Efficacy and safety of the cinnarizine/dimenhydrinate combination versus betahistine in the treatment of vertigo: A systematic literature review

Abstract

Vertigo is a frequent reason for medical consultation and may result from a wide range of aetiologies. Betahistine and the fixed low-dose combination of cinnarizine 20 mg and dimenhydrinate 40 mg are commonly used therapeutic options, each with distinct antivertigo profiles. This systematic review, conducted in accordance with the PRISMA guidelines, aims to compare the efficacy and safety of these two treatments in patients with vertigo of various origins. A comprehensive search was conducted in PubMed, Cochrane Library, Google Scholar, and ClinicalTrials.gov, with no restrictions on language or publication date. Eligible studies included clinical trials and meta-analyses comparing the fixed low-dose combination (20 mg/40 mg) versus betahistine (12 or 16 mg), assessing efficacy through the Mean Vertigo Score (MVS) and safety based on the incidence of adverse events (AEs). The RoB 2 and ROBIS tools were used to evaluate the risk of bias. A total of nine studies were identified (six clinical trials and three meta-analyses). In five of the six clinical trials, the fixed low-dose combination significantly reduced MVS compared with betahistine at weeks 1 and/or 4 (p < .05); these findings were corroborated by the three meta-analyses. Regarding safety, both treatments were well tolerated, with no serious AEs reported and a generally lower incidence observed in the fixed low-dose combination group. Overall, the fixed low-dose combination demonstrated superior clinical efficacy from the first week of treatment, along with a more favourable tolerability and safety profile. These results support its preferential use in the management of acute vestibular syndrome.

Resumen

El vértigo es un motivo frecuente de consulta médica que puede deberse a múltiples etiologías. La betahistina y la combinación fija a dosis bajas de cinarizina 20 mg y dimenhidrinato 40 mg se emplean habitualmente como tratamiento, con perfiles antivertiginosos diferenciados. Esta revisión sistemática, realizada conforme a la declaración PRISMA, tiene como objetivo comparar la eficacia y seguridad de ambos fármacos en pacientes con vértigo de origen diverso. Se consultaron las bases de datos PubMed, Cochrane Library, Google Scholar y ClinicalTrials.gov sin restricciones de idioma ni fecha. Se incluyeron ensayos clínicos y metaanálisis que compararan la combinación fija a dosis bajas 20 mg/40 mg vs. betahistina 12 o 16 mg, evaluando eficacia mediante el Mean Vertigo Score (MVS) y seguridad por incidencia de eventos adversos (EA). Se aplicaron las herramientas RoB 2 y ROBIS para evaluar el riesgo de sesgo. Se identificaron 9 estudios (6 ensayos clínicos y 3 metaanálisis). En 5 de los 6 ensayos clínicos, la combinación fija a dosis bajas redujo significativamente el MVS frente a betahistina en las semanas 1 y/o 4 (p < 0,05), resultados también confirmados por los 3 metaanálisis. En términos de seguridad, ambos tratamientos fueron bien tolerados, sin EA graves y generalmente con menor incidencia en el grupo de la combinación fija a dosis bajas. En conjunto, la combinación fija a dosis bajas mostró mayor eficacia clínica desde la primera semana de tratamiento, así como una mejor tolerancia y perfil de seguridad. Estos resultados respaldan su uso preferente en el tratamiento del síndrome vestibular agudo.

