Clonazepam for Refractory Headache: Three Cases Illustrative of Benefit and Risk

Morris Maizels, MD

Disclosures

Headache. 2010;50(4):650-656. 

In This Article

Abstract and Introduction

Abstract

Many patients with migraine are poorly responsive to conventional preventive therapies. Comorbid anxiety and depression may contribute to headache refractoriness, but studies of headache preventives have not typically addressed the patient with psychiatric comorbidity. The author has used clonazepam empirically to treat a subgroup of headache patients with associated anxiety, who were poorly responsive to conventional preventives. The use of a benzodiazepine as a headache preventive raises concerns regarding tolerance and addiction. The author presents 3 cases that illustrate different outcomes associated with this therapy, and suggests guidelines for its use.

Introduction

Despite the prevalent and well-recognized comorbidity of psychiatric disorders with migraine,[1] no studies of preventive medications specifically address patients with these comorbidities. There is little evidence to guide a clinician's decisions in treating headache patients with psychiatric comorbidity.

There are numerous preventive therapies available for migraine, although only a few have strong evidence for efficacy. The United States Headache Consortium identified the following medications as having proven high efficacy: amitriptyline, divalproex sodium, propranolol/timolol, and gabapentin.[2] Since that time, topiramate has also been approved by the Food and Drug Administration (FDA) for migraine prophylaxis, and is the most commonly prescribed migraine preventive. Other commonly used preventives include other antidepressants (especially tricyclic antidepressants, venlafaxine, and serotonin-specific reuptake inhibitors), other beta-blockers, other antiepileptic drugs, and the calcium channel blocker verapamil. Some "natural" or herbal supplements (riboflavin, magnesium, coenzyme Q10) may have efficacy as well.[3] Patients who do not respond to the usual classes of preventive therapies may be given therapies which lack scientific evidence for efficacy, and which may have significant side effects, or are invasive and/or expensive. Behavioral therapies (biofeedback, relaxation therapies, and cognitive behavior therapy) are effective,[4] but not widely available or utilized.

Despite the diverse therapies available, many patients remain significantly disabled by their headaches, apparently unresponsive to standard therapies.

Both depression and anxiety have been found to be highly comorbid with migraine.[1] While there are many possible explanations for this coprevalence, the most widely held belief is a shared biology, likely related to a dysfunction in the serotonin system. There appears to be a bidirectional influence of depression and migraine,[5] and anxiety disorders and migraine.[6] The FRAMIG-2 study, a recent, large French epidemiologic study, found that 50% of subjects with current migraine had associated symptoms of anxiety or depression.[7] Importantly, they found that 28% had anxiety alone, an additional 19% had mixed anxiety and depression, and only 3.5% had pure depression.

Despite the significant comorbidity of psychiatric disorders and migraine, trials of headache preventives typically exclude patients with significant psychiatric comorbidity, or do not identify or monitor anxiety or depression during the trial. A meta-analysis of trials before 2000 found that the effectiveness of antidepressants for migraine prevention was not usually related to change in depression.[8] Anxiety, however, was not addressed. In addition to the antidepressants, some antiepileptic drugs used for migraine prophylaxis have psychotropic properties, which might contribute to their efficacy as migraine preventives. Clinicians who treat patients with migraine and associated psychiatric comorbidity have little guidance as to whether standard migraine preventives are the best choice of therapy.

The author has found clonazepam to be clinically useful in patients with primary headache disorders, especially in the presence of clinical/subclinical anxiety, or "somatoform" symptoms. Clonazepam is a long-acting, high-potency benzodiazepine that has been approved by the FDA for the treatment of seizure disorders. It is used more commonly in a variety of psychiatric disorders (especially panic disorder and other anxiety disorders),[9] as well as other neurologic disorders (Tourette's syndrome, movement disorders), and chronic pain syndromes, especially neuropathic pain.[10]

