International Tinnitus Journal, Vol. 14, No. 1, 57–67 (2008) Treatment of Vertebrobasilar Insufficiency– Associated Vertigo with a Fixed Combination of Cinnarizine and Dimenhydrinate Volker Otto,1,2 Bernhard Fischer,1,3 Mario Schwarz,4 Wolfgang Baumann,4 and Rudolf Preibisch-Effenberger1 1 Ear, Nose, and Throat Clinic, Otto-von-Guericke University, Magdeburg; 2 Schönebecker Kreiskrankenhaus, Schönebeck; 3 Ear, Nose, and Throat Clinic, Marienhospital Osnabrück; and 4 Department of Clinical Research, Hennig Arzneimittel, Flörsheim am Main, Germany Abstract: Thirty-seven patients suffering from vertigo associated with vertebrobasilar insuf- ficiency participated in our prospective, single-center, double-blind, comparative study. Patients were randomly allocated to treatment with placebo; betahistine (12 mg betahistine dimesylate, one tablet three times daily); or the fixed combination of 20 mg cinnarizine and 40 mg dimen- hydrinate (one tablet three times daily) for 4 weeks. The primary efficacy end point was the decrease of the mean vertigo score (SM), which was based on the patients’ assessments of 12 in- dividual vertigo symptoms after 4 weeks of treatment. Patients treated with the fixed combi- nation showed significantly greater reductions of SM as compared to patients receiving placebo ( p Ͻ .001) or the reference therapy betahistine ( p Ͻ .01). The vestibulospinal parameter lat- eral sway (Unterberger’s test) improved to a significantly greater extent in patients taking the fixed combination as compared to those receiving placebo ( p Ͻ .001). No serious adverse event was reported in any therapy group. The tolerability of the fixed combination was judged as very good or good by 91% (betahistine, 73%; placebo, 82%). In conclusion, the fixed com- bination proved to be statistically more effective than the common antivertiginous drug beta- histine in reducing vertebrobasilar insufficiency–associated vertigo symptoms. Key Words: betahistine; cinnarizine; dimenhydrinate; vertebrobasilar insufficiency; vertigo he maintenance of balance is an essential condi- of disorders, including internal diseases, or it may be of tion for the management of daily activities. This psychogenic origin [3,4]. Tcomplex physical performance is based on finely The vertebrobasilar system is responsible for the blood tuned brain processing of sensory inputs provided by the supply of 10 cranial nerves, all ascending and descend- vestibular, visual, and proprioceptive systems and the cog- ing tracts, parts of the cortical hemispheres, and the end- nitive system. Data mismatch induced by unusual and organs of hearing and balance. Thus, dysfunction of this therefore unadapted stimulation of the intact sensory system can lead to a wide variety of symptoms. Cere- systems, or pathological dysfunction of any of these brovascular disease is a common cause of vertigo symp- afferent components or of the brain centers integrating toms, particularly in older patients [5]. Vertigo is one of these signals, leads to vertigo [1,2]. Therefore, vertigo the first and most frequent signs of vertebrobasilar insuf- not only represents a cardinal symptom for vestibular ficiency (VBI), with a relative incidence ranging from disorders, but it can be associated with a wide spectrum 50% to 80% [5]. VBI is characterized by transient is- chemic attacks, and it represents a heterogeneous dis- Reprint requests: Mario Schwarz, PhD, Hennig Arznei- ease entity with many potential causes [6–8]. It usually mittel, Department of Clinical Research, Liebigstrasse 1-2, results from atherosclerosis of the subclavian, vertebral, D-65439, Flörsheim am Main, Germany. Phone: (ϩ49) 6145- and basilar arteries with insufficient collateral circula- 508-156; Fax: (ϩ49) 6145-508-158; E-mail: mario.schwarz@ tion but may also be due to other causes, such as com- hennig-am.de pression of vertebral arteries by cervical spondylosis or 57 International Tinnitus Journal, Vol. 14, No. 1, 2008 Otto et al. the subclavian steal syndrome [5,7]. VBI presents with ergistic effect of cinnarizine and dimenhydrinate at doses characteristic symptoms and signs owing to impaired reduced by up to two and a half times as compared to perfusion of the cerebellum, the brainstem, and the oc- the doses commonly used in monotherapy [25–30]. Our cipital cortex [8]. Its main symptom—vertigo—results double-blind, randomized clinical study focused on ver- from an insufficient blood supply in the vestibulocere- tigo caused by VBI. Episodic, intense vertigo frequently bellar complex [9]. Because vestibular pathways are represents the first and, in combination with neurosensory widely distributed in the hindbrain and because the ves- signs of brainstem dysfunction, the most important symp- tibular end-organ is supplied by vertebrobasilar