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Cluster Headache - Preventive Medications
Posted Aug 1999

Most patients with cluster headache require daily prophylactic medication because the headaches are extremely severe and difficult to abort. Some patients experience milder cluster headaches, and if oxygen or another abortive is effective, preventive medications may be avoided. The number of headaches per day is also a determining factor, for if patients have only one per day, we may be able to avoid prevention medication. Cluster sufferers, in general, desire to be on preventive medication during the cluster cycle.

With episodic cluster headache, we utilize medication only when the headaches begin, as it is not worthwhile to keep patients on medication all year for intermittent headaches. For chronic cluster headache, most patients are on continuois daily medication to prevent the clusters. The prophylactic medications for episodic and chronic cluster headaches differ slightly.


Cluster headaches often build in intensity over days or weeks. At first, patients may simply feel twinges of pain on the affected side, and then the intensity slowly builds. Usually, the patients will call or visit the physician 1 week or more into the cluster cycle. Once we believe that the cluster cycle has begun, preventive medication should be instituted. Cortisone is the fastest acting medication, and we begin with limited amounts of it. Concurrently, the patient is given another first line prevention medication, either lithium or verapamil. When we have withdrawn the cortisone, the second preventive medication will hopefully have become effective.

The preventive medication is discontinuied when the cluster series has finished. If a patient usually experiences a 4 week cycle of clusters, and the current series has lasted 5 weeks with no headache for 1 week, preventive medication may be withdrawn. I wait for the clusters to be gone for 1 or 2 weeks prior to stopping medication. Patients are instructed to quickly reinstitute the preventive medication if the clusters reappear. A cluster series may drag on for extra weeks or months, well beyond what the patient normally experiences.

First line preventive approaches for episodic cluster include: cortisone, verapamil, lithium and polypharmacy (combining two first line medications).

Second line preventive medications include: methysergide (Sansert), valproate (Depakote), daily ergotamines, ergonovine, steroid blockage of the occipatal nerve, daily triptans and Indocin.

Third line preventive medications include; IV dyhydroergotamine (DHE) given repetitively, and cocaine drops used intranasally on a daily basis.

Miscellaneous therapies that are occasionally helpful for episodic clusters include: phenelzine (Nardil), cyproheptadine (Periactin), nifedipine (Procardia), beta blockers such as propranolol (Inderal), SSRI's (Prozac, Zoloft, Paxil), or methylphenidate (Ritalin).

Once a regimen is determined effective for a patient, the appropriate medications are instituted at the onset of the next cluster series. Many of the medications used for cluster headache have not received specific FDA indications for this use. The following is only a guide to what I consider reasonable and rational therapy for cluster headache. Prior to prescribing medications for the patient, the person needs to be informed of, and accept, the complete set of contraindications and side effects as listed in the PDR and package insert.

Table 10.1: Criteria for the Use of Prevention Medication:

  1. The clusters are not easily stopped with abortive medication

  2. Cluster headaches are daily and last longer than 15 minutes

  3. The patient is willing to take daily medication, and endure possible side effects.

Table 10.2:
Quick Reference Guide: First Line Cluster Preventive Medication:

  1. Cortisone: Very effective for cluster headache; is used primarily for episodic clusters. It is given for 1 or 2 weeks during the peak of the cluster series. Prednisone, Decadron, or injectible forms may be utilized. When used for short periods of time, side effects are minimal. A typical regimen is prednisone (20 mg) or Decadron (4 mg) once a day for 3 days, then one-half pill per day for 10 days, then stop. Additional cortisone may be given later in the cycle, when the clusters increase. Higher doses may be needed.

  2. Verapamil (Covera HS, Calan, Isoptin, Veralan): A well tolerated calcium channel blocker; efective in episodic and chronic cluster. One 240 mg. SR pill is taken once or twice per day. This is often initiated at the onset of the headaches, in conjunction with cortisone. Verapamil is then continued after the cortisone is stopped. Constipation is common. Because of its efficacy and a lack of side effects, verapamil is a mainstay of cluster prevention.

  3. Lithium: Very helpful for chronic cluster and, to a lesser degree, episodic cluster. Small doses, one to three of the 300 mg. tablets per day, are used for cluster headache. May be combined with verapamil and/or cortisone. Lithium is usually well tolerated in low doses; drowsinesss, mood swings, nausea, tremor, and diarrhea may occur. Blood tests need to be done.


These include cortisone, verapamil, lithium, or a combination of the above. Cortisone has a quick onset of action, but we always want to minimize the dose. When the headaches are not severe, I reserve cortisone for use during the peak time of the clusters. Verapamil and lithium, although excellent cluster headache medications, often take days or weeks to become effective.

