Introduction to acute migraine pharmacologic treatment and the road to lasmiditan

Migraine is an episodic disorder in which severe headache may be accompanied by symptoms such as nausea and light sensitivity, contributing to significant morbidity. Acute migraine treatment has historically consisted of analgesics initiated early in onset.

A graduated approach toward migraine-specific drugs has been recommended within an attack, except in patients with history of headache refractory to common analgesics, in which 5-HT1B, 1D receptor agonists (triptans) are utilized initially to prevent medication overuse headaches.^1,2

If a patient fails a trial of simple analgesics or migraines become severe, triptans are preferred due to their direct trigeminal complex activity.^3,4 Despite triptan availability as a migraine-specific rescue, the global burden of migraine morbidity remains high and as a result, recent research in migraine pathogenesis and drug development has increased.⁵

Historically, intracerebral vasoconstriction was thought to cause cerebral neural ischemia and reactive extracranial dilation, inflammatory neuropeptide release, and associated migraine pain.⁶ This hypothesis supported the mechanism of triptans, which selectively acted on these receptors in intracranial blood vessels and the trigeminal system to cause vasoconstriction and inhibition of inflammatory neuropeptide release.⁷

By targeting this mechanism, however, triptans also have the potential to increase the risk of serious ischemic events. As a result, use of these agents in patients with underlying cardiovascular disease, cerebrovascular disease, or associated risk factors is contraindicated, potentially limiting acute treatment options in these patients.^7-11

A more recent pathogenesis theory proposes depressed neuronal electrical activity across the brain, leading to compensatory overactivity of the trigeminovascular system, associated release of vasoactive peptides, and an inflammatory response in the vasculature.⁶ Lasmiditan was recently approved by the FDA for the treatment of acute migraine in patients with or without aura.

The novel treatment targets the new pathogenesis hypothesis by agonism with high affinity at the 5-HT1F receptor. Lasmiditan was first to market as an acute treatment with an alternate mechanism to that of the triptans and an option for patients who were previously left without migraine-specific medications due to contraindications.¹²

Prior to the approval of lasmiditan, The American Headache Society proposed that this agent should be reserved for such patients.¹³ Data from clinical trials and the package insert regarding drug properties, efficacy, and safety will be reviewed in order to make basic comparisons to the triptan class and discuss the potential place in therapy for lasmiditan and opportunities for pharmacist intervention.

Overview of lasmiditan

Pharmacology and pharmacokinetics

Lasmiditan targets 5-HT1F receptors with selective antagonism, which are present in the trigeminovascular system and hypothesized to cause trigeminal impulse inhibition via hyperpolarization.^14-16

Given that lasmiditan is highly lipophilic, it is able to penetrate the blood-brain barrier through action of the 5-HT1F receptors located centrally and peripherally on trigeminal neurons. This action may also decrease second-order trigeminal neuron activation, another essential proposed mechanism of migraine pathophysiology.^17,18

Lasmiditan has a 470-fold higher binding affinity at the 5-HT1F receptor compared with the 5-HT1B and 5-HT1D receptors, resulting in minimized vascular complications. Notably, 5-HT1F receptors are not expressed by endothelial or smooth muscle cells, and thus, are not involved in vascular tone regulation.¹⁴ Additionally, lasmiditan did not cause vasoconstriction in animal models or in-vitro studies in human coronary and cerebral arteries.^18-22

Furthermore, lasmiditan does not prolong the QTc interval. The drug is rapidly absorbed with a time to peak concentration of 1.8 hours, exhibits 55%-60% protein binding of human plasma, and is metabolized by non-cytochromeP450 enzymes to non-active metabolites. Monoamine oxidase A and B, among others, also do not play a role in metabolism. Lasmiditan is eliminated with a half-life of 5.7 hours and excreted into the urine.¹²

Dosage and administration

Lasmiditan is available as an oral 50, 100, and 200 mg tablet to be taken as a single dose, with a maximum of 1 dose in 24 hours.¹² In 2019, Loo et al. analyzed the efficacy and safety of repeat lasmiditan dosing by pooling data from 2 phase 3 clinical trials and providing a second dose of study drug for rescue or recurrence, but the authors concluded there was no clear benefit for taking a second dose for the same migraine attack.²³

Although the dose may be administered with or without food, it should not be administered unless the patient is able to wait at least 8 hours between taking the dose and operating heavy machinery and/or driving. In addition, the safety of treating more than 4 migraine attacks on average in a period of 30 days is not yet established.¹²

Efficacy of lasmiditan in clinical trials

The efficacy of lasmiditan for the acute treatment of migraine was evaluated in 2 phase 3 double-blind clinical trials. In 2018, Kuca et al assessed the efficacy of lasmiditan by randomizing adult migraine patients with or without aura in a 1:1:1 ratio to receive oral lasmiditan 100 mg (n = 744), 200 mg (n = 745), or placebo (n = 742) to be taken within 4 hours of moderate to severe migraine onset.

