AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Cluster headache, also known as histamine headache, is a form of neurovascular headache. Attacks usually are severe and unilateral and typically are located at the temple and periorbital region. The pain is typically associated with ipsilateral lacrimation, nasal congestion, conjunctival injection, miosis, ptosis, and lid edema. Each headache is brief in duration, typically lasting a few moments to 2 hours. Cluster refers to a grouping of headaches, usually over a period of several weeks. To fulfill criteria for diagnosis, patients must have had at least 5 attacks occurring from 1 every other day to 8 per day and no other cause for the headache.

The 2 existing forms of cluster headache are (1) episodic clusters with at least 2 cluster phases lasting 7 days to 1 year separated by a cluster-free interval of 1 month or longer, and (2) chronic form, in which the clusters occur more than once a year without remission or the cluster-free interval is less than 1 month.

Pathophysiology

The pathophysiology of cluster headaches is not well understood. Some proposed mechanisms are described here.

Hemodynamic: Vascular dilatation may play a role, but blood flow studies are inconsistent. Extracranial blood flow (hyperthermia and increased temporal artery blood flow) increases but following the onset of pain. Vascular change is considered secondary to primary neuronal discharge.

Trigeminal nerve: The trigeminal nerve may be responsible for neuronal discharge causing cluster headaches. Substance P neurons carry sensory and motor impulses in the maxillary and ophthalmic divisions of the nerve. These connect with the sphenopalatine ganglion and interior carotid perivascular sympathetic plexus. Somatostatin inhibits substance P and reduces the duration and intensity of cluster headaches.

Autonomic nervous system: Sympathetic (eg, Horner syndrome, forehead sweating) and parasympathetic (eg, lacrimation, rhinorrhea, nasal congestion) effects occur.

Circadian rhythm: Cluster headaches often recur at the same time every day, suggesting that the hypothalamus, which controls circadian rhythms, may be the site of activation.

Serotonin: This is not as striking as in migraines, but some changes are seen.

Histamine: Although evidence supporting a causative role is inconsistent, cluster headaches may be precipitated with small amounts of histamine. Antihistamines do not abort cluster headaches.

Mast cells: Increased numbers of mast cells have been found in the skin of painful areas of some patients, but this finding is inconsistent.

Frequency

United States

Incidence is estimated to be 2-9% of migraine sufferers, making it relatively uncommon compared with classic migraines. Prevalence in males is 0.4-1%.

International

Incidence in the United Kingdom is equivalent to that of multiple sclerosis.

Mortality/Morbidity

No reported mortality is directly associated with cluster headaches, although suicides have been reported in cases where attacks are frequent and severe. The intensity of the attacks often leads those who experience cluster headaches to miss time from activities such as work or school.

Race

Cluster headaches may be underdiagnosed in black women, but ethnic differences have not been studied.

Sex

This condition is more common in males than in females. The male-to-female ratio was 6:1 in the 1960s but now is 2:1.

Age

Cluster headaches usually begin in middle adult life. The mean age of onset is 30 years for men and later for women.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

No aura exists as in migraines. Periodicity is the most striking characteristic. Typically, a patient experiences 1-2 cluster periods per year, each lasting 2-3 months.

• Pain - Described as lancinating and severe
• • Sudden onset - Peaks in 10-15 minutes
  • Unilateral facial - Remains on the same side during the cluster period
  • Duration - 10 minutes to 3 hours per episode
  • Character - Boring and lancinating, as if eye is being pushed out
  • Distribution - First and second divisions of the trigeminal nerve (Approximately 18-20% of patients complain of pain in the extratrigeminal areas [eg, back of the neck, along carotid artery].)
  • Frequency - May occur several times a day for 1-4 months (often nocturnal)
  • Periodicity - Circadian regularity in 47%
  • Remission - Long symptom-free intervals occur in some patients. The average remission is 2 years but ranges from 2 months to 20 years.
• Lacrimation (84-91%) or conjunctival injection
• Nasal stuffiness (48-75%) or rhinorrhea
• Ipsilateral eyelid edema
• Ipsilateral miosis or ptosis
• Ipsilateral forehead and facial perspiration (26%)
• Restlessness/agitation (90%)

Physical

Physical examination findings should be normal except for the lacrimation and conjunctival injection that may occur. Ptosis can also be seen. Accompanying findings are consistent with ipsilateral autonomic features characterized by cranial parasympathetic activation and sympathetic hypofunction. The presence of other abnormalities suggests another etiology for the headache.

