Cluster Headache

Background

Cluster headache (CH), also known as histamine headache, is a primary neurovascular headache disorder, the pathophysiology and etiology of which are not well understood.^[1] As the name suggests, CH involves a grouping of headaches, usually over a period of several weeks. According to the diagnostic criteria developed by the International Headache Society (IHS), CH has the following characteristics:^{[2, 3]}

• The patient experiences attacks of severe or very severe, strictly unilateral pain (orbital, supraorbital, or temporal pain) that last 15-180 minutes and occur from once every other day to 8 times a day
• The attacks are associated with 1 or more of the following (all ipsilateral): conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis, or eyelid edema

CH may be usefully classified into 2 main forms as follows:

• Episodic CH, in which at least 2 cluster phases lasting 7 days to 1 year are separated by a cluster-free interval of 1 month or longer
• Chronic CH, in which the clusters occur more than once a year without remission or the cluster-free interval is shorter than 1 month

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Pathophysiology

The underlying pathophysiology of CH is incompletely understood.^{[4, 5]} The periodicity of the attacks suggests the involvement of a biologic clock within the hypothalamus (which controls circadian rhythms), with central disinhibition of the nociceptive and autonomic pathways—specifically, the trigeminal nociceptive pathways. Positron emission tomography (PET) and voxel-based morphometry have identified the posterior hypothalamic gray matter as the key area for the basic defect in CH.^[1] See the images below.

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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 no....

Altered habituation patterns and changes have been observed within the trigeminal-facial neuronal circuitry secondary to central sensitization, in addition to dysfunction of the serotonergic raphe nuclei-hypothalamic pathways (though the latter is not as striking as in migraine). Functional hypothalamic dysfunction has been confirmed by abnormal metabolism based on the N-acetylaspartate neuronal marker in magnetic resonance spectroscopy.^[6]

Substance P neurons carry sensory and motor impulses in the maxillary and ophthalmic divisions of the trigeminal nerve. These connect with the sphenopalatine ganglion and interior carotid perivascular sympathetic plexus. Somatostatin inhibits substance P and reduces the duration and intensity of CH.

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

Although the evidence supporting a causative role for histamine is inconsistent, cluster headaches may be precipitated with small amounts of histamine. Antihistamines do not abort cluster headaches. Increased numbers of mast cells have been found in the skin of painful areas of some patients, but this finding is inconsistent.

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Etiology

The exact cause of CH is unknown. The disorder is sporadic, though rare cases of an autosomal dominant pattern within a single family have been reported.

Several factors have been shown to provoke CH attacks. Subcutaneous injection of histamine provokes attacks in 69% of patients. Stress, allergens, seasonal changes, or nitroglycerin may trigger attacks in some patients. Alcohol induces attacks during a cluster but not during remission. About 80% of CH patients are heavy smokers, and 50% have a history of heavy ethanol use.

Risk factors for CH include the following:

• Male sex
• Age older than 30 years
• Small amounts of vasodilators (eg, alcohol)
• Previous head trauma or surgery (occasionally)

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Epidemiology

The exact prevalence of CH in the United States is unknown; Kudrow estimated it to be 0.4% in men and 0.08% in women.^[7] Compared with classic migraine, CH is relatively uncommon, with an incidence equivalent to only 2-9% of that of migraine. Prevalence in males is 0.4-1%. In an extensive study of 100,000 inhabitants of the republic of San Marino, the prevalence was 0.07%. The incidence of CH in the United Kingdom is equivalent to that of multiple sclerosis.

Age-, sex-, and race-related demographics

CH usually begins in middle adult life (eg, in the 30s); however, it has been reported in patients as young as 1 year and as old as 79 years.

CH is more common in males than in females; the male-to-female ratio was 6:1 in the 1960s but is now closer to 2:1. Presentations in females may differ from those in males, according to data from the United States Cluster Headache Survey.^[8] For example, women tend to develop CH at an earlier age and are also more likely to exhibit a second peak of CH incidence after the age of 50.

Racial and ethnic differences have not been well studied, but CH may be slightly more prevalent in African Americans and may be underdiagnosed in black women.