Patients were primarily Caucasian females averaging 42 years of age. The primary endpoints were headache pain freedom and most bothersome symptom (MBS) freedom at 2 hours post-dose. Pain freedom was defined as a reduction of moderate or severe pain to no pain and MBS freedom was defined as the resolution of the self-identified MBS. More patients dosed with lasmiditan 200 mg and 100 mg were pain and MBS free at 2 hours compared to placebo, with p < 0.001 in all cases.²⁴

The second trial was published by Goadsby et al. in 2019, which randomized a similar patient population in a 1:1:1:1 ratio to receive oral lasmiditan 200 mg (n = 750), 100 mg ( n = 754), 50 mg (n = 750), or placebo (n = 751) to investigate the same primary endpoints as in Kuca et al.

Lasmiditan provided significantly more pain freedom for the 200 mg (p < 0.001), 100 mg (p < 0.001), and 50 mg (p = 0.003) strengths compared with placebo. Freedom from most the bothersome symptom at 2 hours was also statistically significant for the 50 mg (p = 0.014), 100 mg (p < 0.001), and 200 mg strengths (p < 0.001) compared with placebo.²⁵

Notably with regard to the Kuca et al and Goadsby et al clinical trials, patients were able to take a dose of rescue medication 2 hours after taking lasmiditan, but options for rescue did not include medications such as triptans, ergot alkaloids, barbiturates, and opioids. These excluded rescue medications were not allowed within 24 hours of lasmiditan administration.^12,24-25

Safety overview of lasmiditan

Safety in clinical studies

In the 2018 study by Kuca et al, safety was assessed in study participants by asking patients whether they felt anything unusual that they had not felt with a migraine prior to taking the study medication. These were classified as treatment-emergent adverse events (AEs), further defined as any new or worsening event after starting the study medication that appeared within 48 hours.

The safety population was defined as all patients who had taken at least 1 dose of study drug. These were primarily Caucasian females with an average age of 42 years and 77% of these patients had at least 1 cardiovascular risk factor.

A total of 42% of patients in the lasmiditan 200 mg group and 36.3% in the 100 mg group experienced a treatment-related AE, compared with 16.4% of the placebo group. Those occurring with a 2% or greater incidence in the lasmiditan group were dizziness, fatigue, lethargy, nausea, paresthesia, and somnolence.²⁴

The 2019 Goadsby et al trial also evaluated treatment-related adverse events in patients who were randomized and used at least one dose of study drug. Similarly to Kuca et al, the majority safety population was characterized by Caucasian females with a mean age of 42.7 years.

The proportion of patients reporting at least 1 treatment-related AE was higher in the lasmiditan treatment groups than in the placebo group and was dose-related: 39.0%, 36.2%, and 25.5% for the 200 mg, 100 mg and 50 mg lasmiditan groups, respectively, versus 11.6% for the placebo group.

Treatment-related AEs reported by at least 2% of patients were also higher in the lasmiditan groups and included dizziness, somnolence, and paresthesia. The authors concluded that study findings were primarily limited to a single dose, suggesting that safety and tolerability need to be validated with long-term data.²⁵

Brandes et al published interim results in 2019 of the GLADIATOR study, a prospective, randomized, open-label, phase 3 study aimed at evaluating long-term safety and tolerability of intermittent lasmiditan dosing. Patients completing the Kuca et al and Goadsby et al single-attack studies were eligible to be randomized in a 1:1 ratio to receive lasmiditan 100 or 200 mg as the first treatment for new migraine attacks of moderate severity.

All patients who treated 1 or more migraine attacks were included in the analysis. The majority of patients were Caucasian females with a mean age of 43.2 years and 82% of patients had at least 1 cardiovascular risk factor.

A total of 45.1% of patients receiving the 100 mg dose and 52% of patients in the 200 mg group reported at least 1 treatment-related AE. The majority of these events were central nervous system (CNS) related, with dizziness being the most frequently reported.

There were no instances of drug abuse reported in the interim results. One treatment-emergent road traffic accident occurred 2 days post-dose. No AEs related to vasoconstriction were reported.

