Systemic opioid regimens for postoperative pain in neonates

Abstract Background Postoperative pain clinical management in neonates has always been a challenging medical issue. Worldwide, several systemic opioid regimens are available for pediatricians, neonatologists, and general practitioners to control pain in neonates undergoing surgical procedures. However, the most effective and safe regimen is still unknown in the current body of literature. Objectives To determine the effects of different regimens of systemic opioid analgesics in neonates submitted to surgery on all‐cause mortality, pain, and significant neurodevelopmental disability. Potentially assessed regimens might include: different doses of the same opioid, different routes of administration of the same opioid, continuous infusion versus bolus administration, or 'as needed' administration versus 'as scheduled' administration. Search methods Searches were conducted in June 2022 using the following databases: Cochrane Central Register of Controlled Trials [CENTRAL], PubMed, and CINAHL. Trial registration records were identified via CENTRAL and an independent search of the ISRCTN registry. Selection criteria We included randomized controlled trials (RCTs), quasi‐randomized, cluster‐randomized, and cross‐over controlled trials evaluating systemic opioid regimens' effects on postoperative pain in neonates (pre‐term or full‐term). We considered suitable for inclusion: I) studies evaluating different doses of the same opioid; 2) studies evaluating different routes of administration of the same opioid; 3) studies evaluating the effectiveness of continuous infusion versus bolus infusion; and 4) studies establishing an assessment of an 'as needed' administration versus 'as scheduled' administration. Data collection and analysis According to Cochrane methods, two investigators independently screened retrieved records, extracted data, and appraised the risk of bias. We stratified meta‐analysis by the type of intervention: studies evaluating the use of opioids for postoperative pain in neonates through continuous infusion versus bolus infusion and studies assessing the 'as needed' administration versus 'as scheduled' administration. We used the fixed‐effect model with risk ratio (RR) for dichotomous data and mean difference (MD), standardized mean difference (SMD), median, and interquartile range (IQR) for continuous data. Finally, we used the GRADEpro approach for primary outcomes to evaluate the quality of the evidence across included studies. Main results In this review, we included seven randomized controlled clinical trials (504 infants) from 1996 to 2020. We identified no studies comparing different doses of the same opioid, or different routes. The administration of continuous opioid infusion versus bolus administration of opioids was evaluated in six studies, while one study compared 'as needed' versus 'as scheduled' administration of morphine given by parents or nurses. Overall, the effectiveness of continuous infusion of opioids over bolus infusion as measured by the visual analog scale (MD 0.00, 95% confidence interval (CI) ‐0.23 to 0.23; 133 participants, 2 studies; I² = 0); or using the COMFORT scale (MD ‐0.07, 95% CI ‐0.89 to 0.75; 133 participants, 2 studies; I² = 0), remains unclear due to study designs' limitations, such as the unclear risk of attrition, reporting bias, and imprecision among reported results (very low certainty of the evidence). None of the included studies reported data on other clinically important outcomes such as all‐cause mortality rate during hospitalization, major neurodevelopmental disability, the incidence of severe retinopathy of prematurity or intraventricular hemorrhage, and cognitive‐ and educational‐related outcomes. Authors' conclusions Limited evidence is available on continuous infusion compared to intermittent boluses of systemic opioids. We are uncertain whether continuous opioid infusion reduces pain compared with intermittent opioid boluses; none of the studies reported the other primary outcomes of this review, i.e. all‐cause mortality during initial hospitalization, significant neurodevelopmental disability, or cognitive and educational outcomes among children older than five years old. Only one small study reported on morphine infusion with parent‐ or nurse‐controlled analgesia.


A B S T R A C T Background
Postoperative pain clinical management in neonates has always been a challenging medical issue. Worldwide, several systemic opioid regimens are available for pediatricians, neonatologists, and general practitioners to control pain in neonates undergoing surgical procedures. However, the most e ective and safe regimen is still unknown in the current body of literature.

Objectives
To determine the e ects of di erent regimens of systemic opioid analgesics in neonates submitted to surgery on all-cause mortality, pain, and significant neurodevelopmental disability. Potentially assessed regimens might include: di erent doses of the same opioid, di erent routes of administration of the same opioid, continuous infusion versus bolus administration, or 'as needed' administration versus 'as scheduled' administration.

Search methods
Searches were conducted in June 2022 using the following databases: Cochrane Central Register of Controlled Trials [CENTRAL], PubMed, and CINAHL. Trial registration records were identified via CENTRAL and an independent search of the ISRCTN registry.

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Cochrane Database of Systematic Reviews median, and interquartile range (IQR) for continuous data. Finally, we used the GRADEpro approach for primary outcomes to evaluate the quality of the evidence across included studies.

Main results
In this review, we included seven randomized controlled clinical trials (504 infants) from 1996 to 2020. We identified no studies comparing di erent doses of the same opioid, or di erent routes. The administration of continuous opioid infusion versus bolus administration of opioids was evaluated in six studies, while one study compared 'as needed' versus 'as scheduled' administration of morphine given by parents or nurses. Overall, the e ectiveness of continuous infusion of opioids over bolus infusion as measured by the visual analog scale (MD 0.00, 95% confidence interval (CI) -0.23 to 0.23; 133 participants, 2 studies; I = 0); or using the COMFORT scale (MD -0.07, 95% CI -0.89 to 0.75; 133 participants, 2 studies; I = 0), remains unclear due to study designs' limitations, such as the unclear risk of attrition, reporting bias, and imprecision among reported results (very low certainty of the evidence). None of the included studies reported data on other clinically important outcomes such as all-cause mortality rate during hospitalization, major neurodevelopmental disability, the incidence of severe retinopathy of prematurity or intraventricular hemorrhage, and cognitive-and educational-related outcomes.

Authors' conclusions
Limited evidence is available on continuous infusion compared to intermittent boluses of systemic opioids. We are uncertain whether continuous opioid infusion reduces pain compared with intermittent opioid boluses; none of the studies reported the other primary outcomes of this review, i.e. all-cause mortality during initial hospitalization, significant neurodevelopmental disability, or cognitive and educational outcomes among children older than five years old. Only one small study reported on morphine infusion with parent-or nursecontrolled analgesia.

