Migraine treatment …

Headache & Pain

Updated 09.05.2023
Released 08.19.2021
Expires For CME 09.05.2026

Migraine treatment

Authors: Aniket Natekar MD MSc, Ayesha Ahmad MD, Cindy Huynh BA, Hsiangkuo Yuan MD PhD FAHS

See Contributor Disclosures

Editor: Stephen D Silberstein MD

Migraine treatment

In This Article

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Introduction

Overview

This article updates the guidelines for migraine treatment, specifically the nonpharmacological and pharmacological treatment of migraine. The article is meant to be a summary of the latest guidelines available. Discussion of migraine pathophysiology, complications, and comorbidities are outside the scope of this review.

Key points

	• Migraine treatment is meant to be a holistic approach, with pharmacologic and nonpharmacologic methods having equal weight.
	• There are medications and devices that are specific to abortive or preventive treatment.
	• Modifiable risk factors should be pursued first as diet and lifestyle changes can have significant impact on migraine treatment.
	• Medication overuse headache is a common cause of secondary headache and can confound treatment.
	• New preventive and abortive options have been released since 2018.
	• Several devices can be of benefit for migraine treatment.
	• Although limited, there are treatment options for people suffering from migraine during pregnancy and lactation.

Nonpharmacologic treatment

For some migraine patients, pharmacological treatments may have decreased efficacy, be poorly tolerated, or prove to be costly. For these reasons, nonpharmacological abortive and prophylactic migraine treatment options should be explored in a clinical setting. These alternative treatment options include modification of migraine risk factors, avoidance of triggers, supplementation with vitamins and coenzymes, diet modification, exercise, and psychotherapy (69).

Modifiable risk factors. There is a long-standing association between the effects of caffeine, sleep apnea or obstructive sleep apnea, hypertension, and obesity in regards to migraine. Long-term caffeine use can lead to negative effects. It can worsen the original headache, cause caffeine-withdrawal headache in patients consuming at least two cups of coffee daily, or induce headache from caffeine-containing over-the-counter medications as an analgesic for migraine treatment (95). Patients that are especially sensitive to caffeine can develop withdrawal headaches when caffeine is discontinued abruptly. Therefore, tapering caffeine by decreasing intake by 5 ounces every 3 to 5 days is recommended (20).

There is a significant association between headache disorders and sleep disorders, including snoring and obstructive sleep apnea. Poor quality sleep and migraine have a bidirectional relationship. People who have migraine tend to have worse quality sleep compared to those who do not experience migraine. Lack of sleep is also associated with increased migraine pain intensity, duration, and frequency (86). When subjects with migraine were compared to those with episodic headache, those suffering from migraine were more likely to snore daily (20). Patients who frequently awaken during the night and patients with migraine both have increased levels of serotonin. In both cases, this heightened level of serotonin may contribute to the pathophysiology and causal relationship between migraine and sleep disorders (89). Abnormal breathing during sleep, seen in obstructive sleep apnea, is associated with fragmented sleep, decreased oxyhemoglobin saturation, and increased migraine attacks. Most obstructive sleep apnea treatments involve continuous positive airway pressure. Obstructive sleep apnea is associated with hypertension and smoking, so interventions involving hypertension control and smoking cessation should be encouraged to improve obstructive sleep apnea and, in turn, migraine.

Compared to normal-weight individuals, obese and overweight individuals were found to have an increased headache frequency and intensity rate by 27%. Elevated levels of pro-inflammatory markers IL-1B, IL-6, TNF-alpha, and C-reactive peptide are found in obese individuals and are elevated in migraine attacks, thus, likely playing a key role in both conditions (23). With a behavioral weight loss diet that targeted exercise and eating behaviors, obese patients had a reduction of more than three migraine days per month over 12 weeks, supporting the benefits of weight loss in migraine prevention.

Avoid triggers. Some of the most common triggers for migraine attacks are fasting, alcohol, and menses, with a combination of these factors having a more potent effect (57). Fasting is considered one of the most reliable natural migraine triggers. It is hypothesized that periods of hypoglycemia cause changes in sympathetic activity, thus, triggering a migraine. Taking nonsteroidal anti-inflammatory drugs (NSAIDs), eating a later dinner, or nighttime snacking may prevent migraine attacks associated with fasting. Metabolites in alcohol (eg, acetate) or the metabolism of alcohol itself are likely to cause delayed headache. Due to this association, it is advised that patients suffering from migraine avoid or limit alcohol consumption.

Migraine is also common a few days prior to onset of a menstrual cycle. This was first proposed by Somerville and colleagues in a 1972 paper titled “Estrogen withdrawal hypothesis.” The theory suggests that a drop in estrogen levels prior to menstruation causes migraine attacks. This, in turn, may release neuropeptides, substance P, neurokinins, and prostaglandins and increase oxidative stress--all of which contribute to neural inflammation (33). Addressing menstrual migraine by perimenstrual application of an estrogen gel or patch has been shown to cause shorter, less intense, and less frequent migraine attacks (62). Similarly, eliminating estrogen cycling by the continuous use of a combined estrogen and progesterone oral contraceptive may reduce attacks. A progesterone-only contraceptive should be considered in patients suffering from migraine with aura as it has been shown to significantly reduce migraine intensity and frequency.

