Preventive Oral Treatment of Episodic Migraine: An Overview
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.315985
Source of Support: None, Conflict of Interest: None
Keywords: Antidepressants, antiepileptics, antihypertensives, episodic migraine, oral preventive treatment
Migraine is a common primary headache disorder affecting women about three times more commonly than men. Episodic migraine is headache occurring on 14 days or less in a month. Chronic migraine is characterized by occurrence of 15 or more headache days in a month for 3 months with 8 headache days showing the characteristics of migraine.
The treatment of migraine consists of abortive or acute treatment and preventive or prophylactic treatment. Acute treatment aims at abolishing the ongoing attack and prophylactic treatment is intended to prevent further headache attacks and improve the quality of life of migraine patients. The preventive treatment of migraine is a multi-pronged approach and includes pharmacological and non-pharmacological approaches [Figure 1]. In this article, we review the conventional oral treatments that are used in the prevention of episodic migraine.
The initiation of preventive oral treatment has to be considered and tailored to the attack frequency, duration, disabling nature and the severity of the attack, response to acute treatment, and considering the preference of the patient. The preventive therapy may be considered in patients with:
The objectives of initiating oral preventive treatment are aimed at:
Migraine preventive treatment is considered beneficial if it reduces the frequency and severity of migraine attacks by at least 50% from the previous baseline within three months. Patients can keep a log of the occurrence of headaches using a migraine diary and calendar that can help assess the response to treatment and is recommended for the evaluation of treatment response. The migraine diary is useful in recording the headache event, the use/overuse of acute medication and the disability due to headache that causes loss of work time. The calendar, in addition can help record the relation to the menstrual cycle, compliance to preventive treatment, migraine/headache frequency, and severity [Figure 2]. These diaries and calendars thereby help assess response to preventive treatment measured as a decrease in migraine/headache days, severity of the headache and improved quality of life and work. According to the American Migraine Prevalence and Prevention (AMPP) study, only 13% of migraineurs are using preventive therapy to reduce migraine attack, whereas about 38% of the migraineurs should be considered for the preventive therapy.
In patients with episodic migraine considered for preventive therapy, it is better to initiate the selected drug at a low dose and titrate upwards until the desired therapeutic target or the maximum tolerable dose is achieved. An adequate duration of treatment has to be tried with the selected agent because the efficacy may be noted in 4 weeks and may take up to 3 to 6 months. It is essential to consider the choice of the drug after adequate discussion with the patient, considering the patient preferences, side effect profile and the presence of comorbidities that may benefit from the use of the drug.
It is imperative to avoid the overuse of acute pain management medications to minimize the risk of development of medication overuse headache. Periodic evaluation of the patient, assessing the frequency and intensity of headache profile is essential to plan for tapering off the drug. Discontinuation of the drug may be considered in patients after a reasonably sustained period of remission of at least 6 to 9 months.
The various classes of drugs that are established to be useful in the oral preventive treatment of migraine are
The initial choice of therapy has to be decided to keeping in mind the following characteristics,;
The headache reduction of more than 50 percent in frequency with the use of antihypertensive, antidepressants drugs is noted in about onehalf to twothirds of the individuals when used for the initial preventive therapy. The antiepileptic drug valproate is generally not used as firstline in females of childbearing age. In those patients in whom the headache is poorly controlled and are using effective methods of contraception, valproate may be used when other drugs are not effective in achieving headache control. The presence of comorbidity can help guide the clinician in deciding the choice of therapy but never the sole deciding factor, [Table 1].
In patients with the inadequate response after adequate therapeutic trial or in whom the use is limited by the occurrence of side effects, it is recommended to switch to medication from a different class. However, randomized control trials are limited in guiding the choice of alternate therapy.
The oral preventive medicine used in episodic migraine is summarized.
Oral Preventive drugs in episodic migraine
(A) Anti hypertensive:
The antihypertensive drugs that are useful in the prevention of migraine are:
Mechanism of Action – Beta-blockers exert their action probably through central mechanisms by
Beta Blockers also normalize the habituation of cortical evoked potentials which is reduced in migraine in between attacks.
