Cluster Headache (ปวดศีรษะคลัสเตอร์)

• ICD-10:
• G44.0 – Cluster headache and chronic paroxysmal hemicrania
• ICD-11:
  • 8A82 – Cluster headache or other trigeminal autonomic cephalalgia
  • 8A82.0 – Episodic cluster headache
  • 8A82.1 – Chronic cluster headache

Overview

Cluster headache (CH) is one of the most painful primary headache disorders and belongs to the group known as Trigeminal Autonomic Cephalalgias (TACs). It is characterised by severe unilateral periorbital or temporal pain accompanied by ipsilateral autonomic symptoms such as tearing, conjunctival injection, rhinorrhoea, ptosis, and miosis. Each attack typically lasts between 15 and 180 minutes and may occur up to eight times per day during an active cluster period.

The disorder is called “cluster” headache because the attacks occur in groups or bouts lasting weeks to months, followed by remission periods that can last months or years. In some patients, attacks occur chronically without remission. The disease has a strong circadian and circannual pattern, often waking patients at night at the same hour, suggesting a hypothalamic involvement.

Cluster headache is sometimes called the “suicide headache” due to its extreme intensity. Rapid diagnosis and management are essential because of the significant impact on quality of life. While the exact cause is unknown, dysregulation of the hypothalamus and the trigeminal–autonomic reflex plays a central role in its pathophysiology.

Epidemiology

Cluster headache is relatively rare compared with migraine or tension-type headache, with a lifetime prevalence estimated at 0.1–0.2% of the population. It predominantly affects men (male-to-female ratio 5:1) and typically begins between the ages of 20 and 50 years.

Most cases are episodic (80–90%), with attacks occurring in clusters separated by remission periods of at least three months. Approximately 10–20% of patients develop chronic cluster headache, in which remission periods are absent or last less than three months per year.

Epidemiologic studies have identified triggers including alcohol, vasodilating drugs (e.g. nitroglycerin), and sleep pattern disturbances during active cluster periods. A familial form is reported in approximately 5–10% of cases, suggesting a genetic predisposition involving hypothalamic function and circadian rhythm regulation.

Pathophysiology

The exact pathophysiology of cluster headache (CH) involves a complex interaction between the trigeminal nociceptive pathways, cranial parasympathetic system, and the hypothalamus. The posterior hypothalamus is considered the central generator of cluster attacks, supported by functional neuroimaging studies showing activation in this region during acute attacks.

Activation of the trigeminal–autonomic reflex leads to concurrent stimulation of the trigeminal sensory pathway (causing pain) and the cranial parasympathetic outflow via the superior salivatory nucleus and sphenopalatine ganglion, resulting in autonomic symptoms such as lacrimation, rhinorrhoea, conjunctival injection, and nasal congestion.

The trigeminovascular system contributes to the excruciating pain characteristic of CH. Release of vasoactive neuropeptides, notably calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase–activating peptide (PACAP), induces vasodilatation and neurogenic inflammation in cranial blood vessels, further sensitising trigeminal neurons.

The hypothalamus plays a key role in regulating circadian and circannual rhythms, explaining why attacks often occur at the same time each day and in specific seasons. Alterations in hypothalamic hormones such as melatonin and orexin suggest impaired biological clock regulation.

Chronic CH is associated with persistent sensitisation within the hypothalamic–trigeminal network, leading to a lowered activation threshold. Functional imaging studies have demonstrated increased grey matter volume in the posterior hypothalamus and brainstem nuclei, consistent with structural plasticity secondary to repeated attacks.

Environmental triggers such as alcohol, sleep deprivation, and stress can activate the hypothalamic–autonomic axis, precipitating attacks during active cluster periods. The interplay between genetic predisposition, neurovascular dysregulation, and hypothalamic dysfunction defines the distinct clinical and rhythmic characteristics of cluster headache.

