Challenge and opportunity

In the case of frequent headaches, prophylactic medication may be useful. What medications are available and what is the evidence for their efficacy?

About 15% of the European population suffers from migraine attacks [1]. In the process, affected individuals are not only confronted with pain, but also have to cope with the effects of the disease on their professional and private lives [2]. However, the burden of the disease is not the same for everyone, but increases with the number of headache days.

Although numerous, often well effective medications are available for the acute treatment of migraine, this therapeutic approach is not always sufficient. Running after the pain, as it were, instead of preventing it, reduces the duration of attacks but does not necessarily increase the predictability of life. In addition, frequent use of acute medications carries the risk of medication overuse headache (MÜKS) [3]. This is imminent if simple analgesics are taken on ≥15 days or triptans, opiates, or combined analgesics are taken on more than ten days per month over a prolonged period (at least three months). It is much more costly to society than migraine itself, and comes with additional burdens for the individual [4,5].

So the goal is to prevent the seizures from occurring in the first place, or at least to reduce their number as much as possible. Various agents have been shown to be helpful in this regard (Tab. 1) [6]. However, choosing the right time for prophylaxis and selecting the right medication can be challenging. On the other hand, this treatment approach offers the chance to significantly alleviate the symptoms of those affected.

Therapy principles

Basically, a distinction is made between drug and non-drug therapeutic approaches. It is usually assumed that starting prophylactic treatment is reasonable at five or more headache days or at least three migraine attacks per month [6]. An individual therapy decision is advisable, as not all sufferers are restricted by their headaches to the same extent. If the burden of single attacks is already very high (e.g., in hemiplegic migraine or long-lasting attacks), prophylaxis can be considered even if the number of headache days is low.

Before starting therapy, patients should be informed in detail about the opportunities and risks of the treatment. Successful therapy often takes several weeks, while side effects often become noticeable much sooner.

Non-drug methods such as neuromodulation, non-invasive vagus nerve stimulation, relaxation techniques, biofeedback, and transcranial magnetic stimulation are often effective but not always sufficient. In this article, we will limit our discussion to the options for migraine prophylaxis with medication.

Oral medications for migraine prophylaxis must be used daily – regardless of whether pain is currently present. Evaluation of treatment success is difficult because the number of headache days is retrospectively underestimated [7]. Therefore, patients on seizure prophylaxis should be sure to keep a headache calendar (3-6 months). Therapy adherence, which is often very low, should also be encouraged and inquired about [8].

Nevertheless, in order to achieve therapeutic success, we consider detailed counseling, individual selection of medications, and an assessment of changes that have occurred that is as objective as possible to be essential (overview 1).

Medication

In general, we recommend starting with a low dose and increasing it slowly as needed. If treatment is successful, a gradual dose reduction can be considered after six to twelve months.

Beta-blockers and other antihypertensive drugs: That beta-blockers are helpful in migraine prophylaxis was discovered by chance [9]. They reduce the amplitudes of visual evoked potentials that are often elevated in migraine patients, which may indicate an improvement in the function of thalamo-cortical connections [9–13]. However, whether this is responsible for the reduction in migraine frequency has not yet been conclusively determined [9,12].

The efficacy of propranolol [14] and metoprolol [15,16], both of which are approved in Switzerland for migraine prophylaxis [17], has been confirmed in several studies.
Candesartan is similarly effective to propranolol and the side effects of the two drugs are also similar. While dizziness and paresthesias have been reported more frequently with candesartan, episodes of bradycardia are more common with propranolol [18].

Lisinopril was studied in two smaller trials and also showed a prophylactic effect; however, individual patients had to discontinue treatment because of cough [19,20].

Calcium antagonists: the calcium antagonist flunarizine is also approved for migraine prophylaxis [17]. Its efficacy can be considered assured, although some studies showed underpowered [21]. The mechanism of action is not known, but blockade of cortical voltage-gated sodium and calcium channels has been discussed [22]. The most common side effects are fatigue and weight gain, while depressed affect or extrapyramidal syndrome are very rarely reported [21].