circula- tom in VBI [31]. Vertigo is most frequently associated tion, in VBI the vestibular system may be affected at any with vision disturbances, patients often report nausea and level: the labyrinth, the eighth cranial nerve, or the ves- vegetative symptoms, and perhaps one-third of the pa- tibular nuclei [5]. This may explain why vertigo is the tients complain about severe headaches [3]. In view of most frequent and sometimes the only symptom in VBI the pharmacological properties of the active substances [10,11]. Typically, VBI-associated vertigo occurs in at- in the fixed combination—in particular the cerebral se- tacks, depends on position, and is frequently associated lectivity of the calcium antagonist cinnarizine and the with nystagmus, nausea, vomiting, and severe imbal- brainstem-regulating properties of dimenhydrinate—and ance [5]. Concomitant symptoms include blurred vision, encouraged by the positive results obtained in a previous blackouts, drop attacks, or headache. open study [21], we performed this trial to investigate A major concern of drug therapy in VBI is to improve the antivertiginous effects of the fixed combination in impaired circulation and to restore normal perfusion of VBI as compared to the effects of betahistine dimesylate. compromised areas [6]. Anticoagulant and antiplatelet To quantify possible nonspecific effects during treatment, therapies may serve to reduce the incidence of stroke we included a placebo group. after transient ischemic attacks [12]. Calcium antago- nists are a useful alternative, especially in cases of athero- SUBJECTS AND METHODS sclerotic origin [13]. Also, symptomatic treatment is im- portant to provide immediate relief to affected patients. Patient Population For this purpose, drugs of various pharmacological classes Eligible participants were men and women who suffered have been used. These include antihistamines (e.g., di- from VBI and, in addition to the cardinal symptom ver- menhydrinate); anticholinergics (e.g., scopolamine); cer- tigo, showed at least two of the following symptoms: tain calcium channel blockers (cinnarizine, flunarizine); impaired hearing, impaired vision, tinnitus, or headache. histamine analogs (betahistine); and also diuretics, neuro- Diagnosis of VBI had to be confirmed by the presence of leptics, and other psychotherapeutic agents; corticoster- typical abnormalities in specific examination tests. We oids; and hemorheologics [14]. For the treatment of excluded from participation patients who suffered from VBI-associated symptoms, including vertigo, betahis- vertigo due to diseases other than VBI (e.g., cardiovas- tine has been described as useful [15]. cular diseases). Pregnant or lactating women or women Here we report on the efficacy and tolerability of a without safe contraception during the study were also fixed combination consisting of the calcium channel excluded. Other exclusion criteria were gastrointestinal blocker cinnarizine (20 mg) and the antihistamine di- ulcers, bronchial asthma, adrenal tumors, angle-closure menhydrinate (40 mg). This fixed combination has been glaucoma, prostate adenoma with residual urine, suspi- used successfully in Germany for 25 years for the treat- cion of compressive intracranial processes, Parkinson’s ment of peripheral, central, or combined types of ver- disease, pheochromocytoma, alcohol abuse, acute intox- tigo. The rationale for using the combination is derived ication, and convulsive disorders. Further exclusion cri- from the modes of action of its constituents: Owing to teria were the concomitant use of monoamine oxidase its calcium antagonistic properties, cinnarizine regulates inhibitors or aminoglycoside antibiotics. Previous anti- calcium influx into vestibular cells of the labyrinth and vertiginous medication had to be discontinued in a 2-week improves cerebral circulation [16–18], whereas dimen- washout phase prior to the start of treatment. hydrinate mainly exerts a regulatory effect on the vesti- bular nuclei and adjacent vegetative centers in the brain- Study Design and Treatment stem [19,20]. The antivertiginous efficacy of the combination was We designed the study as a randomized, double-blind, demonstrated in a series of open studies [21–24] and in reference- and placebo-controlled, single-center, phase numerous controlled, double-blind, randomized clinical III clinical study with three parallel groups. It was con- studies that included patients suffering from vertigo of ducted in accordance with the principles of good clinical central, peripheral, or combined central-peripheral origin. practice and the Declaration of Helsinki (1989 revision). The results of these studies provided evidence for a syn- The ethics committee at the Otto-von-Guericke Univer- 58 Treatment of VBI-Associated