>> More than 70 percent of the population in the Federal Republic suffer from headaches, 90 percent of which can be assigned to the primary headache types and are divided into tension headaches, migraines and cluster headaches (see TK, 2017). The German Migraine and Headache Society (DMKG) puts the prevalence of migraines at around 10 to 15 percent of the population, with the symptoms usually being most pronounced between the ages of 40 and 50 and women being affected up to three times more often. The recurring headache attacks last from a few hours to a maximum of three days and are often expressed in one-sided, dull, pressing or stabbing, pulsating pain. The intensity leads to restrictions in everyday life and accompanying symptoms such as nausea, vomiting, hypersensitivity to light, noise and smell. There are different explanations for the causes of migraines. Genetic factors, an imbalance of pain-transmitting neurotransmitters and the subsequent inflammatory reaction in the blood vessels of the meninges, as well as overactivity of the nerve cells in the migraine center of the brainstem are discussed. In comparison to the unclear etio-
Interindividual trigger factors are well known. Among other things, changing sleep-wake rhythms and irregular daily routines, hormone changes, stress, certain foods, alcohol, nicotine and environmental stimuli are mentioned here (see neurologists and psychiatrists online, 2019).
Migraine therapy: combination of medication and lifestyle
The S1 guidelines for the treatment of migraine attacks and prophylaxis of migraines as of January 2018 already define the two therapeutic starting points in the title. The recommendations for drug therapy for a migraine attack focus on classic NSAID analgesics and triptans. For prophylaxis, certain beta blockers, anticonvulsants and a botulinum toxin are available, the selection of which should be based on the frequency of attacks, comorbidities and the patient's individual needs. Supplementation with non-drug interventions such as behavior modification and therapy, exercise and nutrition, as well as psychological pain therapy for patients with severe limitations, are recommended. As expected, the clinical pathway is extensive for both attack therapy and prevention and differentiates, among other things, according to severity, affected patient group and situation or indication. In very simplified terms, Figure 1 shows the most common drugs or substance classes that are suitable for migraine therapy.
Sumatriptan dominates the market
Triptans are a substance class with a total of seven representatives that are specifically effective for migraine attacks. The selective serotonin (5-hydroxytryptamine) receptor agonists lead to vasoconstriction of the dilated vessels in the meninges during a migraine attack, inhibit the release of inflammatory neuropeptides and inhibit pain transmission in the trigeminal system (see DAZ online, 2009). In the GKV, almost 2.08 million packs of prescription triptans were prescribed in the MAT (Moving Annual Total) July 2019, with the volume increasing by 4.5 percent from the MAT July 2017 to 2019. With around 1.18 million packs, sumatriptan plays by far the largest role in the market. The active ingredient, which was approved in 1993 and has been approved for the longest time, is available in numerous dosages and dosage forms, for example as a nasal spray and subcutaneous injection for a particularly rapid onset of action. In addition to the prescription dosages, Naratriptan and Almotriptan have been available in pharmacies without a prescription in low potencies and small packs for several years. In MAT July 2019, almost 2.33 million non-prescription units of Naratriptan were dispensed via public (and mail order) pharmacies without filling a prescription. This is over 15 times as many as 150,900 prescription units (source: Apo-Fusion, INSIGHT Health). A possible exemption from prescription requirements for certain triptans is a recurring topic. The BAH health monitor published in September of this year reports that 46 percent of German citizens would welcome more over-the-counter medicines for migraines. This is mainly due to the desire for quick access to medication in the event of an impending migraine.
attack and the need to deal with the illness independently. At the end of June, oral use of sumatriptan with an effective strength of 50 mg and a total amount of 100 mg per pack was released from prescription requirements by the expert committee at the BfArM. This means that three instead of the current two triptans will be available in pharmacies in Germany without a prescription - by the way, there are currently five worldwide. Prescription triptans, on the other hand, are available to patients almost exclusively through primary care. In the statutory health insurance, 55 percent of triptans are prescribed by general practitioners. 20 percent of the prescriptions are written by neurologists and 18.6 percent by general practitioner internists (see Fig. 2).
New therapy option:
CGRP antibodies
Triptans are an effective class of substances for the acute treatment of migraines. Nevertheless, around 25 to 30 percent of all migraine patients require prophylaxis due to frequent and severe migraine attacks. To date, there has been no specific drug therapy for this - but rather medications that were originally developed for other indications. However, it has long been known that the calcitonin gene-related peptide (CGRP), as an extremely potent vasodilator and inflammatory mediator, plays an important role in the inflammatory process and thus in the pathophysiology of migraine. The active principle of the new therapy options for migraine prophylaxis is based on this target (see German Society for Neurology DGN eV, 2018). Two monoclonal antibodies, erenumab and galcanezumab, were approved in the EU last year. In the benefit assessment completed in May 2019, erenumab received a significant additional benefit in adult patients who do not respond to, are not suitable for, or cannot tolerate first-line medications for migraine prophylaxis for at least four migraine days per month. The reimbursement amount negotiations for erenumab are not yet completed. Since its market launch up to and including July 2019, just over 25,250 prescriptions have been billed in the statutory health insurance (source: NVI, INSIGHT Health). As Figure 2 shows, in contrast to triptans, neurologists are the main prescribers with 70.2 percent. General practitioners, on the other hand, play a significantly smaller role with a prescription share of 10.9 percent and 7.5 percent of erenumab prescriptions in the statutory health insurance are made by outpatient clinics.
The benefit assessment process for galcanezumab was completed in mid-September. The IQWiG dossier assessment results in considerable additional benefit for the patient subpopulation defined analogously to erenumab. In January 2019, the EMA's Committee on Human Medicinal Products (CHMP) commented positively on fremanezumab, which is now also available on the German market. For the third representative, whose assessment will be completed by the G-BA in November, IQWiG describes the studies presented and the available data in the dossier assessment from August as unsuitable for deriving an additional benefit. Phase III trials for eptinezumab, another CGRP antibody, are currently ongoing. In principle, in its statement from 2018, the DGN attributes all four antibodies to very good tolerability with low undesirable drug effects. The Drug Commission of the German Medical Association (AkdÄ) points out that there is currently no possibility of directly comparing the three available antibodies erenumab, galcanezumab and fremanezumab. It should also be borne in mind that CGRP, as a pronounced vasodilator, theoretically carries a risk of cardiovascular events, which is already slightly increased in migraines (see AkdÄ, 2019). The DGN also emphasizes the still unresolved question of the long-term safety of antibodies against CGRP or the CGRP receptor. As an ideal target for migraines, the advantage over the active ingredients available in the past seems to be better tolerability according to previous study data (see AkdÄ, 2019).
outlook
On World Headache Day 2019, the Germany-wide initiative “Attack! Together against headaches” from the DMKG. This involves intensive educational work, which in the first phase is aimed particularly at general practitioners with their central role in patient care. Databases with certified headache experts and headache centers to care for more complex cases are to be further expanded, and a knowledge database and a new nationwide headache register are also being set up. The aim is to correctly identify migraine patients and treat them adequately. Some of them will certainly also benefit from the new CGRP antibodies for migraine prevention. It remains to be borne in mind, as the headache expert from the German Society for Neurology, Hans-Christoph Diener, emphasizes, that non-drug approaches to behavioral therapy and lifestyle modification are just as effective as drug prophylaxis. <<
Author: Kathrin Pieloth
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