Lasmiditan for the Treatment of Migraines With or Without Aura in Adults

Abstract

Migraines are a common form of primary headache, affecting women more than men (17.4% and 5.7% of US population, respectively, a total of 12%) that carry significant morbidity and disability, as well as a hefty healthcare price tag. They are most prevalent in women of reproductive ages and are estimated to be the 6th disease in order of causing global burden. They are estimated to cause 45.1 million years lived with disability, or 2.9% of global years lost to disability. Migraine treatment divides into acute, abortive treatment for relief of an ongoing migraine attack, and prophylactic therapy to reduce the occurrence of migraines, specifically for patients suffering from chronic and frequent episodic migraines. Traditional abortive treatment usually begins with NSAID and non-specific analgesics that are effective in curbing mild to moderate attacks. 5HT₁-agonists, such as triptans, are often used for second-line and for severe attacks. Triptans are generally better tolerated in the longterm than NSAIDs and other analgesics, though they carry a significant side-effect profile and are contraindicated in large parts of the population. Prophylactic therapy is usually reserved for patients with frequent recurrence owing to medication side effects and overall poor adherence to the medication schedule. Importantly, medication overuse may actually lead to the development of chronic migraines from previously episodic attacks. Recent research has shed more light on the pathophysiology of migraine and the role of CGRP in the trigeminovascular system. Recent pharmacological advances were made in developing more specific drugs based on this knowledge, including CGRP neutralizing antibodies, receptor antagonists, and the development of ditans. These novel drugs are highly specific to peripheral and central 5-HT_1F receptors and effective in the treatment of acute migraine attacks. Binding these receptors reduces the production of CGRP and Glutamate, two important ligands in the nociceptive stimulus involved with the generation and propagation of migraines. Several large clinical studies showed Lasmiditan to be effective in the treatment of acute migraine attacks. Importantly, due to its receptor specificity, it lacks the vasoconstriction that is associated with triptans and is thus safer is larger parts of the population, specifically in patients with cardiac and vascular disease. Though more research is required, specifically with aftermarket surveillance to elucidate rare potential side effects, Lasmiditan is a targeted anti-migraine drug that is both safe and effective, and carries an overall superior therapeutic profile to its predecessors. It joins the array of medications that target CGRP signaling, such as gepants and CGRP-antibodies, to establish a new line of care for this common disabling condition.

Introduction

A migraine is defined as a recurrent neurovascular headache disorder and has a high prevalence in the United States. The diverse and complex symptoms of a migraine suggest that, etiologically, it is a neurological disorder at the root with wide-ranging effects on the brain and its neural circuitry.¹ A diagnosis of migraine, as defined by the International Headache Society’s International Classification of Headache Disorders 3 Criteria (ICHD-3), requires all of the following diagnostic criteria to be met: recurrent headaches with at least five lifetime incidents, untreated or unsuccessfully treated headache duration of 4 to 72 hours, and at least two of the following pain characteristics: unilateral, pulsating, moderate or severe intensity, or aggravated by routine physical activity. Migraine symptoms are associated with nausea, photophobia, or phonophobia.² Migraines may also be accompanied by aura, postdrome, or a complete resolution of symptoms. Aura is defined as fully reversible visual, sensory, or other central nervous system symptoms that typically develop gradually and are usually followed by headache and other classically associated migraine symptoms. Aura may also be associated with additional transient focal neurological signs.

Migraines are typically classified based on the presence or absence of an aura. They may also be categorized in accordance with associated (non-neurological and non-headache) symptoms, for example, the bouts of emesis or abdominal discomfort that may be seen with cyclic vomiting syndrome or abdominal migraine. Along the spectrum of migraine disorders are episodic and chronic migraines. Episodic migraine is characterized by a migraine frequency of 0 to 14 headache days per month, while chronic migraines are associated with a frequency of 15 or more headache days per month.³ Individuals with episodic migraines may progress to chronic migraines, which are associated with a greater overall disease burden.⁴ Additionally, symptom resolution is often associated with profound fatigue, having difficulty concentrating, and neck stiffness for a period of up to 48 hours.²

This report is a comprehensive review of the current literature surrounding the efficacy and safety of the drug Lasmiditan, a novel agent with serotonin receptor agonist activity, for the treatment of acute migraine episodes with or without aura. In this review, we provide an update on the epidemiology, pathogenesis, diagnosis, and current treatment of migraine, and summarize the evidence for lasmiditan as a prospective treatment for migraine.

Migraines

Epidemiology

In the Global Burden of Disease (GBD) study from 2016, researchers found that almost three billion individuals worldwide were estimated to suffer from migraines or tension-type headaches. Among 328 diseases and injuries surveyed in this study, migraines and tension-type headaches are the 6th most prevalent globally. Migraines are a very disabling disorder with marked detrimental impacts on individuals, their families, and society as a whole. An analysis of GBD data estimated that migraine and migraine-related illness caused 45.1 million years lived with disability (YLDs), a population-level measure of the relative severity of the disabling consequences from migraine episodes. This severity indicates that migraines are among the seven most disabling disorders worldwide among all diseases surveyed, making it responsible for 2.9% of all years of life lost to disability.⁵ Migraine prevalence also varies substantially by gender and by age. Globally, women experience migraines three times more often than men.⁶ Migraines typically start during puberty, peaking in incidence around 35–45 years of age, and declining in frequency past the age of 60.⁶

Prior to puberty, migraines are more common in boys than in girls. As adolescence approaches, however, the incidence and prevalence of migraines increase far more rapidly in girls than in boys.² For the American patient cohort specifically, migraines occur in about 12% of the US population, and prevalence varies markedly both by gender and by age in the United States.⁷ The American Migraine Prevalence and Prevention (AMPP) study found that there is a higher prevalence of episodic migraine in women than in men, affecting 17.4% of women and 5.7% of men in the US each year. 0.91% of those experiencing episodic migraines in the AMPP study met the criteria for chronic migraines, of which there was also a markedly greater prevalence in women than men (1.29% of women, 0.48% of men). The adjusted women to men prevalence ratios for migraine ranges from 1.5 to 1 for those 12 to 17 years old to 3.25 to 1 for those 18 to 29 years old.

