New Treatments in Migraine: An In-Depth Review

NeurologyLive, June 2022, Volume 5, Issue 3

Although new treatments and innovations are a sign of growth in migraine care, it is important to realize that growth comes with a certain amount of pain. In clinical practice, choosing the right treatment option for patients in a time-limited visit is often a dilemma.

MIGRAINE IS A CHRONIC and often debilitating disease affecting 1 in 7 individuals globally and one of the top 20 causes of disability worldwide. Thus, the importance of effective strategies for managing this disease could not be more paramount. During the past 5 years, several new treatments, both preventive and acute, have become available. Although clinicians now have plenty of options, it can be difficult to choose between them and understand how novel treatments compare with traditional therapies.

Traditional migraine treatments are most often discontinued by patients and clinicians due to lack of efficacy and poor tolerability.1,2 The new wave of therapeutics have a targeted mechanism of action (MOA) based on migraine pathophysiology. This targeted MOA comes with a reduction in adverse effects, resulting in greater tolerability, increased ability for patients to remain on treatment, and improved long-term results. Newer acute treatments can address unmet patient needs by providing nonoral formulations, reduced adverse effects, eliminated risk of medication-overuse headache, different modes and mechanisms of action, and reduced contraindications. Newer preventive treatments bring the first migraine-specific pharmacologic preventives to the field.

Although new treatments and innovations are a sign of growth in the field, it is important to realize that growth comes with a certain amount of pain. In clinical practice, choosing the right treatment option for patients in a time-limited visit is often a dilemma. Add to that the complexity of constant insurance hurdles and the fact that excitement about innovative products can wane as the fatigue associated with prior authorizations mounts—resulting in delays in getting your patient appropriate care becoming standard. Recognizing that new treatments require some general agreement around their use vs what was considered standard of care, the American Headache Society published an updated consensus statement in 2021 focused on assisting clinicians in when to consider new acute and preventative medications or neuromodulation for patients with migraine.3

In this article, we will highlight new therapeutic options for both acute and preventive treatment of migraine and discuss their use versus traditional therapies.

Updates in Acute Migraine Medications

Gepants and ditans

Since 2019, 2 new classes of medications have become available with an alternative MOA to triptans: gepants— small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists, including ubrogepant (Ubrelvy; AbbVie) and rimegepant (Nurtec ODT; Biohaven Pharmaceutical Holding Company Ltd); and ditans—5-HT1F agonists.4 Gepants and ditans may be good alternatives for patients with contraindication to triptans due to structural heart disease and vascular disease. Gepants do not cause vasoconstriction, and ditans MOA do not involve blood vessels at all. It is important to note that these treatments have not been studied in patients with acute vascular disease or in a large number of individuals older than 65 years. For both gepants and ditans, pooled data from pivotal phase 3 trials showed a small number of participants had moderate to significant stable cardiovascular disease and did not have cardiovascular treatment-emergent adverse events.5-7

Gepants and ditans act via different mechanisms, providing patients with alternatives if triptans were ineffective. It is important to note that when using lasmiditan (Reyvow; Eli Lilly and Company), patients may experience dizziness and drowsiness; thus, they should not drive or handle heavy machinery for at least 8 hours after administration.5 For ubrogepant, common adverse effects include nausea, somnolence, and dry mouth.8 The most common adverse effects of rimegepant include upper respiratory tract infection, nasopharyngitis, and sinusitis.9

Dihydroergotamine POD

Dihydroergotamine (DHE) is an effective treatment for migraine, but due to poor gastrointestinal (GI) absorption, it is usually administered via injection or nasal spray.10 A recent phase 3 trial evaluated the use of DHE mesylate (Trudhesa; Impel Pharmaceuticals) via precision olfactory delivery (POD) technology directed to the upper nasal cavity. In the initial phase 1 trial, 1.45 mg of DHE POD was equivalent to 1.0 mg of intravenous DHE mesylate and 2.0 mg of DHE mesylate.11 Thirty-eight percent of patients achieved pain relief within 2 hours of administration vs 30.1% with usual care. Commonly reported adverse effects included nasal congestion (15%), nausea (6.8%), and nasal discomfort (5.1%).12 DHE via the POD device offers patients a more convenient way to self-administer.