Beta blockers are the most commonly used drugs in the prevention of migraine. They have the efficacy of producing more than 50% reduction in migraine headache frequency. Non-selective ß blocker propranolol and selective ß1 blocker metoprolol have demonstrated consistent efficacy. A metanalysis had revealed a reduction of 44% in migraine compared to placebo. Atenolol, bisoprolol, nadolol and timolol are also probably effective in migraine prevention. ß blockers with intrinsic sympathomimetic activity (ISA) such as acebutolol, alprenolol, pindolol are not effective.,
Side effects: Somnolence, sleep disorder, fatigue, depressive disorder, memory impairment and hallucinations, poor exercise tolerance, decreased heart rate, orthostatic hypotension and erectile dysfunction. Contra indications that need to be considered before the use of beta blockers include patients having asthma, chronic obstructive pulmonary disease, cardiac conduction disturbances, congestive cardiac failure, diabetes, depressive disorder, and peripheral vascular disease.
Summary of Evidence: -
(b) Calcium Channel blockers (CCB):
Mechanism of action - Calcium Channel Blockers: -
The exact mechanism of prevention of migraine by CCB is unknown. However, the possible mechanisms through which it may be mediated include:
The commonly used CCBs in the prevention of migraine are flunarizine, verapamil.
Flunarizine, a nonselective CCB with the antidopaminergic property was found to be superior when compared to placebo in several controlled trials for the prevention of migraine. The dosage required is 5-10 mg daily. It is ideal to start with a low dosage, 5 mg & then titrate it upward according to the response and need. The adverse events include drowsiness, increase in weight, decrease in blood pressure, extrapyramidal symptoms, augmentation of depression, giddiness.,
The effectiveness of verapamil in migraine prevention was more than placebo in two preventive migraine trials. However, these trials were limited by increased dropout and small sample size. The usual dosage is 120 mg to 640 mg with a usual starting dose of 120 mg daily & then gradual titration upward according to the response and need. The adverse effects include headache, pedal edema, decreased bowel movements, decreased blood pressure and fatigue.,
Main advantage of calcium channel blockers is noted in patients with prolonged aura, basilar migraine or hemiplegic migraine. Tolerance may be noted with the use of calcium channel blockers. It may be required to step up the dose, or switch over to a different calcium channel blocker.
Other non-selective CCBs such as nimodipine, nicardipine, diltiazem has not shown superiority over placebo and is not recommended for migraine prophylaxis.
Summary of Evidence: -
Level-A is present for Flunarizine
Level B- noted & probably effective agent used for migraine prevention is verapamil
Level U - Nicardapire, nimodipine, nifedipine
c) Angiotensin Converting Enzyme Inhibitor (ACE)/Angiotensin Receptor Blocker (ARB):
The mechanism by which ACEI/ARB prevents migraine is not exactly known. However, the possible mechanisms are: decreased activity in renin/angiotensin mediated relay of pain in the brain and decreased activity of carboxypeptidase that results in decreased breakdown of enkephalin. A double-blind, cross over study of lisinopril with a placebo control in migraine prophylaxis revealed at least 50% reduction in days with migraine in 14 participants for active treatment compared to placebo. A randomized placebo controlled, double blind, cross over study of candesartan (16 mg), revealed decrease in the duration of headache in the study population. The above data suggests the drugs are efficacious in the prevention of migraine. The recent concerns revolve around the susceptibility of the patient on Renin-angiotensin-system (RAS) blockers to increased risk of coronavirus disease, COVID-19. This is possibly due upregulation of the receptors that facilitate virus entry. However, the data on tissue specific upregulation of membrane ACE receptors in the lungs and if it certainly augments viral entry are lacking. Adverse effects of ACE inhibitors are cough, giddiness and decreased blood pressure. Candesartan is generally well tolerated and possible side effects include fatigue and giddiness.,,,,
Summary of Evidence -
Level-C- Possibly effective is Lisinopril, Candesartan.
The antidepressant drugs that are useful in the prevention of migraine are:
Tricyclic Antidepressants (TCA) and serotonin-norepinephrine reuptake inhibitors (SNRI) are found to be effective in migraine prevention.
