Abstract
Background: Cluster headache is an extremely severe and debilitating trigemino-autonomic pain syndrome. About 10% of patients with cluster headache manifest a chronic form (CCH).The present case series study aims to evaluate the long-term efficacy of Boswellia serrata (Sallaki H15) on headaches and disturbed sleep in patients with CCH.
Case results: In an open-label study, four patients with CCH and disturbed sleep received oral B. serrata.
Conclusion: The results provide Class IV evidence that oral B. serrata reduces the intensity and frequency of headaches in patients with CCH.
Introduction
Cluster headache (CH) is an extremely severe and debilitating trigemino-autonomic pain syndrome, characterized by strictly unilateral short-lasting pain attacks associated with prominent parasympathetic features. Chronic CH (CCH) is diagnosed after 1 year without remission or with remission periods lasting less than 1 month (1). About 10% of patients with CH manifest CCH (2), which is often refractory to medical treatment. Extracts of Boswellia serrata (Indian frankincense) have been clinically studied for the treatment of many inflammatory conditions, such as osteoarthritis and rheumatoid arthritis (3). The resin from B. serrata contains a number of biological actives called pentacyclic triterpene acids, which give the extract its anti-inflammatory and analgesic properties, with boswellic acid the major active ingredient (4). These acids have been demonstrated to interfere with the body’s natural inflammatory response by inhibiting cytokines and leukocyte activity. The present study aims to evaluate the long-term efficacy of B. serrata (Sallaki H15) on headaches and disturbed sleep in patients with CCH.
Methods
Inclusion criteria
Outpatients were offered treatment with B. serrata when fulfilling the following criteria: 1) CCH according to IHS criteria (1); 2) failure of prophylactic treatment to at least three standard medications; and 3) at least half of the headaches occur during sleep, causing insomnia or excessive daytime sleepiness (EDS). The Epworth Sleepiness Scale (ESS) was used to assess EDS.
Clinical characteristics of patients with chronic cluster headache.
TPM: Topiramate, zolmi: zolmitriptan, ukw: unknown, GON: greater occipital nerve; CBZ: carbamazepine; LTG: lamotrigine; SSRI: selective serotonin reuptake inhibitor; ONS: occipital nerve stimulation, s.c.: subcutaneously, suma, sumatriptin.
Characterization of pain attacks before and under B. serrata therapy.
Follow-up = last 4 weeks of treatment. †Baseline = last 4 weeks before treatment.
Case series
Patient 1
A 48-year-old male had CCH since March 2010. At baseline headaches of severe intensity (10/10 on a numeric rating scale) occurred with a frequency of 6–8 (diurnal 1–2) per 24 hours. Acute therapy with zolmitriptan nasal spray worked well, but he complained of insomnia. His prophylactic treatment was primarily with topiramate 150 mg/d, lithium 480 mg/d and 60 mg of methylprednisolone/d. Verapamil was contraindicated because of a left bundle branch block. After tapering off of methylprednisolone and lithium, long-term therapy of 3 × 700 mg B. serrata reduced diurnal attack frequency (to 1–2) within the first 4 weeks, and nocturnal attacks completely diminished after 6 weeks of treatment. Furthermore, pain intensity and sleep quality improved markedly.
Patient 2
A 70-year-old female had a 25-year history of CH. CCH began in 1999 with 3–4 severe headaches (10/10) per 24 hours at baseline. Some attacks could be sufficiently treated with oxygen therapy, whereas zolmitriptan nasal spray did not show any effect. She presented with depression and suicidal ideation. B. serrata 3 × 350 mg reduced headache frequency by 60% within the first 10 days. Long-term treatment led to persistent decrease in pain frequency (to 1–2 attacks) and intensity (3/10).
Patient 3
A 40-year-old male had CH since 2005, with a chronic course beginning 3 years after onset. Headaches at baseline were of severe intensity (9/10) with a frequency of 4–8 per 24 hours. Although acute treatment had been successful he complained of insomnia and depression. Nocturnal attacks occurred 3–4 times. He refused treatment with amitriptyline and other antidepressants. Dosages of 3 × 700 mg of B. serrata reduced pain frequency (to 2–3 during the day), intensity (6/10), and duration (45 minutes to 15 minutes) after the first month of treatment for 8 months so far. The remaining headaches induced short awakenings, from which he was able to fall asleep within minutes.
Patient 4
A 47-year-old male had CH since 2003, with a chronic course beginning 1 year after onset. Headaches at baseline were of severe intensity (7/10) with a frequency of 4–8 per 24 hours. Acute treatment had been successful with sumatriptan subcutaneously. He complained of insomnia and depression. Under treatment with amitriptyline and oxazepam it was able to consolidate sleep. Treatment with topiramate and lithium showed a partial improvement over 6 months (from May to November 2008). Frequency again increased to eight attacks per day after a car accident in February 2009. Thereafter, he suffered from suicidal thoughts. In September 2010 we began treatment with B. serrata. Within 6 weeks and at a current dosage of B. serrata 2 × 700 mg nocturnal attacks resolved, diurnal attacks decreased in frequency, intensity, and pain duration. Sleep quality also improved over long-term administration.
Discussion
This study provides Class IV evidence that oral B. serrata (Sallaki H15) reduces the intensity and frequency of headaches in patients with CCH. The effects were long-lasting in three patients (mean 15 months) and transient (6 months) in patient 2. The rapid improvement of nocturnal pain within weeks is similar to the analgetic effect observed in recent trials using B. serrata in cancer pain (5,6). Drug treatment in CCH is known to result in a profound placebo effect in up to 30% of the patients (7) but several lines of evidence suggest true efficacy of B. serrata. First, in all cases the response to B. serrata was dose-dependent. Second, in one patient, headaches and disturbed sleep reappeared when B. serrata was tapered off because of limitations in medication supply. Readministration of B. serrata relieved pain attacks and improved sleep quality again. Third, long-term efficacy was documented not only by patients’ reports but also by sleep and pain diaries.
The mechanisms of how B. serrata reduces pain in CCH remain unclear. Ammon et al. (8) observed that B. serrata inhibits leukotriene biosynthesis in vitro. Boswellic acids, constituents of B. serrata extract, have subsequently been identified as selective redox-independent non-competitive inhibitors of both 5-lipoxygenase (the key enzyme in leukotriene biosynthesis) and human leukocyte elastase. Proinflammatory cytokines, such as leukotrienes, are known to have a role in the pathophysiology of CH (9).
Our study suffers from the following major limitations. First, this is a single-centre, open-label case study of only four patients. Second, the study was not placebo -controlled. Third, although B. serrata was safe at recommended dosages, crude herb preparations may not be as safe as the specially manufactured extract. In clinical trials of pharmaceutical grade standardized Boswellia extract, no serious side effects have been reported. Safety in young children, pregnant or nursing women, or individuals with severe liver or kidney disease has not been established.
A randomized, double-blind, placebo-controlled multicentre trial is needed to confirm efficacy of B. serrata in CCH.