Nonsteroidal anti-inflammatory drugs are a class of medication that represents a mainstay in acute treatment. However, GI adverse effects are a common limiting factor. A recent randomized, double-blind, placebo-controlled trial found the liquid formulation of celecoxib capsules (Celebrex; Viatris), called DFN-15, at 120 mg to be an effective treatment for migraine attacks. DFN-15 has a shorter time to maximum effect and greater bioavailability than oral formulations, with a higher percentage of patients reporting 2-hour pain freedom with treatment of a single migraine attack of any pain intensity comparatively (46.2% vs 31.1%; P < .001).13 The most common adverse effects reported were nausea and dysgeusia.

Remote electrical neuromodulation

Neuromodulation devices offer a noninvasive option that may avoid several issues with medications, including adverse effect intolerability, medication-overuse headache, and medication contraindication. The remote electrical neuromodulation (REN) device (Nerivio; Theranica) activates peripheral nerves in the upper arm but below the perceived pain perception, which leads to conditioned pain modulation.14 In episodic migraine, pain relief at 2 hours was achieved by a significant proportion of patients compared with sham in a randomized, double blind, placebo-controlled trial (66.7% vs 38.8%; P < .0001).15 When compared with usual care (either migraine specific or nonspecific or no pharmacological treatment) in post hoc analyses, REN was more effective for pain relief 2 hours post treatment with 66.7% of patients on treatment reporting relief vs 52.5% of those on usual care (P = .034).16 Regarding adverse events, 13.5% of patients experienced at least 1, most commonly warmth sensation, temporary arm/hand numbness, or redness.

External concurrent occipital and trigeminal stimulation

External concurrent occipital and trigeminal neurostimulation (eCOT-NS; Relivion MG; Neurolief Inc) is another neuromodulation device that was recently cleared by the FDA. Previously, evidence showed that surgically implanted concomitant occipital and supraorbital nerve stimulation was effective but had significant adverse effects and was cost prohibitive.17 eCOT-NS uses transcutaneous, noninvasive peripheral nerve stimulation of both the occipital and trigeminal nerve. eCOT-NS was assessed for treatment of acute migraine in a randomized, blinded, placebo-controlled trial in adult patients with chronic or episodic migraine. In the treatment group, 76.2% experienced headache improvement at 2 hours vs 36.1% in the control group (P = .0100). Commonly reported adverse effects included headache, numbness/paresthesia, and skin irritation.17

Updates in Preventive Migraine Medications

CGRP monoclonal antibodies

CGRP monoclonal antibodies (mAbs) have been on the market since before 2020. These include erenumab-aooe (Aimovig; Amgen Inc), galcanezumab-gnlm (Emgality; Eli Lilly and Company), fremanezumab-vfrm (Ajovy; Teva Pharmaceuticals USA, Inc), and eptinezumab-jjmr (Vyepti; Lundbeck Seattle BioPharmaceuticals). In a recent meta-analysis, all 4 CGRP mAbs were compared and found to have similar efficacy and tolerability.18 They vary by binding site, antibody, and mode of administration (TABLE 1).

CGRP receptor antagonists

Small-molecule CGRP receptor antagonists have also been evaluated for migraine prevention. Rimegepant and atogepant (Qulipta; AbbVie) are FDA approved for the preventive treatment of episodic migraine in adults. These medications offer an alternative oral route of administration of CGRP blockade as opposed to self-injection, which some patients are averse to. Additionally, the shorter half-life may be beneficial for those planning pregnancy because it requires a shorter washout period.

A phase 3 study of rimegepant 75 mg every other day showed a statistically significant decrease in mean number of migraine days per month compared with placebo (–4.3 days vs –3.5 days; P = .0099) during a 12-week period.19 Commonly reported adverse events included nasopharyngitis, nausea, urinary tract infections, and upper respiratory tract infections. Uniquely, rimegepant is approved for both acute and preventative treatment of migraine.