Risk Factors

Migraines follow a variable course for each affected individual. Significant research has been conducted regarding the risk factors that may lead to episodic migraines and their potential for progression to chronic (transformative) migraines. In turn, many strategies to prevent or treat migraine progression have been shaped by a better understanding of core risk factors, including the patient’s sex, socioeconomic status, head injury, attack frequency, central sensitization, body mass index (and presence or absence of obesity), medication overuse, stressful life events, and snoring.⁸ While the vast majority of migraines do not progress to a chronic status, it is important to identify the factors that contribute to this development when it does manifest, in order to help guide better interventions. Migraine progression considerations can be divided into both modifiable and non-modifiable risk factors.

Non-modifiable risk factors are defined simply as parameters that are inborn, or that a patient cannot otherwise change through well-defined, straightforward behavioral modifications. They consist of gender, age, and socioeconomic status (SES), of which the most important association is gender. It has been consistently demonstrated that women experience chronic migraines more often than men, especially during reproductive years. While the underlying cause of this finding can be multifactorial, one possible explanation involves differences in sex hormones. Variations in levels of circulating estrogen among men, pregnant women, and non-pregnant women, and their differential impacts on the brain and body homeostasis, are thought to be instrumental in contributing to migraine onset and progression.⁹ Drops in estrogen levels during the luteal phase of the menstrual cycle, for instance, have been shown to trigger migraines by increasing blood vessel permeability as well as quantities of circulating prostaglandins; the etiologic role of this hormonal fluctuation is supported by the observation that migraine prevalence decreases after menopause.⁹ Recent studies have likewise indicated that genetic differences between genders may play a role in migraine incidence, and migraine susceptibility loci have been identified on both the short and long arms of the X-chromosome. Genetic polymorphisms of the 5-HTT gene in females, and the higher likelihood of their presence (and potential dosage effects) due to the presence of two X-chromosomes in girls and women, may also have an effect on migraine progression.¹⁰ Given these data, some benefit may also be obtained from the use of oral contraceptives in women of reproductive age.

Age is also a significant risk factor; the nature and frequency of migraine symptoms vary across an affected person’s lifespan, and migraine prevalence shows a non-linear variation in accordance with patient age. Prevalence for patients is highest between the ages of 35 and 45 years old.¹¹ with decreases in prevalence for males starting in the 30s, and for females in the late 40s.¹¹ The basis for these age-related differences is multifactorial but may be related to hormone levels and varying life stressors.⁸ Migraine levels also vary drastically depending on SES. Population studies in the United States have found that migraine prevalence is inversely related to SES, and households with lower income consistently demonstrate higher migraine prevalence.⁴ A stressful lifestyle and poor diet, seen in lower-income households, may contribute to this inverse relationship.

The potential for migraine progression can also be attributed to several well-studied modifiable risk factors, defined as etiologic variables that can be readily addressed through defined medical or behavioral interventions. Increased attack frequency, amenable to medical treatments, is one such significant risk factor for the development of chronic migraine. Individuals that do not undergo early interventions for acute migraine, whether of a pharmacological or non-pharmacological nature, are more likely to progress to chronic headaches.¹² This is thought to be secondary to pain sensitization and prostaglandin production in the brain, which in turn can lead to increased attack frequency.¹³ Obesity, another modifiable risk factor, has serious health consequences across numerous bodily systems and also appears to correlate significantly with migraine progression. Obese individuals with a BMI >= 30 were found to have a fivefold greater risk of developing chronic migraines than those with a normal BMI.¹²

The development of chronic migraine is also associated with the overuse of acute medications such as triptans, and moreso barbituates and opioids.¹⁴ It has been demonstrated that patients who use these medications on a daily basis for the treatment of various medical conditions, like rheumatoid arthritis, develop chronic migraines at higher than expected rates.^12,14 In the general population, the prevalence of chronic headaches with regular analgesic use is about 2%.¹⁵ However, despite increased levels of migraine among acute medication users, it is not fully clear whether medication overuse is a consequence or a cause of chronic migraine, as patients who withdraw from their medications often still develop this condition.¹³ Caffeine also has a complicated relationship with migraine incidence. Although caffeine is often associated with providing headache relief, high caffeine consumption is nonetheless correlated with chronic headache as well as snoring and sleep apnea; importantly, caffeine is a part of many over-the-counter (OTC) medications sold for headache relief.¹⁴

Pathophysiology

The pathophysiology of migraines is still not well understood. The proposed mechanisms surrounding the onset of migraine headaches must be considered in reference to neuroanatomical structures encased in the cranium. The cerebral vasculature is innervated by trigeminal nerve fibers (the fifth cranial nerve), which originate from the trigeminal ganglion. Upon stimulation of this structure, there is a subsequent release of inflammatory mediators such as substance P and calcitonin gene-related peptide (CGRP), both associated with the nociceptive neurotransmission of pain sensations.¹⁶ Activation of the associated nerve fibers, in turn, can elicit a pain response in association with impacts upon the vascular structures in the dura mater surrounding the brain. The trigeminovascular system (TVS), a structure housing the trigeminal ganglia and divisions of the trigeminal nerve, in conjunction with its communication with afferent sensory receptors in the blood vessels of meninges, is thought to play a particularly significant role in migraine pathogenesis.¹⁷

Migraine episodes are divided into multiple phases, with varying symptoms and mechanisms present in each phase. The first phase, the prodrome, can occur with vague symptoms up to 24 hours prior to the migraine attack. Based on prodromal symptoms such as fatigue, hunger, and elevated sensitivity of sensory apparatus, it is thought that there is the potential involvement of the hypothalamus, brainstem, cortex, and limbic system.¹ An imbalance between sympathetic and parasympathetic (PSNS) signaling involved in body homeostasis is believed to at least partially mediate these organs’ involvement in the prodromal phase.¹ The hypothalamus controls the firing of PSNS neurons in the superior solitary nucleus (SSN). The SSN, in turn, can stimulate the release of vasoactive peptides from the sphenopalatine ganglion (SPG), leading to increased permeability and dilation of intracranial blood vessels, as well as stimulate trigeminal nerve fibers.¹ The next phase, migraine aura, is thought to result from a neurophysiological phenomenon called cortical spreading depression (CSD), which is a slow wave of depolarization followed by hyperpolarization in cortical neurons.^18,19 Ion influx and efflux across cortical membranes then upregulates genes involved in inflammation such as NF-kb, which subsequently causes the introduction of proinflammatory molecules such as CGRP into the meninges, triggering nociceptive pain fibers.²⁰ The sensitization and activation of meningeal and TVS pain fibers is thought to be the proximate cause of the headache phase of migraine.²¹ There is some evidence that migraine disorders may have a heritable component, as indicated by the prevalence of migraine patients with first degree relatives and through multiple twin studies.¹³

