Cluster Headaches Overview

Synonyms: Bing-Horton Syndrome, Histaminic Cephalalgia, Cluster-Migraine, Paroxysmal Nocturnal Cephalgia, Red Migraine, Erythromelalgia of the Head, Sphenopalatine Neuralgia, Migrainous Neuralgia

Authored by Jorge Mendizabal, M.D., Director, University Headache Center, Assistant Professor, Department of Neurology, University of South Alabama Hospitals and Clinics
Edited by Joseph R. Carcione, Jr., D.O., Consultant in Clinical Neurophysiology and Pain Management, Assistant Professor, Department of Neurology, Albert Einstein College of Medicine; Francisco Talavera, Ph.D., Pharm.D., Department of Pharmacy, Creighton University; Nicholas Y. Lorenzo, M.D., Chief Editor, eMedicine Neurology; Selim R. Benbadis, M.D., Director, Epilepsy Program, Associate Professor, Departments of Neurology and Neurosurgery, University of South Florida College of Medicine; and Helmi L. Lutsep, M.D., Associate Director, Oregon Stroke Center, Assistant Professor, Department of Neurology, Oregon Health Sciences University

Author Status		Editor Status
Completed	Updated	Copy	Medical	Pharmacy	Managing	CME	Chief
10/28/1999	11/17/1999 14:32:07	04/10/1999	07/26/1999	08/24/1999	09/08/1999	11/02/1999	11/10/1999

Introduction

Background: Cluster headache (CH) is an idiopathic syndrome consisting of recurrent attacks of sudden, severe, short-lasting, unilateral periorbital pain.
Pathophysiology:

• Not entirely understood. 
• Its typical periodicity has been attributed to hypothalamic (particularly the suprachiasmatic nuclei) hormonal influences. 
• CH pain is thought to be generated at the level of the pericarotid/cavernous sinus complex. This region receives sympathetic and parasympathetic input from the brainstem, possibly mediating occurrence of autonomic phenomena during an attack. 
• The exact role of immunological and vasoregulatory factors, as well as the influence of hypoxemia and hypocapnia on CH, are still controversial.

Frequency:

• In the U.S.: Exact prevalence unknown. Kudrow estimated 0.4% for men and 0.08% in women
• Internationally: In an extensive study of 100,000 inhabitants of the republic of San Marino, prevalence of 0.07% was encountered.

Sex:

• More common in men (5:1).
• Cases of CH affecting multiple members within a single family have been reported, thus a genetic predisposition in some individuals may exist.

Age:    Affects the middle-aged

Clinical

History:

• Attacks of CH are typically short in duration (5-180 minutes) and occur from a frequency of once every other day up to 8 times a day, particularly during sleep. As opposed to migraine, CH is not preceded by aura, affording patients little or no warning.
•  Pain is generally described as excruciating, penetrating, and non-throbbing. 
  • It may radiate to other areas of the face and neck, but is typically periorbital. 
  • It may be triggered by stress, relaxation, extreme temperatures, glare, allergic rhinitis, and sexual activity.
  • CH is rarely triggered by ingestion of specific foods, although tobacco or alcohol products may precipitate an attack.
  • An attack of CH is a dramatic event during which the patient may be extremely restless. In desperation, CH patients may rock, sit, pace, or bang themselves against a hard surface.
  Classification of cluster headache - According to its duration, the International Headache Society (IHS) classifies CH into episodic and chronic.
• Episodic CH occurs in periods (clusters) lasting in duration from 7 days to 1 year, but separated by pain-free intervals lasting at least 2 weeks in duration. Typically, a cluster lasts 2 weeks to 3 months.
• Chronic CH is defined as that occurring for more than 1 year without remission or without remissions lasting less than 2 weeks. It is subdivided into chronic CH from onset and chronic CH evolving from episodic.
• Chronic CH is notoriously difficult to treat and resistant to standard prophylactic agents.

Symptomatic cluster-like headache should be suspected if the presentation is atypical. Atypical features may include

• Absence of a periodic pattern
• Residual headache between exacerbations
• Incomplete or minimal response to standard therapy
• Presence of lateralizing findings on exam (except for those of CH-related Horner's syndrome)
  

Physical: The association of prominent autonomic phenomena is a hallmark of CH. Such signs include ipsilateral nasal congestion and rhinorrhea, lacrimation, conjunctival hyperemia, facial diaphoresis, palpebral edema, and a complete or partial Horner's syndrome (which may persist between attacks). Tachycardia is a frequent finding
.

