MIGRAINE EXPANDING OUR TX ARSENAL: Beyond tried-and-true therapies are new therapeutic targets on the horizon--giving you a bigger toolbox to help patients abort and prevent migraine episodes.
Recent estimates indicate that the cost of acute and chronic migraine headaches reaches approximately $78 million a year in the United States. (4) This high burden of disease has made effective migraine treatment options absolutely essential. Recent advances in our understanding of migraine pathophysiology have led to new therapeutic targets; there are now many novel treatment approaches on the horizon.
In this article, we review the diagnosis and management of migraine in detail. Our emphasis is on evidence-based approaches to acute and prophylactic treatment, including tried-and-true options and newly emerging therapies.
Neuronal dysfunction and a genetic predisposition
Although migraine was once thought to be caused by abnormalities of vasodilation, current research suggests that the disorder has its origins in primary neuronal dysfunction. There appears to be a genetic predisposition toward widespread neuronal hyperexcitability in migraineurs. (5) In addition, hypothalamic neurons are thought to initiate migraine by responding to changes in brain homeostasis. Increased parasympathetic tone might activate meningeal pain receptors or lower the threshold for transmitting pain signals from the thalamus to the cortex. (6)
Prodromal symptoms and aura appear to originate from multiple areas across the brain, including the hypothalamus, cortex, limbic system, and brainstem. This widespread brain involvement might explain why some headache sufferers concurrently experience a variety of symptoms, including fatigue, depression, muscle pain, and an abnormal sensitivity to light, sound, and smell. (6-7)
Although the exact mechanisms behind each of these symptoms have yet to be defined precisely, waves of neuronal depolarization--known as cortical spreading depression--are suspected to cause migraine aura. (8-10) Cortical spreading depression activates the trigeminal pain pathway and leads to the release of pro-inflammatory markers such as calcitonin gene-related protein (CGRP). (6) A better understanding of these complex signaling pathways has helped provide potential therapeutic targets for new migraine drugs.
Diagnosis: Close patient inquiry is most helpful
The International Headache Society (IHS) criteria for primary headache disorders serve as the basis for the diagnosis of migraine and its subtypes, which include migraine without aura and migraine with aura. Due to variability of presentation, migraine with aura is further subdivided into migraine with typical aura (with and without headache), migraine with brainstem aura, hemiplegie migraine, and retinal migraine. (11)
* How is migraine defined? Simply, migraine is classically defined as a unilateral, pulsating headache of moderate to severe intensity lasting 4 to 72 hours, associated with photophobia and phonophobia or nausea and vomiting, or both. (11) Often visual in nature, aura is a set of neurologic symptoms that lasts for minutes and precedes the onset of the headache. The visual aura is often described as a scintillating scotoma that begins near the point of visual fixation and then spreads left or right. Other aura symptoms include tingling or numbness (second most common), speech disturbance (aphasia), motor changes and, in rare cases, a combination of these in succession. By definition, all of these symptoms fully resolve between attacks. (11)
* Validated valuable questionnaires. To help with accurate and timely diagnosis, researchers have developed and validated simplified questionnaires that can be completed independently by patients presenting to primary care (table 1 (12,13)):
* ID Migraine is a set of 3 questions that scores positive when a patient endorses at least 2 of the 3 symptoms. (12)
* MS-Q is similar to the ID Migraine but includes 5 items. A score of [greater than or equal to]4 is a positive screen. (13)
The sensitivity and specificity of MS-Q (0.93 and 0.81, respectively) are slightly higher than those of ID Migraine (0.81 and 0.75). (13)
* Remember POUND. This mnemonic device can also be used during history-taking to aid in diagnostic accuracy. Migraine is highly likely (92%) in patients who endorse 4 of the following 5 symptoms and unlikely (17%) in those who endorse [less than or equal to]2 symptoms (14): Pulsatile quality of headache 4 to 72 hours in duration, Unilateral location, Nausea or vomiting, and Disabling intensity.
