The pharmacodynamics of sumatriptan in nitroglycerin-induced headache

Migraine is a common disorder that causes significant morbidity in those af flicted. Many novel antimigraine compounds are in clinical development, yet full characterization of each one's pharmacodynamic behavior is a formidab le task due to the difficulty in studying a migraineur during an attack; Ni troglycerin (NTG) administration commonly causes a headache with some featu res similar to those of a migraine. As such, NTG has been used as a model o f vascular headaches, including migraine. The pharmacodynamic effects of ni troglycerin and sumatriptan on middle cerebral artery blood flow velocity ( MCAv) and headache scores were studied in 10 healthy male volunteers. An in travenous infusion of NTG titrated to 0.5 mcg/kg/min over 30 minutes result ed 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 intravenous ly or 6 mg subcutaneously, which abated clinical headache in 9 of the 10 su bjects (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 wa s fit to the sumatriptan concentration and MCAv data using iterative two-st age analysis. This model was unbiased and fit the concentration (r(2) = 0.9 8) and the MCAv (r(2) = 0.79) data well. These results suggest that NTG-ind uced headache and the development of pharmacokinetic/pharmacodynamic models could serve as a useful method for exploring the mechanisms of abortive mi graine drugs. Journal of Clinical Pharmacology, 1999;39:17-29 (C) 1999 the American College of Clinical Pharmacology.