• Parasympathetic overactivity
• • Ipsilateral lacrimation
  • Conjunctival injection
  • Rhinorrhea or congestion
• Ocular sympathetics paralysis - Mild Horner syndrome (eg, ptosis, miosis, anhidrosis)
• Bradycardia
• Facial flushing or pallor
• Scalp and facial tenderness
• Ipsilateral carotid tenderness (in some patients)
• Patient often is in severe distress.
• • Patient may lower the head and press on the site of pain, sometimes crying or screaming.
  • Physical exercise may help some patients obtain relief.
  • Patient may threaten suicide.

Causes

Provocation of attacks

• Subcutaneous injection of histamine provokes attacks in 69% of patients.
• Attacks are triggered in some patients by stress, allergens, seasonal changes, or nitroglycerin.
• Alcohol induces attacks during a cluster but not during remission. Of patients with cluster headache, 80% are heavy smokers and 50% have history of heavy ethanol use.
• Risk factors
• • Male sex
  • Older than 30 years
  • Small amounts of vasodilators (eg, alcohol)
  • Previous head trauma or surgery (occasionally)

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Connective tissue disorder (eg, systemic lupus erythematosus [SLE])
Hemicrania continua
Cyclical migraine
Allergen exposure
Intracranial neoplasm
Intracranial trauma
Interior carotid artery dissection
Cerebral venous thrombosis
Intermittent hydrocephalus
Acute hypertension (including response to pressors, pheochromocytoma, and preeclampsia)
Eye disorders (eg, acute optic neuritis, acute glaucoma)
Chronic paroxysmal hemicrania (CPH)
Medication adverse effect
Sleep apnea headache

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Diagnosis is based on historical and physical findings.
• History of attack, periodicity, and rhythmicity are the keys to diagnosis.

Imaging Studies

• Imaging studies are not diagnostic but are useful to exclude other causes in selected patients.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Emergency Department Care

• Oxygen (acute attack)
• • Oxygen (8 L/min for 10 min or 100% by mask) may abort the headache if used early.
  • Mechanism of action is unknown.
• Sumatriptan
• • Sumatriptan is the most studied of the triptans in cluster headache. Subcutaneous injections can be effective, in large part, due to the rapidity of onset. Studies have indicated that intranasal administration is more effective than placebo but not as effective as injections. No evidence suggests that they are effective orally. Typical dose is 6 mg SQ with the ability to repeat in 24 hours. Nasal spray (20 mg) may also be used.
  • Early studies are encouraging.
• Dihydroergotamine
• • Can be abortive agent
  • IV/IM; self-injections
  • Intranasal 0.5 mg bilaterally
  • Analgesics/narcotics: Oral route levels are inadequate until attack is complete but often are helpful for residual soreness. Abuse potential does exist.
• Civamide and capsaicin: When applied to the nasal mucosa of patients with cluster headaches, a clinically significant decrease occurred in the number and severity of cluster headaches. Nasal burning was the most common adverse effect.
• Lidocaine: 1 mL of a 10% solution placed on a swab in each nostril for 5 minutes is possibly helpful.

Consultations

Neurologic consultation may be useful if the diagnosis is in doubt or for management of difficult cases.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goal of pharmacotherapy is to prevent the attack or alter it once it is underway. An accurate diagnosis is required when therapy is being considered.

5-HT1 receptor agonists such as sumatriptan or dihydroergotamine (DHE) with metoclopramide are often the first line of treatment. Parenteral opiates may be used if relief is inadequate. Antihistamines, such as chlorpromazine, do not appear to be helpful in relieving cluster headache symptoms. Tricyclic antidepressants are more helpful as prophylaxis of other headache syndromes. Beta-blockers may worsen bradycardia occurring during the cluster attack.

Drug Category: Corticosteroids

These agents are effective for cluster headaches that do not respond to lithium. They are intended for intermittent use during acute flare-ups. High doses of corticosteroids can ease pain within 8-12 h, with maximum effectiveness in 2-3 d.

