Comparison of the adverse events of preprandial and postprandial lasmiditan intake: A retrospective chart review

Abstract

Background

Lasmiditan is suitable for the acute treatment of migraine in patients who are intolerant or unresponsive to triptans. However, lasmiditan can cause adverse events that affect treatment adherence. The effects of predose food consumption on the development of adverse events after lasmiditan intake remain unclear.

Methods

This single-center retrospective study included 23 patients who received both preprandial and postprandial lasmiditan and experienced adverse events. To determine whether meal timing influences these adverse events, we examined the differences in the severity of adverse events between preprandial and postprandial lasmiditan administration using medical records and patient-reported headache diaries.

Results

All 23 patients experienced adverse events such as somnolence, dizziness, disequilibrium, fatigue, and palpitations following preprandial lasmiditan intake. Postprandial administration of lasmiditan was associated with significantly lower severity and reduced odds of adverse events compared with preprandial administration (p < 0.001).

Conclusion

Our results suggest that postprandial lasmiditan intake may affect the incidence and severity of the adverse events.

Graphical abstract

This is a visual representation of the abstract.

Introduction

Severe headaches due to migraine and its accompanying symptoms impair the quality of life and social activities of patients. ¹ Therefore, effective and safe acute treatment is essential to reduce the severity and duration of migraine attacks.

Triptans are 5-hydroxytryptamine (5-HT)_1B/1D receptor agonists that serve as first-line acute migraine treatment, effectively managing migraine attacks. However, due to their vasoconstrictive properties, triptans may increase the risk of ischemic events.^2,3 Therefore, triptans are contraindicated in patients with a history of ischemic stroke or myocardial infarction. ⁴ Moreover, due to the lack of evidence regarding their safety in patients with hemiplegic migraine, their use in this population remains limited.

Conversely, lasmiditan, a selective 5-HT_1F receptor agonist, does not exhibit vasoconstrictive effects at clinically relevant doses because 5-HT_1F receptors are nearly absent in vascular smooth muscle and are predominantly expressed by the trigeminal neurons. ⁵ Moreover, it does not increase the risk of cardiovascular events in patients with cardiovascular risk factors, such as age >40 years, current smoking status, elevated cholesterol and low high-density lipoprotein cholesterol levels, hypertension, or diabetes mellitus. ⁶ Furthermore, lasmiditan is effective even in patients with an insufficient response to triptans. ⁷

However, adverse events (AEs), including dizziness and somnolence, have been reported with lasmiditan, necessitating the avoidance of driving after its administration.^8,9 This may contribute to the underuse of acute migraine treatments and potentially increase the risk of progression from episodic migraine to chronic migraine. ¹⁰ Therefore, simple methods to prevent lasmiditan-associated AEs and improve their tolerability can be beneficial for achieving highly satisfactory treatment results.

In general, the bioavailability of orally administered drugs may be affected by direct food-drug interactions and physiological responses induced by food intake (gastric acid secretion and delayed stomach emptying), which may alter drug efficacy. ¹¹ Co-administration of lasmiditan with a high-fat meal reportedly delays the median time to maximum blood concentration (Tmax) by ∼1 h. ¹² However, the influence of food intake before lasmiditan intake on clinical outcomes and AEs is unclear.

This study aimed to compare the differences in AEs between preprandial and postprandial administration of lasmiditan in patients with migraine to provide information on the effects of food intake on these AEs.

Methods

Study design

In this single-center retrospective study, we performed a chart review of patients with migraine with and without aura, who met the criteria of the International Classification of Headache Disorders, 3rd Edition, ¹³ and had been administered lasmiditan. The data were collected between June 2022 and May 2023. The inclusion criteria were as follows: (a) patients with a history of lasmiditan administration at least once at both preprandial and postprandial doses, and (b) patients who reported AEs with previous doses of lasmiditan. Food could be a full or light meal, such as a slice of bread. Water and beverages such as tea were not considered meals. Postprandial intake was defined as the intake of lasmiditan within 2 h after food consumption. In our unique patient-reported headache diary, all patients with headaches were instructed to record the course of their migraine attacks, triggers, medications used at the time, efficacy, AEs, and duration of sleep, as part of their daily medical care (Supplemental Figure S1). Details were collected from the medical records and patient-reported headache diaries. Data included patient clinical information (age, sex, and diagnosis) and treatment specifics (efficacy and AEs of lasmiditan, dosage, food intake within 2 h of lasmiditan administration, and any concomitant migraine medications). Since hunger can trigger migraine attacks, patients recorded their mealtimes on the day of the migraine attack, allowing the temporal relationship between meals and lasmiditan intake to be verified. Lasmiditan doses with unknown information on food consumption within the previous 2 h were excluded from the analysis.