Cortisone: We want to use cortisone in the least possible effective dose. I utilize cortisone for only 1 or 2 weeks, and later it may be given again for a period of very severe clusters. Prednisone, dexamethasone (Decadron), or triamcinolone (Aristocort) may be used. At times, one form will work more effectively than another. As injections, ACTH gel and Depo-Medrol usually provide quick relief, with the effect lasting days to 1 week (usually not longer). Anecdotally, cluster sufferers may be somewhat more prone to femoral head necrosis.

I usually utilize 4 mg tablets of Decadron once or twice per day for 3 days, then one-half tablet once or twice per day for 7 to 10 days, then stop. Alternatively, prednisone may be used, 20 mg once or twice per day for 3 days, then 10 mg once or twice per day for 7 to 10 days, then stop. Cortisone should be taken with food. These are relatively low doses. For patients in the midst of a severe cluster cycle, ACTH gel, 60 units, or Depo-Medrol, 60 mg, may be given, and then the oral cortisone is given. Later in the cucle, small amounts of cortisone may be repeated. Many physicians utilize higher doses.

Side effects of cortisone are many, but used for short periods of time in low doses, we usually avoid these effects. Many patients become nervous or moody with cortisone, and sleeping problems may occur. Fluid retention or fatigue may be a problem. GI upset and pain are common. By utilizing smaller doses for short periods of time, we avoid the devastating longer term side effects of the corticosteroids. Severe psychiatric side effects may occur with (even) relatively small doses.

Table 10.3. Equivalent Doses of the Glucocorticoids:


Salt Retention

Dose (app. equiv. in mg.)

Half-Life (hours)

























The anti-inflammatory strength of dexamethasone and betamethasone is very powerful, with an approximate ratio of 25 for these versus 4 for prednisone, and only 1 for hydrocortisone.

Verapamil: Verapamil (Isoptin, Calan, Verlan, Covera) is a calcium channel blocker that is effective in cluster headache and migraine. The lack of major side effects is a distinct advantage. There is very little of the weight gain or lethargy often experienced with other medications. Verapamil may be used with cortisone or Lithium, or simply as a single preventive. Although verapamil may take weeks to become effective, it often takes effect in days. The long acting form is very convenient, with the tablets being scored. The "regular" verapamil pills, not the long acting, may be more effective than the long acting preparation.

Verapamil is usually started early in the cluster cycle, and if the headaches are severe, cortisone may be used in conjunction with the verapamil. Doses are initiated at one half of a 180 or 240 mg. SR tablet once per day, quickly increasing to a full tablet. Occasionally, we progress to 480 mg per day, checking for hypotension. The average dose is 240 to 360 mg. per day.

Verapamil is generally very well tolerated. Constipation is common, with allergic reactions (rashes), dizziness, insomnia, and anxiety occurring at times. Verapamil may exacerbate or cause chronic daily headache. Fatigue is less common than with the beta blockers, but is seen in some patients. Peripheral edema may occur.

Lithium: Although lithium carbonate is probably more effective for chronic cluster headache, it is helpful for many episodic cluster patients. Low doses, usually one to three of the 300 mg. pills, are usually utilized with cluster patients. With low doses, lithium is generally well tolerated. Lithium may be combined with verapamil and/or cortisone. After verapamil and cortisone, lithium is often the next choice for cluster prevention.

I usually begin with one of the lithium carbonate pills, 300 mg., with food, once per day. The patient takes the lithium several hours prior to the expected time of the headache. After several days, the lithium is increased to one 300 mg. tablet twice per day; this is the average dose. The tablets may be cut in half, and there are 150 mg. capsules of lithium carbonate available. Slow release tablets are available, as is a controlled release tablet. Since we usually use low doses of lithium, toxicity is rarely a problem. The lithium may be combined with verapamil, cortisone, or another cluster preventive, if necessary. Occasionally, I will push the lithium to 1,200 mg. per day, and monitor serum levels. Blood tests need to be checked with the lithium, and the level monitored, but the clinical effect for cluster headaches does not correlate with the level.

Side effects with lithium are many; however, with the small doses utilized for clusters, most patients tolerate the drug very well. Drowsiness, tremor, and mood swings may occur. Diarrhea, nausea, or vomiting may be present. Polyuria and mild thirst are common, particularly in the first week of lithium therapy. Early symptoms of lithium toxicity include vomiting, fatigue, diarrhea, and muscular weakness. Ataxia, blurred vision, and tinnitus usually do not occur unless a more serious toxicity is present.