Review Question
How e ective and safe are systemic opioids for reducing newborn babies' pain a er surgery?

Background
Neonates (babies in the first four weeks a er birth) may undergo surgery (operations) or surgical procedures. Like adults, babies experience pain, and this pain must be managed (reduced) a er surgery. Opioids are pain-relieving medications. Examples of opioids are codeine and morphine. Opioids work by interacting with opioid receptors in the body and reducing feelings of pain.
Opioids a ect the whole body system and this is why this review refers to them as systemic opioids. Opioids can be given to babies in a few ways, by di erent routes. One route is by using a needle injected into a vein; this is called parenteral drug administration. Another way (or route) is to place a medication in the baby's mouth, under the tongue or with a tube. These types of drug delivery are called enteral administration. Opioids, like most drugs, can be given at di erent strengths (dosages). Opioids can be given continuously (without stopping), or on and o over a period of time (intermittently).
All of these things together, how the opioid is given to the baby, how o en the opioid is given, and the strength of the opioid, create what is called a drug regimen.
This review aims to evaluate how di erent opioid regimens a ect babies.

Key results
This review included seven studies involving 504 babies. We identified no studies comparing di erent doses of the same opioid. We identified no studies comparing di erent routes to delivery of opioids. Six studies compared continuous opioid administration versus intermittent opioid administration. One study assessed the use of continuous morphine infusion compared with a parent-or nursecontrolled administration.
Based on the studies we found that we were unable to determine whether continuous or intermittent opioid regimens are better for controlling babies' pain. Since we did not find studies comparing di erent dosages of opioids, we do not know which dosage is better for reducing babies' pain. Since we did not find studies comparing di erent routes of opioid administration, we do not know if parenteral is better than enteral for reducing babies' pain. Considering the body of literature evaluated, the e ectiveness of continuous systemic opioid infusion compared with intermittent systemic opioid administration is still undetermined. We are uncertain about the e ectiveness of continuous systemic opioid administration and intermittent opioid administration in reducing the pain. We searched for studies that were available up to 10 June 2022.

Risk with continuous infusion
Relative effect (95% CI) № of participants (studies)

Certainty of the evidence (GRADE) Comments
Pain assessed with visual analogue scale (VAS) during the administration of selected drugs (neonates from 0 to 4 weeks) VAS scale ranges from 0 to 10 (worst) The mean pain assessed with VAS was 1.3 The mean pain assessed with VAS was 1.3 MD 0 (0.23 lower to 0.23 higher)

(2 RCTs)
⊕⊝⊝⊝ Very low a,b We are uncertain whether opioid continuous infusion reduces pain assessed with a visual analogue scale (VAS) compared with bolus administration due to imprecision of the estimate and limitations in study design.
Pain assessed with COMFORT scale during the administration of selected drugs (neonates from 0 to 4 weeks) COMFORT scale ranges from 6 to 30 (worst) The pain assessed with COMFORT ranged from 12.8 to 17.3 The pain assessed with COMFORT ranged from 12.6 to 17.4 MD 0.07 lower (0.89 lower to 0.75 higher) 133 (2 RCTs) ⊕⊝⊝⊝ Very low a,b We are uncertain whether opioid continuous infusion reduces pain assessed with the COMFORT scale compared with bolus administration due to imprecision of the estimate and limitations in study design.
All-cause mortality during initial hospitalization -not reported  Cochrane Database of Systematic Reviews

Description of the condition
Newborn infants undergo surgeries for treatment of congenital abnormalities and neonatal morbidities and are managed in the neonatal intensive care unit (NICU) therea er. The clinical spectrum of these abnormalities ranges from conditions such as diaphragmatic hernia and gastroschisis, which require surgical repair immediately or relatively soon a er birth, to conditions such as congenital heart disease and hypertrophic pyloric stenosis that can wait several weeks before being treated. Neonatal morbidities include complications o en due to prematurity, such as necrotizing enterocolitis, spontaneous intestinal perforation, and retinopathy of prematurity, which require surgical treatment. Such surgical interventions result in acute pain during and a er surgery, and also easily lead to chronic pain due to hyperalgesia during a vital period of complex brain development (Fitzgerald 1989).
Neonatal pain might a ect neuropsychological development in the long term. Therefore, it is important to accurately identify and appropriately manage pain. However, major gaps in knowledge exist regarding both objective assessment of pain, the most e ective way to prevent and relieve pain, as well as the long-term e ects of drug therapy. Systematic evaluation of pain has increased the awareness of treating pain, but pain assessment continues to pose a challenge (Olsson 2021). Although there are many validated scales for the assessment of both acute and continuous pain, a fully reliable and objective assessment method is still lacking (Eriksson 2019; Olsson 2021).
A recent review of pediatric perioperative controlled trials published between 2008 and 2018 reported that outcomes related to patient comfort, including pain management, were the most frequent across age groups beyond infancy, while clinical variables such as cardiorespiratory or medication-related adverse events were the most common outcome for neonates and infants under 60 weeks of age (Muhly 2020). The review also pointed out that the youngest age group of neonates and infants under 60 weeks of age were significantly under-represented in perioperative trials. This could be due to the higher perioperative risk of morbidity and mortality in neonates compared to older children (Kuan 2020), as well as to neonatal pharmacokinetics, which is not yet well characterized (Euteneuer 2020). The present reality is that optimal pain management in newborns is yet to be achieved, with further primary studies and updated systematic reviews needed for this unique age group.

Description of the intervention
Morphine, fentanyl, and remifentanil are the opioids most o en used during neonatal intensive care, whereas the fentanyl derivatives alfentanil and sufentanil are less frequently used. These opioids have varying pharmacokinetic (PK) and pharmacodynamic (PD) profiles and should optimally be administered in an individualized way, according to the need, clinical state, and expected course of the hospitalization. Fentanyl and remifentanil are administered intravenously in very sick infants, whereas morphine can be administered by both intravenous and oral routes. Morphine has the longest duration of onset, half-life, and elimination time, followed by fentanyl and remifentanil (Thigpen 2019; Van Gonge 2018; Ziesenitz 2018). Remifentanil is a short-acting opioid with ultra-rapid onset and a very fast elimination profile, thus very suitable for rapid painful procedures such as endotracheal intubation (McPherson 2018). Pharmacodynamic studies on opioids report hypotension as the most common adverse e ect (Thigpen 2019). Several larger studies have questioned the e ect of opioids and reported on negative outcomes (Anand 2004;Hall 2005;Simons 2003). Accumulating data report on the negative impact on the structure and function of the developing brain, including neuronal apoptosis (McPherson 2015;Sanders 2013;Zwicker 2016).

