Changes

March to April 2022 — reviewed. A literature search was conducted in February 2022 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of the topic. The recommendations have been updated in line with current evidence in the literature. The section on Prescribing information has been expanded to include detailed information about sumatriptan and zolmitriptan preparations for acute treatment of cluster headache.

Update

Goals

To support primary healthcare professionals to:

• Be aware when to suspect cluster headache.
• Arrange specialist referral for any person presenting with a suspected first bout of cluster headache.
• Seek specialist advice or arrange referral to a neurology specialist for a woman with cluster headache who is pregnant.
• Offer management in primary care for acute attacks of confirmed cluster headache in a person who is not pregnant.
• Seek specialist advice or arrange referral to a neurology specialist if a person has atypical or refractory symptoms, or if preventative treatment such as verapamil is being considered.

Outcome measures

No outcome measures were found during the review of this topic.

Audit criteria

No audit criteria were found during the review of this topic.

QOF indicators

No QOF indicators were found during the review of this topic.

QIPP - Options for local implementation

No QIPP indicators were found during the review of this topic.

NICE quality standards

The following NICE quality standards are relevant for this CKS topic:

• Statement 1. People diagnosed with a primary headache disorder have their headache type classified as part of the diagnosis.
• Statement 2. People with a primary headache disorder are given information on the risk of medication overuse headache.
• Statement 3. People with tension-type headache or migraine are not referred for imaging if they do not have signs or symptoms of secondary headache.
• Statement 4. People with migraine are advised to take combination therapy with a triptan and either a nonsteroidal anti-inflammatory drug (NSAID) or paracetamol.

[NICE, 2013]

What is it?

• The International Classification of Headache Disorders (ICHD) categorizes headache into [IHS, 2018] [Ahmed, 2019]:
  
  • Primary headaches — these are not associated with another underlying condition, and include cluster headache which falls into the group of headache disorders known as the 'trigeminal autonomic cephalalgias'.
  • Secondary headaches — these are precipitated by another condition or disorder (local or systemic).
    • See the CKS topic on Headache - assessment for more examples of primary and secondary headache disorders.
• Trigeminal autonomic cephalalgias have prominent autonomic features and shared pathophysiology, and include [Ahmed, 2019; Steiner, 2019; Wei, 2019]:
  • Cluster headache (the most common trigeminal autonomic cephalalgia) — characterized by frequently recurring, localized, short-lasting but severe headache usually accompanied by autonomic symptoms.
  • Paroxysmal hemicrania (typically responds to indomethacin).
  • SUNCT/SUNA (short-lasting neuralgiform attacks with conjunctival injection and tearing/short-lasting neuralgiform attacks with cranial autonomic features).
  • Hemicrania continua (causes constant pain).
• The ICHD categorizes cluster headache according to the frequency of attacks [IHS, 2018] [Ahmed, 2019]:
  • Episodic — attacks occur in periods lasting from 7 days to one year and are separated by pain-free periods lasting at least 3 months.
  • Chronic — attacks occur for one year or longer without remission, or with remission periods lasting less than 3 months.

What causes it?

The exact pathophysiology of cluster headache is complex and not fully understood [Wei, 2018].

• It is a neurovascular headache, and may involve synchronised abnormal activity in the hypothalamus, the trigeminovascular system, and the autonomic nervous system (parasympathetic nerve fibres) [Hoffmann, 2018; Wei, 2018].
  • Acute attacks involve activation in the region of the posterior hypothalamic grey matter [IHS, 2018]. Hypothalamus involvement may contribute to the circadian rhythms and seasonal cycles of the condition [Wei, 2018].
• There may be a higher risk for family members, with first-degree relatives having a 5–18 times increased risk and second-degree relatives a 1–3 times higher risk compared with the general population, however the exact inheritance and genetics of the disorder are not yet known [Wei, 2018].
  • The International Headache Society (IHS) guideline notes that acute cluster headache may be inherited as an autosomal dominant condition in about 5% of people [IHS, 2018]. In other families, however, transmission seems to follow an autosomal recessive pattern, so the exact mode of inheritance is unclear [Hoffmann, 2018].
• Environmental factors may also trigger an acute attack, such as alcohol, smoking, histamine, nitrate-containing foods such as cured meats, and the smell of volatile substances such as petrol, paint, perfume, or nail varnish [IHS, 2018; Ahmed, 2019; Wei, 2019; Elbadawi, 2021].

How common is it?

Cluster headache is a rare disorder and it is difficult to accurately assess its true prevalence [Wei, 2018] [Ahmed, 2019].

