Four triptans are more effective for acute migraine than newer, more expensive medications for this headache type, new research suggested.
Results of a large systematic review and meta-analysis showed that eletriptan, rizatriptan, sumatriptan, and zolmitriptan were more effective than lasmiditan, rimegepant, and ubrogepant, which investigators found were as effective as nonsteroidal anti-inflammatory drugs (NSAIDs).
International guidelines generally endorse NSAIDs as the first-line treatment for migraine and recommend triptans for moderate to severe episodes or when the response to NSAIDs is insufficient.
However, based on the study’s findings, these four triptans, should be considered the treatment of choice for migraine, study investigator Andrea Cipriani, MD, PhD, professor of psychiatry at the University of Oxford and director of the Oxford Health Clinical Research Facility, Oxford, England, told a press briefing.
The investigators added that these particular triptans should be “included in the WHO [World Health Organization] List of Essential Medicines to promote global accessibility and uniform standards of care.”
The study was published online on September 18 in The BMJ.
Filling the Knowledge Gap
To date, almost all migraine studies have compared migraine drugs with placebo, so there’s a knowledge gap, said Cipriani. As a result, “there’s no clear consensus among experts and guidelines about which specific drug classes should be prescribed initially, and this is a clinical problem.”
The researchers pointed out that in recent years, lasmiditan and gepants have been introduced as further treatment options, especially for patients in whom triptans are contraindicated because of their potential vasoconstrictive effects and higher risk for ischemic events.
The analysis included 137 double-blind, randomized controlled trials that were primarily sponsored by the pharmaceutical industry. It included 89,445 adult outpatients with migraine (mean age, 40.3 years; 85.6% women).
Only drugs licensed for migraine or headache that are recommended in at least one country were included. Researchers divided these 17 drugs into five categories: Antipyretics (paracetamol), ditans (lasmiditan), gepants (rimegepant and ubrogepant), NSAIDs (acetylsalicylic acid, celecoxib, diclofenac potassium, ibuprofen, naproxen sodium, and phenazone), and triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan).
The study’s primary outcomes were freedom from pain at 2 hours and at 2-24 hours, without the use of rescue drugs.
Investigators used sumatriptan as the reference intervention because it is the most commonly prescribed migraine drug and is included in the WHO Model Lists of Essential Medicines.
The study showed all active interventions were better than placebo for pain freedom at 2 hours; with the exception of paracetamol and naratriptan, all were better for sustained pain freedom from 2-24 hours.
When the active interventions were compared with each other, eletriptan outperformed other drugs for achieving pain freedom at 2 hours. It was followed by rizatriptan, sumatriptan, and zolmitriptan (odds ratio [OR], 1.35-3.01). For sustained pain freedom up to 24 hours, the most efficacious interventions were eletriptan (OR, 1.41-2.73) and ibuprofen (OR, 3.16-4.82).
As for secondary efficacy outcomes, in head-to-head comparisons, eletriptan was superior to nearly all other active interventions for pain relief at 2 hours and for the use of rescue drugs.
As for adverse events, dizziness was more commonly associated with lasmiditan, eletriptan, sumatriptan, and zolmitriptan, while fatigue and sedation occurred more frequently with eletriptan and lasmiditan. Nausea was more often associated with lasmiditan, sumatriptan, zolmitriptan, and ubrogepant. Eletriptan was the only intervention most frequently associated with chest pain or discomfort.
Need to Update Guidelines?
Considering the new results, Cipriani and study co-author Messoud Ashina, MD, PhD, professor of neurology, University of Copenhagen in Copenhagen, Denmark, said clinical guidelines for acute migraine management should be updated.
While triptans are contraindicated in patients with vascular disease, the researchers noted that “cerebrovascular events may present primarily as migraine-like headaches, and misdiagnosis of transient ischemic attack and minor stroke as migraine is not rare.”
Recently, lasmiditan, rimegepant, and ubrogepant — which are not associated with vasoconstrictive effects — have been promoted as alternatives in patients for whom triptans are contraindicated or not tolerated. But the high costs of these drugs put them out of reach for some patients, the investigators noted.