The exact mechanisms of action of the antidepressant in migraine prevention is not well established. However, the prevention of migraine may be effected by
The TCAs also augment the effect of opioids when they are co-administered. Amitriptyline was found to be effective in four trials for the prevention of migraine. The evidence for the use of these agents in the prevention of migraine is lacking.
The dosage of TCA is used in a wide range and most of the drugs are sedating. Hence it is always advisable to start at a low dosage and gradually titrate upwards. Since these drugs are sedating, they are to be given at bedtime. Amitriptyline is given at a dosage of 10-400 mg. Start at low dosage of 10 mg at bedtime, increase gradually depending upon the response & side effects. Similarly, for Nortriptyline, the usual starting dose is 10-25 mg at night, with a maximum dosage is 150 mg/day. Protriptyline is another secondary amine like nortriptyline. The starting dose is 5 mg daily with a dosage range, 5-60 mg/day.,
Amitriptyline is more sedative than its metabolites Nortriptyline and Protriptyline. Patients with comorbid depression may require a higher dosage to treat depression. Antidepressant in bipolar patients has to be used cautiously as it may change the depression into frank mania. Elderly patients are at increased risk of developing a delirious state, confusion and cardiac conduction abnormalities. The side effects caused by antagonism of muscarinic receptors include dryness of mouth, blurring of vision, decreased bowel movements, retention of urine, discomfort in the epigastric region, increased heart rate, orthostatic hypotension, confusion, giddiness, cardiac conduction abnormalities.
Other antidepressants like clomipramine and sertraline are not effective in migraine prevention.
Selective Serotonin Reuptake Inhibitor (SSRI) like fluoxetine may be useful for patient with comorbid depression. In refractory depression, a combination of SSRI and TCA may be useful. The evidence is lacking for the use of SSRI in the prevention of migraine.,
SNRI venlafaxine is shown to be effective in a double-blind trial with placebo control. However, the evidence is weak. It may be considered in patients who have comorbidities such as generalized anxiety disorder, panic disorder, and social anxiety. Venlafaxine may be started with a low dosage of 37.5 mg extended-release for 1 week & then increased to 75 mg/day and titrated upward gradually to a maximum of 150 mg/day. Adverse effects include decreased sleep, seizures, nervousness.
Summary of Evidence:
(C) Anti-epileptic drugs:
The antiepileptic drugs that are useful in the prevention of migraine are:
Anti-epileptic drugs are more commonly prescribed for the prevention of migraine, as many randomized control trials have shown their efficacy.
Valproic acid and divalproex sodium are useful in the preventive treatment of migraine. The mechanism by which valproate prevents migraine is manifold and possibly mediated through GABAergic mechanisms. A triple-blind, placebo-controlled study with a cross over design, revealed 50% reduction in frequency of migraine in 50% of the patients with the use of a slow-release sodium valproate. Similar results were also noted with extended-release divalproex sodium in migraine prevention. Patient compliance and side effect profile were better with divalproex.
The dosing of long-acting/extended release agents may be given once daily with a starting dose of 250-500 mg per day and maybe increased and up titrated to a dosage of 500-1500 mg per day. Maximum dosage is 60 mg/kg/day. Serum level may be monitored if any untoward effect or poor compliance is suspected. The most common adverse events are nausea, vomiting and gastrointestinal disturbances and the incidence decreases over a period of 6 months. Alopecia, tremors , and hyperammonemia may be noted and sedation is rare. Serious idiosyncratic adverse effects include hepatitis and pancreatitis. The risk may be augmented in patients with co-administered hepatotoxic drugs and the presence of other metabolic or genetic disorders that may have the potential to damage the liver. The teratogenic potential of the drug limits its use in pregnancy. Increased androgen and weight are limiting side effects in young females.
The exact mechanism of action of topiramate in migraine prevention is unknown. It may be mediated by inhibiting neuronal voltage-dependent sodium channels and may enhance the inhibitory activity of GABA and also has weak carbonic anhydrase inhibitor activity. A multi- center, randomized, double-blind, clinical trial with placebo-control for the prevention of migraine assessed the efficacy & safety of topiramate in various dosages of 50 mg, 100 mg & 200 mg per day. Trials revealed the responder rate (defined as 50% or more reduction in migraine frequency occurring every month) as 36% (50 mg/day), 54% (100 mg/day) and 52% (200 mg/day) respectively compared to 23% of placebo. Similar results were also noted in a randomized control trial of topiramate for migraine prevention.,
A randomized control trial compared topiramate 100 mg/day, 200 mg/day to placebo or propranolol (160 mg/day) & showed the superiority of topiramate over placebo causing a reduction in frequency of migraine, improved migraine response and decreased use of rescue therapy. Topiramate and propranolol were similar in efficacy.
