Migraines impose significant health and financial burdens. Approximately 38% of patients with episodic migraines would benefit from preventive therapy, but less than 13% take prophylactic medications. Preventive medication therapy reduces migraine frequency, severity, and headache-related distress.
Preventive therapy may also improve quality of life and prevent the progression to chronic migraines. Some indications for preventive therapy include four or more headaches a month, eight or more headache days a month, debilitating headaches, and medication-overuse headaches.
Identifying and managing environmental, dietary, and behavioral triggers are useful strategies for preventing migraines. First-line medications established as effective based on clinical evidence include divalproex, topiramate, metoprolol, propranolol, and timolol. Medications such as amitriptyline, venlafaxine, atenolol, and nadolol are probably effective but should be second-line therapy. There is limited evidence for nebivolol, bisoprolol, pindolol, carbamazepine, gabapentin, fluoxetine, nicardipine, verapamil, nimodipine, nifedipine, lisinopril, and candesartan. Acebutolol, oxcarbazepine, lamotrigine, and telmisartan are ineffective.
Newer agents target calcitonin gene-related peptide pain transmission in the migraine pain pathway and have recently received approval from the U.S. Food and Drug Administration; however, more studies of long-term effectiveness and adverse effects are needed. The complementary treatments petasites, feverfew, magnesium, and riboflavin are probably effective.
Nonpharmacologic therapies such as relaxation training, thermal biofeedback combined with relaxation training, electromyographic feedback, and cognitive behavior therapy also have good evidence to support their use in migraine prevention.
Preventive Medications
There is no algorithm to determine who is to go on preventive headache medication. The number of monthly headaches is one factor, along with comorbidities. Patients have to be willing to take daily medication (many do not want any daily meds). There is no absolute rule that applies to headache treatment. For a patient with two headaches a month that are severe, prolonged, and not relieved by drugs, preventive medicine might be used. On the other hand, for the person who has five headaches a month, but can obtain relief from Excedrin or a triptan, preventive medicine may not be optimal.
The choice of who qualifies for medication depends on the patient’s age, medical and psychiatric comorbidities, and frequency and severity of the migraine, as well as the patient’s preference. Comorbidities often determine which preventive meds are used. If a patient has HTN, a med for blood pressure will be used. When patients concurrently suffer with anxiety or depression, various antidepressants are utilized for the headache and mood disorder. We want to minimize meds, and treating 2 conditions with one medication is ideal.
In using medication, a realistic goal is to decrease the headache severity by 40% to 70%, not to completely eliminate the headaches. It is wonderful when the headaches are 90% improved, but the idea is also to minimize medication. “Clinical meaningful pain relief” is usually around a 30% improvement. Most patients need to be willing to settle for moderate improvement. Preventives may take 3 to 6 weeks to work, and “educated guesswork” often is used to find the best approach for each patient. In the long run, preventive medications are effective for approximately 50% of patients. The other 50% scramble with various abortives.
As noted, patients should play an active role in medication choice. Preventive medications should be selected depending on the patient’s medical and psychological comorbidities, GI system, medication sensitivities, weight, sleep, family history of reaction to medications, finances, willingness to take daily meds, and many other factors. Fatigue and/or weight gain are major reasons why patients abandon a preventive medication. Headache patients commonly complain of fatigue, and tend to give up on medications that increase tiredness. A patient’s occupation also may guide the caregiver away from certain medications; for example, an accountant may not be able to tolerate the memory problems associated with topiramate.
Side effects are possible with any medication; the patient must be prepared to endure mild side effects in order to achieve results.
Treatment Medications
Topiramate is an effective migraine preventive, without the weight gain commonly encountered with the other meds. While usually fairly well tolerated, common side effects include memory difficulties (“spaciness”), and tingling. In higher doses, topiramate increases the risk for kidney stones. Topiramate does decrease appetite, leading to weight loss for some patients. This anorexic effect tends to disappear after several months. The usual dose is 50 mg to 100 mg daily, but some do well on as little as 25 mg. The dose may be pushed to 300 or 400 mg per day, in the absence of significant side effects. Topiramate is primarily used for migraine prevention, but has also been utilized for cluster and tension headache as well. Topiramate may cause a metabolic acidosis, with lower bicarbonate levels (and increased chloride).
