Preventive treatment with ergotamine plus lasmiditan for chronic cluster headache after failure/intolerance of standard therapies: A case report

Abstract

Aim

Although ergotamine is administered before bedtime as a preventive therapy, recent studies have suggested that morning administration is more effective. Lasmiditan, a selective 5-HT_1F receptor agonist, does not have vasoconstrictive properties and can be used in combination with ergotamine or triptan. A combination therapy with ergotamine and lasmiditan may be effective as a preventive strategy for patients with cluster headache who do not respond to standard treatment.

Methods

We report a case of a 27-year-old man with chronic cluster headache who experienced chest tightness and palpitations after subcutaneous sumatriptan and showed an inadequate response to verapamil, lithium, topiramate, and galcanezumab. Oxygen therapy was only partially effective, and short corticosteroid courses resulted in transient remission. We administered ergotamine (1 mg) in the morning and lasmiditan (100 mg) at bedtime.

Results

Within 7 days, the attack frequency declined from daily (3–4/day) to once every 3–4 days, and pain intensity decreased from NRS 8/10 to 3/10. Benefits persisted for over 3 months without reported adverse effects, enabling a return to full-time work.

Conclusion

This case demonstrates that a combination therapy with ergotamine and lasmiditan may be a preventive option for cluster headaches that are difficult to manage with standard treatment.

Introduction

Cluster headache (CH) is the most severe of the trigeminal-autonomic cephalalgias, with a lifetime prevalence approaching 0.1% and a considerable impact on the quality of life. ¹ Subcutaneous sumatriptan or high-flow oxygen are used as first-line abortive therapy, whereas for the prophylaxis of CH attacks, verapamil and corticosteroids are recommended. ² Lithium, topiramate, and galcanezumab may be used as alternative treatments. However, some patients show no response to the standard treatment or cannot tolerate it.

Oral ergotamine at bedtime was first reported to be effective as a preventive treatment. ³ Ergotamine or ergotamine plus caffeine was routinely recommended for the prevention of CH until the efficacy of verapamil and lithium became evident. ³ A recent study showed that ergotamine enhances circadian amplitude and diurnally mitigates nitroglycerin-induced mechanical hypersensitivity. ⁴ Furthermore, ergotamine may be more effective at certain times of day. ⁴

Lasmiditan, a selective 5-HT_1F agonist licensed for migraine treatment, exerts central antinociceptive effects without vasoconstriction, rendering it attractive for triptan-intolerant patients. ⁵ However, reports about its use in CH are limited.

We report a case of successful control of chronic CH with a day-/night-tailored regimen of ergotamine and lasmiditan, respectively, after failure or intolerance of standard treatments.

Case presentation

This retrospective study was approved by the institutional review boards at Japanese Red Cross Shizuoka Hospital (2025-22). This case report was prepared in accordance with the CARE (CAse REport) guidelines. Written informed consent was obtained from the patient for publication of this case report.

Patient information

A 27-year-old Japanese man presented with an intractable unilateral headache lasting for 1 year prior to his visit. He first developed left-sided orbital pain at the age of 17 years. Initially, CH periods lasted for 1 month and recurred every 6 months, with one attack each morning. By 20 years of age, the inter-bout interval had shortened to 3 months, and attacks occurred twice daily (morning and evening), which fulfilled the criteria for chronic CH according to the International Classification of Headache Disorders-3. ⁶ At the age of 25, he had a remission period of approximately a year. At the age of 26, he entered the cluster phase and experienced 3–4 attacks per day at irregular intervals. Pain intensity was 8 on the numerical rating scale of 10. The patient had no obvious cardiovascular risk factors and was neither an alcohol drinker nor a smoker. His family history was unremarkable.

Previous treatments

As an acute treatment, high-concentration oxygen (7 L × 30 min) gave only partial relief, and the response to intranasal sumatriptan (20 mg) showed slow onset. Subcutaneous sumatriptan (3 mg) afforded rapid pain relief but caused chest tightness, palpitations, and fear, leading to discontinuation.

As a preventive treatment, verapamil was titrated up to 360 mg/day (PR interval ≤ 200 ms throughout), in combination with corticosteroid bridging therapy. High-dose intravenous methylprednisolone (1 g) followed by oral prednisone tapers (60 mg, 5 days) resulted in marked but temporary improvement; headache attacks recurred after the completion of the steroid taper, despite continued verapamil administration. Based on this clinical course, corticosteroid therapy was considered to have induced only transient remission, whereas verapamil monotherapy was considered ineffective.