Diagnosis and Clinical Presentation

With migraine being one of the most common headache conditions motivating patients to seek medical assistance, it is important to recognize the clinical patterns and presentation of patients as a basis for initiating care. Three predictive characteristics seen in patients presenting with migraine are disability, nausea, and photophobia.²² A third of migraine patients present with focal neurological symptoms, termed aura, prior to headache onset.²³ Depending on the migraine type, different diagnostic criteria apply.

Migraine without aura is defined as a recurrent headache disorder with attacks lasting 4–72 hours. The headache must exhibit two of the four following criteria: unilateral location, pulsating quality, moderate to severe pain intensity, or aggravation by physical activity.²³ Additionally, during the headache, the patient must experience nausea/vomiting or photophobia and phonophobia. In order to be diagnosed with migraine without aura, a patient must have had, at minimum, five attacks that meet the aforementioned criteria. In children and adolescents, headache is more often bilateral than unilateral.

Migraine with aura is a headache that is preceded by neurological symptoms in two or more of the following central nervous system fields: visual, sensory, speech/language, motor, brainstem, or retinal. Three or more of the following six characteristics must also be noted: one aura symptom spread gradually over a period greater than or equal to 5 minutes, two or more aura symptoms in succession, each aura symptom lasting 5–60 minutes, at least one unilateral aura symptom, one positive aura symptom, or headache following aura within 60 minutes of aura onset. Additionally, patient history is important as certain subsets of migraine with aura, such as Familial Hemiplegic Migraine (FHM), have a high prevalence among first or second-degree relatives with the disease.²³

For migraines to be considered chronic, they need to occur for more than 15 days per month, over a span of greater than three months, with headaches on at least 8 of those days displaying migraine symptoms, result in a diagnosis of chronic migraine. These can occur with or without aura.²³

Traditional Migraine Treatment

Treatment of migraines is divided into acute (abortive) and preventative.²⁴ Chronic migraine is defined as at least 15 days of migraines per month, for at least three months.²⁵ Patients are indicated for preventative therapy if they experience repeated migraine episodes that cannot be controlled with acute therapy, have contraindications to acute therapy, experience headache at least once a week, or have other specific circumstances that would warrant the use of preventative treatment.²⁴ Patients taking prophylactic therapy still experience episodic migraine attacks and may also require abortive treatment, which aims to provide immediate migraine relief.^24,25 Preventative therapy aims at reducing the frequency of migraine attacks.²⁶ Current options for preventative and chronic therapy draw from a variety of medications, such as certain beta-blockers, calcium channel blockers, anticonvulsants, and tricyclic antidepressants, as well as newer therapies such as occipital nerve stimulation and botulinum type A toxin injections.^24,27 Options for acute treatment include non-steroidal anti-inflammatory drugs (NSAIDs) as well as abortive therapies such as triptans, ergots, and gepants.²⁶ A large portion of the medications prescribed for both acute and preventative treatment of migraine are drugs originally created for other uses; more recently, there has been progress made designing therapeutic options specifically for migraine.²⁸

OTC Anagesics, NSAIDs, 5HT Agonists

NSAIDs inhibit the synthesis of prostaglandins responsible for several inflammatory and nociceptive mechanisms.²⁹ NSAIDs, in particular naproxen, act on centrally-located pain, in contrast to sumatriptan, which acts primarily via peripheral mechanisms.²⁹

Triptans are agonists of the 5-hydroxytryptamine receptor.²⁶ They are most selective to 5-HT_1B/1D receptors.³⁰ Triptans induce vasoconstriction of cerebral blood vessels and reduce pain transmission in trigeminal neurons through the reduction of CGRP and neuropeptide signaling.^26,31 They are considered first-line therapy for acute migraine.³¹ Though triptans are the most commonly prescribed abortive migraine therapy, they carry significant potential cardiovascular risks due to the vasoconstriction actions of the 5-HT_1B receptor. These medications are are contraindicated in patients with coronary artery disease, peripheral vascular disease, cerebrovascular diseae and uncontrolled hypertension because of their vasoconstrictive properties. These patients represent a large proportion of the adult population.^31,32

Triptans and NSAIDs, when used together, have been shown to have a synergistic relationship and may provide greater pain relief in combination than alone.³³ However, at least one study has questioned this relationship and showed that sumatriptan plus naproxen provided superior pain relief than naproxen alone, yet the combination was not better than sumatriptan alone.²⁹

Ditans are newer agents that can be prescribed for acute migraine attacks in patients for whom triptans may be ineffective or contraindicated.³⁴ They are agonists selective to the 5-HT_1F receptor and thus avoid the vasoconstriction common to triptans.³⁰

Timing, Limitations, Contra-Indications for Acute Therapy

There are several barriers to the treatment of acute migraine with the currently available therapeutic options; these include contraindications, undesirable side effects, and lack of efficacy.²⁸ Triptans are some of the most commonly prescribed medications for acute migraine, yet they are contraindicated in patients with cerebrovascular or cardiovascular disease, as well as in patients also taking SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin-norepinephrine reuptake inhibitors) that are commonly prescribed for depression, which is often a comorbid diagnosis with migraine.^28,35–37 Additionally, the use of triptans in episodic migraine has been associated with an increased likelihood of developing chronic migraine as well as medication overuse headache.³³