• A distinctive CH face is described as follows: leonine facial appearance, multifurrowed and thickened skin with prominent folds, a broad chin, vertical forehead creases, and nasal telangiectasias.
• CH sufferers are typically tall and rugged-looking/
• Other Problems to be Considered:
• Cyclical Migraine
• Hemicrania Continua
• Raeder's Paratrigeminal Syndrome

Workup

Imaging Studies:

• CH is strictly a clinical diagnosis. On rare occasions, structural lesions may mimic its presentation, prompting the need for neuroimaging study (CT or MRI).
• The following can present with findings suggestive of CH:
• Meningiomas of the cavernous sinus
• Arteriovenous malformations
• Pituitary adenomas
• Nasopharyngeal carcinoma
• Vertebral artery aneurysms
• Metastatic carcinoma of the lung

Treatment

Medical Care: Pharmacologic management of CH may be divided into abortive/symptomatic and preventive/prophylactic. See the Medication section for a detailed discussion.

Prophylactic Agents: Start at onset of a CH cycle and continue until the patient is headache-free for at least 2 weeks. The agent may be then tapered slowly to prevent recurrences.

• Verapamil:
• Perhaps the most effective calcium channel blocker for prophylaxis of CH.
• The recommended dose is 80-120 mg (immediate release), 3-4 times a day. 
• Side effects include constipation and water retention. 
• Patients intolerant to verapamil should be tried on nimodipine, diltiazem or nifedipine.
• Lithium Carbonate: 
• Highly effective treatment for bipolar mood disorder (another cyclical illness)
• Also powerful preventive agent for CH, particularly in its more chronic forms.
• Its narrow therapeutic window requires close monitoring of levels and side effects. 
• Most patients require 600-900 mg/day in divided doses.  
• In CH, lithium is effective at lower serum concentrations than those required in bipolar disorder (0.3-0.8 mmol/L).  
• Side effects include tremor, polyuria, diarrhea, nausea, fatigue, weight gain, and thyroid dysfunction.  
• Renal toxicity with tubular damage and interstitial fibrosis may occur.  
• Central nervous system toxicity is manifested by confusion and ataxia.
• Methysergide: 
• A central serotonin receptor agonist, methysergide clearly plays an important role in the therapeutic arsenal for prophylaxis of CH. 
• In doses of 3-6 mg/day, methysergide is often effective in reducing CH frequency, particularly in younger patients with episodic CH.  
• The use of methysergide beyond 6 months is discouraged, and a drug holiday is recommended to avoid retroperitoneal or pulmonary fibrosis.  
• More commonly, gastrointestinal adverse reactions affect compliance with this medication.  
• Other side effects include leg cramps, paresthesias, edema, and discoloration of skin.

Surgical Care:

• Invasive nerve blocks and ablative neurosurgical procedures (e.g., percutaneous radiofrequency, trigeminal gangliorhizolysis, and rhizotomy) all have been implemented successfully in cases of refractory CH.  More recently, gamma-knife radiosurgery provides a less invasive alternative for pervasive CH. 

Medication

• The pharmacologic management of CH may be divided into abortive/symptomatic, preventive/prophylactic.
   
• Abortive therapy is directed at stopping or reducing the severity of an acute attack, while prophylactic agents are used to reduce the frequency and intensity of individual headache exacerbations. Due to the fleeting, short-lived nature of the attacks, effective prophylactic therapy should be considered the cornerstone in treatment.
   
• The prophylactic therapy should start at the onset of a CH cycle and continue until the patient is headache-free for at least 2 weeks. The agent may then be tapered slowly to prevent recurrences.

Drug Category: Abortive Agents - Administered to abort an attack of CH. Because of the duration of the attacks, they must provide immediate relief.

Drug Name	High-flow oxygen - Inhalation of high-flow, concentrated oxygen is extremely effective for aborting a CH attack. Its precise mechanism of action is poorly understood. Despite the immediate availability of oxygen in the modern ED, widespread use of this therapeutic modality in the outpatient setting is limited due to its lack of practicality.  It is an effective alternative to ergotamine.
Adult Dose	Administer 6-8 L/min of concentrated (100%) oxygen, by facial mask, for no longer than 15 min.
Contraindications	There are no known contraindications for this treatment.
Interactions	No significant drug interactions have been reported with this product.
Pregnancy	A - Safe in pregnancy

Drug Category: Ergot alkaloids - Are highly effective in relieving acute CH pain.

