Preventive Treatment for Migraine

By | January 31, 2015

Migraine is a common episodic headache disorder characterized by attacks that consist of various combinations of headache and neurologie, gastrointestinal, and autonomie symptoms. It has a one-year prevalence of approximately 18% in women, 6% in men, and 4% in children. The second edition of the International Classification of Headache Disorders (ICHD-2) subclassifies migraine into migraine with-out aura (1.1) and migraine with aura (1.2), the aura being the complex of focal neurologie symptoms that most often precede or accompany an attack. Migraine varies widely in its frequency, severity, and impact on the patient’s quality of life. A treatment plan should consider not only the diagnosis, symptoms, and any coexistent or comorbid conditions the patient may have, but also the patient’s expectations, needs, and goals. The pharmacologie treatment of migraine may be acute (abortive) or preventive (prophylactic), and patients with frequent severe headaches often require both approaches. Acute treatment attempts to relieve or stop the progression of an attack or the pain and impairment once an attack has begun. It is appropriate for most attacks and should be used for a maximum of two to three days a week. Preventive therapy is given, even in the absence of a headache, in an attempt to reduce the frequency, duration, or severity of attacks. Additional benefits include improving responsiveness to acute attack treatment, improving function, and reducing disability.

There is a possibility that preventive treatment may also prevent episodic migraine’s progression to chronic migraine and resuit in health-care cost reductions. Silberstein et al. retrospectively analyzed resource utilization information in a large claims database. The addition of migraine preventive drug therapy to therapy that consisted of only an acute medication was effective in reducing resource consumption. During the second six months after the initial preventive medication, as compared with the six months preceding preventive therapy, office and other out-patient visits with a migraine diagnosis decreased by 51.1%; emergency department (ED) visits with a migraine diagnosis decreased by 81.8%; computed tomography (CT) scans with a migraine diagnosis decreased by 75.0%; magnetic resonance imagings (MRIs) with a migraine diagnosis decreased by 88.2%; and other migraine medication dispensements decreased by 14.1%.

According to the U.S. Evidence-Based Guidelines for Migraine, circumstances that might warrant preventive treatment are shown in Box U.S. Evidence-Based Guidelines for Migraine — Preventive Treatment. These rules are stricter during pregnancy — severe disabling attacks accompanied by nausea, vomiting, and possibly dehydration are required for preventive treatment to be prescribed.

Box U.S. Evidence-Based Guidelines for Migraine — Preventive Treatment

  1. 1. Recurring migraine that significantly interferes with the patient’s daily routine despite acute treatment (e.g., two or more attacks a month that produce disability that lasts three or more days, or headache attacks that are infrequent but produce profound disability)
  2. 2. Failure of, contraindication to, or troublesome side effects from acute medications
  3. 3. Overuse of acute medications
  4. 4. Special circumstances, such as hemiplegic migraine or attacks with a risk of permanent neurologic injury
  5. 5. Very frequent headaches (more than two a week), or a pattern of increasing attacks over time, with the risk of developing medication overuse headache
  6. 6. Patient preference, that is, the desire to have as few acute attacks as possible

It is clear that preventive therapy is not being utilized to nearly the extent it should be. Results from the American Migraine Study I and II and the Philadelphia phone survey II demonstrated that migraine preventive therapy is underutilized. In the American Migraine Study II, 25% of ail people with migraine, or more than seven million people, experienced more than three attacks per month, and 53% of those surveyed reported either having severe impairment because of their attacks or needing bed rest. However, only 5% of ail migraineurs currently use preventive therapy to control their attacks.

The major medication groups for preventive migraine treatment (Table Preventive Prescription Drugs) include anticonvulsants, antidepressants, β-adrenergic blockers, calcium channel antagonists, serotonin antagonists, neurotoxins, nonsteroidal anti-inflammatory drugs (NSAIDs), and others (including riboflavin, minerais, and herbs). If preventive medication is indicated, the agent should be preferentially chosen from one of the first-line categories, based on the drug’s side-effect profile and the patient’s coexistent and comorbid conditions (Table Migraine Comorbid Diseases).

Table Preventive Prescription Drugs

ACE inhibitors/angiotensins

  • Receptor antagonist



β-adrenergic blockers

Calcium channel antagonists

Neurotoxins Serotonin antagonists


  • NSAIDs, riboflavin, magnesium, feverfew, butterbur root, neuroleptics

Abbreviations: ACE, angiotensin-converting enzyme; TCA, tricyclic antidepressants; SSRI, selective serotonin reuptake inhibitor; MAOI, monoamine oxidase inhibitor; NSAID, nonsteroidal anti-inflammatory drug.

