The following may be considered indications for prophylactic migraine therapy:
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)
Table 3. Preventive Medication for Comorbid Conditions (Open Table in a new window)
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]
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.
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]
- 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]
- Reduce attack frequency, severity, and/or duration
- Improve responsiveness to acute attacks
- Reduce disability
- 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
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 |
| 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 |
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]
