(i) Purpose of prophylactic treatment
The purpose of preventive treatment is to reduce the frequency of seizures, reduce the degree of seizures, reduce functional impairment, and increase the efficacy of treatment during acute seizures.
(2) Effectiveness indexes of preventive treatment
The effectiveness indexes of preventive treatment include frequency of migraine attacks, duration of headache, degree of headache, degree of functional impairment of headache and response to treatment in the acute phase.
(iii) Indications for prophylactic drug therapy
In general, there are no clear indications for when to start prophylactic treatment, and the most important factor is the extent to which the patient’s quality of life is affected, rather than the frequency or severity of attacks. In general, the use of prophylactic therapy should be discussed with the patient when (1) the patient’s quality of life, work, or schooling is severely compromised (based on the patient’s own judgment); (2) the frequency of attacks is two or more per month; (3) acute medication has failed or is intolerable to the patient; (4) there are frequent, prolonged, or extremely uncomfortable auras, or migrainous infarction, hemiplegic migraine, or basal migraine subtype; (5) use of acute phase therapy more than 6-8 times per month for 3 consecutive months; (6) migraine attacks lasting more than 72 hours; (7) patient’s wishes (as few attacks as possible).
(IV) Prophylactic treatment drugs and evaluation
At present, the drugs applied in the preventive treatment of migraine mainly include: β-blockers, calcium channel blockers, antiepileptics, antidepressants, NSAID and other kinds of drugs.
1. β-blockers: The effectiveness of β-blockers in the prophylactic treatment of migraine is clear and supported by the results of several randomized controlled trials. Propranolol, a non-selective beta-blocker, and metoprolol, a selective beta-blocker, are the most well-documented. In addition, bisoprolol, timolol, and atenolol may be effective, but the strength of the evidence is not as strong. Contraindications to beta-blockers include reactive respiratory disease, diabetes mellitus, postural hypotension, and certain cardiac conditions that slow the heart rate. It is not suitable for athletes and reduced exercise tolerance may occur. Patients with emotional disorders may experience depressed mood and even suicidal tendencies when using beta-blockers.
2. Calcium channel blockers: The non-specific calcium channel blocker flunarizine has been shown to be effective in the prophylactic treatment of migraine at doses of 5 mg to 10 mg daily, with a lower effective dose required for women than for men. The results of studies of cyclomiazepine are inconsistent, with the better-designed studies being negative and therefore not recommended. The results of several studies of nimodipine for migraine prevention failed to show superior efficacy to placebo and are not recommended.
3. Antiepileptic drugs: The results of randomized controlled studies of valproic acid (at least 600 mg daily) confirmed its effectiveness for migraine prevention. Regular blood tests, liver function and amylase are required, and in female patients, more attention should be paid to weight gain and abnormal ovarian function (e.g., polycystic ovary syndrome). Topiramate (25 to 100 mg daily) is another antiepileptic drug supported by trial evidence. Topiramate is effective for chronic migraine and may be effective for MOH.
Lamotrigine does not reduce the frequency of migraine attacks, but may reduce the frequency of aura onset. Gabapentin showed effectiveness in a randomized, double-blind, placebo-controlled study. Results of open, uncontrolled trials suggest that levetiracetam may help reduce headache frequency. The oxcarbazepine trial proved ineffective.
4. Antidepressants: The only drug that has been shown to be effective in all studies is amitriptyline, with positive results from four earlier placebo-controlled trials using doses of 10 mg to 150 mg daily. but the sample sizes of these trials were small and side effects were evident. Amitriptyline has a limited role in migraine prophylaxis, but is particularly indicated for patients with a combination of tension-type headache or depressive states (often with chronic pain). The main adverse effect is sedation. Once-daily use may increase patient compliance. ECG is required for high-dose use.
Two small-sample controlled trials showed the selective serotonin reuptake inhibitor (SSRI) fimoxetine to be effective. 3 trials of fluoxetine showed effectiveness and 1 showed ineffectiveness. Controlled trials of clomipramine and sertraline showed ineffective results. Other antidepressants were only available in open or non-controlled trials. The results of double-blind controlled trials of venlafaxine and amitriptyline confirmed comparable efficacy, and 2 other open studies showed positive results.
5. NSAIDs: The results of studies of ASA for migraine prophylaxis were mixed. Two large cohort studies found that ASA at 200-300 mg daily reduced the frequency of migraine attacks. comparative trials of ASA with drugs of established efficacy showed comparable or poorer effects, while controlled trials with placebo never proved effective. three controlled studies demonstrated that naproxen 1000 mg daily was superior to control. In addition, 2 placebo-controlled studies have shown tolfenamic acid to be effective. Other drugs that have been tested include ketoprofen, mefenamic acid, indobufen, flurbiprofen, and rofecoxib, but the trials are suspected to have small sample sizes and inadequate designs.
6. Other drugs: The anti-hypertensive drugs lenopril and candesartan have each been shown to be effective in migraine prophylaxis in a controlled trial, but further confirmation is needed.
