Medication Summary
Galcanezumab is the first drug to gain FDA approval for decreasing the frequency of episodic cluster headaches. [17]
Pharmacologic management of cluster headache (CH) may be divided into abortive/symptomatic and preventive/prophylactic strategies. Abortive agents are used to stop or reduce the severity of an acute attack, whereas prophylactic agents are used to reduce the frequency and intensity of individual headache exacerbations.
Inhalation of high-flow concentrated oxygen is extremely effective for aborting CH attacks, though the precise mechanism of action is poorly understood. Oxygen is an effective alternative to ergotamine. Despite the immediate availability of oxygen in the emergency department, its widespread use in outpatient setting is impractical.
Neurologics, Other
Class Summary
Triptans may reduce the inflammation associated with migraine headaches.
Zolmitriptan (Zomig, Zomig-ZMT, Zomig Nasal Spray)
As a selective agonist of 5-hydroxytryptamine-1 (5-HT1) receptors in cranial arteries, zolmitriptan causes vasoconstriction and reduces the inflammation associated with antidromic neuronal transmission in CH. It can reduce the severity of headache within 15 minutes of subcutaneous injection. The intranasal form is now available in the United States, offering an attractive alternative to self-injection.
Naratriptan (Amerge)
As a selective agonist of 5-HT1 receptors in cranial arteries, naratriptan causes vasoconstriction and reduces the inflammation associated with antidromic neuronal transmission in CH. It can reduce the severity of headache within 15 minutes of subcutaneous injection.
Sumatriptan succinate (Imitrex, Alsuma, Sumavel DosePro)
As a selective agonist of 5-HT1 receptors in cranial arteries, sumatriptan causes vasoconstriction and reduces the inflammation associated with antidromic neuronal transmission in CH. It can reduce the severity of headache within 15 minutes of subcutaneous injection. The intranasal form is now available in the United States, offering an attractive alternative to self-injection.
Rizatriptan (Maxalt, Maxalt-MLT)
Rizatriptan is a selective agonist for 5-HT1 receptors in cranial arteries and suppresses the inflammation associated with migraine headaches.
Almotriptan (Axert)
Almotriptan is a selective 5-HT1B/1D receptor agonist used to treat acute migraine. It results in cranial vessel constriction, inhibition of neuropeptide release, and reduced pain transmission in trigeminal pathways.
Frovatriptan (Frova)
Frovatriptan is used to treat acute migraine. It is a selective 5-HT1B/1D receptor agonist with a long half-life (24 hours) and a low headache recurrence rate within 24 hours after taking the drug. It results in cranial vessel constriction, inhibition of neuropeptide release, and reduced pain transmission in trigeminal pathways. It has unique characteristics and benefits in the acute treatment of migraine.
Eletriptan (Relpax)
Eletriptan is a selective serotonin agonist that specifically acts at 5-HT1B/1D/1F receptors on intracranial blood vessels and sensory nerve endings to relieve pain associated with acute headaches.
CGRP Monoclonal Antibodies
Class Summary
Calcitonin gene-related peptide (CGRP) is a potent vasodilator and is a key neuropeptide that is thought to be a central component of headache pathophysiology.
Galcanezumab (Emgality, galcanezumab-gnlm)
Monoclonal antibody that targets CGRP. It is indicated for treatment of episodic cluster headache in adults.
Ergot Derivatives
Class Summary
Ergot alkaloids are highly effective in relieving acute CH pain. They are direct vasoconstrictors of smooth muscle in cranial blood vessels, and their activity depends on central nervous system (CNS) vascular tone at the time of administration.
Dihydroergotamine (D.H.E. 45 injection, Migranal)
Dihydroergotamine has alpha-adrenergic antagonist and serotonin antagonist effects. It is available in IV or intranasal preparations and tends to cause less arterial vasoconstriction than ergotamine tartrate.
Ergotamine (Ergomar)
Ergotamine has alpha-adrenergic antagonist and serotonin antagonist effects and causes constriction of peripheral and cranial blood vessels. Oral administration of ergotamine is not as effective as inhaled, rectal, or sublingual administration for treatment of acute cluster attacks. To prevent rebound headaches, avoid exceeding maximum dosage guidelines.
Anesthetics, Topical
Class Summary
Local anesthetics stabilize the neuronal membrane so that the neuron is less permeable to ions. This prevents initiation and transmission of nerve impulses, thereby producing local anesthesia.
Lidocaine 4%, (Xylocaine)
Lidocaine blocks conduction of nerve impulses by decreasing the neuronal membrane's permeability to sodium ions, which results in inhibition of depolarization and blockade of conduction. Intranasal administration of lidocaine drops is an experimental abortive therapy for CH.
Analgesics, Topical
Class Summary
The short-lived and unpredictable character of CH precludes the effective use of oral narcotics or analgesics. Despite their lack of efficacy, these substances are abused by some CH sufferers.
Narcotics are not recommended in aborting cluster headaches.
Capsaicin (Capzasin-P)
Intranasal capsaicin has been successfully tested in clinical trials. This substance, derived from chili peppers, induces 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.
Calcium Channel Blockers
Class Summary
These agents inhibit the initial vasoconstrictive phase of CH.