Introduction

Vertigo is an illusory sensation of movement that manifests as either movement of one's own body or of the environment.^1,2 Its prevalence ranges from 3% to 10%, and it is the third most common symptom reported by patients in primary care consultations (frequency 10%) and in otorhinolaryngology consultations (frequency 30%).^3,4 It occurs at any age, although it is most prevalent between 40 and 60 years of age, and its incidence is higher in women, at 60%.^5,6 Aetiology can derive from both the peripheral and central vestibular systems, resulting in its management requiring extensive knowledge of multiple areas of medicine for both diagnosis and treatment.⁵ In clinical practice, establishing an accurate assessment of vertigo is complex due to the diversity of symptoms and the need to assess the duration and recurrence of attacks. Therefore, in the treatment of acute vestibular syndrome—especially in its early stages or in the absence of a defined aetiology—a syndromic approach and general symptomatic treatment based on the clinical presentation are usually used.⁵

Regarding treatment, the use of different pharmacological and non-pharmacological strategies has been reported.⁵ Among the former, numerous drugs from the antihistamine group, calcium channel blockers, benzodiazepines, and orthopramides have been proposed.^5,8 Among the drugs used in the treatment of vertigo are betahistine (marketed in Spain under the name SERC®) and the fixed low-dose combination of cinnarizine 20 mg and dimenhydrinate 40 mg (marketed in Spain under the name DIZINEL®), both with an anti-vertigo profile and minimal sedative effect, a key characteristic to avoid interfering with central compensation mechanisms.⁹

Betahistine is a histamine analogue with weak agonist action on H1 receptors and potent antagonist action on H3 receptors. It is indicated for Ménière's syndrome, although it is also frequently used in patients with other types of vertigo.^7,10 Despite considerable variability in the results of studies on its efficacy, the latest Cochrane review concludes that patients with vertigo may experience some clinical benefit from its use.¹¹ On the other hand, the fixed low-dose combination of cinnarizine and dimenhydrinate is indicated for the treatment of vertigo symptoms of diverse origins, acting through a dual mechanism: (i) cinnarizine blocks calcium channels in vestibular cells, and (ii) dimenhydrinate acts as a centrally acting antihistamine with antivertigo and antiemetic effects.^12–14 Its efficacy has been supported by multiple clinical trials and meta-analyses.^13,15–19 Despite the existence of clinical trials and meta-analyses comparing the efficacy of the fixed low-dose combination of cinnarizine and dimenhydrinate versus betahistine, there is currently no updated systematic review that integrates and structured analyses of the evidence on the clinical differences between the two anti-vertigo agents. The objective of this systematic review is to identify, update, and synthesize the available clinical evidence on the efficacy and safety of betahistine compared with the fixed low-dose combination of cinnarizine 20 mg and dimenhydrinate 40 mg in the treatment of vertigo of peripheral, central, or mixed origin.

Material and methods

Protocol

A systematic review of the literature was conducted according to the methodology established by the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement.

Search strategy

Structured search strategies were designed and applied to four electronic databases: PubMed, the Cochrane Library, Google Scholar, and ClinicalTrials.gov. The search equations used combined MeSH terms and free text to identify studies comparing the fixed low-dose combination of cinnarizine 20 mg and dimenhydrinate 40 mg with betahistine 12 and/or 16 mg in patients with vertigo of any aetiology (Appendix A). No language restrictions or time limits were applied. The search was completed on April 7, 2025.

Inclusion and exclusion criteria

Clinical trials and meta-analyses evaluating the efficacy and/or safety of the fixed low-dose combination of cinnarizine 20 mg and dimenhydrinate 40 mg compared with betahistine 12 mg and/or 16 mg were included. Studies that included additional comparators were accepted. Participants had to be patients diagnosed with vertigo (peripheral, central, or mixed origin), including diagnoses of specific pathologies such as Ménière's disease, vestibular neuritis, benign paroxysmal positional vertigo, or vertebrobasilar insufficiency, among others. Studies that did not incorporate any of the molecules covered in this review, those with a non-experimental design, or those without reporting data on the dependent variables under study were excluded.

Methods to avoid the risk of bias

The review was conducted following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions, and the Cochrane Collaboration's Rob 2 tool for assessing risk of bias in clinical trials, together with the ROBIS tool for evaluating meta-analyses were used. Study selection and assessment were performed independently by two reviewers. Discrepancies were resolved by consensus.

