Prostacyclin (epoprostenol) induces headache in healthy subjects

The role of prostanoids in nociception is well established. The headache eliciting effects of prostacyclin (prostaglandin I₂, (PGI₂)) and its possible mechanisms had previously not been systematically studied in man. We hypothesized that infusion of PGI₂ might induce headache and vasodilatation of cranial vessels. A stable analog of PGI₂ epoprostenol (10 ng/kg/min) was infused for 25 min into 12 healthy subjects in a cross-over, double-blind study. Headache intensity was scored on a verbal rating scale from 0 to 10. In addition, we recorded mean flow in the middle cerebral artery (V_{mean MCA}) by the transcranial doppler and diameter of the superficial temporal artery (STA) by a high-resolution ultrasonography unit. During the immediate phase (0-30 min) and the post-infusion phase (30-90 min), 11 subjects reported headache on the PGI₂ day and no subjects reported headache on the placebo day (p = 0.002). During epoprostenol (0-30 min) and in the post-infusion phase (30-90 min), the area under the curve (AUC) for headache score was significantly larger than during and after placebo (p = 0.005). PGI₂ caused headache associated with the dilatation of STA (AUC, p < 0.001), but no significant dilatation of the MCA (AUC, p = 0.508). These data indicate that PGI₂ induced headache might be due to activation and sensitization of sensory afferents around extracranial arteries.