Preventive Therapy
Preventive agents are absolutely necessary in cluster headaches unless the cluster periods last less than two weeks. Preventive medications are only used while the patient is in cycle and they are tapered off once a cluster period has ended. If a patient decides to remain on a preventive agent even after they have gone out of cycle this does not appear to prevent a subsequent cluster period from starting.The maintenance preventive should be started at the time a transitional agent is given. Most physicians treating cluster headache will increase the dosages of the preventive agents very quickly to obtain a desired response.Very large dosages, much higher than that suggested in the Physician’s Desk Reference (PDR), are sometimes necessary when treating cluster headache. A well-recognized trait of cluster patients is that they can tolerate medications much better than non-cluster patients. Most of the recognized cluster preventives can be used in both episodic and chronic cluster headache. Polypharmacy is not discouraged in cluster headache prevention. Not unlike the multiple preventive regime utilized in trigeminal neuralgia, cluster attacks are so extreme that severe add-on therapy is encouraged rather than ceasing treatment with one agent having the attacks worsen again and trying another single agent (see Table 3).

Verapamil
Verapamil appears to be the best first-line therapy for both episodic and chronic cluster headache.3 13 It can be used safely in conjunction with sumatriptan, ergotamine, and corticosteroids, as well as other preventive agents. Leone et al.¹⁴ compared the efficacy of verapamil with placebo in the prophylaxis of episodic cluster headache. After five days of run-in, 15 patients received verapamil (120mg tid) and ¹⁵ received placebo (tid) for 14 days. The authors found a significant reduction in attack frequency and abortive agent consumption in the verapamil group. The initial starting daily dosage of verapamil is 80mg three times a day or building up to this dosage within three to five days. The non-sustained release formulation appears to function better than the sustained release preparation but there is no literature proving this. Dosages are typically increased by 80mg every three to seven days. If a patient needs greater than 480mg per day then an electrocardiogram (ECG) is necessary before each dose change thereafter to guard against heart block. It is not uncommon for cluster patients to need dosages as high as 800mg to gain cluster remission. Most headache specialists will push the dose as high as 1g if tolerated. Constipation is the most common side effect, but dizziness, edema, nausea, fatigue, hypotension, and bradycardia may also occur.

Lithium Carbonate
Lithium carbonate therapy is still considered a mainstay of cluster prevention but its narrow therapeutic window and high side effect profile makes it less desirable than other, newer, preventives. Since 2001, there have been 28 clinical trials looking at the efficacy of lithium in cluster therapy. For chronic cluster 78% of patients treated (in 25 trials) have improved on lithium while 63% of episodic patients have gained cluster remission on lithium.When lithium was compared with verapamil in a single trial, both agents were found to be effective but verapamil caused fewer side effects and had a more rapid onset of action.¹⁵ A single double-blind, placebo-controlled trial failed to show the superiority of lithium (800mg sustained release) over placebo. However, this study was halted one week after treatment began, and there was an unexpectedly high placebo response rate of 31%.¹⁶ The treatment period was therefore too short to be conclusive.

The initial starting dosage of lithium is 300mg at bedtime with dose adjustments usually no higher than 900mg per day. Lithium is often effective at serum concentrations (0.3–0.8mM) lower than those usually required for the treatment of bipolar disorder. Most cluster patients benefit from dosages between 600mg and 900mg a day. During the initial treatment stages, lithium serum concentrations should be checked repeatedly to guard against toxicity. Serum lithium concentrations should be measured in the morning 12 hours after the last dose. In addition, prior to starting lithium, renal and thyroid functions need to be checked. Adverse events related to lithium include tremor, diarrhea, and polyuria.