Novel staggered loading of phenobarbitone for refractory seizures and agitation at the end of life

Seizures and agitation are distressing symptoms commonly encountered at the end of life and may require treatment with phenobarbitone when standard therapies fail. Current phenobarbitone dosing guidelines, however, lack a robust evidence base. This case series prospectively reviewed 10 patients receiving a novel staggered loading regimen of intramuscular phenobarbitone for refractory seizures (n=5) and agitation (n=5) at the end of life. All patients achieved symptom control. Patients with seizures required substantially lower cumulative phenobarbitone doses (200-600 mg) than suggested by current recommendations. Patients with agitation, in all but one case, also required significantly lower cumulative doses than those suggested by guidance. Mathematical modelling demonstrated that large maintenance doses of phenobarbitone in the range of 800-1600 mg/24 hours, as recommended by current guidance for agitation, may not be proportional and could result in potentially toxic phenobarbitone serum levels. A staggered loading regimen of phenobarbitone appears effective, safe and proportional for managing refractory seizures and agitation at the end of life, requiring lower cumulative doses than current guidelines suggest. Standard maintenance dosing protocols for agitation warrant urgent re-evaluation due to the theoretical risk of drug accumulation. Further prospective studies are needed.