Triptans are widely underutilized, Ashina noted during the press briefing. Current use ranges from 17% to 22% in the United States and from 3% to 22.5% in Europe.
The investigators said that triptans have been shown to be superior and should be promoted globally, adding that the limited access and substantial underutilization of these medications are “missed opportunities to offer more effective treatments.”
The new results underscore the importance of head-to-head trials, which is the gold standard, said Cipriani.
The investigators noted that the study’s main limitation was the quality of the data, which was deemed to be low, or very low, for most comparisons. Other potential limitations included lack of individual patient data; exclusion of combination drugs; inclusion of only oral treatments; and not considering type of oral formulation, consistency in response across migraine episodes, or cost effectiveness.
The study also did not cover important clinical issues that might inform treatment decision-making, including drug overuse headache or potential withdrawal symptoms. And the authors were unable to quantify some outcomes, such as global functioning.
‘Best Profile’?
Reached for comment, Neurologist Nina Riggins, MD, PhD, Headache Center of Excellence, Palo Alto VA Medical Center, Palo Alto, California, praised the authors for a “great job” of bringing attention to the topic.
However, she noted that the investigators’ characterization of the four triptans as having the “best profile” for acute migraine gave her pause.
“Calling triptans the medication with the ‘best profile’ might be not applicable in many cases,” she said. For example, those who need acute medication more than two to three times a week in addition to those with cardiovascular contraindications to triptans may fall outside of that category, Riggins noted.
Riggins said that “it makes sense” that longer-acting triptans like frovatriptan and naratriptan may not rank highly for efficacy within the first 2 hours. However, she noted that these agents likely offer a superior therapeutic profile in specific contexts, such as menstrual-related migraine.
In addition, while triptans are known to cause medication overuse headache, this may not be the case with gepants, she noted.
In a release from the Science Media Center, a nonprofit organization promoting voices and views of the scientific community, Eloísa Rubio-Beltr án, PhD, research associate with The Migraine Trust at the Wolfson Sensory, Pain and Regeneration Centre, King’s College London, London, England, said the findings should affect migraine treatment guidelines.
“As the study highlights, due to their high efficacy and low cost, triptans should be the first-line treatment option for the acute treatment of migraine. These results should inform treatment guidelines and support the inclusion of the best performing triptans into the List of Essential Medicines, to optimize treatment, allowing patients to access more efficacious options,” said Rubio-Beltrán.
It is also important to note that gepants and ditans were developed to offer alternatives for patients who show no improvement from triptans, she added.
She pointed out that these medications were not developed as a substitute for triptans, but rather to expand the number of treatment options for migraine.
“Nonetheless,” she added, “this study highlights the need for further research on the pathophysiology of migraine, which will allow the discovery of novel targets, and thus, novel treatments options that will benefit all patient populations.”
The study was funded by the NIHR Oxford Health Biomedical Research Centre and the Lundbeck Foundation. Cipriani reported receiving research, educational, and consultancy fees from Italian Network for Pediatric Clinical Trials, Fondazione Cariplo, Lundbeck, and Angelini Pharma. Ashina is a consultant, speaker, or scientific advisor for AbbVie, Amgen, AstraZeneca, Eli Lilly, GSK, Lundbeck, Novartis, Pfizer, and Teva; is the past president of the International Headache Society; and an associate editor of The Journal of Headache and Pain and Brain. Riggins has consulted for Gerson Lehrman Group; participated in compensated work with AcademicCME and Association of Migraine Disorders; was a principal investigator on research with electroCore, Theranica, and Eli Lilly; serves on advisory boards for Theranica, Teva, Lundbeck, Amneal Pharmaceuticals, NeurologyLive, and Miles for Migraine; and is a project advisor for Clinical Awareness Initiative with Clinical Neurological Society of America. Rubio-Beltrán reported serving as a junior editorial board member of The Journal of Headache and Pain and a junior representative of the International Headache Society; receiving research support from The Migraine Trust, Eli Lilly and Company, CoLucid Pharmaceuticals, Inc., Amgen, Novartis, and Kallyope; and receiving travel support from CoLucid Pharmaceuticals, Inc., Allergan, and Novartis.
