Intranasal Acute Migraine Treatments

Migraine is a complex, chronic neurologic disorder that is the second leading cause of global disability.¹ Treatment often requires both preventive and acute options. Individuals seek acute treatments which have expedient times to pain freedom or relief and return to function as well as tolerable side effects.² Aside from the pain itself, features commonly associated with migraine include nausea (30.5%), vomiting, inability to take oral medications (42.2%), and reduced gastrointestinal motility.^3,4 These features, alongside individual preference, may dictate preferred formulations for treatment. Intranasal options offer rapid onset of action relative to oral options, without the pain, bruising, bleeding, or skin reaction associated with injection formulations (subcutaneous or intramuscular). They may also be useful adjunctive therapies to non-intranasal options for refractory conditions.

Practitioners may opt to offer therapies based on stratified algorithms (eg, choosing therapies based on pain severity) or stepwise algorithms (eg, stepping up therapies when pain progresses or does not respond adequately to first-line treatments).⁵ People with headache are seen across various medical specialties, including primary care, emergency medicine, pain management, and neurology, which may influence their familiarity with specific agent choices. Various classes of acute therapies include triptans, dihydroergotamine (DHE), intranasal nonsteroidal anti-inflammatory drugs (NSAIDs), calcitonin gene-related peptide (CGRP) antagonists (gepants), and other options. In this article, we review and discuss the efficacy, safety, and tolerability of various established and emerging intranasal antimigraine agents to provide a practical guideline for practitioners managing headache disorders.

Triptans

Triptans have served as a mainstay for most first-line acute antimigraine therapy options, except for individuals with a history of cardiovascular or cerebrovascular ischemia or other contraindications or intolerances. Triptans are primarily 5HT_1B,1D,1F agonists, but they also exert an agonistic response at 5HT_1A,2B receptors.^6-8 Of the intranasal triptan options offering substantial pain freedom at 2 hours, 3 different sumatriptan formulations and zolmitriptan 5 mg are available for adults and certain pediatric age groups.

Sumatriptan

Several intranasal formulations of sumatriptan have been approved for adult use by the Food and Drug Administration (FDA): Imitrex (sumatriptan 5 or 20 mg; GlaxoSmithKline, Philadelphia, PA), Tosymra (sumatriptan 10 mg with a permeation enhancer, previously known as DFN-02; Tonix Medicines, Chatham, NJ), and Onzetra Xsail (sumatriptan nasal powder 22 mg, previously known as AVP-825; Currax Pharmaceuticals, Brentwood, TN). Repeat doses are FDA-approved after 2 hours following initial administration, except for Tosymra, which can be repeated after 1 hour. In a review of the 5 clinical trials of sumatriptan 20 mg, up to 42% of individuals achieved 2-hour pain freedom compared with 12% of people receiving placebo.⁹ Nausea or vomiting was seen in about 13.5% of individuals compared with 11.3% of people receiving placebo, and abnormal taste in 24.5% compared with 1.7% in the placebo arm. Headache recurrence ranged from 30% to 46% compared with 33% to 55% in the placebo group, with a median time of recurrence between 6.3 and 7.3 hours.⁹

DFN-02 was approved after a phase 2, multicenter, randomized, 2-period, double-blind, placebo-controlled clinical trial demonstrated 2-hour pain-freedom rates of 43.8% vs 20.5% (P=.025) compared with placebo, with sustained pain freedom from 2 through 24 hours postdose (38.9% vs 13.8%; P=.029) compared with placebo.¹⁰ Treatment-emergent adverse events (AEs) were seen in 10% of individuals in the first double-blind period and 13.5% in the second double-blind treatment. The most common treatment-emergent adverse event in the second double-blind treatment period was dysgeusia (.08%).¹⁰

COMPASS (NCT01667679; Efficacy and Safety of 20 mg Sumatriptan Powder Delivered Intranasally With the Bi-directional Device Compared With 100 mg Sumatriptan Tablets in Adults With Acute Migraine With or Without Aura)—a randomized, multicenter, double-dummy, crossover, multiattack, comparative efficacy study—compared AVP-825 against oral sumatriptan 100 mg in 185 participants.¹¹ Treatment with AVP-825 compared with oral sumatriptan provided greater odds of achieving pain freedom (odds ratio [OR], 1.29; P<.01) and meaningful pain relief (OR, 1.32; P<.0001) with significant sustained pain freedom from 1 hour through 48 hours postdose.¹¹ Nasal discomfort (16% vs 1%) and abnormal taste (26% vs 4%) were more common with AVP-825 than oral sumatriptan.¹²