Adherence Issues with Chronic Preventative Treatment

Medication adherence for the treatment of chronic migraine remains relatively low.²⁴ Because many of the medications currently in use for this condition were not originally created for migraine treatment, patients often experience issues with undesirable side effects that can contribute to discontinuation of treatment, such as bradycardia, fatigue, cognitive issues, weight gain, rebound headaches and others. A majority of patients will discontinue oral preventative treatment within a year of initiation.²⁴ It is likely that daily administration of current preventative treatments presents a barrier to treatment adherence; new therapies that can be administered at greater intervals, such as monthly or every three months, might be beneficial to patients for whom this may be an issue.³⁸

Onabotulinumtoxin A

Onabotulinumtoxin A (OBT-A) is a neurotoxin produced by Clostridium botulinum, an anaerobic bacteria.³⁹ There are several strains of this toxin, which acts as a metalloprotease and inhibits the release of acetylcholine imperative for transmission at neuromuscular synapses.³⁹ Disruption of this process results in flaccid paralysis in the head and neck area.³⁹ OTB-A is given as an intramuscular injection into cervical and cranial muscles every three months. It is approved for the treatment of chronic migraine in the US and UK.^26,39,40 It acts by reducing the neurotransmission of trigeminal pain neurons and reducing peripheral pain signals that are sent to the CNS.^26,40 There is emerging evidence that OBT-A injections may be an effective prophylactic treatment for chronic migraines by reducing the sensitization of trigeminal pain networks and reducing pericranial muscle tenderness that contributes to migraine symptoms.⁴⁰ OBT-A has not been found to induce any serious adverse events; of the adverse events that were reported, most were pain at the injection site and muscle tenderness, both of which resolved spontaneously.⁴⁰

Topiramate

Topiramate, first approved for the treatment of epilepsy, blocks voltage-dependent sodium and calcium channels, enhances inhibitory GABA effects, and minimizes excitatory actions of glutamate.⁴¹ Unlike other anti-epileptic medications used for migraine, topiramate also acts on kainite and AMPA receptors; its wide array of action may contribute to its superior efficacy in migraine therapy.⁴² It has been found to reduce the frequency of chronic migraines and showed efficacy when used as preventative therapy. It is considered to be safe and well-tolerated , and associated adverse events, most commonly fatigue, nausea, and paresthesia, seem to wane after initiation of treatment. Rarer side effects include anorexia and weight loss, cognitive issues and a potential risk for suicide. In patients for whom beta-blockers are contraindicated, topiramate may be a preferred option.⁴¹ Additionally, the use of topiramate has contributed to weight loss, most noticeably in patients with higher starting BMI; in patients for whom obesity is a concern, topiramate may be a better choice than valproic acid, beta and calcium channel blockers, therapies that have been associated with weight gain.⁴¹

CGRP Modulation, Gepants, CGRP Monoclonal Antibodies

CGRP receptor antagonists, known as gepants, have been studied for use in acute migraine and may confer an advantage in patients with cardiovascular, cerebrovascular, peripheral vascular disease as this class has fewer hemodynamic side effects and less vasoconstriction than triptans.^24,32,43 Elevated levels of CGRP have been found in cranial circulation during an acute migraine and are associated with meningeal vasodilation and inflammation that contributes to pain.^29,43 thus, blockage of CGRP receptors with CGRP receptor antagonists has been shown to reduce activation of pain pathways.^26,43 Currently, the study of gepants has been mostly limited to use as abortive therapy.³² Their efficacy does not appear to surpass that of triptans, and they have been limited by adverse events such as hepatotoxicity.⁴⁴ Fremanezumab is a humanized monoclonal CGRP antibody that has recently been approved for prophylactic, preventative treatment of migraine in adults.²⁶ It can be given as a subcutaneous injection monthly (225 mg) or every three months (675 mg). Adverse events were largely limited to injection site reactions.²⁶

Lasmiditan

Lasmiditan (COL-144/LY573144), trade name Reyvow, belongs to the novel ditan class of agonists highly selective to the 5-HT_1F receptor.^30,31 It is a centrally and peripherally acting 5-HT_1F receptor agonist that is used to treat acute migraine.³⁷ Lasmiditan is administered orally in 50 mg and 100 mg tablets. Recommended doses are 50, 100, or 200 mg taken once every 24 hours with or without food, and it is recommended that users refrain from driving or operating machinery within 8 hours of drug administration. Lasmiditan should ideally be stored at 20–25°C. It qualifies as a schedule 5 federal controlled substance with the potential for abuse.⁴⁵

Lasmiditan is approved by the US FDA for acute migraine with or without aura and is effective in reducing headache pain and symptoms such as photophobia, phonophobia, and nausea.^45,46 Its safety in pregnant and nursing women and in children is not yet known.⁴⁵

Mechanism of Action

Lasmiditan acts on 5-HT_1F receptors are found in trigeminal ganglia neurons.⁴⁶ When bound, the 5-HT_1F receptor is involved in G-protein signaling that leads to inhibition of CGRP and glutamate release.³¹ Both CGRP and glutamate are involved in peripheral and central pain signaling. Centrally, CGRP contributes to the sensitization of nerve fibers. Peripherally, it contributes to the dilation of meningeal arteries and initiation of additional pain signaling mechanisms, some of which involve glutamate and can lead to further propagation of CGRP release. By acting as an agonist at 5-HT_1F receptors, lasmiditan acts to inhibit these processes that contribute to nociceptive sensitization.³¹ Lasmiditan appears to exert its most prominent effects at peripheral trigeminal nerve endings, where it hyperpolarizes nerve endings and reduces the release of CGRP to provide pain relief.^25,31 Its main mechanism of action appears to be inhibition of dural and CGRP-induced nociceptive and inflammatory mechanisms.²⁵ However, there is also research to suggest that 5-HT_1F receptors play a role in mitochondrial biogenesis. Mitochondrial dysfunction has been implicated in the pathogenesis of migraine, and enhancement and normalization of mitochondrial function via 5-HT_1F receptor agonists such as lasmiditan is another possible mechanism of action that could contribute to its therapeutic efficacy.³¹

