Opioids for procedural pain in neonates

Abstract

Background: Neonates might be exposed to numerous painful procedures due to diagnostic reasons, therapeutic interventions, or surgical procedures. Options for pain management include opioids, non-pharmacological interventions, and other drugs. Morphine, fentanyl, and remifentanil are the opioids most often used in neonates. However, negative impact of opioids on the structure and function of the developing brain has been reported. Objectives: To evaluate the benefits and harms of opioids in term or preterm neonates exposed to procedural pain, compared to placebo or no drug, non-pharmacological intervention, other analgesics or sedatives, other opioids, or the same opioid administered by a different route. Search methods: We used standard, extensive Cochrane search methods. The latest search date was December 2021. Selection criteria: We included randomized controlled trials conducted in preterm and term infants of a postmenstrual age (PMA) up to 46 weeks and 0 days exposed to procedural pain where opioids were compared to 1) placebo or no drug; 2) non-pharmacological intervention; 3) other analgesics or sedatives; 4) other opioids; or 5) the same opioid administered by a different route. Data collection and analysis: We used standard Cochrane methods. Our primary outcomes were pain assessed with validated methods and any harms. We used a fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, and their confidence intervals (CI). We used GRADE to assess the certainty of the evidence for each outcome. Main results: We included 13 independent studies (enrolling 823 newborn infants): seven studies compared opioids to no treatment or placebo (the main comparison in this review), two studies to oral sweet solution or non-pharmacological intervention, and five studies (of which two were part of the same study) to other analgesics and sedatives. All studies were performed in a hospital setting. Opioids compared to placebo or no drug. Compared to placebo, opioids probably reduce pain score assessed with the Premature Infant Pain Profile (PIPP)/PIPP-Revised (PIPP-R) scale during the procedure (MD −2.58, 95% CI −3.12 to −2.03; 199 participants, 3 studies; moderate-certainty evidence); may reduce Neonatal Infant Pain Scale (NIPS) during the procedure (MD −1.97, 95% CI −2.46 to −1.48; 102 participants, 2 studies; low-certainty evidence); and may result in little to no difference in pain score assessed with the Douleur Aiguë du Nouveau-né (DAN) scale one to two hours after the procedure (MD −0.20, 95% CI −2.21 to 1.81; 42 participants, 1 study; low-certainty evidence). The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R scale up to 30 minutes after the procedure (MD 0.14, 95% CI −0.17 to 0.45; 123 participants, 2 studies; very low-certainty evidence) or one to two hours after the procedure (MD −0.83, 95% CI −2.42 to 0.75; 54 participants, 2 studies; very low-certainty evidence). No studies reported any harms. The evidence is very uncertain about the effect of opioids on episodes of bradycardia (RR 3.19, 95% CI 0.14 to 72.69; 172 participants, 3 studies; very low-certainty evidence). Opioids may result in an increase in episodes of apnea compared to placebo (RR 3.15, 95% CI 1.08 to 9.16; 199 participants, 3 studies; low-certainty evidence). The evidence is very uncertain about the effect of opioids on episodes of hypotension (RR not estimable, risk difference 0.00, 95% CI −0.06 to 0.06; 88 participants, 2 studies; very low-certainty evidence). No studies reported parent satisfaction with care provided in the neonatal intensive care unit (NICU). Opioids compared to non-pharmacological intervention. The evidence is very uncertain about the effect of opioids on pain score assessed with the Crying Requires oxygen Increased vital signs Expression Sleep (CRIES) scale during the procedure when compared to facilitated tucking (MD −4.62, 95% CI −6.38 to −2.86; 100 participants, 1 study; very low-certainty evidence) or sensorial stimulation (MD 0.32, 95% CI −1.13 to 1.77; 100 participants, 1 study; very low-certainty evidence). The other main outcomes were not reported. Opioids compared to other analgesics or sedatives. The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R during the procedure (MD −0.29, 95% CI −1.58 to 1.01; 124 participants, 2 studies; very low-certainty evidence); up to 30 minutes after the procedure (MD −1.10, 95% CI −2.82 to 0.62; 12 participants, 1 study; very low-certainty evidence); and one to two hours after the procedure (MD −0.17, 95% CI −2.22 to 1.88; 12 participants, 1 study; very low-certainty evidence). No studies reported any harms. The evidence is very uncertain about the effect of opioids on episodes of apnea during (RR 3.27, 95% CI 0.85 to 12.58; 124 participants, 2 studies; very low-certainty evidence) and after the procedure (RR 2.71, 95% CI 0.11 to 64.96; 124 participants, 2 studies; very low-certainty evidence) and on hypotension (RR 1.34, 95% CI 0.32 to 5.59; 204 participants, 3 studies; very low-certainty evidence). The other main outcomes were not reported. We identified no studies comparing different opioids (e.g. morphine versus fentanyl) or different routes for administration of the same opioid (e.g. morphine enterally versus morphine intravenously). Authors' conclusions: Compared to placebo, opioids probably reduce pain score assessed with PIPP/PIPP-R scale during the procedure; may reduce NIPS during the procedure; and may result in little to no difference in DAN one to two hours after the procedure. The evidence is very uncertain about the effect of opioids on pain assessed with other pain scores or at different time points. No studies reported if any harms occurred. The evidence is very uncertain about the effect of opioids on episodes of bradycardia or hypotension. Opioids may result in an increase in episodes of apnea. No studies reported parent satisfaction with care provided in the NICU. The evidence is very uncertain about the effect of opioids on any outcome when compared to non-pharmacological interventions or to other analgesics. We identified no studies comparing opioids to other opioids or comparing different routes of administration of the same opioid.

