“The study is the first to investigate whether migraine can be effectively interrupted in its prodromal phase"

Current practice:
"Acute medication is primarily used to treat headaches during the actual migraine attack. However, it has long been known that migraines begin much earlier—often with prodromal symptoms such as cognitive impairment, sensitivity to light and noise, and circulatory problems. The study presented here focuses specifically on these early symptoms and the possibility of interrupting migraines at this stage".

Results:
“The authors conclude from the results of their study that the pathophysiological causes of migraine are likely to originate in the central nervous system. They base this assumption on the fact that ubrogepant therapy is effective in the early stages of migraine and influences symptoms that are associated with the central nervous system".

Methodology and significance in terms of efficacy:
“The statistical significance of an exploratory analysis is inherently weaker than that of a controlled study specifically designed to address this question. Nevertheless, the available data provide initial indications that ubrogepant may be effective in the prodromal phase of migraine. This at least supports an interesting hypothesis. However, further, specifically designed studies are needed to scientifically confirm this promising approach.”

Difference between the prodromal phase and the aura phase:
“It is important to distinguish clearly between the prodromal phase, i.e., the early phase of migraine, and the aura phase. The symptoms investigated in this study, such as cognitive impairment, fatigue, and sensitivity to light, occur in the prodromal phase. These are not the aura, which is characterized by other neurological symptoms such as scintillating scotoma (visual disturbances with flickering or flashing lights; editor's note) and must be clearly distinguished from it. The potential efficacy of ubrogepant in the aura phase was not investigated in this study.”Future and additional benefits of ubrogepant".

Future and additional benefits of ubrogepant:Ubrogepant is a new and promising substance for the acute treatment of migraine. Its use in the prodromal phase would be particularly interesting, as this would represent a therapeutic add-on that is not currently available. Since this group of drugs is not thought to be associated with the risk of medication overuse headache, the early use of ubrogepant would be even more appealing. It would be good if the EMA approved it too. I'm not sure if they're planning to do that yet, though".

About the prodromal symptoms:
"The course of a migraine attack is divided into a prodromal phase, the optional aura phase, the headache phase and a postdromal phase. Prodromes are symptoms by which patients recognise that a migraine attack will begin in the next few hours. Typical prodromal symptoms are cravings or yawning, but also difficulties concentrating and sensitivity to light. By definition, such symptoms are only considered prodromal symptoms as long as no headache has started yet, as sensitivity to light or difficulty concentrating are also frequent accompanying symptoms during the headache phase. It has now been repeatedly shown that the prodromal symptoms originate in the hypothalamus, thus supporting the hypothesis of a central origin of a migraine attack. The possibility to prevent or reduce the occurrence of migraine attacks through treatment in the prodromal phase would be desirable".

Relevance of prodromal symptoms:
"Prodromal symptoms such as sensitivity to light and sound, dizziness or difficulty concentrating as well as neck pain have a considerable impact on patients with migraine. Sensitivity to light is cited as the most bothersome symptom (MBS) in many studies on migraine attacks. Dizziness and problems concentrating have a significant impact on everyday performance, for example in a professional context".

About Gepante:
"Gepante are oral drugs blocking the CGRP-receptor (calcitonin gene-related peptide) and can thus have an effect on migraine attacks and migraine prophylaxis. CGRP is a neuropeptide that plays a central role in the development of migraines. The first generation of Gepante was investigated 15 years ago, but was not authorised and introduced due to elevated liver enzymes in a small number of study participants. Atogepant is now available in Germany: the approval only applies to migraine prophylaxis, studies on its efficacy in acute migraine attacks are currently being conducted. The market launch of Rimegepant is expected in Germany this year. It is authorised for the prophylaxis of episodic migraine and for acute therapy. Zavegepant (a Gepant nasal spray) and Ubrogepant, which has so far been investigated for the acute treatment of migraine, have not yet been approved in Germany. Gepante is characterised by good tolerability and could be of particular interest in acute therapy for patients who cannot tolerate triptans or for whom triptans have no effect".