Subsequently, lomerizine (up to 8 mg), topiramate (up to 100 mg), and lithium (up to 400 mg) were administered as monotherapy for at least 4–6 weeks but were ineffective or poorly tolerated.

Two years before his visit to our clinic, the patient experienced remission with galcanezumab (240 mg); however, during the current cluster period, re-administration of galcanezumab at the same dose (240 mg) for over one month showed no preventive effect. A structured summary of previous preventive treatments is provided in Table 1.

Table 1.

A structured summary of previous preventive treatments.

Preventive treatment	Maximum dose	Duration	Efficacy	Tolerability	Treatment setting
Verapamil	360 mg/day	≥8 weeks	Monotherapy: No effect In combination with corticosteroids: Transient remission	Well tolerated (PR ≤200 ms)	Initiated in combination with corticosteroids; continued as monotherapy
Corticosteroids (bridging)	IV MP 1 g + oral prednisone 60 mg × 5 days	∼10 days	Transient remission	Tolerated	In combination with verapamil
Lomerizine	8 mg/day	≥4 weeks	No effect	Well tolerated	Monotherapy
Topiramate	100 mg/day	≥6 weeks	No effect	Poorly tolerated	Monotherapy
Lithium	400 mg/day	≥6 weeks	No effect	Poorly tolerated	Monotherapy
Galcanezumab (previous cluster period)	240 mg/month	Several months	Complete remission	Well tolerated	Monotherapy
Galcanezumab (subsequent cluster period)	240 mg/month	≥1 month	No effect	Well tolerated	Monotherapy

Transnasal endoscopic pterygopalatine ganglion block was ineffective. Occipital nerve block was not administered at the patient's discretion.

Examination and investigations

Interictal examination results, vital signs (blood pressure 121/85 mmHg; heart rate, 71 bpm), and neurological status were normal. Magnetic resonance imaging and angiography revealed normal findings. ECG showed normal sinus rhythm without conduction delay.

Therapeutic intervention

We regularly administered an ergotamine-containing combination product (Cleamine A^®, containing 1 mg of ergotamine) during the daytime (in the morning) and lasmiditan (100 mg, Reyvow^®) at bedtime as preventive therapy.

Within 7 days, the attack frequency decreased from daily (3–4/day) to once every 3–4 days. Pain intensity decreased from NRS 8 to NRS 3, and autonomic features were attenuated. Adverse events, such as chest pain, dizziness, or sedation, were not observed. At 3 months after the visit, benefits were maintained, and the patient resumed full-time work. An attack diary confirmed a sustained low frequency of attacks (0–2/month).

This daily ergotamine–lasmiditan modality was continued throughout the three-month observation period without dose escalation. Future treatment plans include cautious dose reduction or discontinuation contingent on sustained clinical stability and absence of relapse. A schematic overview of the clinical course, including headache attack frequencies and treatment interventions over time, is presented in Figure 1.

Figure 1.

A schematic overview of the clinical course, including headache attack frequencies and treatment interventions over time.

Discussion

This case showed that a combination of ergotamine and lasmiditan can achieve durable control of chronic CH after the failure of the standard therapy.

Both CH and migraine attacks occur at specific times of day and are associated with the trigeminovascular system. In 2024, Han et al. reported that the trigeminal ganglion has a strong circadian rhythm, and the serotonin 2A receptor was identified as a clock-controlled gene. ⁷ Ergotamine has affinity for 5-HT-1_B/1D, 5-HT-2A, and dopaminergic receptors. In 2025, Han et al. reported that ergotamine significantly raised hind paw withdrawal thresholds when administered during the daytime, but not at night, in a nitroglycerin chronic headache mouse model. ⁴ These findings suggested that ergotamine may be more effective at certain times of day. In Japan, the only ergotamine preparation available is Cleamine, which contains ergotamine tartrate 1 mg, anhydrous caffeine 50 mg, and isopropylantipyrine 300 mg, so Cleamine was prescribed.

Naratriptan, a 5-HT_1B/D agonist, is an effective and well-tolerated abortive anti-migraine medication that has been used preventively in transformed and menstruation-related migraine. ⁸ Naratriptan has also been reported to reduce the frequency of CH attacks.^9–12 We considered administering naratriptan as a preventive therapy at night, when the effectiveness of ergotamine is reduced, but naratriptan has a vasoconstrictive effect, and its concomitant use within 24 h of ergotamine administration is contraindicated.