Drug Category: Antiemetics and sedatives

These agents are used to treat cluster headaches and emesis associated with acute attacks.

Drug Category: Antidepressants

Lithium has been suggested as a therapy option because of the cyclical nature of cluster headaches, which is similar to the cyclical episodes in bipolar disorders.

Drug Category: Calcium channel blockers

These agents may be most effective at prophylaxis.

Drug Category: Nonsteroidal anti-inflammatory agents

These agents may alleviate headache pain by inhibiting prostaglandin synthesis, reducing serotonin release, and blocking platelet aggregation. Although the effects of NSAIDs in the treatment of headache pain tend to be patient specific, ibuprofen is usually the DOC for the initial therapy. Other options include naproxen, ketoprofen, and ketorolac.

Drug Name	Ketorolac (Toradol)
Description	Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which results in decreased formation of prostaglandin precursors.
Adult Dose	30 mg IV single dose (most common route used in ED) >65 years, renal impairment, or <50-kg body weight: 15 mg IV single dose 30-60 mg IM initially, followed by 15-30 mg q6h prn; not to exceed 5 d of treatment
Pediatric Dose	Not established; recommended dose 0.4-1 mg/kg once
Contraindications	Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding; not for administration into CNS
Interactions	Aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity; may decrease effects of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT in patients taking anticoagulants (monitor PT closely and instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; may increase phenytoin levels
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; low WBC counts (rare) usually return to normal during ongoing therapy; discontinue therapy if persistent leukopenia, granulocytopenia, or thrombocytopenia

Drug Category: Ergotamines

These are direct vasoconstrictors of smooth muscle in cranial blood vessels. Their activity depends on CNS vascular tone at the time of administration.

Drug Name	Ergotamine tartrate (Cafergot, Cafatine, Cafetrate)
Description	Has alpha-adrenergic antagonist and serotonin antagonist effects. Causes constriction of peripheral and cranial blood vessels. Oral administration of ergotamine not as effective as inhaled or sublingual routes in treatment of acute cluster attacks.
Adult Dose	2 tab PO at onset of attack and 1 tab PO q30min prn; not to exceed 6 tab per attack or 10 tab/wk 1 tab SL at first sign of attack and 1 tab SL q30min; not to exceed 3 tab/d or 5 tab/wk 1 supp PR at first sign of attack with a second dose after 1 h if necessary; not to exceed 2 supp/attack or 5 supp/wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; avoid in hepatic or renal disease, peptic ulcer disease, sepsis, or peripheral vascular disease
Interactions	Increases effects of heparin; increases toxicity of nitroglycerin, propranolol, erythromycin, and clarithromycin
Pregnancy	X - Contraindicated; benefit does not outweigh risk
Precautions	Do not give more than 3 tab/d or 6 inhalations/d Do not give more than 10 mg/wk or 15 inhalations/wk Avoid extra doses for abortive therapy in individual attacks; avoid using prolonged regimens because of danger of causing gangrene or dependency

Drug Category: 5-HT1 receptor agonist

Stimulation of 5-HT1 receptors produces a direct vasoconstrictive effect and may abort the attack.

Drug Name	Almotriptan (Axert)
Description	Used to treat acute migraine. Selective 5-HT1B/1D receptor agonist. Results in cranial vessel constriction, inhibition of neuropeptide release, and reduced pain transmission in trigeminal pathways.
Adult Dose	6.25-12.5 mg PO at onset of migraine; may repeat once, not to exceed 25 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hemiplegic or basilar migraine; ischemic heart disease; uncontrolled hypertension
Interactions	Toxicity may increase when used within 24 h of ergotamines or other 5-HT agonists; coadministration with SSRIs may cause weakness, hyperreflexia, or incoordination; CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, erythromycin) may increase plasma concentration and subsequent toxicity
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Decrease dose and do not exceed 12.5 mg/d in renal or hepatic impairment