The study was approved by the Institutional Ethics Committee of Kyoto University Graduate School of Medicine (approval No. R4140). Patients were informed about this retrospective study through explanatory documents posted in the clinic and were given the option to decline participation. The Ethics Committee of Kyoto University waived the requirement for informed consent in accordance with the national regulations (Ethical Guidelines for Medical and Biological Research Involving Human Subjects). All procedures were performed in accordance with the relevant guidelines and regulations.

The severity scale for AEs and the efficacy scale

To evaluate severity and efficacy, severity scores for AEs and efficacy scores were defined based on patient self-reports. The severity scale was defined as follows: 0, none; 1, mild and not bothersome; 2, moderate, with no interference in daily activities; 3, severe, with interference in work or household activities; and 4, very severe and requiring bed rest. The efficacy scale was defined as follows: 0, no effect; 1, slightly effective (headache relief took > 2 h); 2, effective (headache resolved or significantly improved within 2 h); and 3, highly effective (headache resolved or significantly improved within 1 h).

Statistical analysis

To examine the effects of administration timing and other covariates on treatment-related outcomes (i.e. severity and efficacy), two separate cumulative link mixed models (CLMMs) were constructed for severity and efficacy scales. The fixed effects included administration timing (i.e. preprandial and postprandial), age, sex, and dose of lasmiditan (50 mg or 100 mg). Random intercepts were included at the participant level to account for intra-individual correlations due to repeated observations. The models were estimated using the Laplace approximation. Analyses were conducted on the available cases. Observations with missing values for administration timing or other relevant variables were excluded using list-wise deletion. Consequently, the number of valid observations per participant varied (Supplemental Table S1). The CLMMs framework accommodates unbalanced data structures by incorporating random intercepts. To account for multiple comparisons between the two outcomes (severity and efficacy), a Bonferroni-adjusted significance threshold (α = 0.025) was considered. Additionally, severity was dichotomized as 0 (no AEs) or ≥1 (presence of AEs) and compared between the administration timing using Fisher's exact test to assess the occurrence of AEs regardless of severity as a complementary analysis. All statistical analyses were conducted using R software (Version 4.4.1), using the “ordinal” package.

Results

This study included 23 patients (six men and 17 women), of whom seven and 16 had migraine with and without aura, respectively. Table 1 lists the characteristics of the patients and lasmiditan-associated AEs. The mean age of the patients was 50.2 ± 11.5 years. Lasmiditan doses were 50 and 100 mg in eight and 15 patients, respectively. All patients had an inadequate response to conventional acute treatments (e.g. triptans) and were therefore prescribed lasmiditan, which was recently launched in Japan, immediately before the study period. Conventional acute treatments were permitted in cases where lasmiditan was intolerable or ineffective. None of the patients received any other acute treatment medication concurrently or immediately before or after lasmiditan administration. Preventive treatments remained stable throughout the study period in all patients. Data with unknown timing of food intake were excluded from the analysis. The complete information is provided in Supplemental Table S1.

Table 1.

Patient characteristics and adverse events associated with preprandial and postprandial lasmiditan intake.