Vitamins and supplements. Magnesium has several important roles in migraine pathology. Magnesium conserves electron potential in neurons, blocks NMDA receptors, prevents neurotransmitter secretion, and mitigates the cortical spreading depression involved in migraine pathophysiology. Daily oral administration of 600 mg trimagnesium dicitrate taken for 6 months has been seen to decrease the daily occurrence of migraine attacks (41). Additionally, patients taking 500 mg magnesium oxide twice daily had similar efficacy in reducing migraine attacks compared to 400 mg sodium valproate twice daily (51). Oral magnesium is given in a various forms, including oxalateinorganic and organic magnesium. Inorganic magnesium, such as magnesium oxide, has a high loading of elemental magnesium, but has limited bioavailability. However, organic magnesium, such as citrate, oxalate, and glycinate, which have high levels of solubility and therefore, higher bioavailability (22). Magnesium oxalate and glycinate are both seen to reach higher levels in the brain at increased doses (66). Intravenous magnesium administration is also beneficial in acute settings, as 80% of patients treated with 1 mg intravenous magnesium sulfate became pain-free within 15 minutes, whereas 93.3% of patients reported that their attack had ended after 30 minutes. Common side effects include hypotension, flushing, nausea, vomiting, and ileus, all of which could be reduced by decreasing the administration rate (08). In conclusion, intravenous magnesium is recommended for an acute migraine, whereas oral magnesium can be more beneficial for migraine prevention.

Vitamin B2 (riboflavin) and Coenzyme Q10 (CoQ10) help increase the activity of mitochondrial complex 1 and 2 and the activity of the electron transport chain, respectively (29). By increasing this activity, there is less mitochondrial oxidative phosphorylation, which reduces migraine by 25% to 30%. A significant reduction in migraine frequency was observed in patients receiving either 400 mg of riboflavin or 300 mg of CoQ10. By impairing oxidative phosphorylation, this is theorized to decrease migraine incidence (67). When magnesium 600 mg daily, riboflavin 400 mg daily, and CoQ10 150 mg daily were used in combination for three months, there was a decrease in migraine intensity and frequency (41). The combination therapy had no serious adverse effects other than mild abdominal discomfort from magnesium and was well tolerated. Petasites hybridus, or butterbur, is a herbal extract that is seen to help in the prevention of migraine attacks when taken at 75 mg twice daily, but its use was previously limited due to its safety profile risk of liver toxicity due to the presence of pyrrolizidine alkaloids (38). However, the root extract of Petasites hybridus, Petadolex, is free of pyrrolizidine alkaloid levels, which deems it safe for therapeutic use.

Diet. There is ongoing speculation on the role of obesity and dietary interventions in migraine. The ketogenic diet is gaining interest due to the variety of mechanisms it has on the pathophysiology of migraines. A ketogenic diet promotes ketogenesis--a physiological, biochemical process arising from eating a high-fat and drastically low-carbohydrate diet to enhance lipid metabolism and generate ketone bodies. Ketone bodies enhance mitochondrial energy metabolism and combat oxidative stress that contribute to neural inflammation in the brain (36). Additionally, elevated ketone bodies regulate neurotransmitters involved in the cortical spreading of depression and excitability in migraine pathology. Patients following the ketogenic diet had a reduction in migraine attack frequency, number of days with headaches, and rescue medication frequency after the first month, with continuous improvement for up to 6 months. Other low-calorie diets have also demonstrated some benefits at months 3 and 6, thus, demonstrating the benefit of proper diet in migraine prevention.

People consuming diets rich in omega-3 fatty acids, especially in conjunction with reduced levels of omega-6 fatty acids, have fewer migraine attacks (71). Prostaglandin E1, a downstream metabolite of omega-6 fatty acids, is an inflammatory mediator that is increased in patients with migraine producing headache, nausea, and vomiting (80). In contrast, omega-3 fatty acids are proposed to have a protective effect against migraine by stimulating the synthesis of serotonin receptors and relieving inflammatory processes involved with migraine. About 66.7% of patients who used omega-3 fatty acids 750 mg twice daily had a reduction of more than 80% per month in the number of days with a headache (80).

In contrast, low-fat diets are also proposed as a treatment to decrease migraine. High levels of lipids and free fatty acids in the blood influence platelet aggregation, increasing prostaglandin levels and decreasing serotonin levels. This effect causes cortical vasodilation, which is seen prior to migraine attacks. In patients that limited dietary fat intake to less than 20 g/day over 12 weeks, a significant decrease in headache frequency, duration, intensity, and medication intake was seen, whereas there was a positive correlation between headache frequency and dietary fat intake (19).

Exercise. Previously, there was an association between low-intensity exercise and a high frequency of migraine. Hypothesized pathophysiologies involve the association of hypocretin, lactate, and calcitonin gene-related peptide (CGRP) between exercise and migraine. Hypocretin is seen both in triathletes who did not sleep well and in migraine patients prior to an attack, suggesting that hypocretin is involved with migraine attacks. Elevated lactate is found in migraine sufferers and is a byproduct of anaerobic exercise. CGRP is involved in vasodilation and pain conditions, and its levels increase during exercise and migraine attacks. Interestingly enough, moderate to heavy exercise improves migraine frequency, intensity, and duration from two to one migraine episode per month (05). When the anaerobic threshold was exceeded during exercise, endogenous opioids, gamma-aminobutyric acid (GABA), dopamine, and beta-endorphins were released, whereas substance P was not. In conclusion, regular exercise may be prophylactic in the frequency of migraine attacks.

Psychotherapy and neurofeedback. Migraine is in part a bio-behavioral disorder. The behavioral factor refers to an individual’s action in response to stress-excessive reactions, which can worsen migraines. Cognitive behavioral therapy (CBT) aims to improve mental disorders and psychological distress, which can be used to reduce the stress response in patients suffering from migraine. When compared to pharmacotherapy alone, cognitive behavioral therapy helps reduce headache frequency when combined with medication. Cognitive behavioral therapy enables patients to develop preventive and acute care strategies for managing their migraine. Patients can learn to identify and avoid their triggers. They can adapt their thoughts, feelings, and behaviors surrounding headache. Patients can also learn physiological autoregulation strategies to reduce their migraine duration and pain. Therefore, cognitive behavioral therapy can be used as an adjunct treatment to pharmacotherapy for migraine (13).