Study selection and data extraction

After eliminating duplicates and applying the inclusion criteria, 9 studies were finally included in the qualitative synthesis. Three of them provided sufficient data to be considered in the quantitative synthesis (meta-analysis). The entire article selection process is represented in a PRISMA diagram (Fig. 1).

Figure 1.

Flow diagram of the study selection process (PRISMA).

The following data were extracted from each study: author and year of publication, study design, characteristics of the included population, duration of follow-up, type of intervention, primary endpoint evaluated, clinical outcomes, adverse events (AEs), and other relevant comments. The most relevant information is included in Table 1 to facilitate comparison between studies.

Table 1.

Main characteristics of the studies included in the systematic review.

Author (Year)	Study type	Population [Country]	Intervention	Duration	Results (MVS)	Adverse events
Novotný et al. (2002)^24	Double-blind, parallel-group RCT	Patients with Ménière's disease (n = 82). [Czech Republic]	FLDC 20/40 mg vs Bh 12 mg	12 weeks	No differences between FLDC and Bh in weeks 1, 4, and 12 (p > .05).	1 mild AE in Bh (unrelated); none in FLDC
Cirek et al. (2005)^22	Double-blind, controlled RCT	Patients with peripheral vertigo (n = 61) [Czech Republic]	FLDC 20/40 mg vs Bh 12 mg	4 weeks	FLDC was higher than Bh in week 1 (p = .002) and week 4 (p = .001).	2 mild AEs in Bh (headache and abdominal pain); none in FLDC
Hahn et al. (2008)^23	Double-blind, controlled, multicentre RCT	Patients with peripheral vertigo, excluding BPPV and Ménière's disease (n = 66) [Czech Republic]	FLDC 20/40 mg vs Bh 12 mg	4 weeks	FLDC was higher than Bh in week 4 (p < .05). No differences in week 1 (p = .83)	3 AEs in Bh (skin reaction, headache, bruising); none in FLDC
Otto et al. (2008)^21	Double-blind, controlled, prospective RCT	Patients with vertigo due to vertebrobasilar insufficiency (n = 37) [Germany]	FLDC 20/40 mg vs Bh 12 mg vs placebo	4 weeks	FLDC superior to Bh and placebo in weeks 1 and 4 (p < .01)	5 AEs in Bh (gastrointestinal); 2 in FLDC (GI and exaggerated caloric response); none in placebo
Scholtz et al. (2012)^25	Double-blind, controlled, non-inferiority RCT	Patients with unilateral vestibular neuritis (n = 61) [Austria and Czech Republic]	FLDC 20/40 mg vs Bh 12 mg (both groups received corticoids + HES + pentoxifyline)	4 weeks (+7 days of previous treatment)	FLDC superior to Bh in week 1 (p < .001) and week 4 (p < .001)	No AEs reported in either group
Scholtz et al. (2019)^12	Double-blind, controlled, multicentre, non-inferiority RCT	Patients with peripheral vertigo (n = 306) [Austria, Germany, Czech Republic, Bulgaria, and Russia]	FLDC 20/40 mg vs Bh 16 mg	4 weeks	FLDC superior to Bh in weeks 1 (p = .003) and 4 (p = .035)	8 AEs in Bh (non-serious); 4 in FLDC (non-serious).
Schremmer et al. (1999)^20	Meta-analysis	Patients with central, peripheral, or mixed vertigo (n = 636) [Germany, multinational]	FLDC 20/40 mg vs Bh 12 mg vs placebo vs Cin (20/50 mg) vs Dh (40/100 mg)	4 weeks	FLDC superior to Bh and other comparators in weeks 1 (p < .001; I^2 = NA) and 4 (p ≤ .001; I^2 = NA)	AE rate: 11.4% in Bh; 21.5% in FLDC.
Gloria et al. (2012)^16	Meta-analysis	Patients with peripheral vertigo (n = 127; 2 RCTs: Cirek et al. and Hahn et al.)	FLDC 20/40 mg vs Bh 12 mg	4 weeks	FLDC superior to Bh in week 4 (p < .00001; I^2 = 28%); inconclusive in week 1 (I^2 = 66%)	NA
Scholtz et al. (2022)^15	Meta-analysis with IPD	Patients with peripheral vertigo (n = 795; 4 RCTs: Cirek et al., Hahn et al., Pytel et al. and Scholtz et al. (2019))	FLDC 20/40 mg vs Bh 12 mg vs Bh 16 mg vs placebo	4 weeks	FLDC superior to Bh 12 and 16 mg and placebo in weeks 1 and 4 (p < .001; I^2 = 0%)	AE rate: 2.9% in Bh vs 1.8% in FLDC.