Case	Age	Sex	Migraine type	Concomitant medication	Lasmiditan dose(mg)	Adverse events
						Preprandial			Postprandial
						Symptoms	Severity a		Symptoms	Severity a
1	57	Female	MO, CM	Sumatriptan, amitriptyline, and lomerizine	50	Somnolence	3		Somnolence	1
2	44	Male	MA	Sumatriptan and galcanezumab	100	Dizziness	3		Disequilibrium	1
3	49	Male	MA	Zolmitriptan, lomerizine, and erenumab	50	Somnolence	3		Somnolence	1
4	53	Female	MA, MOH	Rizatriptan and naproxen	50	Dizziness	3		Dizziness	2
5	47	Female	MO	Naratriptan, lomerizine, and fremanezumab	100	Somnolence and disequilibrium	4		Somnolence and disequilibrium	2
6	42	Female	MO	Eletriptan, amitriptyline, lomerizine	100	Somnolence and disequilibrium	3		Somnolence and disequilibrium	1
7	53	Female	MO, MOH	Eletriptan, loxoprofen, valproate, topiramate, propranolol, and fremanezumab	100	Fatigue	3		Fatigue	2
8	65	Female	MO	Eletriptan and lomerizine	50	Somnolence	3		Somnolence	2
9	47	Female	MO	Eletriptan, lomerizine, and duloxetine	100	Somnolence and disequilibrium	3		None	0
10	52	Female	MO	Sumatriptan, amitriptyline, and lomerizine	50	Dizziness and somnolence	4		Dizziness	3
11	71	Male	MA, CM, MOH	Sumatriptan, valproate, and amitriptyline	100	Disequilibrium	2		None	0
12	58	Female	MA, MOH	Naratriptan, topiramate, and lomerizine	100	Disequilibrium	4		None	0
13	36	Male	MO, CM	Sumatriptan, valproate, galcanezumab, and domperidone	100	Fatigue	4		Somnolence	1
14	22	Male	MO	Sumatriptan, amitriptyline, and lomerizine	50	Somnolence	3		None	0
15	56	Female	MO	Rizatriptan and fremanezumab	100	Dizziness and somnolence	3		None	0
16	53	Female	MO, MOH	Rizatriptan and lomerizine	50	Somnolence	4		None	0
17	60	Male	MA, MOH	Lomerizine	100	Somnolence	3		None	0
18	37	Female	MO	Rizatriptan, amitriptyline, and lomerizine	100	Disequilibrium	3		None	0
19	49	Female	MO, MOH	Zolmitriptan, amitriptyline, and lomerizine	100	Palpitations	4		Palpitations	4
20	75	Female	MA, MOH	Lomerizine and galcanezumab	100	Dizziness	2		None	0
21	41	Female	MO, MOH	Rizatriptan and domperidone	50	Dizziness	3		Dizziness	3
22	39	Female	MO	Sumatriptan and propranolol	100	Dizziness and fatigue	3		Dizziness and fatigue	3
23	49	Female	MO	Rizatriptan, valproate, lomerizine, and duloxetine	100	Somnolence	2		Dizziness and somnolence	2

MA: migraine with aura; MO: migraine without aura; CM: chronic migraine; MOH: medication-overuse headache.

^a

For each attack, the most severe adverse event observed was recorded as the representative value for each setting (preprandial and postprandial administration). The severity scale was defined as follows: 0, none; 1, mild and not bothersome; 2, moderate, with no interference in daily activities; 3, severe, with interference in work or household activities; and 4, very severe and requiring bed rest.

All patients experienced AEs with preprandial lasmiditan intake, including somnolence (n = 12), dizziness (n = 7), disequilibrium (n = 6), fatigue (n = 3), and palpitations (n = 1); 20 (87%) experienced AEs that interfered with their daily activities. Among the 23 patients, 14 (61%) reported AE with postprandial lasmiditan intake, and 4 (17%) experienced AE that interfered with their daily activities, including somnolence (n = 7), dizziness (n = 5), disequilibrium (n = 4), fatigue (n = 2), and palpitations (n = 1). Six patients experienced the highest AE severity scores during a preprandial dose following repeated dosing, and four patients who had previously shown attenuation of AEs with repeated dosing experienced recurrence of AEs with a high severity score (≥3) when lasmiditan was again administered in the preprandial state (Supplemental Table S1).

Statistical analysis of AE severity demonstrated that postprandial intake was significantly associated with lower severity scores (estimate = −5.64, standard error = 1.23, z = − 4.59, p < 0.001) and remained statistically significant at the Bonferroni-adjusted significance level (α = 0.025). No statistically significant associations were observed for age (p = 0.495), sex (p = 0.526), or dose (p = 0.141). Fisher's exact test for the dichotomized severity scale (0 vs.  ≥ 1) supported this result, revealing a significantly lower incidence of AEs in the postprandial condition (p < 0.001). For efficacy, the timing of intake, age, sex, and dose did not show significant associations (timing of intake: estimate = –0.50, standard error = 1.21, p = 0.679; age: p = 0.946; sex: p = 0.913; dose: p = 0.203).