Neurofeedback is a method that combines the behavioral techniques of cognitive behavioral therapy with biological neurophysical recordings of the brain to train the patient on how to manage his or her brain activity. Neurofeedback focuses on controlling stress levels as well as enhancing emotional functioning and behavior by practicing self-regulatory processes. Neurofeedback is not well understood, but it is proposed that self-regulation of brain activity is related to cortical networks and neuroplasticity. Cortical networks are dysfunctional in patients with migraines, so by using self-regulation in neurofeedback, patients may experience a reduction in migraines (29). The evidence above demonstrates that patients suffering from migraine would benefit from pharmacological and nonpharmacological approaches to help with migraine prevention.

Neuromodulation devices (Scott)

Noninvasive neuromodulation has become an attractive nonpharmacological treatment for migraine through stimulating peripheral nerves or brain parenchyma. To date, there are five FDA-cleared neuromodulation devices for migraine use: SAVI Dual™, CEFALY®, gammaCore Saphire™, Nerivio®, and Relivion®. Other investigational noninvasive devices (eg, caloric stimulation, kinetic oscillation stimulation, direct current stimulation, mastoid stimulation, auricular insufflation, green light, and thermal stimulation), invasive procedures (eg, Reed’s procedure, occipital nerve decompression or implant, spinal cord stimulator, and electrical acupuncture), or over-the-counter devices (eg, neck massager, eye massager, ear puffer, and spectral lenses) are beyond the scope of this article. Here we focus on the five FDA-cleared devices.

SAVI Dual™. The SAVI Dual is a single-pulse transcranial magnetic stimulation (sTMS) device cleared by the United States Food and Drug Administration for both acute and preventive migraine treatment in adults in 2017 and adolescents 12 years of age and older in 2019. Its predecessor, Cerena TMS, was cleared for acute migraine treatment in 2013. For acute treatment, apply three sequential pulses at the onset of migraine pain and, if needed, repeat three pulses after 15 minutes. For preventive treatment, apply in the morning and evening four pulses (two consecutive pulses and repeat after 15 minutes). sTMS may influence cortical excitability, modulate neuronal plasticity, and interrupt cortical spreading depolarization (27; 08; 15).

The clearance of the sTMS device was originally based on a randomized, sham-controlled study of episodic migraine with aura subjects who applied two pulses (0.9 Tesla) to the back of the head 30 seconds apart within 1 hour of aura onset (54). A total of 164 patients treated at least one attack (modified intention-to-treat population). Pain freedom after 2 hours was higher with sTMS (32/82 [39%]) than with sham stimulation (18/82 [22%]), for a therapeutic gain of 17% (95%CI 3% to 31%; p=0.0179). At 24 hours, pain freedom was 29% versus 16% (p=0.041). Non-inferiority was shown for nausea, photophobia, and phonophobia. Later, in a postmarketing survey comprising 59 patients with episodic migraine and 131 with chronic migraine (with and without aura) who applied two pulses daily for the first month and then increased to four pulses daily for the third month, results showed monthly migraine days were reduced from 15 to 8 (p< 0.001), with 62% reporting the device being effective, but there was a 55% discontinuation rate (18). In a multicenter, single-arm, post-market observation study (ESPOUSE study) of 263 consented migraine subjects (4 to 24 headache days/month), 132 (10% chronic migraine) were included in the intention-to-treat analysis set (81). Participants were instructed to apply four pulses twice daily (preventive) and three pulses three times as needed (acute; may repeat two sessions if no relief after 15 minutes). After 3 months, there was a 2.75±0.40 (p< 0.0001) mean reduction of headache days compared to the performance goal (statistically-derived placebo estimate). There were also reductions in acute medication use days and HIT-6 scores. In a small feasibility study of a similar study design on adolescent migraine subjects, there were reductions in monthly headache days (-4.5, p=0.019) and PedsMIDAS (-36, p=0.026) (50).

sTMS is well tolerated with dizziness or lightheadedness, tingling, and tinnitus being the most common adverse events. It is contraindicated in patients with a history of stroke or seizure. The sTMS mini device manual recommends that it not be used in patients who have metals, conductive materials, or other metal-containing implants in the head, neck, or upper body area that can be affected by a magnetic field. This includes those with a cardiac pacemaker or defibrillator, vagus stimulator, or other implanted medical device that stimulates the body or uses any signal from the body. Dental implants and fillings are not affected by the device. The sTMS mini has not been tested in pregnant patients or children under the age of 12. The consensus is that TMS should not be activated near the components of the VNS systems, cardiac pacemakers, and spinal cord stimulators (72). See eneura.com for details.

CEFALY®. The United States Food and Drug Administration cleared CEFALY in 2014 for preventive and later acute use for migraine in adults aged 18 or older. It is a transcutaneous electrical nerve stimulation (TENS) device applied on the forehead, which is innervated by trigeminal nerves (eg, supraorbital nerve and supratrochlear nerve). In late 2020, CEFALY® DUAL (the next-generation CEFALY device) received over-the-counter clearance from the FDA. The CEFALY DUAL has two settings: ACUTE (as needed, 60-minute, 100-Hz stimulation) and PREVENT (daily, 20-minute, 60-Hz stimulation). CEFALY likely induces pain inhibition via the gate control mechanism. In addition, it may produce sedative effects to alleviate pain (68) or restore the normal brain metabolism in the frontotemporal cortex (55). The latest version, CEFALY Connected, syncs with the CeCe Migraine Management app.

