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Headache

Cluster Headache

Cluster Headache · G44.0

Cluster headache is a trigeminal autonomic cephalalgia characterized by excruciating pain around one eye or the temporal region lasting 15 minutes to 3 hours, recurring at the same time of day, and accompanied by autonomic symptoms such as lacrimation, rhinorrhea, and ptosis.

2026-03-28

At a Glance

Cluster headache is a headache disorder in which attacks recur 1-8 times daily at the same time of day over weeks to months during the cluster period. The pain intensity ranks among the most severe of all known headaches, and it is approximately 3 times more common in men than women [1]. Activation of the trigeminal-autonomic reflex pathway is the core mechanism, and oxygen inhalation and sumatriptan injection are first-line acute treatments.

Definition and Overview

Cluster headache is the most common and severe form of the trigeminal autonomic cephalalgias (TACs). Excruciating pain occurs around one eye, retro-orbitally, in the temporal region, or on the forehead, lasting 15 minutes to 3 hours, with at least one ipsilateral autonomic symptom including lacrimation, conjunctival injection, nasal congestion or rhinorrhea, ptosis, miosis, eyelid edema, or forehead sweating [1].

The pain is so excruciating that it is also known as "suicide headache." The prevalence is approximately 1 per 1,000 population, which is not rare, and men are affected approximately 3 times more than women [2].

Classification

Cluster headache is classified as follows based on the pattern of cluster and remission periods [1].

  • Episodic cluster headache: Cluster periods lasting 7 days to 1 year alternate with remission periods of 3 months or more. This accounts for approximately 85-90% of all patients.
  • Chronic cluster headache: Attacks persist for more than 1 year without a remission period of 3 months or more. This accounts for approximately 10-15%.

Etiology

Trigeminal-Autonomic Reflex

The core mechanism of cluster headache is trigeminal nerve activation and the resulting parasympathetic reflex [5]. Upon trigeminal activation, neuropeptides such as CGRP (calcitonin gene-related peptide) and vasoactive intestinal peptide (VIP) are released from meningeal blood vessels, inducing vasodilation and inflammation.

Hypothalamic Involvement

Functional MRI studies have confirmed activation of the posterior hypothalamic gray matter during attacks [4]. This explains the temporal periodicity (circadian pattern, seasonality) of the headache and serves as the target for deep brain stimulation (DBS).

Symptoms

Headache Attacks

  • Attack duration: 15 minutes to 3 hours (average 45-90 minutes)
  • Attack frequency: 1-8 times daily, recurring during the cluster period
  • Pain quality: Excruciating stabbing or burning pain
  • Timing: Commonly occurs 1-2 hours after nocturnal sleep onset; seasonally, cluster periods often begin in spring and autumn
  • Agitation during attacks: Unlike migraine, patients cannot remain still during attacks and tend to pace or rock their bodies

Autonomic Symptoms (Ipsilateral)

Excessive lacrimation, conjunctival injection, nasal congestion or rhinorrhea, ptosis, miosis, and forehead or facial sweating appear ipsilaterally during attacks.

Diagnosis

The diagnosis of cluster headache is a clinical diagnosis based on the International Headache Society (IHS) classification criteria (ICHD-3) [1]. The location, duration, accompanying autonomic symptoms, and cluster pattern of the headache are evaluated.

Brain MRI and cerebrovascular MRA imaging are recommended early in the diagnostic process to exclude secondary causes (cerebral aneurysm, brain tumor).

Treatment

Acute Treatment

Because cluster headache attacks are short in duration, oral medications have limited efficacy, and the following treatments take priority.

  • High-flow oxygen inhalation: Oxygen is typically administered via mask at 7-12 liters per minute for 15 minutes. Research has reported pain improvement within 15 minutes in approximately 78% of patients [3].
  • Subcutaneous sumatriptan injection (6mg): A rapid-acting and well-validated acute treatment.
  • Sumatriptan nasal spray and zolmitriptan nasal spray are also used.

Preventive Treatment

Preventive treatment is administered concurrently to reduce attack frequency during the cluster period.

  • Verapamil: The best-evidenced preventive medication. Used with ECG monitoring.
  • Short-term prevention: Rapid suppression of attacks with short-course prednisolone at cluster onset
  • Lithium: Useful for chronic cluster headache
  • Galcanezumab (anti-CGRP antibody injection): Efficacy has been reported for prevention of episodic cluster headache

Neuromodulation Therapy

Non-invasive vagus nerve stimulation is used as an adjunct for both acute and preventive treatment. Case reports of hypothalamic deep brain stimulation (DBS) have been documented for refractory chronic cluster headache [4].

Frequently Asked Questions

Migraine primarily presents as pulsating pain lasting hours to days with photophobia and phonophobia. Cluster headache involves excruciating periorbital pain lasting 15 minutes to 3 hours, recurring at the same time of day (especially at night), accompanied by autonomic symptoms such as lacrimation, rhinorrhea, ptosis, and conjunctival injection. Cluster headache patients tend to be restless and unable to sit still during attacks.

The first-line acute treatment is oxygen inhalation at 7-12 liters per minute for 15 minutes [3]. Subcutaneous sumatriptan injection (6mg) is also an extremely rapid-acting acute treatment. Ordinary analgesics are insufficiently effective, and because attack duration is short, attacks often resolve before oral medications can be absorbed.

It is related to hypothalamic circadian rhythm regulation. Cluster headache tends to begin during nocturnal sleep and in specific seasons (spring and autumn). Hypothalamic neural activation is known to trigger headache through the trigeminal-autonomic reflex pathway [2].

Preventive treatment is available to reduce the frequency and intensity of headache attacks during the cluster period. Verapamil (calcium channel blocker) is the best-evidenced preventive medication, and short-course corticosteroids are used for short-term prevention. Lithium, topiramate, and galcanezumab (anti-CGRP antibody) are also used.

During the cluster period, even small amounts of alcohol can be a potent trigger, provoking headache attacks within tens of minutes. In contrast, during the remission period, alcohol often does not trigger attacks. Therefore, complete abstinence from alcohol is recommended during the cluster period.

Cluster headache itself is not related to brain tumors. However, when unilateral headache occurs for the first time, when headache patterns change, when neurological symptoms (limb paralysis, speech disturbance, etc.) are present, or when the diagnosis is unclear, brain MRI or other imaging should be performed to exclude secondary causes.

References

  1. [1] Headache Classification Committee of the International Headache Society (2018). "The International Classification of Headache Disorders, 3rd edition." Cephalalgia, 38: 1-211. DOI PubMed
  2. [2] May A (2005). "Cluster headache: pathogenesis, diagnosis, and management." Lancet, 366: 843-855. DOI PubMed
  3. [3] Cohen AS, Burns B, Goadsby PJ (2009). "High-flow oxygen for treatment of cluster headache: a randomized trial." JAMA, 302: 2451-2457. DOI PubMed
  4. [4] Leone M, Franzini A, Bussone G (2001). "Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable cluster headache." New England Journal of Medicine, 345: 1428-1429. DOI PubMed
  5. [5] Goadsby PJ, Edvinsson L (1994). "Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies." Brain, 117: 427-434. DOI PubMed

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