Migraine is the third most common human disease worldwide behind dental caries and tension-type headaches [28]. The one-year prevalence in Europe for all forms of migraine is 43.6% in women and 26.9% in men [29]. Every day around 900,000 people in Germany alone are affected by migraine attacks. 100,000 people are unable to work and bedridden every day because of migraine attacks. On average, three million Germans take one headache tablet every day through self-medication. Around 59,000 individual doses of triptan are used every day in Germany to treat migraine attacks [19].

According to current knowledge, migraine pain is based on a neurogenic inflammatory reaction in the arteries of the meninges. Inflammatory substances are released there in the initial stage of the migraine attack [5, 10, 16, 25]. These lead to increased pain sensitivity in the meninges with swelling and expansion of the vessel walls. Every pulse beat leads to a throbbing, pounding migraine pain, every movement of the head hurts and increases the pain. During an attack, migraine patients therefore try to remain as calm and shield themselves from stimuli as possible and to avoid physical activity and vibrations.

In recent years it has been possible to develop specific antibodies against messenger substances that cause inflammation during migraine attacks. The focus is on the calcitonin gene-related peptide, or CGRP for short [1, 13, 14, 20, 23, 24]. It is a neuropeptide consisting of 37 amino acids and encoded by the identical gene as the hormone calcitonin. CGRP is one of the strongest vasodilators and plays an important role in the development of migraines. If you give so-called monoclonal antibodies, the effects of these inflammatory substances can be stopped for a few weeks and the likelihood of migraine attacks can be reduced. Four antibodies have been developed and tested in numerous studies: erenumab (AMG 334), galcanezumab (LY2951742), fremanezumab (TEV-48125) and eptinezumab (ALD403) [4, 8, 12, 14, 15, 21, 22, 32, 33]. Erenumab was the first representative of this new class of active ingredients to be approved in Germany in July 2018 and has been available in pharmacies since November 2018. The antibodies now available have all proven their effectiveness in very large international studies. There are antibodies that work against the ligand CGRP (galcanezumab, fremanezumab, eptinezumab) or block the receptor for CGRP (erenumab) [31].

For erenumab, study data are available for episodic migraine, ie up to 14 migraine days per month, and chronic migraine, ie more than 15 headache days per month [2, 3, 6, 7, 9, 11, 17, 26, 27, 30]. It was also examined whether patients who have not yet responded to the already approved preventative medications can still achieve an effect [26]. Comparative studies with previous preventive medications are not yet available. The reduction in migraine days per month compared to placebo, at around one to three migraine days, is of a similar magnitude to that achieved by the previous prophylactics approved for this indication. The cost-effectiveness requirement therefore plays a particular importance in the regulation: The price for the monthly dose of 70 mg erenumab (Aimovig®) is 688.36 euros. This corresponds to annual therapy costs of 8,260.32 euros, which could potentially occur over years or decades. For a treatment with 140 mg, the annual therapy costs are 16,520.64 euros. It has not yet been conclusively determined which types of migraine and for which patients will be reimbursed by statutory health insurance companies. In order to meet the cost-effectiveness requirement, due to the high costs, the new immunotherapy will only have to be considered if the currently available special behavioral measures and preventive migraine medications are not effective, are not tolerated or cannot be taken due to contraindications.

Against this background, the manufacturer is seeking a temporary reimbursement for severely affected migraine patients, for whom four (for episodic migraine, ie fewer than 15 headache days per month) to five (for chronic migraine, ie 15 or more headache days per month) are approved Previous therapies were unsuccessful. Exactly which prior therapies these should be has not yet been definitively defined. According to the guidelines, amitriptyline, beta blockers (metoprolol, propranolol, bisoprolol), flunarizine, topiramate and valproate are relevant for the treatment of episodic migraine. For the preventive treatment of chronic migraine, onabotulinumtoxin is currently the only specifically approved drug that should also be taken into account. For patients for whom these previous therapies have not been completed properly, the ability to prescribe should be restricted.

However, direct evidence of an additional benefit for the treatment of the targeted patient group cannot be identified directly from the data. The LIBERTY study [26] examined the effectiveness and safety of 140 mg erenumab in patients with episodic migraine with four to 14 migraine days per month in whom two to four previous preventive therapies had failed due to lack of effectiveness or intolerable side effects. Only 30.3% taking erenumab 140 mg compared to 13.7% taking placebo showed a reduction in monthly headache days by at least 50%. Clinically, however, this only meant an absolute reduction of 1.76 headache days per month with erenumab 140 mg and 0.15 headache days per month with placebo. The days on specific acute medication for migraine per month decreased by -1.3 days with erenumab 140 mg compared to +0.5 days with placebo.