With long term treatment, hypothyroidism may be a problem. Toxicity is seen with greater frequency in the elderly. Renal and cardiovascular disease preclude the use of lithium. I usually avoid the concomitant use of NSAIDs or diuretics with lithium. By using low doses, with close monitoring, we rarely encounter serious problems with the use of lithium for cluster headaches.

Polypharmacy: As with migraine, the different mechanisms of action of the cluster medications are additive. If one medication is not completely effective, we will use a combination of verapamil, lithium, and cortisone. Lithium with verapamil is a common combination for clusters, and short bursts of cortisone may be utilized.


If the first line medications are not effective, we need to progress to second line therapy, which includes the following: 1) methysergide (Sansert), 2) valproate (Depakote), 3) daily ergotamines, 4) ergonovine, 5) steroid blockade of the occipital nerve, 6) daily triptans, and 7) indomethacin (Indocin).

Methysergide (Sansert): Methysergide is much more effective for episodic cluster headaches than for chronic clusters. Because of the possibility of fibrosis, this drug has declined in popularity, but with judicious use it is a relatively safe and effective medication. The advantage with episodic clusters is that we do not need to use methysergide for extended periods of time. Side effects often limit the use of methysergide, such as the frequent nausea and GI upset. However, for many cluster patients, methysergide will be effective when the first line medications do not help. Methysergide may be combined with other cluster preventives. The safety of methysergide with triptans is not known.

Methysergide should be initiated with one pill (the only pill available is 2 mg.) per day, with food. I have used as little as one-half pill per day, but they are difficult to cut in half. The average dose is one pill twice per day. Although higher doses are occasionally more effective, it is best to limit methysergide to four pills per day.

Nausea, occasionally severe, is common, as is a "hot" feeling in the head, and leg cramps. Dizziness is common. Some patients complain of feeling strange on methysergide. These reactions may be severe, and if the patients are warned about them, they will not panic when the extreme side effects do occur. If the side effects are mild, they will often cease if the patient continues for several more days with the drug. Sansert may exacerbate ulcer disease. Contraindications include active peptic ulcers, peripheral vascular disease, cardiac valve problems, or coronary artery disease. Methysergide should be used with caution in patients with hypertension. Methysergide should also be avoided with pregnancy, renal insufficiency, or liver disease.

The rare fibrosis that has been reported is generally not an issue when methysergide is used for episodic clusters, as we only need to utilize the medication for 1 or 2 months. For a complete discussion of the fibrosis, and monitoring, see the section on methysergide in Chapter 3.

Table 10.4: Quick Reference Guide: Second Line Cluster Prevention Medication:

  1. Methysergide (Sansert): Effective for episodic clusters, but with many side effects. Nausea, leg cramps, and dizziness are common. Dosage is one to four pills per day, with food; try to attain the least possible dose. The fibrosis issue is not usually a problem with the limited time methysergide is given for episodic clusters.

  2. Valproate (Depakote): This seizure medication is becoming increasingly popular for cluster, migraine, and tension headache. Liver functions need to be monitored in the beginning. Useful in both chronic and episodic clusters. Common side effects include lethargy, GI upset, mood swings, weight gain, and alopecia. Dosage ranges from 250 to 2,000 mg. per day, in divided doses. The average dose is 1,000 mg. per day.

  3. Ergotamines (Daily): The rebound situation does not apply with cluster headache. These are usually given several hours prior to the peak time of the clusters. Nausea and nervousness are common with the ergotamines. The lowest effective dose should be utilized.

  4. Ergonovine (Ergotrate): Ergotrate is available commercially, or compounding pharmacists prepare the ergonovine. A well tolerated ergotamine derivative, ergonovine is usually dosed at 0.2 mg. 2 to 3 times per day. GI upset and anxiety may occur.

  5. Steroid blockade of the occipital nerve: By placing cortisone in the region of the occipital nerve, we may provide days to weeks of decreased cluster headache. Depo-Medrol or betamethasone may be used, with a small (25 gauge) needle. Well tolerated, with few side effects, these should be limited to 2 injections per cluster series, at most.

  6. Daily Triptans

  7. Indomethacin

Sodium Valproate (Depakote): This medication is usually used for seizures, but has also been very helpful for headache prevention. Depakote has proven useful for migraine, chronic daily, and cluster headache. Valproate needs to be monitored, but it has proven to be a safe and effective medication. Valproate is usually instituted as a second line cluster medication, and has been useful in both episodic and chronic clusters. I usually utilize valproate after lithium, verapamil, cortisone, and Sansert. There is often a delayed onset of action with this medication. However, in treating chronic clusters, this is not as much of a concern as it is with episodic cluster headaches.