Abbreviations: AE, adverse effect; Bh, betahistine; Cin, cinnarizine; Dh, dimenhydrinate; FLDC, fixed low-dose combination of cinnarizine and dimenhydrinate; GI, gastrointestinal; HES, hydroxyethyl starch; IPD, individual patient data; MVS, Mean Vertigo Score; NA, not available; RCT, randomised controlled trial.

Regarding efficacy, data were collected on: subjective efficacy perceived by the patient, vegetative symptoms, vestibulospinal test results, nystagmus assessment, and response to caloric testing. The main dependent variable was the Mean Vertigo Score (MVS), defined as the arithmetic mean of the scores assigned by the patient to six spontaneous vertigo symptoms and six triggering factors, rated on a scale of 0–4 (absent-very intense).

The difference in MVS between the fixed low-dose combination and its comparator (betahistine) at weeks 1, 4 and/or 12 was recorded, including the confidence interval and p value.¹² In studies where this difference was not explicitly recorded, it was calculated from the available data and in cases where the MVS was expressed as a sum of 12 items (scale 0–48), it was transformed to a mean scale of 0–4 by dividing by 12. To homogenise the results of subjective efficacy, "subjective improvement" was considered the proportion of patients who felt "better" or "much better" in both the fixed low-dose combination group and the comparator group, and the corresponding p value was recorded. Regarding safety and tolerability, reported AEs were recorded, specifying whether they were attributed to the treatment by the investigator, and all reported adverse events were totalled to calculate the percentage of symptoms attributed to treatment. Tolerability was assessed according to the patient's rating, with those who rated it as "good" or "very good" considered to be well tolerated.

Results

Six studies included in this review were randomised, double-blind, controlled clinical trials conducted in 613 patients with various types of peripheral vertigo. In addition, three meta-analyses were included, covering patients with central, peripheral, or mixed vertigo, one of which was based on individual patient data. The meta-analysis by Schremmer et al. involved an additional sample of 249 patients treated with one or the other drug, while the meta-analyses by Gloria et al. and Scholtz et al. considered data from the individual studies analysed.^15,16,20 All interventions compared the fixed low-dose combination of cinnarizine 20 mg and dimenhydrinate 40 mg versus betahistine, at doses of 12 or 16 mg, in a therapeutic regimen of 3 tablets per day, except for one study that compared it with placebo.²¹