Under the study conditions, no significant effect is expected in around 70% of the treated patients. It should be noted that this is the only study to date that addresses effectiveness in the event of other treatment failure, and was not carried out with the standard dose of 70 mg provided, but with 140 mg of erenumab for episodic migraine. The previous unsuccessful therapies also did not explicitly include the four active ingredients that are now being focused on as part of the intended reimbursement restriction in Germany. They included amitriptyline, candesartan, flunarizine, lisinopril, metoprolol, propranolol, topiramate, valproate, venlafaxine, among others. 39% of the study participants had only used two prophylactics without success. The additional benefit of 70 mg erenumab compared to previous therapy options is currently not proven by study data for either episodic or chronic migraine. For the severely affected patient group with chronic migraine with complete failure of first-line migraine prophylactics, the effect of 70 mg and 140 mg erenumab is completely open.

Erenumab is approved for migraine prophylaxis in adults with at least four migraine days per month. Treatment should be initiated by physicians experienced in diagnosing and treating migraines. The recommended dose is 70 mg erenumab every four weeks. Some patients may benefit from a dose of 140 mg every four weeks, given as two subcutaneous injections of 70 mg each. In clinical studies, the 140 mg dosage resulted in a numerically higher response rate, although this was not statistically significant [2, 11, 17, 26, 30]. The response to therapy can become apparent in the first two weeks of treatment. Treatment should not be continued in patients who do not show a response after three months. Treatment should be continually evaluated. The migraine app (available free of charge for iOS and Android) is suitable for monitoring progress and success, as it enables precise quantitative evaluation of prevention and acute therapy. In addition, extensive knowledge about migraines and behavioral techniques are imparted to those affected.

Approximately 50% of patients with more than 15 headache days per month for at least three months have, in addition to the original primary form of headache, medication overuse headache (MÜK) as a further causal reason for the increasing frequency of headache days [18, 19]. In contrast to the initial situation, most of those affected show a reduction in the number of headache days per month after a medication break and a renewed response to preventive and acute medication. Advice on this, knowledge of the connection and consequences of medication overuse headache (MÜK) are therefore essential. Patients with medication overuse headache (MOH) should take an adequate medication break before initiating treatment with erenumab and be encouraged to adhere to the 10-20 rule: painkillers and specific migraine medications should be used less than 10 days per month, and at least 20 days per month be completely free from taking them.

The injections are carried out using an auto-injector at intervals of four weeks. Many migraine patients are familiar with using this auto-injector, as an almost identical pen is also used for the subcutaneous administration of sumatriptan sc. In contrast, the pen is not used in the attack when necessary. Rather, it is used at fixed intervals of four weeks for prevention according to a defined treatment plan. This immunotherapy is a passive immunization. The antibodies are not produced in the human body themselves, but are produced in the laboratory as a fully human monoclonal IgG2 antibody in Chinese hamster ovary (CHO) cells using recombinant DNA technology. For this reason, the dose must be repeated regularly. Immunotherapy or passive “vaccination” does not mean that the disease no longer occurs. The risk of future attacks is reduced. During the dosing period, erenumab is eliminated primarily via a non-specific proteolytic pathway and has an elimination half-life of approximately 28 days.

Erenumab is administered subcutaneously by the patients themselves. The injection can be given on the stomach, thigh, or outside of the upper arm. A different injection site should be used for each subsequent injection. Injections should not be given into sensitive, injured, red or hard areas of skin. The autoinjector is for single use. As a precaution, erenumab should be avoided during pregnancy. It is therefore important to ensure that adequate contraception is used.

Side effects reported with erenumab 70 mg and 140 mg, respectively, include injection site reactions, constipation, muscle spasms and pruritus. Most of these side effects are mild or moderate in severity. However, long-term effects and long-term side effects are currently not known.

The medicine should be stored in the refrigerator at 2-8 degrees Celsius and should not be frozen. The autoinjector should be stored in the outer box, protected from light. If the medicine is stored at room temperature up to 25 degrees Celsius, it must be used within 14 days or disposed of. Before use, the solution should be inspected visually. If it contains cloudiness, flakes, particles or a yellow discoloration, it must not be used. To avoid discomfort at the injection site, the autoinjector should be removed from the refrigerator prior to injection and stored at room temperature for at least 30 minutes, avoiding shaking and direct sunlight or other heat sources.

In contrast to all other preventative medications available to date, the new immunotherapy has been developed specifically for migraine prevention for the first time. A slow dosage increase due to possible intolerances and side effects is not necessary. If there is a response, the onset of action can be expected quickly, initially within a few days. Side effects of previous migraine preventatives such as weight gain, mood changes, fatigue, reduced drive or drowsiness are not to be expected. However, the data available so far shows that one should not assume that the new active principle will stop migraines and that one can live as one wants. Around 70% of patients with episodic migraine who have previously failed other therapy attempts will probably not respond to the new mechanism of action. It is not yet possible to predict who will be among the 30% responders. However, it is currently unknown how effective it is in patients with chronic migraines who have not yet responded to standard prophylaxis including onabotulinum toxin and who are most hoping for an improvement in their condition. They were excluded from the study program.


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