The US Headache Consortium categorized clonazepam as having Level 5 evidence of efficacy – ie, that there was evidence that it was not more effective than placebo.[2] This recommendation was based on a single trial, published in 1979,[11] summarized below. The present author has found that no other trials of clonazepam (or any other benzodiazepine) for migraine prophylaxis have been reported in the English headache literature, since the 1979 trial. The 1979 study was a randomized crossover trial of 38 patients with migraine, of whom 34 patients completed the study. Patients on 1 mg and 2 mg of clonazepam had 50% and 37% reduction in headache days, respectively, compared with 8% for placebo. However, neither difference was statistically significant. This trial had several limitations that prevent a conclusion of lack of efficacy. First, the study appears not to have been adequately powered to detect a statistically significant difference among the groups. Further, patients who were included had "long-lasting, relatively intractable" headache, but medication overuse had not yet been described as an entity at that time. Medication overuse would likely reduce any potential efficacy of a preventive agent. Finally, patients were not evaluated for anxiety or depression, or for insomnia. It is the presence of comorbid anxiety or insomnia that would suggest the possible benefit of a benzodiazepine. The authors reported that 18 patients remained on clonazepam long-term with "some benefit."

Two trials of other benzodiazepines (diazepam and alprazolam) for tension-type headache reported modest short-term improvement, although the number of subjects in each trial was small.[12,13] Clonazepam was reported to prolong or induce remission in 2 patients with cluster headache, when combined with lithium.[14] Although one group found clonazepam superior to placebo for temporomandibular dysfunction,[15] a second group found that cyclobenzaprine but not clonazepam was superior to placebo.[16]

Clonazepam has been reported in case series and open-label trials to be effective in a variety of neuralgic syndromes, including facial pain.[9] In a comparator study of lancinating pain, it was at least as effective as carbamazepine and phenytoin.[17] In another open-label study, it provided marked improvement or complete pain relief in 6/21 patients with neuralgic pain – all 6 of these patients had allodynia.[18] In an open-label trial for myofascial pain syndrome, clonazepam use led to a significant reduction in pain scores.[10]

Clonazepam is effective for the treatment of panic attacks.[20] Both generalized anxiety disorder and panic disorder are often comorbid with migraine, and clinically appear to contribute to the expression of migraine attacks. It has been suggested that treatment with benzodiazepines "may reduce complaints of pain, but this seems to be an indirect effect related to their psychotropic properties, such as alleviation of anxiety and, in selected cases, depression."[21] However, a true analgesic effect is suggested by a case series of 10 patients with cancer-related neuropathic pain: all 5 patients who completed the protocol reported marked pain relief.[22] (Of note, however, 3 of the patients excluded from analysis had increased use of opiates during the 5 days of titration.)

The role of benzodiazepines in the treatment of chronic pain remains controversial. Benzodiazepines are associated with physical dependence and other adverse effects, requiring caution for their long-term use. It has been suggested that, in the absence of definitive data, there is a potential role for benzodiazepines in the treatment of acute muscle spasm, concomitant chronic pain and anxiety, and lancinating neuropathic pain.[21] These authors specifically suggest clonazepam and alprazolam as agents of choice.

Clonazepam is also commonly used for the treatment of vertigo,[23] although there are no double-blind trials to support its use. Vertigo is commonly comorbid with migraine,[24] and the symptom is particularly difficult to treat.

This author reports below the histories of 3 patients with primary headache disorders who had proven refractory to standard preventive therapies, and had a significant improvement with clonazepam, although at times also with significant complications. These cases are selected from a suburban health maintenance organization referral headache clinic. The author has used clonazepam in over 200 patients, with variable results (see Discussion). The lack of standardized documentation in the clinical records precluded a more formal retrospective analysis of all of these patients. The first case presented represents the first headache patient treated by the author with clonazepam, and illustrates the difficulty of separating an improvement in patient mood from a true improvement in headache control. The second case represents a more definitive improvement in headache control without a change in mood. The third case displayed significant psychiatric decompensation because of unauthorized dose escalation. The current cases do not necessarily represent typical responses to clonazepam, but are selected to suggest a rationale for further study of this treatment modality.

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