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Prognosis

Generally, CH is a lifelong problem. Potential outcomes include the following:

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

About 80% of patients with episodic CH maintain the episodic form of the disorder. In 4-13%, episodic CH eventually transforms into chronic CH. Intermediate (mixed) forms may also develop. Prolonged, spontaneous remissions occur in as many as 12% of patients, particularly in those with episodic CH. Chronic CH is more relentless and may persist in this form in as many as 55% of cases. Less frequently, chronic CH may remit into an episodic form.

No reported mortality is directly associated with CH. However, patients with CH are at increased risk for self-injury during attacks, suicide attempts, alcohol use (and other forms of substance abuse), cigarette smoking, and peptic ulcer disease. Suicides have been reported in cases where attacks are frequent and severe. The intensity of the attacks often leads CH patients to miss time from activities such as work or school. Medications used may have side effects, including the unmasking of coronary artery disease.

Pharmacologic intervention may play a part in the transformation of chronic CH into the episodic form; otherwise, it does not influence outcome. Late onset of the disorder, male sex, and previous episodic CH all predict a less favorable course.

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Patient Education

Patients should be educated regarding the need to avoid known precipitants of CH. In addition, they should be instructed to avoid high altitudes.

For patient education resources, see the Headache Center, as well as 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 .

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History

Attacks of cluster headache (CH) are typically short and occur with a clear periodicity, particularly during sleep or early morning hours, usually corresponding with onset of rapid eye movement (REM) sleep.^{[5, 9]} Unlike migraine, CH is not preceded by aura and is not usually accompanied by symptoms such as nausea, vomiting, photophobia, or osmophobia. Typically, a patient experiences 1-2 cluster periods per year, each lasting 2 weeks to 3 months.

The International Headache Society (IHS) classifies CH as episodic or chronic on the basis of duration as follows^[3] :

• Episodic CH occurs in periods lasting from 7 days to 1 year; cluster attacks are separated by pain-free intervals at least 1 month long
• Chronic CH persists for more than 1 year either without remission or with remissions shorter than 1 month; it is further divided into 2 subcategories, chronic CH from onset and chronic CH evolving from episodic CH

The pain of CH is manifested as follows:

• Character - Excruciating, stabbing, sharp, and lancinating (as if the eye is being pushed out), rather than throbbing
• Location – Unilateral, in the periorbital, retro-orbital, or temporal regions, though pain sometimes radiates to the cheek, jaw, occipital, and nuchal regions; the pain tends to remain on the same side during the cluster period but in rare cases may switch sides
• Distribution - First and second divisions of the trigeminal nerve; approximately 18-20% of patients complain of pain in the extratrigeminal areas (eg, the back of the neck, along the carotid artery)
• Onset – Sudden, peaking in 10-15 minutes
• Duration - 5 minutes to 3 hours per episode
• Frequency - May occur 1-8 times a day for as long as 4 months (often nocturnal)
• Periodicity - Circadian regularity in 47%
• Remission - Long symptom-free intervals occur in some patients; the length of these remissions averages 2 years but may range from 2 months to 20 years

Pain is accompanied by various cranial parasympathetic symptoms, including the following^[5] :

• Ipsilateral 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%)

Alcoholic products and tobacco may precipitate an attack. Other triggers include hot weather, watching television, nitroglycerin, stress, relaxation, extreme temperatures, glare, allergic rhinitis, and sexual activity.

During an attack of CH, as many as 90% of patients may become agitated and extremely restless. They do not like to lie down to rest; instead, they prefer to pace or move around. In desperation, patients may rock, sit, pace, bang themselves against a hard surface, scream in pain, or crawl on the floor.

Structural lesions have been described with CH and should be suspected if the presentation is atypical. Atypical features may include the following:

• Absence of a periodic pattern
• Residual headache between exacerbations
• Bilaterality
• Incomplete or minimal response to standard therapy
• Presence of lateralizing findings on examination (other than Horner syndrome)

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Physical Examination

Physical examination findings should be normal, except for certain findings that serve as hallmarks of CH. These 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.

Characteristic findings include the following:

• Distinctive facial appearance - Leonine facies, multifurrowed and thickened skin with prominent folds, a broad chin, vertical forehead creases, and nasal telangiectasias
• Parasympathetic overactivity - Ipsilateral lacrimation, conjunctival injection, rhinorrhea or congestion
• Ocular sympathetic paralysis - Mild Horner syndrome (eg, ptosis, miosis, and anhidrosis), which may persist between attacks
• Bradycardia
• Facial flushing or pallor
• Scalp and facial tenderness
• Ipsilateral carotid tenderness (in some patients)

Patients often are in severe distress. They may lower the head and press on the site of pain, sometimes crying or screaming. Physical exercise may afford a degree of relief. In cases of especially severe or intolerable pain, patients may even threaten suicide.

