Prevention with medication

With the introduction of triptans for attack therapy, the importance of medicinal migraine prophylaxis has changed. In the past, the great importance of preventive drug therapy was based on the fact that there were not enough effective and well-tolerated substances to stop attacks. The primary goal of prophylactics was therefore to reduce the number of migraine attacks.

However, the migraine attacks that continued to occur usually had to be endured due to the lack of effective or tolerable acute therapy. Those affected were therefore faced with the alternative of choosing between frequent and possibly difficult to treat migraine attacks without medication prophylaxis, or possibly rarer migraine attacks with medication prophylaxis. The decision was usually in favor of drug prophylaxis. As a lesser evil, patients then had to accept the side effects - as long as the desired effect could be achieved.

Today, patient needs have fundamentally changed. If a migraine patient has a tolerable and effective acute medication available, he or she will be more likely to be negative about preventive treatment - which is associated with a relatively high probability of side effects and whose effect is also uncertain. This is particularly true if one considers the usual effectiveness criterion for drug prevention, which only requires a 50 percent reduction in the number of attacks. Experience has shown that, and understandably, patients do not see a reduction in the frequency of taking an effective triptan from 6 days to 3 days per month with a deterioration in general well-being on the remaining 27 days per month as a desirable success.

Decision on drug prevention

Despite today's highly effective drug therapy for attacks, there are a number of reasons for drug prevention. On the one hand, there are still patients who cannot benefit from the progress of triptans because they either have counter-signs to taking them (e.g. coronary heart disease) or they belong to the minority of patients for whom triptans are not effective or are not tolerated . On the other hand - and this is a decisive argument for migraine prophylaxis - there is also a risk of developing drug-induced headaches when using triptans.

  • The most important basic rule in acute migraine therapy is that acute headache medication (triptans such as painkillers) should be taken on a maximum of ten days per month. In other words: no migraine acute medication should be used on 20 days per month.

If migraine symptoms occur on the 11th, 12th or 13th day of the month, the rule applies that the patient should get through these symptoms without acute medication if they do not want to run the risk of developing an MÜK (medication overuse headache). Consequently, the primary goal of medicinal migraine prophylaxis today is to reduce the number of days on which migraine symptoms occur and thus to reduce the frequency of taking acute medications. Because the overarching goal must be to prevent the development of MÜK. This means that when deciding on migraine prophylaxis, it is less the frequency of migraine attacks that is important than the number of migraine days per month.

Medicinal migraine prophylaxis is necessarily long-term therapy. From the perspective of the migraine patient, such long-term therapy is only acceptable if it is both effective and tolerated. In addition, safety in long-term use is a basic requirement. General rules for achieving these goals are derived from this.

Only effective for migraines

Medicated migraine prophylaxis is a specific procedure for treating migraines - not frequent headaches in general. In particular, headaches caused by MÜK remain practically unaffected. Here, the drug holiday is the therapy of first choice. With a few exceptions, the substances used are also ineffective in chronic tension-type headaches or cluster headaches. Medicinal migraine prophylaxis actually only has a chance of success for migraines.

The dose has to be right

In addition to the selection of the substance, the effectiveness of medicinal migraine prophylaxis depends crucially on the dose used. The most common reason for failure of prophylaxis is a dosage that is too low.

The migraine prophylactics do not work immediately: it usually takes 2 to 8 weeks before there is a noticeable decrease in the frequency of migraines. The effectiveness of a substance should therefore only be assessed after 8 to 12 weeks.

There is virtually no research into how long migraine prophylaxis should be continued. However, taking it for a short period of time over a few weeks usually does not produce a lasting effect. Periods of six to nine months are recommended.

Migraine prophylaxis does not usually lead to complete freedom from migraines - it just makes the breaks between attacks longer. The patient must be informed about this so that when the next migraine attack occurs after starting prophylaxis, he does not stop it due to a supposed lack of effectiveness.

Slowly increase the dose

While for some migraine prophylactics the target dose can be used immediately, for most substances a careful and slow dose increase is required to minimize side effects. The speed of dosing should be individually adjusted. For beta receptor blockers, tricyclic antidepressants, valproic acid or Topamax, several weeks should be allowed for the dosage increase. For some medications, migraine prevention is not listed in the package insert, but their effectiveness may still be known from current studies.

