1417 
Messoud Ashina MD PhD DMsc is Professor of Neurology, Danish Headache Center and Department of Neurology, University of Copenhagen. He spoke to Hospital Healthcare Europe about his work into headache and migraine, some of the innovations in patient management and his hopes for the future for helping sufferers of this debilitating condition.
Messoud Ashina has been involved in headache research since 1995 and has completed a PhD in headache science focusing on tension-type headaches. Since 2006, Professor Ashina has been working on migraine and, in particular, experimental models of migraine.
His research at the Danish Headache Centre’s Human Migraine Research Unit focuses on experimental models of migraine in humans. This work involves provoking a migraine attack in patients and then trying to ascertain the specific biomarkers involved in induction with a view to developing drugs that can target these markers. In addition to his basic scientific research, Professor Ashina is also a lead investigator on clinical trials, yet still manages to practice as a neurologist seeing headache patients.
Defining migraine and its symptoms
Professor Ashina described migraine as ‘quite a complicated neurological disease characterised by attacks, and which are paroxysmal in nature and self-limiting’. He explained how typically the disease first presents during the teenage years and then gradually evolves over the following decades but then gradually becomes less severe and less frequent with advancing age.
He sees migraine as a ‘fascinating disease to study’ because it is not just a headache but also associated with a sensitivity to light, sound, smell and nausea or vomiting. As a result, he felt that it was important for clinicians to recognise that migraine can be a debilitating disease. In many instances, during an attack, patients tend to either stay in bed or remain sat at home since the slightest movement ‘aggravates the pain’. Both the headache and sensitivities have contributed to the archetypal depiction of a migraine sufferer as someone who remains in a darkened room during their attack, for anywhere between two to three days.
Despite much research time and effort spent trying to understand the condition, Professor Ashina concedes that we are still very much in the dark as to why a migraine starts. He believes that the underlying cause most likely involves some form of complex communication between areas within and outside of the brain that which will ultimately ignite a migraine attack. Furthermore, because attacks naturally abate after a few days, either the same, or another communication pathway, transpires to somehow extinguish the migraine flame. Thus, exactly how a migraine starts and stops remain some of the biggest unanswered questions in migraine research.
Classifying migraine
Professor Ashina said there are only two subtypes of migraine: ‘migraine with aura and migraine without aura’, with the latter accounting for around two-thirds of all cases. Those who have migraines with aura experience symptoms that normally persist up until the development of the headache. He explained how patients often experience ‘transient neurological symptoms usually occurring before the headache starts and which are usually visual symptoms (known as fortification spectra) of different colours or sometimes black and white that move around the visual field’.
In terms of the clinical presentation, patients report both uni- and bilateral headaches and to consider a headache as a migraine, it requires the presence of at least two of four main pain characteristics: localisation; throbbing; intensity; and aggravation by physical activity. Professor Ashina described how where a patient had a ‘bilateral headache and with intense throbbing, this would fulfil two of the four criteria’ [for migraine]. In other words, although in the past, migraine was classically defined by hemicrania (one-sided headache), the definition has evolved to include a headache which ‘migrates’ to cover a larger area of the head. If patients display at least two of the four headache pain characteristics, if this occurs in conjunction with associated symptoms such as photo- or phonophobia or nausea/vomiting, it is possible to diagnose migraine.
Migraine prevalence
Globally, Professor Ashina said a staggering one billion people suffer with migraine. However, a clearer estimate can be derived from considering either the annual or life-time prevalence of headaches. For instance, he defined the mean one-year prevalence of migraine as affecting ‘15% of the population’ and while the method of data collection in self-reported surveys can vary, these figures are generally very reproducible.
Migraines occur three-times more frequently in women but when considering the lifetime rather than one-year prevalence, the figure increases to around 25% of the population. Typically, he says, migraines begin during the teenage years and the incidence increases further over the next 30-40 years though interestingly, after the age of around 60, the incidence starts to decline.
