The Response to Triptans: What Counts as Success? What Counts as Failure?

A consensus panel of the European Headache Federation provides definitions of triptan responders and non-responders. The effort could improve migraine treatment and standardize research.

While triptans are the pharmacological standard of care for acute treatment of moderate to severe migraine, not all people with migraine benefit from them – these individuals are said to “fail” to respond. But what actually constitutes a failure to respond to a triptan? Interestingly, the migraine field does not have a standardized definition of triptan failure, making it difficult to determine appropriate treatment with this drug class. A new study aims to change that.

A consensus panel of the European Headache Federation (EHF) now provides, for the first time, a definition of a triptan non-responder, as well as a definition of a triptan responder, after a preliminary literature review, opinion collection via questionnaires, and open discussion. The new definitions may not only make better migraine treatment possible in the clinic but also prove useful for standardizing research on medications for acute migraine care.

“The authors of this paper include some of the leading headache specialists in the world. They did a great job, and it’s a very useful guideline,” said Richard Lipton, a migraine researcher and clinician at Albert Einstein College of Medicine, New York City, US. “Broadly, I think this is a guideline that is evidence based and comes from clinical practice experience and less from rigorously designed trials,” he added.

The authors, including first author Simona Sacco, University of L’Aquila, Italy, hail from a dozen countries throughout Europe and the UK. The consensus article appeared in the Journal of Headache and Pain on October 12, 2022.

To understand failure, first understand success
Triptans are well established for acute treatment of migraine. However, some people who don’t respond to a triptan might have benefited from the drug if they received it at a different dose or time, or if they tried a different kind of triptan. Others may need an entirely different class of drug. But it’s challenging to know how to make treatment decisions in the absence of a widely accepted definition of what constitutes triptan failure.

That provided the impetus for the work of the 16-member consensus panel, including 15 physicians and one pharmacologist. The group’s first step was a systematic review of the literature, which resulted in 251 records, including randomized trials and observational studies investigating the efficacy and effectiveness of triptans in people with migraine.

“We wanted to check for other definitions of triptan failure, but there wasn’t much information,” said Sacco. “We also went through clinical trials of triptans to understand the most important endpoints of those trials,” Sacco said.

But the panel quickly realized that it wasn’t possible to define triptan failure without a clear definition of what an effective treatment of a migraine attack is in general.

So, after the literature review, the group worked to reach a consensus on this matter. They would go on to define effective treatment of a migraine attack as when a patient reports “well-being” within two hours of taking the drug and maintains it for at least 24 hours. Here, well-being has three features.

The first is improvement of headache from severe or moderate to mild or absent. According to guidelines from the International Headache Society (IHS), the main suggested endpoint in clinical trials of migraine drugs is when the individual with migraine is pain free two hours after taking the drug, but this did not strike the panel as practical for the clinic.

“The endpoints are good for clinical trials, but we thought they’re less useful for clinical practice because they are very narrow endpoints,” Sacco said.

So, the authors opted for a more flexible approach, focusing on the improvement of headache rather than on being pain free.

The second feature of well-being that characterizes a successful response to a migraine treatment, according to the panel, is absent or minimal disturbances from migraine-related non-pain symptoms.

“This definition isn’t so rigorous because it doesn’t specify which non-pain symptoms,” Lipton said. “However, it’s very simple and practical in the clinic, as it gives clinicians the flexibility to assess patients based on their individual symptoms.”

Lipton said this was also true for the third feature of well-being, which is no meaningful drug-related adverse events.

The panel would go on to agree that a person with migraine is a triptan-responder when the triptan leads to effective treatment of an acute migraine attack in at least three out of four consecutive attacks. Here, the researchers believe their definition has wider applicability.

“Our definition doesn’t only apply to triptan drugs. We think the definition can be applied to other drugs that treat migraine, including new drugs like gepants and ditans,” Sacco said.

Defining a triptan non-responder
Because a person’s response to a triptan is not binary – for instance, a person may not respond to one triptan but may instead respond to a different triptan – defining what triptan failure means required a nuanced approach. In the end, the consensus panel proposed definitions for four different types of triptan failure.

First, the panel defined a triptan non-responder as someone who fails a single triptan, meaning that the response to just one triptan did not match the definition of a triptan responder. Second, the panel defined a triptan-resistant individual as one who fails at least two different triptans, with neither drug matching the definition of a triptan responder.

Third, the group defined a person as triptan-refractory when at least three triptans were ineffective.

“Here we also included the need to fail subcutaneous sumatriptan, because, among all triptans, subcutaneous sumatriptan is the most effective one. However, in some countries sumatriptan is not available, so the definition should be adapted at a local level to consider drug availability,” Sacco said.

Finally, the panel defined triptan ineligibility as when triptan use is contraindicated according to the drug’s summary of product characteristics.

How the definitions can be helpful
The new definitions are poised to be quite practical for clinical use, not only to help physicians who may switch patients from one triptan that didn’t work to another that might, but also to assist efforts to try different drug classes, according to Lipton, who noted that new treatments like gepants and ditans often work better in people who don’t respond to triptans.

“But these new drugs are expensive. Before starting gepant treatment, I have to document that a patient is a non-responder to at least two triptans. Therefore, it’s really important to define what a triptan responder and non-responder is – it becomes a gateway to accessing drugs that are reimbursed,” said Lipton. “To the best of my knowledge, this hadn’t been defined before,” he added.

Sacco said that the new definitions can also be helpful when a patient might respond to a triptan at first, but then stop responding over time, which is something that is also common in clinical practice.

As far as research on triptans goes, Sacco said that the definition of a triptan non-responder has been approved by the IHS for the society’s guidelines on clinical trials of acute migraine drugs.

Still, she acknowledged some gaps in the current definitions.

“For example, we know that women have their worst attacks associated with menstruation, and these attacks are notoriously difficult to treat with triptans. A challenge for our definitions is how we can apply them to menstrual attacks – can we consider these the same as other migraine attacks? This is an open point that needs to be addressed,” Sacco said.

Finally, she emphasized that the new definitions are only the first steps toward better patient care.

“We want to know how our definition works in clinical practice. A study is being designed to field-test the definition – to understand how the definition does and doesn’t work for patients.”

Fred Schwaller, PhD, is a freelance science writer based in Germany. Follow him on Twitter @SchwallerFred

Reference
European Headache Federation (EHF) consensus on the definition of effective treatment of a migraine attack and of triptan failure.
Sacco et al.
J Headache Pain. 2022 Oct 12;23(1):133.