How the intervention might work
Opioids have been commonly used in postoperative management a er major procedures (such as to correct cardiac or other thoracoabdominal abnormalities, and otorhinolaryngological surgeries or neurosurgeries), particularly among preterm infants (Van Dijk 2001). Their analgesic function is related to interaction with the mu, kappa, and delta receptors present in the entire central nervous system which, as a final outcome, decrease neuronal excitability and reduce neurotransmission of nociceptive impulses (Trescot 2008). The overall e icacy of opioids administered directly to the central compartment is evident even when administered at low doses. However, in the case of peripheral administration in post-surgery, post-trauma or inflammatory state situations, their e ectiveness is not as reliable. In recent years, recommendations on time-scheduled opioid-dosing protocols and pain-contingent ('as needed') control have become more common (American Academy of Pediatrics 2016). For neonates during the postoperative period, it is thought that continuous administration of opioids results in steadier serum concentration of the active metabolite, establishing better pain relief, fewer adverse e ects and side e ects, reduced augmentation of pain behaviors and decreased risk of abstinence syndrome.
As far as routes of administration are concerned, several possibilities can be listed. Oral administration may be di icult immediately a er the surgery due to the consciousness of the infant as well as the condition of the gastrointestinal system, which is a ected by administered drugs and by the surgery itself. Potential physical-chemical interaction with milk and other frequently used medications during hospitalization (such as antibiotics) may also need to be considered (O'Brien 2019; Papai 2010). Likewise, intramuscular and subcutaneous injections are uncommon methods of opioid delivery in neonates, due to limited muscle mass, impact on skeletal muscle vascularization, and increased discomfort generated by these routes of administration (Costa 2013;Strolin 2003). Conversely, intravenous administration of opioids is most o en the preferred route of administration, particularly among critically ill infants (WHO 2012). Close monitoring should be undertaken in order to prevent excess administration of total fluids to the neonate: a regular intravenous fluid infusion rate can be as low as 10 mL per hour for full-term neonates and as low as 2 mL per hour for extremely preterm infants.
Morphine, one of the most used candidates in this category and a first-line opioid, is typically administered through a continuous intravenous infusion, with a dose ranging from 1 to 30 mcg/kg per hour, until no more improvement in pain control is observed, indicating a dose appropriate to the individual's current need (Anand 2004; Balda 2019). Interestingly, morphine starts working as an analgesic five minutes a er the start of administration and reaches a peak e ect in 15 minutes. Alternatively, an intermittent dose might be o ered to the neonate, at 0.05 to 0.20 mg/kg per Library Trusted evidence. Informed decisions. Better health.
Cochrane Database of Systematic Reviews dose every four to six hours, preferably intravenously. Fentanyl, which begins its onset of action two to three minutes a er injection, also can be given intermittently (at 0.3 to 4.0 mcg/kg per dose every two to four hours, intravenously) or as a continuous infusion (with a starting dose of slow 0.3 mcg/kg per hour, reaching a maximum dose of 5.0 mcg/kg per hour) (Anand 2004; Balda 2019). Similarly, tramadol is typically given at an increasing dose pattern (frequently administered as an intermittent medication at the dose of 5 mg/kg per day divided every 6 or 8 hours, intravenously or orally, or continuously at the dose of 0.10 to 0.25 mg/kg per hour) (Anand 2004; Balda 2019). In spite of many alternatives for pain control among neonates, the best dose regimen, route of administration and most appropriate opiate for neonates postsurgery is still uncertain, mainly due to the physiologic and metabolic immaturity of the neonate and the potential risk of toxicity.

Why it is important to do this review
Based on previous systematic reviews (Cochrane Reviews and non-Cochrane reviews), the American Academy of Pediatrics highlights the conflicting findings and lack of findings published in recent years associated with the use of opioids for analgesia in neonates (American Academy of Pediatrics 2016). Some particular populations have already been widely evaluated for the use of opioids, such as mechanically ventilated neonates (Bellù 2021), and those requiring non-emergency intubation (Ayed 2017). The assessment of the contemporary practice of analgesic and sedative procedures is of utmost importance, especially for infants in substantial pain during the postoperative period. An ongoing Cochrane Review of opioids compared to placebo or no drug, to oral sugar solution or non-pharmacological intervention, or to other analgesics or sedatives is under preparation (Kinoshita 2021). In this review, we assess di erent regimens to administer systemic opioids for postoperative pain in neonates.

O B J E C T I V E S
To determine the e ects of di erent regimens of systemic opioid analgesics in neonates (term or preterm) undergoing surgery, on mortality, pain and major neurodevelopmental disability. These di erent regimens may include: di erent doses of the same opioid; di erent routes of administration of the same opioid; continuous infusion versus bolus administration; or 'as needed' administration versus 'as scheduled' administration.

Types of studies
We included prospective randomized controlled trials (RCTs), quasi-RCTs, cluster-RCTs, and cross-over RCTs.

Types of participants
We included preterm and term infants of a postmenstrual age (PMA) up to 46 weeks and 0 days, irrespective of their gestational age at birth, receiving opioids following neonatal surgery where the surgery was performed in the operating room under general anesthesia (e.g. hernia repair surgery) or in the neonatal ward for minor surgery (e.g. patent ductus arteriosus ligation, surgery for retinopathy of prematurity, positioning of surgical drainage for air leak, thoracocentesis, placement of reservoir, or peritoneal dialysis for acute kidney failure).
We excluded: • infants receiving opioids during mechanical ventilation for respiratory morbidity; • infants receiving opioids pre-intubation; • infants receiving opioids for procedural pain; • infants treated for neonatal abstinence syndrome; and • infants undergoing hemodialysis.