Because it is selective to 5-HT_1F receptors, lasmiditan has no action on 5-HT_1B/1D receptors located on cerebral blood vessels and offers a therapeutic option that does not involve vasoconstrictive mechanisms.⁴⁶ Studies using saphenous veins of rabbits and coronary and carotid veins of dogs as models for human coronary arteries have repeatedly shown that lasmiditan does not produce the same vasoconstriction effects that are characteristic of triptans.²⁵ Lasmiditan appears to reduce inflammatory neurogenic processes, at least partly by preventing the leakage of plasma proteins from the dura that contributes to this response.²⁵ In addition to reducing pain from headache, lasmiditan was effective in minimizing commonly associated symptoms such as phonophobia, photophobia, and nausea.³⁷ It is less likely to produce other side effects common to triptans, such as chest, neck, and/or throat tightness, and, therefore may be a useful option to patients who experience these undesired phenomena.²⁵

Pharmacology

Lasmiditan exhibits highly selective binding to the 5-HT_1F receptor; its affinity to this subtype is over 400 times greater than to the 5-HT_1B and 5-HT_1D receptors, where its action is essentially undetectable. Its lack of affinity to these receptors is responsible for its absence of vasoconstrictive effects, as the 5-HT_1F receptor is not present on cerebral blood vessels.^31,37 Due to its highly lipophilic properties, lasmiditan has demonstrated the ability to cross the blood-brain-barrier and acts on 5-HT_1F receptors on trigeminal neurons within the CNS as well as those located more peripherally.^31,37 It is structurally different from triptans, which are agonists to 5-HT_1B/1D receptors because it lacks the indole core that is characteristic of the triptan structure.³⁷

Lasmiditan exhibits fast oral absorption with an oral bioavailability of around 40%. It reaches a high degree of binding to plasma proteins of up to 60%, and its half-life is 5.7 hours.^45,47 Increasing doses show a linear relationship between dose and headache relief response, and oral doses of 400 mg were effective in reducing headache in as little as 30 minutes.³⁷ There was a statistically significant advantage to all studied doses of lasmiditan, starting at 50 mg, compared to placebo in reducing headache pain at 2 hours.^25,37 Lasmiditan is metabolized through both hepatic and extra-hepatic mechanisms.⁴⁵ It is not significantly subject to metabolism via CYP-enzymes, reducing the possibility of interaction with CYP-metabolized drugs.⁴⁵

Side Effects/Adverse Events

The most common adverse events reported with the use of lasmiditan tended to be CNS-related, e.g., dizziness, nausea, fatigue, and paresthesia, and appear to be dose-dependent.^44,46 Dizziness is the most frequently cited AE with lasmiditan usage.³⁵ Vertigo, somnolence, and reduced alertness have also been reported.⁴⁸ Common side effects were most likely to occur within one hour of dosing, and most had durations not more than five hours.³⁵ It is hypothesized that lasmiditan may act on 5-HT_1F receptors located in the cerebellum or lateral vestibular nucleus leading to the vestibular side effects that have been reported, and its high lipophilicity likely accounts for the CNS-related side effects.^37,46 Concerns of more serious side effects include the possibility of serotonin syndrome, a condition that can result from concomitant use with SSRI or SNRI medications; however, review of the SAMURAI and SPARTAN phase 3 double-blind studies did not reveal any cases that met criteria for being serious or severe.^35,45 Additionally, no serious adverse events related to cardiovascular vasoconstriction or hepatotoxicity have been documented to date.³⁵ Changes to ECG and vital signs and/or evidence of cardiac ischemia have not been demonstrated in clinical trials of lasmiditan.^47,49 It has not been found to prolong the QT interval or induce any cardiac arrhythmia.³⁷ Of over three thousand patients receiving lasmiditan, only seven cases of hypersensitivity, presenting as mild to moderate rash, were reported in the SAMURAI and SPARTAN trials, and there were no reported anaphylactic events.³⁵

Clinical evidence for the use of Lasmiditan in Migraine

Efficacy

There were four Phase I studies that investigated the efficacy of oral lasmiditan formulations and one that investigated the intravenous formulation. There is no published data available from the intravenous study in 2003, however, a larger Phase II study was conducted in 2007 to assess efficacy and dose ranges and is described later in this text. Two of the oral Phase I trials also have limited data available but showed that the oral formulations reached plasma levels previously shown to be efficacious with intravenous administration without severe adverse events.^50,51 These studies also demonstrated an oral dose of lasmiditan 170 mg and above was as effective as sumatriptan for acute migraine treatment.^50,52

The first Phase II trial, COL-MIG 201 (ClinicalTrials.gov identifier: NCT00384774), tested the efficacy of various doses (2.5 to 45 mg) of intravenous lasmiditan.⁵³ This was a randomized, double-blind, multicenter, proof-of-concept, placebo-controlled trial. A good response was defined as a change in headache severity from moderate or severe to mild or no headache (patient-reported at 2 hours following administration). There was a better response (54.2%–75%) for patients receiving at least 10 mg lasmiditan over placebo (45.2%). Additionally, there was a significant linear association between dosage and response rates (p = 0.0126).^50,53,54 This study was terminated early when the 20 mg dose achieved predefined efficacy.⁵⁴ The COL-MIG 202 (ClinicalTrials.gov identifier: NCT00883051) Phase II trial assessed the oral formulation’s efficacy and safety.⁴⁹ This was a double-blind, multicenter, dose-ranging (50, 100, 200, 400 mg), parallel-group study with the primary endpoint of a moderate or severe migraine becoming mild or disappearing 2 hours after administration. The study found that as early as 30 minutes after a 400 mg dose, headache severity was significantly reduced compared to placebo. At 1 hour, all doses besides 50 mg were superior to placebo. From 1.5 to 4 hours, every dose was superior to placebo, and a dose-dependent headache response was observed (p < 0.0001).^49,50,54 Similarly, there was a statistically significant difference between every dose and placebo for “time to meaningful pain relief.” There was also a dose-related reduction in rescue-drug usage.⁴⁹ The 400 mg group had a higher therapeutic gain (38%) than that of intravenous 20 mg.⁵⁴ Significantly more patients from the 400 mg group than the 50 mg group reported a headache response at 2 hours. As for non-headache symptoms, photophobia and phonophobia saw the greatest improvements after 2 hours with the 100 mg and 400 mg doses. Overall, the primary endpoint of this trial was met. Secondary endpoints (headache intensity, pain freedom, associated symptoms, and the patient’s global impression) also supported the beneficial effects of lasmiditan. There were similar rates of headache recurrence (50–63%) for all groups.⁴⁹