* Differential Dx. Although the differential diagnosis of headache is broad (table 2 (14,15)), the history alone can often guide clinicians towards the correct assessment. After taking the initial history (headache onset, location, duration, and associated symptoms), focus your attention on assessing the risk of intracranial pathology. This is best accomplished by assessing specific details of the history (table 3 (14)) and findings on physical examination (15):
* blood pressure measurement (seated, legs uncrossed, feet flat on the floor; having rested for 5 minutes; arm well supported)
* cranial nerve exam
* extremity strength testing
* eye exam (vision, extra-ocular muscles, visual fields, pupillary reactivity, and funduscopic exam)
* gait (tandem walk)
* Further testing needed? Neuroimaging should be considered only in patients with an abnormal neurologic exam, atypical headache features, or certain risk factors, such as an immune deficiency. There is no role for electroencephalography or other diagnostic testing in migraine. (16)
Take a multipronged approach to treatment
As with other complex, chronic conditions, the treatment of migraine should take a multifaceted approach, including management of acute symptoms as well as prevention of future headaches. In 2015, the American Headache Society published a systematic review that specified particular treatment goals for migraine sufferers. (17) These goals include:
* headache reduction
* headache relief
* decreased disability from headache
* elimination of nausea and vomiting
* elimination of photophobia and phonophobia.
Our review, which follows, of therapeutic options focuses on the management of migraine in adults. Approaches in special populations (older adults, pregnant women, and children) are discussed afterward.
Pharmacotherapy for acute migraine
Acute migraine should be treated with an abortive medication at the onset of headache.
The immediate goal is to relieve pain within 2 hours and prevent its recurrence within the subsequent 48 hours (table 4 (12,18-20)).
In the general population, mild, infrequent migraines can be managed with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). (21)
For moderate-to-severe migraine, triptans, which target serotonin receptors, are the drug of choice for most patients. (21) Triptans are superior to placebo in achieving a pain-free state at 2 and 24 hours after administration; eletriptan has the most desirable outcome, with 68% of patients pain free at 2 hours and 54% pain free at 24 hours. (22) Triptans are available as sublingual tablets and nasal sprays, as well as subcutaneous injections for patients with significant associated nausea and vomiting. Avoid prescribing triptans for patients with known vascular disease (eg, history of stroke, myocardial infarction, peripheral vascular disease, uncontrolled hypertension, or signs and symptoms of these conditions), as well as for patients with severe hepatic impairment.
Importantly, although triptans all have a similar mechanism of action, patients might respond differently to different drugs within the class. If a patient does not get adequate headache relief from an appropriate dosage of a given triptan during a particular migraine episode, a different triptan can be tried during the next migraine. (22) Additionally, if a patient experiences an adverse effect from one triptan, this does not necessarily mean that a trial of another triptan at a later time is contraindicated.
For patients who have an incomplete response to migraine treatment or for those with frequent recurrence, the combination formulation of sumatriptan, 85 mg, and naproxen, 500 mg, showed the highest rate of resolution of headache within 2 hours compared with either drug alone. (23) A similar result might be found by combining a triptan known to be effective for a patient and an NSAID other than naproxen. If migraine persists despite initial treatment of an attack, a different class of medication should be tried during the course of that attack to attain relief of symptoms of that migraine. (21)
When a patient is seen in an acute care setting (eg, emergency department, urgent care center) while suffering a migraine, additional treatment options are available. Intravenous (IV) anti-emetics are useful for relieving the pain of migraine and nausea, and can be used in combination with an IV NSAID (eg, ketorolac). (21) The most effective anti-emetics are dopamine receptor type-2 blockers, including chlorpromazine, droperidol, metoclopramide, and prochlorperazine, which has the highest level of efficacy. (24) Note that these medications do present the risk of a dystonic reaction; diphenhydramine is therefore often used in tandem to mitigate such a response.
* Looking ahead. Although triptans are the current first-line therapy for acute migraine, their effectiveness is limited. Only 20% of patients report sustained relief of pain in the 2 to 24 hours after treatment, and the response can vary from episode to episode. (25)
With better understanding of the pathophysiology of migraine, a host of novel antimigraine drugs are on the horizon.
