. Shaded cells indicate 95% Credible Intervals exclude one.

42

43 Appendix 7 Threshold plots These methods identify the smallest bias adjustment that would lead to a change in treatment recommendation. Two plots are generated for each outcome: one at the study level and one at the contrast (relative effect estimate) level. Each entry (study or contrast) is accompanied by the point estimate, the uncertainty around it (at the study or NMA level) and a blue shaded area indicating the invariant interval. The invariant interval is the range of values that a given entry can take without changing the conclusions the analysis. The purpose of threshold plots is to provide readers with an opportunity to assess whether conclusions from an NMA are likely to change as a result of risk of bias or imprecision. For risk of bias, they are interpreted through consideration of whether study characteristics could feasibly cause sufficient bias that adjustment would result in the effect estimate crossing the invariant threshold. To assess imprecision, the point estimate and it s credible interval are laid overtop of this interval at the contrast level. Contrasts whose credible intervals cross the invariant interval are considered sensitive to imprecision in the treatment estimate. Numbers to the left and right of the invariant interval indicate the treatment that would be ranked best if the point estimate crossed either the lower (left) or upper (right) threshold. Treatment codes for length of treatment Treatment Code Morphine 1 Buprenorphine* 2 DTO 3 Methadone 4 Clonidine 5 DTO + Clonidine 6 Phenobarbital 7 Phenobarbital (loading dose) 8 *Current best treatment

44 Length of treatment by study

45 Length of treatment by contrast

46 Treatment codes for length of stay Treatment Code Morphine 1 Buprenorphine* 2 Clonidine 3 DTO 4 Methadone 5 Phenobarbital (loading dose) 6 *Current best treatment Length of stay by study

47 Length of stay by contrast

48 Treatment codes for need for adjuvant Treatment Code Morphine 1 Buprenorphine 2 Methadone* 3 Phenobarbital 4 Phenobarbital (loading dose) 5 *Current best treatment Need for adjuvant by study

49 Need for adjuvant by contrast