Drug Name	Ergotamine (Cafatine, Cafergot, Cafetrate, Ercaf) - A vasoconstrictor of smooth muscle in cranial blood vessels, an alpha-adrenergic blocker, and a nonselective 5-HT agonist.  Rectal or sublingual preparations of ergotamine tartrate are favored to the oral route due to the immediate onset of action.  Avoid exceeding the maximum dosage guidelines to prevent rebound headaches.
Adult Dose	po: Administer 2 tabs at the first sign of onset and 1 tab q 30 min prn thereafter. Do not exceed 6 tabs/attack or 10 tabs/wk.  sl: Place 1 tab under the tongue at the first sign of onset and 1 tab q 30 min prn thereafter. Do not exceed 3 tabs/24h or 5 tabs/wk.  pr: Insert 1 supp at the first sign of onset followed with a second dose prn after 1 h. Do not exceed 2 supp/attack or 5 supp/wk.
Contraindications	Avoid use in patients with documented hypersensitivity to this drug or related products. Use with caution in patients with a history of hypertension and coronary or peripheral arterial insufficiency.
Interactions	Concurrent administration with erythromycin, troleandomycin and other macrolide antibiotics may increase ergotamine toxicity.
Pregnancy	X - Contraindicated in pregnancy
Precautions	Avoid prolonged administration or excessive dosage, since it increases the danger of ergotism or gangrene.  Patients who take ergotamine for extended periods may become dependent on it.  Ergotamine may precipitate angina, myocardial infarction, or aggravate intermittent claudication. Thus it is not recommended for the elderly.

Drug Name	Dihydroergotamine (D.H.E.-45 injection, Migranal) - Available in parenteral or intranasal preparations, it tends to cause less arterial vasoconstriction than ergotamine tartrate.
Adult Dose	IM, sc: Administer 1.0 mg at the first sign of onset. Do not exceed 3 mg total.  IV: Administer up to 2 mg. Do not exceed 2 mg/dose or 6 mg/wk.  Intranasally: Administer 1 spray (0.5 mg) into each nostril. Do not exceed 6 sprays/24h or 8 sprays/wk.
Contraindications	Documented hypersensitivity to this drug or related products  Do not use within 24 h of sumatriptan, zolmitriptan, other serotonin agonists or ergot-like agents.  Avoid within 2 wks of discontinuing MAO inhibitors.
Interactions	Dihydroergotamine may increase the effects of heparin. The toxicity of this medication increases when taken concurrently with erythromycin, clarithromycin, nitroglycerin, propranolol, and troleandomycin.
Pregnancy	X - Contraindicated in pregnancy
Precautions	Exercise cation in patients diagnosed with hypertension, angina, peripheral vascular disease, and impaired renal or hepatic function.

Drug Name	Sumatriptan (Imitrex), Zolmitripan (Zomig) - As selective agonists for serotonin 5HT1 receptors in cranial arteries, they cause vasoconstriction and reduce inflammation associated with the antidromic neuronal transmission in cluster headaches.  A reduction in the severity of headache can occur within 15 minutes of a sc injection. An intranasal dosage form was recently introduced in the U.S. market, offering an attractive alternative to self-injections. However, the slower onset of action could affect the widespread use of the newer oral selective serotonin receptor agonists (zolmitriptan, naratriptan and rizatriptan) in abortive therapy.
Adult Dose	Sumatriptan sc: Administer 6 mg; a second injection may be administered prn at least 1 h after the first dose. Do not exceed 2 injections in a 24-h period.  Sumatriptan po: Administer 25-100 mg and a second dose 2 h later if a satisfactory response is not obtained. Do not exceed 300 mg/d Sumatriptan intranasal: Administer 5, 10, 20 mg in one nostril.  May administer 5 mg in each nostril to achieve a 10 mg dose and may repeat once after 2h  Do not exceed 300 mg/d Zolmitriptan po: Administer 2.5-5.0 mg and repeat after 2 h prn. Do not exceed 10 mg/24h. Naratriptan po: Administer 2.5 mg.  Rizartriptan po: Administer 10 mg.
Contraindications	Avoid use in patients with documented hypersensitivity to this product and those diagnosed with ischemic heart disease and uncontrolled hypertension. It should also be avoided within 2 wks of discontinuing MAO inhibitors.
Interactions	Its toxicity may increase when taken concurrently with MAO inhibitors, ergot-containing drugs, and selective serotonin reuptake inhibitors (SSRIs).
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	These medications may cause facial flushing, numbness, paresthesias, and chest pain of noncardiac origin.  A significant elevation in blood pressure, including hypertensive crisis, has been reported in patients without a history of hypertension.  Peripheral vascular ischemia, colonic ischemia with abdominal pain, and bloody diarrhea have occurred in patients while taking this medication.