Clearance of the CEFALY device was based on a randomized sham-controlled study (the PREMICE study) of 67 subjects (migraine, used no preventive medication, had no medication overuse) who applied the device daily for 20 minutes over 3 months (74). The study showed a greater than 50% (p=0.023) responder rate in the verum group (38.1%) than in the sham group (12.1%). Other secondary outcomes were also significantly different between groups, such as headache days reduction (p=0.041) and attack frequency (0.044). In another randomized, sham-controlled study for acute treatment of migraine (the ACME study) of 106 migraine subjects who applied the device for 1 hour, there was significant pain reduction (p< 0.001) in the verum group (-3.46±2.32) as compared to the sham group (-1.78±1.89) (28). Other secondary outcomes were significantly different between groups, such as pain freedom (p=0.0016) and 50% or greater pain relief (p=0.0017). There is no difference at two hours. Keep in mind that in these studies, the proportion of chronic migraine was not described. In another randomized, sham-controlled study for acute treatment of episodic migraine (the TEAM study) of 538 subjects using eTNS for two hours, pain freedom at two hours were 25.5% (verum) versus 18.3% (sham), p=0.043. Resolution of the most bothersome symptom was 56.4% (verum) versus 42.3% (sham), p=0.001 (52). Two single-arm, open-label studies showed a reduction in monthly headache days and acute medication use after daily CEFALY use for more than 3 months (35; 21). Other open-label studies are reviewed elsewhere (49).

CEFALY is generally well-tolerated, with the most common adverse events being paresthesia, arousal changes, headache, and local skin allergy (56). It is contraindicated for use in those who have had brain or facial trauma within the last 3 months, skin abrasions on the forehead where the electrode is applied, allergy to acrylate, cutaneous hypersensitivity, implanted electronic device in the head, trigeminal neuralgia, or ophthalmic shingles. See cefaly.com for details.

gammaCore Sapphire™. The gammaCore device is a noninvasive vagus nerve stimulation (nVNS) device cleared by the United States Food and Drug Administration in 2018 for acute treatment of migraine and later in 2020 for migraine prevention. In early 2021, its approval expanded to adolescents aged 12 to 17 years. It also can be used for cluster headache, paroxysmal hemicrania, and hemicrania continua. For acute migraine treatment, apply two consecutive 2-minute stimulations at the earliest sign of pain. If pain remains, the patient may repeat 20 minutes after the first treatment and 2 hours after the first treatment. For preventive treatment, apply two treatments (morning and night consisting of two consecutive 2-minute stimulations daily). Its mechanism of action likely involves modulation of nociception, inflammation, autonomic nervous system, neurotransmitter, and cortical spreading depolarization (94; 77).

FDA clearance of the gammaCore device for acute migraine treatment was based on a multicenter, randomized, sham-controlled study (the PRESTO study) of 248 episodic migraine subjects (no medication overuse or botulinum toxin use) who applied bilateral 120-second stimulations within 20 minutes of migraine pain onset (82). nVNS was superior to sham for pain freedom at 30 minutes (12.7% vs. 4.2%; p=0.012) and 60 minutes (21.0% vs. 10.0%; p=0.023) but not at 120 minutes (30.4% vs. 19.7%; p=0.067; primary endpoint) after the first treated attack. The 50% or greater responder rate at 2 hours was significantly different (32.4% vs. 18.2%, p=0.020). For migraine prevention, in another multicenter, randomized, sham-controlled study (the PREMIUM study) of 332 episodic migraine subjects who applied two consecutive bilateral stimulation three times daily (preventive medication not allowed), reductions in monthly migraine days (primary outcome) were 2.26 for nVNS and 1.80 for sham (p=0.15) (Diener et al 2019). In subjects with 67% or greater adherence (modified intent-to-treat population), nVNS reduced more migraine days than sham (2.27 vs. 1.53; p=0.043). Later, in the PREMIUM II Migraine Prevention Study (terminated early due to COVID-19 pandemic), migraineurs (8 to 20 days per month with no medication use) in the predefined modified intent-to-treat population (n=113), after 12 weeks of daily use nVNS had 3.1 nonsignificantly fewer migraine days as compared to a decrease of 2.3 migraine days in the sham group (primary endpoint; p=0.233). A 50% or greater reduction in migraine days was seen more in the nVNS group (44.9% vs. 26.8%, p=0.048). For chronic migraine prevention, nVNS did not reach statistical significance at 2 months (the EVENT study) (76); the continued reduction in headache days over the 6-month open-label phase suggests that long-term nVNS may offer a clinical benefit to treating chronic migraine. In a small, single-arm study of nine adolescents, 47 migraine attacks were treated, and 22 (46.8%) required no rescue medication (45).

The gammaCore device has been found safe and well-tolerated without any significant treatment-related adverse effects. Although there is no theoretical risk in pregnant and pediatric patients, its safety and efficacy in such populations have not been fully studied. Per its label, it is contraindicated in patients with an active implantable medical device (eg, pacemaker, hearing aid), certain preexisting cardiovascular conditions, metal implants near the neck area (eg, stent, bone plate, or screw), or previous history of cervical vagotomy or carotid atherosclerosis. See gammacore.com for details.

Nerivio. Nerivio is a wearable remote electrical neuromodulation (REN) device that the United States Food and Drug Administration cleared for acute treatment in adult patients with episodic migraine in 2019 and chronic migraine in 2020. The clearance was expanded to adolescents aged 12 years or older in early 2021. In early 2023, the United States Food and Drug Administration cleared its use as a preventive treatment in adults and children 12 years and older. The device is applied to the upper arm at the onset of migraine with self-adjusted intensity via the Nerivio App. It is preprogrammed with eighteen 45-minute stimulation sessions. After depletion, a new device is required to continue treatment. For acute treatment, use Nerivio as needed for 45 minutes. For preventive treatment, use Nerivio every other day for 45 minutes. The Nerivio likely induces descending pain inhibition via conditioned pain modulation where a subpainful REN stimulates the brainstem pain regulation center and inhibits the pain signals to the trigeminocervical complex (91).

