EXPANDING OUR TX ARSENAL (Dr

REVISED 02/25/21

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 EXPANDING OUR TX ARSENAL (Dr. Rague); Department of Family Medicine, University of Illinois at Chicago (Dr. Thesing)

Kathryn.mcgrath@ jefferson.edu

The authors reported no potential conflict of interest relevant to this article.

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.

igraine is a highly disabling prima- fected.2,3 Frequency of migraine headache ry headache disorder that affects is variable; chronic migraineurs experience more than 44 million Americans more than 15 headache days a month. M1 annually. The disorder causes pain, photo- Recent estimates indicate that the cost phobia, phonophobia, and nausea that can of acute and chronic migraine headaches last for hours, even days. Migraine headaches reaches approximately $78 million a year are 2 times more common in women than in in the United States.4 This high burden of men; although migraine is most common in disease has made effective migraine treat-

people 30 to 39 years of age, all ages are af- ment options absolutely essential. Recent RILEY/SCIENCE SOURCE IMAGE: © CATH

10 THE JOURNAL OF FAMILY PRACTICE | JANUARY/FEBRUARY 2019 | VOL 68, NO 1 advances in our understanding of migraine Diagnosis: Close patient pathophysiology have led to new therapeutic inquiry is most helpful targets; there are now many novel treatment The International Headache Society (IHS) approaches on the horizon. criteria for primary headache disorders serve In this article, we review the diagnosis as the basis for the diagnosis of migraine and and management of migraine in detail. Our its subtypes, which include migraine without emphasis is on evidence-based approaches aura and migraine with aura. Due to vari- to acute and prophylactic treatment, includ- ability of presentation, migraine with aura is ing tried-and-true options and newly emerg- further subdivided into migraine with typical ing therapies. aura (with and without headache), migraine with brainstem aura, hemiplegic migraine, and retinal migraine.11 Neuronal dysfunction ❚ How is migraine defined? Simply, mi- and a genetic predisposition graine is classically defined as a unilateral, Although migraine was once thought to be pulsating headache of moderate to severe in- caused by abnormalities of vasodilation, cur- tensity lasting 4 to 72 hours, associated with rent research suggests that the disorder has photophobia and phonophobia or nausea its origins in primary neuronal dysfunction. and vomiting, or both.11 Often visual There appears to be a genetic predisposition in nature, aura is a set of neurologic toward widespread neuronal hyperexcitabil- symptoms that lasts for minutes and PRACTICE ity in migraineurs.5 In addition, hypothalamic precedes the onset of the headache. RECOMMENDATIONS neurons are thought to initiate migraine by The visual aura is often described ❯ Offer treatment with a responding to changes in brain homeostasis. as a scintillating scotoma that be- triptan to adult patients with moderate-to-severe episodic Increased parasympathetic tone might acti- gins near the point of visual fixation migraine. A vate meningeal pain receptors or lower the and then spreads left or right. Other threshold for transmitting pain signals from aura symptoms include tingling or ❯ Consider prescribing the thalamus to the cortex.6 numbness (second most common), topiramate, divalproex sodium, metoprolol, propran- Prodromal symptoms and aura appear speech disturbance (aphasia), mo- olol, or the herbal, Petasites to originate from multiple areas across the tor changes and, in rare cases, a hybridum, for the prevention brain, including the hypothalamus, cortex, combination of these in succession. of recurrent episodic migraine limbic system, and brainstem. This wide- By definition, all of these symptoms that has not responded to a spread brain involvement might explain fully resolve between attacks.11 reduction in headache why some headache sufferers concurrently ❚ Validated valuable question- triggers. A experience a variety of symptoms, includ- naires. To help with accurate and ❯ Add onabotulinumtoxinA ing fatigue, depression, muscle pain, and timely diagnosis, researchers have injection to your therapeutic an abnormal sensitivity to light, sound, and developed and validated simplified toolbox as an effective preven- smell.6,7 questionnaires that can be complet- tive treatment for chronic Although the exact mechanisms be- ed independently by patients pre- migraine (≥15 headache days hind each of these symptoms have yet to be senting to primary care (TABLE 112,13): a month for 3 months). B defined precisely, waves of neuronal depo- • ID Migraine is a set of 3 ques- ❯ Recommend magnesium larization—known as cortical spreading de- tions that scores positive and feverfew as adjunctive pression—are suspected to cause migraine when a patient endorses at preventive treatments for aura.8-10 Cortical spreading depression acti- least 2 of the 3 symptoms.12 migraine. B vates the trigeminal pain pathway and leads • MS-Q is similar to the ID Mi- Strength of recommendation (SOR) to the release of pro-inflammatory mark- graine but includes 5 items. A Good-quality patient-oriented ers such as calcitonin gene-related protein A score of ≥4 is a positive evidence (CGRP).6 A better understanding of these screen.13 B Inconsistent or limited-quality patient-oriented evidence complex signaling pathways has helped pro- C Consensus, usual practice, vide potential therapeutic targets for new mi- The sensitivity and specificity of opinion, disease-oriented graine drugs. MS-Q (0.93 and 0.81, respectively) evidence, case series