Discussion

The present study showed that the severity of AE among patients taking lasmiditan differed between preprandial and postprandial conditions.

In a fasted state, oral lasmiditan reaches its peak plasma concentration within a median Tmax of 1.5 h. ¹² In contrast, co-administration of lasmiditan with a high-fat meal slows its absorption, prolonging Tmax by ∼ 1 h and increasing the maximum drug concentration (Cmax) and the area under the plasma concentration–time curve (AUC) compared with preprandial administration. ¹² Although the effect of lasmiditan absorption has not been reported to affect efficacy, ¹² in terms of drug safety, this study suggested that a gradual increase in lasmiditan levels could affect the occurrence of AEs. A study evaluating simulated driving performance has shown that AEs, such as dizziness, somnolence, and impaired driving performance, correlated with high peak plasma concentrations shortly after dosing. ⁹ Notably, the impact of lasmiditan on driving was concentration-dependent at ∼1.5 h post-dose (near Tmax), but not at later time points, even when plasma drug levels remained measurable. These findings suggest that a rapid surge in drug concentration acutely amplifies AEs, whereas the same total exposure, spread over a longer interval, is less disruptive. Therefore, the lower severity of AEs following postprandial intake of lasmiditan compared with preprandial intake may be attributed to food intake delaying lasmiditan absorption, thereby reducing the intensity of AEs at peak plasma concentrations.

The incidence of AEs associated with lasmiditan reportedly decreases with repeated intake. However, in the present study, repeated dosing did not consistently reduce the severity of AE (Supplemental Table S1). These findings suggest that the timing of food consumption, rather than repeated dosing, is a key factor that influences AE severity.

Statistical analysis revealed that lasmiditan dosage did not influence the incidence or severity of AEs. Unexpectedly, in some patients, AEs at the 50 mg dosage were more severe than those at 100 mg (Supplemental Table S1). Additionally, in several cases, AEs tended to be more severe when the medication was taken preprandially rather than postprandially at the same dose. Therefore, dosage cannot be considered a factor influencing the severity of AEs.

The present study had some limitations. First, it was a single-center retrospective study using data collected from medical interviews, records, and patient-reported headache diaries, which led to sampling and recall bias. Second, potential selection bias may have arisen from our inclusion criteria, which required patients to experience AEs with both preprandial and postprandial lasmiditan administration. Third, the small sample size may restrict the generalizability of our findings. Fourth, there were cases in which the assessment of AEs at each drug intake timing, whether postprandial or preprandial, was based on a single observation, which limited the confirmation of reproducibility in individual patients. Moreover, a substantial proportion of migraine attacks were excluded from the analysis due to missing data on the timing of lasmiditan intake, which may have introduced a bias. Fifth, nearly all patients received their initial dose before a meal, and because the incidence of AEs reportedly decreased with repeated dosing, an inherent bias may have occurred. Sixth, this study did not consider variations in the types of meals or primary components consumed before lasmiditan administration. Further investigations are warranted to determine which dietary elements, such as carbohydrates and fats, significantly affect AEs.

The present study suggests that AEs following lasmiditan administration may be less severe when taken postprandially. The timing of lasmiditan intake is important to reduce AEs through patient education in clinical settings. Therefore, further studies with larger sample sizes are warranted.

Clinical implications

• Lasmiditan has the potential to address unmet needs in acute migraine treatment; however, AEs associated with its use may lead to medication underuse.

• Postprandial lasmiditan intake may be associated with reduced AE incidence and severity compared with fasting intake.

• Future prospective studies investigating the relationship between dosing conditions and AEs are required to identify more tolerable acute treatments.

Supplemental Material

sj-docx-1-rep-10.1177_25158163251355591 - Supplemental material for Comparison of the adverse events of preprandial and postprandial lasmiditan intake: A retrospective chart review

Supplemental material, sj-docx-1-rep-10.1177_25158163251355591 for Comparison of the adverse events of preprandial and postprandial lasmiditan intake: A retrospective chart review by Yuu Tatsuoka, Tamae Naruse, Atsushi Shima, Ryosuke Takahashi and Yoshihisa Tatsuoka in Cephalalgia Reports