The following may be considered indications for prophylactic
migraine therapy:
Frequency of migraine attacks is greater than 2 per month
Duration of individual attacks is longer than 24 hours
The headaches cause major disruptions in the patient’s lifestyle, with significant disability that lasts 3 or more days
Abortive therapy fails or is overused
Symptomatic medications are contraindicated or ineffective
Use of abortive medications more than twice a week
Migraine
variants such as hemiplegic migraine or rare headache attacks producing
profound disruption or risk of permanent neurological injury
[65]
The goals of preventive therapy are as follows:
Reduce attack frequency, severity, and/or duration
Improve responsiveness to acute attacks
Reduce disability
Currently, the major prophylactic medications for migraine work via one of the following mechanisms:
5-HT2 antagonism - Methysergide
Regulation of voltage-gated ion channels - Calcium channel blockers
Modulation of central neurotransmitters - Beta-blockers, tricyclic antidepressants
Enhancing GABAergic inhibition - Valproic acid, gabapentin
Another
notable mechanism is alteration of neuronal oxidative metabolism by
riboflavin and reducing neuronal hyperexcitability by magnesium
replacement.
As with abortive medications, the selection of a
preventive medication must take into consideration comorbid conditions
and side effect profile (see Table 2 and Table 3 below). Most preventive
medications have modest efficacies and have therapeutic gains of less
than 50% when compared to placebo. The latency between initiation of
therapy and onset of positive treatment response can be quite prolonged.
Furthermore, the scientific basis for using most of these medications
is wanting.
Propranolol, timolol, methysergide, valproic acid,
and topiramate (Topamax) have been approved by the FDA for migraine
prophylaxis. However, a 2009 report suggested that long-term topiramate
use in pediatric patients can cause metabolic acidosis and hypokalemia;
the risk was deemed mild but statistically significant.
[66]
The
nonsteroidal anti-inflammatory drug naproxen sodium has also been used
for prophylaxis. In controlled clinical trials, naproxen sodium
demonstrated better efficacy than placebo and efficacy similar to
propranolol. Tolfenamic acid has also been tried for migraine
prophylaxis, but the clinical efficacy is not as good as that of
beta-blockers, valproate, or methysergide.
Table 2. Preventive Drugs
(Open Table in a new window)
First line | High efficacy | Beta-blockers
Tricyclic antidepressants
Divalproex
Topiramate
|
Low efficacy | Verapamil
NSAIDs
SSRIs
|
Second line | High efficacy | Methysergide
Flunarizine
MAOIs
|
Unproven efficacy | Cyproheptadine
Gabapentin
Lamotrigine
|
Table 3. Preventive Medication for Comorbid Conditions
(Open Table in a new window)
Comorbid Condition | Medication |
Hypertension | Beta-blockers |
Angina | Beta-blockers |
Stress | Beta-blockers |
Depression | Tricyclic antidepressants, SSRIs |
Underweight | Tricyclic antidepressants |
Epilepsy | Valproic acid, Topiramate |
Mania | Valproic acid |
Of
note, an open pilot study reports that quetiapine is effective for
migraine prophylaxis in patients with migraine refractory to treatment
with standard therapies (eg, atenolol, nortriptyline, flunarizine). The
authors stated that controlled studies are necessary to confirm their
observations.
[67]
Classes of prophylactic drugs
The
3 principal classes of medications that are effective for migraine
prevention are antiepileptics, antidepressants, and antihypertensives.
Antiepileptics are generally well tolerated. The main adverse effects of topiramate are weight loss and dysesthesia.
[68] Valproic
acid (Depakote) is useful as a first-line agent. It is a good mood
stabilizer and can benefit patients with concomitant mood swings.
However, it can cause weight gain, hair loss, and polycystic ovary
disease; therefore, it may not be ideal for young female patients who
have a tendency to gain weight.
Valproic acid also carries
substantial risks in pregnancy; it may be best suited for women who have
had tubal ligation and who cannot tolerate calcium channel blockers
because of dizziness. Data for other antiepileptics (eg, gabapentin,
[69] lamotrigine, oxcarbazepine) are limited in migraine.
Tricyclic
antidepressants are good second-line alternatives because of their
adverse-effect profile and efficacy. Amitriptyline and nortriptyline are
most effective. Although serotonin-selective reuptake inhibitors are
widely used, data regarding their efficacy in migraine prevention are
lacking.
Antihypertensives such as beta-blockers should be
tailored if the patient is young and anxious. They may not be the ideal
choice for elderly patients or patients with depression, thyroid
problems, or diabetes. Calcium channel blockers are another possible
choice of treatment. ACE inhibitors (eg, lisinopril) and
angiotensin-receptor blockers (eg, candesartan)
[70] have also been shown to be effective for migraine prevention.
[71]
For
any of these prophylactic agents, prophylaxis should not be considered a
failure until it has been given at the maximum tolerable dose for at
least 30 days.
Botulinum toxin
Botulinum toxin A
(onabotulinumtoxinA; BOTOX®) may be beneficial in patients with
intractable migraine headaches that fail to respond to at least 3
conventional preventive medication. The injections are administered to
the scalp and temple. They may reduce the frequency and severity of
migraine attacks after 2-3 months of injections.
The injections
are expensive and must be administered every 2-3 months to maintain
their effectiveness. The most appropriate duration of prophylactic
therapy has not been determined. In most patients who are receiving
prophylaxis, therapy must be continued for at least 3-6 months.
Multiple trials of onabotulinumtoxinA for migraine prevention have been conducted, with mixed results.
[72] A
review by Schulte-Mattler and Martinez-Castrillo found no evidence for a
beneficial effect of botulinum toxin. These authors do not recommend
the widespread use of botulinum toxin therapy in headaches.
[73]
More
recently, however, 2 multicenter, placebo-controlled trials included in
the Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT)
clinical program found onabotulinumtoxinA to be effective for headache
prophylaxis in adults with chronic migraine. Nearly 1400 patients were
included in the results. Secondary benefits included significantly
reduced headache-related disability and improved functioning, vitality,
and overall health-related quality of life.
[74]