MDEDGE.COM/JFPONLINE VOL 68, NO 1 | JANUARY/FEBRUARY 2019 | THE JOURNAL OF FAMILY PRACTICE 11 TABLE 1 2 Helpful questionnaires for pursuing a migraine diagnosis*12,13

ID Migraine12 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 what Yes/No you needed to do for at least 1 day

MS-Q13 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 After taking Does light or noise bother you when you have a headache? Yes/No the initial history Does headache limit any of your physical or intellectual activities? Yes/No (headache onset, *A score of ≥2 on the ID Migraine and ≥4 on MS-Q is a positive screen for migraine. location, duration, associated are slightly higher than those of ID Migraine • extremity strength testing symptoms), focus (0.81 and 0.75).13 • eye exam (vision, extra-ocular mus- attention on ❚ Remember POUND. This mnemonic cles, visual fields, pupillary reactivity, assessing the device can also be used during histo- and funduscopic exam) risk of ry-taking to aid in diagnostic accuracy. • gait (tandem walk) intracranial Migraine is highly likely (92%) in patients • reflexes. pathology. who endorse 4 of the following 5 symptoms and unlikely (17%) in those who endorse ❚ Further testing needed? Neuroimag- ≤2 symptoms14: Pulsatile quality of headache ing should be considered only in patients 4 to 72 hOurs in duration, Unilateral location, with an abnormal neurologic exam, atypi- Nausea or vomiting, and Disabling intensity. cal headache features, or certain risk factors, such as an immune deficiency. There is no ❚ Differential Dx. Although the dif- role for electroencephalography or other di- ferential diagnosis of headache is broad agnostic testing in migraine.16 (TABLE 214,15), the history alone can often guide clinicians towards the correct assessment. Af- ter taking the initial history (headache onset, Take a multipronged location, duration, and associated symptoms), approach to treatment focus your attention on assessing the risk of in- As with other complex, chronic conditions, tracranial pathology. This is best accomplished the treatment of migraine should take a mul- by assessing specific details of the history tifaceted approach, including management (TABLE 314) and findings on physical of acute symptoms as well as prevention of examination15: future headaches. In 2015, the American • blood pressure measurement (seated, Headache Society published a systematic legs uncrossed, feet flat on the floor; review that specified particular treatment having rested for 5 minutes; arm well goals for migraine sufferers.17 These goals supported) include: • cranial nerve exam • headache reduction

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TABLE 2 Establishing the differential diagnosis of headache14,15

Cause of headache Triggers Primary headache syndrome Cluster headache Tension-type headache

Autoimmune Autoimmune thyroiditis Systemic lupus erythematosus Temporal arteritis Congenital Arachnoid cyst Arnold–Chiari malformation Pineal cyst Degenerative Cervical spondylosis Osteoarthritis Temporomandibular joint disorder

Endocrine or metabolic Estrogen withdrawal Growth hormone imbalance Electroencepha- Hypoglycemia lography and Hypothyroidism and hyperthyroidism other diagnostic testing have no Parathyroid disease role in the Iatrogenic or intoxication Nonsteroidal anti-inflammatory drug–induced headache workup of Substance intoxication (eg, alcohol, carbon monoxide) migraine. Substance withdrawal (eg, alcohol, medications) Infectious Acute and chronic sinusitis Meningitis Neoplastic Lymphoma Metastases Primary brain tumor Trauma Concussion Skull fracture Vascular Acute hypertension Carotid dissection Intracerebral hypertension Subarachnoid hemorrhage Subdural hematoma

• headache relief graine in adults. Approaches in special popu- • decreased disability from headache lations (older adults, pregnant women, and • elimination of nausea and vomiting children) are discussed afterward. • elimination of photophobia and phonophobia. Pharmacotherapy for acute migraine Our review, which follows, of therapeutic Acute migraine should be treated with an options focuses on the management of mi- abortive medication at the onset of headache. CONTINUED