Types of interventions
We included studies on any opioids (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) following neonatal surgery. The following acceptable comparisons were included.
• Comparison 1: di erent doses of the same opioid • Comparison 2: di erent routes of administration of the same opioid (e.g. enteral versus parenteral) • Comparison 3: continuous infusion versus bolus administration of the same opioid • Comparison 4: 'as needed' administration (e.g. based on pain scales) versus 'as scheduled' administration of the same opioid (e.g. a predefined time interval) We included any systemic route of administration (e.g. enteral and intravenous).
We included studies where the interventions were started during surgery, if their administration was continued postoperatively.
Studies comparing opioids to other interventions were included in the ongoing Cochrane Review, 'Systemic opioids versus other analgesics and sedatives for postoperative pain in neonates' (Kinoshita 2021).

Types of outcome measures
We focused on outcomes associated with pain assessment or management, neurological and cognitive functions, as well as other clinically relevant outcomes.

Primary outcomes
• Pain assessed with validated methods during the administration of selected drugs. The following scales, developed to assess pain, fulfill validity and reliability criteria for newborn infants (term and preterm on mechanical ventilation for any respiratory disease) when critically reviewed ( (Gri iths 1954;Gri iths 1970), assessment greater than two standard deviations (SDs) below the mean), intellectual impairment (intelligence quotient (IQ) greater than two SDs below the mean), blindness (vision less than 6/60 in both eyes), or sensorineural deafness requiring amplification (Jacobs 2013). We planned to separately assess data on children aged 18 to 24 months and aged three to five years. • Cognitive and educational outcomes in children older than five years old

Secondary outcomes
• All-cause neonatal mortality (death until postnatal day 28) • Episodes of bradycardia defined as a fall in heart rate of more than 30% below the baseline or less than 100 beats per minute for 10 seconds or longer

Search methods for identification of studies
Search strategies were developed by an information specialist and peer-reviewed by another. Database and trial registry searches were conducted without date, language, or publication type limits.

Electronic searches
We searched the following databases on 10 June 2022: • Cochrane Central Register of Controlled Trials (CENTRAL 2022, Issue 6) in the Cochrane Library via Wiley; • PubMed (1966 to 10 June 2022); • CINAHL (1982 to 10 June 2022) via EbscoHost.
We used Cochrane Neonatal's search strategy for neonates and a methodological filter for randomized controlled trials. Search strategies are provided in Appendix 1.
Trial registration records from the World Health Organization's International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en/), and the United States' National Library of Medicine's ClinicalTrials.gov (clinicaltrials.gov), were identified via Cochrane CENTRAL. We searched the ISRCTN registry (isrctn.com) independently.

Searching other resources
We also reviewed the reference lists of the included studies for studies not located in the database search. We searched for errata or retractions for included studies published in full text on PubMed (www.ncbi.nlm.nih.gov/pubmed).

Data collection and analysis
We collected information regarding the method of randomization, blinding, intervention, stratification, and whether the trial was single or multicenter for each included study. We noted information regarding trial participants including birth weight, gestational age, number of participants, modality of administration and dose of opioids. We analyzed the clinical outcomes noted above in Types of outcome measures.

Selection of studies
Initial search results were analyzed using Known Assessments and RCT Classifier segments of Cochrane's Screen4Me; remaining references were screened by the author. Detailed information regarding evaluations of the Screen4Me components can be found in the following publications: Marshall 2018; Noel-Storr 2020; Noel-Storr 2021; Thomas 2020.
We included all randomized, quasi-randomized, clusterrandomized and cross-over controlled trials fulfilling our inclusion criteria. Two review authors (IJBN, LS) independently reviewed the results of the search and selected studies for inclusion. We resolved any disagreements through discussion or, when necessary, by involving a third author.
We recorded the selection process in su icient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table (Moher 2009).

Data extraction and management
Two review authors (MK, LS) independently extracted data using a data extraction form integrated with a modified version of the Cochrane E ective Practice and Organization of Care Group data collection checklist (Cochrane EPOC Group 2017). We piloted the form within the review team using a sample of included studies.
We extracted these characteristics from each included study: Cochrane Database of Systematic Reviews • study: study design; type, duration, and completeness of followup (e.g. greater than 80%); country and location of study; informed consent; ethics approval; • participants: sex, birth weight, gestational age, number of participants; • interventions: initiation, dose, and duration of administration; • outcomes as mentioned above under Types of outcome measures.
We resolved any disagreements through discussion. We described ongoing studies identified by our search, when available, detailing the primary author, research question(s), methods, and outcome measures, together with an estimate of the reporting date and reported them in the 'Characteristics of included studies' table.
If any queries arose (e.g. discrepancies in the definitions of the outcomes in the trials and under 'Types of outcome measures'), or in cases for which additional data were required, we contacted study investigators/authors for clarification. Two review authors (MK, IJBN) used Cochrane statistical so ware for data entry (Review Manager 2020). We replaced any standard error of the mean (SEM) by the corresponding SD.

Assessment of risk of bias in included studies
Two review authors (MK, LS) independently assessed the risk of bias (low, high, or unclear) of all included trials, using the Cochrane Risk of bias tool for the following domains (Higgins 2011).
• Sequence generation (selection bias) • Allocation concealment (selection bias) • Blinding of participants and personnel (performance bias) • Blinding of outcome assessment (detection bias) • Incomplete outcome data (attrition bias) • Selective reporting (reporting bias) • Any other bias We resolved any disagreements through discussion or by consulting a third author (IJBN). See Appendix 2 for a more detailed description of risk of bias for each domain.

Measures of treatment e ect
We performed the statistical analyses using Review Manager 5 so ware (Review Manager 2020). We summarized the data in a meta-analysis if they were su iciently homogeneous, both clinically and statistically.

Dichotomous data
For dichotomous data, we presented results using risk ratios (RR) and risk di erences (RD) with 95% confidence intervals (CIs). We calculated the number needed to treat for an additional beneficial outcome (NNTB), or number needed to treat for an additional harmful outcome (NNTH) with 95% CIs if there was a statistically significant reduction (or increase) in RD.

