Pharmacologic Management of Cluster Headache

RELEASE DATE:

January 1, 2018

EXPIRATION DATE:

January 31, 2020

FACULTY:

Clayton English, PharmD, BCPS, BCPP
Associate Professor of Pharmacy Practice
Albany College of Pharmacy & Health Sciences
Colchester, Vermont

FACULTY DISCLOSURE STATEMENTS:

Dr. English has no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

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Pharmacy
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Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To improve the pharmacist's ability to provide consultation on current pharmacologic options and treatment strategies for cluster headaches, including acute and preventive pharmacologic treatments.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Describe the epidemiology, diagnostic criteria, and underlying pathophysiology of cluster headache.
  2. Recognize the common signs and symptoms associated with cluster headache.
  3. Differentiate cluster headache from other common headache disorders, including migraine and tension-type headache.
  4. Compare the available pharmacologic options for treating cluster headache, including acute and prophylactic treatments.
  5. Select an evidence-based drug therapy regimen, based on treatment guidelines, for a patient presenting with acute cluster headache.

ABSTRACT: Cluster headaches are associated with cranial autonomic symptoms in addition to severe unilateral head pain. Pharmacotherapy is often required in the form of both abortive and prophylactic therapies to help manage symptoms. High-flow oxygen and nonoral triptans are abortive treatments of choice. Prophylactic therapy to prevent symptom recurrence is typically achieved with verapamil or lithium carbonate. Corticosteroids and nerve blocks are used as bridge treatment until prophylactic therapy is effective. It is important for pharmacists to recognize the symptoms of cluster headache because this headache disorder has limited self-care management and often requires referral to specialists.

Cluster headache is a rare headache disorder characterized by severe, unilateral head pain that presents with cranial autonomic symptoms including conjunctival redness, lacrimation (tearing of the eye), rhinorrhea (runny nose), and drooping of the eyelid. The autonomic symptoms present ipsilaterally, occurring on the same side of the head as the pain. Cluster headache is one of five primary headache disorders categorized as trigeminal autonomic cephalgias (TACs).1 TACs are generally considered the most debilitating of all primary headache disorders owing to their high level of pain combined with autonomic symptoms.2

Effective pharmacotherapy exists for targeting pain associated with cluster headache, and treatment should be implemented after a correct diagnosis has been made to reduce pain burden and improve quality of life. Pharmacologic treatment for cluster headaches is divided into three phases: abortive treatment (i.e., medications used acutely to immediately terminate the pain of a cluster headache); prophylactic treatment (i.e., medications given daily to prevent future headaches); and bridge treatment (i.e., medications used for brief intervals until prophylactic treatments reach peak efficacy).3 The scope of this article is to review the pharmacologic management of cluster headache.

Epidemiology

The lifetime prevalence of cluster headache is 124 per 100,000 based on pooled epidemiological studies.4 Onset of symptoms is typically seen by the early third decade of life, and women often have an earlier onset of symptoms compared with men. Most data regarding cluster headaches have primarily been in Caucasian populations, so it is difficult to determine if there are differences in prevalence across race and ethnicity.5 Cluster headache occurs more predominantly in men, with rates quadrupled in males versus females.4 Familial studies indicate that first-degree relatives have a five-to-18-fold greater risk of developing cluster headache compared with the general population.6 Although not a definitive risk factor, smoking is more prevalent in patients with cluster headache.5

Diagnosis and Clinical Features

A diagnosis of cluster headache is based primarily on patient history, presenting symptoms, and diagnostic criteria. Severe headache pain presenting with autonomic symptoms (e.g., runny nose, facial flushing, lacrimation) and restlessness or agitation are the cornerstone symptoms associated with cluster headache. The diagnostic criteria for headache disorders are based on the International Classification of Headache Disorders 3rd edition (ICHD-3). The diagnostic requirements for cluster headache are noted in TABLE 1.1 The headache attacks occur in cycles or bouts lasting weeks or months, often referred to as a cluster attack period. These attack periods correlate with circadian changes, as attacks are often more severe with changes in daylight hours, most notably around the start and end of daylight saving time.7 Attacks often occur during sleep, and the onset of pain can become drastic quickly.


tbl1

Owing to the circadian implications and timing of symptoms, cluster headaches can be further divided into two categories: episodic cluster headache and chronic cluster headache. Episodic cluster headache is more common compared with chronic cluster headache, the latter occurring in roughly 10% of the population with cluster headache. An episodic cluster headache diagnosis is made in patients who have had two cluster headache attacks lasting 7 days up to 1 year and separated by a pain-free remission period of at least a month. Patients with chronic cluster headache do not have a remission period or have remission periods lasting less than a month for at least a year.1 Most patients have a cluster attack period annually; however, patients can have periods of remission lasting for years.

