OJAI, CA—The benzodiazepine clonazepam may be an effective migraine preventive medication in patients who are refractory to conventional care, according to research presented at the First Annual Headache Cooperative of the Pacific Winter Meeting. Morris Maizels, MD, reported the preliminary evidence based on his case series that focused on the use of clonazepam, which is also used to relieve anxiety, as primary headache prophylaxis.
“In the absence of good clinical trials, clonazepam might be considered for therapy in patients who first have failed at least three classes of standard preventive therapies,” said Dr. Maizels, of the Department of Family Medicine at Kaiser Permanente in Woodland Hills, California. “This is not a first-time therapy.”
Migraine—A Neurolimbic Disorder
The pathophysiology of migraine is not fully understood, although Dr. Maizels suggested that the limbic system likely has a significant role in migraine expression, as limbic influences (eg, patient behaviors, stressors, and previous traumas) constantly modulate pain pathways. The concept of the limbically augmented pain syndrome was used to explain the symptoms complex in a subset of patients with chronic pain, which includes atypical and refractory pain with disturbances of mood, sleep, energy, libido, memory/concentration, behavior, and stress intolerance. However, Dr. Maizels asserted that it may be an effective model for some patients with migraine as well.
“People often talk about migraine as a spectrum disorder, thinking of the spectrum of tension headache to migraine,” said Dr. Maizels. “I think that migraine is a spectrum disorder from episodic to chronic. The more chronic and refractory the headache, the more likely there is to be limbic influences.”
Screening for Psychiatric Comorbidities
Anxiety and depression are well documented as highly comorbid conditions in patients with migraine. DSM-IV criteria for anxiety and depression share three components—fatigue, insomnia, and poor concentration—which emphasize the importance of uniformly screening migraine patients for both disorders. If patients were screened only with tests for depression, Dr. Maizels suggested, anxiety might be misdiagnosed as depression.
To clearly distinguish anxiety from depression, Dr. Maizels and colleagues developed and use the General Medical Anxiety and Depression Scale, a not yet validated screening tool that separates the cognitive items of depression, the cognitive items of anxiety, and the somatic items. Dr. Maizels referred to it as “a psychological CAT scan” that can help determine whether the patient is primarily anxious, depressed, or somatic. “Whatever screening method you use, screening for depression but not anxiety is a bit like taking a systolic blood pressure but not bothering to take a diastolic blood pressure,” he asserted.
Efficacy of Clonazepam
Definitive data supporting the use of benzodiazepines for chronic pain relief may be insufficient; however, a literature review of chronic pain in a clinical setting suggests that the drugs may have a potential role for treatment. Regarding the use of clonazepam specifically, Dr. Maizels noted, “[Clonazepam] seems to be commonly used. But there’s never really been a good study to tell us from a scientific point of view whether it has efficacy.”
One of the few existing trials of a benzodiazepine as a headache preventive was a crossover study that involved 34 patients. Although the authors concluded that clonazepam was not significantly more effective than placebo, patients who received 1 mg of clonazepam experienced a 50% reduction in headache frequency, compared with an 8% reduction in the placebo group. However, at the time of the study, there was no designation of medication overuse headache. In addition, the presence of anxiety and/or depression was never determined. “It’s clear that this study was never adequately powered to really show an advantage over placebo,” Dr. Maizels said.
Impact of Clonazepam in Clinical Practice
Dr. Maizels noted that there are obvious limitations to open-label studies, but he asserted, “There is also some value in suggesting the possibility of a new therapy in illustrating what may be some underlying mechanisms of action…. Migraineurs are not a uniform population, and there may be some subpopulation of migraineurs who respond differentially to different therapies.” During the past several years, Dr. Maizels has treated approximately 250 patients with clonazepam. He highlighted three cases to illustrate the clinical experience.
Dr. Maizels’ index case was a 28-year-old woman who experienced headaches for eight years, and clinical diagnoses suggested that she had dysthymia and subclinical anxiety. She did not respond to commonly prescribed drugs, but one year after her initial consultation, she said that she had been taking 0.25 mg/day of a friend’s clonazepam prescription for two weeks. During this time, she had not experienced any headaches, and her well-being had improved. For the next five years, the dosage was increased to 2 mg/day. “She comes in happy,” Dr. Maizels said. “This is how I got started on this path.”