Headaches: Cluster

Description

Medications

Calcium-channel blockers, commonly used to treat heart disease, are important agents for preventing cluster headaches. Verapamil (Calan) is the standard calcium-channel blocker used for headache prevention. Constipation is a common side effect. No one taking any calcium-channel blocker should withdraw abruptly, because such action could dangerously increase blood pressure. Overdose can cause dangerously low blood pressure and slow heart beats. It should be noted that drinking grapefruit juice or eating grapefruit with these drugs could enhance their potency, sometimes to toxic levels that can cause heart failure in patients with heart disease.

Lithium

Lithium (Eskalith, Lithane, Lithobid, Lethonate, Lithotabs), commonly used for bipolar disorder, is beneficial for cluster headaches and is the most effective agent for chronic cluster patients. One small study suggested that lithium may act directly on the nerve clusters affecting the circadian rhythm and slow down the cycle of this "biologic clock." (There is some evidence that cluster headaches are caused by a failure in the biologic clock.) The patient usually experiences benefits within two weeks, and often within the first week. It is not clear how or why it works for cluster headache patients. Lithium may be used alone or with other drugs.

Toxic Effects. Minor toxic reactions include the following:

• Trembling hands.
• Nausea.
• Increased urine output.
• Some loss of coordination.

More severe reactions, which occur at higher blood levels, are the following:

• Convulsions.
• Uncontrolled jerky movements in arms and legs.
• Blurred vision.
• Vomiting.
• Stupor.
• Coma.

Very high blood levels of lithium can be fatal.

If toxicity occurs, drugs should be stopped immediately and one or more of the following steps taken, depending on severity:

• Patients are given fluids and drugs to increase excretion of lithium salts.
• Gastric lavage, a procedure that rinses the stomach may be used to treat very recent overdoses.
• Hemodialysis, a procedure that filters lithium out of the blood, may also be performed in severe cases.

Long-Term Side Effects. Even for patients who do not experience a toxic response, long-term use of lithium is not without problems. Some patients may experience the following:

• An unpleasant taste in the mouth.
• Hair loss.
• Weight gain. In one study 16% of patients gained weight. It is a frequent reason for noncompliance and for relapse.
• Skin eruptions that can resemble acne. (It can worsen psoriasis in patients who also have this condition.)
• Thyroid problems. Up to 20% of patients who take lithium develop symptomatic hypothyroidism, and another 20% to 30% develop hypothyroidism without symptoms.
• An increased risk for diabetes.
• A blunted sexual drive.
• Dulled emotions and mental acuity.
• Memory loss.
• Lack of motor coordination.
• An increased risk for diabetes associated with kidney impairment.
• Reduced sensitivity to light. In some cases, this may slightly affect color recognition. More seriously it can cause problems with night driving. This effect occurs regardless of how long a person has been on the drug. Experts recommend that patients wear sunglasses outside and avoid extensive exposure to bright light.

Drug Interactions. Because lithium is eliminated from the body by the kidneys, any drugs or dietary factors that slow the kidneys' actions may increase lithium blood levels and should be used with great caution. Such drugs include the following:

• Nonsteroidal anti-inflammatory drugs (NSAIDs).
• Thiazide diuretics.
• ACE inhibitors.

There have been reports of interactions between lithium and certain drugs commonly used in combination, including the following:

• Antipsychotics.
• Anticonvulsants.
• Calcium-channel blockers.

It should be noted that the risks associated with these drugs are very low, but caution is needed.

Other Factors That Affect Lithium Levels. In addition to drugs, other factors may affect lithium levels, including the following:

• Seasonal change. For instance, one study of men with bipolar disorder suggested that lithium levels may be higher in summer.
• Menstrual cycle. Lithium levels may drop during the premenstrual phase.
• Weight loss.
• Changes in salt intake.
• Dehydration.
• Diarrhea.

Patients should be sure to contact their physician if they have any suspicious symptoms or illnesses.