Table Migraine Comorbid Diseases


  • Hyper-/hypotension
  • Raynaud’s
  • Mitral valve prolapse
  • Angina/myocardial infarction
  • Stroke



  • Epilepsy
  • Essential tremor
  • Positional vertigo


  • Irritable bowel syndrome


  • Asthma
  • Allergies

Mechanism Of Action Of Preventive Medications

The migraine aura is probably due to cortical spreading depression (CSD), a decrease in electrical activity that moves across the cerebral cortex at a rate of 2 to 3 mm/min. Headache probably results from activation of meningeal and blood vessel nociceptors combined with a change in central pain modulation. Headache and its associated neurovascular changes are subserved by the trigeminal System. Trigeminal sensory neurons contain substance P, calcitonin gene-related peptide (CGRP), and neurokinin A. Stimulation results in the release of substance P and CGRP from sensory C-fiber terminais and neurogenic inflammation (NI). The neuropeptides interact with the blood vessel wall, producing dilation, plasma protein extravasation, and platelet activation. Neurogenic inflammation sensitizes nerve fibers (peripheral sensitization), which now respond to previously innocuous stimuli, such as blood vessel pulsations, causing, in part, the pain of migraine. Central sensitization (CS) of trigeminal nucleus caudalis neurons can also occur. CS may play a key role in maintaining the headache. Brainstem activation also occurs in migraine without aura, in part due to increased activity of the endogenous antinociceptive System. The migraine aura can trigger headache: CSD activates trigeminovascular afferents. Stress can also activate meningeal plasma cells via a parasympathetic mechanism, leading to nociceptor activation.

Migraine may be a resuit of a change in processing of pain and sensory input. The aura is triggered in the hypersensitive cortex (CSD). Headache is generated by central pain facilitation and NI. CS can occur, in part, mediated by supraspinal facilitation. Decreased antinociceptive System activity and increased peripheral input may be present.

Most migraine preventive drugs were designed to treat other disorders. Serotonin antagonists were developed based on the concept that migraine is due to excess 5-hydroxytryptamine (5-HT). Antidepressants downregulate 5-HT2 and β-adrenergic receptors. Anticonvulsant medications decrease glutamate and enhance gamma-aminobutyric acid (GABAA). Potential mechanisms of migraine preventive medications include raising the threshold to migraine activation by stabilizing a more reactive nervous System, enhancing antinociception, inhibiting CSD, inhibiting peripheral sensitization and CS, blocking NI, and modulating sympathetic, parasympathetic, or serotonergic tone. Oshinsky has shown that descending control from the upper brainstem, through serotonergic and noradrenergic Systems, modulates the trigeminal nucleus caudalis and prevents CS. Moskowitz has recently shown that preventive medications given chronically, but not acutely, block CSD.

Principles of Preventive Therapy

The following principles are useful regardless of the chosen preventive medication:

  • • The chosen drug should be started at a low dose and increased slowly until therapeutic effects develop, the ceiling dose for the chosen drug is reached, or side effects become intolerable.
  • • Each treatment must be given an adequate trial. A full therapeutic trial may take two to six months. In controlled clinical trials, efficacy is often first noted at four weeks and continues to increase for three months.
  • • Interfering, overused, and contraindicated drugs must be avoided. To obtain maximal benefit from preventive medication, the patient should not overuse analgesies, opioids, triptans, or ergot derivatives.
  • • Therapy must be reevaluated: Migraine headaches may improve, independent of treatment. If the headaches are well controlled, the drug dosage must be slowly tapered and, if possible, discontinued. Many patients experience continued relief with a lower dose of the medication, and others may not require it at ail.
  • • A woman of childbearing potential must be made aware of potential risks and the medication that will have the least adverse effect on the fetus must be picked.
  • • Patients must be made to involve themselves in their care to maximize compliance. Patient preferences must be taken into account when deciding between drugs of relatively equivalent efficacy. The rationale for a particular treatment, when and how to use it, and what are the likely side effects must be discussed. The patient’s expectations must be addressed. The expected benefits of therapy and how long it will take to achieve them must be discussed with the patients.
  • • Comorbidity, which is the presence of two or more disorders whose association is more likely than chance, must be considered. Conditions that are comorbid with migraine include stroke, epilepsy, mitral valve prolapse, Raynaud’s syndrome, and certain psychological disorders, including depression, mania, anxiety, and panic ().