* CGRP receptor antagonists. The neuropeptide CGRP, which mediates central and peripheral nervous system pain signaling, has been noted to be elevated during acute migraine attacks (26); clinical trials are therefore underway to evaluate the safety and efficacy of CGRP receptor antagonists. (18) These agents appear to be better tolerated than triptans, have fewer vascular and central nervous system adverse effects, and present less of a risk of medication overuse headache. (18) Liver toxicity has been seen with some medications in this class and remains an important concern in their development. (19)
Phase 3 clinical trials for 1 drug in this class, ubrogepant, were completed in late 2017; full analysis of the data is not yet available. Primary outcomes being evaluated include relief of pain at 2 hours and relief from the most bothersome symptoms again at 2 hours. (27)
* Selective [serotonin-HT.sub.1f] receptor agonists, such as lasmiditan, offer another potential approach. Although the exact mechanism of action of these agents is not entirely clear, clinical trials have supported their efficacy and safety. (20) Importantly, ongoing trials are specifically targeting patients with known cardiovascular risk factors because they are most likely to benefit from the nonvasoconstrictive mechanism of action. (28,29) Adverse effects reported primarily include dizziness, fatigue, and vertigo.
Strategies for managing recurrent episodic migraine
Because of the risk of medication overuse headache with acute treatment, daily preventive therapy for migraine is indicated for any patient with (30):
* [greater than or equal to]6 headache days a month
* [greater than or equal to]4 headache days a month with some impairment
* [greater than or equal to]3 headache days a month with severe impairment.
Treatment begins by having patients identify, and then avoid, migraine triggers (table 5). This can be accomplished by having patients keep a headache diary, in which they can enter notations about personal and environmental situations that precede a headache.
For the individual patient, some triggers are modifiable; others are not. Helping a patient develop strategies for coping with triggers, rather than aiming for complete avoidance, might help her (him) manage those that are inescapable (eg stress, menstruation, etc). (31) For many patients, however, this is not an adequate intervention and other approaches must be explored. When considering which therapy might be best for a given patient, evaluate her (his) comorbidities and assess that particular treatment for potential secondary benefits and the possibility of adverse effects. Pay attention to the choice of preventive therapy in women who are considering pregnancy because many available treatments are potentially teratogenic.
* Oral medications. Oral agents from several classes of drugs can be used for migraine prophylaxis, including anti-epileptics, antidepressants, and antihypertensives (TABLE 6 (20,29,30,32-41)). Selected anti-epileptics (divalproex sodium, sodium valproate, topiramate) and beta-blockers (metoprolol, propranolol, and timolol) have the strongest evidence to support their use. (32) Overall, regular use of prophylactic medications can reduce headache frequency by 50% for approximately 40% to 45% of patients who take them. (29) However, adherence may be limited by adverse effects or perceived lack of efficacy, thus reducing their potential for benefit. (42)
* OnabotulinumtoxinA. In patients with chronic migraine ([greater than or equal to]15 headache days a month for at least 3 months) who have failed oral medications, the American Academy of Neurology (AAN) recommends the use of onabotulinumtoxinA. (30) The treatment regimen comprises 31 injections at various sites on the head, neck, and shoulders every 3 months. (33)
A 2010 large randomized controlled trial showed a decrease in the frequency of headache days for patients receiving onabotulinumtoxinA compared to placebo after a 24-week treatment period (7.8 fewer headache days a month, compared to 6.4 fewer in the placebo group). (33) A recent systematic review also noted a reduction of 2 headache days a month compared with placebo; the authors cautioned, however, that data with which to evaluate onabotulinumtoxinA in comparison to other prophylactic agents are limited. (43)
In both studies, the risk of adverse drug events due to onabotulinumtoxinA was high and led to a significant rate of discontinuation. (33,43) Despite this, onabotulinumtoxinA remains the only Food and Drug Administration (FDA)-approved treatment for chronic migraine, making it reasonable to consider for appropriate patients.