The first Phase III trial of lasmiditan, COL-MIG 301 (SAMURAI, ClinicalTrials.gov identifier: NCT02439320), was a double-blind, multicenter, randomized, placebo-controlled study.⁵⁵ In this study, more patients who received lasmiditan in doses of 100 mg (28.2%, p < 0.001) and 200 mg (32.2%, p < 0.001) were headache-free 2 hours after drug ingestion compared with patients that received placebo (15.3%). 100 mg was superior to placebo (p < 0.05) after 1.5 hours, and 200 mg was superior after 1 hour. More patients who received lasmiditan also reported freedom from their most bothersome symptom 2-hours following a dose of 100 mg (40.9%, p < 0.001) or 200 mg (40.7, p < 0.001), compared with patients that received placebo (29.5%); a significant relief was appreciated in both groups as early as 30 minutes following a dose of lasmiditan (p < 0.05). Both groups also showed significant improvements in headache relief, photophobia, phonophobia, global impression of change, and disability level ratings. Patients receiving lasmiditan were also less to use a second dose of the study drug for rescue or recurrence than patients receiving placebo (31.9–39% vs. 59.9%).⁵⁵ COL-MIG 303 (SPARTAN, ClinicalTrials.gov identifier: NCT02605174), another double-blind, randomized, placebo-controlled Phase III trial, demonstrated that participants were significantly more likely to be headache-free 2-hours after lasmiditan ingestion, regardless of dose, when compared with placebo.⁵⁶ This study confirmed the efficacy and tolerability findings of the SAMURAI trial.⁵⁵ There was also a dose-related response in the percentage of patients with headache relief from 0.5–2 hours. “Global impression of change” and disability ratings were also dose-related with 200 mg-treated patients reporting the most benefit. Furthermore, this study showed that all doses of lasmiditan were more effective than placebo in achieving freedom from the most bothersome symptom. Patients had a faster response to higher doses (100 mg and 200 mg) and reported resolution of their most bothersome symptoms as early as 30 minutes following a dose; patients were headache-free as early as 1 hour after a drug dose. Lasmiditan’s beneficial effects on migraines were also supported by reductions in symptoms of photophobia and phonophobia, but not nausea. Additionally, patients in the lasmiditan group were less likely to use a second dose of the study drug than those in the placebo group.⁵⁶ Furthermore, as many patients are concurrently taking preventative migraine medications in addition to acute treatments, an analysis was done of these Phase III trials to determine if the effects of lasmiditan differ among those who are already taking preventative medication. This analysis showed that for patients already using preventative medications, lasmiditan was more effective than a placebo for treating acute migraine attacks, while efficacy and safety measures of lasmiditan were similar for patients using and not using preventative medications.⁵⁷ Another pooled analysis looked at patients in these two Phase III trials with cardiovascular risk factors. This analysis found the proportion of patients free of their most bothersome symptom and headache pain-free at 2 hours was similar between groups with 0–1 cardiovascular risk factors and those with ⩾ two cardiovascular risk factors, suggesting that cardiovascular risk factors do not affect the efficacy of lasmiditan.⁵⁸ COL-MIG 305 (GLADIATOR, ClinicalTrials.gov identifier: NCT02565186), a prospective, randomized, open-label Phase III trial enrolled patients who had completed SAMURAI or SPARTAN.^59,60 This study demonstrated results consistent with these previous Phase III trials, showing a benefit of lasmiditan for reducing the most bothersome symptoms of migraine attacks and headache pain.^59,61 Improvements from baseline migraine-related disability were demonstrated at 3, 6, 9, and 12 months for both dose groups (100 and 200 mg). There were also statistically significant improvements seen in work/school absenteeism and presenteeism (continuing to work with reduced effectiveness), mean headache pain intensity, and monthly headache days. These findings suggest that lasmiditan use may reduce the complete loss of workdays and impaired functioning during work. Additionally, there were similar responses among patients completing all visits versus those who dropped out early, suggesting that improvements were not a result of selective attrition.⁶⁰

A systematic review and meta-analysis found that patients treated with lasmiditan had a significant risk ratio (RR) for achieving pain freedom and pain relief at 2 hours compared with placebo (pain freedom: RR 1.71, p < 0.00001; pain relief: RR 1.40, p < 0.00001).⁵⁹ Reports of pain freedom and pain relief were also dose-related across groups (pain freedom: <50 mg RR 1.19, 50 mg RR 1.37, 100 mg RR 1.63, 200 mg RR 1.96, 400 mg RR 3.77; pain relief: <50 mg RR 1.23, 50 mg RR 1.27, 100 mg RR 1.41, 200 mg RR 1.42, 400 mg RR 2.81). Overall global impression favored lasmiditan groups over placebo (RR 1.55, p < 0.00001) and was also dose-related. Studies were evaluated for no/mild disability at 2 hours, which also favored lasmiditan-treated groups over placebo (RR 1.15, p < 0.00001). Overall, this systematic review and meta-analysis suggests that the use of lasmiditan (in single daily doses of 50 mg to 400 mg) in patients with disabling migraine had significantly greater pain freedom and relief at 2 hours.⁵⁹

Safety, Adverse Events

Phase I studies found no significant QT prolongation, pro-arrhythmic effects, or serious adverse events. However, Phase I trials did show reports of somnolence, dizziness, and paresthesia.⁵⁰