Continuous data
For continuous data, we used the mean di erence (MD) when outcomes were measured in the same way between trials. We used the standardized mean di erence (SMD) to combine trials that measured the same outcome but used di erent methods. Where trials reported continuous data as a median and interquartile range (IQR) and data passed the test of skewness, we converted the median to a mean and estimated the standard deviation as IQR/1.35.

Unit of analysis issues
The unit of analysis was the participating infant in individually randomized trials, and an infant was considered only once in the analysis. The participating neonatal unit or section of a neonatal unit or hospital were the units of analysis in clusterrandomized trials. We planned to analyze them using an estimate of the intracluster correlation coe icient (ICC) derived from the trial (if possible), or from a similar trial or from a study with a similar population as described in Section 16.3.6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). If we used ICCs from a similar trial or from a study with a similar population, we reported this and conducted a sensitivity analysis to investigate the e ect of variation in the ICC.
We acknowledged any possible heterogeneity in the randomization unit and performed a sensitivity analysis to investigate possible e ects of the randomization unit.

Dealing with missing data
Where feasible, we carried out analysis on an intention-totreat basis for all outcomes. Whenever possible, we analyzed all participants in the treatment group to which they were randomized, regardless of the actual treatment received. When we identified important missing data (in the outcomes) or unclear data, we requested the missing data by contacting the original investigators. We made explicit the assumptions of any methods used to deal with missing data. We performed sensitivity analyses to assess how sensitive results were to reasonable changes in the undertaken assumptions. We addressed the potential impact of missing data on the findings of the review in the 'Discussion' section.

Assessment of heterogeneity
We estimated the treatment e ects of individual trials and examined heterogeneity among trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I 2 statistic. We graded the degree of heterogeneity as: • less than 25%: no heterogeneity; • 25% to 49%: low heterogeneity; • 50% to 75%: moderate heterogeneity; • more than 75%: substantial heterogeneity.
When we noted significant statistical heterogeneity (I 2 > 50%), we explored the possible causes (e.g. di erences in study quality, participants, intervention regimens, or outcome assessments).

Assessment of reporting biases
We intended to conduct a comprehensive search for eligible studies and were alerted for duplication of data. We planned to assess possible publication bias by inspection of a funnel plot. If we had uncovered reporting bias that could, in the opinion of the review authors, introduce serious bias, we planned to conduct a sensitivity analysis to determine the e ect of including and excluding these studies in the analysis.

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Data synthesis
As we identified multiple studies that were considered to be su iciently similar, we performed meta-analysis using Review Manager 5 (Review Manager 2020). For categorical outcomes, we calculated the typical estimates of RR and RD, each with its 95% CI. For continuous outcomes, we calculated the MD (or the SMD), each with its 95% CI. We used a fixed-e ect model to combine data where it was reasonable to assume that studies were estimating the same underlying treatment e ect. When we judged meta-analysis to be inappropriate, we analyzed and interpreted individual trials separately. When there was evidence of clinical heterogeneity, we tried to explain this based on the di erent study characteristics and subgroup analyses.

Subgroup analysis and investigation of heterogeneity
We explored statistical heterogeneity in the outcomes by visually inspecting the forest plots and by removing the outlying studies in a sensitivity analysis (Higgins 2020). Where statistical heterogeneity was moderate or substantial, we interpreted the results of the meta-analyses accordingly; and we downgraded the certainty of evidence in the Summary of findings tables, according to the GRADE recommendations.
We considered the following groups for subgroup analysis where data were available.
• Gestational age (GA): term; moderately preterm (32 to 36 weeks' GA); very preterm (less than 32 weeks' GA) • Duration of opioids administration: up to 72 hours a er surgery; beyond 72 hours • Studies where the administration was started during the surgery; a er the surgery • Surgery performed in the operating room under general anesthesia; surgery in the neonatal ward for minor surgery such as patent ductus arteriosus ligation, surgery for retinopathy of prematurity, positioning of surgical drainage for air leak, thoracocentesis or peritoneal dialysis for acute kidney failure • Within studies that accepted the use of co-interventions: studies where investigators allowed co-interventions for pain management; and studies that obligated its use, as well as by the type of co-interventions (corticosteroids or nonsteroidal antiinflammatory drugs) • According to drug dose regimen: continuous drug administration; 'as needed' based on signs of pain, discomfort, stress or following medical advisory We restricted these analyses to the primary outcomes.

Sensitivity analysis
Where we identified substantial heterogeneity, we conducted sensitivity analysis to determine if the findings were a ected by inclusion of only those trials considered to have used adequate methodology with a low risk of bias (selection and performance bias) by removing the outlying studies. We reported the results of sensitivity analyses for primary outcomes only.
We explored statistical heterogeneity in the outcomes by visually inspecting the forest plots and by removing the outlying studies in a sensitivity analysis (Higgins 2020).

Summary of findings and assessment of the certainty of the evidence
We used the GRADE approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the certainty of evidence for the following (clinically relevant) outcomes.
• Pain assessed with validated methods during the administration of selected drugs • All-cause mortality during initial hospitalization • Major neurodevelopmental disability in children aged 18 to 24 months: cerebral palsy, developmental delay (assessment greater than two standard deviations (SDs) below the mean), intellectual impairment (intelligence quotient (IQ) greater than two SDs below the mean), blindness (vision less than 6/60 in both eyes), or sensorineural deafness requiring amplification (Jacobs 2013) • Major neurodevelopmental disability (see above) in children three to five years old • Cognitive and educational outcomes in children more than five years old • Severe (defined as stage 3 or greater) retinopathy of prematurity in infants examined • Severe (grade 3 or greater) intraventricular hemorrhage (IVH) on cranial ultrasound Two review authors (MK, MB) independently assessed the certainty of the evidence for each of the outcomes above. We considered evidence from RCTs as high certainty, downgrading the evidence one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates, and presence of publication bias. We used the GRADEpro GDT Guideline Development Tool to create a Summary of findings table to report the certainty of the evidence.
The GRADE approach results in an assessment of the certainty of a body of evidence in one of the following four grades.
• High: we are very confident that the true e ect lies close to that of the estimate of the e ect; • Moderate: we are moderately confident in the e ect estimate: the true e ect is likely to be close to the estimate of the e ect, but there is a possibility that it is substantially di erent; • Low: our confidence in the e ect estimate is limited: the true e ect may be substantially di erent from the estimate of the e ect; • Very low: we have very little confidence in the e ect estimate: the true e ect is likely to be substantially di erent from the estimate of e ect.

