Cluster Headache

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Continuing Education Activity

Cluster headaches are the most common of the primary headache type known as trigeminal autonomic cephalgia. They are fairly rare, plaguing 0.1% of the population, making studying the disease process difficult at best. They are considered one of if not the most severe types of headaches, and so, despite their rarity, recognition and treatment are vital. This activity reviews the evaluation, treatment, and management of cluster headaches, including recognizing other forms of headache. Also, it assesses the approved abortive treatments and prophylactic management and distinguishes them from common treatments with poor supporting evidence. The activity highlights the role of the interprofessional team in evaluating and treating patients with cluster headaches.


  • Review the specific diagnostic criteria of a cluster headache, including the staging.
  • Describe abortive treatments for cluster headaches, including lifestyle changes, medication choices, and supplemental treatments.
  • Identify prophylactic therapy options for cluster headaches and distinguish these from popular medications with limited therapeutic evidence.
  • Outline the importance of enhancing care coordination among the interprofessional team to ensure proper evaluation and management of cluster headaches.


Cluster headaches are the most common of the primary headache type known as trigeminal autonomic cephalgias (TACs). They are relatively rare, plaguing 0.1% of the population, making studying the disease process difficult at best. They have earned consideration as one of if not the most severe types of headache, and so, despite their rarity, recognition and treatment are vital. There is some degree of genetic correspondence, as first-degree family members are 18 times more likely to be diagnosed with cluster headaches. However, the mode of inheritance is unclear. Some families seem to pass the symptoms along with an autosomal recessive pattern, while others seem to be autosomal dominant. 

Like other trigeminal autonomic cephalgias (TACs), cluster headache is a short-lasting unilateral headache with at least one autonomic symptom ipsilateral to the headache, such as lacrimation, nasal congestion, conjunctival injection, or aural fullness.[1] The associated nasal congestion can sometimes lead to a misdiagnosis of "sinus headache," and patients are often managed by decongestants, which are ineffective for cluster headaches. These headaches can occur every other day to eight times a day. They usually occur at approximately the same time of day, most often at night. Most patients are episodic, with daily attacks for weeks to months, followed by remission for months to years.[2][3][4]


The exact etiology of cluster headaches is not clear. There have been several theories suggested and tested. Unfortunately, sample sizes are limited due to the relative rarity of patients suffering from this condition. Some studies have suggested a genetic component, and multiple loci associated with cluster headaches have been identified.[5][6]

There is a known association between the trigeminovascular system, the parasympathetic nerve fibers involved in the trigeminal autonomic reflex, and the hypothalamus. However, how these structures interact to cause these headaches is not certain. Moreover, as there is a definite familial connection, considerable effort has gone into studying the genetics of the condition, which has also led to a biochemical assessment. 

There is a definitive link between vasodilation and a pain attack. Activation of the trigeminovascular system causes perivascular afferent nerves to cause vasodilation. The belief is that the activation of the trigeminal nerve is unilateral; that said, it has not been detected and confirmed with functional imaging. Also, a complete trigeminal nerve root section does not affect the number or frequency of attacks. This lack of change does not rule out the trigeminovascular system as a component of the cluster headache; it merely shows that there are other components.

The hypothalamus has a definite association with cluster headaches. The attacks have a circadian periodicity, happen most often at night, have a relapsing-remitting course, and have seasonal variation, all of which imply the involvement of the hypothalamus, the biological clock.[7] It is further supported by a study that revealed decreased melatonin levels and a complete loss of circadian rhythm in patients with cluster headaches.[8] PET scans have shown activation of the inferior hypothalamic grey matter while the patient is having an attack. Morphology studies have also demonstrated anatomic abnormalities within this same hypothalamus region. Of note, though, stimulation of the hypothalamus does not trigger attacks. Some research suggests that stimulation of the hypothalamus may abort an attack.

The parasympathetic nerve fibers are part of the trigeminal autonomic reflex. Stimulation of trigeminal afferents projecting to nociceptive pathways like sphenopalatine ganglion and trigeminal ganglion may cause pain and autonomic symptoms, including conjunctival injection or lacrimation, rhinorrhea, and facial vasodilation; as a result of central disinhibition and neuropeptide release.[9] Like the hypothalamus, it is a known component of the cluster headache, but the exact trigger of how the trigeminal reflex is activated is uncertain.