I usually begin with low doses of Depakote (the coated tablets of valproate). One 250 mg. tablet is taken twice per day, with food, and this may be increased to 1,000 mg. per day. If the clusters do not respond, Depakote may be pushed to 2,000 mg. per day, in 2 or 3 divided doses. Levels need to be checked for toxicity. Some patients do well on small doses, sometimes as little as 250 or 500 mg. per day.

Depakote is fairly well tolerated but nausea, gastritis and sedation are relatively frequent. Over months to 1 year, weight gain is common. Hair loss, rash, and dose-related tremor also may occur. Liver functions and blood counts need to be monitored in the first several months, but for episodic clusters the entire duration of use is only 1 or 2 months. See Chapter 3 for a complete discussion of valproate.

Ergotamines Taken Daily: Although we usually wish to avoid daily ergots in headache patients, the rebound headache situation encountered by migraine patients does not usually occur with cluster sufferers. The medication is typically utilized for only 4 to 8 weeks, and once the cluster episode is over, the ergots may easily be discontinued.

I attempt to time the use of ergotamines to be given within several hours of the expected cluster attack. If the headache typically occurs at 11 p.m., the patient takes the ergotamine at 9 or 10 p.m. The usual dose is 1 or 2 mg. per day, and this may be increased to 4 mg. per day.

Generic Cafergot may be used as the source of ergotamine, but the caffeine increases side effects. Cafergot pills contain 1 mg. of ergotamine and 100 mg. of caffeine. The suppositories contain 2 mg. of ergotamine and 100 mg. of caffeine. The Cafergot preparations are most useful earlier in the day. Only generic is available.

Ergomar sublingual pills contain 2 mg. of ergotamine and no caffeine. These may be ingested at night without the associated insomnia of the Cafergot. I instruct patients to swallow the pills.

The usual side effects of ergotamines are nausea and nervousness. Many patients cannot tolerate ergots, and I use the ergotamine compounds with great caution after age 40 or 45. For a complete discussion of ergotamines, please see Chapter 2. A major problem with utilizing ergots is that triptans cannot be used in the same day.

Steroid Blockage of the Occipital Nerve: By placing cortisone in the region of the greater occipital nerve, we often provide days to weeks of decreased cluster headache. This therapy is utilized at the peak of the cluster series if the headaches are poorly controlled. An injection may be repeated once, if necessary, but two injections per cluster series is the absolute maximum that I will utilize. I do not use more than two occipital cortisone injections per year in a patient.

I usually use 60 to 80 mg. of Depo-Medrol per injection. Betamethasone may be used, but the Depo-Medrol may provide longer relief from the clusters. A thin needle (25 gauge) is preferred. For the technique of occipital nerve injection, please see Chapter 13.

Triptans on a daily basis, or indomethacin, may also help.


Third line strategies include: IV DHE administered repetitively, and intranasal cocaine solution, used during the day to prevent the clusters.

Intravenous DHE: Intravenous DHE is useful for quickly decreasing the number of cluster headaches. It is necessary to follow the DHE with preventive medication, such as verapamil or lithium. I give the DHE in the office in a series of three to six injections of 1 mg. each. This may be done in the hospital, but the office procedure is much more convenient for the patient.

IV DHE often allows us to control the clusters while waiting for the preventive medication to take effect. At times it is effective for weeks, or until the end of the cluster cycle. This procedure may be repeated during one cluster period. If the patient has received three to six injections of DHE intravenously, they may receive more DHE later in the cycle, if necessary. The intravenous protocol is completely discussed in Chapter 3.

Intranasal Cocaine Solution to Prevent Cluster Headaches: If the episodic cluster series is several months long, and all other preventive measures have not been effective, cocaine is an alternative. The prophylactic administration of a 10% solution during the day often reduces the number and severity of the clusters. Cocaine is useful for chronic cluster sufferers, particularly during the "peak" season of their headaches. Patients need to be screened carefully for any potential for addiction. If they have experienced any problem with addictive drugs, I do not use this treatment. This is a last resort.

The 10% solution of cocaine rarely produces euphoric or cognitive effects, and the total amount of cocaine that the patient uses in 1 or 2 months is small, from 1 to 2 g. Cocaine is often effective when other measures have not helped. However, with the addiction potential, the cost of the drops, and the difficulty in obtaining the solution, I consider this to be a "last resort", end of the line therapy.

The usual dose of the cocaine is one or two drops in each nostril one to four times a day. If the clusters are severe and out of control, I will begin with two drops four times a day, and we quickly decrease the dose down to as little as is effective. I usually give a script for a 10% cocaine solution, 10 or 20 cc. This is not refillable. If the patient shows any sign of overuse, I will not write another script. The cocaine is usually limited to 20 cc in a 2 month period, which is 2 g of cocaine in 2 months. Patients can occasionally achieve the same effect from a 4% solution of cocaine, but it is easier to simply titrate the amount of 10% drops down to one per day.