• author: Kinoshita, Mari ; Olsson, Emma ; Borys, Franciszek and Bruschettini, Matteo
• organization: Paediatrics (Lund); Neonatology (research group)
• publishing date: 2023-04-05
• type: Contribution to journal
• publication status: published
• subject: Pediatrics
• in: Cochrane Database of Systematic Reviews
• volume: 2023
• issue: 4
• article number: CD015056
• publisher: Wiley-Blackwell
• external identifiers: pmid:37019853; scopus:85151702708
• ISSN: 1465-1858
• DOI: 10.1002/14651858.CD015056.pub2
• language: English
• LU publication?: yes
• additional info: Funding Information: No funding was reported for the studies by Cordero 1991, Gitto 2012, Lago 2008, Madathil 2021a, Madathil 2021b, Manjunatha 2009, and Sindhur 2020. Carbajal 2005 received funds from the Foundation CNP and National Institute for Child Health and Human Development grants HD36484 and HD36270. Hartley 2018 received funds from the Wellcome Trust and National Institute for Health Research. Fallah 2016 received a grant from Deputy for Research of Shahid Sadoughi University of Medical Sciences, Yazd, Iran. Pokela 1994 received funding from Foundation for Paediatric Research in Finland, Helsinki and the Alma and K.A. Snellman Foundation, Oulu, Finland. In the study by Sethi 2020, Prof Velpandian, Department of Ocular Pharmacy, AIIMS, New Delhi and Mr Ujjwal provided the 24% oral glucose. Taddio 2006 received funding from the Canadian Society of Hospital Pharmacists, the Canadian Institutes of Health Research New Investigator Award, and the Ontario Student Opportunity Trust Fund - Hospital for Sick Children Foundation Student Scholarship Program. Funding Information: Duration of hypoxemia, arterial blood pressure, heart rate, or plasma beta-endorphin, cortisol, and glucose concentration during treatment procedures, Behavioral Pain Score assessed during 2-hour study period This work was supported by the Foundation for Paediatric Research in Finland, Helsinki and the Alma och K. A. Sneilman Foundation, Oulu, Finland. Funding Information: Facial grimacing (brow bulge) scored in 2-second intervals for the first 20 seconds of each phase of the procedure, safety assessment (blood pressure and ventilatory support (at 15, 30, and 60 minutes after the beginning of the infusion), local skin reactions) Funding for this study was provided by the Canadian Society of Hospital Pharmacists. Dr Taddio is supported by the Canadian Institutes of Health Research New Investigator Award. Ms Lee was supported through a studentship by the Ontario Student Opportunity Trust Fund–Hospital for Sick Children Foundation Student Scholarship Program. Funding Information: The Methods section of this review is based on a standard template used by Cochrane Neonatal. Maria Björklund (Library and ICT services, Lund University) designed and ran the literature searches. We would like to thank study authors Dr Shamnad Madathil, Madathil 2021a; Madathil 2021b, and Dr Haribalakrishna Balasubramanian, Sindhur 2020, for providing additional information on the included studies. 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: Rahul Gujarathi, Nikolaos Sideris, Rubyath Binte Hasan, Dave Lock, Theodoros Aslanidis, Galia Maderi, Ciara Gleeson, Maria Sol Fritz, Bernardo Costa, Luis Coloma, Katja Matthias, Stefanie Rosumeck, Sunu Alice Cherian, Denise Schulz, Jens Thorsen, Paul Whittaker, Susanna Wisniewski, Vighnesh Devulapalli, Akhilanand Chaurasia, Gianluca Gazzaniga, Jehath Syed, Nicole Askin, Ahmad Ozair, Matias Mena, Igor Svintsitskyi, Shammas Mohammed, Mary MacCara, Riccardo Guarise, Cathy Wellan, Angela Gunn, Max Sarmet, Prabina Bhattarai, Lai Ogunsola, Julia Robertson, Phoebe Spink, Iván Javier Ramos Cortés, Amin Sharifan, Ilkin Mengusoglu, Ana-Marija Ljubenković. We would like to thank Cochrane Neonatal: Michelle Fiander and Jane Cracknell (Managing Editors), Roger Soll (Co-coordinating Editor), and Bill McGuire (Co-coordinating Editor), who provided editorial and administrative support. A Cochrane Neonatal Associate Editor, Nai Ming Lai, and Senior Editor, Gautham Suresh, peer reviewed and offered feedback for the protocol (Kinoshita 2021). We would like to thank Tim Disher, PhD, Senior Director of Biostatistics - EVERSANA, Nova Scotia, Canada for peer reviewing the review. Funding Information: The researchers received no financial support from the drug company. The authors declare that there are no conflicts of interest. Funding Information: Grant funds from the Fondation CNP (Paris, France) and National Institute for Child Health and Human Development grants HD36484 and HD36270 Funding Information: This study was funded by a grant from the Deputy for Research of Shahid Sadoughi University of Medical Sciences,Yazd, Iran. Publisher Copyright: Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
• id: 8c03b9aa-79b0-43c4-b6cd-ecad7bfcabfe
• date added to LUP: 2024-01-12 14:30:48
• date last changed: 2024-04-27 09:51:53