The acidosis may lead to the tingling, which sometimes is alleviated by increasing potassium-containing fruits/vegetables (or adding potassium). Trokendi XR is an excellent long-acting form of topiramate, approved for migraine prophylaxis. The FDA also approved Qudexy XR (topiramate) for once-daily dosing.
Valproate, or divalproex sodium (Depakote), is a longtime staple, popular for migraine prevention. It is usually well tolerated in the lower doses used for headaches; however, the generic may not be as effective. Liver functions need to be monitored in the beginning of treatment. Valproate also is one of the primary mood stabilizers for bipolar disorder. Oral Depakote ER (500 mg) is an excellent once-daily, long-acting agent. As with most preventives, valproate needs 4 to 6 weeks to become effective.
The β-blocker propranolol also is FDA approved as a preventive agent for migraines. Long-acting oral propranolol (Inderal), for example, is very useful in combination with the tricyclic antidepressant amitriptyline. Dosage begins with the long-acting agent given at 60 mg per day, and is usually kept between 60 and 120 mg per day. Lower doses are sometimes effective, such as 20 mg twice a day of propranolol. Other β-blockers also are effective, such as metoprolol (Toprol XL) and atenolol. Some of these are easier to work with than propranolol because they are scored tablets, and metoprolol and atenolol have fewer respiratory effects. Depression may occur. β-blockers are useful for those migraine patients with concurrent hypertension, tachycardia, mitral valve prolapse, and panic/anxiety disorders. Bystolic (nebivolol) is another β-blocker that may be helpful for the prevention of headaches, and has fewer respiratory side effects than other agents. Bystolic probably has the fewest side effects among the β-blockers.
As noted, amitriptyline is an effective, inexpensive agent that is useful for the prevention of daily headaches and insomnia. As a preventive agent, amitriptyline is prescribed at low doses and taken at night. Sedation, weight gain, dry mouth, and constipation are common side effects. Other tricyclic antidepressants such as doxepin and protriptyline can be effective for migraine. Nortriptyline is similar to amitriptyline, with somewhat fewer side effects. These also are used for daily tension-type headaches. Protriptyline is one of the few older antidepressants that does not cause weight gain. However, anticholinergic side effects are increased with protriptyline; protriptyline is more effective for tension headache than for migraine. Although selective serotonin reuptake inhibitors (SSRIs) are used, they are more effective for anxiety and depression than for migraine.
Naproxen is a very useful agent for the treatment of daily headaches, as well as for younger women suffering from menstrual migraine. Naproxen is nonsedating, but frequently causes GI upset or pain. Effective as an abortive, it may be combined with other first-line preventive medications. Other NSAIDs can similarly be used for migraine prevention. It is crucial to use low doses. As with all anti-inflammatories, GI side effects increase as people age, and therefore NSAIDs are used more often in the younger population. Blood tests are needed to monitor liver and kidney function.
What’s New in Headache
Transcranial magnetic stimulation (TMS) has been the primary new therapy to emerge. In addition to TMS, ketamine is (occasionally) being utilized for refractory headaches. Calcitonin gene-related peptide (CGRP) inhibitors are in the late stages of development for the prevention of migraine; however, if they are approved, CGRP inhibitors will not be available until mid-2018 (at the earliest).
Transcranial Magnetic Stimulation (TMS)
TMS has primarily been utilized for depression. The repetitive TMS units give thousands of pulses in an hour. The SpringTMS (from eNeura) hand-held system imparts only a single pulse. There have been a number of well-done studies on TMS for headache and depression. The patient uses a hand-held TMS device, 4 pulses twice daily (as a preventive). This takes about 5 to 10 minutes for the 4 pulses. TMS may be used abortively as well. Long-term efficacy is not well established. However, early results are promising, at least for a subset of refractory chronic migraineurs. TMS has been safe, although some patients do not like the “thump” that each pulse imparts. The cost is $450 for the first 3 months (the company rents the machine to the user).