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Approach Considerations

The diagnosis of cluster headache (CH) is based on historical and physical findings. A history of attacks that occur with the characteristic periodicity and rhythmicity is the key to the diagnosis. Laboratory studies are not of particular value in this regard.

Imaging studies, though not diagnostic, are useful for excluding other potential causes of headache in selected patients. Neuroimaging with assessment of the intracranial and cervical vasculature and the sellar and paranasal region is recommended in all patients with atypical presentations of trigeminal autonomic headaches.

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Approach Considerations

Pharmacologic management of cluster headache (CH) may be classified into 2 general approaches as follows:

• Abortive/symptomatic (eg, oxygen, triptans, ergot alkaloids, and anesthetics)
• Preventive/prophylactic (eg, calcium channel blockers, mood stabilizers, and anticonvulsants)

Olanzapine^[11] and kudzu^[12] have also been used to treat CH, but their effectiveness has not been determined. Antihistamines, such as chlorpromazine, do not appear to be helpful in relieving CH symptoms. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be given for pain relief.

Galcanezumab is the first drug to gain FDA approval for decreasing the frequency of episodic cluster headaches.^[13]  

Various procedures may be performed on trigeminal nerve or autonomic pathways, including alcohol injections and section or avulsion of nerves for chronic refractory cases. Surgical treatment may be initiated if the patient has contraindications to medications or if medications are not effective; it is employed only in strictly unilateral cases. Radiofrequency (RF) thermocoagulation of the trigeminal ganglion has had promising results in some patients with intractable pain.

Treatment guidelines are available from the American College of Emergency Physicians, the National Headache Foundation, and Institute for Clinical Systems Improvement.^{[14, 15, 16]} Neurologic consultation may be useful if the diagnosis is in doubt or for management of difficult cases.

Management of pregnant patients

CH is rare during pregnancy, but when it does occur, episodes tend to have the same character and severity as in nonpregnant patients.^[17] Treatment options for pregnant women are poorly documented. The first line of treatment is pure oxygen via a nonrebreather mask (see image below). Triptans and ergot alkaloids should be avoided. The use of selected preventive medications, which are rated pregnancy category B, should be discussed thoroughly with the patient and her obstetrician.^[18]

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Non-rebreather oxygen mask with reservoir for the acute treatment of cluster headache. Courtesy of Wikipedia Commons.

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Pharmacologic Therapy

Galcanezumab is the first drug to gain FDA approval for decreasing the frequency of episodic cluster headaches. In a phase trial (n=106), galcanezumab showed a mean of 8.7 fewer weekly cluster headache attacks compared with 5.2 fewer with placebo. A higher percentage of patients responded to galcanezumab (71.4%) compared with placebo (52.6%).^[13] After a single SC loading dose, galcanezumab is administered once monthly until the cluster period ends.

Abortive agents are given to stop or reduce the severity of an acute CH attack, whereas prophylactic agents are used to reduce the frequency and intensity of individual headache exacerbations. In view of the fleeting, short-lived nature of the attacks, effective prophylaxis should be considered the cornerstone of management. The prophylactic regimen should start at the onset of a CH cycle and continue until the patient is headache-free for at least 2 weeks. The agent then may be tapered slowly to prevent recurrences.

Abortive agents

Oxygen (8 L/min for 10 minutes or 100% by mask) may abort the headache if used early.^{[19, 20]} The mechanism of action is unknown.

5-Hydroxytryptamine-1 (5-HT₁) receptor agonists, such as triptans or ergot alkaloids with metoclopramide, are often the first line of treatment. Stimulation of 5-HT₁ receptors produces a direct vasoconstrictive effect and may abort the attack.

The triptan that has received the most study in the setting of CH is sumatriptan.^{[15, 19, 20]} Subcutaneous injections can be effective, in large part because of the rapidity of onset. Studies have indicated that intranasal administration is more effective than placebo but not as effective as injections; there is no evidence that oral administration is effective. A typical dose is 6 mg subcutaneously, which may be repeated in 24 hours. Nasal spray (20 mg) may also be used.