MDEDGE.COM/JFPONLINE VOL 68, NO 1 | JANUARY/FEBRUARY 2019 | THE JOURNAL OF FAMILY PRACTICE 13 TABLE 3 headache relief from an appropriate dosage Risk factors for intracranial of a given triptan during a particular migraine 14 episode, a different triptan can be tried dur- pathology ing the next migraine.22 Additionally, if a pa- Acute headache tient experiences an adverse effect from one Abnormal neurologic exam triptan, this does not necessarily mean that Acute “thunderclap” headache a trial of another triptan at a later time is contraindicated. Age >55 years For patients who have an incomplete History of human immunodeficiency virus response to migraine treatment or for those infection, cancer, or other type of immunosuppression with frequent recurrence, the combination formulation of sumatriptan, 85 mg, and Occipitonuchal location naproxen, 500 mg, showed the highest rate of Systemic illness (eg, fever, stiff neck, rash) resolution of headache within 2 hours com- Non-acute headache pared with either drug alone.23 A similar re- Associated with exertion (eg, exercise, sex) or sult might be found by combining a triptan Valsalva maneuver known to be effective for a patient and an Lack of coordination NSAID other than naproxen. If migraine per- Leads to awakening from sleep sists despite initial treatment of an attack, a Treat migraine Localized neurologic findings different class of medication should be tried with a Rapidly increasing frequency during the course of that attack to attain relief multifaceted of symptoms of that migraine.21 approach, When a patient is seen in an acute care including The immediate goal is to relieve pain within setting (eg, emergency department, urgent management of 2 hours and prevent its recurrence within the care center) while suffering a migraine, ad- acute symptoms subsequent 48 hours (TABLE 412,18-20). ditional treatment options are available. In- and prevention In the general population, mild, in- travenous (IV) anti-emetics are useful for of future frequent migraines can be managed relieving the pain of migraine and nausea, headaches. with acetaminophen and nonsteroidal and can be used in combination with an anti-inflammatory drugs (NSAIDs).21 IV NSAID (eg, ketorolac).21 The most effective For moderate-to-severe migraine, trip- anti-emetics are dopamine receptor type-2 tans, which target serotonin receptors, are blockers, including chlorpromazine, droperi- the drug of choice for most patients.21 Trip- dol, metoclopramide, and prochlorperazine, tans are superior to placebo in achieving a which has the highest level of efficacy.24 Note pain-free state at 2 and 24 hours after admin- that these medications do present the risk istration; eletriptan has the most desirable of a dystonic reaction; diphenhydramine is outcome, with 68% of patients pain free at therefore often used in tandem to mitigate 2 hours and 54% pain free at 24 hours.22 Trip- such a response. tans are available as sublingual tablets and ❚ Looking ahead. Although triptans nasal sprays, as well as subcutaneous injec- are the current first-line therapy for acute tions for patients with significant associated migraine, their effectiveness is limited. Only nausea and vomiting. Avoid prescribing trip- 20% of patients report sustained relief of pain tans for patients with known vascular disease in the 2 to 24 hours after treatment, and the (eg, history of stroke, myocardial infarction, response can vary from episode to episode.25 peripheral vascular disease, uncontrolled hy- With better understanding of the patho- pertension, or signs and symptoms of these physiology of migraine, a host of novel anti- conditions), as well as for patients with severe migraine drugs are on the horizon. hepatic impairment. ❚ CGRP receptor antagonists. The neu- Importantly, although triptans all have a ropeptide CGRP, which mediates central and similar mechanism of action, patients might peripheral nervous system pain signaling, respond differently to different drugs within has been noted to be elevated during acute the class. If a patient does not get adequate migraine attacks26; clinical trials are therefore

14 THE JOURNAL OF FAMILY PRACTICE | JANUARY/FEBRUARY 2019 | VOL 68, NO 1 TABLE 4 Migraine therapy: Optionsa and promising approaches12,18-20

Drug class or device Medications/treatment Important considerations Available for acute migraine Over-the-counter analgesics Acetaminophen, ibuprofen, naproxen For mild, infrequent migraine only Frequent use can lead to medication overuse headache

Barbiturates Amobarbitol, For moderate-to-severe migraine butalbital–acetaminophen–caffeine, For symptom control, but only during an pentobarbital 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 Almotriptan, eletriptan, frovatriptan, For moderate-to-severe migraines naratriptan, rizatriptan, sumatriptan, Taken at onset of headache zolmitriptan Avoid in patients with history of atherosclerotic vascular disease FDA warning about potential for serotonin syndrome with concomitant use of triptans and SSRIs or SNRIs12

Triptan-NSAID Sumatriptan and naproxen sodium (tablet) For moderate-to-severe migraine combination Consider when use of a single drug fails to provide adequate control

On the horizon Calcitonin gene-related peptide Ubrogepant Awaiting FDA approval receptor antagonist Better tolerated than triptans; fewer central nervous system adverse effects18 Concerns for liver toxicity19

20 Selective serotonin 5-HT1f receptor Lasmiditan Investigational agonist Not vasoconstrictive Potentially safe for patients with cardiovascular disease

Therapeutic devices sTMS mini Single pulses to the back of the head Appproved in 2013 for acute migraine with aura Hand-held device Potentially high out-of-pocket costs

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TABLE 4 Migraine therapy: Optionsa and promising approaches12,18-20 (cont'd)

