BOSTON—The development of triptans for the acute treatment of migraine has created a new therapeutic era in the field, said Patrick P. A. Humphrey, PhD, DSc, at the 50th Annual Scientific Meeting of the American Headache Society. He recounted the pioneering work in triptans that he has led and assessed the impact that the drugs have had on migraine therapy.
“I think we all agree that they are a major therapeutic breakthrough,” said Dr. Humphrey, who is Director of the Glaxo Institute of Applied Pharmacology, Department of Pharmacology, at the University of Cambridge in the United Kingdom.
Sumatriptan, the first triptan, emerged from research conducted by Dr. Humphrey and colleagues and was based on the perceived role of serotonin in the pathophysiology of migraine. The then-unknown serotonin receptor type 5-hydroxytryptamine (HT)1B was identified as a target for stimulation by novel agonists to produce selective vasoconstriction of distended and inflamed cranial vessels. Subsequently, sumatriptan revolutionized migraine treatment as the first highly effective and well-tolerated drug that, when administered subcutaneously, led to the disappearance of severe migraine attack symptoms, Dr. Humphrey said.
The effectiveness of both oral and intranasal formulations of sumatriptan eventually led to the development of at least seven different triptans that are currently available. In addition, sumatriptan showed that migraine was an organic disease, not one that was imagined by patients, and it enabled clinicians to determine whether migraine was the cause of a patient’s headache, noted Dr. Humphrey.
However, there is debate whether, in addition to resulting in selective cranial vessel vasoconstriction, triptans also function by inhibiting trigeminal afferent neurons, thus blocking the transmission of pain signaling. Whether the latter effect occurs peripherally—at the level of nerve terminals in the vascular adventitia—or centrally in undefined brain regions is unclear, according to Dr. Humphrey. He added that although “it is difficult not to accept that during a migraine attack, painful impulses do originate peripherally from cranial vessels ... [the] fundamental defect underlying the disease could still be central.”
Although molecular biologic data have shown that triptans also activate 5-HT1D receptor subtypes, which are absent from cranial vascular smooth muscle, research during the past 20 years does not suggest that a more selective triptan-like drug could be developed, which would “strongly” implicate vasoconstriction as the key mechanism behind how triptans work to combat migraine, said Dr. Humphrey. Still, the advances resulting from the development of triptans have allowed researchers to try and develop new antimigraine drugs, such as prophylactic treatments, that could lead to better therapeutic alternatives, he stated.
“This opportunity emanates from our attempts to better understand how the triptans work and consequently better understand the pathophysiology of the disease itself, which, in turn, is helping to generate new pharmacologic ideas,” commented Dr. Humphrey. For example, research on adventitial trigeminal neuron activation and vasodilation has allowed for the current development of calcitonin gene-related peptide receptor blockers.
—John Merriman