Description of studies
See Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; and Characteristics of ongoing studies.

Results of the search
The literature search run in June 2022 yielded a total of 2526 references (2457 a er de-duplication). These references   Figure 2). One study from a trial registry system was classified as 'ongoing' (NCT00004696).  Cochrane Database of Systematic Reviews
The seven clinical trials included in this review reported data from 504 infants from di erent settings and primary conditions. In addition, there were di erences in the methods, participants, and interventions.
Overall, enrolled patients were initially admitted to neonatal intensive care units a er undergoing non-cardiac, thoracic, or abdominal surgery, which involved the postoperative pain management protocols of each hospital. As far as exclusion criteria among included studies were concerned, most studies considered patients ineligible for inclusion if they had received significant opioid treatment less than six hours before the surgery, received neuromuscular blockade, or su ered from hepatic, renal, neurological, or metabolic pathologies. In addition, one study excluded patients who received mechanical ventilation prior to surgery (Vaughn 1996).  1996).
Pain assessment during postoperative administration of selected drugs were done using validated methods in two of the included studies. In Bouwmeester 2001, two alternative methods were utilized for assessing pain in infants (visual analogue scale and COMFORT scale). Czarnecki 2020 also evaluated the infants' pain, but by using a revised version of the FLACC approach.
We identified only one record in the trial registry platform, which aimed to compare non-mechanically ventilated infants who received morphine postoperatively as intermittent intravenous bolus doses to those that received continuous intravenous infusion targeted to reach a steady-state concentration, and to assess e ectiveness of analgesia between the two treatment groups of infants (NCT00004696).

Excluded studies
The 17 excluded studies following full-text screening are listed in the Characteristics of excluded studies

Risk of bias in included studies
The overall risk of bias assessment for each study, including all domain evaluations and justifications for judgment, is displayed in the risk of bias section (Characteristics of included studies), on the right side of all forest plots and Figure 3; Figure 4.

Library
Cochrane Database of Systematic Reviews

Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias): All outcomes
Blinding of outcome assessment (detection bias): All outcomes Incomplete outcome data (attrition bias): All outcomes Selective reporting (

Selective reporting
In Czarnecki 2020, no major discrepancy was identified between the protocol and the final manuscript. The remaining six studies had unclear risk of reporting bias as no protocol was available (Bouwmeester 2001;Bouwmeester 2003a;Bouwmeester 2003b;Lynn 2000;Van Dijk 2002;Vaughn 1996).

Other potential sources of bias
In Lynn 2000, the percentage of infant pain scores for each infant was compared between groups rather than the absolute number of scores to compensate for di erent length of postoperative periods for di erent surgeries and di erent absolute numbers of scores based on bolus dosage (this study was assessed as being at high risk of bias). In Vaughn 1996, the study design did not incorporate a systematic approach to wean ventilator support, and therefore interpretation of this observation is di icult (graded as being at unclear risk of bias). Czarnecki 2020 was terminated earlier than planned (graded as being at unclear risk of bias

E ects of interventions
See: Summary of findings 1 Continuous infusion compared to bolus administration for postoperative pain in neonates; Summary of findings 2 'As needed' administration (e.g. based on pain scales) versus 'as scheduled' administration (e.g. a predefined time interval)

Comparison 1: Di erent doses of the same opioid
None of the studies were included in this comparison.

Comparison 2: Di erent routes of administration of the same opioid
None of the studies were included in this comparison.

Comparison 3: Continuous infusion versus bolus administration
Six studies were included in this comparison (

All-cause mortality during initial hospitalization
None of the included studies reported this outcome.

Major neurodevelopmental disability
None of the included studies reported this outcome.

Cognitive and educational outcomes in children older than five years old
None of the included studies reported this outcome.

Hypotension requiring medical therapy
One study (Bouwmeester 2003b) reported no events for this outcome. We are uncertain whether continuous infusion of opioids reduces hypotension requiring medical therapy compared with bolus administration (very low-certainty evidence; Analysis 1.3).

Mechanical ventilation longer than 24 hours
Three studies ( Cochrane Database of Systematic Reviews 0.09 to 0.38, 147 participants, 3 studies; I for RR and RD = 0%; low-certainty evidence; Analysis 1.4, Figure 5). For Bouwmeester 2001, data were reported for mechanical ventilation longer than 36 hours.
Within Comparison 3, no studies reported: all-cause neonatal mortality; episodes of bradycardia; retinopathy of prematurity; intraventricular hemorrhage; periventricular leukomalacia; necrotizing enterocolitis; bronchopulmonary dysplasia/chronic lung disease; constipation; focal gastrointestinal perforation; duration of mechanical ventilation; duration of oxygen supplementation; hospital stay; time to full enteral feeding; cost of neonatal care.

Comparison 4: 'as needed' administration (e.g. based on pain scales) versus 'as scheduled' administration (e.g. a predefined time interval)
One study (Czarnecki 2020) was included in the comparison, however, it reported none of the outcomes specified in the protocol of this review (see Summary of findings 2).

Summary of main results
In this review, we included seven studies with a total of 504 newborn infants. We identified no studies comparing di erent doses of the same opioid, or di erent routes. Six studies compared continuous opioid infusion with intermittent opioid boluses, either using morphine (five studies) or fentanyl (one study); one study compared continuous morphine infusion with parent-or nursecontrolled analgesia boluses of morphine, however, reported none of the outcomes of this review.

Cochrane Database of Systematic Reviews
Evidence from two studies in 133 infants is uncertain whether continuous opioid infusion reduces pain compared with intermittent opioid boluses. Neither did the included studies report on the other primary outcomes of this review, i.e. all-cause mortality during initial hospitalization, major neurodevelopmental disability, or cognitive and educational outcomes in children older than five years old. Evidence from one study in 62 infants, with no corresponding events, is uncertain whether continuous opioid infusion reduces hypotension requiring medical therapy compared with intermittent opioid boluses. None of the remaining outcomes were reported in any of the trials.