Drug class or device Medications/treatment Important considerations gammaCore Transcutaneous vagal nerve stimulation 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 TMS uses single pulses to the back of the Approved in 2014 for acute migraine with head; used during acute headache aura Being studied for migraine prophylaxis Effective for headache cessation at 2 hours in (approved for this use in the European 40% of patients Union) 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. aExamples; not an exhaustive list. underway to evaluate the safety and efficacy tive therapy for migraine is indicated for any of CGRP receptor antagonists.18 These agents patient with30: appear to be better tolerated than triptans, • ≥6 headache days a month have fewer vascular and central nervous sys- • ≥4 headache days a month with some tem adverse effects, and present less of a risk impairment of medication overuse headache.18 Liver tox- • ≥3 headache days a month with severe icity has been seen with some medications in impairment. this class and remains an important concern in their development.19 Treatment begins by having patients iden- Phase 3 clinical trials for 1 drug in this tify, and then avoid, migraine triggers class, ubrogepant, were completed in late 2017; (TABLE 5). This can be accomplished by hav- full analysis of the data is not yet available. Pri- ing patients keep a headache diary, in which mary outcomes being evaluated include re- they can enter notations about personal and lief of pain at 2 hours and relief from the most environmental situations that precede a bothersome symptoms again at 2 hours.27 headache.

❚ Selective serotonin-HT1f receptor For the individual patient, some trig- agonists, such as lasmiditan, offer anoth- gers are modifiable; others are not. Helping er potential approach. Although the exact a patient develop strategies for coping with mechanism of action of these agents is not triggers, rather than aiming for complete entirely clear, clinical trials have supported avoidance, might help her (him) manage their efficacy and safety.20 Importantly, on- those that are inescapable (eg stress, men- going trials are specifically targeting patients struation, etc).31 For many patients, however, with known cardiovascular risk factors be- this is not an adequate intervention and other cause they are most likely to benefit from approaches must be explored. When consid- the nonvasoconstrictive mechanism of ac- ering which therapy might be best for a given tion.28,29 Adverse effects reported primarily patient, evaluate her (his) comorbidities and include dizziness, fatigue, and vertigo. assess that particular treatment for potential secondary benefits and the possibility of ad- Strategies for managing verse effects. Pay attention to the choice of recurrent episodic migraine preventive therapy in women who are con- Because of the risk of medication overuse sidering pregnancy because many available headache with acute treatment, daily preven- treatments are potentially teratogenic.

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MDEDGE.COM/JFPONLINE VOL 68, NO 1 | JANUARY/FEBRUARY 2019 | THE JOURNAL OF FAMILY PRACTICE 17 TABLE 5 month compared with placebo; the authors Common migraine triggers cautioned, however, that data with which to evaluate onabotulinumtoxinA in comparison Alcohol to other prophylactic agents are limited.43 Anxiety In both studies, the risk of adverse drug Caffeine (or caffeine withdrawal in regular events due to onabotulinumtoxinA was high users) and led to a significant rate of discontinua- Dehydration tion.33,43 Despite this, onabotulinumtoxinA Diet remains the only Food and Drug Administra- Excessive head movement tion (FDA)–approved treatment for chronic migraine, making it reasonable to consider Eye strain for appropriate patients. Fatigue ❚ Acupuncture. A 2016 Cochrane review Hunger found benefit for patients using acupunc- Menstruation ture compared with sham acupuncture.34 Noise When acupuncture was compared with Sleep deprivation prophylactic agents such as beta-blockers, calcium-channel blockers, and anti-epi- Stress leptics, however, there was no significant difference between the procedure and phar- ❚ Oral medications. Oral agents from macotherapy. Patients willing and able to try several classes of drugs can be used for mi- acupuncture might see a reduction in the graine prophylaxis, including anti-epileptics, overall number of headaches. Acupuncture antidepressants, and antihypertensives has few adverse effects; however, long-term (TABLE 620,29,30,32-41). Selected anti-epileptics data are lacking.34 (divalproex sodium, sodium valproate, topi- ❚ Exercise is not supported by robust ramate) and beta-blockers (metoprolol, data for its role as a prophylactic treatment. It propranolol, and timolol) have the stron- is generally considered safe in most popula- gest evidence to support their use.32 Overall, tions, however, and can be pursued with little regular use of prophylactic medications can out-of-pocket cost.35 reduce headache frequency by 50% for ap- ❚ Cognitive behavioral therapy (CBT). proximately 40% to 45% of patients who take The AAN recommends CBT, relaxation thera- them.29 However, adherence may be limited py, and biofeedback therapy. Accessibility of by adverse effects or perceived lack of effica- these services remains limited for many pa- cy, thus reducing their potential for benefit.42 tients, and cost can be prohibitive.16 ❚ OnabotulinumtoxinA. In patients ❚ Supplements used to help prevent mi- with chronic migraine (≥15 headache days a graine include the root of Petasites hybridus month for at least 3 months) who have failed (butterbur), magnesium, vitamin B2 (ribofla- oral medications, the American Academy of vin), Tanacetum parthenium (feverfew), and Neurology (AAN) recommends the use of coenzyme Q10.16 Although the strength of ev- onabotulinumtoxinA.30 The treatment regi- idence for these therapies is limited by small men comprises 31 injections at various sites trials, their overall risk of adverse effects is on the head, neck, and shoulders every 3 low, and they might be easier for patients to months.33 obtain than acupuncture or CBT. A 2010 large randomized controlled trial Butterbur, in particular, has been found showed a decrease in the frequency of head- to be beneficial for migraine prevention in ache days for patients receiving onabotu- 2 small placebo-controlled trials. In a ran- linumtoxinA compared to placebo after a domized controlled study of 245 patients 24-week treatment period (7.8 fewer headache P hybridus, (specifically, the German for- days a month, compared to 6.4 fewer in the mulation, Petadolex), 75 mg BID, reduced placebo group).33 A recent systematic review the frequency of migraine attack by 48% at also noted a reduction of 2 headache days a 4 months, compared to placebo (number