Drug Name	Frovatriptan (Frova)
Description	Selective 5-HT1B/1D receptor agonist. Results in cranial vessel constriction, inhibition of neuropeptide release, and reduced pain transmission in trigeminal pathways. Has unique characteristics and benefits in the acute treatment of migraine. Studies demonstrate prolonged presence of frovatriptan in bloodstream, and few migraine patients experienced recurrence of headache within 24 h of taking frovatriptan.
Adult Dose	2.5 mg PO once at onset of migraine attack
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hemiplegic or basilar migraine; ischemic heart disease; uncontrolled hypertension
Interactions	Toxicity may increase when used within 24 h of ergotamines or other 5-HT agonists; coadministration with SSRIs may cause weakness, hyperreflexia, or incoordination
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Hypertensive crisis, coronary artery vasospasm, cardiac arrest, peripheral ischemia, bloody diarrhea, and death may occur

Drug Name	Sumatriptan succinate (Imitrex)
Description	Selective agonist for serotonin 5-HT1 receptors in cranial arteries. Suppresses inflammation associated with migraine headaches.
Adult Dose	25 mg PO; if satisfactory response not seen in 2 h, additional dose of up to 100 mg; additional dose at intervals of 2 h prn; not to exceed 300 mg/d 6 mg SC, if satisfactory response not seen in 1 h, additional 6 mg SC may be administered; not to exceed 2 injections/24 h Intranasal: Single dose of 5, 10, or 20 mg in one nostril; give 10 mg dose by administering single 5 mg dose in each nostril; if satisfactory response not seen in 2 h, additional dose may be administered; not to exceed 40 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; ischemic heart disease; uncontrolled hypertension
Interactions	Ergot-containing drugs, SSRIs, and MAOIs increase toxicity
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Hypertensive crisis, coronary artery vasospasm, cardiac arrest, peripheral ischemia, and bloody diarrhea may occur rarely

Drug Name	Zolmitriptan (Zomig, Zomig-ZMT)
Description	As selective agonists of serotonin 5-HT1 receptors in cranial arteries, cause vasoconstriction and reduce inflammation associated with antidromic neuronal transmission in cluster headache. Can reduce severity of headache within 15 min of SC injection.
Adult Dose	2.5 mg PO initially; repeat dose after 2 h if headache returns; not to exceed 10 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; ischemic heart disease and uncontrolled hypertension; do not administer within 24 h of taking another serotonin agonist or ergotamine or within 2 wk of taking a MAOI
Interactions	Toxicity increases when administered concomitantly with ergot-containing drugs, SSRIs, and MAOIs
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Hypertensive crisis, coronary artery vasospasm, cardiac arrest, peripheral ischemia, bloody diarrhea, and death may occur when administering this medication

Drug Name	Naratriptan (Amerge, Naramig)
Description	As selective agonists of serotonin 5-HT1 receptors in cranial arteries, cause vasoconstriction and reduce inflammation associated with antidromic neuronal transmission in cluster headache. Can reduce severity of headache within 15 min of SC injection.
Adult Dose	1-2.5 mg PO q4h prn for headache; not to exceed 5 mg/d
Pediatric Dose	<12 years: Not established >12 years: 2.5 mg PO initially; not to exceed 5 mg/d
Contraindications	Documented hypersensitivity; ischemic heart disease; uncontrolled hypertension; cerebrovascular or peripheral vascular syndromes; severe renal impairment (CrCl <15 mL/min); severe hepatic impairment (Child-Pugh grade C)
Interactions	Oral contraceptives may significantly increase concentrations and cause prolonged vasospastic reactions to occur, avoid concurrent use within 24 h of each other; toxicity may increase when administered concomitantly with ergot-containing drugs, SSRIs, and MAOIs
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Chest, jaw, or neck tightness may occur after 5-HT1 agonist administration; atypical sensations over precordium (pain, tightness, pressure, heaviness) may occur (rarely associated with arrhythmias or ischemic ECG changes); evaluate patients with signs or symptoms suggestive of angina for presence of CAD or predisposition to Prinzmetal angina before receiving additional doses; monitor ECG if dosing resumed and similar symptoms recur

Drug Name	Rizatriptan (Maxalt, Maxalt-MLT)
Description	Selective agonist for serotonin 5-HT1 receptors in cranial arteries and suppresses the inflammation associated with migraine headaches.
Adult Dose	5-10 mg PO q2h prn for headache; not to exceed 30 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Toxicity increases when administered concomitantly with ergot-containing drugs, SSRIs, and MAOIs
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Hypertensive crisis, coronary artery vasospasm, cardiac arrest, peripheral ischemia, bloody diarrhea, and death may occur when administering this medication

