The Pharmacodynamics of Sumatriptan in Nitroglycerin‐Induced Headache

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Abstract
Migraine is a common disorder that causes significant morbidity in those afflicted. Many novel antimigraine compounds are in clinical development, yet full characterization of each one's pharmacodynamic behavior is a formidable task due to the difficulty in studying a migraineur during an attack. Nitroglycerin (NTG) administration commonly causes a headache with some features similar to those of a migraine. As such, NTG has been used as a model of vascular headaches, including migraine. The pharmacodynamic effects of nitroglycerin and sumatriptan on middle cerebral artery blood flow velocity (MCAv) and headache scores were studied in 10 healthy male volunteers. An intravenous infusion of NTG titrated to 0.5 mcg/kg/min over 30 minutes resulted in a median reduction from baseline in MCAv of 27% (range: 16.4%-37.3%). Nine of the subjects developed a headache with a median verbal score of 3.5 of 10 (range: 0-5). Subjects received sumatriptan either 2 mg intravenously or 6 mg subcutaneously, which abated clinical headache in 9 of the 10 subjects (p = 0.030). A median sumatriptan-induced increase in MCAv of 21% (p = 0.054) suggested a constricting effect on the NTG-induced dilated MCA. A two-compartment pharmacokinetic/indirect-effects pharmacodynamic model was fit to the sumatriptan concentration and MCAv data using iterative two-stage analysis. This model was unbiased and fit the concentration (r2 = 0.98) and the MCAv (r2 = 0.79) data well. These results suggest that NTG-induced headache and the development of pharmacokinetic/pharmacodynamic models could serve as a useful method for exploring the mechanisms of abortive migraine drugs.