Should Midazolam Drug–Drug Interactions be of Concern to Palliative Care Physicians?

Abstract

I read the article Drug Interactions in Dying Patients: ARetrospective Analysis of Hospice Inpatients in Germany,written by Frechen et al. [1] with great interest. In thepalliative care setting, drug–drug interactions (DDIs) mustbe of special concern, especially in end-of-life care whenthe patient’s condition and organ functions deteriorate, thenumber of drugs taken often exceeds ten, and monitoring ofthe treatment becomes difficult. In the article, the authorsreviewed the main drug combinations that may give rise toDDIs in patients undergoing palliative care. However, Iwould like to also draw special attention to the risk of DDIswith benzodiazepines, and particularly midazolam, whichis classified by the Federal Union of German Associationsof Pharmacists (ABDA) database as a substance with a lowpotential for DDIs.It is well recognized that benzodiazepines carry a risk ofserious pharmacodynamic interactions with many drugsthat exert CNS depressant effects. Some of them are sub-strates of cytochrome P450 (CYP)3A and other CYPenzymes that raise additional risks of pharmacokineticinteractions through that system. These include diazepam,alprazolam, clonazepam, flunitrazepam, clorazepate andmidazolam. The latter is a short-acting benzodiazepine anda CYP3A4 probe substrate. It is available for oral andparenteral administration mostly subcutaneously andintravenously and used more commonly in the palliativecare setting in patients with difficulty swallowing and whendeath approaches, in the treatment of pain, dyspnea, anxi-ety, agitation and, more importantly, for brief and contin-uous palliative sedation in the management of refractorysymptoms and intolerable suffering. The review of theliterature shows that CYP3A inhibitors and inducers suchas antifungal azoles (ketokonazole, itraconazole, fluco-nazole, voriconazole), erythromycin, ritonavir, rifampicinand carbamazepine, among others, significantly change thedisposition of midazolam [2–8]. In one of the earlierstudies of intravenous midazolam, the area under theplasma concentration-time curve (AUC) increased as muchas fivefold after ketokonazole (strong CYP3A4 inhibitor)pretreatment, and intrinsic clearance decreased by 84 %[3]. Surely, the inhibition of midazolam metabolism wasgreater with oral administration (increase of total bio-availability from 25 to 80 % and 16-fold increase in AUCof midazolam) [3]. Such extensive alterations in midazo-lam pharmacokinetics should be expected to be of clinicalrelevance, which is supported by studies. The magnitude ofthe alterations in midazolam pharmacokinetics was welldemonstrated in a study by Backman et al. [9], in whichvolunteers subsequently received itraconazole for 4 daysand, after 2 weeks, rifampin (for a further 5 days).Midazolam was ingested before the first treatment, duringand 4 days after itraconazole as well as 1 and 4 days afterrifampin. During itraconazole treatment, the AUC