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Histamine desensitization
• • Popular in the 1940s and 1950s, histamine desensitization was introduced by Dr Horton at the Mayo Clinic. He treated patients with subcutaneous and intravenous injections. This treatment was based on the contention that metabolic derangement of histamine played an important role in producing cluster headaches.
  • This treatment is used very rarely at the present time.
  • Results were inconsistent. Minimal hard data exist on recurrence rates and follow-up duration.
  • The episodic nature of clusters was not recognized fully at that time. Therefore, spontaneous improvements were attributed to treatment.
• Surgical
• • Various procedures are performed on trigeminal nerve or autonomic pathways, including alcohol injections and section or avulsion of nerves for chronic refractory cases.
  • Surgery is used if the patient has contraindications to medications or if medications are not effective. Surgery is used in strictly unilateral cases.
  • Radiofrequency thermocoagulation of trigeminal ganglion has had promising results in some patients with intractable pain.

Deterrence/Prevention

• Patient should avoid headache triggers.
• Disturbances in the sleep cycle can induce attacks.
• Strong emotions and excessive physical activity may induce attacks.
• Tobacco may slow responsiveness to medications.
• Narcotics may expedite transformation of episodic cluster to chronic cluster.

Complications

• Self-injury during attack
• Side effects of medication, including unmasking of coronary artery disease
• Potential for drug abuse

Prognosis

• Recurrent attacks
• Prolonged remissions
• Possibility of transformation of an episodic cluster to a chronic cluster and vice versa

Patient Education

• Patients should avoid known precipitants.
• Patients should avoid high altitudes.
• For excellent patient education resources, see eMedicine's Headache Center. Also, visit eMedicine's patient education articles Causes and Treatments of Migraine and Related Headaches, Cluster Headache, Alternative and Complementary Approaches to Migraine and Cluster Headaches, Cluster Headache FAQs, and Understanding Migraine and Cluster Headache Medications.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Attributing symptoms to cluster headaches when other entities are the cause (eg, subarachnoid hemorrhage)
• Ignoring psychologic factors (eg, suicidal threats)
• Not exploring contraindications to medications

Special Concerns

• Ensure follow-up (medical and psychiatric) if needed.
• Pregnant and geriatric patients often are not candidates for some pharmacologic interventions.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bahra A, Goadsby PJ. Diagnostic delays and mis-management in cluster headache. Acta Neurol Scand. Mar 2004;109(3):175-9. [Medline].
• Diamond ML. Emergency Department Treatment of the Headache Patient. 1992.
• Evans RW. Diagnostic testing for the evaluation of headaches. Neurol Clin. Feb 1996;14(1):1-26. [Medline].
• Graham JR. Cluster headache. Headache. Jan 1972;11(4):175-85. [Medline].
• Henry GL, Rosen P, Barkin R, eds. Headache. In: Emergency Medicine, Concepts and Clinical Practice. 4^th ed. 1996:2119-31.
• Hoffman GL, Tintinalli JE, Ruiz E, Krome RL, eds. Headache and facial pain. In: Emergency Medicine, A Comprehensive Study Guide. 4^th ed. 1996:1009-10.
• Manzoni GC, Torelli P. Headache screening and diagnosis. Neurol Sci. Oct 2004;25 Suppl 3:S255-7. [Medline].
• Mathew NT. Advances in cluster headache. Neurol Clin. Nov 1990;8(4):867-90. [Medline].
• Mathew NT. Cluster headache. Neurology. Mar 1992;42(3 Suppl 2):22-31. [Medline].
• Rapoport AM, Bigal ME, Tepper SJ, Sheftell FD. Intranasal medications for the treatment of migraine and cluster headache. CNS Drugs. 2004;18(10):671-85. [Medline].
• Beck E, Sieber WJ, Trejo R. Management of cluster headache. Am Fam Physician. Feb 15 2005;71(4):717-24. [Medline]. [Full Text].

Article Last Updated: Sep 20, 2007