MRI is often utilized to rule out other causes of severe head pain. Laboratory and other tests are often not indicated. Because of the specificity of symptoms and severity of headache pain seen in cluster headache, few other disease states are compatible with the features present in cluster headache. The differential diagnosis of cluster headache includes other TACs (e.g., paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks), trigeminal neuralgia, and headache pain secondary to another cause (e.g., trauma, malignancy, aneurysm).8

Other common headache disorders, such as migraine headache and tension headache, do not typically match the presentation seen in cluster headache. Tension headaches present with less headache pain compared with cluster headache and are devoid of autonomic symptoms. Additionally, tension headaches present with bilateral pain, compared with unilateral pain seen in both migraine and cluster headaches. Migraine headaches are primarily associated with nausea, vomiting, photophobia, and phonophobia, which occur infrequently with cluster headaches. Withdrawal to a noiseless and dark setting is often required to alleviate symptoms in migraine patients, whereas cluster headache patients typically move and pace to relieve restlessness. Migraine headaches may also present with aura, which are rare in cluster headache. The short duration of attacks and male predominance are also key differences between cluster headaches and migraine headaches, as patients with migraine headaches have a female predominance and the headache often lasts longer and is exacerbated by physical activity. Although infrequent with migraine headaches, autonomic symptoms may be present and are not absolute differentiating features of these headaches.1,8

Pathophysiology

The pathophysiology of cluster headache is complex and is not fully understood. Neuroimaging has identified the posterior hypothalamus and the trigeminovascular system as key areas for modulation of the pain and autonomic symptoms present in cluster headache.

During acute cluster attacks, positron emission tomography scans have shown activation of the ipsilateral hypothalamic gray area, demonstrating a possible role for the hypothalamus to modulate cluster attacks.9,10 The cyclic nature of cluster attack periods and the correlation with symptom reemergence with change in daylight hours imply that the posterior hypothalamus is involved, as it is responsible for controlling circadian rhythms. Additionally, neuroendocrine activity associated with circadian changes, including concentrations of melatonin, cortisol, testosterone, and prolactin, has altered secreting patterns in patients with cluster headache, further inducing hypothalamic activity.

The posterior hypothalamus is interconnected with the trigeminovascular system, the major set of neurons in the trigeminal nerve that innervate the cerebral blood vessels. Although the mechanism is not fully elucidated and conflicting theories exist for the generation of pain symptoms associated with cluster headache, it is proposed that a disruption between these systems leads to activation of the trigeminal-autonomic reflex, resulting in both the pain and the autonomic symptoms seen in cluster headache.10,11

Although a direct trigger for the pain in cluster headache has not been identified, the activation of the trigeminovascular system leads to the release of pronociceptive neuropeptides, including calcitonin gene-related peptide, neurokinin A, and substance P.11 Afferent pain pathways from the trigeminovascular system project to the trigeminocervical complex and then to the thalamus, relaying pain signals to cortical areas, which results in pain in an individual with cluster headache. Autonomic symptoms in cluster headache are produced through reflex activation of parasympathetic pathways from afferent trigeminovascular nociceptive input.10,11 These pathways may also be innervated and controlled by the posterior hypothalamus. When activated, the parasympathetic pathways innervate the cerebral blood vessels and meninges. This innervation causes further irritation and also results in autonomic symptoms (i.e., lacrimation, rhinorrhea).10,11

Genetic risk factors may also play a role in the pathophysiology of cluster headache. The G1246A polymorphism of the hypocretin 2 receptor, or orexin receptor type 2, is associated with a higher incidence of cluster headache. Hypocretin (or orexin) is a neuropeptide located in the lateral and posterior hypothalamus that is involved in the sleep-wake cycle and energy homeostasis. The degree of involvement of hypocretin neuropeptides in cluster headache is not known, and further research is needed to understand their interplay in cluster headache.5,6,12

Pharmacologic Therapy

Pharmacologic treatment of cluster headaches is divided into three categories: abortive therapy, prophylactic therapy, and bridge therapy. The goal of abortive therapy is to quickly terminate individual attacks. Abortive therapy should be used as soon a cluster headache begins in order to quickly terminate the attack. Abortive therapy should be provided to all patients with cluster headache, provided there are no contraindications to treatment.13 Prophylactic therapy is given daily and is indicated at the start of a cluster period to shorten the frequency and severity of episodic cluster attacks. Prophylactic therapy is generally indicated for patients with frequent, severe attacks and in those whose attack periods last a month or longer. Additionally, patients are candidates for prophylactic therapy if they might overuse abortive treatments, especially triptans and ergot derivatives.