Zolmitriptan

Zolmitriptan is approved by the FDA for people older than 12 years. In the INDEX (NCT00617747; A Multicenter, Randomized, Placebo-Controlled, Double-Blind, Parallel Group Trial to Evaluate Efficacy and Tolerability of Zolmitriptan (ZOMIG) Nasal Spray in the Acute Treatment of Adult Subjects With Migraine) phase 3 open-label, noncomparative, multicenter, multinational trial, zolmitriptan demonstrated substantial pain freedom at 2 hours in 53.8% of attacks with pain freedom reported in 83.3% of mild-intensity headaches, 56.5% of medium-intensity headaches and 32.2% of severe-intensity headaches.¹³ AEs were generally mild and declined in incidence over time, but led to withdrawal from the study for 4.5% of individuals. The most common AEs were unusual taste (19.0%) and paresthesia (6.8%). Nasopharyngeal AEs were reported in 14.5% of attacks overall, occurring with 21.8% of attacks in the first 3 months of use and declining to 12.2% over 360 days of use without evidence of any abnormalities in nose and throat examinations after repeated and extended use.¹³ A recent phase 3, randomized, double-blind, placebo-controlled, multicenter crossover trial with an open-label extension evaluated the use of zolmitriptan in participants aged 6 to 11 years (mean age, 9 years), but it was terminated early because of slow enrollment.¹⁴ A total of 33.8% of participants in the treatment arm vs 23.4% in the placebo arm achieved pain freedom at 2 hours, with a 6-month reduction in pediatric migraine disability assessment (PedMIDAS) functional disability score of 5 points. In this study, a total of 13 (7.7%) individuals experienced at least 1 treatment-emergent adverse event: 1/26 (3.8%) for zonisamide 1 mg, 5/120 (4.2%) for zonisamide 2.5 mg, 0/19 for zonisamide 5 mg, and 5/159 (5.0%) for placebo.¹⁴

Dihydroergotamine

DHE, another standard of care option for acute migraine treatment, was originally approved by the FDA in 1946 and is also available in multiple intranasal formulations. DHE has contraindications similar to triptans. DHE functions primarily as a 5HT_{1B,1D, D2,} and α-adrenergic2B agonist.^6,7 The original intranasal formulation (Migranal, 1 mg [dihydroergotamine mesylate; Bausch Health US, Bridgewater, NJ]) is delivered with a traditional nasal spray device, and thus bioavailability is low (15%), with T_max of 60 minutes. A newer FDA-approved formulation targets the upper nasal space with a proprietary delivery device (Trudhesa, 1.45 mg [dihydroergotamine mesylate; Impel Pharmaceuticals, Seattle, WA]) and achieves T_max of 30 minutes with 60% bioavailability. An intranasal powder formulation of DHE (STS101), which has not been approved by the FDA, was found to have Tmax of 30 minutes with 60% to 70% bioavailability compared with intramuscular DHE.¹⁵ There is a low risk of rebound headache (medication overuse) from this compound, making it a potential option in individuals who have had success with triptan medications but may be using them too frequently.⁶ Furthermore, DHE effectively reverses cutaneous allodynia, a marker of central sensitization, whereas sumatriptan does not. DHE also has been shown to be more effective than sumatriptan when acute treatment is delayed.¹⁶ The orally inhaled MAP0004 did not progress successfully to marketing, whereas INP104 (Trudhesa) was recently approved by the FDA based on results from the phase 3 STOP 301 trial.¹⁷ Reported outcomes from this trial were pain freedom at 2 hours in 38.0% and pain freedom at 2 hours for doses of Trudehsa taken 2 hours after the beginning of the migraine in 39.4%, with low recurrence rates of 7.1% at 24 hours and 14.3% at 48 hours. Major AEs reported were nasal congestion (~15%) and nausea (7%).¹⁷ Although a direct comparison between INP104 and triptans has not been made, intranasal DHE may be a powerful alternative to triptans for headache attacks with delayed initiation to treatment and for people at risk of medication overuse.