Clinical Presentation

Cluster headache presents as severe unilateral orbital, supraorbital, or temporal pain lasting 15–180 minutes, accompanied by ipsilateral autonomic symptoms. The pain is excruciating, described as stabbing, burning, or boring, and often leads patients to pace, rock, or even strike their head due to unbearable intensity.

Typical associated autonomic features include conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, forehead sweating, miosis, and ptosis. Attacks usually occur 1–8 times per day, often at the same time each day, frequently waking the patient at night. Between attacks, patients are usually asymptomatic.

Cluster periods last from weeks to months, followed by remission periods that may extend for months or years. In chronic cases, remissions are absent or brief (<3 months). Alcohol, histamine, and nitroglycerin are common triggers during active bouts. The frequency and timing are closely linked to circadian rhythm disturbances.

Investigation

Diagnosis of cluster headache is primarily clinical based on attack pattern and associated autonomic symptoms. Neuroimaging with brain MRI is recommended in all patients at initial presentation to exclude secondary causes such as pituitary lesions, carotid dissection, or structural abnormalities in the hypothalamic region.

Additional investigations may include:

• Hormonal profile: To exclude pituitary adenoma or hypothalamic dysfunction.
• Sleep study: If nocturnal clustering suggests sleep apnea as a comorbidity.
• CGRP measurement (research use): Elevated levels may confirm trigeminovascular activation.

Diagnosis Criteria

According to the International Classification of Headache Disorders, 3rd Edition (ICHD-3), Cluster headache is diagnosed when all of the following criteria are fulfilled:

• At least five attacks fulfilling the following characteristics:
• Severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15–180 minutes when untreated.
• Accompanied by ≥1 ipsilateral autonomic symptom:
  • Conjunctival injection or lacrimation
  • Nasal congestion or rhinorrhoea
  • Eyelid oedema
  • Forehead/facial sweating
  • Miosis and/or ptosis
• Frequency: from one attack every other day to eight attacks per day.
• No better accounted for by another ICHD-3 diagnosis.

Differential Diagnosis

Treatment Overview

The management of Cluster Headache (CH) requires rapid-acting abortive therapy for acute attacks, preventive treatment to reduce the frequency and severity of attacks, and transitional therapy during cluster periods. Because attacks are extremely severe and short-lived, abortive treatment must be administered as soon as an attack begins. High-flow oxygen and subcutaneous triptans remain the gold standards for acute management.

Preventive therapy aims to suppress attacks throughout the cluster period or indefinitely in chronic CH. First-line preventive therapy is Verapamil, with alternatives such as lithium carbonate, topiramate, and Galcanezumab (CGRP monoclonal antibody). Transitional therapy, often with corticosteroids, bridges the time between starting preventive medication and achieving full therapeutic effect.

Comprehensive management includes patient education, avoidance of triggers (especially alcohol and vasodilators during active bouts), and treatment of comorbid sleep disturbances or mood disorders. Refractory cases may benefit from neuromodulation techniques such as sphenopalatine ganglion stimulation or occipital nerve stimulation.

Pharmacology

The pharmacologic approach to Cluster Headache is divided into acute (abortive), transitional, and preventive treatments. Due to the extreme pain intensity, abortive agents must act rapidly, while preventives aim to suppress the cluster cycle.

Treatment Guideline

The management of cluster headache follows a tiered, evidence-based approach as per the European Academy of Neurology (EAN) 2020 and American Headache Society (AHS) 2023 guidelines:

1. Acute (Abortive) Treatment

• First-line: High-flow 100% oxygen 12–15 L/min via non-rebreather mask for 10–15 minutes.
• Second-line: Sumatriptan 6 mg SC or Zolmitriptan 5–10 mg IN.
• Triptans may be combined with oxygen for additive relief.
• Avoid oral triptans—onset too slow for short-duration attacks.

2. Transitional Therapy

• Prednisone 60–80 mg/day PO tapering over 10–14 days, or methylprednisolone 500 mg IV × 3 days.
• Occipital nerve block (lidocaine + corticosteroid) provides rapid symptomatic relief.

