Cluster Headaches

Cluster headache is a primary headache disorder characterized by moderate-to-severe unilateral headaches that occur in conjunction with autonomic symptoms. Cluster headache can last from weeks to months, during which the affected individual may experience attacks up to several times a day, followed by a pain-free remission period. Autonomic symptoms typically manifest as ocular and nasal phenomena (e.g., ptosis, miosis, nasal congestion, rhinorrhea) on the same side as the headache. Men are more commonly affected by cluster headaches than women. The diagnosis is clinical and often easy to establish owing to the distinct features of the presenting headache. The 1st-line treatment involves administration of oxygen by nasal cannula and/or abortive therapy using a triptan. Preventative strategies (e.g., glucortoicoids, verapamil) are crucial, as cluster headache is a chronic condition associated with significant morbidity and a high rate of suicide.

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Cluster headaches are named based on their tendency to occur in clusters lasting from weeks to months, and interrupted by periods of remission. The defining features include:

  • Severe intensity
  • Unilateral pain
  • Association with autonomic symptoms (ipsilateral to pain):
    • Miosis
    • Ptosis
    • Lacrimation
    • Conjunctival injection
    • Rhinorrhea
    • Nasal congestion
    • Facial diaphoresis


Cluster headache belongs to 2 distinct classification schemes: primary headache disorders and trigeminal autonomic cephalgias (TACs).

Primary headache disorders:

  • Migraine headache
  • Cluster headache
  • Tension headache

Trigeminal autonomic cephalgias:

  • Common features:
    • Suspected similar pathophysiology
    • Clinical presentation: trigeminal pain + autonomic activation
  • Examples:
    • Cluster headache:
      • Most common of the TACs
      • Has the longest duration of a single attack of the TACs (15 minutes to 3 hours)
      • The lowest frequency in a given day of the TACs (≤ 8 per day)
    • Paroxysmal hemicrania
    • Hemicrania continua
    • Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT)
    • Short-lasting unilateral neuralgiform headache with cranial autonomic symptoms (SUNA)


  • Lifetime prevalence: approximately 120/100,000
  • 1-year prevalence: approximately 50/100,000 
  • Men > women, 4:1 ratio
  • Mean age of onset: 20–40 years 
  • Positive family history in 5%–20% of cases
  • Strong association with cigarette smoking
  • Strong association with suicide attempts and successful suicide


The pathophysiology of cluster headache is multifactorial and the precise mechanisms are poorly understood. The prevailing theories of pain mechanisms are outlined below.

Trigeminal-autonomic reflex activation

Afferent nerves of the trigeminal system have neuronal connections with the ANS. If stimulated, the trigeminal afferents can activate cranial autonomic outflow via the trigeminal-autonomic reflex.

  • Cranial nociceptors originate largely from the trigeminal system.
  • Trigeminal nociceptive afferents have a direct connection to cranial autonomic fibers:
    • Between the trigeminal ganglion and sphenopalatine ganglion
    • Between the trigeminocervical complex and higher brain pain-processing centers 
  • Autonomic phenomena of cluster headache are ipsilateral to the pain:
    • Parasympathetic manifestations:
      • Rhinorrhea
      • Nasal mucosal edema
      • Lacrimation
      • Eyelid edema
      • Ptosis
      • Miosis
  • Some degree of autonomic outflow in response to stimulation of trigeminal nociceptive stimulation is normal, for example:
    • Stimulus: being slapped in the face
    • Autonomic response: ipsilateral lacrimation, local hyperemia/subcutaneous edema
  • In cluster headache, the reflex is centralized, intrinsically triggered, and pathologically tethered to hypothalamic clocklike functions.
  • Trigeminal-autonomic reflex activation and hypothalamic activation mechanisms are interdependent.