Side effects of the cocaine are not usually encountered with this strength. Patients may feel nervous, or insomnia can become a porblem. The euphoric effects of cocaine may occur, but these are not common. If patients do experience euphoria, we need to decrease the percentage of the cocaine to 4%, or stop the treatment completely.

Miscellaneous Therapies for Prevention of Episodic Cluster Headache: In the occasional patient, various other medications are helpful for their cluster headaches. These include phenelzine, cyproheptadine, nifedipine, beta blockers such as propranolol, SSRI's (Prozac, etc.) or methylphenidate (Ritalin).

Phenelzine (Nardil) is an MAO inhibitor that is a powerful antimigraine medication. Phenelzine is discussed in Chapter 3. Cluster patients occasionally respond to phenelzine, but this medication is more useful in severe migraine and daily headache patients when the standard treatments are ineffective. Triptans cannot be used with phenelzine.

Cyproheptadine (Periactin) is occasionally helpful for clusters, but the effect is usually very mild. The side effects of fatigue and weight gain often are a problem. Cyproheptadine is best used as adjunctive therapy for clusters that are poorly controlled.

Nifedipine (Procardia) is a well tolerated calcium blocker that is as effective as verapamil for many cluster patients. However, if verapamil does not work, the nifedipine usually is ineffective. The usual dose is 60 mg. per day, and Procardia is available in capsules of 10 or 20 mg., and sustained release 30 mg. (Procardia XL). Procardia is usually dosed two to three times per day. Side effects are very similar to verapamil.

Beta blockers are, at times, effective for cluster patients. They are much less effective, in general, than the usual cluster therapies. Propranolol (Inderal) or nadolol (Corgard) may be used. These are discussed at length in Chapter 3.

SSRI's are discussed in Chapters 3 and 7; they occasionally help clusters. Ritalin has been a newer treatment for aborting or preventing clusters (see Chapter 9).


The preventive medication approach for chronic cluster headache closely follows that for episodic clusters. Most of the following medications have been discussed in the preceeding sections on preventive therapy for episodic cluster headache. For patients who have severe clusters that are refractive to conventional therapy, surgical techniques, either radiofrequency trigeminal rhizotomy, glycerol injections (Retrogasserian), or the 'gamma knife', are options to be considered.

First line chronic cluster preventives include verapamil, lithium, and valproate (Depakote). If one of these three is not effective, we then use polypharmacy, by combining two, or occasionally, all three of the first line medications together.

There are many second line medications for chronic clusters. These include cortisone, daily ergotamines, methysergide (Sansert), ergonovine, and steroid blockade of the occipital nerve. Daily triptans (once or twice per day) are occasionally helpful, and indomethacin (Indocin) has been useful. Cortisone is used primarily during the "peak" time for the clusters, and cortisone is usually limited to 1 or 2 weeks duration. Daily ergots are occasionally effective, and the rebound headache situation rarely occurs with clusters. Sansert or ergonovine are more helpful and effective for episodic clusters, but certain chronic cluster patients do respond to these medications. Steroid blockade around the greater occipital nerve, ipsilateral to the cluster pain, may provide weeks or, occasionally, months of relief. However, this technique is more useful for episodic clusters. All of these medications are discussed above in the episodic cluster prevemtion sections.

Third line medications for chronic clusters are the same as for episodic clusters. Intravenous DHE and cocaine nasal drops are the third line therapies, and these are discussed above in the episodic cluster section. Because of the inconvenience and cost of these treatments, and the addiction potential of the cocaine, these approaches are usually used only for very refractive patients.

Miscellaneous treatments for chronic clusters are the same as for episodic clusters: phenelzine (Nardil), cyproheptadine (Periactin), nifedipine (Procardia), beta blockers (propranolol, nadolol, SSRI's and Ritalin). These are occasionally helpful, and are discussed in the preceeding section on preventive medications for episodic clusters.

Surgical treatment for chronic clusters is a viable option if the patient has been refractive to medical management. The patient usually needs to suffer strictly unilateral pain. The primary technique that has been employed is radiofrequency trigeminal rhizotomy. The major risk is corneal anesthesia. The procedure may fail, or the surgery may need to be repeated. However, the results have been impressive. A newer technique using the gamma knife is promising.

If all else fails, daily long-acting opioids are occasionally useful. These include Kadian, methadone and Oxycontin. See chapters 3 and 7.