In the intravenous Phase II study, COL-MIG 201, adverse events were reported by 65% of patients who received lasmiditan and 43% of patients who received placebo and were generally mild in severity.^53,54 The most common adverse events were dizziness, paresthesia, and sensations of heaviness.⁵³ The oral Phase II study, COL-MIG 202, showed that lasmiditan was generally well tolerated without any triptan-like events, deaths, or significant changes in any safety parameters (vital signs, ECGs, laboratory assessments). However, this study did show a significant rate of CNS-related adverse events such as somnolence, dizziness, fatigue, vertigo, and paresthesia, which increased at an increasing dosage, ranging from 65%–86% of participants.^49,50,54 Most of the events were rated mild to moderate in intensity, with a range of 20%–44% of participants reporting a severe adverse event in comparison with 6% of placebo participants.^49,54 However, the majority of adverse events in the 100 and 400 mg groups were rated moderate or severe, raising questions about the dosing limits of lasmiditan.⁵⁴ The most commonly reported serious adverse event was dizziness.⁴⁹ These unwanted CNS effects are thought to be due to lasmiditan’s lipophilic structure allowing easy permeability through the blood-brain barrier and the 5-HT_1F receptors located in the lateral vestibular nucleus, cerebellum, and the temporoparietal cortex.^49,50,59,62 However, the typical adverse events associated with triptans (vasoconstriction, chest pain, neck pain, heaviness, tightness, etc.) occurred at a similar frequency for lasmiditan and placebo, This, combined with the neural site of action may be clinically beneficial for patients who are unable to take triptans or are not responsive to them.⁴⁹

SAMURAI reproduced findings of CNS-related adverse events (dizziness, somnolence, lethargy, nausea, fatigue, and paresthesia) that were mostly mild to moderate in intensity.⁵⁵ The incidence of cardiovascular-related adverse events was low, with the only events considered possibly or reasonably related to lasmiditan being palpitations and bradycardia, which occurred in a combined 1% of patients. Additionally, this study indicated no clinically significant effects of lasmiditan on blood chemistry, vital signs, hematology, urinalysis, ECGs, or physical examination compared to baseline.⁵⁵ SPARTAN had similar findings, with the majority of side effects associated with the CNS, being mild to moderate in severity, in addition to being dose-related. In this study, all cardiovascular adverse events (palpitations and tachycardia) were considered possibly or reasonably related to lasmiditan, although the rate of these events was low (0.5%).⁵⁶ Furthermore, a study investigated potential differences in the frequency of cardiovascular adverse events for patients with and without cardiovascular risk in the Phase III trials. This study found no statistical difference between lasmiditan and placebo, suggesting that lasmiditan can be considered for treating migraine in patients with cardiovascular risk factors.⁵⁸ Overall, the safety profile of the Phase III trials was consistent with the Phase II trials.^49,53,55,56The trial investigating potential differences in Phase III patients concurrently using preventative migraine medications found no significant differences in the rate or type of adverse events.⁵⁷

Despite the common adverse events being similar across the Phase II and III trials, there were differences in terms of methods and findings that should be noted.⁶³ An analysis was performed highlighting differences between the oral Phase II trial, COL-MIG 201,.⁴⁹ and the first two Phase III trials, SAMURAI and SPARTAN.^55,56 First, there was a higher incidence of at least one adverse event occurring in Phase II (72–86%) than in Phase III to (36–43%). Additionally, there was a higher incidence of “severe” adverse events in Phase II (26%) than Phase III (2%). Potential reasons for these differences include: the Phase II consent form was more descriptive of adverse events, Phase II participants recorded adverse events in a diary that included warnings about drowsiness and dizziness, the German word “schwindel” being variably translated to English as “vertigo” or “dizziness” in Phase II, and participants with a history of vertigo and/or dizziness being excluded from Phase III. Furthermore, Phase II patients had more severe migraines, lower number of average migraines per month, a lower BMI, and higher rates of nausea; all factors that could have influence the incidence and severity of adverse events.^49,55,56,63

The meta-analysis found a RR of 2.77 (95% confidence interval 2.53–3.03) for adverse events after the first dose of lasmiditan, which were dose-related. Again, the most frequently reported adverse events were associated with the CNS, including dizziness (RR 5.81), fatigue (RR 5.38), somnolence (2.82), paresthesia (RR 4.48), and nausea (RR 2.58). All studies included in the meta-analysis reported CNS-related adverse events. However, it is intriguing that the incidence of adverse events decreased over time with no new serious safety events or deaths despite continued treatment with lasmiditan. Additionally, even though the most common adverse events were CNS-related, there were no serious injuries resulting from these adverse events during long-term treatment.⁵⁹

Conclusion

Migraines are a common disabling primary headache and affect about 12% of Americans. They are more prevalent in women than in men and are accompanied by significant disability and healthcare costs. Traditional treatment, including NSAIDs, triptans, and prophylactic treatment, falls short from complete resolution and prevention and carries significant side effects. Because most of the current migraine therapies were not originally intended to treat migraines, the adherence to prophylactic treatment is rather low due to undesirable drug effects.

Accumulation of research has spotlighted the importance of TVS and modulating factors, such as CGRP and Substance P, in the generation and perpetuation of migraines. Research has been aimed at pharmaceuticals that specifically target these pathways, such as CGRP antibodies and receptor agonists (such as gepants), and the new ditans, including Lasmiditan.

Ditans are high specific 5-HT_1F that work both centrally and peripherally and are highly effective for the treatment of acute migraine attacks. Lasmiditan is available in tablets of 50, 100 and 200 mg, and is FDA approved for the treatment of migraine with or without aura. It is also effective in reducing non-headache symptoms, such as nausea, photophobia, and phonophobia. By acting as a receptor agonist, lasmiditan reduces CGRP and glutamate signaling, thus reduces nociceptive sensitization that is important in migraine pathophysiology.

Lasmiditan is the birth child of significant research into the pathophysiology and biophysical mechanisms that are at the root of migraines. As such, it is not a repurposed drug and is better suited to treat migraines directly. It is 400 times more specific to 5-HT_1F receptors than 5-HT_1B and 5-HT_1D, which means it lacks the cardiovascular effects that are often seen with triptans. This makes it not only more tolerable but also safer in a larger population of patients.