Valproate and Other Anti-Seizure Drugs

Valproate. The anti-epileptic drug valproate (valproic acid, divalproex sodium, Depakene, Depakote) has been used with some success. It controls pain and reduces the frequency of attacks by more than half in many people with episodic or chronic cluster headaches. Side effects include nausea, vomiting, heartburn, increased appetite with weight gain, hand tremors, irritability, and temporary hair thinning and loss (taking zinc and selenium supplements may help reduce this effect). It can also cause birth defects and, in rare cases, liver toxicity.

Topiramate. Other, newer anti-seizure drugs that have fewer side effects are being investigated for chronic headaches. Studies on topiramate (Topamax) are promising. In small trials of topiramate, up to 87% of patients achieved remission and 60% achieved a complete response. Still, about 25% of patients stop using it, either because it doesn't work or because the side effects are intolerable. They can include drowsiness, mood changes, tremor, and confusion.

Gabapentin. Another anti-seizure drug that has shown some benefit in isolated cases is gabapentin (Neurontin). Research on this drug in patients with cluster headaches, however, remains very limited.

Side Effects of Valproate and Other Anti-Seizure Agents. The side effects given here are associated with valproate. Other anti-seizure agents have similar effects and some specific ones of their own. Most are usually minor, occurring early in therapy, and then subsiding. Those of valproate include the following:

• Gastrointestinal problems (nausea, vomiting, heartburn). (In some studies, such side effects occurred initially in half the patients taking valproate.)
• Headaches.
• Visual disturbances.
• Ringing in the ear.
• Hair loss.
• Weight gain (a significant problem with valproate). In one study 23% of valproate-treated patients gained weight. (Other anti-seizure agents, such as topiramate, may actually be helpful for reducing treatment-related weight gain.)
• Agitation.
• Odd movements.
• In women, menstrual irregularities and a higher risk for polycystic ovary syndrome (PCO). (These side effects also appear in women using other anti-epileptic drugs, but the risk for those taking valproate may be higher.)
• The drug significantly increases the risk for birth defects when taken by pregnant women. (Valproate is, however, the preferred drug for women taking oral contraceptives.)
• Cognitive impairment and symptoms of Parkinson's disease. (One study of patients taking valproate for epilepsy for longer than a year reported these side effects in some patients. They resolved when valproate therapy was discontinued.)

Very serious side effects are rare but include the following:

• Liver damage.
• Convulsions.
• Coma.
• Pancreatitis in adults and children. This can be life threatening.

Capsaicin

A nasal spray form of capsaicin called civamide (Zucapsaicin) has shown promise in the prevention and treatment of cluster headaches. Capsaicin is a component of hot red peppers that seems to reduce substance P, a chemical in the body that contributes to inflammation and the delivery of pain impulses. In a small 2002 study, daily use of intranasal civamide resulted in more than a 50% reduction in headaches. Side effects include a burning sensation and excessive tearing.

Transitional Agents

Certain medications are useful as transitional agents. These medications are used after cluster episodes to stabilize the patient until preventive maintenance becomes effective.

Methysergide. Methysergide (Sansert) is also used for preventing episodic cluster headaches. (It is not very effective for chronic cluster headaches.) Improvement usually occurs within a few days, although it may be delayed for up to two weeks. Prolonged methysergide therapy can cause serious side effects, including scarring of internal organs, so it cannot be used long term. This is not usually a problem for cluster headache patients, since they only require the drug for about four to six weeks. Nevertheless, patients should report any of the following symptoms immediately: cold, numb, and painful hands and feet; leg cramps on walking; or any type of back or chest pain.

Ergotamine. Drugs containing ergotamine (sometimes called ergots) causes contractions of smooth muscles, including those in blood vessels, and are commonly used for migraine. Taking them before an expected cluster attack produces good results for many patients. One ergot-derived drug called dihydroergotamine (DHE) is administered by injection, which can be performed by the patient at home. It is also available as a nasal spray (Migranal), which may have fewer side effects than the injection. Ergotamine itself is available in oral tablets (Ergomar, Wigraine, Ercaf) and in rectal suppositories (Cafergot). Cafergot, Wigraine, and Ercaf contain caffeine. An ergotamine inhaler is being investigated.

