Long-Term Stability of an Infusion Containing Morphine, Ketamine and Lorazepam in Syringe at 5±3 ° C

Background and Objective: Patients in palliative care are injected with a sedation infusion containing morphine, ketamine and lorazepam in order to relieve pain. This infusion is prepared by the nursing staff according to demand, but the awareness of its long-term stability could allow a preparation in batch and in advance by a Centralized Intravenous Additive Services (CIVAS). The aim of this study was to evaluate the physicochemical stability in syringes at 5±3°C of the injectable with two different levels of concentration commonly used. Method: Five syringes were prepared under aseptic conditions for each level of concentration (low concentration: morphine 1.5 mg/ml, ketamine 1.5 mg/ml and lorazepam 0.1 mg/ml; high concentration: morphine 6 mg/ml, ketamine 5 mg/ml and lorazepam 0.3 mg/ml). Solutions were stored at 5±3°C for 25 days and the stability was periodically investigated (each day the first week, then 3 times a week). Particle appearance or colour change were checked by visual inspection while crystals were searched under the microscope. pH was measured to assess its stability and absorbance at 350, 410 and 550 nm were monitored to estimate the solution turbidity. The molecules concentrations were measured by Ultra-High Performance Liquid Chromatography (UHPLC)-diode array detection. Results: Crystals were visible to the naked eye after 23 days in syringes of low concentration and after 11 days in syringes of high concentration. Some crystals were already observed under the microscope after 7 days in high concentration solutions. pH and absorbance at 410 and 550 nm were stable. Absorbance at 350 nm showed a decrease after 11 and 7 days in low and high concentration infusion respectively, suggesting the degradation of a compound absorbing at this wavelength. Solutions were considered chemically stable while the lower one-sided prediction limit at 95% remains superior to 90% of the initial concentration. Morphine and ketamine were stable for 25 days while lorazepam was unstable from day 0. Conclusion: Infusions containing morphine, ketamine and lorazepam used in palliative care are unstable at 5±3°C immediately after preparation. Consequently, the mixture of these three components should be prevented, even extemporaneously.