The FDA clearance was based on several studies. In a single-center, randomized, sham-controlled trial of 71 patients with episodic migraine and 299 treatments (20-minute stimulation) of evaluable data, 50% pain reduction was obtained for 64% of participants based on best of 200-ms, 150-ms, and 100-ms pulse width stimuli per individual versus 26% for sham stimuli (93). Earlier treatment application (within less than 20 minutes of attack onset) yielded better results: pain reduction 46.7% versus 24.9% (p=0.02). In a multicenter, randomized, sham-controlled trial of 202 episodic migraine patients, REN stimulation 30 to 45 minutes on the upper arm within 1 hour of pain onset resulted in more 2-hour pain relief (66.7% vs. 38.8%, p< 0.0001), pain freedom (37.4% vs. 18.4%, p=0.003), and most bothersome symptom relief (46.3% vs. 22.2%, p=0.0008) (92). In the open-label extension of the previous study, 89.7% of the participants (n=111) treated their attacks only with REN. The 50% or greater responder rate for pain relief and pain-free at 2 hours were comparable (pain relief: 57.3%, pain freedom: 23.1%) (58). In an open-label observational study of evaluable data in 38 chronic migraine patients, after 45 minutes of REN treatment within 1 hour of attachment, 50% or greater responder rate for pain relief and pain-free at 2 hours were 73.7% and 26.3% (64). In a multicenter observational study in adolescent patients with migraine, 39 participants performed at least one treatment. Pain relief and pain-free at 2 hours were achieved by 71% (28/39) and 35% (14/39) of participants, respectively (47). In a pivotal study for the preventive treatment of migraine in adults with EM/CM, the intention-to-treat group after eight weeks of REN treatment showed a significant reduction in monthly migraine days (-3.8±4.5 vs. -1.1±4.4, p< 0.001) (85).

Per the Nerivio manual, the device should not be used by people with congestive heart failure, severe cardiac or cerebrovascular disease, uncontrolled epilepsy, or anyone with an active implantable medical device (eg, pacemaker, hearing aid implant). It should only be applied on the upper arm over dry, healthy skin with normal physical sensation and without proximity to any metallic implants or cancerous lesions. See nerivio.com for details.

Relivion®. Relivion is an adjustable headset that delivers electrical pulses to six branches of both the occipital and trigeminal nerves (supraorbital, supratrochlear). Concurrent stimulation likely has an additive effect, although the exact mechanism is unclear. It was cleared by the United States Food and Drug Administration in early 2021 for acute treatment of migraine. The FDA clearance was based on a multicenter, sham-controlled study (RIME study) of 131 patients with episodic migraine applying one hour of stimulation acutely (84). After two hours, the active group achieved pain freedom (46% vs. 11.8%), absence of most bothersome symptoms (75% vs. 46.7%), and complete freedom (47.2% vs. 11.1%). Compare active versus sham in the modified intention-to-treat population, pain freedom and MBS freedom were both achieved for the first and all eligible treatments. No serious adverse event was reported. In a retrospective study, daily 20-minute treatments were able to reduce monthly migraine days and monthly rescue medication use days up to nine months (Sharon 2023). Patients with skin abrasions on the forehead or occiput, implanted neurostimulators, implanted metallic/electronic device in the head, cardiac pacemaker, or implanted/wearable defibrillator should not use the device. See relivion.com for details.

Abortive medications for migraine

The primary goals for acute treatment are to have the following: restored ability to function, minimal or no side effects, reduced use of other resources (eg, diagnostic imaging, emergency room visits, primary care provider visits), restored ability to function, and rapid and consistent freedom from pain with associated symptoms without recurrence (78). This can be approached in a stepwise manner, such as the mild/moderate/severe scale. NSAIDs (including aspirin), nonopioid analgesics, acetaminophen, or caffeinated analgesic combinations (eg, Fioricet) can be used for mild-to-moderate attacks. For moderate-to-severe attacks, triptans and dihydroergotamine could be used (03). It is recommended to treat the moment pain is detected to increase the chances of achieving freedom from pain and reduce any pain-related disability. It is important to choose the route of administration based on symptoms; sumatriptan comes in intranasal and intramuscular injections, whereas ketorolac comes in tablets and intramuscular injections (26; 83; 61). Table 1 summarizes different abortive medications and their effectiveness.

Table 1. Summary of Medications For Abortive Treatment

Established Efficacy	Probably Effective
Triptans	Ergotamine and other forms of dihydroergotamine
Ergotamine derivatives	NSAIDs: intravenous and intramuscular ketorolac
NSAIDs: aspirin, diclofenac, ibuprofen, naproxen	Intravenous magnesium
Opioids: butorphanol┿	Isometheptene-containing compounds
Combination medications	Combinations: codeine/acetaminophen, tramadol/acetaminophen*
	Antiemetics: prochlorperazine, promethazine, droperidol, chlorpromazine, metoclopramide
*In migraine with aura ┿ Use not recommended Summarized from (10)

Medication overuse headache. Medications should be limited to 2 days weekly to prevent medication overuse headache (37; 11). This is a secondary headache arising from overuse of at least one abortive headache; it is present in 1% to 2% of the general population and is one of the leading causes of headache (02). If medication overuse headache is suspected or confirmed, the first step is to discontinue or limit the abortive medication use. Initially, the headache will worsen over a period of a few weeks but then will improve long-term (02).

Gepants and ditans. New CGRP receptor antagonists ubrogepant (87) and rimegepant (30) were approved by the FDA for acute migraine treatment. The advantage of these medications is there is no constriction of blood vessels so that they can be used in patients with cardiovascular disease. Although insurance companies are starting to cover these medications, they can be expensive. Rimegepant has also been studied as a preventive medication and demonstrated success as a preventive option (31). There has been no evidence that gepants cause medication overuse headache (60); thus, they are a suitable substitute for other abortive medications. Rimegepant is dosed at 75 mg, once daily and no more than two days weekly. Ubrogepant is in either a 50 or 100 mg tablet. It can be taken at the onset of a headache, with an additional dose two hours later if needed, and also no more than two days weekly. Zavegepant was approved as a nasal spray for abortive treatment (34). It has 10 mg in one spray and is indicated to have one spray in one nostril, and no more than one spray in a 24 hour period, and no more than two days weekly.

