Neurol Sci (2006) 27:S153–S158 DOI 10.1007/s10072-006-0592-0 P R E V E N T I V E T R E AT M E N T O F H E A D A C H E S
G. Pierangeli • S. Cevoli • E. Sancisi • D. Grimaldi • S. Zanigni • P. Montagna • P. Cortelli
Which therapy for which patient?
Abstract Prophylactic treatment is mainly intended to reduce the frequency of migraine attacks, enhance response to acute medications, improve patient function and reduce disability. Sufficient evidence and consensus exist to recommend propranolol, timolol, amitriptyline, pizotifen, divalproex, sodium valproate and topiramate as first line agents for migraine prevention. These drugs can halve the frequency of attacks in 50% of patients. The anticipated benefit must be weighed against the adverse effects associated with each agent in determining the optimal preventive regimen for individual patients considering any comorbid conditions that are often present. The decision to treat and the choice of prophylactic drug must be taken with the patient. It is important to balance expectations and therapeutic realities for each particular drug. Recent data on the effect of prophylactic treatment on trigeminovascular activation and on cortical spreading depression emphasise the importance of developing research on migraine-preventive drugs. Key words Migraine Neuromodulators
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Prophylaxis
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Therapy
G. Pierangeli () • S. Cevoli • E. Sancisi • D. Grimaldi S. Zanigni • P. Montagna • P. Cortelli Dipartimento di Scienze Neurologiche Università di Bologna Via U. Foscolo 7, I-40123 Bologna, Italy e-mail:
[email protected]
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Introduction Following a period of evaluation of headache characteristics by means of a diary, care in avoiding trigger factors and correct application of rules for the management of migraine attacks, patients should be evaluated for initiation of preventive therapy. Factors that should prompt consideration of preventive therapy include the occurrence of two or more attacks per month producing disability lasting three or more days per month, contraindications, intolerance or failures of acute treatments, uncommon migraine conditions such as hemiplegic migraine, migraine with prolonged aura and migrainous infarction. The development of new and effective drugs for migraine attacks like triptans may reduce the need for preventive treatment but use of abortive medication more than twice a week must be considered a “red flag” for starting a prophylactic drug to avoid the progression from episodic to chronic migraine. The goal of preventive therapy is to improve the patient’s quality of life by reducing migraine frequency, severity and duration and increasing the responsiveness of acute migraines to treatment. Therapy should be initiated with medications that have the highest levels of effectiveness and the lowest potential for adverse reactions. The dose should begin at the low end of the range, and be slowly titrated until an effective dose is reached. Patients should be informed that several months of treatment may be required to reach maximum benefit and that the first drug that we try is not always the right one.
Biological basis for migraine-preventive drugs Migraine-preventive drugs, for example propranolol and valproate, have often been found serendipitously. Targeted migraine prevention, considered as the development of
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drugs that interact with specific receptors of cellular mechanisms believed to be involved in the pathogenesis of migraine, remains unavailable. Patients often receive “offlabel” medications i.e., drugs used primarily for indications other than migraine. Therefore the basic mechanisms of action of antimigraine prophylactic drugs are largely speculative. Most preventive treatments are thought to act, at least in part, by normalising neuronal firing and increasing a genetically lowered and environmentally modified threshold for neuronal discharge [1, 2]. The basis for this effect could be a central hyperexcitability due to changes in voltage-gated channels looking for a rationale for the prophylactic action of calcium channel blockers and partially for antiepileptic drugs (AEDs), or a mitochondrial dysfunction for riboflavin and coenzyme Q effect, or a central aminergic dysfunction when considering tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), noradrenergic reuptake antagonists (NARAs ), β-blockers and AEDs. AEDs have recently been referred to as neuromodulators to reflect the fact that their efficacy in migraine is believed to result from modulation of neuronal and cortical hyperexcitability. Divalproex sodium enhances brain γ-aminobutyric acid (GABA) and this is presumed to be its principal mechanism of action in migraine. Topiramate has multiple mechanisms of action, including state-dependent blockade of sodium channels, enhancement of GABAA receptor-mediated inhibition, antagonism of glutamate at α-amino-3-hydroxy-5methylisoxazole-4propionic acid/kainate (AMPA/kainate) receptors and inhibition of high-voltage-activated (L-type) calcium channels. It is also a weak inhibitor of some isozymes of carbonic anhydrase. A recent intravital microscopy study demonstrated that topiramate is likely to block neurogenic dural vasodilatation by inhibiting the release of CGRP from prejunctional trigeminal neurons, thus attenuating the dural vasodilatation [3]. Topiramate, valproate, propranolol, amitriptyline and methysergide suppress cortical spreading depression frequency by 40%–80% and longer treatment durations produce stronger suppression [4].
Preventive medications The principal guidelines on preventive therapy for migraine have been drawn up by the US Headache Consortium, a group of seven professional specialty associations composed of physicians involved in the care of patients with migraine founded in 1996. These guidelines are published in two papers and are available on the American Academy of Neurology website [5–10]. An important contribution to prophylactic drug choice is given by the systematic overviews and meta-analysis of the Cochrane Library on different groups of preventive treatments [11, 12]. First-line therapies are listed in Table 1.
β-Adrenergic blockers Propranolol and timolol have the greatest amount of literature support (Grade A) for their use but there is also literature support for atenolol, metoprolol and nadolol [9]. While generally well tolerated, common adverse effects include tiredness, fatigue, nausea, depression, dizziness and insomnia. They are particularly useful for patients with coronary disease, hypertension, tachycardia or essential tremor, but should be avoided in those with Raynaud’s syndrome or reactive airways disease or atrioventricular block.