Antidepressants: In Switzerland, no antidepressant is currently approved for the prophylaxis of migraine, but their use is nevertheless supported by current treatment recommendations [6]. However, in our experience, many patients have clear reservations about these drugs.
The best studied is amitriptyline, which reduces the number of migraine days more than a placebo [23]. Tricyclics enhance the anti-nociceptive effect of descending pathways and reduce spreading depression in animal studies, which may explain their effect in migraine prophylaxis [24–26].

The evidence for the efficacy of selective serotonin reuptake inhibitors is considerably worse [24]. Fluoxetine showed little [27] or no effect in trials [28]; sertraline had no effect on headache severity [29]. In contrast, the SNRI venlafaxine significantly reduced the number of headache days in a placebo-controlled trial [30]. To our knowledge, the effect of duloxetine-also an SNRI-has not yet been tested in any randomized controlled trial. However, evidence of good efficacy in some patients emerged from a retrospective [31] and a prospective open-label study [32].

Anticonvulsants: From the group of anticonvulsants, only topiramate is currently approved for migraine prophylaxis in Switzerland [17]. Numerous studies have confirmed the good efficacy of the drug [33–37]. However, side effects such as fatigue, paresthesias, nausea, and impaired concentration limit its usefulness [35,38].

The effect of valproate is also well documented [39–41]. However, it must be noted with both drugs that the risk of malformation is significantly increased when used during pregnancy and therefore effective contraception is necessary in women of childbearing age [42].

In general, anticonvulsants are thought to prevent scatter polarization as well as central sensitization, thereby reducing the frequency of migraine attacks [43]. However, other anticonvulsants such as acetazolamide, clonazepam, lamotrigine, oxcarbazepine, vigabatrin, and gabapentin have not been shown to be effective [44,45].

Anti-CGRP antibodies: After the first description of the “calcitonin gene-related peptide” (CGRP) in 1983 [46], its vasodilating effect [47] and significance for headache disorders were recognized in the following years [48]. The first antagonists were soon developed and tested [49–51]. Finally, monoclonal antibodies directed either against the CGRP molecule itself or its receptor reached market maturity [52–58]; all significantly reduce the number of headache days.
Currently available in Switzerland are erenumab and galcanezumab, which can be injected subcutaneously at home [59,60]. So far, the drugs appear to be well tolerated; the frequency and type of adverse events differed at most only slightly from the placebo group-only pain and itching at the injection site occurred more frequently in the verum group in one study [52, 54, 56, 58]. However, long-term data on tolerability and effects as well as information on possible embryotoxicity are not yet available.

Magnesium: Migraine attacks are thought to be related to low serum magnesium concentration [61,62]. The reason for this could be that magnesium normally inhibits NMDA receptors [63,64] as well as decreases nitric oxide production [65,66] and this effect is reduced in hypomagnesemia.

In individual – but not all [67,68] – studies, magnesium supplementation shortened seizure duration [69] or reduced frequency [70]. However, a meta-analysis did not confirm the benefit in acute treatment [71]. With individualized dosing and timing, treatment is usually well tolerated [67]. However, caution is advised when using it during pregnancy.

Riboflavin: The effect of riboflavin on migraine has been investigated in several studies. This was based on the consideration that mitochondrial dysfunction may play a role in the pathophysiology of migraine [72] and riboflavin in high doses increases the activity of complexes I and II of the respiratory chain in certain diseases [73,74].

It was shown that in adults, high doses (400 mg/day) can lead to a reduction in seizure frequency [74,75], whereas this effect could not be reproduced in children [76]. Diarrhea and polyuria are reported as the most common side effects [74].

Coenzyme Q10: Also behind the use of coenzyme Q10 is the thought that mitochondrial dysfunction may be a cause of migraine [77]. It accepts electrons generated in complexes I and II of the respiratory chain and transports them further to complex III [78].

