Pediatrics · Medical Literature
A novel topical nitroglycerin-lidocaine combination for procedural pain management and rapid cannulation in neonates: results from a randomized controlled clinical trial.
Abstract
Venipuncture is a common and painful procedure in neonates. Sweet solutions (sucrose and glucose) are recommended and widely used as standard care for reducing neonatal procedural pain. Topical local anesthetics may also reduce procedural pain but generally require longer application times to achieve adequate analgesia. This study investigated the efficacy and safety of a novel topical lidocaine-nitroglycerin preparation as an adjunct to standard oral sweet solutions in neonates undergoing peripheral venous catheterization. In this double-blind randomized clinical trial, 84 neonates (≥ 34 weeks gestation) undergoing peripheral venous catheterization were randomized to receive either topical lidocaine/nitroglycerin 2% or placebo ointment, applied 15 min before the procedure. All neonates in both groups received 0.5 mL of 24% oral sucrose two minutes before venipuncture as standard care. Pain was assessed using the Premature Infant Pain Profile (PIPP) and Neonatal Facial Coding System (NFCS) scales using standardized procedures and video verification. The duration of crying, time to cry onset, number of venipuncture attempts, and adverse events were recorded. Neonates treated with lidocaine-nitroglycerin topical formulation plus standard oral sucrose had significantly lower PIPP scores [7.0 vs. 8.5, P = 0.038] and NFCS scores [5.0 vs. 7.0, P < 0.001] compared with placebo ointment plus standard oral sucrose. Crying duration was significantly shorter [10 s vs. 25 s, P = 0.045], and fewer neonates required repeated venipuncture (6 vs. 14, P = 0.041). No adverse reactions or clinical signs of methemoglobinemia were observed. Topical lidocaine/nitroglycerin 2% provided rapid analgesia and reduced repeated venipuncture attempts in neonates, offering a practical strategy for pain management in the neonatal intensive care unit (NICU). Further large multicenter trials are warranted to confirm efficacy and long-term safety. The trial was registered as IRCT20190810044500N19 (22/08/2021) https://irct.behdasht.gov.ir/trial/47524 .
Clinical relevance
Venipuncture is among the most frequently performed painful procedures in neonates, a population uniquely vulnerable to the short- and long-term neurodevelopmental consequences of repeated procedural pain. Current standard care with oral sucrose provides incomplete analgesia, and existing topical anesthetics (e.g., EMLA) require 45–60 minutes of application time, limiting their utility in urgent NICU settings. This RCT addresses the critical gap of achieving rapid, effective topical analgesia within a clinically feasible 15-minute window as an adjunct to sucrose, directly relevant to daily NICU practice.
Key findings
1. Neonates receiving lidocaine/nitroglycerin 2% topical ointment plus oral sucrose demonstrated significantly lower Premature Infant Pain Profile (PIPP) scores compared to placebo plus sucrose (median 7.0 vs. 8.5; P = 0.038), indicating a clinically meaningful reduction in procedural pain. 2. Neonatal Facial Coding System (NFCS) scores were also significantly lower in the treatment group (median 5.0 vs. 7.0; P < 0.001), corroborating pain reduction across two independent validated neonatal pain assessment tools. 3. Crying duration was significantly shorter in the lidocaine/nitroglycerin group (10 s vs. 25 s; P = 0.045), representing a 60% reduction in cry duration, a surrogate marker of procedural distress. 4. Fewer neonates in the treatment group required repeated venipuncture attempts (6/42 vs. 14/42; P = 0.041), suggesting that vasodilatory nitroglycerin augments peripheral venous cannulation success rates in addition to providing analgesia. 5. The formulation was applied for only 15 minutes prior to the procedure, demonstrating a substantially faster onset than standard topical anesthetics currently available. 6. No adverse events or clinical signs of methemoglobinemia were observed in either group, supporting the short-term safety profile of the combination in neonates ≥34 weeks gestation; however, the sample size (n = 84) limits definitive safety conclusions.
Practice implications
In neonates ≥34 weeks gestational age undergoing peripheral venous catheterization in the NICU, clinicians may consider the adjunctive use of topical lidocaine/nitroglycerin 2% ointment applied 15 minutes prior to the procedure alongside standard oral sucrose (0.5 mL of 24% solution administered 2 minutes before venipuncture), as this combination significantly reduces procedural pain scores, cry duration, and the need for repeated cannulation attempts. Patient selection should currently be restricted to neonates ≥34 weeks gestation until larger multicenter trials establish safety and efficacy across lower gestational ages and confirm the absence of methemoglobinemia risk with repeated dosing. Neonatal units adopting this strategy should implement standardized pain assessment using validated tools (PIPP or NFCS) and maintain vigilance for early signs of methemoglobinemia, particularly in infants with baseline anemia or concurrent exposure to other oxidizing agents.