Verapamil (Calan, Verelan, Verelan PM, Covera-SR)
Perhaps the most effective calcium channel blocker for CH prophylaxis, verapamil inhibits calcium ions from entering slow channels, select voltage-sensitive areas, or vascular smooth muscle, thereby producing vasodilation. It can be combined with ergotamine or lithium.
Psychiatry Agents, Other
Class Summary
Lithium’s mechanism of action in CH is unclear, though preliminary evidence suggests that it may interfere with substance P and vasoactive intestinal peptide (VIP)-induced arterial relaxation.
Lithium carbonate (Lithobid)
Variable responses notwithstanding, lithium is still a recommended first-line agent in CH. The narrow therapeutic window necessitates close monitoring of levels and adverse effects. A plasma lithium level of 0.6-1.2 mEq/L measured at steady state 12 hours after the last dose (ie, just before the next dose) is usually sought, but optimal plasma levels for prevention of CH are not established. It is thought to be effective against CH at serum concentrations lower than those required in bipolar disorder (0.3-0.8 mEq/L).
Anticonvulsants
Class Summary
The mechanism of action by which anticonvulsants prevent CH is unclear; it may involve regulation of central sensitization.
Divalproex sodium (Depakote, Depakote ER)
Few adequate studies of divalproex are available, and results have been mixed.
Topiramate (Topamax)
Topiramate has been effective for prophylaxis of CH in several small prospective studies. Its exact mechanism of action in this setting is unknown.
Corticosteroids
Class Summary
Corticosteroids are effective for CH that does not respond to lithium. They are intended for intermittent use during acute flareups. High doses of corticosteroids can ease pain within 8-12 hours, achieving maximum effectiveness in 2-3 days.
Prednisone
Prednisone is very effective for aborting the CH cycle or providing intermediate prophylaxis (bridging therapy between acute and prophylactic agents). It is effective for treatment of CH that does not respond to lithium. Its effects in CH may occur via inhibition of prostaglandin synthesis. Long-term use is not recommended.
Prednisolone (Millipred, Orapred, Orapred ODT, Prelone)
Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body. Alternative corticosteroids may be used in equivalent dosage.
Antiemetics and Sedatives
Class Summary
Antiemetics and sedatives are used to treat CH and emesis associated with acute attacks.
Prochlorperazine (Compro)
Prochlorperazine is an antidopaminergic drug that blocks postsynaptic mesolimbic dopamine receptors, has an anticholinergic effect, and can depress the reticular activating system, thereby possibly relieving nausea and vomiting.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Class Summary
Nonsteroidal anti-inflammatory drugs (NSAIDs) may alleviate headache pain by inhibiting prostaglandin synthesis, reducing serotonin release, and blocking platelet aggregation. Although their effective in the treatment of headache pain tends to be patient-specific, ibuprofen is usually the drug of choice for initial therapy. Other options include naproxen, ketoprofen, flurbiprofen, indomethacin, and ketorolac.
Ibuprofen (Motrin, Advil, Addaprin, Caldolor)
Ibuprofen is the drug of choice for mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis. Many doses are available, either with or without a prescription.
Ketoprofen
Ketoprofen is used for the relief of mild to moderate pain and inflammation. Small doses are indicated initially in patients with small body size, elderly patients, and persons with renal or liver disease. Doses of over 75 mg do not increase therapeutic effects. Administer high doses with caution, and closely observe the patient for response.
Naproxen (Anaprox, Naprelan, Aleve, Naprosyn)
Naproxen is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which is responsible for prostaglandin synthesis.
Flurbiprofen
Flurbiprofen may inhibit cyclooxygenase, thereby inhibiting prostaglandin biosynthesis. These effects may result in analgesic, antipyretic, and anti-inflammatory activities.
Indomethacin (Indocin)
Indomethacin is absorbed rapidly; it is metabolized in the liver via demethylation, deacetylation, and glucuronide conjugation. It is useful in the diagnosis of CH because it helps other headache syndromes (eg, chronic paroxysmal hemicrania).
Ketorolac
Ketorolac inhibits prostaglandin synthesis by decreasing the activity of cyclooxygenase, thereby resulting in decreased formation of prostaglandin precursors.
Ketorolac nasal solution (Sprix)
Ketorolac inhibits cyclooxygenase, an early component of the arachidonic acid cascade, resulting in reduced synthesis of prostaglandins, thromboxanes, and prostacyclin. It has anti-inflammatory, analgesic, and antipyretic effects and is indicated for short-term (≤ 5 days) management of moderate to moderately severe pain. The bioavailability of a 31.5-mg intranasal dose (2 sprays) is approximately 60% of that of a 30-mg IM dose. The intranasal preparation delivers 15.75 mg per 100-µL spray; each 1.7-g bottle contains 8 sprays.
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Cluster headache: Functional imaging shows activation of specific brain areas during pain. Courtesy of Wikipedia Commons.
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Cluster headache (CH): Voxel-based morphometry (VBM) structural imaging shows specific brain area of CH patients' (hypothalamus) being different to non-CH patients' brains. Courtesy of Wikipedia Commons.
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Non-rebreather oxygen mask with reservoir for the acute treatment of cluster headache. Courtesy of Wikipedia Commons.