Lasmiditan was evaluated in several randomized clinical trials evaluated both the relief and the time to relief achieved by Lasmiditan, and in all cases, it was superior to placebo, as well as in achieving resolution of non-headache symptoms. The SAMURAI trial showed that a 200 mg oral dose of Lasmiditan was superior to placebo in as little as one hour, later shown again by SPARTAN. GLADIATOR also provided evidence to both the overall wellbeing of patients, as well as financial gain in treatment of migraine. These studies and analyses have also shown the superiority of lasmiditan in terms of safety and tolerability.

Unfortunately, no trials are available at the moment comparing lasmiditan to existing medication rather than a placebo. These will be required to truly evaluate its efficacy and superiority to existing treatments. Clinical trials so far have shown a good safety profile for lasmiditan. One significant draw back is sedation, which may limit its daily use in the working population. A specific concern could involve increased risk of suicide that should be monitored closely, considering the known mechanism of 5-HT₁ modulation.

Lasmiditan joins a line of novel anti-migraine therapies that are centered around CGRP antagonism, such as gepants and monoclonal anti-CGRP antibodies. While further research is required to better define patient selection, effective and safe drug combination, and long-term safety of these new therapeutic options, this is without a doubt, a new dawn in the treatment of such a common, disabling condition.

Table 1. Clinical Efficacy and Safety.

Author (Year)		Groups Studied and Intervention		Results and Findings		Conclusions
Ferrari et al. (2010)53		130 patients with moderate-to-severe headaches were randomly assigned to one of five intravenous lasmiditan dose groups (2.5, 10, 20, 30, or 45 mg) or the placebo group.		Better response than placebo was observed in groups receiving 10, 20, 30, and 45 mg of lasmiditan. A significant linear association was found between dose levels and headache response rate, patient global impression at 2 hours, and lack of need for rescue medication. Lasmiditan was generally well tolerated, with the majority of adverse events mild in severity. Adverse events were reported by 65% of subjects receiving lasmiditan (compared with 43% receiving placebo). Common adverse events included dizziness, paresthesia, and sensations of heaviness. The study was terminated when 20 mg group reached predefined efficacy.		Intravenous doses (20 mg and higher) of lasmiditan were effective for the treatment of acute migraine. The drug’s neural, non-vascular mechanism of action could be useful for patients with contraindications for medications with vasoconstrictor activity.
Färkkilä et al. (2012)49		512 patients with migraine with and without aura were randomly assigned to treat a moderate-to-severe attack at home with placebo or 50, 100, 200, or 400 mg oral lasmiditan.		Each lasmiditan dose exhibited significantly improved migraine headache response at 2 hours compared with placebo. All doses besides 50 mg were superior to placebo at 1 hour. 400 mg was superior to placebo as early as 30 minutes. A significant linear association was found between lasmiditan dose and headache response at 2 hours. Most adverse events were characterized as mild-to-moderate in severity. Dizziness, vertigo, paresthesia, fatigue, and somnolence were the most common. Increasing doses increased the frequency of treatment-emergent adverse events. 65%, 72%, 86%, and 84% of patients experienced adverse events with 50, 100, 200, and 400 mg lasmiditan, respectively (compared with 22% of the placebo group). There were no significant changes in safety parameters such as vital signs, ECGs, or laboratory assessments.		Oral lasmiditan was effective and safe for the treatment of acute migraine attacks. Both efficacy and CNS-related adverse events were dose-related. The absence of vasoconstrictor activity combined with a neural site of action could make lasmiditan useful for patients who are unable to take or poorly responsive to triptans.
Kuca et al. (2018)55		1,856 patients with migraine were randomly assigned to treat their next migraine attack with placebo, 100, or 200 mg oral lasmiditan within 4 hours. Patients with cardiovascular risk factors were eligible to participate and made up the majority of participants.		Patients treated with 100 and 200 mg oral lasmiditan were more likely than placebo to be headache pain free at 2 hours and to be free of their most bothersome symptom at 2 hours. Both doses also showed significant improvements in headache relief, photophobia, phonophobia, global impression of change, and disability level ratings. There was a higher incidence of adverse events in both lasmiditan groups compared with placebo. Most of these were related to the CNS and were considered mild-to-moderate in severity. There were no clinically significant effects of lasmiditan on blood chemistry, vital signs, hematology, urinalysis, ECGs, or physical examination compared to baseline. The incidence of cardiovascular-related adverse events was low. Overall, the safety profile was consistent with the Phase II trials.		100 mg and 200 mg oral lasmiditan was effective and relatively well tolerated for the acute treatment of migraine attacks, including among those with cardiovascular risk factors.
Goadsby et al. (2019)56		3,005 patients with migraine with and without aura were randomly assigned to treat their next migraine attack with placebo, 50, 100, or 200 mg oral lasmiditan within 4 hours. Patients with cardiovascular risk factors were eligible to participate and made up the majority of participants.		Patients treated with 50, 100 and 200 mg oral lasmiditan were more likely than placebo to be headache pain free at 2 hours and to be free of their most bothersome symptom at 2 hours. Adverse events were reported in 25.4%, 36.1%, and 39.0% of patients on 50, 100, and 200 mg lasmiditan compared to 11.6% of patients on placebo. Most of these adverse events were CNS-related and were mild-to-moderate in intensity. The incidence of cardiovascular-related adverse events was low. Overall, the efficacy and safety profiles were consistent with the previous Phase III study (Kuca et al.).		50, 100, and 200 mg oral lasmiditan was effective and relatively well tolerated for the acute treatment of migraine attacks, including those with cardiovascular risk factors. These results were consistent with the previous Phase III trial (Kuca et al.).
Lipton et al. (2020)60 Brandes et al. (2019)61		1,978 patients who previously completed one of the previous Phase III studies were randomly assigned to take 100 or 200 mg oral lasmiditan as needed for migraine attacks and followed for a median of 288 days.		Migraine Disability Assessment Scale (MIDAS) scores improved from baseline at 3, 6, 9, and 12 months for both 100 and 200 mg oral lasmiditan groups. Improvements were also demonstrated in work/school absenteeism and presenteeism, intensity, and monthly headache days.		Both 100 and 200 mg lasmiditan reduced migraine-related disability, complete loss of work days, and impaired functioning during work from 3 months through 1 year.