Non-opioid analgesics for procedural pain in neonates

Abstract

Background: Neonates are an extremely vulnerable patient population, with 6% to 9% admitted to the neonatal intensive care unit (NICU) following birth. Neonates admitted to the NICU will undergo multiple painful procedures per day throughout their stay. There is increasing evidence that frequent and repetitive exposure to painful stimuli is associated with poorer outcomes later in life. To date, a wide variety of pain control mechanisms have been developed and implemented to address procedural pain in neonates. This review focused on non-opioid analgesics, specifically non-steroidal anti-inflammatory drugs (NSAIDs) and N-methyl-D-aspartate (NMDA) receptor antagonists, which alleviate pain through inhibiting cellular pathways to achieve analgesia. The analgesics considered in this review show potential for pain relief in clinical practice; however, an evidence summation compiling the individual drugs they comprise and outlining the benefits and harms of their administration is lacking. We therefore sought to summarize the evidence on the level of pain experienced by neonates both during and following procedures; relevant drug-related adverse events, namely episodes of apnea, desaturation, bradycardia, and hypotension; and the effects of combinations of drugs. As the field of neonatal procedural pain management is constantly evolving, this review aimed to ascertain the scope of non-opioid analgesics for neonatal procedural pain to provide an overview of the options available to better inform evidence-based clinical practice. Objectives: To determine the effects of non-opioid analgesics in neonates (term or preterm) exposed to procedural pain compared to placebo or no drug, non-pharmacological intervention, other analgesics, or different routes of administration. Search methods: We searched the Cochrane Library (CENTRAL), PubMed, Embase, and two trial registries in June 2022. We screened the reference lists of included studies for studies not identified by the database searches. Selection criteria: We included all randomized controlled trials (RCTs), quasi-RCTs, and cluster-RCTs in neonates (term or preterm) undergoing painful procedures comparing NSAIDs and NMDA receptor antagonists to placebo or no drug, non-pharmacological intervention, other analgesics, or different routes of administration. Data collection and analysis: We used standard Cochrane methods. Our main outcomes were pain assessed during the procedure and up to 10 minutes after the procedure with a validated scale; episodes of bradycardia; episodes of apnea; and hypotension requiring medical therapy. Main results: We included two RCTs involving a total of 269 neonates conducted in Nigeria and India. NMDA receptor antagonists versus no treatment, placebo, oral sweet solution, or non-pharmacological intervention. One RCT evaluated using oral ketamine (10 mg/kg body weight) versus sugar syrup (66.7% w/w at 1 mL/kg body weight) for neonatal circumcision. The evidence is very uncertain about the effect of ketamine on pain score during the procedure, assessed with the Neonatal Infant Pain Scale (NIPS), compared with placebo (mean difference (MD) −0.95, 95% confidence interval (CI) −1.32 to −0.58; 1 RCT; 145 participants; very low-certainty evidence). No other outcomes of interest were reported on. Head-to-head comparison of different analgesics. One RCT evaluated using intravenous fentanyl versus intravenous ketamine during laser photocoagulation for retinopathy of prematurity. Neonates receiving ketamine followed an initial regimen (0.5 mg/kg bolus 1 minute before procedure) or a revised regimen (additional intermittent bolus doses of 0.5 mg/kg every 10 minutes up to a maximum of 2 mg/kg), while those receiving fentanyl followed either an initial regimen (2 μg/kg over 5 minutes, 15 minutes before the procedure, followed by 1 μg/kg/hour as a continuous infusion) or a revised regimen (titration of 0.5 μg/kg/hour every 15 minutes to a maximum of 3 μg/kg/hour). The evidence is very uncertain about the effect of ketamine compared with fentanyl on pain score assessed with the Premature Infant Pain Profile-Revised (PIPP-R) scores during the procedure (MD 0.98, 95% CI 0.75 to 1.20; 1 RCT; 124 participants; very low-certainty evidence); on episodes of apnea occurring during the procedure (risk ratio (RR) 0.31, 95% CI 0.08 to 1.18; risk difference (RD) −0.09, 95% CI −0.19 to 0.00; 1 study; 124 infants; very low-certainty evidence); and on hypotension requiring medical therapy occurring during the procedure (RR 5.53, 95% CI 0.27 to 112.30; RD 0.03, 95% CI −0.03 to 0.10; 1 study; 124 infants; very low-certainty evidence). The included study did not report pain score assessed up to 10 minutes after the procedure or episodes of bradycardia occurring during the procedure. We did not identify any studies comparing NSAIDs versus no treatment, placebo, oral sweet solution, or non-pharmacological intervention or different routes of administration of the same analgesics. We identified three studies awaiting classification. Authors' conclusions: The two small included studies comparing ketamine versus either placebo or fentanyl, with very low-certainty evidence, rendered us unable to draw meaningful conclusions. The evidence is very uncertain about the effect of ketamine on pain score during the procedure compared with placebo or fentanyl. We found no evidence on NSAIDs or studies comparing different routes of administration. Future research should prioritize large studies evaluating non-opioid analgesics in this population. As the studies included in this review suggest potential positive effects of ketamine administration, studies evaluating ketamine are of interest. Furthermore, as we identified no studies on NSAIDs, which are widely used in older infants, or comparing different routes of administration, such studies should be a priority going forward.