Hypothalamic activation

Features of cluster headache suggest the involvement of the hypothalamus, which has direct connections to the trigeminal system. Hypothalamic activation also acts as the body’s biological clock and participates in numerous neurohormonal pathways. Factors suggesting hypothalamic involvement include:

  • Relapsing/remitting pattern of pain episodes
  • Seasonal variation in the pattern of pain episodes
  • Predictable regularity of attack intervals
  • Associated hypothalamic hormonal irregularities:
    • Association with low testosterone levels
    • Association with abnormal pituitary-thyroid axis feedback loop
  • Associated irregularities in the circadian rhythm
  • Functional imaging during attacks shows posterior hypothalamic activity.
  • Existence of neurons connecting the hypothalamus to the trigeminal system
  • Hypothalamic neuropeptides are known to play a role in trigeminal nociception.

Clinical Presentation

There is an overlap in the presenting symptoms and signs of cluster headache and other primary headache syndromes, as well as that of other TACs. The distinguishing features are presented below.

Autonomic manifestations accompanying pain in the trigeminal (V1) distribution are typical of cluster headaches.


  • Classic pain descriptors for cluster headache:
    • Sharp
    • Severe
    • Boring
    • Burning
    • “Hot poker in the eye”
    • “Suicide headache”
  • Autonomic symptoms (ipsilateral to the side of pain):
    • Injected conjunctiva
    • Lacrimation
    • Nasal congestion
    • Rhinorrhea
    • Eyelid edema
    • Eyelid ptosis
    • Facial diaphoresis
    • Miosis
  • Features:
    • Always unilateral
    • Location:
      • Orbital
      • Supraorbital
      • Temporal
    • Not worsened by physical activity:
      • Affected individuals tend to become restless during attacks.
      • Common behaviors: pacing, rocking to-and-fro, fidgeting
    • Frequency: up to 8 attacks per day
    • Duration: 15–180 minutes per attack
    • Attacks often occur overnight, causing sleep disturbance.

Physical exam

  • Physical examination may be entirely normal unless the affected individual is acutely experiencing an attack.
  • In the event an acute attack is present, the examiner may observe:
    • Restlessness
    • Pacing
    • Fidgeting
    • Injected conjunctiva
    • Lacrimation
    • Nasal mucosal edema
    • Rhinorrhea
    • Eyelid edema
    • Eyelid ptosis
    • Facial diaphoresis
    • Miosis

Subtypes of cluster headache

  • Episodic:
    • Most common subtype
    • Regular daily headaches for days up to several weeks (6–12 on average)
    • Intermittent periods of headache remission (up to 12 months)
    • May progress in frequency/duration to chronic cluster headache
  • Chronic:
    • No associated periods of headache remission (or brief, < 1 month)
    • ≥ 12 months without remission required for diagnosis
    • May arise as a primary headache disorder or as a progression from episodic cluster headache
  • Secondary causes of cluster headache meet the criteria for cluster headache but are caused by an associated underlying structural brain lesion.


Diagnostic criteria


  • ≥ 5 attacks meeting the following criteria:
    • Severe intensity
    • Unilateral
    • Temporal, orbital, and/or supraorbital location of pain
    • Duration ≥ 15, but ≤ 180 minutes if left untreated
  • Plus ≥ 1 of the following symptoms ipsilateral to the pain:
    • Injected conjunctiva
    • Lacrimation
    • Nasal congestion
    • Rhinorrhea
    • Eyelid ptosis
    • Eyelid edema
    • Facial diaphoresis
    • Pupillary miosis
    • Restlessness or agitation
  • Frequency: every 2 days, up to 8 times per day
  • Not better accounted for by another headache diagnosis

Episodic cluster headache:

Meets the criteria stated above plus the following criteria:

  • Headaches occur in clusters.
  • ≥ 2 clusters lasting ≥ 7 days, but ≤ 1 year if left untreated
  • Clusters separated by headache-free periods of remission lasting ≥ 3 months

Chronic cluster headache:

Meets the criteria stated above plus the following criteria:

  • Absence of remission, OR
  • Remissions lasting ≤ 3 months during ≥ 1-year period