Lasmiditan is an effective acute treatment for migraine that offers trigeminal inhibition without vasoconstriction. 5-HT_1F signaling dampens the peripheral and central trigeminovascular transmission without coronary constriction, eliminating the chest discomfort encountered with triptans. ¹³ Lasmiditan can therefore be safely administered after ergotamine. In an animal study, lasmiditan reduced superior salivatory nucleus-evoked activation of the trigeminal-autonomic reflex but had no effect on cranial autonomic activation. ⁵ Although lasmiditan is approved for acute migraine treatment, preclinical studies have demonstrated that selective 5-HT_1F receptor activation suppresses trigeminal nociceptive transmission and attenuates trigeminal–autonomic reflex pathways. Considering these mechanisms and the patient's intolerance to triptans, off-label daily lasmiditan administration was selected as an adjunctive preventive strategy in this refractory case.

Major side effects of lasmiditan are dizziness, paresthesia, somnolence, and nausea. ¹³ In daily clinical practice, it is often observed that taking lasmiditan before bedtime reduces the side effects of dizziness and drowsiness.

The observed benefits of the combination of ergotamine and lasmiditan may be attributed to their complementary mechanisms of action. Ergotamine acts on multiple serotonergic and dopaminergic receptors and appears to modulate circadian nociceptive sensitivity, whereas lasmiditan selectively inhibits trigeminal nociceptive transmission through central 5-HT_1F receptor activation. Preclinical studies have shown that lasmiditan suppresses trigeminal–autonomic reflex pathways, whereas ergotamine demonstrates time-dependent antinociceptive efficacy. Administration of daytime ergotamine plus bedtime lasmiditan may therefore lead to synergistic suppression of cluster headache activity across the circadian cycle.

Because ergotamine and lasmiditan were initiated simultaneously, the relative contribution of each agent to the observed clinical improvement could not be determined. The sustained benefit is therefore interpreted as the effect of a combined therapeutic strategy with complementary mechanisms, rather than as evidence supporting the efficacy of either drug alone.

The rapid clinical improvement observed within one week is pharmacologically plausible. Ergotamine exerts direct effects on serotonergic and dopaminergic receptors involved in trigeminovascular modulation and rapidly influences circadian nociceptive processing. Meanwhile, lasmiditan acts centrally via selective 5-HT_1F receptor activation, inhibiting trigeminal nociceptive transmission without vasoconstriction. Unlike conventional preventives that require gradual neuroadaptive changes, both agents can exert clinically meaningful effects shortly after initiation, particularly when administered in a time-of-day-tailored manner.

Spontaneous fluctuations are a recognized feature of cluster headache and cannot be excluded as a contributing factor. However, in our patient with chronic cluster headache, attack frequency had remained persistently high despite multiple preventive strategies, and no recent spontaneous remission had been observed. The close temporal relationship between initiation of ergotamine plus lasmiditan and the rapid, sustained improvement suggests a treatment effect, although causality cannot be conclusively established in a single-case observation.

This study has some limitations. First, it was an observation in a single patient that lacked placebo control, and the 3-month follow-up restricted generalizability. Secondly, because we used a preparation that, in addition to ergotamine, contained caffeine and isopropylantipyrine, it is necessary to consider the possibility that these drugs may have affected the therapeutic effect. Moreover, even in cases of CH, ergotamine and triptans may cause medication-overuse headache, ¹⁴ the potential for which must be closely monitored. Safety concerns regarding the combined ergotamine and lasmiditan therapy include potential adverse events and the risk of medication-overuse headache. Although no such complications were observed during the three months of daily treatment in our patient, long-term safety cannot be inferred from a single case and warrants careful monitoring in future studies. As an acute treatment, oxygen therapy was administered at 7 L/min for 30 min, resulting in only partial relief. This flow rate was selected in accordance with Japanese clinical practice guidelines for cluster headache. ¹⁵ However, given that international guidelines often recommend higher flow rates (12–15 L/min), the efficacy of oxygen therapy may not have been fully assessed in this case.

Conclusion

A tailored combination of ergotamine-caffeine and lasmiditan provided rapid, sustained relief from chronic CH in a patient who did not respond to or was intolerant to standard treatments. This new strategy may be a pragmatic option for similar challenging cases.

Clinical implications

• Treatment-resistant chronic cluster headache despite multiple preventive therapies (verapamil, lithium, topiramate, galcanezumab).

• Intolerance to subcutaneous sumatriptan limiting standard acute treatment.

• Combination therapy with morning ergotamine (1 mg) and bedtime lasmiditan (100 mg).

• Rapid and sustained reduction in attack frequency and pain severity.

• Potential preventive strategy for otherwise refractory chronic cluster headache.