Drug Name	Methysergide (Sansert) - Useful in the treatment of patients unresponsive to lithium  Although it is an ergotamine chemical class, its actions appear to differ, since it has minimal ergotamine-like vasoconstrictive properties and has significantly greater serotonin-like properties.  It plays an important role in CH prophylaxis.  It is often effective in reducing pain frequency, particularly in younger patients with episodic CH.  If no improvement is noted after 3 wks, the drug is unlikely to be beneficial. Do not give continuously for longer than 6 months. A drug-free interval of 3-4 weeks must follow each 6 month course.
Adult Dose	Administer 4-8 mg/d
Contraindications	Documented hypersensitivity to this medication or related products  Peripheral vascular disease  Severe arteriosclerosis  Pulmonary disease  Severe hypertension  Phlebitis  Serious infections
Interactions	No significant drug interactions have been reported with this product.
Pregnancy	X - Contraindicated in pregnancy
Precautions	The use of methysergide beyond 6 months is discouraged. Patients who receive long-term therapy may develop retroperitoneal fibrosis and fibrotic thickening of the cardiac valves. A drug holiday is recommended to avoid retroperitoneal or pulmonary fibrosis.   Exercise caution in patients with renal or hepatic impairment. Some of the adverse effects include leg cramps, paresthesias, edema, and skin discoloration.

Drug Category: Anesthetics - Local anesthetics stabilize the neuronal membrane so the neuron is less permeable to ions. This prevents the initiation and transmission of nerve impulses, thereby producing the local anesthetic action.

Drug Name	Intranasal lidocaine (4%) - An experimental therapy  Lidocaine blocks the conduction of nerve impulses by decreasing the neuronal membrane's permeability of sodium ions, which results in the inhibition of depolarization and blockade of conduction.  It has been shown to be effective in 2 separate clinical trials.  The intranasal administration of lidocaine drops requires a specific and, for many patients, difficult technique.
Adult Dose	Administer a 4% solution. The actual dose has not been established.
Contraindications	Avoid use in patients with documented hypersensitivity to this drug or related products.
Interactions	May enhance the effects of succinylcholine.
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Use extreme caution in patients with marked hypoxia, severe respiratory depression, and bradycardia.

Drug Category: Oral opioids and other analgesics - The short-lived and unpredictable character of CH precludes the effective use of oral narcotics or analgesics. Despite their lack of efficacy, it is not unusual for CH sufferers to abuse these substances.

Drug Name	Intranasal capsaicin - This experimental therapy has been successfully tested in clinical trials.  It is an extract that is derived from chili peppers.  It induces the release of substance P, the principal chemomediator of pain impulses from the periphery to the CNS.  After repeated applications, capsaicin depletes the neuron of substance P and prevents reaccumulation.  When prescribing, consider the possible occurrence of local irritation, burning, and sneezing.
Adult Dose	Apply a few drops of capsaicin solution to the ipsilateral nostril.
Contraindications	Avoid use in patients with documented hypersensitivity to this drug or related products.
Interactions	No significant interactions have been reported with this medication.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Avoid contact with eyes. It is an irritant to the mucosal membranes and should be used with caution. Warn patients about nasal cavity irritation, congestion, drainage, and sneezing while using capsaicin.

Drug Category: Calcium channel blockers - Inhibit the initial vasoconstrictive phase

Drug Name	Verapamil (Calan, Verelan, Covera-HS) - Perhaps the most effective calcium channel blocker for CH prophylaxis, it inhibits calcium ions from entering the slow channels, select voltage-sensitive areas, or vascular smooth muscle.  It produces vasodilation.
Adult Dose	Administer 120-360 mg (immediate release), tid-qid.  The extended release dosage-form may be given qd.
Contraindications	Documented hypersensitivity to this drug or related products  Sinus bradycardia, cardiogenic shock, advanced heart block, ventricular tachycardia, congestive heart failure, and atrial fibrillation or flutter associated with accessory conduction pathways
Interactions	Phenobarbital, hydantoins, vitamin D, sulfinpyrazone, and rifampin may decrease verapamil serum concentrations by increased hepatic metabolism.  Its toxicity may increase when taken concurrently with amiodarone and cause increased cardiac depressant effects on AV conduction when administered concurrently with beta-blockers.  Cimetidine may increase verapamil serum levels. Conversely, verapamil may increase cyclosporine, doxorubicin, theophylline, carbamazepine, vecuronium, and digoxin serum levels.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Exercise caution when administering to patients diagnosed with sick-sinus syndrome, severe left ventricular dysfunction, hepatic or renal impairment, and hypertrophic cardiomyopathy.  Monitor ECG and blood pressure closely in patients with supraventricular tachycardia receiving iv therapy.  Side effects include constipation and water retention.  Patients who are intolerant of verapamil should try nimodipine, diltiazem, or nifedipine.