Risk Factors

  • Male gender
  • Age of more than 30
  • Consumption of alcohol
  • Prior brain surgery or trauma
  • Family history[10]


Cluster headaches occur in 0.1% of the general population. Any age is possible for onset, but the typical age is approximately 30 years. Men are three times more likely to suffer from this condition than women, though current research has shown that the ratio has decreased over time.[11] This incidence may be due to an improvement in diagnostic accuracy; often, women receive an erroneous diagnosis of migraines rather than cluster headaches. Of interest, up to 88% of all patients diagnosed with cluster headaches smoke cigarettes.[12] 

Patients are 14 to 39 times more likely to be diagnosed if they have a 1st-degree relative who also had cluster headaches and have a 2- to 8- fold risk if a second-degree relative has the same diagnosis.[13] Moreover, a higher incidence is also reported in patients with a history of head trauma.[14] Research suggests anywhere between 30 to 80% of patients with cluster headaches also have sleep apnea.


As stated above, there is no single clear source of cluster headaches. There is a circadian periodicity, leading to investigation of the hypothalamus, which ultimately shows abnormalities in morphology studies.[7] There is also the involvement of the trigeminovascular system and the parasympathetic nerve fibers.[9] Some research studies have suggested a defect in the central pathway of pain control and autonomic nervous system dysregulation leading to dysfunction in supraspinal control of pain and cognitive processing. Researchers have also noted dysfunction in inter and intracellular signaling pathways of GABA, ion channels, and inflammation-related molecules, including IL-2, adhesion molecules, and histamine.

Genetic analysis has many possible sources, including PER3 (associated with the circadian rhythm), orexin-B (associated with the sleep-wake cycle, food intake, and modulation of nociceptive neurotransmission), and PACAP receptor gene, being that PCAP (pituitary adenylate cyclase-activating polypeptide) increases in the blood during attacks. More research is necessary for all suggested genetic pathways.

History and Physical

A thorough history is essential to the diagnosis of cluster headaches. Patients reveal that they experience ten out of ten unilateral pain, most often located intra or supraorbitally. The pain is nonfluctuating and explosive in quality. Patients must have at least one autonomic symptom ipsilateral to the side with pain. Patients feel restless and may be seen rocking back and forth due to the high pain intensity.

Autonomic Symptoms

  • Conjunctival injection or lacrimation (90% of patients)
  • Nasal congestion or rhinorrhea (84% of patients)
  • Eyelid edema or forehead/facial swelling (59% of patients)
  • Miosis or ptosis (unknown percentage)[15]

Photophobia and phonophobia, when present, are more likely to be ipsilateral, as opposed to migraine, when they are always bilateral. This presentation is characteristic of TACs. Up to 33% of patients will also experience general allodynia; this is more common in women, patients with recent attacks, those with a younger age at the time of onset, and those with comorbid depression or migraines.[16] There is often suicidal ideation associated with the attacks, but the risk of actual suicide is low.

Unlike patients with migraines, these patients are unlikely to hold still. Many patients pace or rock in place; there are descriptions of patients even banging their heads to distract themselves from the headache. Attacks typically last anywhere from 15 minutes to 3 hours. They can occur up to eight times a day, although most commonly, patients experience attacks twice daily, usually at night. Most patients will have attacks for weeks to months and then have remission for months up to years. This pattern usually lasts up to fifteen years. Cluster headache is classified as chronic once a symptomatic period persists for a year without remission.[17]

Potential Triggers

  • Watching television
  • Alcohol
  • Hot weather
  • Stress
  • Use of nitroglycerin
  • Sexual activity
  • Glare


The diagnosis is clinical. While some lab abnormalities, such as increased histamine in the blood during attacks, and anatomical changes found in a morphology study, are not useful in a clinical setting. A questionnaire asking about headache duration (less than 180 minutes) and autonomic symptoms (conjunctival injection or lacrimation) has a sensitivity of 81% and a specificity of 100%. Clinicians must have a degree of suspicion, as cluster headaches are usually misdiagnosed, and patients do not receive a clinical diagnosis for up to five years.[3]

According to the International Classification of Headache Disorders, 3 edition (ICHD-3), diagnostic criteria for cluster headaches require all of a set of criteria.[17] These are:

  • At least five attacks
  • Attacks characterized by severe supraorbital, unilateral orbital, and/or temporal pain lasting 15 to 180 minutes when untreated; during part (but less than half) of the time-course of cluster headache, attacks may be less severe and/or of shorter or longer in duration 
  • Either one or both of the following: 
    • At least one of the following signs/symptoms ipsilateral to the headache:
      • Conjunctival injection and/or lacrimation
      • Forehead and facial sweating
      • Nasal congestion and/or rhinorrhea
      • Eyelid edema
      • Miosis and/or ptosis
    • A sense of agitation or restlessness
  • Attacks have a frequency between one every other day and eight per day; during part (but less than half) of the active time-course of headache, attacks may be less frequent 
  • Not better explained by another ICHD-3 diagnosis

