Efficacy and Tolerability of a Fixed Combination of Cinnarizine and Dimenhydrinate (ARLEVERT) Versus Betahistine (BETASERC) in the Treatment of Otogenic Vertigo: A Double-Blind, Randomised Clinical Study
Abstract and Introduction
Introduction: Peripheral vestibular disorders frequently lead to the manifestation of symptoms of vertigo. The objective of this study was to compare the efficacy and tolerability of a fixed combination of cinnarizine 20mg and dimenhydrinate 40mg per tablet with betahistine (betahistine dimesylate) 12mg per tablet in the treatment of patients with otogenic vertigo.
Patients and Methods: Sixty-one patients with vertigo due to peripheral vestibular disorders (otogenic vertigo) participated in this prospective, double-blind, comparative, single-centre study. Patients were randomly allocated to treatment with betahistine 12mg or the fixed combination of cinnarizine 20mg and dimenhydrinate 40mg, both treatments given three times daily for 4 weeks. Efficacy was determined by patients' assessments of vertigo symptoms after 1 and 4 weeks of treatment using a visual analogue scale to determine a 'mean vertigo score'.
Results: Treatment with the fixed combination led to significantly greater improvements in mean vertigo scores compared with the reference therapy betahistine. This was evident as early as 1 week after the onset of treatment (p = 0.002). Over 4 weeks of therapy, the fixed combination decreased the intensity of vertigo symptoms about 2-fold compared with betahistine (p = 0.001). Furthermore, reductions in symptoms typically associated with vertigo were more pronounced (p = 0.009) in the fixed-combination group compared with the betahistine group after 4 weeks of treatment. No serious adverse events were reported in either treatment group. Tolerability of the fixed combination was judged as 'very good' by 97% (betahistine 90%) and as 'good' by 3% (betahistine 10%) of patients.
Conclusion: The fixed combination of cinnarizine and dimenhydrinate was shown to be an effective and very well tolerated treatment option for patients with otogenic vertigo. It proved to be statistically more efficient in reducing vertigo than the widely used betahistine. Therefore, the fixed combination of cinnarizine and dimenhydrinate may be considered a first-line treatment option for the treatment of otogenic vertigo.
Maintenance of balance is essential for the management of daily activities. This complex physical function depends on finely tuned brain processing of sensory inputs provided by the vestibular, visual and proprioceptive systems as well as by the cognitive system. Data mismatch induced by unusual and therefore unadapted stimulation of the intact sensory systems, or pathological dysfunction of any of these afferent components or of the brain centres integrating these signals, give rise to the condition 'vertigo'.[1,2] Therefore, vertigo not only represents a cardinal symptom for vestibular disorders, but is furthermore associated with a wide spectrum of diseases. Vertigo may also appear in association with various organic diseases or may have a psychogenic origin.[3,4]
In practice, the pathogenesis of most cases of vertigo involves disorders of the vestibular system.[3,4] The vestibular system is generally divided into peripheral and central compartments. The peripheral vestibular system comprises the semicircular canals, the otoliths, the hair cells and the vestibular nerve up to the root entry zone in the brainstem. The central vestibular system, on the other hand, is composed of the vestibular nuclei, the oculomotor nuclei, the vestibuloocular reflex tracts, the cerebellum, the brainstem reticular formation, the area postrema, and other components.[5] Vertigo can occur as a consequence of peripheral vestibular disorders or central nervous system diseases; in many cases, combined forms of vertigo of central and peripheral origin are observed. Associated symptoms differ depending on the origin of vertigo and thus provide diagnostic information to guide systematic investigation of the underlying cause. Nevertheless, establishing a diagnosis is often difficult because of the complexity and diversity of the underlying pathogenic mechanisms and the patient's subjective perception of vertigo symptoms.[2,6]
Common peripheral vestibular diseases include vestibular neuritis and vestibular neuropathy, bacterial and viral labyrinthitis, benign paroxysmal positional vertigo (BPPV), Ménière's disease, labyrinth or vestibular nerve trauma, otosyphilis, tumours, otosclerosis, perilymphatic fistula, autoimmune inner ear disease, vasculitides and ototoxicity caused by drugs or toxic chemicals.[7,8] Typical manifestations of peripheral vestibular disorders are vertigo (predominantly rotating) accompanied by nausea, vomiting and other autonomous symptoms, sensorineural hearing loss, tinnitus and aural fullness.[7,8] Vertigo imposes great limitations on patients' ability to meet their daily responsibilities, which results in a self-perceived decrease in quality of life.[9,10] Vertiginous patients are also prone to frequent falls and thus injuries.[11] Eventually, their insecurity about standing and loss of self-confidence may lead to immobilisation. The social consequences of vertigo and the increasing age of the population underline the importance of developing efficient antivertiginous therapies for both individual care and pharmacoeconomic reasons.[12]
Because of the complexity and diversity of the pathogenic mechanisms underlying vertigo, drugs of various pharmacological classes have been used to treat this condition. These include calcium channel antagonists, antihistamines, the histamine-like drug betahistine, diuretics, antipsychotics and other psychotherapeutic drugs, corticosteroids and haemorrheological agents.[13] In this study we report on the efficacy and tolerability of a fixed combination consisting of the calcium channel antagonist cinnarizine (20mg per tablet) and the antihistamine dimenhydrinate (40mg per tablet) [Arlevert®, Hennig Arzneimittel (Floersheim/Main, Germany)1 compared with betahistine, which is widely accepted as a standard medication for the treatment of peripheral vestibular vertigo.[14] This fixed combination of cinnarizine and dimenhydrinate has been used successfully in Germany for >20 years for the treatment of vertigo of various origins, including peripheral, central or combined peripheral/central types of vertigo. The rationale for the use of the fixed combination is based on its dual mode of action: because of its calcium channel antagonistic properties, cinnarizine rapidly regulates calcium influx into the vestibular cells of the labyrinth and, in the long term, improves cerebral circulation,[15,16,17,18] while dimenhydrinate primarily exerts a regulatory effect on the vestibular nuclei and adjacent vegetative centres in the brainstem.[19,20]
Since its introduction to the market, a total of 17 controlled clinical studies with various objectives have been conducted using this combination product. The superior efficacy and favourable tolerability of the fixed combination compared with various standard treatments has been demonstrated in seven individual, randomised, double-blind, placebo- and/or reference-controlled clinical studies in patients with diverse types of vertigo as well as Ménière's disease.[21,22,23,24,25]
The present study assesses the efficacy and tolerability of the fixed combination of cinnarizine and dimenhydrinate in the treatment of patients with vertigo exclusively due to peripheral vestibular disorders of otogenic origin. The combination drug was compared with the standard treatment betahistine. In Germany, the latter agent is licensed for use in 'vertigo conditions in the context of Ménière-like symptoms', and is widely used for the treatment and prophylaxis of peripheral vertigo, including vertigo attacks associated with Ménière's disease.