Atogepant was evaluated in a phase 3, double-blind trial in which patients received 10 mg, 30 mg, 60 mg, or placebo daily during a 12-week period. All doses of atogepant showed a statistically significant decrease in monthly migraine days. Commonly reported adverse effects included nausea, constipation, fatigue, and decreased appetite.20

Newer Treatments vs Traditional Treatments

With the emergence of several new treatment options, studies comparing these new agents with traditional therapeutics are imperative to make decisions in patient care, such as timing of treatment initiation (TABLE 2 and TABLE 3). A recent head-to-head study compared the efficacy and tolerability of erenumab vs topiramate. This was one of the first studies to directly compare a CGRP receptor antibody with an older preventative medication. The findings showed that 55% of participants on erenumab had at least a 50% reduction in migraine days per month compared with 31.2% of patients on topiramate (P < .001). Overall, fewer adverse effects were reported in the erenumab group, with 10.6% of patients discontinuing erenumab due to adverse effects compared with 38.9% of those taking topiramate (P < .001).21 Because many medication choices are made based on tolerability, this may change the hierarchy of various classes.

In another comparison study, a meta-analysis of phase 3 randomized controlled trials assessed absolute differences in benefit-risk ratios between CGRP mAbs topiramate and propranolol. OnabotulinumtoxinA injections (Botox; Allergan Inc) were also included for the treatment of chronic migraine. Overall, all CGRP mAbs had a higher likelihood of being beneficial than harmful compared with other medications, including onabotulinumtoxinA, topiramate, and propranolol, suggestive of improved efficacy and tolerability. This further supports a more favorable benefit-risk ratio with CGRP mAbs.22

For chronic pain conditions, there is often an associated placebo effect, which is important to consider and can be effective for many patients. A recent systematic review and meta-analysis of CGRP mAbs showed pooled proportion contextual effect to be 0.66 for episodic migraine and 0.68 for chronic migraine, suggesting a large portion of benefit is due to contextual effects.23 These factors are important to think about when considering which medications to start and what may benefit patients most.


With a new wave of medications, many providers are faced with the dilemma of choosing between traditional and new therapies for patients with migraine. Historically, traditional therapies may be limited by lack of efficacy or poor tolerability, but newer options are uniquely targeted toward migraine pathophysiology.