Mean vertigo score v

The progression of MVS was the primary dependent variable of efficacy in the included randomised clinical trials. At week 1, the fixed low-dose combination of cinnarizine and dimenhydrinate showed a significantly greater reduction in MVS compared to betahistine in four clinical trials: Cirek et al. (–.34 points, p = .002), Otto et al. (–.37, p = .014), Scholtz et al. (2012) (–.79, 95% CI: –.95 to –.64; p < .001), and Scholtz et al. (2019) (–.113, 95% CI: –.188 to –.037; p = .003), while Hahn et al. found no statistically significant differences (–.03 points; p = .83). Schremmer et al. observed a difference of –.36 points (p < .001; I² = NA) and Scholtz et al., using individual data, reported –.29 points vs betahistine 12 mg and –.20 vs 16 mg (p < .001; I² = 0%); Gloria et al. described inconclusive results due to high heterogeneity (I² = 66%).^15,16,20 At week 4, the fixed low-dose combination showed superiority in five trials: differences of –.56 (p = .001), –.33 (p = .013), –.60 (p = .005), –.61 (p < .001) and –.093 points (p = .035), respectively).^12,21–23 Meta-analyses by Schremmer et al. (−.66, p < .001; I² = NA), Gloria et al. (p < .00001; I² = 28%), and Scholtz et al. (–.60 and –.22, p < .001) confirmed these findings.^15,16,20 Only Novotný et al. found no differences between groups at any assessment, despite an improvement of >80% from baseline in both.²⁴

Subjective efficacy

Five clinical trials assessed the subjective perception of overall improvement after treatment. At week 1, the fixed low-dose combination of cinnarizine and dimenhydrinate showed greater perception of improvement compared to betahistine in Cirek et al. (86.7% vs 51.7%; p = .006) and Scholtz et al. (2019) (49.3% vs 21.6%; p = NA), whereas Otto et al. and Hahn et al. did not assess this variable at that time point.^12,21–23 At week 4, the fixed low-dose combination continued to show superiority: 86.7% vs 58.6% (p > .05) in Cirek et al., 65.7% vs 45.5% (p = .047) in Hahn et al., 73% vs 36% (p = .001) in Otto et al., and 71.2% vs 62.8% (p = .138) in Scholtz et al. (2019)^12,21–23 The individual data meta-analysis by Scholtz et al. confirmed these results (fixed low-dose combination 71.0%, betahistine 16 mg 62.8%, p = .012; betahistine 12 mg 31.0%, p < .001).¹² Novotný et al. evaluated this variable at 12 weeks, with no significant differences and with rates above 95% in both groups.²⁴ Neither Scholtz et al. (2012) nor the meta-analysis by Gloria et al. provided data on subjective efficacy.^16,25

Vegetative symptoms

Five clinical trials evaluated vegetative symptoms (nausea, vomiting, sweating, and tachycardia) as a secondary variable. At week 1, the fixed low-dose combination of cinnarizine and dimenhydrinate showed a significantly greater reduction compared to betahistine in Hahn et al. (–1.02 ± .80 vs –.56 ± .60; p = .004) and Scholtz et al. (2012) (1.13 [95% CI: .95–1.31] vs 1.77 [95% CI: 1.59–1.95]; p < .001) both using a visual analogue scale from 0 to 4 ; while Cirek et al. (–.50 ± .48 vs –.32 ± .39; p = .111), Otto et al. (–.36 ± .66 vs –.18 ± .25; p = .945) and Scholtz et al. (2019) found no significant differences.^{12,21–23,25} At week 4, the results more consistently favoured the low-dose fixed combination, with significant differences in Cirek et al. (.72 ± .49 vs .44 ± .50; p = .009), Hahn et al. (–1.15 ± .83 vs –.73 ± .63; p = .023) and Scholtz et al. (2012) (.13 vs .72; p < .001); in Otto et al., the difference did not reach significance (–.61 ± .60 vs –.18 ± .34; p = .052), and in Scholtz et al. (2019) the improvement was similar in both groups (81.1% vs 79.1%; p = .138)^{12,21–23,25} Novotný et al. observed significant improvement in both groups from week 1, with no differences between treatments (p > .05).²⁴ Three meta-analyses supported these findings: Schremmer et al. found a superior reduction in sweating with the fixed low-dose combination(–1.04 vs –.45; p < .05), Gloria et al. reported superior improvement at 4 weeks (weighted mean difference –.43; p < .05), and Scholtz et al. found a mean improvement of –.95 with the fixed low-dose combination vs –.88 with betahistine 16 mg (p = not significant).^15,16,20

