ARTICLE IN BRIEF
- ✓ Based on findings of cardiac abnormalities in patients taking verapamil for cluster headache, investigators recommend that these patients be given an EKG at baseline, during dose escalation, and every six months for long-term maintenance.
Verapamil, a calcium-channel antagonist approved for treatment of cardiovascular disease (angina and hypertension), is commonly used as a first-line medication to prevent cluster headache. Although this drug is highly effective in preventing the excruciating episodes of cluster headache, its effectiveness comes with a price — cardiac abnormalities.
An Aug. 14 study in Neurology found that 18 percent of cluster headache patients who had been referred to a headache clinic and treated with verapamil had possibly serious EKG abnormalities (69:668–675).
Cluster headache is typically characterized by severe daily attacks of unilateral head pain that occur in a cyclical pattern, or “clusters.” Bouts of cluster attacks can last from days to weeks, followed by long periods of complete remission. The disorder can be difficult to treat, and patients with cluster headache are often desperate for relief.
“The doses of verapamil used to treat cluster headache are much higher than those used to treat cardiovascular disease. Once you step into the arena of ‘neurological’ doses of verapamil [as opposed to ‘cardiovascular’ doses], dangerous side effects can occur,” said senior study author Peter J. Goadsby, MD, PhD, professor of clinical neurology at the Institute of Neurology at the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK, and the department of neurology at the University of California-San Francisco.
Verapamil is approved for cardiovascular indications at doses of 180 mg to 480 mg/day. The drug comes in two forms: short-acting verapamil and sustained-release verapamil.
In the current study, patients were treated with short-acting verapamil in 80 mg increments. The range of doses of verapamil was 240- to 960-mg/day, with a median dose of 516 mg/day. This is similar to doses used in clinical practice by neurologists who treat cluster headache, Dr. Goadsby said. Use of verapamil in cluster headache is off-label, and there are no large, well-designed, randomized, controlled trials to support its use.
Dr. Goadsby and colleagues have a referral practice at the Headache Clinic of the National Hospital for Neurology and Neurosurgery where they see a greater number of patients with cluster headache than would be seen in general practice, since this is a rare disorder. (Cluster headache occurs in 0.3 percent of the population, while migraine occurs in 13 percent.) They became aware of the serious cardiac abnormalities sometimes associated with verapamil when one cluster headache patient taking the drug had complete heart block.
“This wake-up call led to the current study, which was designed to document the extent of cardiac abnormalities in patients treated with verapamil. We found that not only do cardiac abnormalities occur, but they also occur in about one in five cluster headache patients. We were quite surprised by the magnitude of the problem,” Dr. Goadsby commented.
The study was based on patients who attended the Headache Clinic at the National Hospital for Neurology and Neurosurgery from September 2001 to September 2005. Out of 369 patients with cluster headache treated with high-dose verapamil, 129 outpatients (161 of them men) had an EKG. Verapamil was initiated at 240 mg/day and increased by 80 mg every two weeks to a maximum daily dose of 960 mg. One patient was treated with 1,200 mg/day. The dose of verapamil was escalated until cluster headache was suppressed or side effects developed.
EKGs were conducted in the clinic in 108 patients, and an additional 20 patients had EKGs elsewhere; no EKGs were conducted for 89 patients, which is contrary to current recommendations. Among reasons given for the lack of an EKG: patients or their service providers were reluctant to have frequent assessments (47 percent); 10 percent had EKGs before taking verapamil but declined EKG monitoring; 2 percent took verapamil for only two weeks; and 13 percent stopped taking the drug because of constipation, lethargy, chest pain, postural hypotension, or nonspecific malaise. One patient did not have EKG monitoring because he had a dual pacemaker prior to starting verapamil; and no reasons were available for why the remaining 32 patients did not have EKG monitoring.
Of the 108 patients who had EKGs performed in the hospital, 13 patients had first-degree heart block (mean daily dose of verapamil, 578 mg); nine had other heart block (mean daily dose, 604 mg); 21 had total arrhythmias (mean daily dose, 567 mg); PR interval — a measure of the time it takes between the atrium contracting (P wave) and the ventricle contracting (QRS complex) — increased by <0.2 seconds in eight patients (mean daily dose, 653 mg); and 39 patients had bradycardia (mean daily dose, 659 mg). Verapamil was stopped in four of the patients with bradycardia.
Dr. Goadsby said that the study has several important implications. All patients with cluster headache treated with verapamil should have an EKG at baseline, for dose escalation, and then every six months for long-term maintenance. Despite these recommendations, a substantial number of patients failed to have EKG monitoring or EKGs were lost.
Dr. Goadsby commented that EKG abnormalities are not dose-dependent and can occur in patients on doses as low as 240 mg/day, “so it would be insufficient to just monitor patients on higher doses,” he said.
The study showed that EKG abnormalities can develop even in patients on a stable dose of verapamil. “In one of our patients stabilized on 960 mg with no cardiac abnormalities, we saw dramatic EKG abnormalities 12 months later,” Dr. Goadsby said. “This problem may creep up in time. Since cluster headache is lifelong and doesn't go away, we recommend monitoring with EKG at intervals of six months, even in patients on stable doses.”
EKG monitoring is inexpensive and non-invasive, he said, and “will keep a proportion of these patients on high-dose verapamil out of trouble.”
Although verapamil has the potential for causing life-threatening arrhythmias, use of this drug can revolutionize the lives of patients with cluster headache, Dr. Goadsby continued. “It is excellent preventive therapy that can stop the occurrence of cluster headache.”
Dr. Goadsby and colleagues are to be congratulated for publishing this study, said Fred Sheftell, MD, director of the New England Center for Headache in Stamford, CT, and president-elect of the American Headache Society. “This is an important wake-up call to neurologists who use high-dose verapamil to treat cluster headache.”
Dr. Sheftell added that he and his colleagues at the New England Center for Headache routinely use EKG to monitor cluster headache patients on high-dose verapamil.
“When I get to doses higher than 720 mg/day, I involve a cardiologist for reassurance,” Dr. Sheftell said. If EKG equipment is not available in the office of the doctor who is treating cluster headache, then the patient should at least be referred to his or her primary care doctor for EKG monitoring. The problem with such a referral is that cluster headache patients may not comply, Dr. Sheftell explained, “because the pain is so severe that they are willing to court dangerous situations with use of medications. Therefore, we should insist that the EKG and the interpretation be sent to us to ensure safety.”
Dr. Sheftell applauded the protocol for verapamil used by Dr. Goadsby and colleagues, which entailed use of short-acting verapamil in increments of 80 mg. “This method was suggested by Lee Kudrow, MD, 20 years ago as an alternative to slow-release verapamil,” Dr. Sheftell noted.
“I would agree with using short-acting verapamil, rather than the sustained-release formulation, in cluster headache,” he said. “I prefer the short-acting formulation with regard to ability to titrate more accurately and safely. My clinical experience anecdotally demonstrates improved responses when patients are switched from sustained-release verapamil to short-acting verapamil.”
Dr. Goadsby agreed that his clinical experience was similar. “There are no well-controlled, placebo-controlled, dose-ranging studies to direct treatment. This is one of those areas where clinicians who treat cluster headache have to combine what modicum of evidence is available with their own clinical experience,” Dr. Sheftell commented.
A little-known fact about verapamil is that it may inhibit sperm motility, Dr. Sheftell continued (Res Exper Med 1994;194:165–178). “Men should be so advised if they are or will be considering having children,” he noted.