Patients treated with prophylactic therapy for episodic cluster headache should receive continuous treatment for at least 2 weeks after being symptomfree. Prophylactic therapy should then be slowly tapered and may be reintroduced at the beginning of the next cluster period. Patients with chronic cluster headache will require indefinite treatment with prophylactic therapy.13 Prophylactic therapies often require low starting doses to prevent adverse effects, and they necessitate ascending titration to achieve an effective dose. Prophylactic therapy has a delayed onset of action, which is often not seen for 2 to 3 weeks. Owing to the delay in onset of prophylactic medications, bridge therapy is often used in addition to other treatments to help decrease pain burden until prophylactic medications reach full effect.3 Bridge therapy is used only as transitional treatment, and its duration spans the course of a few weeks.14

Abortive Treatments

Traditional analgesic agents, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids, are often recognized as appropriate acute interventions in both tension and migraine headache. It is important to note that acetaminophen and NSAIDs are ineffective for alleviating the agonizing pain seen in cluster headaches. Additionally, opioid and other adjuvant medications used for acute pain are often ineffective for cluster headache. Abortive therapies for cluster headache require specific prescription interventions. The American Headache Society (AHS) treatment guidelines consider high-flow oxygen, subcutaneous sumatriptan, and intranasal zolmitriptan the preferred first-line acute abortive treatments. Second-line pharmacologic treatments include sumatriptan nasal spray and oral zolmitriptan.15 Effective abortive treatments for episodic and chronic cluster headache are presented in TABLE 2.


tbl2

Oxygen

Oxygen therapy is considered the gold standard abortive treatment for episodic and chronic cluster headaches. The mechanism of action of oxygen is unknown; however, oxygen has inhibitory actions on parasympathetic innervations responsible for autonomic symptoms, and it may play a role in inhibiting the trigeminovascular system.16 Shortburst inhalation of 100% oxygen using a nonrebreathing face mask with reservoir is the preferred delivery method. The administered flow rate should be at least 12 L/minute and may be given for up to 15 to 20 minutes.15 This high-flow delivery is effective at aborting a cluster headache in approximately 70% to 78% of patients.13,14 Therapeutic effects of oxygen are usually seen within 5 minutes of inhalation.13 Inhalations should be limited to a maximum of 15 to 20 minutes at a time, and nonresponders should cease use at 20 minutes. Nonresponders may repeat the inhalation with a subsequent cluster attack. Responders to oxygen therapy should continue oxygen treatment for an additional 5 minutes after an attack has been aborted in order to prevent rebound headache.17 Oxygen may be repeated and used for subsequent attacks that day in patients with multiple attacks, and there is no maximal dosage limit.

Adverse effects are rarely reported for oxygen, and there are no absolute contraindications to receiving therapy, making it the preferred treatment for patients with contraindications to triptans.13 Patients may occasionally get reddened and chapped skin around areas of the mask device. Although adverse effects are few with oxygen, therapy can be difficult to obtain and may not be the best therapy for patients unaware of environmental dangers. Oxygen can hasten a lit fire, causing it to burn more efficiently. Since oxygen is odorless and colorless, it can be difficult for patients to adequately identify higher concentrations in small spaces, and higher concentrations of oxygen lower the temperature for household items to ignite. Oxygen therapy should be used cautiously in patients who smoke, for the aforementioned reasons. Patients should avoid smoking while using oxygen, after recently receiving oxygen therapy (i.e., 30 minutes or less since last treatment), or in areas where oxygen concentrations may be higher, such as a small, unventilated room.18 Patients with comorbid chronic obstructive pulmonary disease should also use oxygen cautiously, as they are predisposed to poor ventilation and perfusion matching, resulting in an increased risk of carbon dioxide retention.13

The biggest limitations of oxygen therapy are the impediments to delivery, especially when a patient is not at home or at a clinical facility. Most patients require a large cylinder for home use, with an extra backup cylinder for emergencies. An additional cylinder may also be required at the patient’s workplace. Depending on insurance coverage, patients may be limited by the amount supplied and covered. Advances are being made in portable devices that may provide more flexibility for administration. Owing to the large amount of oxygen required for inhalation, some portable devices are impractical because they are not large enough to deliver an adequate amount of oxygen.13 Patients starting on oxygen therapy should be referred to a respiratory therapist to receive proper education regarding administration techniques and how to properly set up oxygen therapy at home and in the workplace.