Vestibulospinal tests, nystagmus, and caloric testing

Vestibulospinal tests were assessed primarily by craniocorpography (Unterberger and Romberg) and, in one study, by computerised dynamic posturography. The fixed low-dose combination of cinnarizine and dimenhydrinate showed significantly greater improvement compared to betahistine in the Unterberger test in two studies (Novotný et al., p = .042; Schremmer et al., p = .039) and in the composite posturography score (Scholtz et al. 2012, p = 0013), with no significant differences in other parameters or studies.^20,24,25 Spontaneous nystagmus resolved more quickly with the fixed low-dose combination in Scholtz et al. (2012) (p < .001), with no differences elsewhere.²⁵ Calorific testing in five studies showed improvement in both groups with no significant differences between treatments.^21–25 Neither Scholtz et al. (2019) nor the meta-analyses by Gloria et al. and Scholtz et al. included objective vestibular measures.^12,15,16

Safety and tolerability

In the reviewed studies, AEs were infrequent and mild. Novotný et al. reported one mild AE in the betahistine group (2.5%); Hahn et al. reported a moderate skin reaction (3.0%) leading to discontinuation; Otto et al. reported AEs in 18.2% of patients with the fixed low-dose combination and 38.5% with betahistine, none related to the medication; and Cirek et al. reported two mild AEs in the betahistine group alone (6.45%).^12,21–24 Scholtz et al. (2019) documented AEs in 2.6% (low-dose fixed combination) and 5.2% (betahistine), whereas Scholtz et al. (2012) reported no AEs.^12,25 The meta-analysis by Schremmer et al. found AEs in 21.5% with the fixed low-dose combination and 11.4% with betahistine, whereas Scholtz et al. reported AEs in 3.9% (low-dose fixed combination) and 4.32% (betahistine); Gloria et al. reported no AE data. The most common events with betahistine were gastrointestinal (27.3%), headache (18.2%), and fatigue (9.1%), and with the low-dose fixed combination, fatigue (27.4%), dry mouth (24.2%), and headache (9.7%). Tolerability was assessed as “good” or “very good” by more than 90% of patients in all studies: Novotný et al., Cirek et al. (100%), Hahn et al. (fixed low-dose combination 96.7% vs betahistine 97.0%), Otto et al. (fixed low-dose combination 90.9% vs betahistine 63.6%; p = .019), Scholtz et al. (2012) (higher frequency of “very good” in low-dose fixed combination; p = .018) and Scholtz et al. (2019) (97.9% in both groups).^12,21–25 Schremmer et al. (fixed low-dose combination 90.3%, betahistine 92.5%) and the meta-analysis by Scholtz et al. (97.9% fixed low-dose combination and betahistine 16 mg; 100% betahistine 12 mg) confirmed these figures.^15,20 None of the studies documented the appearance of extrapyramidal side effects, either in the betahistine 12 mg and16 mg group or in the fixed low-dose combination group.

Risk of bias assessment

All included clinical trials ((Novotný et al.²⁵, Cirek et al.²¹, Hahn et al.²⁴, Otto et al.²², Scholtz et al.²³ and Scholtz et al.¹²) presented a robust methodology according to the assessment shown in Fig. 2, with adequate randomisation, strict blinding, and a low dropout rate, reflecting high overall quality. However, the use of subjective scales such as the MVS introduces potential bias into the measurement. In the evaluation of the meta-analyses using the ROBIS tool (Fig. 3), Scholtz et al.,¹⁵ showed a low risk of bias in all domains, demonstrating a well-structured systematic review; Gloria et al.,¹⁶ presented certain problems in the identification of studies, assessment of risk of bias, and synthesis of results, whilst Schremmer et al.²⁰ showed a high risk of bias due to deficiencies in the selection of studies, absence of systematic quality assessment and a synthesis not in accordance with current standards, significantly reducing the validity of their conclusions.

Figure 2.