Antidepressants Amitriptyline is a first-line agent for migraine prophylaxis with Grade A quality of evidence and is the only antidepressant with consistent evidence supporting its effectiveness for this use. One study involving 162 patients with migraine compared amitriptyline therapy (50–100 mg/day) with placebo over four weeks. Results showed an odds
Table 1 First-line medications for migraine prevention Medication
Dosage
Main adverse effect
Amitriptyline Divalproex Normal release Sustained release
10–150 mg h.s.
Weight gain, dry mouth, sedation
250 to 500 mg t.i.d. 500 mg b.i.d.
Liver toxicity, sedation, nausea, weight gain, tremor, teratogenicity, possible drug toxicity
Propranolol Normal release Sustained release Timolol Topiramate
20–80 mg t.i.d. 80–240 per day 10–15 mg b.i.d. 50–100 mg b.i.d.
h.s., at bedtime; b.i.d., twice daily; t.i.d., three times daily
Fatigue, exercise intolerance Paraesthesias, fatigue, nausea
G. Pierangeli et al.: Which therapy for which patient?
ratio (OR) of 2.4 (95% CI, 1.1–5.4) for the number of patients reporting a 50% improvement in migraine index, and a moderate effect size of 0.62 (95% CI, 0.15–1.10) on a migraine index that included frequency and duration. Results of a study comparing amitriptyline with propranolol suggest that propranolol is more effective in patients with a single migraine type, whereas amitriptyline is more beneficial for patients with mixed migraine and tensiontype headache. However, side effects like weight gain, dry mouth, reflex tachycardia, blurred vision and mental clouding related to anticholinergic, antihistaminic and βadrenergic effects limit the use of this medication. If a patient cannot tolerate the adverse effects of amitriptyline, a different TCA might be considered, although there is some evidence that other TCAs are not effective for migraine prevention [10]. The results from one small trial support the use of fluoxetine 10–40 mg/day; however a larger trial showed no evidence to support its use, and evidence does not support the use of the numerous other SSRI for migraine prevention [11].
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Serotoninergic agents Of these agents, time-released dihydroergotamine has the strongest support, with consistently positive findings in four placebo-controlled trials [8]. The most commonly reported events for all the ergot alkaloids were gastrointestinal symptoms. There is strong evidence for the efficacy of methysergide, a semisynthetic ergot alkaloid [7]. However there are reports (1/2500) of retroperitoneal and retropleural fibrosis associated with long-term, mostly uninterrupted administration. The manufacturer suggests that methysergide therapy be discontinued for three to four weeks after each six-month course of treatment. Adverse events most commonly reported include nausea, vomiting and leg symptoms (restlessness or pain). Lisuride and pizotifen have consistent evidence supporting their efficacy in the prevention of migraine [8]. Pizotifen is often associated with weight gain and drowsiness.
Calcium-channel blockers Neuromodulators (anticonvulsants) Anticonvulsants appear to be both effective in reducing migraine frequency and reasonably well tolerated. There is noticeable variation among individual agents, but there are insufficient data to establish whether this is due to chance or variation in true efficacy. AEDs considered as a class in a systematic review of the Cochrane Database [13] reduce migraine frequency as compared to placebo (SMD –0.60; 95% CI –0.93 to –0.26). In clinical terms the observed effect corresponds to a reduction in migraine frequency of 1.4 attacks per 28 days. AEDs, considered as a class, also increase the number of patients for whom migraine frequency is reduced by 50% or more, relative to placebo. Relatively few robust trials are available for agents other than sodium valproate/divalproex sodium although side effects such as nausea, alopecia, tremor and weight gain may lead patients to discontinue treatment. These drugs are known to be teratogenic and appropriate caution must be used when prescribing to women of child-bearing age. Considered together, the three trials of topiramate (514 patients in total) proved superior to placebo (OR 3.65; 95% CI 2.47–5.38) and a recent evaluation of changes in health-related quality of life in 220 patients treated with topiramate 100 mg/day showed a significant improvement [12]. Dose comparisons for topiramate (50, 100, 200 mg daily) with placebo showed best odds ratio for the 100 mg dose (3.66 (2.46–5.45)). Adverse events, generally mild, include paraesthesias, weight loss, altered taste, anorexia, memory impairment, emotional lability, diarrhoea, dysarthria, urinary frequency and abnormal vision.
There is weak evidence to support verapamil as a first-line agent. Of three small trials comparing verapamil 240 or 320 mg/day, two reported positive findings, with a moderate calculated summary effect size of 0.78 (95% CI, 0.09–1.50) [7, 10]. In particular it may be effective in patients with prolonged atypical migraine aura and it may be useful in patients who have comorbid cardiovascular disease. The principal contraindications are bradycardia and atrioventricular block. The adverse event most frequently reported is constipation. Flunarizine has proven efficacy. Adverse events reported include sedation, weight gain and depression. Extrapyramidal symptoms may be observed particularly in the elderly.
Angiotensin blockade A systematic overview and meta-analysis of patients receiving angiotensin II receptor antagonists (AIIRA) for either hypertension or headache showed a 31% reduction in the risk of headache in patients taking AIIRA compared with those on placebo [14]. The AIIRAs lisinopril and candesartan demonstrated some effectiveness in randomised, doubleblind, crossover trials [15, 16]. Candesartan (16 mg/day) showed a 40.4% rate of response based on a 50% or more reduction in the number of days with migraine compared with 3.5% for placebo (p