While far less common in children, Professor Ashina mentioned that children as young as six can be affected. As he said, ‘if we look at the data around children, it’s quite high and in fact it’s about 8%’. Fortunately, migraine attacks in children are far less frequent than in adults and the duration of an attack is also shorter.
Impact on quality of life
There is little doubt that migraines have a significant impact on quality of life. Professor Ashina discussed a recent paper published in the Lancet that examined the global impact of various disease on years lived with disability.
While migraine was the second most common condition after low back pain, a closer look at the data on years lived with disability among the women aged between 18 and 50 years revealed how migraine was the most common condition. Professor Ashina portrayed a typical chronic migraine sufferer as someone who experienced multiple attacks during the week.
Furthermore, another factor that no doubt contributed to the disability associated with migraine he said, was how some of these patients rarely had pain-free days between attacks. At the other end of the disease spectrum, patients were more fortunate, perhaps only enduring one or more attacks per month or even just a few per year.
The management of migraine therefore largely depends upon the number of attacks. For those with infrequent episodes, treatment is directed at stopping an acute attack whereas for those who suffer more frequent attacks, preventative therapy is designed to reduce the ‘number, frequency and intensity and, in some cases, the duration of attacks.’
Economic burdens
While migraines clearly have a huge effect upon patient’s quality-of-life, there is also a significant economic impact. To illustrate this impact, Professor Ashina portrayed a patient who had two days of migraine every week. This, he said, amounts to 96 days every year and if the patient’s medication is ineffective and they decide to attend work, it is highly likely that their performance, and hence productivity, will be significantly impaired. Equally, if they stayed at home, there is still a major economic impact in personal terms, in lost productivity, and at a cost to their employer.
The economic burden also become apparent when considering treatment. Most patients will initially self-medicate with treatments purchased at a pharmacy and although these can help, for many, the medicines are ineffective, prompting a visit to the GP, and even then, some treatments will remain ineffective.
Professor Ashina deems it necessary for migraine patients be assessed holistically, which is impossible within the limited time available in a GP consultation. Consequently, patients are ultimately referred to a neurologist, yet he feels that neurology services are insufficiently resourced in relation to the volume of migraine sufferers requiring a more in-depth assessment.
Acute migraine treatments
Professor Ashina thinks that acute, over-the-counter migraine treatments are probably effective in many cases but admits that as a neurologist, he only sees those whose disease has not responded to both over the counter and prescription medicines. He considers that many migraine sufferers can manage their condition with non-steroidal anti-inflammatory drugs such as ibuprofen, aspirin, et cetera.
When these drugs fail to provide adequate relief, patients turn to the triptans, which are perceived as stronger medicines. Professor Ashina feels that this perception is incorrect as triptans are simply a class of drugs specifically designed to abort a migraine attack. But it is easy to understand a patient’s misconception when examining efficacy data, especially if assessed against the endpoint of two-hour pain freedom.
Using this scale, he said ‘the triptans are better than non-steroidal anti-inflammatory drugs – there’s no doubt about that’ and as a result, many patients report how ‘triptans have completely changed their lives’. While he welcomes the increased availability of triptans in countries where the medicines have OTC status, he also recognises a possible problem. As he says, ‘when patients start taking too many triptans, they develop medication overuse headache’.
A further problem with over-the-counter medicines is that combination products, particularly those which contain caffeine, can be what he described as ‘medicine overuse-inducing’. He generally advises patients to limit the weekly use of such medicines but in cases where patients feel that they need better treatments, it is better to consider prophylactic agents.
Prophylactic treatments
Professor Ashina says that globally, the most common prophylactic agents are beta-blockers but while effective, adherence problems do occur as some patients experience side-effects or are unable to tolerate the drugs.