Risk of bias domains of the clinical trials analysed.

Reasoning: Low risk some concerns high risk. Domains (D): D1: Bias arising from the randomisation process. D2: Bias due to deviations from the intended intervention. D3: Bias due to missing outcome data. D4: Bias in outcome measurement. D5: Bias in the selection of the reported outcome.

Figure 3.

Risk of bias domains of the meta-analyses analysed with the ROBIS tool.

Reasoning: Low risk some concerns high risk.

Phase (P) and Domains (D): P1: Relevance of the study to the review question. D1: Clear eligibility criteria. D2: Study identification and selection. D3: Data collection and risk of bias assessment. D4: Synthesis and presentation of findings.

Discussion

The present systematic review aimed to update and synthesize the available clinical evidence on the efficacy and safety of the fixed low-dose combination of cinnarizine 20 mg and dimenhydrinate 40 mg versus betahistine 12 and/or 16 mg in the treatment of vertigo of peripheral, central, or mixed origin. The results suggest greater efficacy of the fixed low-dose combination of cinnarizine and dimenhydrinate versus betahistine in reducing vertigo and its vegetative symptoms, with benefits evident from the first week and more pronounced at week four. Both treatments showed adequate safety profiles, although the fixed low-dose combination may have a slight superiority in terms of tolerability.

Individual studies consistently show a superior effect of the fixed low-dose combination both in the initial phase (week 1) and in the 4-week follow-up phase in terms of efficacy measured by the MVS.^12,21–25 This finding is consistent with those reported in the meta-analyses of Schremmer et al. and Scholtz et al., which identified a significantly greater reduction in SVM in response to the fixed low-dose combination versus betahistine 12 mg and16 mg.^15,20 However, the meta-analysis by Gloria et al. did not show conclusive results at week 1—potentially explained by the high reported heterogeneity—although it did confirm superiority at week 4.¹⁶ The only study that did not show differences was that of Novotný et al. in patients with Ménière's disease, where the fixed low-dose combination was as effective as betahistine, possibly because the latter has demonstrated greater effectiveness in this condition according to a previous meta-analysis.^10,24,26 This efficacy supports the German vertigo guideline developed by the German Society of General Medicine and Family Medicine (DEGAM), which recommends the fixed low-dose combination as first-line treatment for acute nonspecific peripheral vertigo (evidence Ia, recommendation B), reserving betahistine as a second option or for chronic use in Ménière's disease (evidence Ib, recommendation B).²⁷

In line with the above, various treatments such as flunarizine, cinnarizine or the standardised extract of Ginkgo biloba (EGb 761) have shown comparable efficacy to betahistine in the symptomatic control of peripheral vertigo. ^28–30 Two studies compared the efficacy of betahistine and dimenhydrinate in the treatment of residual dizziness after repositioning manoeuvres in benign paroxysmal positional vertigo, with conflicting results. ^31,32 It is particularly noteworthy that the fixed combination of cinnarizine 25 mg and betahistine 8 mg – not marketed in Spain – has been shown to be significantly more effective than both drugs in monotherapy, although cinnarizine in monotherapy has not shown superiority over betahistine.³³ Although there is evidence of a predominant effect of cinnarizine, these results support the hypothesis of a synergistic action between cinnarizine and dimenhydrinate by demonstrating that the fixed low-dose combination achieves a therapeutic superiority over betahistine, which is not observed with either drug administered individually.^17,20,34

In line with the above, the fixed low-dose combination showed greater efficacy than betahistine in reducing vegetative symptoms in most studies, especially at 4 weeks, with significant effects in Hahn et al., Cirek et al., and Scholtz et al. (2012), and confirmed by the meta-analysis by Gloria et al.^16,21,23,24 Schremmer et al., on the other hand, only found a greater reduction in sweating.²⁰ Regarding subjective efficacy, the fixed low-dose combination was also superior, with a higher proportion of patients reporting improvement in Cirek et al. (week 1), Hahn et al. (week 4) and notably in Otto et al.^21,22,24 This positive perception is in line with the benefits observed in vestibular and autonomic symptoms. Although objective differences in vestibulospinal tests were limited, significant improvements were observed with the fixed low-dose combination in craniocorpography²⁵ and in both spontaneous nystagmus and posturography,²³ suggesting that the fixed low-dose combination does not interfere with central vestibular compensation.²⁷

