Stability of midazolam and fentanyl in infusion solutions

The administration of drugs by subcutaneous infusion is routinely practiced in palliative medicine for the management of patients who are no longer able to take oral medication. It is not uncommon for two or more drugs to be combined in subcutaneous infusion solutions. The combination of an opioid and a short-acting benzodiazepine is frequently required. Unfortunately, the stability of benzodiazepines and newer opioids, such as fentanyl, has not been determined. This study examined the stability of solutions containing either fentanyl alone or fentanyl and midazolam in combination. Eight different solutions were assessed for up to 7 days following preparation. The solutions were prepared in polypropylene syringes using 0.9% saline as a diluent. Duplicate syringes were stored at approximately 5 degrees C, 22 degrees C, and 38 degrees C. High performance liquid chromatography was the analytical technique used to measure fentanyl and midazolam. Initial concentrations ranges were 13.2-38.9 micrograms/mL for fentanyl and 282-959 micrograms/mL for midazolam. It was found that fentanyl (+/- midazolam) was very stable (> 95%) when stored at temperatures ranging from 5 degrees C to 38 degrees C for at least 1 week. Midazolam (+ fentanyl) was not as stable as fentanyl under the same storage conditions and underwent time-dependent decomposition of up to 12.1% (observed at 7 days when stored at 38 degrees C). When stored at 22 degrees C and 38 degrees C, more than 90% of initial midazolam concentrations were retained for 4 days following preparation and for 7 days when stored at 5 degrees C. The clinical implications of these results are that, on the basis of physicochemical stability, subcutaneous infusion solutions containing fentanyl and midazolam may be prepared at intervals of 4 days (or 7 days if stored under refrigerated conditions).