Triptans

Subcutaneous sumatriptan and intranasal zolmitriptan are considered effective first-line treatments for episodic and chronic cluster headache. Triptans bind to 5-hydroxytryptamine (5-HT)1B/D receptors in the trigeminovascular system. The activation of 5-HT1D receptors inhibits the release of pronociceptive neuropeptides, including CGRP, from perivascular trigeminal neurons. Although comparative trials are lacking, subcutaneous sumatriptan has response rates similar to that of oxygen. The recommended dosage of subcutaneous sumatriptan is similar to that used in migraine headaches, with a recommended starting dose of 6 mg administered subcutaneously. A repeat injection may be given in 1 hour, if needed, for a maximum daily dosage of 12 mg/day.13,15

Intranasal zolmitriptan is also an effective first-line therapy for cluster headaches, demonstrating efficacy in two randomized, controlled trials at dosages of 5 mg and 10 mg. The headache response rates with intranasal zolmitripan range from 42% to 63%, with higher response rates achieved with the 10-mg dose.19,20 Sumatriptan 20 mg delivered intranasally is considered a second-line intervention for cluster headache. Intranasal sumatriptan was studied in one randomized, controlled trial, with 57% of patients responding to intranasal sumatriptan versus 26% of those given placebo.21 Although only one trial has demonstrated efficacy, because of familiarity and comfort with sumatriptan, many practitioners opt to use it as a first-line intervention. Oral zolmitriptan given at a dose of 5 or 10 mg is effective at reducing headache pain. Oral zolmitriptan is not recognized as a first-line intervention owing to lower headache response rates in clinical trials, and the onset of action is much slower compared with subcutaneous and intranasally delivered triptans. Other oral triptans have not been extensively evaluated in clinical trials and, owing to their reduced speed of onset, are not recognized by treatment guidelines as alternative abortive therapy.3

Common adverse effects of triptans include paresthesias, dizziness, fatigue, and gastrointestinal upset. Injection-site reactions, including transient burning, tingling, and tightness in the chest, neck, and face, are more often associated with subcutaneous sumatriptan relative to oral triptans. Triptans exert vasoconstricting properties secondary to 5-HT1B activation, resulting in these mild reactions. Because of the presence of 5-HT1B receptors on coronary arteries, triptans are contraindicated in patients with a history of coronary artery disease, stroke, peripheral vascular disease, ischemic bowel disease, and uncontrolled hypertension.22 Caution should be exercised with use of triptans and other serotonergic compounds because combination treatment could lead to the rare, but serious, serotonin syndrome.

Other Abortive Therapies

Other abortive treatments have been studied for episodic and chronic cluster headache, but these treatments are reserved for patients who have failed oxygen and triptan medications or have contraindications to therapy, as the evidence for their use is less robust. Octreotide 100 mcg administered subcutaneously was effective in 52% of patients compared with 36% of those receiving placebo in a randomized, controlled crossover trial. Octreotide inhibits the release of vasoactive peptides, including CGRP, which might explain its role in cluster headache. Gastrointestinal adverse effects were more common with octreotide therapy.23

Lidocaine 10% solution and cocaine 10% solution administered intranasally via anterior rhinoscopy were each found to be effective compared with placebo in a parallel, controlled trial for nitroglycerininduced attacks in cluster headache. Both anesthetic agents were statistically more effective than placebo in more quickly achieving complete cessation of headache pain. The trial included nine patients and studied only drug-induced cluster headache, which might reduce the external validity of the findings. Additionally, cocaine hydrochloride 10% is no longer available in the United States, and other dosages have not been evaluated in randomized, controlled trials for cluster headache. Lidocaine 10% administered intranasally may be given as an abortive therapy for nitroglycerin-induced attacks or if traditional treatments fail.24

Ergotamine derivatives have historically been used as abortive treatment for cluster headache. In addition to having 5-HT1B/D agonistic activity similar to triptans, ergotamine derivatives possess dopaminergic activity. This results in high rates of nausea and vomiting, requiring premedication with antiemetics. There is limited controlled-trial evidence for the use of ergotamine derivatives for cluster headache. Guidelines for cluster headache do not currently endorse them, and adverse effects limit their use compared with triptans.15 Ergotamine derivatives have strong vasoconstrictive properties secondary to effects on alpha-drenergic receptors and should be avoided in similar cardiovascular disease states in which triptans are contraindicated.13 Furthermore, ergotamine derivatives are contraindicated in pregnancy because they possess abortifacient properties and are subject to CYP3A4 interactions. IV dihydroergotamine is given in clinical practice to break a continuous attack cycle in refractory patients over the course of 3 to 5 days. Protocols for dosage and administration vary by institution, but administration requires prudent monitoring of vital signs and management of nausea and vomiting throughout treatment.25