Overall, he believes that beta-blockers can be just as effective as other prophylactic agents but are often limited by side-effects. Other prophylactic agents such as anti-hypertensives and anti-epileptics are also effective but less widely used. But, as with beta-blockers, adherence becomes an issue with anti-epileptics due to adverse effects. Professor Ashina also mentioned how Botox is an effective migraine prophylactic agent but is normally reserved for patients with chronic migraine who have failed to respond to other therapies.
Innovative treatments in migraine
Some of the latest migraine treatments to be introduced are directed against calcitonin gene-related peptide (CGRP). As Professor Ashina explained, ‘CGRP is widely distributed in migraine-specific structures such as the trigeminal nerve, cranial blood vessels and certain other parts of the brain’. While its physiological role is yet to be clarified, it is known that migraine attacks can be provoked after infusion of the molecule. Similarly, he said, ‘administration of an anti-CGRP agent can abort or prevent attacks.’.
The original CGRP agents were the gepants that specifically target the CGRP receptor. These oral treatments are used for acute attacks and serve as an alternative to triptans. While not as effective as triptans, Professor Ashina sees the gepants as a useful alternative to the triptans, especially for patients who are either triptan intolerant or for whom triptans are contra-indicated.
Nevertheless, overall he considers the gepants to be a third-line treatment option after triptans. Although most gepants are used for acute migraine, some can also be used as prophylactics. Professor Ashina sees this as an interesting concept, especially given that the triptans cannot be used as prophylactics because they induce medication-overuse headache.
Injectable CGRP agents
Currently, there are four monoclonal antibody CGRP drugs, three of which target the CGRP molecule itself and one its receptor. These drugs are available either as intravenous or a subcutaneous formulation. Two are administered on a monthly basis and others are approved for use every 12 weeks or either monthly or quarterly.
Although the efficacy endpoint of these agents within clinical trials is normally measured in terms of a reduction in monthly migraine days, Professor Ashina prefers to translate this in clinical practice as the ‘proportion of patients who report at least a 50% reduction’ though as he says, ‘some patients even report a 75% reduction.’
While these newer agents significantly reduce the frequency of attacks, Professor Ashina cites a further benefit of the drugs in being able to reduce the intensity of attacks which therefore become more manageable for the patient. An added bonus in that patients can then use triptans and may even feel that the triptans are more effective because the attacks are less intense.
Future management of migraine
Professor Ashina feels that the introduction of CGRP agents is an important paradigm shift in the preventative management of migraine because these molecules have a highly specific target. Moreover, he feels that these drugs have elevated the status of migraine to one of a disease and not, as in the past, just a headache. He is excited to see how these treatments might change patients’ lives and says how as a physician, it is highly rewarding to see patients return to some semblance of normality that was not possible before therapy.
Despite the benefit for many patients, he also acknowledges that ‘about 40% or sometimes 50% of patients do not respond’ to these drugs hence the continued search for novel drug targets, which is an active area of his research.
Manage not cure
Professor Ashina believes that the ultimate goal in migraine research is not to provide a cure – he thinks that this is highly unlikely – but to be able to control an attack so that ‘patients can return to an almost normal life’. While he thinks that current treatments have a level of good tolerability and are without serious adverse events, there will always be room for improvement.
He added that a further consideration is that while the trajectory of an individual’s migraines is unpredictable, there is a natural tendency to resolve with advancing age. Consequently, it is worth occasionally stopping preventative therapy to determine whether an individual’s migraines have spontaneously resolved. Due to this unpredictability, he described how in his own clinic they have introduced an 18-month stop rule to assess whether or not continued preventative therapy is required.
Professor Ashina is clearly very enthusiastic and motivated in his search for efficacious migraine treatments. One potential molecular target that he is currently working on, is pituitary adenylate cycles-activating peptide (PACAP) and he mentions how, just like CGRP, administration of PACAP provokes a migraine attack.
With two ongoing trials assessing monoclonal antibodies directed at PACAP, there is hope that, in the near future, many more migraine sufferers will achieve relief of their symptoms and be able to regain some semblance of normality in their lives.