Study Content: 
"The study is an exploratory analysis of the PRODROME study [I] published in the Lancet in 2023, which investigated the extent to which taking 100 milligrams of ubrogepant in the prodromal phase of a migraine attack is able to prevent the occurrence of headache as the main symptom of a migraine attack. The study participants first kept a prospective diary to prove that they could predict their attacks in the next one to six hours. Then one attack was treated with 100 milligrams of ubrogepant and one attack with placebo. Within 24 hours, moderate or severe headaches were prevented with ubrogepant in 46 percent of those taking ubrogepant and in 29 percent of those taking placebo. The tolerability of Ubrogepant was good".

Results:
“The exploratory analysis now presented investigated the extent to which prodromal symptoms could be successfully eliminated. Two hours after taking the study medication, sensitivity to light was no longer present in 19.5 percent of attacks treated with ubrogepant and in 12.5 percent of attacks treated with placebo. Three hours after administration, fatigue was no longer present in 27.3 percent of attacks treated with ubrogepant and in 16.8 percent of attacks treated with placebo. Neck pain was no longer present in 28.9 percent (ubrogepant) and 15.9 percent (placebo) of attacks. Sensitivity to noise was no longer present four hours after administration in 50.7 percent (ubrogepant) and 35.8 percent (placebo) of cases. Improvements were also seen in difficulty concentrating and drowsiness.

Treatment with ubrogepant was therefore more effective than placebo in eliminating bothersome prodromal symptoms.

The use of ubrogepant in patients with predictable migraine attacks can, as shown in the two publications of the PRODROME study, in some cases prevent the onset of a fulminant migraine attack [I] and reduce or prevent the bothersome prodromal symptoms themselves. This represents a significant improvement for migraine patients, as the currently available migraine medications—triptans—should only be taken once the headache has started. In addition, ubrogepant is well tolerated". 

Methods and significance in terms of efficacy:
“Los análisis exploratorios no pueden sustituir a los ensayos clínicos prospectivos y aleatorizados, pero, si se analizan junto con el efecto sobre los dolores de cabeza incluso cuando se toma ubrogepant en la fase prodrómica, los datos son convincentes. En última instancia, serán los pacientes quienes informen en su vida cotidiana si el concepto es viable”.  

Efecto de ubrogepant sobre los dolores de cabeza y el aura: 
"Exploratory analyses cannot replace prospective, randomized clinical trials, but when viewed in conjunction with the effect on headaches even when ubrogepant is taken in the prodromal phase, the data are convincing. Ultimately, patients will report in their everyday lives whether the concept is viable.”Effect of ubrogepant on headaches and aura.

Prodromal symptoms should not be confused with migraine aura; the study does not draw any conclusions about aura. The efficacy of ubrogepant with regard to the endpoint of occurence of headache two hours after administration [II] [III] is, as with other gepants investigated, inferior in an indirect comparison of study results to the efficacy of, for example, eletriptan 40 milligrams or rizatriptan 10 milligrams, which achieved rates of approximately 35 percent pain freedom two hours after administration. With the gepant drugs, approximately 20 percent of patients were pain-free after two hours compared to placebo (approximately 10 percent). However, the gepant drugs showed very good tolerability overall in the studies and may also be effective in a subgroup of patients who do not experience relief with other migraine treatments or show side effects."

Future and additional benefits of ubrogepant:
"We currently do not know whether there are plans to launch ubrogepant in Europe. It is hoped that similar effects may be achieved with rimegepant, which will be available soon, and atogepant, which is currently being investigated as an acute medication for migraine attacks.

Rimegepant, for which no similar study is available to date, will probably become available in the summer of 2025. The effect of atogepant on acute migraine attacks is also currently being investigated, but the results of this study and studies on the effect of atogepant on prodromal symptoms are not yet available. If both drugs become available in Europe for the acute treatment of migraine, the additional introduction of ubrogepant is rather unlikely.”

Conclusion:
"The effect on prodromal symptoms and headache when taken in the prodromal phase is an exciting aspect that could represent significant progress for migraine patients; an effect on aura has not yet been investigated. Any additional treatment option improves the situation for those affected.”