Over time, the incidence of AEs, including dizziness, generally decreased with subsequent treatments. The authors concluded that the interim results support those of the single-attack studies, with no new treatment-emergent AEs and events that appear to decrease with repeated dosing.²⁶

Contraindications, warnings, and precautions

Currently there are no contraindications to lasmiditan listed by the manufacturer. Warnings are most notably related to CNS depression.

Because of this, driving assessment studies were conducted with results that prompted the administration warning that patients should not drive or operate heavy machinery for at least 8 hours post-dose. Lasmiditan also carries a warning for serotonin syndrome, cardiovascular effects including decreased heart rate (5—10 beats per minute in clinical trials) and increased blood pressure (7 mm Hg 1 hour after administration in clinical trials), and potential for increased drowsiness and systolic blood pressure in the geriatric population.

Use is not recommended in severe hepatic impairment as administration to these patients has not been adequately studied. A patient’s baseline liver function should be monitored and repeated as indicated, along with heart rate and blood pressure in cardiovascular patients.

In terms of concomitant drug administration with lasmiditan, P-glycoprotein and breast cancer resistant protein substrates should be avoided. Caution is also warranted with other CNS depressants, serotonergic drugs, and heart rate lowering medications.

The medication is also a schedule V controlled substance due to significantly higher drug-liking scores compared with placebo in clinical trials; euphoria is currently reported at less than 2% frequency. It should also be noted that lasmiditan is not indicated for prevention of migraine and that any acute migraine agent may lead to medication overuse headache or withdrawal when used for 10 or more days per month.¹²

Safety comparison of lasmiditan and the triptan medication class

Given that there are no clinical trials that have compared the efficacy of lasmiditan to the triptan class, direct safety comparisons are not yet available in the literature. Since lasmiditan was the first medication to market to rival the triptan class, an indirect comparison of selected properties of each are compiled in Table 1 to provide an overview of any similarities and differences.^7,12,31-36

Table 1. Select safety comparisons of lasmiditan and triptan medications

Lasmiditan

Triptans

Controlled substance schedule

C — V

Non-scheduled

Main AEs (>10% frequency)

Dizziness

Almotriptan: drowsiness, dizziness, headache, nausea, vomiting, xerostomia, paresthesia

Sumatriptan: tingling sensation, dizziness, vertigo, feeling hot, injection site reaction

Zolmitriptan: unpleasant taste

Warnings for driving impairment/heavy machine operation

Wait at least 8 hours after dosing

Naratriptan, sumatriptan: use caution

Warnings in cardiovascular disease

May decrease heart rate and increase blood pressure

All are contraindicated

Considerations for special populations

Renal impairment

No dose adjustment required

Dose adjustments required for almotriptan and naratriptan

Hepatic impairment

Use is not recommended in severe impairment

Dose adjustments required for almotriptan, naratriptan, sumatriptan, zolmitriptan

Pregnancy

Adverse events reported in animal studies, but no adequate human data

Sumatriptan crosses the placenta but may be considered if first-line agents fail; other triptans have limited data

Lactation

No sufficient data on excretion into human breast milk, effects on the breastfeeding infant, or effects on human milk production

Sumatriptan is present in breast milk with a mean relative infant dose of 3.5% and the manufacturer recommends withholding breastfeeding for 12 hours post-dose, but studies suggest discontinuing breastfeeding is not required; use caution with other triptans

Pediatrics

Safety and effectiveness have not been established

Almotriptan, rizatriptan and zolmitriptan nasal spray approved for use in pediatrics (specific age cutoffs for each); sumatriptan nasal spray has been used with efficacy

Geriatrics

Start at the lower end of the dosing range

Naratriptan and zolmitriptan: start at the lower end of dosing range

Drug interactions

CNS depressants, serotonergic and heart rate lowering drugs, P-glycoprotein and breast cancer resistant protein substrates

Almotriptan: ergotamines, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), ketoconazole

Eletriptan: SSRIs and SNRIs, CYP3A4 inhibitors, ergotamines

Frovatriptan, naratriptan: SSRIs and SNRIs, ergotamines

Rizatriptan: propranolol, ergotamines, monoamine oxidase inhibitors (MAOIs), SSRIs and SNRIs

Sumatriptan: ergotamines, MAOIs, SSRIs and SNRIs

Zolmitriptan: ergotamines, MAOIs, SSRIs and SNRIs, cimetidine

Conclusion and discussion

Oral lasmiditan has demonstrated statistically significant headache pain and most bothersome symptom freedom 2 hours post-dose in clinical trials with a mechanism of action that does not involve blood vessel contractility.^12,24-25