3. Preventive Therapy

• First-line: Verapamil 240–960 mg/day (titrate gradually; ECG monitoring mandatory).
• Second-line: Lithium 600–900 mg/day or Topiramate 50–100 mg/day.
• New option: CGRP monoclonal antibody (Galcanezumab) for episodic CH.
• For chronic CH refractory to medical therapy, consider Deep Brain Stimulation or Sphenopalatine Ganglion Stimulation.

4. Lifestyle & Supportive Measures

• Avoid alcohol and nitroglycerin during active cluster periods.
• Maintain consistent sleep pattern and hydration.
• Psychological counselling for anxiety and depression secondary to chronic pain.

Example Doctor’s Orders

Prognosis

Cluster headache has a variable but generally chronic relapsing course. Most patients with episodic CH experience remission lasting months to years between clusters. However, 10–20% develop chronic CH without significant remission. The intensity of pain can severely affect quality of life, mood, and occupational performance.

Long-term preventive therapy with verapamil or newer CGRP monoclonal antibodies can greatly reduce attack frequency and severity. With appropriate management and trigger avoidance, more than 70% of patients achieve satisfactory control. However, chronic cases often require long-term neurological follow-up and may experience partial disability.

Prevention

• Avoid alcohol, nitroglycerin, and vasodilating agents during active periods.
• Maintain regular sleep–wake cycles and stress management.
• Ensure adherence to preventive medication regimens (verapamil, lithium, or CGRP blockers).
• Record attacks in a headache diary to identify temporal or environmental triggers.
• Follow up with ECG and lab monitoring when on high-dose preventive therapy.

Conclusion

Quiz (USMLE OSCE)

Frequently Asked Questions (FAQ)

Why is cluster headache called a “suicide headache”?

Because of its extreme intensity, cluster headache is considered one of the most painful conditions known to medicine. Patients often describe unbearable pain, leading to restlessness and, in severe cases, suicidal thoughts during attacks.

Can caffeine or smoking trigger cluster headache?

Smoking is strongly associated with cluster headache, though the mechanism is unclear. Caffeine is not a direct trigger but excessive use or withdrawal can affect sleep patterns and precipitate attacks.

How long should preventive therapy continue?

Preventive medications such as verapamil or lithium are maintained throughout the active cluster period and tapered off gradually after 2–4 weeks of remission to avoid rebound headaches.

Are triptans safe for long-term use?

Triptans are effective for acute attacks but should not be used more than twice daily or combined with ergot derivatives. They are contraindicated in cardiovascular disease and require monitoring for chest symptoms.

What is the role of CGRP antibodies in cluster headache?

Galcanezumab (Emgality) is the first CGRP monoclonal antibody approved for episodic cluster headache prevention. It targets the CGRP ligand, reducing attack frequency and severity, especially in patients resistant to traditional preventives.

References

1. ICD-11: 8A82 – Cluster headache or other trigeminal autonomic cephalalgia. WHO, 2025.
2. Headache Classification Committee of the IHS. ICHD-3. Cephalalgia, 2018.
3. May A, Schindler E. Pathophysiology of Cluster Headache. Lancet Neurology, 2020.
4. Goadsby PJ. Treatment of Cluster Headache: New Insights. NEJM, 2019.
5. European Academy of Neurology (EAN) Guideline on Cluster Headache, 2020.
6. American Headache Society (AHS) Practice Guideline, 2023.
7. Leroux E, Ducros A. Cluster Headache. Orphanet J Rare Dis, 2018.
8. Dodick DW, et al. CGRP Pathway and Headache Management. JAMA Neurol, 2022.
9. Banmor.org Clinical Library – Cluster Headache, 2025 Edition.

Author & Review

Compiled from peer-reviewed references and clinical guidelines. Adapted and reviewed by:

Teerawat Suwannee MD

Medical Doctor License 44780
นายแพทย์ธีรวัฒน์ สุวรรณี ว.44780

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