Laboratory evaluation

  • Laboratory evaluation is indicated only if the following conditions are suspected:
    • Organ dysfunction
    • Volume depletion/overload
    • Electrolyte disturbance
    • Infectious process
  • Laboratory testing should be specific to the suspected underlying cause(s):
    • Organ dysfunction:
      • Cardiac biomarkers
      • BUN, creatinine (renal function)
      • AST/ALT (hepatic function)
    • Volume depletion/overload:
      • BUN/creatinine (renal function)
      • AST/ALT (hepatic function)
      • The presence of BNP indicates heart failure.
      • Thyroid studies
    • Electrolyte disturbance: chemistry panel or electrolyte panel
    • Infectious process:
      • CBC
      • CSF studies


  • Neuroimaging is indicated at the initial evaluation of cluster headache:
    • Rule out the secondary causes of headaches.
    • Evaluate for pituitary abnormalities.
  • Repeat imaging is indicated only in the following cases:
    • Red-flag headache symptoms
    • Focal neurologic findings
    • Headache characteristics have changed or no longer classify as any of the primary headache disorders.
  • Imaging modalities:
    • MRI of the brain with and without contrast is the test of choice.
    • CT is faster for triage of suspected acute intracranial hemorrhage.


While abortive therapy may successfully terminate an isolated attack, preventative therapy is the mainstay of cluster headache management. Preventive strategies should be started at the onset of headache episodes.

Abortive therapy

  • 1st-line therapies:
    • 100% oxygen:
      • Administered by a nasal cannula (office setting or ED)
      • May be approved for home use in some cases
      • Immediate onset of action
      • Well tolerated and highly effective
      • Main adverse effect: dry nose
    • Triptans (subcutaneous):
      • May be administered at home (self-injection) or in the office
      • Rapid onset of action
    • Triptan (intranasal):
      • For individuals who cannot tolerate or self-administer injections
      • Slower onset of action, but more convenient
      • To be administered contralateral to the side of the headache
  • 2nd-line therapies:
    • Intranasal lidocaine:
      • Easy to self-administer
      • Well tolerated (no systemic adverse effects)
    • Ergotamines:
      • Administered orally or IV
      • Long half-life → potential bridge to preventative therapy

Preventative therapy

  • Indication:
    • Episodic and chronic cluster headache
    • Prevention/treatment of headache and toxicity caused by abortive medication overuse
  • Pharmacologic therapy:
    • Glucocorticoids:
      • Relatively rapid onset to suppress clusters
      • Not indicated for long-term use due to known toxicities
      • Used for suppression of infrequent episodic bouts
      • Bridge to preventative therapy while slower acting agents are titrated to effective doses
      • Administration: oral, IM, occipital nerve block
    • Verapamil:
      • Slow onset of action
      • May need bridge therapy with glucocorticoids or ergotamines
      • Inexpensive and usually well tolerated
      • May be tapered and discontinued prior to an expected remission
    • Galcanezumab:
      • Monoclonal antibody against calcitonin gene-related peptide (CGRP) ligand
      • Modestly effective
      • Reserved for individuals refractory to the above preventative therapies
    • Nonpharmacologic therapies:
      • Neuromodulation (vagus nerve stimulation, sphenopalatine ganglion stimulation)
      • Deep brain stimulation
    • Neurolytic therapy:
      • Mechanical, thermal, or chemical
      • Targets include culprit somatic and/or autonomic nerves.
      • Reserved for a select subset of individuals
  • Behavioral approaches:
    • Lifestyle modifications:
      • Avoidance of triggers (alcohol, strong smells)
      • Regular sleep
      • Exercise
    • CBT
    • Relaxation techniques
    • Biofeedback