Nonsteroidal Anti-Inflammatory Drugs

Ketorolac metered tromethamine spray (Sprix; Zyla Life Sciences US, Wayne, PA) is an FDA-approved agent for acute treatment in adults, but it has not been approved for pediatric populations. Use of NSAIDs likely results in fewer gastrointestinal AEs compared with oral administration. Both intranasal ketorolac and ROX-828 offer similar pain freedom at 2 hours when compared with zolmitriptan 5 mg (OR, .82 [95% CI, .34, 1.30], and OR, .43 [95% CI, .14, 1.30], respectively).¹⁸ The intranasal ketorolac formulation compared with ROX-828 appears to have equivocal pain freedom at 2 hours (OR, 1.91 [95% CI, .49, 7.40]), with greater AEs (OR, 7.52 [95% CI, 2.13, 26.57]). Both ketorolac and ROX-828 offer sustained pain freedom for 24 hours (OR, 3.88 [95% CI, 1.28, 11.82], and OR, 2.91 [95% CI, 1.18, 7.16], respectively).¹⁸ In a pediatric emergency department study for the treatment of migraine, a decrease in pain intensity at 30, 60, and 120 minutes with intranasal ketorolac was noninferior to intravenous administration (P<.001).¹⁹ Associated AEs were minimal, including nausea, dizziness, feeling cold, feeling “off,” and transient extremity sensory complaints (5 of 27 individuals).¹⁹ Emergency departments may consider using intranasal ketorolac when establishing intravenous access is difficult. Ketorolac may serve as another first-line intranasal antimigraine agent alongside intranasal triptans in adults.

Zavegepant

Zavegepant, a CGRP antagonist (gepant), is the most recent addition to the intranasal antimigraine armamentarium, receiving FDA approval in 2023. Based on a phase 3 randomized controlled trial of 1269 individuals, pain freedom at 2 hours compared with placebo was 24% vs 15%, respectively (risk difference, 8.8; 95% CI, 4.5 to 13.1; P<.0001).²⁰ Other significant outcomes included substantial freedom from most bothersome symptom, pain relief, and ability to function normally at 2 hours; sustained pain freedom at 24 and 48 hours; and ability to function normally at 30 minutes. The most common AEs were dysgeusia (21% vs 5%), nasal discomfort (4% vs 1%), and nausea (3% vs 1%).²⁰ As mentioned previously, data suggest that zavegepant may be more appropriate for mild to moderate headaches, given its lower association with pain freedom than other intranasal options. Zavegepant may be an alternative for individuals who have contraindications or intolerances to intranasal triptans and DHE and those with the inability to tolerate oral gepants.

Off-Label Medications

Ketamine

Ketamine is a noncompetitive N-methyl-D-aspartate receptor antagonist with action across other receptors, including CGRP, nicotinic acetylcholine, µ/δ opioid, AMPA, and GABA, but its exact antinociceptive mechanism of action remains unclear.^21,22 Its use in migraine remains off-label; however, a 2023 retrospective cohort study evaluated its efficacy in refractory chronic migraine at a tertiary headache center.²³ Participants were given compounded sprays of 100 mg/mL (range, 15 to 30 mL) and instructed to use 1 or 2 sprays (10 mg per .1 mL spray) in each nostril per dose, every 15 minutes as needed, with a maximum of 20 sprays per day and 40 sprays per week. Of the 169 participants with refractory chronic migraine, 67.5% reported daily headache, and 84.6% had previously trialed at least 3 classes of preventive medication options. Reasons for initiating this medication included an incomplete response to previous acute medications (59.2%) and previous benefit from intravenous ketamine (22.5%). A total of 47.6% had never received ketamine infusion previously. Forty-nine percent of individuals rated it “very effective”, 39.6% rated it “somewhat effective”, and 35.5% rated their quality of life as “much better”. When compared with other acute treatment options, participants rated intranasal ketamine as “much better” (43.2%), “somewhat better” (29.6%), “no different” (10.7%), or “somewhat inferior” (8.9%). Reported AEs included fatigue, blurry or double vision, and cognitive effects (ie, confusion, dissociation, vivid dreams, hallucinations); fewer than 5% had elevations in alanine or aspartate transaminase levels over 3 times the normal limit.²³

Ketamine nasal spray has been evaluated in acute cluster headache as part of an open-label pilot study of 23 participants with chronic cluster headache, demonstrating nonsignificant pain intensity reduction at 15 minutes but reduced intensity by 59% at 30 minutes (mean difference in numeric rating scale, 4.3 out of 10 [range, 2.4 to 6.2; P<.001]), with 69% of individuals rating their pain level as 4 or lower out of 10.²⁴ Half of the participants preferred ketamine over oxygen or sumatriptan injection.²⁴ In a randomized controlled trial comparing intranasal ketamine with intravenous ketorolac among 140 participants with acute nontraumatic headache, intranasal ketamine resulted in a significantly improved difference in pain intensity at 30 minutes compared with intravenous ketorolac, but the converse at the 60- and 120-minute assessments (P<.001).²⁵ Ketamine was associated with more AEs, including fatigue, dizziness, general discomfort, nausea, elevated heart rate, and hypertension (P<.05).²⁵