High-dose riboflavin (400 mg daily) and coenzyme Q10 controlled study results show effective. Oral magnesium salts showed conflicting results, with one negative result and one positive result. An extract of Butterbur root (Petasites hybridus) was shown to be effective in two controlled trials at a dose of 75 mg per day, and several controlled trials of wild chamomile extract (Tanacetum parthenium) had mixed results, but the most recently completed well-designed trial showed it to be ineffective and the results of systematic analysis were negative. However, because of the positive control study results, it can only be used as a third-line drug.
Earlier trials of colistin, phenothiazine and dimethyl ergometrine suggested prevention of migraine attacks. However, recent well-designed trials have failed to demonstrate the effectiveness of colistin. Dimethylergotoxine is effective but is recommended only for short-term use (up to 6 months of treatment) due to serious adverse effects and can be reintroduced after a 4- to 6-week washout period. The adverse effects of dizziness and weight gain of phenothiazine significantly hinder its clinical use. Ergots have also been used for migraine prophylaxis, with weaker evidence for dihydroergot cryptine and conflicting results from several trials. Dihydroergot cryptine was shown to be effective and well tolerated in 1 small sample of controlled trials, but the effects need further confirmation. Based on the above evidence these three classes of drugs are not recommended for preventive migraine treatment.
Some earlier trials suggested that botulinum toxin A injections may have a prophylactic effect in migraine, but a systematic analysis of all 7 controlled studies failed to show significant efficacy over placebo. However, the results of prophylactic studies of chronic migraine suggest that it is effective in chronic migraine. A recent randomized double-blind controlled trial showed significant efficacy of botulinum toxin A compared to placebo. Positive results were also obtained in a multicenter randomized double-blind placebo-controlled trial. Randomized double-blind studies comparing botulinum toxin A injections with topiramate and valproic acid for the prevention of chronic migraine have all concluded that they are equivalent and that botulinum toxin is better tolerated.
Other treatments that have proven ineffective in randomized double-blind placebo-controlled trials include the cysteine-leukotriene receptor antagonist montelukast, acetazolamide (50 mg/d), and the neurokinin-1 receptor antagonist lanepitant.
(v) Recommended prophylactic medications (see Table 17)
Table 17 Migraine prophylactic treatment drugs recommended drug daily dose (mg) recommended class side effects contraindications beta-blocker metoprolol 50-200A common: bradycardia, hypotension, drowsiness, weakness, reduced exercise tolerance; rare (<1% incidence): insomnia, nightmares, impotence, depression, hypoglycemia asthma, heart failure, atrioventricular block, bradycardia; use with caution in those using insulin or Glucose-lowering agents Propranolol 40 to 240A Bisoprolol 5 to 10B Calcium channel blockers Flunarizine 5 to 10A Common: drowsiness, weight gain; rare: depression, extrapyramidal symptoms depression, extrapyramidal symptoms antiepileptic drugs Valproic acid 500 to 1800A nausea, weight gain, drowsiness, tremor, alopecia, abnormal liver function liver disease Topiramate 25 to 100A ataxia, drowsiness, cognitive and language impairment, sensory abnormalities, weight loss allergy to active ingredient or sulfonamide gabapentin 1200 to 2400B nausea, vomiting, convulsions, drowsiness, ataxia, vertigo gabapentin allergy antidepressants amitriptyline 50 to 100B dry mouth, drowsiness, weight gain glaucoma, prostate adenoma NSAIDs naproxen 250 to 500bidB aspirin 300B other drugs candesartan 16B lenopril 20B magnesium salt 24mmolB riboflavin 400B coenzyme Q10 300B dimethyl ergometrine 4 to 122 to 6 (law) every 6 months to stop 1 monthB common: nausea, vertigo, insomnia; rare: retroperitoneal fibrosis hypertension, coronary artery supply deficiency, arterial disease, gastric ulcer, liver or kidney failure
(vi) Principles of prophylactic drug selection and use
The physician must communicate with the patient before using prophylactic drugs and select them according to the patient’s individual situation, paying attention to the therapeutic effects and adverse effects of the drugs, as well as to the patient’s co-morbidities, interactions with other drugs, the number of daily doses and financial situation. First-line drugs with solid evidence are usually considered first, and second- or third-line drugs are considered only if first-line drugs fail, if there are contraindications, or if the patient has comorbidities that can be treated simultaneously with second- or third-line drugs. Avoid medications that are contraindicated for other comorbidities of the patient and medications for other conditions that may exacerbate migraine attacks. Long-acting agents may increase patient compliance.
Medication should be started in small single doses and slowly increased to the appropriate dose, with attention to side effects. Each medication should be given a sufficient observation period to determine efficacy, usually 4 to 8 weeks. Patients need to keep a headache diary to assess the effectiveness of treatment and to help identify triggers and adjust lifestyle habits. A reduction in migraine attack frequency of 50% or more is considered effective for preventive treatment. Effective prophylactic treatment should be continued for about 6 months, after which the dosage can be slowly reduced or stopped. If the frequency of attacks returns, the previously effective medication may be reintroduced. If prophylaxis is ineffective and the patient has no significant adverse effects, the dose may be increased; otherwise, a second prophylactic medication should be switched. If several monotherapy sessions are ineffective, then consider combination therapy, also starting with a small dose.