Other triptans that may be considered for abortive treatment of CH are zolmitriptan, naratriptan, rizatriptan, almotriptan, frovatriptan, and eletriptan. In addition, researchers have begun to explore the possibility of using triptans for prophylaxis of CH.^[21]

Dihydroergotamine can be an effective abortive agent. It is commonly given intravenously (IV) or intramuscularly (IM) and may be self-administered; it can also be given intranasally (0.5 mg bilaterally).^[20] Dihydroergotamine tends to cause less arterial vasoconstriction than ergotamine tartrate and is more effective when given early in a cluster attack.

Parenteral opiates may be used if relief is inadequate. The short-lived and unpredictable character of CH precludes effective use of oral narcotics or analgesics, though oral regimens may sometimes be helpful for residual soreness. Abuse potential does exist. Narcotics are not generally recommended for aborting CH.

Intranasal civamide and capsaicin have yielded good results in clinical trials. Application of capsaicin to the nasal mucosa led to a clinically significant decrease in the number and severity of cluster headaches; nasal burning was the most common adverse effect.

Intranasal administration of lidocaine drops (1 mL of a 10% solution placed on a swab in each nostril for 5 minutes) is possibly helpful; however, it requires a specific and, for many patients, difficult technique.

Prophylactic agents

Calcium channel blockers may be the most effective agents for CH prophylaxis.^[20] They can be combined with ergotamine or lithium. Of the calcium channel blockers, verapamil may be the most useful, though others, including nimodipine and diltiazem, have also been reported to be effective.

Lithium has been suggested as an option because of the cyclical nature of CH, which is similar to that of bipolar disorders. It effectively prevents CH (particularly in its more chronic forms)^[22] and treats bipolar mood disorder, another cyclic illness. Responses vary (with chronic CH patients generally being more responsive), but lithium is still a recommended first-line agent for CH. There is a tendency for the effect to wane after dramatic relief is seen in the first week.

Methysergide, though no longer available in the United States, is very effective for episodic and chronic CH prophylaxis. It can often reduce pain frequency, particularly in younger patients with episodic CH. If it yields no improvement after 3 weeks, it is unlikely to be beneficial. It should not be given continuously for longer than 6 months; a drug-free interval of 3-4 weeks must follow each 6-month course.

A few relatively small controlled studies have found anticonvulsants (eg, topiramate and divalproex) to be effective in the prophylaxis of CH, though the mechanism of action remains unclear.

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. Simultaneous use of standard prophylactic agents (eg, verapamil) is recommended. The mechanism of action in CH is still subject to speculation.

Tricyclic antidepressants are more helpful as prophylaxis of other headache syndromes. Beta blockers may worsen bradycardia occurring during the cluster attack.

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Nerve Blocks, Ablative Procedures, and Brain Stimulation

Various invasive nerve blocks and ablative neurosurgical procedures (eg, percutaneous RF ablation, trigeminal gangliorhizolysis, and rhizotomy) have been implemented successfully in cases of refractory CH.

Percutaneous RF ablation may achieve success in 50% of patients, with fair-to-good results in 20% and failure in about 30%. Side effects include facial dysesthesia, corneal sensory loss, and anesthesia dolorosa. Gamma-knife radiosurgery is a less invasive alternative for pervasive CH but is associated with a significantly increased risk for facial sensory disturbances.^[23] Botulinum toxin injections to manage CH have produced limited success.^[24] Greater occipital nerve block may be beneficial in aborting CH.^{[11, 25]}

Deep brain stimulation with implantation of stimulating electrodes under stereotactic guidance into the ipsilateral posterior inferior hypothalamus is another potential option for chronic CH refractory to pharmacologic therapy.^{[26, 27, 28, 29]} This technique is invasive and is associated with significant risk of complications, including intracranial hemorrhage.^[30] Other serious side effects are subcutaneous infection, micturition syncope, and transient loss of consciousness.^[31]

Stimulation of the sphenopalatine ganglion, which is located in the pterygopalatine fossa, may also be considered.^[32] This approach has shown effectiveness in select patients with chronic CH.^[33]

In 2017, the FDA approved a hand-held device to treat cluster headaches.^[34] The non-invasive device works by transmitting mild electrical stimulation to the vagus nerve through the skin on the neck. Approval was based on 2 clinical trials (ACT1 and ACT2) showing that the device was more effective than placebo in reducing cluster headache pain.^[35]

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Prevention

The patient should avoid known headache triggers to the extent possible. For example, disturbances in the sleep cycle can induce attacks. Strong emotions and excessive physical activity may also induce attacks.