  • Nandyala has nothing to disclose.
  • Ailani has received honoraria for consulting from AbbVie, Amgen, Aeon, Axsome, Biohaven, BioDeliverySciencesInternational, Eli Lilly and Company, GlaxoSmithKline plc, Lundbeck, Impel, Neurolief Inc, Neso, Satsuma Pharmaceuticals, Theranica, and Teva. She has received stock options for consulting from CtrlM. Her institution receives funding for clinical trials in which she is the principal investigator from the following companies; AbbVie, Biohaven, Eli Lilly and Company, SatsumaPharmaceuticals, and Zosano Pharma.
1. Wells RE, Markowitz SY, Baron EP, et al. Identifying the factors underlying discontinuation of triptans. Headache. 2014;54(2):278-289. doi:10.1111/head.12198
2. Blumenfeld AM, Bloudek LM, Becker WJ, et al. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS‐II). Headache. 2013;53(4):644-655.doi:10.1111/head.12055
3. AilaniJ, Burch RC, Robbins MS; Board of Directors of the American Headache Society. The American Headache Society Consensus Statement: update on integrating new migraine treatments into clinical practice. Headache. 2021;61(7):1021-1039.doi:10.1111/head.14153
4. Dodick DW, Lipton RB, Ailani J, et al. Ubrogepant for the treatment of migraine. N Engl J Med. 2019;381(23):2230-2241. doi:10.1056/NEJMoa1813049
5. Goadsby PJ, Wietecha LA, Dennehy EB, et al. Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine. Brain. 2019;142(7):1894-1904. doi:10.1093/brain/awz134
6. Hutchinson S, Silberstein SD, Blumenfeld AM, et al. Safety and efficacy of ubrogepant in participants with major cardiovascular risk factors in two single-attack phase 3 randomized trials: ACHIEVE I and II. Cephalalgia. 2021;41(9):979-990. doi:10.1177/03331024211000311
7. Hutchinson S, Schim J, Lipton RB, et al. Oral rimegepant 75 mg is safe and well tolerated in adults with migraine and cardiovascular risk factors: results of a multicenter, long-term, open-label safety study. Presented at: American Headache Society Annual Scientific Meeting; June 13-15, 2020; virtual. Accessed May 8, 2022. 
8. Ailani J, Lipton RB, Hutchinson S, et al. Long‐term safety evaluation of ubrogepant for the acute treatment of migraine: phase 3, randomized, 52‐week extension trial. Headache. 2020;60(1):141-152. doi:10.1111/head.13682
9. Croop R, Berman G, Kudrow D, et al. Long-term safety of rimegepant 75 mg for the acute treatment of migraine (Study 201). Presented at: American Headache Society Annual Scientific Meeting; June 13-15, 2020; virtual.
10. Silberstein SD, Shrewsbury SB, Hoekman J. Dihydroergotamine (DHE) - then and now: a narrative review. Headache. 2020;60(1):40-57. doi:10.1111/head.13700
11. Shrewsbury SB, Jeleva M, Satterly KH, Lickliter J, Hoekman J. STOP 101: a phase 1, randomized, open-label, comparative bioavailability study of INP104, dihydroergotamine mesylate (DHE) administered intranasally by a I123 precision olfactory delivery (POD) device, in healthy adult subjects. Headache. 2019;59(3):394-409. doi:10.1111/head.13476
12. Smith TR, Winner P, Aurora SK, Jeleva M, Hocevar-Trnka J, Shrewsbury SB. STOP 301: a phase 3, open‐label study of safety, tolerability, and exploratory efficacy of INP104, precision olfactory delivery (POD) of dihydroergotamine mesylate, over 24/52 weeks in acute treatment of migraine attacks in adult patients. Headache. 2021;61(8):1214-1226. doi:10.1111/head.14184
13. Lipton RB, Munjal S, Dodick DW, Tepper SJ, Serrano D, Iaconangelo C. Acute treatment of migraine with celecoxib oral solution: results of a randomized, placebo-controlled clinical trial. J Pain Res. 2021;14:549-560. doi:10.2147/JPR.S287571
14. Rapoport AM, Lin T, Tepper SJ. Remote electrical neuromodulation (REN) for the acute treatment of migraine. Headache. 2020;60(1):229-234. doi:10.1111/head.13669
15. Yarnitsky D, Dodick DW, Grosberg BM, et al. Remote electrical neuromodulation (REN) relieves acute migraine: a randomized, double‐blind, placebo‐controlled, multicenter trial. Headache. 2019;59(8):1240-1252.doi:10.1111/head.13551
16. Rapoport AM, Bonner JH, Lin T, et al. Remote electrical neuromodulation (REN) in the acute treatment of migraine: a comparison with usual care and acute migraine medications. J Headache Pain. 2019;20(1):83. doi:10.1186/s10194-019-1033-9
17. Daniel O, Tepper SJ, Deutsch L, Sharon R. External concurrent occipital and trigeminal neurostimulation relieves migraine headache: a prospective, randomized, double-blind, sham-controlled trial. Res Sq. Preprint posted online February 24, 2022. doi:10.21203/
18. Vandervorst F, Van Duen L, Van Dycke A, et al. CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs. J Headache Pain. 2021;22(1):128.doi:10.1186/s10194-021-01335-2
19. Croop R, Lipton RB, Kudrow D, et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet. 2021;397(10268):51-60. doi:10.1016/S0140-6736(20)32544-7
20. Ailani J, Lipton RB, Goadsby PJ, et al. Atogepant for the preventive treatment of migraine. N Engl J Med. 2021;385(8):695-706. doi:10.1056/NEJMoa2035908
21. Reuter U, Ehrlich M, Gendolla A, et al. Erenumab versus topiramate for the prevention of migraine - a randomised, double-blind, active-controlled phase 4 trial. Cephalalgia. 2022;42(2):108-118. doi:10.1177/03331024211053571
22. Drellia K,Kokoti L, Deligianni CI, Papadopoulos D, Mitsikostas DD. Anti-CGRP monoclonal antibodies for migraine prevention: a systematic review and likelihood to help or harm analysis. Cephalalgia. 2021;41(7):851-864. doi:10.1177/0333102421989601
23. Forbes RB, McCarron M, Cardwell CR. Efficacy and contextual (placebo) effects of CGRP antibodies for migraine: systematic review and meta-analysis. Headache.2020;60(8):1542-1557. doi:10.1111/head.13907