Side effects possible

Substances are also used in migraine prophylaxis that, despite adhering to all application instructions, can potentially cause permanent damage to health. Since migraine is a disease that, with the exception of the rare migraine infarction itself, does not lead to organ damage, such a complication resulting from drug treatment is ultimately unacceptable.

Substances whose long-term use can lead to the development of MÜK are generally not suitable for migraine prophylaxis. These include painkillers as well as ergot alkaloids - even if their use can temporarily reduce the frequency of migraines.

Selection of migraine prophylactics

The treatment recommendations for the treatment of acute migraine attacks differ only slightly internationally. Controlled studies to check the effectiveness and tolerability of acute therapeutic drugs are relatively easy to carry out and the results can easily be transferred from country to country. What is also crucial for the uniformity of the recommendations is that there are undisputedly highly effective substances available in acute therapy. This means that clear, “hard” effectiveness parameters such as freedom from pain within two hours can be chosen for effectiveness comparison in studies.

When it comes to drug prevention, the situation is less clear. To date, there is no substance available that can reliably prevent the occurrence of migraine attacks.

The effectiveness parameters take this fact into account. The most common parameter is therefore not - as is obvious - the achievement of freedom from attacks, but simply a reduction in attacks by 50 percent. Even with the most effective substances, this target value is ideally achieved in only around 60 percent of patients. Controlled trials in migraine prophylaxis are necessarily complex. On the one hand, they are inevitably long-term studies. They are time-consuming for both the patient, who has to continually keep a diary, and the examiner. Due to the relatively low and usually poor effectiveness, study terminations are common and sufficient case numbers are difficult to achieve.

A particular problem is the scientifically unavoidable use of placebos for comparison purposes. A placebo is an identical-looking medication without any effective ingredient. In a placebo-controlled study testing a drug to treat attacks, the patient can switch to a replacement drug after a short time if it is not effective. The possible use of a placebo is therefore usually tolerated by patients, especially since in the majority of cases the study only covers one to a maximum of three migraine attacks.

Participation in a placebo-controlled prophylaxis study, on the other hand, means that some patients will have to take a placebo for months without having the opportunity to switch to a more effective preventive medication. Patients are only willing to a limited extent for this. The result is, on the one hand, studies with small numbers of cases and therefore also low significance. However, larger sample sizes would be important, especially for comparison studies between different prophylactics that differ less in their effectiveness than against placebo.

On the other hand, selection errors can hardly be avoided due to the selection of patients. In placebo-controlled studies with potentially side effects but also potentially effective substances, a disproportionate number of patients are found with above-average frequent, severe and long attacks. Conventional prophylactics were not sufficiently effective in advance - in short, these are the so-called problem patients in specialized headache treatment centers.

In this case, the study results of the substances will be worse than if the average patient had been treated. In contrast, medications that are likely to be well tolerated but potentially less effective (particularly herbal preparations) are often tested outside of specialized centers on patients who are less affected by migraines in terms of frequency and intensity of attacks. Here the study results are relatively good. The result of these selection errors is that, on paper, all prophylactics are approximately equally effective when compared with placebo.

The true differences in effectiveness only become apparent in practice. Ultimately, this could only be avoided through comparative studies of the various prophylactics with each other - studies that are usually missing for the reasons mentioned above. A comparison of the various migraine prophylactics is therefore inevitably subjective to a considerable extent, which explains the differences in official therapy recommendations from various specialist societies.

Tables 1 and 2 below list examples of the treatment recommendations of the German Migraine and Headache Society from 2012.

Table 1: Substances for migraine prophylaxis with good evidence

substances dose Side effects Contraindications
Metoprolol

Propranolol

Bisoprolol

50-200 mg

40-240 mg

5-10 mg

H: fatigue, arterial hypotension
G: sleep disorders, dizziness S: hypoglycemia, bronchospasm, bradycardia, gastrointestinal disorders, impotence
A: AV block, bradycardia, heart failure, sick sinus syndrome, bronchial asthmaR: diabetes mellitus, orthostatic dysregulation, depression
Flunarizine 5-10 mg H: Fatigue, weight gainG: Gastrointestinal complaints, depression