Tobacco may slow responsiveness to medications. Narcotics may expedite transformation of episodic CH to chronic CH.

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Medication Summary

Galcanezumab is the first drug to gain FDA approval for decreasing the frequency of episodic cluster headaches.^[13]

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.

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Zolmitriptan (Zomig, Zomig-ZMT, Zomig Nasal Spray)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Naratriptan (Amerge)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Sumatriptan succinate (Imitrex, Alsuma, Sumavel DosePro)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Rizatriptan (Maxalt, Maxalt-MLT)

• Dosing, Interactions, etc.

Clinical Context:  Rizatriptan is a selective agonist for 5-HT1 receptors in cranial arteries and suppresses the inflammation associated with migraine headaches.

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Almotriptan (Axert)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Frovatriptan (Frova)

• Dosing, Interactions, etc.

Clinical Context:  Frovatriptan is used to treat acute migraine. It is a selective 5-HT_1B/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.

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Eletriptan (Relpax)

• Dosing, Interactions, etc.

Clinical Context:  Eletriptan is a selective serotonin agonist that specifically acts at 5-HT_1B/1D/1F receptors on intracranial blood vessels and sensory nerve endings to relieve pain associated with acute headaches.

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Class Summary

Triptans may reduce the inflammation associated with migraine headaches.

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Galcanezumab (Emgality, galcanezumab-gnlm)

• Dosing, Interactions, etc.

Clinical Context:  Monoclonal antibody that targets CGRP. It is indicated for treatment of episodic cluster headache in adults.

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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.

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Dihydroergotamine (D.H.E. 45 injection, Migranal)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Ergotamine (Ergomar)

• Dosing, Interactions, etc.

Clinical Context:  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.

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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.

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Lidocaine 4%, (Xylocaine)

• Dosing, Interactions, etc.

Clinical Context:  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.

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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.

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Capsaicin (Capzasin-P)

• Dosing, Interactions, etc.

Clinical Context:  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.

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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.

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Verapamil (Calan, Verelan, Verelan PM, Covera-SR)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Class Summary

These agents inhibit the initial vasoconstrictive phase of CH.

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Lithium carbonate (Lithobid)

• Dosing, Interactions, etc.

Clinical Context:  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).

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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.

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Divalproex sodium (Depakote, Depakote ER)

• Dosing, Interactions, etc.

Clinical Context:  Few adequate studies of divalproex are available, and results have been mixed.

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Topiramate (Topamax)

• Dosing, Interactions, etc.

Clinical Context:  Topiramate has been effective for prophylaxis of CH in several small prospective studies. Its exact mechanism of action in this setting is unknown.

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Class Summary

The mechanism of action by which anticonvulsants prevent CH is unclear; it may involve regulation of central sensitization.

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Prednisone

• Dosing, Interactions, etc.

Clinical Context:  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.

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Prednisolone (Millipred, Orapred, Orapred ODT, Prelone)

• Dosing, Interactions, etc.

Clinical Context:  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.

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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.

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Prochlorperazine (Compro)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Class Summary

Antiemetics and sedatives are used to treat CH and emesis associated with acute attacks.

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Ibuprofen (Motrin, Advil, Addaprin, Caldolor)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Ketoprofen

• Dosing, Interactions, etc.

Clinical Context:  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.

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Naproxen (Anaprox, Naprelan, Aleve, Naprosyn)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Flurbiprofen

• Dosing, Interactions, etc.

Clinical Context:  Flurbiprofen may inhibit cyclooxygenase, thereby inhibiting prostaglandin biosynthesis. These effects may result in analgesic, antipyretic, and anti-inflammatory activities.

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Indomethacin (Indocin)

• Dosing, Interactions, etc.

Clinical Context:  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).

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Ketorolac

• Dosing, Interactions, etc.

Clinical Context:  Ketorolac inhibits prostaglandin synthesis by decreasing the activity of cyclooxygenase, thereby resulting in decreased formation of prostaglandin precursors.

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Ketorolac nasal solution (Sprix)

• Dosing, Interactions, etc.

Clinical Context:  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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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.

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