Ketamine nasal spray may offer substantial efficacy or improved quality of life in people with refractory chronic migraine who have exhausted other first- and second-line options. Proper supervision and monitoring for AEs are imperative, including regular laboratory monitoring for liver function test abnormalities and cognitive effects, monitoring for potential for abuse or addiction, and assessing safety concerns in activities of daily living. People cannot operate a motor vehicle while using ketamine. Further investigation into the long-term effects of regular intranasal ketamine use for migraine is warranted.

Lidocaine

Lidocaine, a sodium channel blocker and local anesthetic, has traditionally been used as an intranasal therapy for sphenopalatine ganglion blockade, desensitizing the intracranial nociceptors that contribute to vasodilation, but it has held a “level C recommendation” by the American Headache Society since 2015.^26,27 Individuals typically lie supine during administration, but the method of administration varies, including by nasal spray, applying the medication with a cotton swab, or using another catheter applicator set up to spray the liquid into the nasal cavity, which may lead to variable results. In a meta-analysis evaluating 6 studies from 1996 to 2017 of mostly adults aged older than 18, 5 studies evaluated pain intensity using different scales, but pooled analysis suggested favorable pain relief at 5 and 15 minutes (standardized mean difference, -.45 [-.71, -.19; P<.05; I²=2] and -.41 [-.72, -.09; P<.05; I²=54%], respectively).²⁸ Pooled analysis found no significant difference in the relative risk of headache relapse after intranasal lidocaine compared with control. AEs included burning or numbness of the nose or around the eye, unpleasant taste, or irritation of the throat, with a range of side effect reports as high as 49.4%.^28,29 Intranasal lidocaine can be trialed in the office setting, but given the short duration of action and equivocal results, it likely should serve as adjunctive therapy to other recognized antimigraine agents.

Oxytocin

Oxytocin serves as an off-label acute therapeutic option for migraine that may have benefit especially in those with hormonally related headaches. The pathophysiology of its antinociceptive properties requires further elucidation. However, interest in this option has been generated from observations that higher migraine burden follows perimenstrual reductions in estrogen and oxytocin levels along with improved migraine burden during pregnancy and breastfeeding in presence of higher levels of oxytocin.^30-32 Oxytocin has not demonstrated significant improvement of pain at 2 hours compared with placebo in low-frequency episodic migraine or chronic migraine.³³ Individuals who had taken NSAIDs within 24 hours were considerably less likely to experience analgesic efficacy, possibly related to decreased production of interleukins, which drive oxytocin receptor expression.³³ In individuals with chronic and high-frequency episodic migraine dosed for 28 days with oxytocin, there was an average reduction of monthly headache days from 14.1 to 5.9.³³ These studies suggest that more liberal or regular dosing of the medication while avoiding NSAIDs may have some utility in an individual’s overall function. However, further investigation is warranted into whether oxytocin may affect headache frequency as opposed to headache severity, and its role in preventive rather than acute use.

Expert Opinion

We propose a clinical algorithm in selecting a stepwise approach to intranasal therapies (Figure). These intranasal treatments may serve as primary acute options or adjunctive options depending on individual preferences and needs. In general, we recommend acute treatment initiation as soon as the individual realizes they will have or are having a headache. First-line intranasal approaches may include triptans (zolmitriptan or sumatriptan), DHE, or NSAIDs (ketorolac). DHE may work better for individuals whose headache has not been successfully aborted from other methods, or when there is delay in treatment initiation. Zavegepant can be useful as another second-line therapy, but given its recent FDA approval, it may require documentation of failure or intolerance to triptan options before insurance approval can be obtained. Off-label approaches may include novel and off-label agents, including ketamine, lidocaine, or oxytocin. Further investigations into these novel additions to the headache armamentarium are necessary to better understand the proper population and escalation approach.

Conclusion

Intranasal options for acute treatment of migraine may provide rapid-onset relief, especially for individuals who have nausea, vomiting, or gastroparesis associated with their headache disorder, or those with needle phobia or intolerance to injectable formulations. These intranasal approaches can be helpful adjunctive agents to nonintranasal acute treatment options for more refractory headaches that require combination drug therapy for adequate acute treatment.