• author: Persad, Emma ; Pizarro, Ana Beatriz and Bruschettini, Matteo
• organization: Paediatrics (Lund); Neonatology (research group)
• publishing date: 2023-04-04
• type: Contribution to journal
• publication status: published
• subject: Pediatrics
• in: Cochrane Database of Systematic Reviews
• volume: 2023
• issue: 4
• article number: CD015179
• publisher: Wiley-Blackwell
• external identifiers: pmid:37014033; scopus:85151743303
• ISSN: 1465-1858
• DOI: 10.1002/14651858.CD015179.pub2
• language: English
• LU publication?: yes
• additional info: Funding Information: Cochrane Sweden is supported by Region Skåne, Skåne University Hospital Lund University and Region Västra Götaland. Funding Information: The Methods section of this review is based on a standard template used by Cochrane Neonatal. We thank Cochrane Neonatal: Michelle Fiander and Jane Cracknell, Managing Editors; and Co-ordinating Editors Roger Soll and Bill McGuire, who provided support. We thank Stephen E Welty (Clinical Professor of Pediatrics at the University of Washington, Division of Neonatology and Medical Director Neonatology Service Line for Virginia Mason Franciscan Health, Pacific Northwest) for the peer revision of the review. We thank Lisa Winer for copyediting the review. We thank Mari Kinoshita (Department of Pediatrics, Yokohama Municipal Citizen’s Hospital; Department of Pediatrics, Keio University School of Medicine, Japan) for the translation of a study from Japanese. We thank Christoper A Alarcón Ruiz (Universidad San Ignacio de Loyola, Lima, Peru) for contributing to screening studies for inclusion. Matthias Bank and Maria Björklund (Library and ICT services, Lund University) designed and ran the literature searches. We would like to acknowledge and thank the following people for their help in assessing the search results for this review via Cochrane’s Screen4Me workflow: Nikolaos Sideris, Ahmed Bestawy, Mohammadreza Kosari, Serina Cao, Bernardo Costa, Basem Emad Ali, Asad Mahmood, Elena Akimova, Hadi Keshavarz, Malak Ashraf Mohamed, Anna Noel-Storr, Basavaraj Poojar, Sabeeh Kamil, Bekir Nihat Dogrul, Michelle Paynter, Anal Ravalia, Mohamed K Al-Haggagi, Fernando Tortosa, Vighnesh Devulapalli, Jehath Syed, Vibor Milunović, Mary MacCara, Gerard Anthony Espiritu, Lai Ogunsola, Emmet Farragher, Nur Maziah Hanum Osman, Amin Sharifan, Anna Noel-Storr, Susi Wisniewski, Neha Agarwal. Publisher Copyright: Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
• id: cc6ade65-dbbe-45d3-add1-12ebf42ad7e1
• date added to LUP: 2024-01-12 14:42:38
• date last changed: 2024-04-27 10:05:23