Differential Diagnosis

  • Paroxysmal hemicrania: a rare form of headache and TAC with substantial similarity to cluster headache in terms of intensity, location, and presence of autonomic symptoms. Attacks occur 5–40 times per day and last 2–30 minutes. The diagnosis is clinical. Paroxysmal hemicrania is responsive to the NSAID indomethacin, which is useful both in diagnosis and treatment. Other NSAIDs, calcium channel blockers, and corticosteroids are also effective.
  • Hemicrania continua: a TAC with substantial similarity to cluster headache in terms of location and presence of autonomic symptoms. Hemicrania continua is distinguished by a milder intensity but a longer, continuous headache duration of several hours. There may be periodic exacerbations of severe intensity, but the underlying moderate headache does not abate without treatment. The diagnosis is clinical. Hemicrania continua is responsive to the NSAID indomethacin, which is useful both in diagnosis and treatment. 
  • SUNCT and SUNA: rare forms of TAC similar to cluster headache in pain location but may also be retroorbital and rarely in other trigeminal and nontrigeminal areas. Attacks of prolonged stabbing pain (1–5 minutes) may occur in isolation or in groups with a total duration of up to 10 minutes. The attacks are often associated with triggers, but may also be spontaneous. Oxygen and indomethacin are ineffective in SUNCT and SUNA, but IV lidocaine may be effective.
  • Primary stabbing headache: while not classified as a TAC, primary stabbing headache does have some overlapping clinical features. Pain attacks are brief (< 1 second), sharp and stabbing, and unilateral, but are not accompanied by autonomic symptoms. Attacks may be isolated or can occur at irregular intervals with several hours or even days between episodes. Diagnosis is clinical. The attacks usually subside with the administration of indomethacin.
  • Trigeminal neuralgia: a rare neuralgiform headache entity that manifests in the temporal, orbital, or supraorbital area(s) with extreme sudden burning or shock-like face pain. Trigeminal neuralgia may mimic a TAC as it may manifest in any of the trigeminal areas. Attacks generally last < 5 seconds, are unilateral, and not accompanied by autonomic symptoms. Management includes drugs such as anticonvulsants (e.g., carbamazepine) and tricyclic antidepressants, and surgery. Typical analgesics and opioids have not been proven effective to treat trigeminal neuralgia.
  • Migraine headache: a type of primary headache that is severe and generally described as unilateral and throbbing. Migraine headaches are associated with neurological symptoms such as nausea and/or light and sound sensitivity. Attacks last between 4 and 72 hours and are more common in women. Individuals may experience an aura, such as a visual phenomenon, or experience tingling on the skin or difficulty speaking before headache onset. Diagnosis is clinical and based on the typical symptoms. Migraines do not generally present with autonomic symptoms, but there is a distinct subset that does. Management includes avoiding loud noises and light, and treatment with simple analgesics and/or triptans.
  • Medication-overuse headache: also called rebound headache. A type of secondary headache in individuals who have frequent or daily headaches despite, or because of, the regular use of medications to relieve headaches. Medication-overuse headache is usually preceded by an episodic primary headache disorder that has been treated with excessive amounts of abortive medications, especially drug combinations containing caffeine and codeine. Treatment consists of establishing an effective preventative regimen so that the offending abortive agent(s) can be weaned or discontinued.
  • Sinus headache: a headache that occurs in the setting of acute or chronic sinusitis. The pain is typically described as constant and deep around the cheeks, forehead, or bridge of the nose. Sinus headache is associated with symptoms including a runny nose, swelling or tearing of the eyes, and fever. Management includes decongestants, antihistamines in the case of allergy, and antibiotics in the presence of a bacterial infection.


  1. May, A. (2020). Cluster headache: Epidemiology, clinical features, and diagnosis. UpToDate. Retrieved July 23, 2021, from
  2. May, A. (2020). Cluster headache: Treatment and prognosis. Retrieved July 23, 2021, from
  3. American Migraine Foundation. (2019). Understanding cluster headache. Retrieved July 19, 2021, from
  4. Benoliel, R. (2012). Trigeminal autonomic cephalgias. British Journal of Pain. 6(3), 106–123.
  5. National Institute of Neurological Disorders and Stroke. (2019). Paroxysmal hemicrania information page. Retrieved July 29, 2021, from 
  6. National Institute of Neurological Disorders and Stroke. (2019). Hemicrania continua information page. Retrieved July 29, 2021, from 

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