* Acupuncture. A 2016 Cochrane review found benefit for patients using acupuncture compared with sham acupuncture. (34) When acupuncture was compared with prophylactic agents such as beta-blockers, calcium-channel blockers, and anti-epileptics, however, there was no significant difference between the procedure and pharmacotherapy. Patients willing and able to try acupuncture might see a reduction in the overall number of headaches. Acupuncture has few adverse effects; however, long-term data are lacking. (34)
* Exercise is not supported by robust data for its role as a prophylactic treatment. It is generally considered safe in most populations, however, and can be pursued with little out-of-pocket cost. (35)
* Cognitive behavioral therapy (CBT). The AAN recommends CBT, relaxation therapy, and biofeedback therapy. Accessibility of these services remains limited for many patients, and cost can be prohibitive. (16)
* Supplements used to help prevent migraine include the root of Petasites hybridus (butterbur), magnesium, vitamin B2 (riboflavin), Tanacetum parthenium (feverfew), and coenzyme Q10. (16) Although the strength of evidence for these therapies is limited by small trials, their overall risk of adverse effects is low, and they might be easier for patients to obtain than acupuncture or CBT.
Butterbur, in particular, has been found to be beneficial for migraine prevention in 2 small placebo-controlled trials. In a randomized controlled study of 245 patients P hybridus, (specifically, the German formulation, Petadolex), 75 mg BID, reduced the frequency of migraine attack by 48% at 4 months, compared to placebo (number needed to treat, 5.3). (44) No difference was found at lower dosages. The most common reported adverse effect was burping.
Regrettably, unpurified butterbur extract contains pyrrolidine alkaloids, potentially hepatotoxic and carcinogenic compounds. Because of variations in purification in production facilities in the United States, butterbur supplements might not have all of these compounds removed--and so should be used with caution. (41)
* Magnesium. Studies evaluating the use of magnesium have demonstrated varied results; differences in methods and dosing have limited broad application of findings. As with most supplements considered for prophylactic treatment, magnesium dosing is poorly understood, and bioavailability varies in its different forms. Oral supplementation can be given as magnesium dicitrate, 600 mg/d. (45)
Recently, products containing various combinations of feverfew, coenzyme Q10, riboflavin, magnesium, and other supplements have shown benefit in early clinical trials. (36,37) I Neural stimulation. Over the past few years, a variety of transcutaneous nerve stimulator devices have gained FDA approval for use in migraine prophylaxis. The long-term safety and efficacy of these devices is not yet well understood, but they appear to provide headache relief in the short term and decrease the frequency of headache. (38) Use of the noninvasive stimulators is limited today by high cost and poor coverage by US health care insurers.
* Newly available medical therapy. The FDA recently approved erenumab, a fully human monoclonal antibody for prevention of migraine in adults. This is the first drug in the CGRP antagonist class to be approved for this indication. Trials of this once-monthly, self-injectable drug show promising results for patients whose migraines have been refractory to other therapies.
A recent large trial evaluated 955 adults with migraine, randomizing them to receive erenumab, 70 mg; erenumab, 140 mg; or placebo over 28 weeks. (39) The groups receiving erenumab had a nearly 2-fold higher odds of having their migraine reduced by 50%, compared with placebo (number needed to treat with the 140-mg dose, 4.27). Similar numbers of participants from all groups discontinued the study. (39) Phase 3 trials that are not yet formally published have produced similarly beneficial results. (40,46) The FDA has listed injection site reaction and constipation as the most reported adverse effects. (40)
Three other anti-CGRP antibodies are likely to be approved in the near future: fremanezumab, galcanezumab, and eptinezumab.
The approach to migraine in special populations
Management of acute and chronic migraine in children, pregnant women, and older adults requires special attention: Treatment approaches are different than they are for adults 19 to 65 years of age.
* Pediatric patients. Migraine is the most common acute and recurrent headache syndrome in children. Headaches differ from those of adult migraine as a result of variations in brain maturation, plasticity, and cognitive development. (47) Migraine attacks are often of shorter duration in children, lasting 1 to 2 hours, but can still be preceded by visual aura. (48) Just as with adults, imaging, electroencephalography, lumbar puncture, and routine labs should be considered only if a child has an abnormal neurological exam or other concerning features (table 2 (14,15)).