Lasmiditan is a selective serotonin (5-HT1F) receptor agonist that has demonstrated benefit as a migraine abortive (70). To receive insurance coverage, patients usually must have failed at least two triptans. It comes as 50, 100, or 200 mg tablets. Only one tablet can be taken in a 24 hour period (16). Of note, patients who take lasmitidan are not allowed to drive for eight hours (10). Ubrogepant has a cost-savings program that can be used by patients with commercial insurance (https://www.ubrelvy.com/savings). Rimegepant also has a cost-savings program for patients with commercial insurance (https://www.nurtec.com/savings). Coverage continuation will likely be determined based on average monthly migraine attacks and clinical evidence of headache improvement (03).

Preventive medications for migraine

Multiple agents have been studied for the prevention of migraine. These include both FDA-approved medications and medications that have been used off-label for migraine prevention and were discussed previously by the American Headache Society Position Paper in 2019 (03). There is also evidence of complementary treatment options that have been evaluated previously; these are summarized in Tables 2 and 3 (48).

Table 2. NSAIDs and Complementary Treatment Options

Level A. The following therapy is established as effective and should be offered for migraine prevention:
	• Butterbur (Petadolex)
Level B. The following therapies are probably effective and should be considered for migraine prevention:
	• NSAIDs: fenoprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium
	• Herbal therapies, vitamins and minerals: riboflavin, magnesium, feverfew (MIG-99)
	• Histamines: histamine SC
Level C. The following therapies are possibly effective and may be considered for migraine prevention:
	• NSAIDs: flurbiprofen, mefenamic acid
	• Herbal therapies, vitamins, and minerals: Co-enzyme Q10, estrogen
	• Antihistamines: cyproheptadine
Level U. Evidence is inadequate or conflicting to support or refute the use of the following therapies for migraine prevention:
	• NSAIDs: aspirin, indomethacin
	• Herbal therapies, vitamins, and minerals: omega-3
	• Other: hyperbaric oxygen therapy
Level B negative: The following therapy is probably ineffective and should not be considered for migraine prevention:
	• Leukotriene receptor antagonists: montelukast

Table 3. Nutraceutical Preventive Therapies for Migraine

Riboflavin (Vitamin B2)
	• CHS guidelines: strong recommendation, daily dose of 300 mg, as 100 mg three times daily
	• AAN/AHS: Level C recommendation
	• EFNS: Level C recommendation
Coenzyme Q10
	• CHS guidelines: strong recommendation, daily dose of 300 mg, as 100 mg three times daily
	• AAN/AHS: Level C recommendation
	• EFNS: Level C recommendation
Magnesium
	• CHS guidelines: strong recommendation, recommend 600 mg daily
	• AAN/AHS: Level B recommendation
	• EFNS: Level C recommendation
Butterbur (Petasites hybridus)
	• CHS guidelines: Strong recommendation, at dose of 75 mg twice daily. Only commercially prepared products.
	• AAN/AHS: Level A recommendation
	• EFNS: Level B recommendation
Feverfew (Tanacetum parthenium)
	• CHS guidelines: strong recommendation against offering feverfew (no better than placebo for migraine prophylaxis)
	• AAN/AHS: Level B recommendation
	• EFNS: Level C
Omega-3 polyunsaturated fatty acids
	• CHS guidelines: none
	• AAN/AHS: Level U indication
	• EFNS: none

In 2010, onabotulinumtoxin A (Botox®) was the first FDA-approved preventive medication for chronic migraine based on the PREEMPT studies (40; 12). It has been widely used in practice and has demonstrated great efficacy at 56 weeks (12). Despite discussion among headache providers in regards to the injection protocol, Botox is still widely used in clinical practice (17). It will usually require failure of at least one medication from each medication class to get approved: anticonvulsant, antidepressant, and beta-blocker (04). Botox has demonstrated great success and is effective as a preventive for patients in the outpatient setting.

Since 2018, additional medications have been FDA approved for migraine. Calcitonin gene-related peptide (CGRP) is a potent vasodilator known to induce trigeminal inflammation, causing peripheral and central pain sensitization that may be important in causing migraine. CGRP acts on trigeminal Aδ fibers, endothelial cells, and others causing neurogenic inflammation activating the trigeminovascular system (42). CGRP cannot cross the blood-brain barrier but modulates nociceptive pathways in the brainstem, thalamus, and cingulate cortex (09). CGRP levels are elevated during migraine episodes, and infusions of CGRP have triggered migraine attacks (44; 46). As such, CGRP antagonists were researched and FDA-approved as a novel preventive class for migraine. Currently, four CGRP inhibitors have been approved for the treatment of migraine: Aimovig® (erenumab), Ajovy® (fremanezumab), Emgality® (galcanezumab), and Vyepti™ (eptinezumabi). Of these, Vyepti is the only one administered intravenously (73). Table 3 highlights some important facts about each CGRP antagonist (adapted from migrainedisease.org). As of this publication, there are no head-to-head trials that have been published comparing the four to determine superiority.

Table 4. Comparison of All Four CGRP Monoclonal Antibodies

Categories	Erenumab (Aimovig)	Fremanezumab (Ajovy)	Galcanezumab (Emgality)	Eptinezumab (Vyepti)
Manufacturer	Amgen and Novartis	Teva	Eli Lilly	Lundbeck Seattle
FDA approval date	May 17, 2018	September 14, 2018	September 27, 2018	February 22, 2020
Target	Blocks CGRP receptor	Attaches CGRP molecule	Attaches CGRP molecule	Attaches CGRP molecule
Half Life (Days)	28	31	31	27
Route of administration	Autoinjector	Prefilled syringe	Autoinjector and prefilled syringe	Intravenous
Dosing	70 mg	225 mg monthly or 625 mg quarterly	240 mg loading dose followed by 120 mg thereafter	100 mg or 300 mg
Storage	Requires refrigeration. Use within 7 days of removal. No freezer.	Requires refrigeration. Use within 24 hours of removal. No freezer.	Requires refrigeration. Use within 7 days of removal. No freezer.	Requires refrigeration. Use immediately. No freezer.
Administration schedule	Once monthly	Once monthly or quarterly	Once monthly	Once quarterly
Injection site	Self: abdomen or thigh Others: Upper arm	Self: abdomen or thigh Others: Upper arm	Self: abdomen or thigh Others: Upper arm or buttocks	Intravenous injection
Side effects	Injection site reaction Constipation	Injection site reaction	Injection site reaction	Nasopharyngitis Low risk for anaphylaxis
Savings programs	$5 copay with commercial insurance, 12 months free if not covered by commercial insurance	$0 copay with commercial insurance	Free for 12 months with commercial insurance	$5 copay with copay assistance program with commercial insurance