Ketamine
Ketamine has been used to treat refractory pain or depression for the past several years. Ketamine is an NMDA receptor glutamate antagonist. In addition, ketamine affects several other receptors as well. Ketamine has been used for treatment-resistant depression, primarily as the IV formulation. Ketamine has been a drug of abuse, and has major addiction potential. There have been a number of successful trials utilizing ketamine, either intravenously or as a nasal spray. A nasal spray form of Ketamine may be marketed for severe depression in 2019.
The intravenous treatment may be more effective than using ketamine as a nasal spray. However, this author has found that the nasal spray is exceedingly well tolerated, with few side effects. The usual side effects include feeling euphoric, sleepy, dizzy, and (with the IV form) hallucinations.
This author has utilized ketamine for 42 refractory headache patients, some of whom also suffered from severe depression. Our results indicated that ketamine is more helpful for the depression than the pain. The decrease in headache tends to be short-lived. However, certain patients do well with both depression and headache. We have used only the nasal spray. It is formulated as a liquid, 10 mg ketamine per 0.1 mL. The patient does the treatment in our office once per week. The usual dose is 10 mg (one spray) every 10 to 15 minutes. Usually the total dose for the treatment ranges from 50 mg to 100 mg. We check vitals after every 2 sprays (occasionally blood pressure will rise with ketamine).
New Formulations
Several newer formulations of older migraine medications have emerged. Onzetra nasal powder is a new form of sumatriptan nasal spray. Onzetra uses a unique “breath powered” delivery system. Onzetra delivers 11 mg of sumatriptan powder per breath; the usual dose is 22 mg at one time. This places the sumatriptan powder posteriorly, where there is respiratory epithelium. This epithelium is more conducive for absorption of medication than is the anterior squamous epithelium. Onzetra has excellent efficacy, and is well tolerated.
Trokendi XR is a long-acting formulation of topiramate. Trokendi has the indication for migraine prophylaxis. In our (anecdotal) experience, approximately 70% of patients prefer the Trokendi XR, versus the generic topiramate.
Medical cannabis has been used for about 5,000 years. Cannabis has multiple active ingredients—tetrahydrocannabinol (THC) is the main cannabinoid for analgesia and also produces the euphoric effect. Cannabidiol (CBD), the other important compound, is an anti-inflammatory. CBD also may enhance analgesia. One advantage of medical marijuana is that the dispensary is able to manipulate the percentage of THC vs. CBD. It often takes weeks to months in order to achieve optimum results. Vaporized inhalation is the most commonly employed route. Marijuana may help with anxiety as well as the pain.
Vagal Nerve Stimulation
Non-invasive vagal nerve stimulation (VNS)—the gammaCore VNS system from the company electroCore— was approved in April 2017 for use in episodic cluster headache (not yet approved for migraine) in adults. VNS may suppress glutamate levels in the trigeminal nucleus caudalis, resulting in decreased head pain. The portable gammaCore VNS has demonstrated efficacy for cluster headache. The long-term results in migraineurs has yet to be established. This form of VNS has minimal side effects or dose limitations. The device is not indicated for patients with an active implantable medical device, such as a pacemaker or hearing aid; those with carotid atherosclerosis, or who have had a cervical vagotomy. Also patients with hyper- or hypotension, bradycardia, or tachycardia are not candidates for the device.
Conclusion
Migraine is a common and disabling illness. Outside of meds, it is important for migraineurs to watch their headache triggers, and exercise regularly. Physical therapy and/or psychotherapy may be of help (“it takes a village”). There is no good algorithm for determining which medication is best. Each patient is unique, and comorbidities drive where we go with treatment. The goal is to decrease head pain, while minimizing medications.