It is usual to start with low dose of topiramate at 25 mg/day once daily and then up titrate gradually by a dose of 25 mg every week to reach a dose of 50-100 mg/day in two divided doses. If any adverse effect occurs, halt the escalation and reduce the dosage to the least tolerable dose and then gradually increase more slowly after the adverse effect has subsided.
The adverse effects of topiramate include paresthesia, loss of appetite, loss of weight, taste perversions, diarrhea, pain in the abdomen, somnolence, insomnia, cognitive disturbances. Renal calculi and decreased sweating may occur uncommonly. The rare adverse events include the development of acute myopia and angle-closure glaucoma.
It possibly plays a role in migraine prevention by blocking voltage-sensitive sodium channels resulting in the inhibition of neuronal glutamate release. Many open label studies had suggested that lamotrigine may have effectiveness in the prevention of migraine with prolonged aura, but randomized control studies have failed to show its effectiveness in the prevention of migraine.,
The evidence for the use of carbamazepine in prevention of migraine is poor and lacking. Levetiracetam is also found to be useful in the preventive treatment of episodic migraine. The various oral drugs used in the prevention of episodic migraine are summarized in [Table 3].
Level A: - Strong evidence for effectiveness in the prevention of migraine noted with divalproex sodium, sodium valproate and topiramate
Level C - for consideration of lamotrigine in migraine patient with aura
Level U - Insufficient evidence for carbamazepine.
(D) Miscellaneous Agents
The summary of evidence of oral drugs used in the prevention of episodic migraine is summarized in [Table 4].
The summary of the various guidelines (European headache federation (EHF) and WHO 2019 consensus guidelines, Canadian Headache Society guidelines, American Academy of Neurology, American Headache Society, European Federation of Neurological Societies) in the oral preventive treatment of episodic migraine is as below,,,,:
Indications for migraine prevention from various guidelines are summarized in [Table 5].
Principles of prophylaxis
Maintenance of headache diary and calendar is useful in the diagnosis and follow up of patients. It is essential to start with low dosage of the planned drug and titrate upwards. Single daily dosing is associated with better patient compliance. While the patient is started on preventive treatment, it is also essential to assess the risk of medication overuse headache and the frequent use of acute therapy should be discouraged. It may take up to 2 to 3 months to establish the efficacy of the drug. A patient who fails to respond to one class of drug may respond to a different class of drug. Tapering of drugs may be considered in patients who are headache free for six months. A drug is considered effective for prophylaxis when it reduces the headache frequency by 50% in 50% of the patients when used for more than 3 months. In addition, the efficacy of a drug needs to be assessed also based on decreasing the intensity and disability associated with migraine.
Migraine remits during pregnancy and preventive treatment may not be required. If a preventive drug is required, propranolol or amitriptyline may be used under specialist guidance.
HURT questionnaire and HALT 30 index may be used in the follow up of patients who are on preventive treatment of migraine as a measure of outcome. In patients in whom the headache fails to be controlled by preventive treatment, it is essential to consider the following:
Referral to a specialist may be considered. A patient who fails to respond to monotherapy, may be considered for polytherapy. The polytherapy combinations based on expert consensus are divalproex sodium and beta-blockers, topiramate and beta-blockers, amitriptyline and beta -blockers, topiramate and amitriptyline.
Migraine headaches can be disabling to the patient and impair the activities of daily living. A carefully chosen oral preventive therapy in consensus with the patient after discussion can help decrease the frequency and intensity of headaches, improve the response to acute therapy, and reduces disability. It is also necessary to consider the comorbidity that the patient has in considering the choice of the drug. A regular log of the headaches in a headache diary and calendar can be useful in the follow-up and monitoring of patients.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]