Table 5. Comparison of Both CGRP Preventive Gepants

Categories	Atogepant	Rimegepant
Manufacturer	Abbvie Pharmaceuticals	Biohaven Pharmaceuticals
FDA Approval Date	September 28, 2021	May 27, 2021
Target	Blocks CGRP Receptor	Blocks CGRP Receptor
Half-Life (Hours)	11	11
Route of administration	Oral solid table	Oral dissolving tablet
Dosing	10, 30, 60 mg	75 mg
Storage	Room temperature	Room temperature
Administration schedule	Daily	Every other day
Side effects	Nausea, constipation	Nausea, constipation
Savings programs	$0 copay card with commercial insurance, 12 months free if approved by commercial insurance	$0 copay card with commercial insurance, 12 months free if approved by commercial insurance

There is no preference toward a particular CGRP antagonist, but usually patients must have failed at least one of the following classes of medications: anticonvulsant, antidepressant, and beta-blocker. Eptinezumab is generally approved after failure of those three classes, and at least one or two of the other antagonists (erenumab, galcanezumab, or fremanezumab) (Blue Cross Prescribing Information pdf). Eptinezumab is typically administered at an infusion center, thus, limiting its availability. Although this may delay time to using a CGRP antagonist, performing the step-wise process will help in getting the medications approved.

There are no published head-to-head comparisons between the three monoclonal antibodies (mAb). If one is ineffective, a 30-day washout period is required before starting another agent. A study demonstrated that switching between a noneffective mAb to another led to an at least 30% positive response in 30% of participants after three doses, indicating this could be a possibility for treatment (65). A trial called the CHALLENGE-MIG trial compared galcanezumab to rimegepant and found that both were tied in reducing migraine headache days. More information can be accessed at the following site:practicalneurology.com. Additional studies will likely come out in the next few years.

Migraine treatment in pregnancy and lactation

Despite the understanding that migraine tends to improve in pregnancy, especially after the first trimester, treatment of migraine in pregnancy continues to be difficult as the controlled trials in this population are limited, and there is the risk of teratogenicity. Available data are mostly observational or available through registries. When evaluating a pregnant patient with headache, it is important to keep in mind and exclude secondary causes of headache, which may be indicated by red flags in history or neurologic examination.

In general, first-line treatment of migraine in pregnancy includes optimization of lifestyle factors that may contribute to migraine and nonpharmacological interventions. This may even begin as early as the expressed desire of conception to ensure ease of use during pregnancy. Lifestyle factors that may reduce the burden of migraine during pregnancy include improvement of sleep duration and quality, maintaining regular meals and good hydration, and a good schedule of physical activity (01).

Although natural preventives remain an option for pregnant women, safety data on these are lacking, so counseling patients can be challenging. Magnesium was previously considered a first-line recommendation for migraine prevention in pregnancy but has been called into question due to an unclear FDA safety reclassification in 2014. After evidence that intravenous magnesium sulfate for longer than 5 days increased the risk of fetal bone malformations, the FDA reclassified intravenous magnesium from Category A to Category D. As a result, use of oral magnesium in pregnancy remains a topic of discussion for some, and others choose to continue to use oral magnesium.

In the scenario that a woman is already on a daily preventive for migraine treatment and contemplating pregnancy, the clinician should explain options of either tapering off or switching the medication to one that is not known to have caused fetal harm in humans or animals or to one that has been extensively studied with no findings of an increase in fetal or infant defects. Alternatively, for women not already on preventive medication but experiencing frequent moderate-to-severe attacks, initiating a preventive should be considered. The benefits of the medication must outweigh the risks associated with it and should be individualized for each patient. For example, certain preventive medications such as topiramate and valproic acid are contraindicated for migraine use due to an increased risk of teratogenicity.

Preventive medications considered likely to be safe in pregnancy have been previously studied (25) and are included in Table 5, along with mechanisms of action and potential risks.

Table 6. Preventive Medications Considered Likely To Be Safe In Pregnancy

Propranolol. Blocks B1 and B2 adrenergic receptors. Observational studies show a small increase in risk of intrauterine growth retardation, small placenta, and congenital abnormalities; possible neonatal bradycardia, respiratory depression and hypoglycemia with late term use.

Amitriptyline. Blocks reuptake of serotonin and norepinephrine neurotransmitters. There are case reports of limb deformities and developmental delay, but no causal relationship has been established. Monitor infant for irritability, urinary retention, or constipation with late-term exposure.

Verapamil. Inhibits calcium ion influx through slow channels. There is no increase in fetal congenital malformations; may cause fetal bradycardia, hypotension, heart block.

Memantine. Glutamate antagonist. No human data are available, but animal studies showed no teratogenic effects.

Cyproheptadine. Antihistamine. No human data are available, but animal studies showed no teratogenic effects.

Venlafaxine. Serotonin and norepinephrine reuptake inhibitor. There is no increase in fetal congenital malformations, but there is possible increased risk of spontaneous abortion; neonatal seizures or serotonergic toxicity possible with maternal use in third trimester.

*Information in this table adapted from: (25).