• A meta-analysis of 16 population-based epidemiological studies found [Fischera, 2008]:
  • A pooled lifetime prevalence of 124 per 100,000 and a one-year prevalence of 53 per 100,000 adult population.
  • A male preponderance with the overall male to female ratio being 4.3. The male-to-female ratio was markedly higher for chronic (15:1) compared with episodic cluster headache (3.8:1).
  • The ratio of episodic to chronic cluster headache was 6.
• The British Association for the Study of Headache (BASH) guideline states the peak age of onset of cluster headache is 20–40 years [Ahmed, 2019].
• Men are more frequently affected than women, with a ratio of about 3:1, but over time more women are being diagnosed, leading to an observed decrease in this ratio [Hoffmann, 2018].

What are the complications?

• Cluster headache can have a significant impact on quality of life, including at work, home, and school [Schwartz, 1998; Steiner, 2019; Buture, 2020].
• Cluster headache can be associated with anxiety and depression, and fear of pain and relationship issues can also affect quality of life between acute attacks [Hoffmann, 2018; Pohl, 2021].
• Cluster headache may lead to suicidal ideation, especially in people with a long duration of the condition, increased pain scores, and increased depression scores [Hoffmann, 2018; Buture, 2020]. Despite this, suicide attempts are rare [Hoffmann, 2018].

What is the prognosis?

The natural history of cluster headache is difficult to predict [Wei, 2018].

• Cluster headache is thought to be a lifelong disorder, but there may be less frequent bouts and longer periods of remission between bouts with increasing age [Wei, 2018].
• About 25% of affected people have only a single episode throughout their lifetime [Hoffmann, 2018].
• Chronic cluster headache can evolve over time into episodic cluster headache and vice versa [Wei, 2018].
  • A retrospective study of 189 people with cluster headache for at least 10 years (n = 140 episodic and n = 49 chronic cases) found 12.9% of people with initial episodic cluster headache developed chronic symptoms, and 32.6% with initial chronic cluster headache developed episodic symptoms since the condition was diagnosed [Manzoni, 1991].

What are the typical clinical features of cluster headache?

Be aware that cluster headache may co-exist with other headache disorders, such as migraine. See the CKS topic on Headache - assessment for detailed information on the assessment of a person with headache, including exclusion of red flags which may indicate a serious underlying cause.

• The International Classification of Headache Disorders (ICHD) classifies cluster headache as typically presenting with at least five attacks of severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15 minutes to 3 hours (untreated) and either or both of the following:
  • At least one of the following ipsilateral symptoms or signs: 
    • Conjunctival injection and/or lacrimation.
    • Nasal congestion and/or rhinorrhoea.
    • Eyelid swelling.
    • Forehead and facial sweating.
    • Forehead and facial flushing.
    • Sensation of fullness in the ear.
    • Miosis (excessive pupillary constriction) and/or ptosis.
  • A sense of restlessness or agitation (typically walk up and down; rock to and fro; clutch the affected side).
  • Note: attacks occur between one every other day and eight per day, and are not better accounted for by another diagnosis.
• Note: attacks can change sides, across different bouts, within the same bout, or rarely within an acute attack. Between attacks, there may be an interparoxysmal dull ache, in the same distribution as the acute attack.
• Note: the attacks may wake the person from sleep, about 1.5–2 hours after falling asleep.
• Cluster headache attacks occur in series usually lasting between 2 weeks and 3 months (cluster periods or 'bouts'). The ICHD categorizes cluster headache according to attack frequency:
  • Episodic cluster headache (85–90% of cases)
    • At least two cluster periods lasting from 7 days to one year (untreated) and are separated by pain-free remission periods lasting at least 3 months.
    • The British Association for the Study of Headache (BASH) guideline states a person may experience 1–3 attacks per day (up to 8) and they usually occur daily for 2–3 months at a time. They usually last 2 weeks to 3 months, and most often occur every 1–2 years.
  • Chronic cluster headache (10–15% of cases)
    • Attacks occur for 1 year or longer without remission, or with remission periods lasting less than 3 months.
    • Chronic cluster headache may arise de novo or evolve from episodic cluster headache.
  • Note: active bouts may be seasonal at the same time each year, and can be at set times of the day for weeks or months.

What else might it be?

Headache is a common symptom which can be associated with many conditions. The most common alternative diagnosis which can present similarly to cluster headache is migraine, and both headache disorders may co-exist.

