Pain management for placement of peripherally inserted central catheters in neonates: A systematic review and meta-analysis.

Background: Placement of a peripherally inserted central catheter (PICC) is a clinically essential but painful procedure commonly performed in neonates. Early exposure to pain is associated with negative sequelae and therefore pain should be managed. Various non-pharmacological and/or pharmacological interventions have been used in clinical practice. However, the optimal pain management strategy is unclear. The primary objective of this systematic review and meta-analysis is to evaluate the benefits and harms of pain management interventions in neonates undergoing PICC placement. Methods: Databases were searched for randomized controlled trials (RCTs) from inception to March 2024. The literature search was updated in June 2025 and no additional eligible articles were identified for inclusion. Title and abstract screening, full-text screening and data extraction were performed in duplicate. Risk of bias was assessed using Cochrane's risk of bias (RoB) 2.0 tool. The critically important outcome was pain measured using validated tools including unidimensional behaviour and multidimensional (comprising combinations of contextual, behavioural and/or physiological components) tools. Secondary outcomes included procedure success and adverse events. Pooled effect estimates were standardized mean difference (SMD) and relative risk (RR) with 95% confidence intervals (CI) using random effects models. A GRADE assessment of the overall certainty of the evidence for each outcome was completed. Results: Six included studies reported pain scores for between-group comparisons of pain management interventions among 324 neonates. The interventions included intravenous opioids (morphine, remifentanil), topical anesthetics (tetracaine) and intravenous acetaminophen. Morphine was effective in reducing acute pain compared to control (SMD -0.65 [95% CI -1.17, -0.13]) using a unidimensional tool (brow bulge) in one study. Using two different multidimensional tools, remifentanil was effective in reducing acute pain compared to control (SMD -1.59 [95% CI -2.21, -0.97] using the premature infant pain profile [PIPP] and SMD -1.21 [95% CI -1.79, -0.62] using the neonatal infant pain scale). In a meta-analysis of two RCTs comparing tetracaine to placebo, there was no difference in acute pain (SMD -0.05 [95% CI -1.70, 1.59], I Discussion: Based on available evidence, opioids probably reduce pain associated with PICC placement in neonates. Topical anesthetics and acetaminophen were not demonstrated to be effective. Further research is necessary to guide healthcare professionals in implementing optimal pain management for this procedure.