Side effects of ergotamine include nausea, dizziness, tingling sensations, muscle cramps, and chest or abdominal pain. Ergotamine has toxic effects at high levels. It also causes persistent blood vessel contractions, which may pose a danger for people with heart disease or risk factors for heart attack or stroke. Pregnant women, people over 60, and those with serious, chronic health problems, particularly those of the heart and circulation, should avoid these medications altogether. As with other migraine drugs, if ergotamine is taken more than twice a week, the patient is at risk for rebound headaches when the drug is withdrawn, although cluster patients appear to be at lower risk for this effect than other headache patients.

Corticosteroids. A corticosteroid is very useful as a transitional agent for stabilizing patients after an attack until a maintenance agent, such as a calcium-channel blocker, begins to take effect. The corticosteroid drug prednisone is effective in up to 90% of patients with episodic cluster headaches. The drug is typically taken for a week and then gradually tapered off. If headaches return, then it may be administered again. Unfortunately, long-term use of steroids can lead to serious side effects so they cannot be taken for on-going prevention.

Other Drugs Investigated for Prevention

Baclofen (Lioresal). Baclofen is a drug that relaxes muscle spasms. Small studies are reporting some success. For example, in a 2001 study, 12 out of 16 patients reported an end of attacks within a week and another one became headache-free by the second week. (The remaining three patients became worse, however, and required other agents.) Three of the patients who improved experienced an additional cluster cycle, which cleared when they took another course of baclofen.

Botulinum. Botulinum toxin A (Botox) injections are being used for a number of conditions requiring muscle relaxation, including smoothing wrinkles. (This potentially deadly toxin is very safe when minuscule amounts are injected into small muscles.) Botox has shown promise for migraine and tension headache sufferers and is now being studied for cluster headaches as well. It is too early yet to gauge any real benefits.

Alternative Therapies

Melatonin. Small reports indicate that melatonin, a brain hormone that helps to regulate the sleep-wake cycle, may help prevent episodic or chronic cluster headaches. Melatonin supplements are sold in health food stories, but as with most natural remedies, the quality of different preparations varies, and they have not been rigorously tested for safety or effectiveness. Hormones such as melatonin are powerful substances, and additional studies are needed.

Glucosamine. There have been some reports that glucosamine, an alternative remedy commonly used for osteoarthritis, may prevent migraine attacks. Some researchers theorize this substance may reduce inflammation that affects nerves involved in vascular headaches. Whether this agent has any effect on cluster headaches is unknown.

Additional Therapies. Many patients with cluster headaches try alternative remedies for relief of pain. Treatments may include acupuncture, herbs, chiropractic, homeopathic remedies, reflexology, hypnosis, spiritual therapies, massage, aromatherapy, relaxation techniques, and yoga. A 2002 survey of patients attending a headache clinic or support groups, however, did not find any of these alternative therapies to be consistently effective.

Treatment for Sleep Apnea

Patients with cluster headaches who suffer from daytime sleepiness should consider being evaluated for a possible diagnosis of sleep apnea. Anyone who has both should then strongly consider treatment for the apnea as possible therapy for cluster headaches.

In some studies, patients with both cluster headaches and apnea who were treated with nasal continuous positive airway pressure (CPAP) experienced substantial reduction in the frequency and severity of cluster headaches. Currently, CPAP is the best treatment for many types of sleep apnea. It works in the following way:

• The treatment employs a machine weighing about five pounds that fits on a bedside table.
• A mask containing a tube connects to the device and fits over just the nose.
• The machine supplies a steady stream of air through a tube and applies sufficient air pressure to prevent the tissues from collapsing during sleep. [For more information, seeWell-Connected Report #65, Sleep Apnea.]