Let’s begin with migraine. There is now a substantial amount of knowledge about the pathophysiology of migraine and, specifically, migraine attacks. Serotonin has a key role here, and we use triptans, which target serotonin, in treatment.
For migraine prevention, we focus on two targets. The first is calcitonin gene-related peptide (CGRP), which we address with CGRP-targeting monoclonal antibodies. Now, a new target has emerged: pituitary adenylate cyclase-activating polypeptide (PACAP). In migraine patients, administering PACAP intravenously can trigger migraine attacks. A new preventive approach involves a monoclonal antibody that targets PACAP.
In a study from Denmark published in The New England Journal of Medicine, a phase 2 trial was conducted with 237 patients for whom at least two previous preventive therapies had failed. They received a single dose of the PACAP-targeting monoclonal antibody, and it resulted in a meaningful reduction in migraine days over four weeks compared to a placebo. However, while there was a strong trend toward achieving a 50% responder rate, it was not statistically significant. The treatment showed good tolerability.
This indicates that a larger phase 3 trial, lasting 3 to 4 months, is required to confirm effectiveness. This therapy may be particularly beneficial for patients who do not respond to monoclonal antibodies targeting CGRP or the CGRP receptor.
My second review focuses on acute migraine attacks and was published in The British Medical Journal. Most patients manage these attacks with analgesics or NSAIDs, and there are seven types of triptans available. Recently, new CGRP receptor antagonists, such as rimegepant, ubrogepant, and zavegepant, and the 5-HT1F agonist lasmiditan, have become available. However, direct comparisons between these new drugs, triptans, or NSAIDs are lacking.
Thus, a network meta-analysis of 137 randomized controlled trials, involving nearly 90,000 migraine patients, was conducted. For the primary endpoint — being pain-free at 2 hours — eletriptan, rizatriptan, sumatriptan, and zolmitriptan were found to be the most effective. Gepants and lasmiditan showed lower efficacy, comparable to NSAIDs. Lasmiditan is aimed at patients who cannot use triptans due to severe vascular issues.
In summary, triptans are underprescribed in many European countries. Eletriptan, the most effective triptan, is rarely prescribed. As they are now off-patent, triptans are more affordable than ever.