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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 Important considerations

Allergy medications Cyproheptadine (serotonin and histamine Off-label use; awaiting FDA approval for this antagonist)32; subcutaneous histamine indication

Sedating side effects may limit use Antidepressants Amitriptyline (25-150 mg/d)32; venlafaxine Amitriptyline is the only tricyclic antidepressant with proven efficacy32 Anti-epileptics Divalproex sodium, sodium valproate, Topiramate has high-quality evidence topiramate (25-200 mg/d)32 supporting its use32 Lamotrigine is ineffective and should be avoided32 Beta-blockers AHS/AAN Level-A evidence32a Use with caution in patients >60 years of age (risk of bradycardia) Metoprolol Propranolol Timolol AHSD/AAN Level-B evidence32a Atenolol Nadalol AHS/AAN Level-C evidence32a Nebivolol Pindolol Calcitonin gene-related peptide Eptinezumab, erenumab, fremanezumab, Eptinezumab trials are still being completed; (CGRP) monoclonal antibodies galcanezumab approval pending Erenumab was recently approved by the FDA CGRP monoclonal antibodies are well- tolerated; no severe adverse effects noted39,40 Reduce the number of headache days per month, compared to placebo39,40

Other antihypertensives Candesartan, clonidine, lisinopril Level-C evidencea for these agents (AHS/AAN review)32 Insufficient evidence for calcium-channel blockers Telmisartan is ineffective32 Triptans AHS/AAN Level-A evidence32a Menstruation-related migraine (given before onset of menses) Frovatriptan AHS/AAN Level-B evidence32a Naratriptan Zolmitriptan Alternative therapies Acupuncture Mildly better than sham, may be less effective 34 — than prophylactic oral agents Low risk of adverse events

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MDEDGE.COM/JFPONLINE VOL 68, NO 1 | JANUARY/FEBRUARY 2019 | THE JOURNAL OF FAMILY PRACTICE 19 TABLE 6 Migraine prophylaxis: What’s available? What’s being studied?20,29,30,32-41 (cont'd) Alternative therapies

Drug class or device Examples; description of intervention Important considerations

OnabotulinumtoxinA Administered every 12 weeks30,33; May be effective at reducing number of 31 injections in 7 areas of the head and headache days for patients with >15 headache neck days a month (chronic migraine)30,33

Cefaly (transcutaneous electrical Targets the trigeminal nerve specifically; Safe, well tolerated; approved by the FDA in nerve stimulator) applied to the forehead and turned on 201438 daily for 20 minutes No serious adverse events noted after short-term use For migraine prophylaxis in patients unable to tolerate medications Dietary supplements and herbal AHS/AAN Level-A evidence32a Low risk of harm (except see comment below preparations regarding butterbur) Butterbur (Petasites hybridus), 50-300 mg BID32 Avoid butterbur in patients with hepatic disease; use caution with unknown AHS/AAN Level-B evidence32a formulations for all patients because of the Magnesium, 600 mg/d as trimagnesium potential for exposure to hepatotoxic dicitrate20 compounds in unpurified formulations41 Riboflavin, 400 mg/d32 Weakest evidence for coenzyme Q1032 Tanacetum parthenium (feverfew), New combination products are in early clinical 50-75 mg BID29 trials36,37 AHS/AAN Level-C evidence32a Coenzyme Q10, 100 mg TID32 Exercise Cardiovascular exercise, yoga Small RCT showed no significant difference (P = .95) between exercise and relaxation or topiramate35 Low risk of harm if no prohibiting comorbidities Under investigation