Diagnostic criteria for episodic cluster headache:

  • Attacks fulfill the criteria for cluster headache (as above) and occur in bouts (cluster periods) 
  • At least two cluster periods last from 7 days to one year (when untreated), separated by pain-free remission intervals of at least three months[17]

Diagnostic criteria for chronic cluster headache:

  • Attacks fulfill the criteria for cluster headache
  • Attacks occur without a remission period, or with remissions lasting less than three months, for a minimum of 1 year[17]


Patients should have magnetic resonance imaging (MRI), or computed tomography (CT) of the head with contrast as an alternative, to rule out any structural abnormality.[18] It is also essential to rule out pituitary abnormality, as a significant number of patients with prolactinomas and growth hormone tumors present with TACs.[19]

Treatment / Management

There are two sides to the treatment of cluster headaches: treatment of acute attack and preventative treatment.

Acute Treatment

Perhaps the most well-known treatment for cluster headaches is 100% oxygen therapy.[20] This approach is a level A recommendation and is unique to cluster headaches vs. all other types of headaches. At least 66% of patients respond to oxygen therapy. It is effective in less than 10 minutes. Oxygen use carries no risks or side effects, making it an excellent choice for treatment. Unfortunately, insurance often will not pay for oxygen therapy for the cluster headache patient, which can be difficult to obtain.

Triptans are the only other level A recommended treatment. Delivery of these drugs can be subcutaneous sumatriptan or zolmitriptan delivered via nasal spray.[21] Intranasal triptans can be administered contralateral to the side of the headache if subcutaneous injections are not tolerated. Options include intranasal sumatriptan 20 mg or intranasal zolmitriptan 5 mg. Oral medication of any form is not recommended, as the onset time is often longer than the headache.

Other treatment options include intranasal lidocaine (with a reported 33% response), octreotide, and ergotamine.[22] Unfortunately, 10% to 20% of patients with chronic cluster headaches develop drug resistance. Patients should be instructed to avoid triggers, especially alcohol. While there is no proof that smoking cessation will decrease the risk of headaches, patients should also be encouraged to stop smoking.

Preventative Treatment 

The only level A recommended treatment for the prevention of cluster headaches is a suboccipital blockade. Adverse events are nonserious, including transient injection site pain and low-level headache.

Verapamil is the most widely prescribed preventative drug.[23] It is recommended as initial preventive therapy for patients with chronic cluster headaches and those with episodic cluster headaches for at least two months.[20] Verapamil is started at 240 mg once daily and is effective as preventive therapy for episodic and chronic cluster headaches.[24] It is recommended to do regular ECGs to monitor cardiac function when a patient is using this drug. Despite verapamil's popularity among providers, it only has a level C recommendation. 

Glucocorticoids are also recommended as preventive therapy for patients with episodic cluster headaches and active cluster periods that are infrequent and last less than two months. A study revealed 70 to 80% response to therapy.[25] However, since they have serious long-term side effects, they are not prescribed for an extended period when alternative therapies are helpful. They are especially beneficial when other preventive therapies take time for the onset of action. There is no one regimen proven to be better than the other. One such regimen is oral prednisone 60 to 100 mg once daily for five days or more, decreasing the dose by 10 mg daily. Oral and intravenous formulations can be taken together.[26]

Other pharmacological options include lithium, valproic acid, melatonin, and intranasal capsaicin.[25]

There has been much research into electrical stimulation. Sites of stimulation include the sphenopalatine ganglion, occipital, and vagus nerve. Deep brain stimulation of the hypothalamus has been very successful and has proven helpful in treating drug-resistant patients.[27] Vagus nerve stimulation can be an option with a nonimplanted device.[28]

Differential Diagnosis

Other TACs that require differentiation from cluster headaches are as follows:

  • Paroxysmal hemicrania: This unilateral headache lasts only 2 to 30 minutes. It responds to indomethacin.
  • Short-Lasting unilateral neuralgiform headaches with conjunctival injection and tearing (SUNCT syndrome): This extremely rare unilateral headache lasts 5 to 240 seconds. They can occur three to 200 times daily and are usually refractory to treatment.
  • Short-Lasting unilateral neuralgiform headaches with cranial autonomic symptoms (SUNA)
  • Hemicrania continua[29]
  • Probable trigeminal autonomic cephalgia

Some other primary headaches may also fall into differential:

  • Tension headache: This bilateral headache is described as a dull ache or squeezing ache. It is associated with fatigue, pericranial muscle tenderness, or sleep disturbances.
  • Trigeminal neuralgia: this is an inconsistent, paroxysmal headache described as an electrical, sharp, or stabbing pain in the trigeminal distribution. Events last for a few seconds.[17][3]
  • Primary stabbing headache: Stabs lasting from 1 to 10 seconds, without cranial autonomic symptoms[30]
  • Migraine: the most common description of this headache is a unilateral "throbbing" headache. Patients tend to lie quietly in a dark room. It is associated with fatigue, nausea, photophobia, phonophobia, and vomiting. Up to 50% of patients can have bilateral autonomic symptoms; this is the most common condition with which cluster headache is confused.

Other structural lesions may present as TACs.[31] These include the following:

  • Vascular abnormalities
    • Carotid artery dissection
    • Intracranial large artery aneurysms
    • Cerebral venous thrombosis[32]
    • Cerebral cavernous hemangioma
    • Brain arteriovenous malformations
    • Brain dural arteriovenous fistulas
  • Inflammatory or infectious pathologies
    • Temporal arteritis
    • Dental abscess
    • Sinusitis[33]
  • Neoplasms
    • Meningiomas[34]
    • Prolactinomas and growth hormone tumors[19]
    • Nasopharyngeal carcinoma

Treatment Planning

Drug Dose Notes
Prednisone[20] 1 mg/kg up to 60 mg four times a day; aper the dose by 10 mg every day Common side effects include hypertension, diabetes, infection, weight gain, Cushingoid facies, easy bruising and skin fragility, cataracts, aseptic necrosis of the femoral or humeral heads, and osteoporosis.
Verapamil 80 mg three times a day; increase the daily dose by 80 mg every 10 to 14 days as tolerated. Up to 960 mg/d may be used. High-dose verapamil may cause electrocardiographic (ECG) abnormalities, including heart block and bradycardia.[35] ECG should be obtained after each dose increment above 480 mg/d. Other side effects include gastrointestinal discomfort, constipation, edema, dull headache, and gingival hyperplasia.
Galcanezumab 300 mg, given as 100 mg successive dosages at onset, then every month till the end of the cluster period. Injection site reactions are the most common.
Greater occipital nerve injection[36] Different formulations of corticosteroids and local anesthetics No serious adverse events have been reported so far.

Table 1. Short-term preventive therapy for episodic cluster therapy

Drug Dose Notes
Verapamil 80 mg three times a day; increase the daily dose by 80 mg every 10 to 14 days as tolerated. Up to 960 mg/d may be used. High-dose verapamil may cause electrocardiographic (ECG) abnormalities, including heart block and bradycardia.[35] ECG should be obtained after each dose increment above 480 mg/d. Other side effects include gastrointestinal discomfort, constipation, edema, dull headache, and gingival hyperplasia.
Noninvasive vagus nerve stimulation  6 to 24 stimulations/d May offer temporary relief. 


 9 to 12 mg/d Over-the-counter preparations may sometimes not be reliable.


It is started at 25 mg/d, increasing at the rate of 25 mg per week according to response, and reaching up to 50 mg twice daily. The maximum tolerated dose is 400 mg/d. Associated with both short-term and long-term cognitive dysfunction even at low doses (≤100 mg/day). Also associated with paresthesia and dose-related sedative effects. Numbness and tingling resolve over 2 to 3 months of therapy.[37]


400 to 800 mg/d

Narrow therapeutic index, used only as a last resort. Significant cardiac adverse effects include cardiac arrhythmia, including bradycardiaabnormal T waves on ECG (T-wave inversion), sinoatrial dysfunction (SA block), and ST-segment depression.[38] It may also cause peripheral edema, hypotension, cardiovascular collapse, and unmask Brugada syndrome.[39]

This drug also has a plethora of CNS effects, including abnormal gait, confusion, decreased alertness, disorientationdrowsiness, sedated state, ataxialethargy, slurred speech, headache, and memory impairment. Seizure (including tonic-clonic twitching), coma, hallucination, agitation, and abnormal electroencephalogram (EEG) may be observed at higher doses.[40]

Table 2. Long-term preventive therapy for episodic headache and prolonged chronic cluster headache


Episodic: 85 to 90% of patients. Patients experience daily attacks for weeks to months and then have a remission lasting months or years. Patients typically have 1 to 2 episodes yearly, most often in spring or autumn.

Chronic: 15 to 20% of patients. Patients experience attacks lasting more than a year without remission or remission that lasts less than one month; 10 to 20% of these patients will develop drug resistance.