S: Hyperkinesia, tremor, Parkinsonoid

A: focal dystonia, pregnancy, breastfeeding, depression; pre-existing symptoms of Parkinson's disease or other extrapyramidal diseases
Topiramate 25-100 mg H: fatigue, cognitive disorders, weight loss, paresthesia, taste changes, psychosesS: angle-closure glaucoma A: Renal insufficiency, kidney stones, angle-closure glaucoma
Valproic acid 500-600 mg H: fatigue, dizziness, tremorG: rash, hair loss, weight gain,

S: Liver dysfunction

A: Liver dysfunction, pregnancy (neural tube defects), alcohol abuse, polycystic ovaries
Onabotulinum
toxin A for chronic migraines
195 units Muscle weakness Myasthenia
Side effects, divided into
H: Common; G: Occasionally; S: Rare; Contraindications divided into A: absolute, R: relative

Table 2: Substances for migraine prophylaxis with lower evidence

Substances (example) dose Side effects Contraindications
Amitriptyline 50-150 mg H: dry mouth, tiredness, dizziness, sweatingG: bladder disorders, inner restlessness, impotence A: Angle-closure glaucoma, prostate adenoma with residual urine
Venlafaxinoff label use 75-150mg H: fatigue, difficulty concentrating, rarely impotence, arterial hypertension Severe hypertension
Gabapentin
off-label use
2400 mg H: fatigue, dizziness, G: ataxia, gastrointestinal disorders Severe liver or kidney dysfunction
       
       
magnesium 2×300 mg = 24 mmol H: Diarrhea if the dosage is increased too quickly No
Vitamin B2 plus magnesium* 1×400 mg vitamin B2 plus 2×300 mg Mg H: Diarrhea, intense yellow color of urine No
Side effects: H: common, G: uncommon; S: rare, A: absolute, R: relative; CHD = coronary heart disease; AVK = arterial occlusive disease

Individual selection

The individual selection of a medication for migraine prophylaxis should not be based on a predetermined step-by-step scheme. Rather, the selection should be based on the individual needs of the patient. What is good for one person does not necessarily mean that it is suitable for another.

The following list shows the individual characteristics of migraines and the associated targeted selection of active ingredients for prevention. This is based either on the individual symptom constellation or on the existing comorbidities.

A specific choice of medication is recommended if the following accompanying features are present:

Accompanying features

Preferred selection

Migraines + high blood pressure

Beta blockers

Migraines + cardiovascular disease

Calcium antagonists

Migraines + stress

Beta blockers, antidepressants

Migraines + depression

Antidepressants

Migraines + insomnia

Antidepressants

Migraines + underweight

Antidepressants, pizotifen

Migraines + obesity

Topiramate, lisinopril

Migraines + epilepsy

Valproic acid

Migraines + mania

Valproic acid

Migraine + hypersensitivity to side effects

Butterbur

Migraines + stroke

Acetylsalicylic acid

Migraines + leg cramps

magnesium

Migraine + craniocervical dystonia

Botulinum toxin

A specific choice of medication is not recommended if the following accompanying characteristics are present:

Accompanying features

Don't select

Migraines + epilepsy

Antidepressants

Migraines + depression

Beta blockers, topiramate

Migraines + old age/heart disease

Antidepressants

Migraines + obesity

Antidepressants, pizotifen

Migraines + asthma

Beta blockers, topiramate

Migraines + underweight

Topiramate

Migraines + high levels of physical activity

Beta blockers

Migraines + high concentration and thinking performance

Antidepressants, beta-blockers, topiramate

Migraine + liver disorder

Valproic acid

Botulinum toxin (Botox)

Mechanisms of action of Botox in the pathophysiology of migraine. Overall overview

Mechanisms of action of botulinum toxin A (Botox) in the pathophysiology of migraine. Overall overview

On September 23, 2011, the drug Botox® (botulinum toxin type A) received approval from the Federal Institute for Drugs and Medical Devices (BfArM) to relieve the symptoms of chronic migraines in adults who have responded inadequately to or were unable to tolerate prophylactic migraine treatments. The approval was based on the so-called Mutual Recognition Procedure in 14 European countries.