Prophylactic Therapy

The AHS recognizes suboccipital corticosteroid injections and civamide nasal spray as the prophylactic therapies for cluster headache with strongest evidence based on clinical-trial data. Unfortunately, corticosteroid injections are used as short-term bridge treatment and are limited as a long-term prophylactic strategy. Civamide is not currently available in the U.S., limiting the availability of long-term, strong evidence–based treatments to prevent cluster headaches. The AHS guidelines recognize verapamil, lithium, warfarin, and melatonin as possibly effective prophylactic treatments for cluster headache.15

Verapamil

Verapamil is the prophylactic treatment of choice for cluster headache in the U.S., with two positive randomized, controlled trials demonstrating benefit.26 In a randomized, placebo-controlled trial consisting of 30 outpatients, patients taking verapamil 360 mg/ day experienced 0.6 attacks per day compared with 1.65 attacks for placebo (P <.001).27 Verapamil must be started at a low dose and titrated slowly, often requiring a balance of efficacy with the risk of hypotension, bradycardia, and fatigue in increased doses. A typical approach is to start verapamil at 40 to 80 mg three times/day and increase the dose by 80 mg per week in divided doses until a target dose of 360 mg per day is reached. Some patients may require higher doses (up to 720 mg/day or higher) to achieve reductions, but this must be balanced with potential adverse effects.3

Prior to starting therapy, patients should have an ECG to rule out cardiac contraindications (e.g., atrioventricular block, atrial flutter) and should be periodically monitored throughout treatment, as cardiac-conduction abnormalities may emerge. Common adverse effects include constipation, peripheral edema, bradycardia, fatigue, hypotension, and occasional nausea. Verapamil is associated with pharmacokinetic drug interactions, as it inhibits CYPP4503A4, and many CYP3A4 substrates require avoidance or dose reductions when used concurrently with verapamil.3,13

Lithium

Lithium carbonate has demonstrated efficacy in cluster headache and was historically the treatment of choice prior to verapamil trials. Lithium is typically reserved as an alternative therapy to verapamil in clinical practice. Lithium has demonstrated efficacy in a small randomized, comparative clinical trial versus verapamil. Both therapies were effective; however, verapamil had a faster onset of action and had fewer side effects.26,28 Lithium may be used as monotherapy or in combination with verapamil in patients without satisfactory reduction in headache frequency. Lithium is dosed between 600 and 900 mg/day for cluster headache. Fatigue, somnolence, tremor, polyuria, polydipsia, gastrointestinal disturbance, renal insufficiency, and hypothyroidism can occur with lithium therapy. Patients taking lithium require baseline kidneyand thyroid-function tests and periodic monitoring of these laboratory values throughout therapy. In addition, lithium blood concentration should be measured once a steady-state dose of lithium is reached, and it should be monitored periodically throughout therapy to avoid lithium toxicity. No established blood concentration is needed for cluster headache, and levels should remain below 1.2 mEq/L. An electrocardiogram is recommended for patients with a history of conductance abnormalities or in patients of advanced age. Owing to the risk of Epstein’s anomaly, lithium should be avoided during the first trimester of pregnancy. Lithium is a narrow-therapeutic-index medication and is sensitive to changes in glomerular filtration and imbalances in sodium concentration. Diuretics, NSAIDs, ACE inhibitors, angiotensin receptor blockers, and sodium restriction should be avoided during therapy, as they all have the potential to raise lithium concentrations.13 A summary of verapamil and lithium treatment is provided in TABLE 3.


tbl3

Other Prophylactic Therapies

Other therapies with some positive evidence in cluster headache prophylaxis include melatonin and warfarin. Based on isolated cases of patients demonstrating improvements in cluster headache frequency when started on warfarin therapy, warfarin was evaluated as a treatment for patients with refractory chronic cluster headache in one randomized, crossover, controlled trial consisting of 34 patients. Warfarin dosed to an international normalized ratio of 1.5 to 1.9 led to a remission rate of 50% compared with 11.8% in patients treated with placebo (P = .004). A small number of patients developed traumarelated skin bruising and nosebleeds, but no serious bleeding events were reported. The role of warfarin in cluster headache is unclear, but it may be considered for patients who are nonresponsive to other therapies who have no risk factors for serious bleeding complications.29

Melatonin 10 mg given in the evening was effective at reducing daily frequency of headaches in patients compared with placebo (P <.03) in a controlled trial consisting of 20 patients. One-half of patients responded to melatonin treatment, leading to a decrease in headache frequency. No patients responded to placebo treatment. Melatonin was ineffective in patients with chronic cluster headache, although the numbers were small (n = 2). A reduction in abortive analgesics was also seen, but the finding was not statistically significant. No adverse effects were reported with melatonin treatment. Although melatonin demonstrated efficacy in the trial, the authors concluded that the response rates seen with melatonin were smaller than those for established prophylactic therapies. Melatonin may be considered as prophylactic treatment for episodic cluster headache in patients who had significant adverse effects with other prophylactic therapies or as an adjunctive therapy for patients with unsatisfactory reduction in headache frequency with other treatments.30