Overall completeness and applicability of evidence
A total of 504 newborns have been enrolled into seven clinical trials to compare di erent systemic opioid regimens, mainly continuous infusion and intermittent boluses of morphine. Study authors o en assessed infant pain but using di erent scales, and they rarely reported other important outcomes such as long-term neurodevelopment. We identified one possibly ongoing study, which was categorized as 'awaiting classification' due to the uncertainty regarding its trial status. More trials comparing the same systemic regimens and assessing critical outcomes are necessary for reaching meaningful conclusions about postoperative pain management in newborns.

Quality of the evidence
Following the GRADE approach, the overall certainty of evidence for the reported outcomes for postoperative systemic opioid administration is very low to low (See Summary of findings 1). The few reported outcomes were all downgraded (one level) for limitations in study design owing to the unclear risk of attrition or reporting bias. The outcome assessing the number of infants with mechanical ventilation longer than 24 hours was further downgraded (one level) for imprecision owing to the small sample size of one included study, and thus was rated as having low certainty. The other outcomes (pain assessment by di erent scales) were further downgraded (two levels) for imprecision because only one study was included in each analysis, and thus were rated as having very low certainty. We did not use funnel plots to evaluate publication bias because there were fewer than 10 studies that met the inclusion criteria of this Cochrane Review.

Potential biases in the review process
Throughout the review process, we adhered to the protocols and procedures endorsed by Cochrane and the MECIR standards to alleviate any potential procedural bias. Moreover, there were no deviations from the original protocol.
The reporting of the outcomes significantly varied among the included clinical trials, and we did not anticipate this issue. This led to a limited number of analyses of the included studies in terms of quantitative and qualitative evaluation, which evidently do not directly reflect the whole scientific literature. This is a potential limitation of this review since, for the most part, the reported outcomes did not align with our choice of primary and secondary outcomes. For instance, most studies assessed the association between morphine, fentanyl, or other opioid administration regimens and hormonal and metabolic stress response (including the dosage of plasma concentrations of norepinephrine, epinephrine, and their metabolites). We were successful in obtaining additional outcome data from study authors for one study (Van Dijk 2002).

Agreements and disagreements with other studies or reviews
There are few randomized trials or other studies evaluating the e ectiveness and safety of the systemic opioids for postoperative pain in neonates. The lack of studies evaluating pain management in newborn infants may be associated with the inherent di iculties in assessing pain in a population that typically cannot verbalize their feelings and needs. However, prior to our review, few non-Cochrane systematic reviews have summarized the available literature on pain management in neonates. At the moment, there is another Cochrane review (Kinoshita 2021) being worked on that is aiming to similarly evaluate the e ectiveness and safety of opioids in managing postoperative pain in neonates, but comparing opioids to any other analgesics.
The most complete systematic review with a series of metaanalyses included 22 randomized clinical trials assessing the e ectiveness and side e ect profile of tramadol for postoperative pain relief in children and adolescents undergoing di erent surgical procedures (Schnabel 2015). It turned out that the evidence regarding the use of tramadol for postoperative pain in children is low or very low essentially because of small samples sizes and methodological drawbacks. In addition, the evaluation of adverse events associated with tramadol was not possible due to the lack of reporting of this outcome. However, the applicability of these findings to neonates is likely to be limited.
Another review, which only included randomized, double-blind clinical trials comparing treatment with morphine with a placebo or active control intervention for e icacy on postoperative pain in pediatrics, only found significant improvements in the analgesic e icacy-related outcomes when morphine was compared with inactive control interventions (Duedahl 2007). Moreover, the study did not identify any dose-response e ect among the included studies. According to the review, which did not focus on newborns, the most frequently observed morphine-related adverse events were vomiting and sedation.

Implications for practice
Limited evidence is available on continuous infusion compared to intermittent boluses of systemic opioids. We are uncertain whether continuous opioid infusion reduces pain compared with intermittent opioid boluses; none of the studies reported the other primary outcomes of this review, i.e. all-cause mortality during initial hospitalization, major neurodevelopmental disability, or cognitive and educational outcomes in children older than five years old. Only one small study reported on morphine infusion with parent-or nurse-controlled analgesia.

Implications for research
Recently completed and future trials should report robust and long-term outcomes in infants exposed to di erent systemic dosing regimens, in both term and preterm newborn infants. Blinding should be performed and protocols published in advance.
Observational studies might provide useful information regarding potential harms. Cochrane Database of Systematic Reviews Pretreatment: Anesthesia was induced with thiopentone or by inhalation of halothane in oxygen. Fentanyl 5 mcg/kg was given before orotracheal intubation, which was facilitated with atracurium 0.5-1 mcg/kg or suxamethonium 2 mcg/kg.

Interventions
Intervention Characteristics

Continuous infusion versus bolus administration
• Dose regimen: Two groups (continuous morphine versus intermittent morphine) • Description of procedure: One group received continuous morphine (10 mcg/kg/h) while the other group received a continuous placebo infusion combined with three-hourly intravenous doses of 30 mcg/kg. All participants received an intravenous loading dose of morphine (100 mcg/kg).

Outcomes
Pain assessed with validated methods during the administration of selected drugs

Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk "The pharmacists prepared all study drugs, and the strata-specific schedules for randomization".

Computer-generated
Allocation concealment (selection bias)

Low risk Clinical sta blinded to allocation
Blinding of participants and personnel (performance bias) All outcomes Low risk "Pharmacists prepared all study drugs, and the strata-specific schedules for randomization and the clinical sta were blinded to the study group allocation until data collection was complete."

Blinded
Blinding of outcome assessment (detection bias) Low risk "Clinical sta were blinded to the study group allocation until data collection was complete". Cochrane Database of Systematic Reviews

All outcomes
Incomplete outcome data (attrition bias) All outcomes Unclear risk "All enrolled patients were included in an intention-to-treat analysis. Nine patients dropped out during the study (five in CM, four in IM) because of the loss of arterial access (seven), the need for neuromuscular blockade (one) and one postoperative death 3 h after surgery." N in the figures did not match the size of each experimental group and reasons were not clearly stated.
Selective reporting (reporting bias) Unclear risk No registry stated so unable to compare to protocol Other bias Low risk None

Study design: Double-blind, randomized clinical trial
Study grouping: Continous morphine versus three-hourly placebo or intermittent morphine with placebo infusion. Additional morphine was administered on guidance of pain outcomes.