Oral lasmiditan may therefore offer a migraine-specific treatment option for patients with vascular contraindications to triptans. Current safety concerns are mainly CNS-related including dizziness and somnolence, prompting the warning that the drug should not be administered unless a patient can wait at least 8 hours between dosing and operating heavy machinery or driving.^12,24-26

Given that the American Headache Society proposed lasmiditan should be reserved for patients with contraindications to triptans, as well as those who have documented evidence of failing to respond or tolerate at least 2 triptan agents, this drug will likely have the biggest impact in these patient populations.¹³

Prescribing patterns may be further driven by the fact that lasmiditan tablets are currently $96 each, whereas generic oral sumatriptan tablets have an average wholesale price ranging from $25.14—$28.25 depending on tablet strength.²⁸ Given the higher cost, there is a potential that lasmiditan may carry prior authorization criteria that aligns with the position of the American Headache Society, which may limit rapid access to the medication.¹³

Prescribing patterns and patient access may also be further influenced by the status of lasmiditan as a controlled versus non-scheduled triptans.^7,12,31-36 Additionally, many triptans are available via alternate routes of administration such as subcutaneous, intranasal, and orally disintegrating tablets.^7,31-36

Lasmiditan is currently only available as an oral tablet but given the current market niche with the absence of vascular contractility, formulations may be expanded beyond an oral tablet to accommodate the subset of patients who also experience nausea, vomiting, or trouble swallowing.¹²

The prescribing pattern for lasmiditan will also evolve as current literature gaps are closed. For example, clinical trials to date were placebo-controlled and efficacy and safety comparisons between lasmiditan and other migraine-specific therapies are not yet available. In fact, agents such as triptans were not allowed within 24 hours of lasmiditan dosing in clinical trials.

Since literature to date has demonstrated no clear benefit of administering a second oral lasmiditan dose within an attack, such data may be pivotal to the place in therapy.^12,24 Post-marketing data evaluating CNS effects, especially in the geriatric population, will likely be quite influential. Further related to CNS depression, patient preference regarding lasmiditan as a feasible treatment option may be persuaded by the need to abstain from driving or operating heavy machinery for at least 8 hours after taking a dose.¹²

Although lasmiditan was the first medication for the treatment of acute migraine to market with an alternate mechanism to that of triptans, calcitonin-gene related peptide (CGRP) receptor antagonists have since been approved for this indication.^29-30 Given that these medications also carry a mechanism of action separate from that of the triptans, cost, administration route and any differences in patient safety will likely be important factors in determining market share.

When considering known differences between CGRP receptor antagonists and lasmiditan, CGRP receptor antagonists are not scheduled as controlled substances. Additionally, while lasmiditan does not require renal dose adjustment, dose reduction is required in severe renal impairment for ubrogepant.²⁹ Rimegepant is not recommended in patients with end-stage renal disease, but is available as an orally disintegrating tablet, offering a potential formulation advantage based on an individual patient’s clinical picture.^12,30

The CGRP receptor antagonists are currently priced at $127.50 and $102.00 per tablet for rimegepant and ubrogepant, respectively.²⁸ Although this is only slightly more expensive than lasmiditan, the class may be subject to similar prior authorization requirements based on the proposed place in therapy for these agents by the American Headache Society.¹³ Although gaps in the literature for lasmiditan remain, in a review of current and emerging evidence-based treatment options, Agostoni et al state that neurologists, general practitioners, pharmacists, and patients will need to be well informed.³⁷

As health care professionals and patients await closures in literature gaps and post-marketing data, pharmacists who have reviewed lasmiditan will be better informed to recognize a potential place in therapy. Similarly to how pharmacists had been proposed as candidates to identify patients for preventative migraine therapy, it can be suggested that pharmacists may also be well positioned to identify candidates for lasmiditan.³⁸

Upon profile review for a migraine patient refilling common analgesics or seeking these agents over the counter, a pharmacist has the opportunity to identify patients without migraine-specific abortive therapy. If these patients were left without these treatments due to vascular contraindications to triptans, this will pose an opportunity to recommend lasmiditan to the prescriber.

For cases in which drug formularies require prior authorization, pharmacists may be able to improve the time to approval and time to first fill and pick up.³⁹ Lastly, pharmacists will also support safe use of lasmiditan through patient counseling on considerations for controlled substances, administration warnings, and anticipated AEs.¹²

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