Pharmacokinetics and tolerability of intranasal or intravenous administration of nalbuphine in infants

Abstract

Objectives: Intranasal nalbuphine could be a safe, efficacious and non-invasive alternative to parenteral pain medication in infants. We aimed to assess pharmacokinetics (PK) and tolerability of intranasal and intravenous nalbuphine administration in infants.

Methods: Prospective open-label study including infants 1-3 months of age admitted to the emergency department, receiving nalbuphine for procedural pain management. Patients were alternately allocated to a single nalbuphine dose of 0.05 mg/kg intravenously or 0.1 mg/kg intranasally. Nalbuphine PK samples were collected 15, 30 and 120-180 min after dosing. Area under the concentration time curve (AUC0-Tlast) was calculated by non-compartmental analysis (NCA) and compared by Wilcoxon test. Neonatal Infant Pain Score was assessed during nalbuphine administration and the following interventions: venous access, urinary catheterisation, lumbar puncture.

Results: Out of 52 study subjects receiving nalbuphine, 31 were eligible for NCA (11 intravenous, 20 intranasal). Median AUC0-Tlast after 0.05 mg/kg intravenously was 8.7 (IQR: 8.0-18.6) µg×L/hour vs 7.6 (5.4-10.4) µg×L/hour after intranasal administration of 0.1 mg/kg (p=0.091). Maximum serum concentration (Cmax) was observed 30 min after intranasal administration (3.5-5.6 µg/L). During intravenous and intranasal nalbuphine administration, mild to no pain was recorded in 71% and 67% of study subjects, respectively.

Conclusion: This is the first study investigating intranasal administration of nalbuphine in infants suggesting an intranasal bioavailability close to 50%. Non-invasive intranasal application was well tolerated. Additional studies are warranted to optimise dosing and timing of interventions as Cmax is delayed by half an hour after intranasal administration.

Trial registration number: NCT03059511.

Keywords: paediatric emergency medicine; pain.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Flow chart: Implausible serum concentrations were defined as implausible high serum concentrations (>60 µg/L, inclusive expected accidental overdoses) or rising concentrations after intravenous administration.

Figure 2

Illustration of (A) measured pharmacokinetic profiles with outliers (open circles) from n=40 patients with all three concentration measurements and (B) summary pharmacokinetic profile showing median and IQR from n=31 patients included in non-compartmental pharmacokinetic analysis.

Figure 3

Proportion of patients with NIPS classified as no/mild pain (NIPS 4), evaluated as indicator of pain control during interventions (establishment of venous (intravenous) access shortly before (intravenous group) and shortly after nalbuphine administration (intranasal group), respectively, urinary catheterisation and lumbar puncture) and as indicator or tolerance of nalbuphine administration. Baseline: NIPS assessment in the time between informed consent and first intervention (intranasal nalbuphine administration or venous access) plotted at time=-1h.