Specific Migraine-Preventive Agents

Setting Treatment Priorities

The goals of preventive treatment are to reduce the frequency, duration, or severity of attacks, improve responsiveness to acute attack treatment, improve function, and reduce disability. It may also prevent episodic migraine’s progression to chronic migraine and resuit in health-care cost reductions. The medications used to treat migraine can be divided into four major categories: (i) drugs that have documented high efficacy and mild-to-moderate AEs, which include some β-blockers, amitriptyline, topiramate, and divalproex; (ii) drugs that have lower documented efficacy and mild-to-moderate AEs, which include SSRIs, other β-blockers, calcium channel antagonists, gabapentin, riboflavin, and NSAIDs; (iii) drugs used based on (A) opinion, (B) mild-to-moderate AEs, or (C) major AEs or complex management; (iv) drugs that either have documented high efficacy but significant AEs or are difficult to use, which include methysergide and MAOIs; and (v) drugs that have proven limited or no efficacy, which include cyproheptadine, lithium, nifedipine, nimodipine, and phenytoin. Choice should be made based on a drug’s proven efficacy, the patient’s preferences and headache profile, the drug’s side effects, and the presence or absence of coexisting or comorbid disease (Table W). The drug used should be the one that has the best risk-to-benefit ratio for the individual patient and takes advantage of the drug’s side-effect profile. An under-weight patient would be a candidate for one of the medications that commonly produce weight gain, such as a TCA; in contrast, one would try to avoid these drugs in the overweight patient and consider the use of topiramate. Tertiary TCAs that have a sedating effect would be useful at bedtime for patients with insomnia. Older patients with cardiac disease or patients with significant hypotension may not be able to use TCAs or calcium channel or β-blockers, but could use divalproex or topiramate. In the athletic patient, β-blockers should be used with caution. Medication that can impair cognitive functioning should be avoided when patients are dependent on their wits (Table Preventive Drugs).

Table Preventive Drugs

High efficacy: low-to-moderate AEs

Propranolol, timolol, amitriptyline, valproate, topiramate

Low efficacy: low-to-moderate AEs

NSAIDs — Aspirin, flurbiprofen, ketoprofen, naproxen sodium

β-blockers — Atenolol, metoprolol, nadolol

Calcium-channel blockers — Verapamil

Anticonvulsants — Gabapentin

Other — Fenoprofen, feverfew, vitamin B2


Unproven efficacy: low-to-moderate AEs

Antidepressants — Doxepin, nortriptyline, imipramine, protriptyline, venlafaxine, fluvoxamine, mirtazepine, paroxetine, protriptyline, sertraline, trazodone

Major AEs or complex management

Methergine, MAOIs

Proven not effective or low efficacy

Acebutolol, carbamazepine, clomipramine, clonazepam, indomethacin, lamotrigine, nabumetone, nicardipine, nifedipine, pindolol

Abbreviations: AEs, adverse events; NSAIDs, nonsteroidal anti-inflammatory drugs; MAOIs, monoamine oxidase inhibitors.

Comorbid and coexistent diseases have important implications for treatment. The presence of a second illness provides therapeutic opportunities but also imposes certain therapeutic limitations. In some instances, two or more conditions may be treated with a single drug. When migraine and hypertension and/or angina occur together, β-blockers or calcium channel blockers may be effective for ail conditions. For the patient with migraine and depression, TCAs or SSRIs may be especially useful. For the patient with migraine and epilepsy or migraine and bipolar illness, divalproex and topiramate are the drugs of choice. The pregnant migraineur who has a comorbid condition that needs treatment should be given a medication that is effective for both conditions and has the lowest potential for AEs on the fetus. When individuals have more than one disease, certain categories of treatment may be relatively contraindicated. For example, β-blockers should be used with caution in the depressed migraineur, whereas TCAs, neuroleptics, or sumatriptan may lower the seizure threshold and should be used with caution in the epileptic migraineur.

Although monotherapy is preferred, it is sometimes necessary to combine preventive medications. Antidepressants are often used with beta-blockers or calcium channel blockers and topiramate or divalproex sodium may be used in combination with any of these medications. Pascual et al. found that combining a beta-blocker and sodium valproate could lead to an increased benefit for patients with migraine previously resistant to either alone. Fifty-two patients (43 women) with a history of episodic migraine, with or without aura, and previously unresponsive to beta-blockers or sodium valproate monotherapy, were treated with a combination of propranolol (or nadolol) and sodium valproate in an open-label fashion. Fifty-six percent had a greater than 50% reduction in migraine days. This open trial supports the practice of combination therapy. Controlled trials are needed to determine the true advantage of this combination treatment in episodic and chronic migraine.

Selections from the book: “Migraine and Other Headache Disorders” (2006).