Probable: patients whose attacks fulfill all but one criterion.[3]


Around 25% of patients who experience a cluster headache will never have another one. Another 15 to 20% of patients will have chronic cluster headaches, 10 to 20% of which will develop drug resistance. This condition often resolves in approximately 15 years.

Patients can experience detriments to their mental health. There will be physical burdens and loss of quality of life. Many patients describe suicidal ideation, but actual follow-through action is rare.[2][41]


There is a frequent association with psychiatric conditions, including depression, anxiety, and aggressive behavior. Suicidal attempts are rare, but these conditions do increase the disease burden. Evidence supports systemic autonomic function being affected, which is usually subclinical and includes bradycardia, tachycardia, hypertension, and arrhythmias (such as AV block and SA block). The most concerning of autonomic dysregulation is an increased risk of dysregulation of systemic blood pressure. As in sleep apnea, patients have an increased risk of not undergoing physiological blood pressure dipping during sleep, leading to end-organ damage and increasing the risk of cardiovascular disease. This situation is accompanied by an increased risk of an abnormal ankle-brachial index (ABI), indicating peripheral arterial disease, which confirms that there is also an increased risk for cardiovascular disease.[42][43]


Patients usually present in urgent care or family care. Internists, neurologists, and pain specialists may be consulted when required.

Deterrence and Patient Education

Alcohol is the most common trigger for a pain attack. Most patients recognize this trigger and stop alcohol use on their own, but it may be necessary to provide patients with cessation counseling. While no evidence exists that quitting smoking affects the number of pain attacks, patients should be encouraged to stop. Patients should also be educated on pharmacological triggers, specifically vasodilators. Patients may require aid in lifestyle management and should receive an offer for psychiatric counseling.[3] Patients are counseled to keep a headache diary that helps track symptoms and response to therapy.

Pearls and Other Issues

  • Cluster headaches are unilateral periocular headaches occurring between 15 minutes to 3 hours, with episodes usually occurring twice a day for weeks to months with remissions of months to years.
  • There are associated autonomic symptoms on the ipsilateral side.
  • The exact etiology and pathophysiology are unknown.
  • Acute treatment includes oxygen and nonoral triptans.
  • Prophylactic treatment is a suboccipital blockade.

Enhancing Healthcare Team Outcomes

The average cluster headache patient can take approximately five years to diagnose, often only after visiting several different clinicians. Cluster headaches are often confused with migraines. The only way to improve diagnosis and management is with an interprofessional healthcare team dedicated to treating headaches.

The clinician (i.e., MDs, DOs, NPs, and PAs) must strive to recognize the episodic nature of cluster headaches, autonomic dysregulation, and even the patient's activity during an attack.

Unfortunately, though oxygen is a level A recommended treatment for cluster headaches, it may not be covered by insurance - this may be due to a lack of understanding about cluster headaches by the insurance companies or a misunderstanding about the price differential between prescribing a triptan versus prescribing oxygen. The out-of-pocket cost for a patient buying oxygen depends on the state and can be anywhere from $500 to $10000 per year. Some patients ask about welder's oxygen, which is non-medical grade oxygen; however, this is usually not any cheaper than medical oxygen and may have impurities. Practitioners should refer insurers to the American Headache Society Guidelines during peer-to-peer conversations. Medicare and Medicaid have ruled that they will not cover oxygen for cluster headaches. Because oxygen is an excellent abortive treatment, the social worker may be involved in the care to ensure that the patient does not lack this therapy because of finances.

The neuroscience or pain nurse should educate the patient on avoiding alcohol and the importance of getting good sleep. In addition, the patient should be told that smoking cessation is important. The nurse should also emphasize the importance of a stress-free lifestyle and avoiding hot temperatures. Finally, close follow-up is essential in preventing future attacks. Interprofessional team members should communicate if anyone changes the medication, as one of the common causes of recurrent attacks is a low dose of prophylactic medication. Pharmacists should review medication dosages, check drug interactions, and educate patients about side effects.

All interprofessional team members must be prepared to communicate with other team members regarding any concerns or patient status changes and are all tasked with accurately documenting their findings and interactions in the patient's medical record so that everyone on the care team has access to the same accurate and up to date information.


Despite only a level C recommendation, healthcare providers generally consider verapamil prophylactic maintenance therapy. There is discordance between evidence-based medicine and provider activity.

Cluster headaches require an interprofessional team approach, including clinicians, specialists, specialty-trained nurses, and pharmacists collaborating across disciplines to achieve optimal patient results.[44] [Level 5]



7/4/2023 12:32:36 AM



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