The general approach to migraine treatment in the pediatric population includes education of the child and family about symptom management. Acetaminophen, NSAIDs, and triptans are approved for abortive therapy in children and should be used for acute headache relief in the same way that they are used in adults. Oral rizatriptan, the most well studied triptan in the pediatric population, is approved for use in children as young as 6 years (49); the pediatric dosage is 5 mg/d for patients weighing 20 to 39 kg and 10 mg/d for patients weighing more than 40 kg (same as the adult dosage).
Oral almotriptan and zolmitriptan are also approved for use in children 12 to 17 years of age. Usual dosages are: almotriptan, 12.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 25 mg/d); and zolmitriptan, 2.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 10 mg/d). (50)
For children who are unable to swallow pills or who are vomiting, a non-oral route of administration is preferable. Rizatriptan is available as an orally disintegrating tablet. Zolmitriptan is available in a nasal spray at a dose of 5 mg for children 12 years and older. Sumatriptan is not approved for use in patients younger than 18 years; however, recent studies have shown that it might have good efficacy and tolerability. (50)
Daily prophylactic treatment for recurrent migraine in the pediatric population is an evolving subject; published guidelines do not exist. It is reasonable to consider treatment using the same guidelines as those in place for adults. (51) Topiramate, 1 to 2 mg/ kg/d, is the only therapy approved by the FDA for episodic migraine preventive therapy in adolescents. (50)
Notably, a nonpharmacotherapeutic approach may be more effective for pediatric prevention. In 2017, a large double-blind, placebo-controlled trial investigated the use of amitriptyline, topiramate, and placebo for the treatment of recurrent migraine in children 8 to 17 years of age. An interim analysis of the 328 children enrolled found no significant differences in reduction of headache frequency with treatment compared with placebo over a 24-week period; the trial was stopped early due to futility. (52)
The study did show, however, that reducing migraine triggers provided a high level of benefit to study participants. Stress is one of the most common migraine triggers in children; lack of sleep, exposure to a warm climate, and exposure to video games are also notable triggers. (53) CBT may augment the efficacy of standard migraine medications in the pediatric population and may help prevent recurrence of episodes. (54)
* Pregnancy. The treatment of migraine is different in pregnant women than it is in nonpregnant adults because of a concern over adverse effects on fetal development. For acute headache treatment, first-line therapies include trigger avoidance and acetaminophen, 1000 mg (maximum dosage, 4000 mg/d). (55) If this is ineffective, a 10-mg dose of metoclopramide, as often as every 6 hours (not an FDA-approved indication), can be considered. During the second trimester, NSAIDs can be considered second-line therapy.
Triptans--specifically, sumatriptan and rizatriptan--can also be considered if first-line therapies fail. (56) Triptan-exposed pregnant women with migraine have a rate of congenital malformations, spontaneous abortions, and prematurity that is similar to what is seen in pregnant women with migraine who have not been exposed to triptans. However, when triptan-exposed women are compared with healthy, non-migraine-suffering women, the rate of spontaneous abortion appears to be increased in the triptan-exposed population. (57)
Ergotamine is contraindicated during pregnancy because of its potential to induce uterine contractions and vasospasm, which can be detrimental to the fetus. (56)
Nonpharmacotherapeutic interventions such as heat, ice, massage, rest, and avoidance of triggers are as successful in the pregnant population as in the nonpregnant population. For migraine prevention, coenzyme Q10, vitamins B2 and B6 (pyridoxine), and oral magnesium can be considered. Feverfew and butterbur should be avoided because of concerns about fetal malformation and preterm labor. (58)
* Older adults. Choosing appropriate migraine therapy for older adults requires special consideration because of changes in drug metabolism and risks associated with drug adverse effects. Additionally, few studies of migraine drugs have included large populations of adults older than 65 years; medications should therefore be prescribed cautiously in this population, with particular attention to drug-drug interactions.