Anticonvulsants have been explored in the prophylactic treatment of cluster headaches because of their efficacy in migraine headaches and potential to target pain pathways. Gabapentin has shown positive effects for cluster headache in open-label trials when dosed at 900 to 3,600 mg/day, although the trials have ranged from eight to 14 patients and lacked control groups.31-33 Topiramate has conflicting evidence in small, open-label trials and is not currently recognized in treatment guidelines.15,34 Sodium valproate was shown to have negative evidence for the prevention of cluster headache.35

Several agents have been studied for cluster headache and have been found to be ineffective. Misoprostol, candesartan, hyperbaric oxygen, and sumatriptan have negative evidence for prevention of cluster headache. Frovatriptan and intranasal capsaicin have been studied for cluster headache, but there is insufficient evidence to use them routinely. Additional studies are needed to determine their place in the prevention of cluster headache.15,26

Bridge Treatments

Bridge treatments are utilized in patients who present with more than two attacks per day and are currently titrating a prophylactic medication to clinical effect. Bridge treatments are effective at reducing the severity and frequency of pain associated with cluster headache; however, owing to longterm adverse effects or difficulty with administration, these medications are difficult to use for long durations.3 Suboccipital corticosteroid injection, or occipital nerve block, has a large amont of evidence on preventing cluster attacks and is used as a bridge treatment until oral therapies are efficacious. Evidence for occipital nerve block is supported by two randomized, controlled trials. It is most strongly recommended by the AHS treatment guidelines for prophylaxis of cluster headaches and should be considered as a first-line bridging treatment.15 The corticosteroid used, the administration technique, and the protocol for delivery of injections vary in trials and practice.3

Prednisone has been the traditional bridge treatment of choice owing to ease of access, and its efficacy is primarily supported by clinical experience. Prednisone is started at the beginning of a cluster cycle, often along with a standard prophylactic treatment. Starting dosages of prednisone range from 50 to 80 mg/day, and the dose is subsequently tapered over 14 to 21 days.13 IV methylprednisolone dosed at 250 to 500 mg/day is another option, but it should be reserved for patients who are resistant to oral corticosteroids and require hospitalization for the management of their pain.3,13

Occasionally, ergotamine derivatives given daily over the course of a week or long-acting triptans (i.e., frovatriptan, naratriptan) are used as short-term bridge treatment, but there is a lack of controlled data and these treatments are currently not recognized by treatment guidelines.3,15 Additionally, complications arise with these therapies if abortive 5-HT1B/D agonists are needed for acute management. This leads to dosages that often exceed the recommended daily or weekly maximum, putting patients at higher risk for adverse effects or for using an ergotamine derivative within 24 hours of a triptan, which is contraindicated.

Nonpharmacologic Therapy and Self-Care Management

Owing to the excruciating pain associated with cluster headache, self-care options are limited. Melatonin is commercially available OTC and may be used as an alternative prophylactic therapy, as discussed earlier. OTC analgesics are ineffective at targeting the pain of cluster headache.14 Magnesium supplementation may have a role in the treatment of cluster headache, as one study showed improvement in symptoms when IV magnesium sulfate was given to patients with magnesium deficiency and concurrent cluster headaches.36 Oral formulations of magnesium have not been studied, and the role of nutraceuticals needs to be further evaluated before it can be recommended for self-care.

Nonpharmacologic approaches include trigger avoidance and neurostimulation for refractory patients. Triggers for cluster headache are not as predominant as they are for migraine headaches; however, known triggers for cluster headache exist. Alcohol, specifically red wine, has been shown to trigger a cluster headache during active cluster periods. The reaction to alcohol is not apparent when a patient is not in an active attack period. Vasodilating agents can also trigger attacks during an acute cluster period. Notable examples include nitroglycerine and phosphodiesterase inhibitors (e.g., sildenafil, tadalafil). These agents should be avoided during active attack periods.14 Similar to migraine headaches, some patients are sensitive to strong odors, including cleaning supplies, perfume, and cologne. Patients should be cognizant of agents that worsen their attacks and should avoid them, especially during active cluster attacks.