In adults, the treatment showed significant efficacy in migraine prophylaxis in a randomized controlled trial [77] and two open-label studies [79,80]. This effect was not reproduced in children [81]. No side effects have been reported.

Pregnancy

During pregnancy, the number of migraine days temporarily decreases in a large proportion of patients [82,83], while migraine attacks are common immediately after delivery [84]. Often, no drug prophylaxis is needed during pregnancy. Instead, non-drug methods (acupuncture, neuromodulation, biofeedback and sleep hygiene, etc.) are recommended [85,86]. If abstaining from medication is not an option, the use of propranolol and metoprolol as well as amitriptyline may be considered [85]. However, the two beta-blockers have been associated with decreased birth weight and amitriptyline with infant adjustment disorders [42]. Although these drugs have not been evaluated as teratogenic, careful risk-benefit consideration is still necessary.
Recommendations for magnesium supplementation during pregnancy should be viewed with more caution [85]. It has since become known that the use of magnesium sulfate can lead to osteopenia in infants [87], which is why the FDA advises against its use for tocolysis for periods longer than five to seven days [88].

Since it is not known at what dose osteopenia occurs and the risk can therefore not be quantified, the use of magnesium for migraine prophylaxis during pregnancy has now also been discouraged [89].

Menstrual migraine

About 50% of women with migraine describe an increase in the frequency of attacks during menstruation; however, exclusive occurrence during menstruation is rare [82]. Especially in women with frequent attacks, it must be considered that these can also occur coincidentally perimenstrually [90]; an exact delimitation is often only possible with a migraine diary that has been kept over a longer period of time [91]. Menstruation-associated attacks often last longer and are more likely to be associated with nausea [92].

It is recommended that women with migraine attacks that do not always occur in temporal relation to menstruation take “normal” prophylaxis, as discussed above [90]. However, if the seizures are closely associated with the period and the affected person has a regular cycle, this can be useful in treatment planning because the occurrence of the symptoms is predictable. In these cases, NSAIDs and triptans (subject to contraindications and warnings) can be taken as “short-course prophylaxis” for four to seven days [90]. In addition, whereas estrogen gel was previously recommended for short-term prophylaxis [93] and estrogen-containing contraception was recommended to prolong cycles [94], guidelines have since changed with regard to cardiovascular risk [6,95]. Currently, progestogen-containing contraceptives are recommended [6]. In any case, treatment of menstrual migraine should be done in consultation with a gynecologist.

Chronic migraine

Chronic migraine is present when a patient has headaches ≥15 days per month for at least three months, with at least eight days meeting criteria for a migraine attack [3]. Its prevalence ranges from 1.4 to 2.2% in the general population [96]. A large proportion of those affected also have a FMD [97], for which other treatment recommendations apply (see below).

Placebo-controlled studies have confirmed that topiramate [38,98,99], botulinum toxin [100–103], valproate [104] and erenumab [54], galcanezumab [58] and fremanezumab (not yet commercially available in Switzerland). [57] can significantly reduce the number of headache days. We therefore recommend that these medications be preferred in the treatment of chronic migraine.

Medication Overuse Headache

Medication overuse headache (MÜKS) is common-an estimated prevalence of 1 to 2% [105] -and must always be suspected in patients with many headache days. Treatment consists of not taking acute medication [106]. That additional drug prophylaxis is helpful is doubted [106], but definitive statements are not yet possible. Before starting the medication break, it is of great importance to inform the patient well about the duration and expected benefits. Initially (for about four weeks), there may be a temporary increase in the frequency of headaches, and even later, freedom from pain is not to be expected. The goal of treatment is a decrease in attack frequency to pre-drug overuse levels.

Take-Home Messages

If the number of headache days increases or the need for acute medications becomes more frequent, prophylaxis should be discussed.
When selecting a drug, its side effects as well as the patient’s living conditions and acceptance of the therapy must always be taken into account.
Migraine prophylaxis offers the opportunity to significantly reduce the stress patients experience in their daily lives.

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