Cluster Headache—Acute and Prophylactic Therapy

Avi Ashkenazi, MD; Todd Schwedt, MD

Disclosures

Headache. 2011;51(2):272-286. 

In This Article

Maintenance Prophylaxis (Table 2)

First-line Therapy

Table 2

Verapamil, a calcium-channel blocker, is the first-line maintenance prophylactic medication for CH. Verapamil is considered first-line therapy because of its efficacy, relative safety, and the ability to coadminister symptomatic and transitional therapies with less concern about drug interactions compared with some of the other maintenance prophylactic medications (eg, lithium carbonate). In open-label studies, approximately 70% of ECH and CCH patients have substantial improvement with verapamil therapy.[32] In a double-blind placebo-controlled trial of verapamil for maintenance prophylaxis of ECH, 15 patients were randomized to 120 mg of verapamil 3 times daily while 15 subjects were randomized to placebo.[33] During 2 weeks of treatment, 80% of patients receiving verapamil had a greater than 50% reduction in headache frequency, including 4 patients who became attack free. Verapamil took effect quickly, with one-half of responders having substantial improvement within the first week and the other one-half responding during the second week. Meanwhile, zero patients receiving placebo had a greater than 50% reduction in headache frequency. Adverse effects due to verapamil were mild, with constipation being the most common and most bothersome. A double-blind, crossover study of verapamil vs lithium carbonate for CCH suggests that verapamil is a superior treatment.[34] In this randomized trial, each of the 24 subjects received verapamil 360 mg per day or lithium carbonate 300 mg 3 times daily for 8 weeks, and then following a 2 week washout period was switched to the other therapy for an additional 8 weeks. Verapamil and lithium both provided similar reductions in both headache index and analgesic consumption. However, verapamil worked more quickly, with over 50% of patients having significant improvement in headache index within the first week compared with 37% of those taking lithium. Furthermore, only 12% of those taking verapamil reported AEs compared with 29% of those taking lithium.

Target dosages of verapamil ranging from 200 mg to 960 mg per day in divided doses are typically used for cluster prophylaxis.[35] Most patients will respond to doses of 200 mg to 480 mg per day.[36] Immediate or extended release formulations may be used. Slow titrations up to the target dose may reduce AEs including hypotension, constipation, and peripheral edema. A method of titrating and tapering verapamil dosage in 40 mg intervals is described in a paper by Blau and Engel.[36] EKG monitoring is necessary during verapamil therapy because of the risk of heart block and bradycardia, AEs that can develop with initiation of therapy, increases in dose, and even during continued stable dose therapy.[37] In our practice, we obtain a baseline EKG before initiating verapamil therapy, repeat EKG with each increase in dose of at least 80 mg, and an EKG each 3 months if the dose has been unchanged. Patients should be informed of the possibility of developing gingival hyperplasia because of long-term use of verapamil Table 2 .

Second-line Therapy

Lithium carbonate is a second-line therapy for maintenance prophylaxis of CH. We consider lithium as a second-line therapy because of its potential for causing numerous AEs, the need for blood test monitoring during therapy, and its potential for causing several drug interactions. Nonetheless, lithium carbonate has been demonstrated to provide significant benefit in the treatment of CCH. Its efficacy for treating CCH has been demonstrated in the investigation discussed in "First-Line Therapy" and in a study of 8 additional CCH patients.[34,38] In the latter study, all 8 patients had at least a 75% improvement within the first 2 weeks of therapy. However, only 1 of 3 who were followed long-term had continued improvement after 18 months of therapy. The evidence for the utility of lithium carbonate for the treatment of ECH is less clear, with generally small studies providing contradictory results.[34,38,39] Lithium carbonate doses of 600 mg to 900 mg per day are typically needed to obtain target therapeutic serum lithium levels of 0.4 to 0.8 mEq/L. Lithium serum levels, renal function, and thyroid function should be monitored during lithium therapy. Common AEs to lithium include diarrhea, tremor and polyuria. Symptoms and signs of toxicity include nausea, vomiting, diarrhea, confusion, nystagmus, extrapyramidal signs, ataxia, and seizures.

Topiramate, in doses ranging from 50 mg to 200 mg per day, is considered second-line therapy for CH prophylaxis. Although we have designated topiramate as second-line therapy, consistent with the Grade B recommendation in the European Federation of Neurological Societies guidelines, topiramate use for CH prophylaxis has been investigated in open-label studies only.[40–42] Common AEs to topiramate include cognitive dysfunction, paresthesias, alteration in taste, weight loss, fatigue, and dizziness. Patients with a history of nephrolithiasis should not receive topiramate because of an increased risk of recurrent stones while taking this medication.

Third-line Therapy

Other therapies that may be effective for maintenance cluster prophylaxis include methysergide, valproic acid, melatonin, gabapentin, baclofen, clonidine, and botulinum toxin. Although methysergide is likely effective for preventing CH, it is not available in the USA and long-term use is associated with fibrotic complications. Thus, we cannot recommend its use. Valproic acid has been shown to provide benefit in open-label and retrospective studies only.[43,44] A double-blind placebo-controlled study of sodium valproate did not support its efficacy; however, this may have been due to an exceedingly high response rate of 62% in the placebo group.[45] Effective doses range from 500 mg to 2000 mg daily in divided doses. Common AEs include weight gain, fatigue, tremor, hair loss, and nausea. Monitoring with complete blood counts and liver function tests are necessary during valproic acid therapy. Limited evidence supports the use of melatonin for cluster prophylaxis. In a double-blind, placebo-controlled trial of 10 mg melatonin, 5 of 10 subjects randomized to melatonin had cluster remission within 5 days while none of the 10 subjects taking placebo went into remission.[46] Open-label studies of gabapentin suggest its value in maintenance prophylaxis of CH in doses ranging from 800 mg to 3600 mg per day.[47,48] Gabapentin is typically a well-tolerated medication but more common AEs include somnolence and fatigue, dizziness, weight gain, peripheral edema, and ataxia. In a small open-label study of baclofen 10 mg 3 times daily, 6 of 9 subjects went into remission within 1 week and an additional 1 subject had improvement followed by remission at week 2.[49] Although adverse events were not reported by subjects in this study, more common AEs to baclofen include drowsiness, dizziness, ataxia, and muscle weakness. Clonidine, given as a 5 mg to 7.5 mg transdermal patch (that delivers the drug at a rate of 0.2–0.3 mg daily for 1 week), has been studied in 2 small open-label studies.[50,51] In the first, which included 8 ECH and 5 CCH patients, there were significant reductions in mean attack frequency, pain intensity, and attack duration.[50] However, a second study including 16 ECH patients failed to confirm these positive results.[51] Tiredness and reduction in blood pressure were AEs noted in these studies. An open-label study of botulinum toxin type A as add-on therapy in 3 ECH and 9 CCH patients had mixed results.[52] Fifty units injected ipsilateral to the headache resulted in headache remission in 1 CCH patient, improvement in attack frequency and severity in an additional 2 CCH patients, improvement in a continuous baseline headache with no change in superimposed cluster attacks in an additional 1 CCH patient, and no benefit in the remaining 8 patients. More common AEs to botulinum toxin therapy include weakness of injected muscles and pain at injection sites.

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