Just as for younger adults, mild symptoms can be managed effectively with acetaminophen. NSAIDs may be used as well, but carry increased risks of gastric bleeding and elevation in blood pressure. (59) The use of triptans is acceptable for the appropriate patient, but should be avoided in patients with known vascular disease. (60) Antiemetics present an increased risk of extrapyramidal adverse effects in the elderly and should be used with caution at the lowest effective dosage. (59) Novel mechanisms of action make some of the newer agents potentially safer for use in older adults when treating acute migraine.
For migraine prevention in older adults, particular attention should be paid to reducing triggers and minimizing polypharmacy.
More and more, successful treatment is within reach
With many clinical trials evaluating novel drugs underway, and additional studies contributing to our understanding of nonpharmacotherapeutic approaches to migraine treatment, improved headache control may become increasingly common over the next few years.
Kathryn McGrath, MD, Department of Family and Community Medicine, Thomas Jefferson University, 1015 Walnut St, Philadelphia PA 19107; Kathryn.email@example.com.
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Kathryn McGrath, MD; Allison Rague, MD; Claire Thesing, MD; Elizabeth Collins, MD; Olivia Seecof, MD; John Liantonio, MD Department of Family and Community Medicine (Drs. McGrath and Seecof) and Division of Geriatric Medicine and Palliative Care, Department of Family and Community Medicine (Drs. Collins and Liantonio), Thomas Jefferson University, Philadelphia, Pa; Kaiser Permanente--Baltimore (Dr. Rague); Department of Family Medicine, University of Illinois at Chicago (Dr. Thesing)
The authors reported no potential conflict of interest relevant to this article.
* Offer treatment with a triptan to adult patients with moderate-to-severe episodic migraine. (A)
* Consider prescribing topiramate, divalproex sodium, metoprolol, propranolol, or the herbal, Petasites hybridum, for the prevention of recurrent episodic migraine that has not responded to a reduction in headache triggers. (A)
* Add onabotulinumtoxinA injection to your therapeutic toolbox as an effective preventive treatment for chronic migraine ([greater than or equal to]15 headache days a month for 3 months). (B)
* Recommend magnesium and feverfew as adjunctive preventive treatments for migraine, (B)
Strength of recommendation (SOR)
(A) Good-quality patient-oriented evidence
(B) Inconsistent or limited-quality patient-oriented evidence
(C) Consensus, usual practice, opinion, disease-oriented evidence, case series
TABLE 1 2 Helpful questionnaires for pursuing a migraine diagnosis * (12,13) ID Migraine (12) During the last 3 months, did you have the following with your headaches? Felt nauseated or sick to your stomach Yes/No Light bothered you a lot (or a lot more than when you do not Yes/No have headaches) Your headaches limited your ability to work, study, or do Yes/No what you needed to do for at least 1 day MS-Q (13) Instructions: The questions below refer to the headaches or migraine episodes without headache that you may have experienced in your lifetime. Answer each question as indicated. If you are not sure how to answer a given question, please answer what you believe is most correct. Do you have frequent or intense headaches? Yes/No Do your headaches usually last more than 4 hours? Yes/No Do you usually suffer from nausea when you have a headache? Yes/No Does light or noise bother you when you have a headache? Yes/No Does headache limit any of your physical or intellectual Yes/No activities? * A score of >2 on the ID Migraine and >4 on MS-Q is a positive screen for migraine. TABLE 2 Establishing the differential diagnosis of headache (14,15) Cause of headache Triggers Primary headache syndrome Cluster headache Tension-type headache Autoimmune Autoimmune thyroiditis Systemic lupus erythematosus Congenital Arachnoid cyst Arnold-Chiari malformation Pineal cyst Degenerative Cervical spondylosis Osteoarthritis Temporomandibular joint disorder Endocrine or metabolic Estrogen withdrawal Growth hormone imbalance Hypoglycemia Hypothyroidism and hyperthyroidism Parathyroid disease Iatrogenic or Acute and chronic sinusitis intoxication Meningitis Nonsteroidal