Neurosurgical interventions may be considered for patients with persistent, debilitating headaches despite pharmacologic interventions. Neurostimulation of the sphenopalatine ganglion has been recognized as an effective abortive therapy for patients dissatisfied with current abortive therapies.37 The sphenopalatine ganglion is an extracranial parasympathetic nerve bundle that innervates cerebral blood vessels and interacts with the trigeminovascular system in creating the autonomic symptoms associated with cluster headache. Sphenopalatine ganglion stimulation may result in inhibition of the trigeminovascular pathways, reducing headache pain and autonomic symptoms.38 A randomized, controlled trial showed the benefit of sphenopalatine ganglion stimulation when used for acute cluster headache, with 67.1% of patients experiencing significant pain relief compared with 7.4% receiving sham therapy.37 Implantation of a neurostimulator is necessary for sphenopalatine ganglion stimulation, and the procedure is not routinely available in the U.S.15

Occipital nerve stimulation is another technique used for refractory cluster headache patients. The procedure involves implantation of electrodes around the occipital nerve. Controlled studies have shown improvement in headache-attack frequency, with approximately two-thirds of patients showing a 50% improvement in symptoms. Although neurostimulation procedures are promising, adverse effects are common with both procedures and are primarily related to device implantation, including hardware deficiencies, infection, and lead migration resulting in reduced or loss of effect.39 Additionally, some neurostimulation studies have not clearly shown efficacy and require further study. A randomized, controlled trial of deep-brain stimulation of the hypothalamus did not show improvement in reducing cluster attack frequency as a prophylactic intervention.40 Neurostimulation should be reserved for patients who are unresponsive to pharmacotherapy because of the complications of surgical intervention.

Conclusion

Cluster headache remains one of the most debilitating headache disorders seen in clinical practice. Progress has been made in understanding the pathophysiology of cluster headache; however, much remains to be discovered about its etiology. High-flow oxygen and triptans delivered either subcutaneously or intranasally continue to be the best options available for aborting an acute attack. Although ergotamine derivatives have historically been implicated in attacks and still have a role in specific scenarios, they should not be routinely offered as abortive treatment owing to their lack of evidence in randomized, controlled trials. Verapamil remains the prophylactic agent of choice; however, bridge treatment with corticosteroids is often required owing to the delay in onset of action.

Pharmacists should be cognizant of the symptoms of cluster headache and should be able to help distinguish symptoms of other headache disorders that can be managed with self-care techniques. Owing to the severity of cluster headache and lack of OTC agents, patients need to be managed with prescription pharmacotherapy and should be referred to a headache specialist or primary care physician.