OnabotulinumtoxinA, an FDA-approved preventive treatment for chronic migraine, has been designated an FDA pregnancy category C pharmaceutical product. Clinical trials on botulinum toxin (BoNT) did not include women who are pregnant, nursing, or planning a pregnancy, and it should only be used in pregnancy if the benefit outweighs the possible risk. However, a 29-year retrospective review of the Allergen safety database shows that the prevalence rate of major fetal defects amongst live births in onabotulinumtoxinA-exposed mothers before or during pregnancy is comparable with background rates in the general population (24). Additionally, a study out of the United Kingdom looked at the use of onabotulinumtoxinA in chronic migraine during pregnancy. Pregnancy outcome data were reviewed for 45 patients, 32 of which wished to continue treatment throughout pregnancy. The group looked at mode of delivery, birth weight, congenital malformation, and any other unexpected outcomes and found apart from one miscarriage that all patients had full-term healthy babies of normal birth weight and no congenital malformations (90).

Regarding CGRP monoclonal antibodies, they are currently not recommended for use in pregnancy. Longitudinal surveillance data are required to assess safety in pregnancy.

For purposes of rescue medication, there are options available that have been shown safe in pregnancy. Although limited, these options do provide pregnant patients some reprieve from the challenges of managing migraine in pregnancy. Triptans, on the other hand, have been under scrutiny for some time. However, two extensive reviews of sumatriptan in pregnancy found no evidence of teratogenicity (43; 32). There was no association between triptan use during pregnancy and congenital malformations when compared to controls. Sumatriptan is the most hydrophilic triptan, making it more difficult to cross the placental membrane, whereas the other triptans are lipophilic. For lowest maternal serum levels, sumatriptan nasal spray delivery system is preferred.

Use of NSAIDs in the first trimester increases the risk of miscarriage (53), and exposure to NSAIDs in the third trimester may cause premature closure of fetal ductus arteriosus. For this reason, the use of NSAIDs is reserved for the second trimester only.

Table 7. Rescue Options Considered Likely To Be Safe

Acetaminophen. No increased risk of teratogenic effects, spontaneous abortion, or stillbirth. There are case reports of prenatal closure of the ductus arteriosus reported with use during third trimester, and increase risk of early childhood wheezing and asthma was reported with frequent maternal use.

Metoclopramide. No increased risk of adverse pregnancy-related outcomes, but it may cause extrapyramidal signs and methemoglobinemia in neonates with maternal exposure during delivery.

Diphenhydramine. No increased risk of major congenital malformations or other adverse outcomes. Neonatal withdrawal is possible with prolonged maternal use in third trimester.

Sumatriptan. No increased risk of major congenital malformations. Studies conflict about possible increased risk of premature birth. Evidence is best for sumatriptan, naratriptan, and rizatriptan.

NSAIDs. Best data are for ibuprofen, second trimester use only. Use in first trimester is linked to increased risk of spontaneous abortion. Use in third trimester may cause premature closure of the ductus arteriosus.

Nerve blocks with lidocaine. Data are limited. Existing studies show no increased risk of major congenital malformations; animal studies showed no teratogenic effects.

*Information in this table was adapted from (25).

Noninvasive neurostimulation devices, although not studied in the pregnant population, have benign safety profiles and may be considered in pregnancy: supraorbital nerve stimulator, transcranial magnetic stimulator. Please refer to the section on Neuromodulation devices.

Treatment in lactation

There are more treatment options available for lactating women than there are for those who are pregnant. Determination of safe medications during lactation relies on factors such as lipophilicity and protein binding of the drug, which determines the plasma concentration of the drug in the mother and the amount secreted in breast milk. This can then be quantified into a milk-to-plasma ratio, for which the cut-off marker for low risk to a nursing infant is 10% or less (63). The less lipophilic a drug is and the greater binding it has to protein, the lower the dose of the drug found in breast milk.

For preventive medications, propranolol, which is considered a first-line preventive in pregnancy, is compatible with breastfeeding (79). Similarly, verapamil has also been found compatible with breastfeeding, with exposure to infants in breast milk being less than 1% that of maternal dose (59; 07). There are no data available for other antihypertensives, such as lisinopril and candesartan. Amitriptyline, considered a second-line preventative for migraine in pregnancy, is likely compatible with breastfeeding; however, there have been reports of infant sedation with maternal doses as low as 10 mg/day (88).

For rescue medications, data remain limited but reassuring for available options. For triptans, a lactation study examining the excretion of six different triptan into milk revealed mean relative infant dose of 0.6% for eletriptan, 0.7% for sumatriptan, 0.9% for rizatriptan, 1.8% for almotriptan, 2.1% for almotriptan, and 5% for naratriptan (06). The mean relative infant dose of small molecule CGRP antagonist rimegepant was found to be less than 1% of the maternal dose, demonstrating its safety in lactating women (14).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Aniket Natekar MD MSc

Dr. Natekar of OhioHealth Neurology Physicians has no relevant financial relationships to disclose.
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Ayesha Ahmad MD

Dr. Ahmad of MedStar Health had no relevant financial relationships to disclose.
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Cindy Huynh BA

Ms. Huynh of Ohio University has no relevant financial relationships to disclose.
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Hsiangkuo Yuan MD PhD FAHS

Dr. Yuan of Jefferson Health-Thomas Jefferson University Hospitals received a consultant honorarium from Abbvie, Cerenovous, Pfizer, and Salvia.
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Editor

Stephen D Silberstein MD

Dr. Silberstein, Director of the Jefferson Headache Center at Thomas Jefferson University has no relevant financial relationships to disclose.
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Former Authors

Thanmayi Palegar
Thanmayi Palegar BSc

ICD & OMIM codes

ICD: Migraine: G43

Migraine without aura: G43.0

Migraine with aura: G43.1

Chronic migraine without aura: G43.7

Migraine, unspecified: G43.9
OMIM: Migraine with or without aura, susceptibility to, 1: %157300

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Migraine treatment

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This is an article preview.
Start a Free Account
to access the full version.