Both treatments presented good clinical tolerability, with no reports of serious AEs. Gastrointestinal disorders, headache, and fatigue predominated in patients treated with betahistine, whereas fatigue, dry mouth, and headache were more frequent in those taking the low-dose fixed combination. Specifically, Scholtz et al. (2012) reported no AEs,²³ while the rest of the included studies observed a higher proportion of AEs in patients treated with betahistine.^{12,15,21,22,24,25} This pattern contrasts with the meta-analysis by Schremmer et al., which reported a higher incidence of AEs in patients receiving the low-dose fixed combination, although with a four-fold larger sample size in the fixed low-dose combination vs betahistine, which could have underestimated events in the latter. Both drugs showed favourable safety profiles, although the fixed low-dose combination may offer a subtle advantage in certain clinical settings due to its lower rate of AEs, such as peripheral vertigo in general or, specifically, in Ménière's disease, vertebrobasilar insufficiency, and vestibular neuritis.^{12,15,21,22,24,25} Betahistine has shown similar rates of AEs to placebo in other studies,¹¹ while the low-dose fixed combination, compared with calcium channel blockers such as flunarizine, presents a more favourable profile with a lower incidence of somnolence (23.0% vs 7.1%), attributable to its lower dose and the better tolerability of cinnarizine compared to flunarizine.³⁰ The variability in the incidence of AEs between studies could be due to differences in the collection and classification methodology, as well as in the definition of events versus adverse reactions. Some studies recorded all events, while others only reported those considered treatment-related.

Regarding subjective perception, more than 90% of patients rated tolerability as "good" or "very good" with both betahistine and the fixed low-dose combination in all the studies reviewed. In fact, this was similar in most studies, except for two studies that reported a higher frequency of "very good" ratings with the fixed low-dose combination in cases of vestibular neuritis and vertigo due to vertebrobasilar insufficiency.^12,21–25

Despite the interesting results derived from this review, some methodological limitations should be mentioned. First, the diagnostic non-uniformity of some of the studies analysed limits the extrapolation of the findings to specific clinical entities. Furthermore, the short follow-up period in most studies restricts the assessment of the persistence of therapeutic benefit, which is especially relevant in chronic conditions. The prevalence of subjective measures as the main efficacy variables also introduces a potential bias in the interpretation of results, although this is partially offset by the presence of complementary objective assessments. These limitations underscore the need to design future studies with new, more precise and standardised diagnostic criteria proposed by the Bárány Society, extended follow-up periods in chronic conditions, and objective tests as the main variables.

Conclusions

The results of this review suggest that the fixed low-dose combination of cinnarizine and dimenhydrinate is superior to betahistine in reducing symptoms of vertigo and associated vegetative symptoms, with beneficial effects observed from the first week and more pronounced after four weeks of treatment. Both treatments have adequate safety profiles. However, the fixed low-dose combination may confer a slight advantage in terms of tolerability and a lower incidence of adverse events. Overall, these results support the recommendation of the fixed low-dose combination as the preferred therapeutic option over betahistine in the pharmacological management of acute vestibular syndrome.

Funding

This study was funded by ITF Research Pharma S.L.U., which covered the costs associated with publication and facilitated coordination between the authors during manuscript development. The company did not participate in the design of the review, data analysis, or interpretation of the results. The opinions expressed are the sole responsibility of the authors.

Acknowledgments

The authors gratefully acknowledge the support received for the coordination and development of this study.