REFERENCES

  1. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia: An International Journal of Headache. 2013;33(9):629-808.
  2. Pareja JA, Alvarez M. The usual treatment of trigeminal autonomic cephalalgias. Headache. 2013;53(9):1401-1414.
  3. Obermann M, Holle D, Naegel S, et al. Pharmacotherapy options for cluster headache. Expert Opin Pharmacother. 2015;16(8): 1177-1184.
  4. Fischera M, Marziniak M, Gralow I, Evers S. The incidence and prevalence of cluster headache: a meta-analysis of population-based studies. Cephalalgia: An International Journal of Headache. 2008;28(6):614-618.
  5. Broner SW, Cohen JM. Epidemiology of cluster headache. Curr Pain Headache Rep. 2009;13(2):141-146.
  6. Waldenlind E, Sjostrand C. Pathophysiology of cluster headache and other trigeminal autonomic cephalalgias. Handb Clin Neurol. 2010;97:389-411.
  7. Barloese M, Lund N, Petersen A, et al. Sleep and chronobiology in cluster headache. Cephalalgia: An International Journal of Headache. 2015;35(11):969-978.
  8. Mathew NT. Cluster headache and other trigeminal autonomic cephalalgias diagnostic criteria. Handb Clin Neurol. 2010;97:421-429.
  9. May A, Bahra A, Buchel C, et al. Hypothalamic activation in cluster headache attacks. Lancet. 1998;352(9124):275-278.
  10. Leone M, Bussone G. Pathophysiology of trigeminal autonomic cephalalgias. Lancet Neurol. 2009;8(8):755-764.
  11. Goadsby PJ. Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet Neurol. 2002;1(4):251-257.
  12. Rainero I, Gallone S, Valfre W, et al. A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache. Neurology. 2004;63(7):1286-1288.
  13. Bussone G, Rapoport A. Acute and preventive treatment of cluster headache and other trigeminal autonomic cephalgias. Handb Clin Neurol. 2010;97:431-442.
  14. Nesbitt AD, Goadsby PJ. Cluster headache. BMJ. 2012; 344:e2407.
  15. Robbins MS, Starling AJ, Pringsheim TM, et al. Treatment of cluster headache: the American Headache Society evidence-based guidelines. Headache. 2016;56(7):1093-1106.
  16. Petersen AS, Barloese MC, Jensen RH. Oxygen treatment of cluster headache: a review. Cephalalgia: An International Journal of Headache. 2014;34(13):1079-1087.
  17. Information for patients in England and Wales: arranging, trying and using short-burst oxygen therapy to abort cluster headaches. https://ouchuk.org/sites/default/files/downloads/o2_information_for_ patients_in_england_and_wales.pdf. Accessed October 1, 2017.
  18. Ahrens M. Fires and burns involving home medical oxygen. National Fire Protection Association. www.nfpa.org/~/media/files/ news-and-research/fire-statistics/major-causes/osoxygen.pdf?la=en. Accessed October 1, 2017.
  19. Cittadini E, May A, Straube A, et al. Effectiveness of intranasal zolmitriptan in acute cluster headache: a randomized, placebo-controlled, double-blind crossover study. Arch Neurol. 2006;63(11):15371542.
  20. Rapoport AM, Mathew NT, Silberstein SD, et al. Zolmitriptan nasal spray in the acute treatment of cluster headache: a double-blind study. Neurology. 2007;69(9):821-826.
  21. van Vliet JA, Bahra A, Martin V, et al. Intranasal sumatriptan in cluster headache: randomized placebo-controlled double-blind study. Neurology. 2003;60(4):630-633.
  22. Tepper SJ, Rapoport AM, Sheftell FD. Mechanisms of action of the 5-HT1B/1D receptor agonists. Arch Neurol. 2002;59(7):10841088.
  23. Matharu MS, Levy MJ, Meeran K, Goadsby PJ. Subcutaneous octreotide in cluster headache: randomized placebo-controlled doubleblind crossover study. Ann Neurol. 2004;56(4):488-494.
  24. Costa A, Pucci E, Antonaci F, et al. The effect of intranasal cocaine and lidocaine on nitroglycerin-induced attacks in cluster headache. Cephalalgia: An International Journal of Headache. 2000;20(2):85-91.
  25. Nagy AJ, Gandhi S, Bhola R, Goadsby PJ. Intravenous dihydroergotamine for inpatient management of refractory primary headaches. Neurology. 2011;77(20):1827-1832.
  26. Francis GJ, Becker WJ, Pringsheim TM. Acute and preventive pharmacologic treatment of cluster headache. Neurology. 2010;75(5):463-473.
  27. Leone M, D’Amico D, Frediani F, et al. Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology. 2000;54(6):1382-1385.
  28. Bussone G, Leone M, Peccarisi C, et al. Double blind comparison of lithium and verapamil in cluster headache prophylaxis. Headache. 1990;30(7):411-417.
  29. Hakim SM. Warfarin for refractory chronic cluster headache: a randomized pilot study. Headache. 2011;51(5):713-725.
  30. Leone M, D’Amico D, Moschiano F, et al. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia: An International Journal of Headache. 1996;16(7):494-496.
  31. Leandri M, Luzzani M, Cruccu G, Gottlieb A. Drug-resistant cluster headache responding to gabapentin: a pilot study. Cephalalgia: An International Journal of Headache. 2001;21(7):744-746.
  32. Schuh-Hofer S, Israel H, Neeb L, et al. The use of gabapentin in chronic cluster headache patients refractory to first-line therapy. Eur J Neurol. 2007;14(6):694-696.
  33. Vukovic V, Lovrencic-Huzjan A, Budisic M, Demarin V. Gabapentin in the prophylaxis of cluster headache: an observational open label study. Acta Clin Croat. 2009;48(3):311-314.
  34. Leone M, Dodick D, Rigamonti A, et al. Topiramate in cluster headache prophylaxis: an open trial. Cephalalgia: An International Journal of Headache. 2003;23(10):1001-1002.
  35. El Amrani M, Massiou H, Bousser MG. A negative trial of sodium valproate in cluster headache: methodological issues. Cephalalgia: An International Journal of Headache. 2002;22(3):205-208.
  36. Mauskop A, Altura BT, Cracco RQ, Altura BM. Intravenous magnesium sulfate relieves cluster headaches in patients with low serum ionized magnesium levels. Headache. 1995;35(10):597-600.
  37. Schoenen J, Jensen RH, Lanteri-Minet M, et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia: An International Journal of Headache. 2013;33(10):816-830.
  38. Lainez MJ, Puche M, Garcia A, Gascon F. Sphenopalatine ganglion stimulation for the treatment of cluster headache. Ther Adv Neurol Disord. 2014;7(3):162-168.
  39. Schwedt TJ, Vargas B. Neurostimulation for treatment of migraine and cluster headache. Pain Med. 2015;16(9):1827-1834.
  40. Fontaine D, Lazorthes Y, Mertens P, et al. Safety and efficacy of deep brain stimulation in refractory cluster headache: a randomized placebo-controlled double-blind trial followed by a 1-year open extension. J Headache Pain. 2010;11(1):23-31.