Occipital nerve stimulators Inserted in the back of the head; have Limited tolerability; not approved in EU wires and batteries because of adverse effects38 Sphenopalatine nerve stimulators Invasive insertion procedure Being studied in the United States; in use in the EU Being studied for migraine prophylaxis Effective for cluster headache prophylaxis38

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. aLevel A AHS/AAN ranking indicates “established” effectiveness; “Level B,” “probably” effective; and Level C, “possibly” effective.32

needed to treat, 5.3).44 No difference was duction facilities in the United States, butter- found at lower dosages. The most common bur supplements might not have all of these reported adverse effect was burping. compounds removed—and so should be Regrettably, unpurified butterbur extract used with caution.41 contains pyrrolizidine alkaloids, potentially ❚ Magnesium. Studies evaluating the use hepatotoxic and carcinogenic compounds. of magnesium have demonstrated varied re- Because of variations in purification in pro- sults; differences in methods and dosing have

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limited broad application of findings. As with adults requires special attention: Treatment most supplements considered for prophylac- approaches are different than they are for tic treatment, magnesium dosing is poorly adults 19 to 65 years of age. understood, and bioavailability varies in its ❚ Pediatric patients. Migraine is the different forms. Oral supplementation can be most common acute and recurrent head- given as magnesium dicitrate, 600 mg/d.45 ache syndrome in children. Headaches dif- Recently, products containing various fer from those of adult migraine as a result combinations of feverfew, coenzyme Q10, ri- of variations in brain maturation, plasticity, boflavin, magnesium, and other supplements and cognitive development.47 Migraine at- have shown benefit in early clinical trials.36,37 tacks are often of shorter duration in chil- ❚ Neural stimulation. Over the past few dren, lasting 1 to 2 hours, but can still be years, a variety of transcutaneous nerve stim- preceded by visual aura.48 Just as with ulator devices have gained FDA approval for adults, imaging, electroencephalography, use in migraine prophylaxis. The long-term lumbar puncture, and routine labs should safety and efficacy of these devices is not yet be considered only if a child has an abnor- well understood, but they appear to provide mal neurological exam or other concerning headache relief in the short term and de- features (TABLE 214,15). crease the frequency of headache.38 Use of The general approach to migraine treat- the noninvasive stimulators is limited today ment in the pediatric population includes by high cost and poor coverage by US health education of the child and family about symp- Don’t prescribe care insurers. tom management. Acetaminophen, NSAIDs, triptans for ❚ Newly available medical therapy. The and triptans are approved for abortive thera- patients with FDA recently approved erenumab, a fully hu- py in children and should be used for acute known vascular man monoclonal antibody for prevention of headache relief in the same way that they are disease or severe migraine in adults. This is the first drug in the used in adults. Oral rizatriptan, the most well hepatic CGRP antagonist class to be approved for this studied triptan in the pediatric population, impairment. indication. Trials of this once-monthly, self- is approved for use in children as young as injectable drug show promising results for 6 years49; the pediatric dosage is 5 mg/d for patients whose migraines have been refrac- patients weighing 20 to 39 kg and 10 mg/d for tory to other therapies. patients weighing more than 40 kg (same as A recent large trial evaluated 955 adults the adult dosage). with migraine, randomizing them to receive Oral almotriptan and zolmitriptan erenumab, 70 mg; erenumab, 140 mg; or pla- are also approved for use in children 12 to cebo over 28 weeks.39 The groups receiving 17 years of age. Usual dosages are: almotrip- erenumab had a nearly 2-fold higher odds of tan, 12.5 mg at onset, can repeat in 2 hours having their migraine reduced by 50%, com- as needed (maximum dosage, 25 mg/d); pared with placebo (number needed to treat and zolmitriptan, 2.5 mg at onset, can repeat with the 140-mg dose, 4.27). Similar numbers in 2 hours as needed (maximum dosage, of participants from all groups discontinued 10 mg/d).50 the study.39 Phase 3 trials that are not yet For children who are unable to swallow formally published have produced similarly pills or who are vomiting, a non-oral route beneficial results.40,46 The FDA has listed in- of administration is preferable. Rizatriptan jection site reaction and constipation as the is available as an orally disintegrating tablet. most reported adverse effects.40 Zolmitriptan is available in a nasal spray at a Three other anti-CGRP antibodies are dose of 5 mg for children 12 years and older. likely to be approved in the near future: freman- Sumatriptan is not approved for use in pa- ezumab, galcanezumab, and eptinezumab. tients younger than 18 years; however, recent studies have shown that it might have good The approach to migraine efficacy and tolerability.50 in special populations Daily prophylactic treatment for recur- Management of acute and chronic migraine rent migraine in the pediatric population is in children, pregnant women, and older an evolving subject; published guidelines do