• Other primary headache disorders:
  • Other trigeminal autonomic cephalalgias, such as paroxysmal hemicrania (attacks are usually more frequent than cluster headache; unlike cluster headache has an absolute response to indomethacin) and hemicrania continua (causes constant pain).
  • Migraine. See the CKS topic on Migraine for more information.
  • Tension-type headache. See the CKS topic on Headache - tension-type for more information.
  • Other — primary cough or exercise headache and cold-stimulus headache.
• Secondary headache disorders:
  • Trauma or injury to the head and/or neck. See the CKS topics on Neck pain - acute torticollis, Neck pain - cervical radiculopathy, and Neck pain - non-specific for more information.
  • Cranial or cervical vascular disorders such as intracerebral haemorrhage, central venous thrombosis, or temporal arteritis. See the CKS topics on Stroke and TIA and Giant cell arteritis for more information.
  • Non-vascular intracranial disorders such as idiopathic intracranial hypertension or brain malignancy. See the CKS topics on Brain and central nervous system cancers - recognition and referral and Head and neck cancers - recognition and referral for more information.
  • Exposure to a substance (such as carbon monoxide, alcohol, cocaine); medication overuse headache (including overuse of ergotamines, triptans, opioids, and/or simple analgesics); substance withdrawal (such as caffeine, opioids, or oestrogen). See the CKS topics on Carbon monoxide poisoning, Alcohol - problem drinking, Headache - medication overuse, and Opioid dependence for more information.
  • Infection (may be intracranial infection such as bacterial or viral meningitis, encephalitis, or cerebral abscess) or systemic infection. See the CKS topic on Meningitis - bacterial meningitis and meningococcal disease for more information.
  • Disorders of homeostasis such as hypoxia or hypertension including pregnancy-induced hypertension and eclampsia. See the CKS topics on Hypertension and Hypertension in pregnancy for more information. 
  • Disorders of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth or other facial or cranial structure such as acute angle-closure glaucoma, temporomandibular disorders, dental problems, otitis media, or sinusitis. See the CKS topics on Glaucoma, Otitis media - acute, Otitis media with effusion, Sinusitis, and Temporomandibular disorders (TMDs) for more information.
  • Psychiatric disorders such as somatization disorder or psychotic disorder. See the CKS topic on Psychosis and schizophrenia for more information.
• Painful cranial neuropathies, other facial pains and other headaches — includes conditions such as post-herpetic neuralgia, trigeminal neuralgia, and optic neuritis. See the CKS topics on Post-herpetic neuralgia and Trigeminal neuralgia for more information.

Scenario: Management of cluster headache

From age 16 years onwards.

Sumatriptan

Zolmitriptan

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of cluster headache.

Search dates

 August 2017 - February 2022

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

• exp Headache/, exp Cluster Headache/, exp Headache Disorders, Primary/, exp Headache Disorders/
• Chronic cluster headache/Embase
• Episodic cluster headache.ti,ab.  Chronic cluster headache.ti,ab. (Neuromodulation and cluster headache$).ti,ab
• Oxygen/therapeutic use*
• $cluster headache$

Sources of guidelines

• National Institute for Health and Care Excellence (NICE)
• Scottish Intercollegiate Guidelines Network (SIGN)
• Royal College of Physicians
• Royal College of General Practitioners
• Royal College of Nursing
• NICE Evidence
• World Health Organization
• Guidelines International Network
• TRIP database
• Agency for Healthcare Research and Quality
• Institute for Clinical Systems Improvement
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

• The Cochrane Library:
  • Systematic reviews
  • Protocols
  • Database of Abstracts of Reviews of Effects
• Medline (with systematic review filter)
• EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

• NIHR Health Technology Assessment programme
• The Cochrane Library:
  • NHS Economic Evaluations
  • Health Technology Assessments
• Canadian Agency for Drugs and Technologies in Health
• International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

• The Cochrane Library:
  • Central Register of Controlled Trials
• Medline (with randomized controlled trial filter)
• EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

• Bandolier
• Drug and Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

• Department of Health
• Health Management Information Consortium (HMIC)

Patient experiences

• Healthtalk
• BMJ - Patient Journeys

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

• British National Formulary (BNF)
• electronic Medicines Compendium (eMC)
• European Medicines Agency (EMEA)
• LactMed
• Medicines and Healthcare products Regulatory Agency (MHRA)
• REPROTOX
• Scottish Medicines Consortium
• Stockley's Drug Interactions
• TERIS
• TOXBASE
• Micromedex
• UK Medicines Information

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

• Clinical accuracy.
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Evidence exclusion criteria

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Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

• Animal studies
• Original research is not written in English

Possible exclusions for reviewed literature:

• Sample size too small or study underpowered
• Bias evident or promotional literature
• Population not relevant
• Intervention/treatment not relevant
• Outcomes not relevant
• Outcomes have no clear evidence of clinical effectiveness
• Setting not relevant
• Not relevant to UK
• Incorrect study type
• Review article
• Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

• Feasibility
  • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
• Organizational and Financial Impact Analysis
• Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
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  • Current interventions
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  • Impact on other costs
  • Condition-related costs
  • In-direct costs and service impacts
  • Time dependencies
• Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

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Competing interests declared for this topic:

None.