anti-inflammatory drug- induced headache Substance intoxication (eg, alcohol, carbon monoxide) Substance withdrawal (eg, alcohol, medications) Infectious Temporal arteritis Neoplastic Lymphoma Metastases Primary brain tumor Trauma Concussion Skull fracture Vascular Acute hypertension Carotid dissection Intracerebral hypertension Subarachnoid hemorrhage Subdural hematoma TABLE 3 Risk factors for intracranial pathology (14) Acute headache Abnormal neurologic exam Acute "thunderclap" headache Age >55 years History of human immunodeficiency virus infection, cancer, or other type of immunosuppression Occipitonuchal location Systemic illness (eg, fever, stiff neck, rash) Non-acute headache Associated with exertion (eg, exercise, sex) or Valsalva maneuver Lack of coordination Leads to awakening from sleep Localized neurologic findings Rapidly increasing frequency TABLE 4 Migraine therapy: Options3 and promising approaches (12,18-20) Drug class or device Medications/treatment Available for acute migraine Over-the-counter analgesics Acetaminophen, Ibuprofen, naproxen Barbiturates Amobarbitol, butalbital- acetamlnophen-caffeine, pentobarbital Dihydroergotamine -- Triptans Almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan Triptan-NSAID combination Sumatriptan and naproxen sodium (tablet) On the horizon Calcitonin gene-related peptide Ubrogepant receptor antagonist Selective serotonin Lasmiditan (20) [5-HT.sub.1f] receptor Therapeutic devices sTMS mini Single pulses to the back of the head gammaCore Transcutaneous vagal nerve stimulation Spring TMS TMS uses single pulses to the back of the head; used during acute headache Being studied for migraine prophylaxis (approved for this use in the European Union) Over-the-counter analgesics For mild, Infrequent migraine only Frequent use can lead to medication overuse headache Barbiturates For moderate-to-severe migraine For symptom control, but only during an acute episode Can cause central nervous system depression and medication overuse headache High addictive potential Recommend against prescribing as first-line treatment in recurrent headache disorders Dihydroergotamine For moderate-to-severe migraine Vasoconstrictive Does not prevent headache or reduce number of migraine attacks Triptans For moderate-to-severe migraines Taken at onset of headache Avoid in patients with history of atherosclerotic vascular disease FDA warning about potential for serotonin syndrome with concomitant use of triptans and SSRIs or SNRIs (12) Triptan-NSAID combination For moderate-to-severe migraine Consider when use of a single drug On the horizon fails to provide adequate control Calcitonin gene-related peptide Awaiting FDA approval receptor antagonist Better tolerated than triptans; fewer central nervous system adverse effects18 Concerns for liver toxicity19 Selective serotonin Investigational [5-HT.sub.1f] receptor Not vasoconstrictive Potentially safe for patients with cardiovascular disease Therapeutic devices sTMS mini Appproved in 2013 for acute migraine with aura Hand-held device Potentially high out-of-pocket costs Drug class or device Important considerations gammaCore For acute migraine and migraine prophylaxis Thought to suppress high levels of glutamate in the trigeminal nucleus Held against the neck; requires 2 minutes to administer Spring TMS Approved in 2014 for acute migraine with aura Effective for headache cessation at 2 hours in 40% of patients Avoid in patients with an implanted metal device or history of seizures FDA, Food and Drug Administration; NSAID, nonsteroidal anti-inflammatory drug; SNRIs, serotonin-norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TMS, transcranial magnetic stimulation. (a) Examples; not an exhaustive list. TABLE 5 Common migraine triggers Alcohol Anxiety Caffeine (or caffeine withdrawal in regular users) Dehydration Diet Excessive head movement Eye strain Fatigue Hunger Menstruation Noise Sleep deprivation Stress TABLE 6 Migraine prophylaxis: What's available? What's being studied? (20,29,30,32-41) Available medications Drug class or device Examples; description of intervention Allergy medications Cyproheptadine (serotonin and histamine antagonist) (32); subcutaneous histamine Antidepressants Amitriptyline (25/150 mg/d) (32); venlafaxine Anti-epileptics Divalproex sodium, sodium valproate, topiramate (25/200 mg/d) (32) Beta-blockers AHS/AAN Level-A evidence (32a) Metoprolol Propranolol Timolol AHSD/AAN Level-B evidence (32a) Atenolol Nadalol AHS/AAN Level-C evidence (32a) Nebivolol Pindolol Calcitonin gene-related Eptinezumab, erenumab, fremanezumab, peptide (CGRP) monoclonal galcanezumab antibodies Other antihypertensives Candesartan, Clonidine, lisinopril Triptans AHS/AAN Level-A evidence (32a) Frovatriptan AHS/AAN Level-B evidence (32a) Naratriptan Zolmitriptan Alternative therapies Acupuncture -- Drug class or device Examples; description of intervention OnabotulinumtoxinA Administered every 12 weeks (30-33); 31 injections in 7 areas of the head and neck Cefaly (transcutaneous Targets the trigeminal nerve electrical nerve specifically; applied to the forehead stimulator) and turned on daily for 20 minutes Dietary supplements and AHS/AAN Level/A evidence (32a) herbal preparations Butterbur (Petasites hybridus), AHSIAAN Level-B evidence (32a) Magnesium, 600 mg/d trimagnesium dicitrate (20) Riboflavin, 400 mg/d (32) Tanacetum parthenium (feverfew), 50- 50-75 mg BID (29) Coenzyme Q10, 100 mg TID (32) Exercise Cardiovascular exercise, yoga Under investigation Occipital nerve Inserted in the back of the head; have stimulators wires and batteries Sphenopalatine nerve Invasive insertion procedure stimulators Drug class or device Important considerations Allergy medications Off-label use; awaiting FDA approval for this indication Sedating side effects may limit use Antidepressants Amitriptyline is the only tricyclic antidepressant with proven efficacy (32) Anti-epileptics Topiramate has high-quality evidence supporting its use (32) Lamotrigine is ineffective and should be avoided (32) Beta-blockers Use with caution in patients >60 years of age (risk of bradycardia) Calcitonin gene-related Eptinezumab trials are still being peptide (CGRP) monoclonal completed; approval pending antibodies Erenumab was recently approved by the FDA CGRP monoclonal antibodies are well- tolerated; no severe adverse effects noted (39,40) Reduce the number of headache days per month, compared to placebo (39-40) Other antihypertensives Level-C evidencea for these agents (AHS-AAN review) (32) Insufficient evidence for calcium- channel blockers Telmisartan is ineffective (32) Triptans Menstruation-related migraine (given before onset of menses) Alternative therapies Acupuncture Mildly better than sham, may be less effective than prophylactic oral agents (34) Low risk of adverse events OnabotulinumtoxinA May be effective at reducing number of headache days for patients with >15 headache days a month (chronic migraine) (30,33) Cefaly (transcutaneous Safe, well tolerated; approved by the electrical nerve FDA In 2014 (38) stimulator) No serious adverse events noted after short-term use For migraine prophylaxis in patients unable to tolerate medications Dietary supplements and Low risk of harm (except see comment herbal preparations below regarding butterbur) Avoid butterbur in patients with hepatic disease; use caution with unknown formulations for all patients because of the potential for exposure to hepatotoxic compounds in unpurified formulations (41) Weakest evidence for coenzyme Q10 (32) New combination products are in early clinical trials (36,37) Exercise Small RCT showed no significant difference (P = .95) between exercise and relaxation or topiramate (35) Low risk of harm if no prohibiting Under investigation comorbidities Occipital nerve Limited tolerability; not approved in stimulators EU because of adverse effects (38) Sphenopalatine nerve Being studied in the United States; in stimulators use in the EU Being studied for migraine prophylaxis Effective for cluster headache prophylaxis (38) AAN, American Academy of Neurology; AHS, American Headache Society; CNS, central nervous system; EU, European Union; FDA, Food and Drug Administration; RCT, randomized controlled trial. (a) Level A AHS/AAN ranking indicates "established" effectiveness; "Level B," "probably" effective; and Level C, "possibly" effective. (32)
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|Author:||McGrath, Kathryn; Rague, Allison; Thesing, Claire; Collins, Elizabeth; Seecof, Olivia; Liantonio, Jo|
|Publication:||Journal of Family Practice|
|Date:||Jan 1, 2019|
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