MDEDGE.COM/JFPONLINE VOL 68, NO 1 | JANUARY/FEBRUARY 2019 | THE JOURNAL OF FAMILY PRACTICE 21 not exist. It is reasonable to consider treat- abortion appears to be increased in the trip- ment using the same guidelines as those tan-exposed population.57 in place for adults.51 Topiramate, 1 to 2 mg/ Ergotamine is contraindicated during kg/d, is the only therapy approved by the FDA pregnancy because of its potential to induce for episodic migraine preventive therapy in uterine contractions and vasospasm, which adolescents.50 can be detrimental to the fetus.56 Notably, a nonpharmacotherapeutic ap- Nonpharmacotherapeutic interventions proach may be more effective for pediatric such as heat, ice, massage, rest, and avoidance prevention. In 2017, a large double-blind, of triggers are as successful in the pregnant placebo-controlled trial investigated the use population as in the nonpregnant population. of amitriptyline, topiramate, and placebo for For migraine prevention, coenzyme Q10, vita- the treatment of recurrent migraine in chil- mins B2 and B6 (pyridoxine), and oral mag- dren 8 to 17 years of age. An interim analysis nesium can be considered. Feverfew and of the 328 children enrolled found no sig- butterbur should be avoided because of con- nificant differences in reduction of headache cerns about fetal malformation and preterm frequency with treatment compared with labor. 58 placebo over a 24-week period; the trial was ❚ Older adults. Choosing appropriate stopped early due to futility.52 migraine therapy for older adults requires The study did show, however, that reduc- special consideration because of changes in If a patient ing migraine triggers provided a high level of drug metabolism and risks associated with doesn’t get benefit to study participants. Stress is one of drug adverse effects. Additionally, few stud- adequate the most common migraine triggers in chil- ies of migraine drugs have included large headache relief dren; lack of sleep, exposure to a warm cli- populations of adults older than 65 years; from an mate, and exposure to video games are also medications should therefore be prescribed appropriate notable triggers.53 CBT may augment the effi- cautiously in this population, with particular dosage of a cacy of standard migraine medications in the attention to drug–drug interactions. given triptan, pediatric population and may help prevent Just as for younger adults, mild symp- try a different recurrence of episodes.54 toms can be managed effectively with acet- triptan during ❚ Pregnancy. The treatment of migraine aminophen. NSAIDs may be used as well, but the next is different in pregnant women than it is in carry increased risks of gastric bleeding and migraine. nonpregnant adults because of a concern elevation in blood pressure.59 The use of trip- over adverse effects on fetal development. tans is acceptable for the appropriate patient, For acute headache treatment, first-line but should be avoided in patients with known therapies include trigger avoidance and ac- vascular disease.60 Antiemetics present an etaminophen, 1000 mg (maximum dosage, increased risk of extrapyramidal adverse ef- 4000 mg/d).55 If this is ineffective, a 10-mg fects in the elderly and should be used with dose of metoclopramide, as often as every caution at the lowest effective dosage.59 Novel 6 hours (not an FDA-approved indication), mechanisms of action make some of the can be considered. During the second tri- newer agents potentially safer for use in older mester, NSAIDs can be considered second- adults when treating acute migraine. line therapy. For migraine prevention in older Triptans—specifically, sumatriptan and adults, particular attention should be paid rizatriptan—can also be considered if first- to reducing triggers and minimizing poly- line therapies fail.56 Triptan-exposed preg- pharmacy. nant women with migraine have a rate of congenital malformations, spontaneous More and more, abortions, and prematurity that is similar to successful treatment is within reach what is seen in pregnant women with mi- With many clinical trials evaluating novel graine who have not been exposed to trip- drugs underway, and additional stud- tans. However, when triptan-exposed women ies contributing to our understanding of are compared with healthy, non-migraine- nonpharmacotherapeutic approaches to suffering women, the rate of spontaneous migraine treatment, improved headache

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Reuter U. Efficacy and safety of erenumab in episodic migraine dence assessment of migraine pharmacotherapies. Headache. patients with 2-4 prior preventive treatment failures: Results from 2015;55:3-20. the Phase 3b LIBERTY study. Abstract 009, AAN 2018 Annual 18. Voss T, Lipton RB, Dodick DW, et al. A phase IIb randomized, Meeting; April 24, 2018. double-blind, placebo-controlled trial of ubrogepant for the 41. Diener HC, Freitag FG, Danesch U. Safety profile of a special but- acute treatment of migraine. Cephalalgia. 2016;36:887-898. terbur extract from Petasites hybridus in migraine prevention 19. Russo AF. Calcitonin gene-related peptide (CGRP): a new target with emphasis on the liver. Cephalalgia Reports. https://journals. for migraine. Annu Rev Pharmacol Toxicol. 2015;55:533-552. sagepub.com/doi/10.1177/2515816318759304. 2018 May 2. Ac- cessed December 15, 2018. 20. Färkkilä M, Diener HC, Géraud G, et al; COL MIG-202 study group. Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) 42. Kingston WS, Halker R. Determinants of suboptimal migraine receptor agonist, for the acute treatment of migraine: a phase 2 diagnosis and treatment in the primary care setting. J Clin Out- randomised, placebo-controlled, parallel-group, dose-ranging comes Manag. 2017;24:319-324. study. Lancet Neurol. 2012;11:405-413. 43. Herd CP, Tomlinson CL, Rick C, et al. Botulinum toxins for the