More about the scientific and clinical background:
Prophylaxis of chronic migraines with botulinum toxin

Since the second edition of the International Headache Classification (ICHD-II 2004), the headache entity of chronic migraine listed in the chapter “Migraine complications”. The prevalence is low compared to episodic migraine, but the suffering is considerable because all areas of life are affected. To date, there has been no prophylactic specifically approved for chronic migraines. There is only weak evidence that topiramate may be effective.

After the effect of botulinum toxin type A on migraines was described in case reports, an unsuccessful attempt was made to prove its effect on the more common episodic migraines. It was only through the PREEMPT study program with Botox® in the treatment of chronic migraine that proof of effectiveness could be provided for this severely affected subpopulation. This is the first time that an effective and tolerable treatment option is available for the prophylaxis of chronic migraines, but it must be integrated into an overall therapeutic concept. The first approval of Botox® for the indication “prevention of headaches in adults with chronic migraines (≥15 headache days, ≥ 8 days with migraines per month) took place in England and the USA in 2010. On September 23, 2011, Botox received approval from the Federal Institute for Drugs and Medical Devices (BfArM) for the relief of symptoms of chronic migraine in adults who have responded inadequately to or are intolerant to prophylactic migraine treatments. The approval was based on the so-called Mutual Recognition Procedure in 14 European countries. The treatment of chronic migraines (15 headache days per month, of which 8 headache days must clearly be migraines) with Botox is also covered by statutory health insurance.

Neuromodulation

There are only a few effective treatment options for particularly severely affected patients with chronic migraines and other severe chronic pain. Standard therapy procedures are usually without lasting effectiveness. Recently, peripheral nerve stimulation (PNS) has come into focus as a treatment option. Peripheral nerve stimulation is a specific application of neuromodulation. This has been used to relieve chronic pain for several decades. Successful use is possible for headaches, back pain, neck pain, arm and leg pain. Due to the increasing progress of microelectronics, it is possible to implant a pacemaker-like device under the skin and thus enable continuous neuromodulation. The device is about the size of a matchbox.

To treat chronic migraines, a special rechargeable system can be implanted, meaning there is no need to change the battery. The stimulator sends electrical signals to the occipital nerve (ON), located just under the skin of the neck. Due to this special location, the treatment option is also called occipital nerve stimulation (ONS). The mode of action of occipital nerve stimulation is explained by changes in electrical regulation in the brainstem. The pattern of pain signals is modulated and masked by continuous stimulation. The constant hypersensitivity in the nervous system is balanced and reduced. The function of the neurostimulator system and the peripheral nerve stimulation can be compared to that of the pacemaker. It is assumed that neuromodulation activates and stabilizes the body's own defenses against pain, thus naturally reducing sensitivity to pain signals. The individual steps of implanting the system are described below.

For the decision to undergo neuromodulation, the patient must be cared for in a specialized migraine and headache center. The specialized indication and further professional care must be guaranteed. In our center, in collaboration with the neurosurgery clinics of the University Hospital Schleswig-Holstein, the process described below has proven successful.

The indication and information about treatment options are provided in the Migraine and Headache Center at the Kiel Pain Clinic. We will then organize an outpatient visit to the neurosurgery clinic to plan the operation and anesthesia. Due to our nationwide headache treatment network, care may also be provided at another cooperating and certified neurosurgical center. Further information can be found here .

Medication without effect

Many substances are repeatedly discussed in the media or in specialist literature regarding their preventative effectiveness in migraine therapy. There are reports for a number of these substances that make it unlikely that they have an effect. Therefore, if someone recommends one of the following substances to prevent your migraines, you should ask more closely. These include in particular the following active ingredients:

  • Bromocriptine (used e.g. for weaning)
  • Carbamazepine (e.g. for epilepsy)
  • Cimeditin (e.g. against stomach ulcers)
  • Clonidine (against increased intraocular pressure)
  • Diphenylhydandoin (e.g. against epilepsy)
  • Diuretics (draining medications, various areas of application)
  • Gestagens (e.g. for cycle disorders)
  • Hypotensives (medications to increase blood pressure)
  • Indomethacin (e.g. inflammatory rheumatic diseases)
  • Lithium (mental illnesses)
  • Neuroleptics (e.g. against depression)
  • Nifedipine and nimodipine (heart problems)
  • Nootropics (substances that improve cerebral circulation)
  • Proxibarbal (e.g. for sleep disorders)
  • Reserpine (e.g. for blood pressure)