Drug Name	Lithium carbonate (Eskalith, Lithane, Lithobid, Lithonate, Lithotabs) - Effectively prevents CH (particularly in its more chronic forms) and treats bipolar mood disorder, which is another cyclical illness.  Its narrow therapeutic window requires close monitoring of levels and side effects.  A plasma lithium level of 0.6-1.2 mEq/L measured at steady state, 12 hours after the last dose, is usually sought, but optimal plasma levels for prevention of cluster headache have not been established.
Adult Dose	Administer 600-900 mg/d in divided doses and increase to 600-1200 mg/d prn bid-qid.
Contraindications	Avoid use in patients with documented hypersensitivity to this drug or related products and those diagnosed with severe cardiovascular or renal disease.
Interactions	Serum levels and toxicity of this medication increase when administered concurrently with thiazide diuretics, NSAIDs, haloperidol, phenothiazines, neuromuscular blockers, carbamazepine, fluoxetine, and ACE inhibitors.  Conversely theophylline, caffeine and other xanthines decrease the effects of this medication.
Pregnancy	D - Unsafe in pregnancy
Precautions	Lithium toxicity can occur at therapeutic doses.  Exercise caution when administering to patients diagnosed with cardiovascular or thyroid disease, severe debilitation, dehydration or sodium depletion, or patients who are receiving diuretics.  Side effects include tremor, polyuria, diarrhea, nausea, fatigue, weight gain, and thyroid dysfunction.  Renal toxicity with tubular damage and interstitial fibrosis may also occur.  Central nervous system toxicity is manifested by confusion and ataxia.

Drug Category: Corticosteroids - Are extremely effective in terminating a CH cycle and in preventing immediate headache recurrence. High-dose prednisone is prescribed for the first few days followed by a gradual taper. 
The simultaneous use of standard prophylactic agents (e.g., verapamil) is also recommended.
The mechanism of action of corticosteroids in CH is still subject to speculation.

Drug Name	Prednisone (Deltasone) - Is effective for the treatment of cluster headaches that do not responsive to lithium or methysergide. Its effects in CH may occur via inhibition of prostaglandin synthesis. Long-term use is not recommended.
Adult Dose	Administer 40-60 mg/d in divided doses for 5 d and taper slowly over a 2-wk to 1-mo period.
Contraindications	Documented hypersensitivity to corticosteroids or related products  Systemic fungal infections or serious infections, except septic shock or tuberculous meningitis
Interactions	Its effects are decreased when administered concurrently with barbiturates, phenytoin, and rifampin. Conversely, prednisone may decrease the effect of salicylates.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Corticosteroids should be used cautiously in diabetics and patients diagnosed with hypothyroidism, cirrhosis, congestive heart failure, thromboembolic disorders, and ulcerative colitis.  Chronic use may lead to gastric ulceration, immunosuppression, electrolyte disturbances, weight gain, and osteopenia.

Follow Up

Prognosis:

• Eighty percent of patients with episodic CH tend to maintain their episodic form.
• Between 4-13% of patients with episodic CH may eventually transform into chronic CH. Intermediate (mixed) forms may occur.
• Prolonged, spontaneous remissions have been described in up to 12% in some series, particularly in episodic CH. Chronic CH is more relentless and may persist in this form in up to 55% of cases. Less frequently, chronic CH may remit into an episodic form.
• Generally, CH is a lifelong problem.
• Pharmacologic intervention may play a part in the transformation of chronic CH into the episodic form; otherwise, it does not influence outcome.
• A late onset of this disorder along with male sex and a previous history of episodic CH predict a less favorable course.

Bibliography:

• Ekbom K, Nappi G: Diagnosis, differential diagnosis, and prognosis of cluster headache. The Headaches 1993; 585-589.
• Kudrow L: Cluster Headache: Diagnosis and management. Headache 1979; 19: 141-148.
• Mathew NT: Cluster Headache. Neurology 1992; 42 (suppl 2): 22-31[Medline].
• Mendizabal JE, Umana E, Zweifler RM: Cluster Headache: Horton's Cephalalgia Revisited. Southern Medical Journal 1998; 91: 606-617.

NOTE:

Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this textbook have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this text do not warrant the information in this text is accurate or complete, nor are they responsible for omissions or errors in the text or for the results of using this information. The reader should confirm the information in this text from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert.

 

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