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prevention of migraine in adults. Cochrane Database of Syst Rev. 2018;6:CD011616. 44. Lipton RB, Göbel H, Einhäupl KM, et al. Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Neu- rology. 2004;63:2240-2244. 45. Von Luckner A, Riederer F. Magnesium in migraine prophylaxis— is there an evidence‐based rationale? A systematic review. Head- “The Physical Activity ache. 2018;58:199-209. 46. Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenum- Guidelines for ab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16:425-434. Americans”— a 47. Sonal Sekhar M, Sasidharan S, Joseph S, et al. Migraine management: How do the adult and paediatric migraines differ?Saudi summary with tips Pharm J. 2012;20:1-7. 48. Lewis DW. Pediatric migraine. In: Lewis DW. Clinician’s Man- Doug Campos-Outcalt, MD, MPA ual on Treatment of Pediatric Migraine. London, UK: Springer Healthcare Ltd; 2010:15-26. 49. Ho TW, Pearlman E, Lewis D, et al. Efficacy and tolerability of rizatriptan in pediatric migraineurs: results from a randomized INSTANT POLL double-blind, placebo controlled trial using a novel adaptive en- richment design. Cephalagia. 2012;32:750-765. Do you confirm most diagnoses of 50. Khrizman M, Pakalnis A. Management of pediatric migraine: current therapies. Pediatr Ann. 2018;47:e55-e60. hypertension with out-of-office 51. Lipton RB, Bigal ME, Diamond M, et al; AMPP Advisory Group. (ambulatory or home) blood pressure Migraine prevalence, disease burden, and the need for preventive monitoring? therapy. Neurology. 2007;68:343-349. 52. Powers SW, Coffey CS, Chamberlin LA, et al; CHAMP Investiga- tors. Trial of amitriptyline, topiramate, and placebo for pediatric migraine. N Engl J Med. 2017;376:115-124. ONLINE EXCLUSIVES 53. Neut D, Fily A, Cuvellier JC, et al. The prevalence of triggers in paediatric migraine: a questionnaire study in 102 children and adolescents. J Headache Pain. 2012;13:61-65. • APPLIED EVIDENCE 54. Ng QX, Venkatanarayanan N, Kumar L. A systematic review Neonatal hyperbilirubinemia: An and meta‐analysis of the efficacy of cognitive behavioral evidence-based approach therapy for the management of pediatric migraine. Headache. s2017;57:349-362. • CASE REPORTS 55. Lipton RB, Baggish JS, Stewart WF, et al. Efficacy and safety of -ac etaminophen in the treatment of migraine: results of a random- Five-day fever • elevated creatinine ized, double-blind, placebo-controlled, population-based study. levels • kidney transplant 10 months Arch Intern Med. 2000;160:3486-3492. 56. Lucas S. Medication use in the treatment of migraine during preg- prior • Dx? nancy and lactation. Curr Pain Headache Rep. 2009;13:392-398. • Leg-length discrepancy • asymmetric 57. Marchenko A, Etwel F, Olutunfesse O, et al. Pregnancy out- gluteal folds and popliteal fossae • come following prenatal exposure to triptan medications: a meta-analysis. Headache. 2015:55:490-501. positive Galeazzi test • Dx 58. Wells RE, Turner DP, Lee M, et al. Managing migraine during • History of melanoma in situ • pregnancy and lactation. Curr Neurol Neurosci Rep. 2016;16:40. dyspnea • rib pain • Dx? 59. Haan J, Hollander J, Ferrari MD. Migraine in the elderly: a review. Cephalalgia. 2007;27:97-106. 60. Gladstone JP, Eross EJ, Dodick DW. Migraine in special • PHOTO ROUNDS populations. Treatment strategies for children and ado- A young girl with a painful rash lescents, pregnant women, and the elderly. Postgrad Med. 2004;115:39-44,47-50. • HELPDESK ANSWERS What are the best treatments for WE WANT TO HEAR reducing osteoporotic compression FROM YOU! fracture pain? Have a comment on an article, PHOTO ROUNDS FRIDAY editorial, or department? You can Test your diagnostic skills at www. send it by: jfponline.com/articles/photo-rounds- 1. E-MAIL: [email protected] friday.html 2. FAX: 973-206-9251 or 3. MAIL: The Journal of Family Practice, PLUS 7 Century Drive, Suite 302, Parsippany, NJ 07054 Today’s headlines in family medicine

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