Abstract
In recent years, intranasal diamorphine (DIM) has been recommended as an alternative to intravenous administration for the treatment of acute-to-severe pain in children. This provides a rapid and less painful route of administration without decreasing the effectiveness of the analgesic properties. A sensitive technique for the detection and quantitation of DIM and its metabolites is essential because of the low concentrations of DIM and metabolites in children's plasma, which are a result of the low dose of DIM given and the limited sample volume obtained from children (0.25 mL or less). DIM can be easily hydrolyzed to 6-monoacetylmorphine (6-MAM) during sample preparation and extraction, so this must be considered when developing a solid-phase extraction (SPE) method to prevent the hydrolysis of DIM. This work was aimed at validating and developing a liquid chromatography-tandem mass spectrometry (LC-MS-MS) method with electrospray ionization for the identification and quantification of DIM and its metabolites, namely 6-MAM, MOR, M3G, M6G, and NMOR in plasma samples obtained from children who are under treatment for acute-to-severe pain. Following the addition of deuterated internal standards, analytes were extracted by SPE with Bond Elut C 18 ® cartridges followed by LC-MS-MS analysis. Intraday and interday precision for all analytes were determined at five concentration (1, 5, 25, 50, and 200 ng/mL), and these were found to be 2.5-13.4% and 1.8-15%, respectively. Recoveries of analytes of interest were between 81 and 109%. Calibration curves were linear for all analytes over the concentration range 0.1-50 ng/mL, and correlation coefficients were better than 0.999. Limits of detection and quantitation were 0.08-0.37 ng/mL and 0.28-1.22 ng/mL, respectively. DIM and metabolites were detected in all case samples with the exception of NMOR, which tested negative in all cases. The pharmacokinetics of DIM and its metabolites following INDIM and IVDIM administration in children have been compared for the first time in this study, which confirmed that INDIM can achieve therapeutic plasma concentrations of DIM and its active metabolites, although these are lower than those obtained with IVDIM and occur at later times after administration.