Participants
Baseline Characteristics: Neonates aging from 0 to 4 weeks (gestational age between 35 to 42 weeks; body weight 1500 g or more) Inclusion criteria: Included neonates were admitted to the pediatric surgical intensive care unit following non-cardiac thoracic and abdominal surgery.
Exclusion criteria: Patients were excluded if they had received morphine < 6 h before surgery, or suffered from hepatic, renal or neurological disorders.

Pretreatment:
Anesthesia was induced intravenously with 3 to 5 mg/kg thiopentone or by inhalation with halothane in oxygen. Fentanyl at 5 mcg/kg was given before orotracheal intubation, which was facilitated with 0.5 to 1 mg/kg atracurium or 2 mg/kg suxamethonium.

Intervention Characteristics
• Dose regimen: Continous morphine infusion (10 mcg/kg/h) versus intermittent morphine (10 mcg/ kg every 3 hours) • Description of procedure: All neonates received a dose of morphine hydrochloride 100 mcg/kg at the end of surgery and were randomly allocated to equivalent intravenous doses of continuous morphine infusions (10 mcg/kg/hour) or intermittent morphine boluses (10 mcg/kg/3 hours).

Outcomes
Pain assessed with validated methods during the administration of selected drugs • Outcome type: Continuous outcome Pain was assessed by nurses trained in the use of the behavioral part of the COMFORT scale (CS), the total score of which can range from 6 to 30, and a 0 ± 10 visual analogue scale (VAS).

Participants
Baseline Characteristics: Neonates aging from 0 to 4 weeks (gestational age between 35 and 42 weeks; body weight 1500 g or more) Overall Inclusion criteria: Included neonates were admitted to the surgical intensive care unit following thoracic or abdominal surgery.
Exclusion criteria: Neonates with neurological, renal, or hepatic dysfunction, or with opioid therapy less than 6 hours prior to surgery were excluded.
Pretreatment: Anesthesia was induced intravenously with 3 to 5 mg/kg thiopentone or by inhalation with halothane in oxygen. Fentanyl at 5 mcg/kg was given before orotracheal intubation, which was facilitated with 0.5 to 1 mg/kg atracurium or 2 mg/kg suxamethonium.

Continuous infusion versus bolus administration
• Dose regimen: Intravenous doses of continuous morphine infusions (10 mcg/kg/hour) or intermittent morphine boluses (0 mcg/kg/3 hours) • Description of procedure: All neonates received a dose of morphine hydrochloride 100 mcg/kg at the end of surgery and were randomly allocated to equivalent intravenous doses of continuous morphine infusions (10 mcg/kg/hour) or intermittent morphine boluses (0 mcg/kg/3 hours).

Outcomes
Pain assessed with validated methods during the administration of selected drugs Cochrane Database of Systematic Reviews

Pretreatment:
Interventions Intervention Characteristics

Continuous infusion versus bolus administration
• Dose regimen: Morphine parent/nurse-controlled analgesia versus continuous opioid infusion (0.030 mg/kg/h) • Description of procedure: A 250 mcg/mL solution of parent/nurse-controlled morphine, 0.010 to 0.0125 mg/kg/h basal rate (0.060 mg/kg/h total maximum) was ordered; doses were rounded to the nearest microgram. Parents were instructed about signs of pain and told to: push the parent/nursecontrolled analgesia button only when the child was awake and in pain; to never push the button when the child was asleep; and to notify their nurse if they felt their child's pain was not well controlled. For the continuous opioid infusion group, morphine was ordered at 0.030 mg/kg/h, with a 0.030 mg/kg/ h nurse bolus available each hour to a maximum of 0.060 mg/kg/h total. Parents were instructed on signs of pain and to notify their nurse if their child's pain was not well controlled.

Outcomes
Pain assessed with validated methods during the administration of selected drugs

Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk "The randomization scheme was created by a statistician on the research team using Windows version 6.0 of "rand.exe" (http://block-stratified-randomization.software.informer.com/). The clinical research coordinator used the scheme to assign participants to groups."

Computer-generated
Allocation concealment (selection bias) Low risk "The clinical research coordinator used the scheme to assign participants to groups." Czarnecki 2020 (Continued) Systemic opioid regimens for postoperative pain in neonates ( Cochrane Database of Systematic Reviews

Concealed
Blinding of participants and personnel (performance bias) All outcomes High risk "Based on our current practice, PNCA patients were managed by the APS, and COI patients were managed by the neonatology team. COI patients were checked on".

Not blinded
Blinding of outcome assessment (detection bias) All outcomes High risk "This study used an unblinded design."

Not blinded
Incomplete outcome data (attrition bias) All outcomes Low risk "There were 371 screened patients, with the final sample consisting of 25 infants, 16 in the PNCA group and nine in the COI group (CONSORT diagram shown in Fig. 1). Four participants from each group were removed from the study early, but all eight had at least one post-randomization outcome and were included in the modified intent-to-treat analyses."

No major concern
Selective reporting (reporting bias) Low risk Protocol registered as NCT01823497 Other bias Unclear risk "The current trial was originally designed to randomize 30 patients into each study arm based on an a priori power analysis. As stated previously, constraints in funding, and difficulty recruiting, required early termination of the trial. Although most parents were open to the idea when initially approached, they declined enrollment owing to the randomized nature of the study. In fact, 39% (28 of 71 approached) declined enrollment, with many stating they wanted their surgeon to make decisions regarding their infant's pain management.
Another reason for the small sample size was the number of enrolled patients who, despite their infants originally seeming likely to require a PNCA/COI for post-surgical pain, ultimately had an epidural placed during surgery. Of the 36 who were consented and randomized, 28% (n = 10) received an epidural." Early termination of the study

Study design: Randomized clinical trial
Study grouping: Continuous infusion to a targeted morphine concentration of 20 ng/mL or as intermittent bolus doses, as needed Participants

Risk of bias legend
(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias