Cluster Headache
Acute Drug Treatment
The goal of treatment for acute cluster is to decrease the pain, severity, and duration of each attack. Early intervention is critical, since a single cluster headache can be as short as 15 minutes. Because of the brief nature of cluster headaches, consider a non-oral route of administration when treating these headaches (see table 6.1 of the original guideline document).
Oxygen
Oxygen inhalation is the standard recommended therapy for cluster headaches. Treatment is initiated with 100% oxygen by non-rebreathing facial mask. Flow rate is set at 7 to 10 liters per minute and treatment should continue for 15 minutes. Although up to 70% of patients experience relief within 5 minutes, some patients report that oxygen suppresses rather than aborts the attack and that pain may return. Oxygen seems to be most successful when administered at the maximum pain intensity. There are no side effects with this treatment.
Sumatriptan
Sumatriptan, 6 mg administered subcutaneously (SQ), is an effective acute treatment for episodic and chronic cluster headaches, but it is most useful for patients who report 1 or 2 cluster attacks per day. Cluster attacks usually respond within 10 minutes. There is no evidence of tachyphylaxis, rebound syndromes, or drug dependency with the use of subcutaneous sumatriptan for cluster headaches. Cluster patients may find that their attacks can be aborted with sumatriptan SQ at smaller doses, such as 2 to 3 mg.
Intranasal sumatriptan 20 mg is not as effective as the subcutaneous injection. In a trial comparing subcutaneous versus intranasal sumatriptan in cluster patients, injection resulted in 87% of patients experienced complete relief of pain within 15 minutes after injection compared with only 13.4% with sumatriptan nasal spray. Sumatriptan is contraindicated in patients with ischemic heart disease, uncontrolled hypertension, peripheral vascular disease, and concurrent use of another 5-HT1 agonist or ergot derivative medication.
Zolmitriptan
In a single open-label trial, oral zolmitriptan 10 mg demonstrated efficacy for cluster attacks; however, the adverse profile was significant. No data are available at this time with the nasal spray formulation.
Dihydroergotamine (DHE)
DHE administered by nasal spray or injection can decrease the intensity of individual attacks and may also completely abort the pain. Intravenous injection gives quicker relief, usually within 10 minutes, when compared with intramuscular or SQ injection. DHE dosage is 0.5 to 1 mg whether given intravenously, intramuscularly, or subcutaneously. Treatment can be repeated every 1 hour as needed up to a total of 3 mg per day. The total intranasal dose is 2 mg for a single treatment.
Nasal Lidocaine
Nasal lidocaine 4% topical solution can be applied in the form of nose drops or spray for acute treatment of a cluster attack. Patients should apply 15 drops in the nostril on the affected side at the onset of the headache, with the head turned to the ipsilateral side and tilted backwards. If necessary, this application can be repeated in 15 minutes. Lidocaine can be used up to 4 times per day but only twice per headache. The most common side effects of lidocaine include lightheadedness and a feeling of nervousness.
Topical Intranasal Cocaine
Topical intranasal cocaine has been used as a local anesthetic for treatment of cluster headaches, but because of its addictive potential, it is rarely used.
Capsaicin
Capsaicin acts by depleting substance P stores in neurons, and it can therefore desensitize sensory neurons. When a 0.025% capsaicin cream is applied intranasally twice a day via a cotton-tipped applicator in the nostril ipsilateral to the cluster headache, patients may experience less frequent and less intense attacks.
Narcotic and Nonparenteral Analgesics
Due to their slow onset of action, oral narcotics and other nonparenteral analgesics play little role in the treatment of cluster headaches. However, there may be a role for butorphanol, an opioid analgesic that can be administered by a nasal spray. Since butorphanol has no known cardiovascular risks, it is an alternative for patients who cannot use vasoconstrictive medications and for whom oxygen has failed. Given the high frequency of attacks in some cluster patients, opioid analgesics, if used, require close supervision.
Olanzapine
Olanzapine is an atypical neuroleptic that has been reported to be as effective in treating both chronic and episodic acute cluster attacks. In a report, the starting dose was 5 mg, with an increase up to 10 mg if no pain relief was found at the lower dose.
Preventive Drug Treatment
Effective preventive treatment is an important component of managing cluster headache (refer to Table 6.2 of the original guideline document). The 2 main goals of preventive treatment for cluster are to rapidly suppress individual attacks and to maintain that remission throughout the patient's typical cluster period. It is necessary to start prophylactic pharmacotherapy early in the cluster period. Daily prophylaxis should be continued until the patient is headache-free for at least 14 days. When indicated, a slow taper of preventive medications is recommended. Prophylactic drugs are restarted at the beginning of the next cluster cycle.
Transitional Prophylaxis or Rapid Suppression of Attacks
Corticosteroids
Prednisone and dexamethasone are rapidly acting transitional or suppressive prophylactic drugs that are used at the onset of a cluster period for up to 3 weeks while a maintenance prophylactic agent is initiated and allowed to take effect. Total relief from attacks is seen in up to 50% of patients. Prednisone is usually initiated at a dose of 40 to 60 mg per day for 3 days, followed by a 5 to 10 mg dosage reduction every 2 to 3 days until discontinued. Dexamethasone 4 mg twice a day for 2 weeks, then 4 mg per day for 1 week, is also effective. When corticosteroids are tapered, however, the cluster attacks tend to recur, so maintenance preventive therapy should be started at the time that corticosteroids are begun. During the steroid taper, recurrence of the cluster attacks often occurs when a physiologic level of the steroid is achieved (i.e., daily prednisone dose of 20 mg per day or equivalent). Corticosteroids are most often used in episodic cluster patients to break the cluster cycle. Potential side effects include insomnia, restlessness, personality changes, hyponatremia, edema, hyperglycemia, osteoporosis, myopathy, and gastric ulcers. Aseptic necrosis of the hip or shoulder has also been reported. The use of long-term corticosteroids is discouraged in patients with chronic cluster headaches because the incidence of side effects increases with prolonged use.
Ergotamine Derivatives
Ergotamine derivatives are effective for quick suppression of cluster attacks when administered on a daily schedule for a short period. Ergotamine tartrate is available as a tablet, a suppository, and, in some countries, an inhalant. Oral or sublingual ergotamine may be taken 30 to 60 minutes before an expected attack. This form of treatment is particularly suitable for patients with clusters that occur soon after initiating sleep. For those with short cluster periods, patients may take ergotamine tartrate 3 to 4 mg daily in divided doses for periods of up to 3 weeks. Some patients also respond to rectally administered ergotamine. For DHE-45®, the maximum daily dose is 3 mg, usually given in divided doses. Even though this class of drugs may be given daily for 2 to 3 weeks, rebound headaches do not occur in this group of patients. Bellergal-S® or Bellergal® plain (ergotamine, phenobarbital, and belladonna combination) can be given 1 tablet 2 to 4 times a day for 2 weeks. Patients cannot use triptans while on this therapy.
Occipital Nerve Blockade
Occipital nerve blocks with local anesthetic and steroid injected around the nerve ipsilateral to the side of cluster pain have been used with some success. One study found that the duration of headache relief ranged from 5 to 73 days, with many patients requiring more than 1 injection. Occipital nerve blocks can be helpful until maintenance therapy becomes effective. One cubic centimeter of a mixture of lidocaine and Kenalog-40® at a 1:9 dilution has been used in some headache centers.
Maintenance Therapy
Verapamil
Verapamil is the first-line prophylactic drug for both episodic and chronic clusters. Slow-release verapamil is effective as well and improves patient compliance. Treatment can be started as verapamil 80 mg 3 times a day or 240 mg daily sustained-release. Doses range between 120 and 480 mg a day. Higher doses can be used, but it is advisable to obtain electrocardiograms with each increase above 480 mg per day. When combination therapy with lithium is used, there may be an increased sensitivity to lithium. Serious side effects are rare, but constipation is common. Other side effects include dizziness, nausea, edema, bradycardia, fatigue, and hypotension.
Methysergide Maleate
Although methysergide maleate is currently unavailable in the United States, it is hoped that it may come back to the market for physicians to use for headache treatment. Methysergide, an ergot derivative, is effective in 65 to 69% of cases of episodic cluster headaches, but it is not commonly used because of its association with potentially serious, systemic fibrotic reactions. Response rates are lower in chronic cluster patients than in episodic cluster patients. Other side effects are nausea, lightheadedness, leg cramps, diarrhea, and epigastric pain. These usually abate after several days. Methysergide is used more often for episodic clusters because the cycles are usually less than 4 months long. When treating chronic cluster patients with methysergide, provisions should be made for a 1-month drug holiday for every 6 months of treatment in order to minimize the risk of retroperitoneal, pleural, pulmonary, and cardiac valvular fibrosis, although these complications are rare (1/1,500). A chest x-ray, an echocardiogram, and magnetic resonance imaging (MRI) of the abdomen must be performed during the drug-free holidays. Treatment consists of a dose of 2 to 6 mg per day, starting at 2 mg (1 tablet) per day and increasing over a few days to a maximum dose of 8 mg per day. Doses up to 12 mg per day have been used when tolerated. The concurrent use of triptans and methysergide is contraindicated. Other contraindications include pregnancy, coronary artery disease, collagen vascular disease, phlebitis, hypertension, peripheral vascular disease, and compromised liver or renal function.
Lithium Carbonate
Lithium carbonate is effective against episodic and chronic cluster headaches. Of cluster headache patients, 78% of patients with chronic clusters and 63% of patients with episodic clusters respond to lithium. It is effective at rather low serum concentrations (0.3 to 0.8 micromole/L). The usual daily dose ranges from 600 to 900 mg in divided doses. Because of its long half-life (24 hours), a steady state is generally reached within 1 week after initiation of treatment. With prolonged use, some patients can become resistant to lithium efficacy. Side effects might include tremor, polyuria, and diarrhea. Renal and thyroid function should be checked before and during the treatment, since nephrotoxicity and hypothyroidism can occur with long-term use. Lithium blood levels should be checked after the first week of treatment and periodically thereafter. Since sodium depletion can result in high lithium levels and neurotoxicity, concomitant use of sodium-depleting diuretics should be avoided. Caution should also be exercised when nonsteroidal anti-inflammatory drugs (NSAIDs) are prescribed along with lithium because of possible nephrotoxicity.
Valproic Acid
Valproic acid has shown up to a 73% favorable response with doses ranging from 600 to 2,000 mg per day. Nine of 15 patients had complete suppression of attacks and 2 had a marked improvement. Patients can experience good outcomes within 1 to 4 days after initiation of treatment. Treatment is usually started in divided doses of 250 mg twice a day, followed by 250 mg increments as needed and tolerated. Serum valproic acid levels can be used as a guide for dosing since side effects and risk of toxicity increase when supratherapeutic blood levels are maintained. Extended-release valproic acid can also be used, thereby improving compliance by means of once-a-day dosing. Side effects include tremor, alopecia, weight gain, and drowsiness. The monitoring of complete blood counts and liver function tests are needed, since valproic acid can cause platelet dysfunction, thrombocytopenia, and pancreatitis.
Topiramate
Patients with both episodic and chronic cluster headaches have benefited from prophylactic treatment with topiramate. An open-label study showed remission of cluster headaches within 1 to 3 weeks after initiation of treatment in 9 patients. Response was seen at doses ranging between 50 and 125 mg per day in twice daily dosing. Treatment should be started at 25 mg at night and increased by 25 mg every 5 days as tolerated. Dosages as high as 200 mg may be needed in some patients. Side effects include paresthesias, somnolence, cognitive symptoms, weight loss, ataxia, and light-headedness. Topiramate is contraindicated in patients with renal calculi.
Melatonin
Studies have suggested that serum melatonin levels are decreased in patients with cluster headache, especially during a cluster period. Cluster headache cycle suppression with 10 mg oral melatonin was achieved within 3 to 5 days in 50% of patients in a double-blind, placebo-controlled trial with 10 patients.
Other Agents
Many other agents have been reported in small trials or case reports as having shown efficacy in treating patients with cluster headaches. These include clonidine, diltiazem, flunarizine, somatostatin, indomethacin, pizotifen, phenelzine, naratriptan, gabapentin, methylphenidate, mirtazapine, tizanidine, and baclofen. Before these drugs can be recommended as routine treatment for cluster headache patients, further studies should be conducted. It is reasonable for patients in whom all standard medical treatments have failed to try these agents before being referred for surgery.
Treatment for Refractive Cluster Headache
Intravenous Histamine Desensitization
Intravenous histamine has been found to be an effective treatment for patients with cluster headache that has become refractive to medical therapy. Patients treated with histamine infusions repetitively over a course of about 10 days appear to have restitution of response to standard medical therapies. Because of the prolonged nature of intravenous therapy, it is not recommended for patients who have other medical options available. Since the course of histamine infusions can be repeated if cluster headaches recur and since this therapy is well tolerated by most patients, it may be considered as an alternative to surgery.
Surgery
About 10% of patients with cluster headaches are nonresponsive to pharmacologic prophylaxis or have significant contraindications to effective prophylactic agents or acute treatment. When patients have exhausted all acute medications or have medical conditions that preclude medical options, surgical treatment should be considered. In addition, to be eligible for surgery, patients must have strictly unilateral headache and a stable personality profile with no addictive potential. A variety of surgical procedures can be tried. Surgical techniques are based on ablation of components of the sensory trigeminal nerve and the cranial parasympathetic system or nervus intermedius. Methods include radiofrequency trigeminal rhizolysis, glycerol injection into the trigeminal cistern, and gamma knife radiosurgery.
Radiofrequency Thermal Neurolysis of the Trigeminal Nerve
Radiofrequency thermal neurolysis of the trigeminal nerve is a potential treatment choice. Results vary, but 50 to 73.3% of 30 patients described 50 to 90% relief from their cluster headaches. Complications include keratitis, corneal anesthesia in the ipsilateral eye, hyperacusis, ice-pick pain, jaw deviation, anesthesia dolorosa (<4% of cases), transient diplopia, and recurrent sty. Repeat neurolysis may be necessary if pain recurs.
Glycerol Injection
Glycerol injection into the trigeminal cistern has been used for intractable cluster headache patients. It can afford significant pain relief and less risk to the cornea.
Gamma Knife Radiosurgery
Gamma knife radiosurgery has also shown some efficacy for treatment of intractable, medically unresponsive cluster patients. The results were observed immediately or within 1 week after the procedure. Although the overall efficacy, safety, and durability of this procedure are still unknown, it should be considered an alternative for some patients because it is noninvasive and does not permanently destroy nerve structure.
Nondrug Treatment
The intensity of cluster headache pain and the anticipation of future attacks can cause increased anxiety for many patients. When counseling these patients, it is important to set appropriate treatment expectations at the outset. Clinicians should try to alleviate any unnecessary fears by assuring patients that most attacks can be prevented with prophylactic treatment and that breakthrough attacks can be managed with pharmacologic treatments. In addition, there are specific nondrug treatments that patients can employ to optimize management of cluster headaches (see table below).
| Nondrug Treatment Strategies |
Patients should avoid the following:
- Afternoon naps or other significant changes in their sleeping habits
- Alcohol, especially during the cluster period
- Prolonged exposure to chemical agents such as cleaning solvents, gasoline, and oil-based paint
- Excessive bursts of anger or extreme emotion
- Prolonged physical exertion
- Extreme changes in altitude
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