Betahistine in the treatment of peripheral vertigo: an evidence-based review

Abstract

Background

Vertigo is a common presenting symptom in clinical practice, predominantly of vestibular etiology, and often medicated with betahistine, despite the lack of knowledge concerning its mechanism of action. This paper’s objective was to review the scientific evidence regarding the efficacy of betahistine on peripheral vertigo.

Methods

A systematic search of articles written in English, published within the past 10 years, was conducted in April 2024, on online evidence-based medicine databases, using the MeSH terms “betahistine,” “ménière disease,” “acute vestibular neuritis,” “paroxysmal vertigo,” “acute peripheral vestibulopathy,” and “labyrinthitis.” The Strength of Recommendation Taxonomy of the American Academy of Family Physicians was used to evaluate the level of evidence and strength of recommendation.

Results

This review included 12 articles for evidence analysis. Concerning Menière’s disease, despite contradictory results, three of the articles analyzed showed a positive effect of betahistine, which is in line with the recommendations of the European Academy of Otology and Neurotology and NICE guidelines, while the American Academy of Otorhinolaryngology guidelines suggest offering betahistine as maintenance therapy. For benign paroxysmal positional vertigo, the established treatment is repositioning maneuvers, and three of the five studies analyzed proved the addition of betahistine to be beneficial. In regard to peripheral vertigo from other causes, two out of three articles revealed a positive recommendation for the use of betahistine.

Conclusion

There is a potential benefit to the utilization of betahistine for various etiologies of peripheral vertigo. However, additional studies are required to establish more robust evidence.

Background

Vertigo is a symptom that presents as an illusion of motion, generally rotatory, of the self or the environment, associated with instability [1]. It affects mostly women and increases with age, with an estimated lifetime prevalence of about 20 to 30%. Symptoms like hearing loss, feeling of ear fullness, tinnitus, nausea, or vomiting may coexist [2].

Vertigo can be classified as vestibular, which can be either peripheral (labyrinth or vestibular nerve) or central (brainstem and cerebellum) or as non-vestibular (caused by neurological and cardiac diseases or as a drug side effect) [3].

In clinical practice, vestibular peripheral vertigo is the most frequent type of vertigo, with benign paroxysmal positional vertigo (BPPV) being recognized as the leading etiology [4], thought to be caused by floating otoliths in the semicircular canals (known as canalolithiasis) or attached to the cupula (known as cupulolithiasis) [5]. Menière’s disease (MD) prevalence varies among studies between 3.5 and 513 per 100,000 [6]. This disease presents with recurrent acute episodes of vertigo, tinnitus, and hearing loss [7]. Other causes of peripheral vertigo include vestibular neuritis or neuronitis, as well as labyrinthitis [2].

A comprehensive, multidisciplinary approach is essential for vertigo treatment. Treatments include medical therapy, physical therapy, repositioning maneuvers, lifestyle interventions, and cognitive behavioral therapy. Severe disease may warrant surgical treatment [2, 3].

Although the pathophysiology of the various types of vertigo is not yet completely understood, a wide variety of medications are used for its treatment, especially in the case of peripheral vertigo, such as steroids, diuretics, anticonvulsants, antiemetics, histaminergic drugs, and serotonin reuptake inhibitors [2, 8].

Despite the lack of understanding of its exact mechanism of action, many clinical studies have shown betahistine effectiveness for the treatment of peripheral vestibular vertigo (VV) [9], and since it is inexpensive and often well tolerated, many clinicians prescribe it [10]. In addition to its effects on the vasculature, betahistine is believed to modulate histaminergic neurotransmission due to its action as an analogue of histamine with weak affinity to histamine H1 receptors and strong affinity to histamine H3 receptors [2, 3]. By stimulating the H1 receptors in the inner ear, it causes vasodilation, which allows for an increase in vessel permeability and reduction of endolymphatic pressure in the cochlea’s stria vascularis. Also, by acting as a H3-receptor antagonist, betahistine enhances the release of histamine from postsynaptic histaminergic nerve receptors [11]. The success of treatment with betahistine depends on both the dosage and duration of treatment [2].

The goal of this paper was to review the evidence of betahistine efficacy in the treatment of peripheral vertigo.

Main text

Methods

In April 2024, a literature search of randomized controlled trials (RCT) and observational studies, in the National Guideline Clearinghouse, Cochrane, and PubMed databases, was conducted, considering articles published in English in the last 10 years, using the keywords (MeSH terms) “betahistine,” “ménière disease,” “acute vestibular neuritis,” “paroxysmal vertigo,” “acute peripheral vestibulopathy,” and “labyrinthitis.”

As inclusion criteria for evidence analysis, we considered articles published in the English language, whose target population were adult (aged 18 years or older) human patients with either definite or suspected peripheral vertigo, using betahistine as a therapeutic measure and comparing it to other drugs or to placebo/no treatment. The selected studies had to report on the effect of betahistine in vertigo. Hand-search for other relevant articles from selected papers was also carried out, including searching the back references of all the finally selected articles.

As exclusion criteria, we considered article types other than RCTs or observational studies, articles which full text was not retrievable at the time of search, inclusion of central vertigo in the study population, the non-inclusion of betahistine as a therapeutic option, as well as a focus solely on symptoms other than vertigo, or a lack of report on the effect of betahistine in vertigo.

The level of evidence and strength of recommendation were determined using the Strength of Recommendation Taxonomy (SORT) scale of the American Academy of Family Physicians, which classifies articles according to their quality into three levels of evidence and three degrees of strength of recommendation (Table 1) [12].

Table 1 Strength of Recommendation Taxonomy (SORT) scale of the American Academy of Family Physicians

Three authors (C. A., B. G., and M. M.) independently scanned the initial search titles and abstracts to identify studies that appeared to meet the inclusion criteria. Disagreements were solved by a fourth author (A. F.). Four authors independently synthesized the results (A. F., C. A., D. P., and M. M.). For each study, the authors extracted information on study design, methodology, main outcomes, and conclusions.

Results

The electronic database search wielded a total of 79 articles, and 2 additional articles were identified through other sources, including backward citation searching. After removal of 4 duplicates, title and abstract screening excluded 26 articles. The remaining 51 articles were considered eligible, and after full-text assessment, 39 were excluded from analysis: 5 could not be retrieved, 19 were not an accepted article type, 4 included central vertigo in the study population, 6 only reported on the effect of betahistine on symptoms other than vertigo, and 5 only reported on the effect of drugs other than betahistine on vertigo.

After the inclusion/exclusion process, 12 articles were analyzed: 9 experimental studies (8 RCTs and 1 quasi-experimental study) and 3 observational studies (2 cohort studies and 1 cross-sectional survey). The PRISMA flow diagram [13] of search and selection is shown in Fig. 1.

Fig. 1

PRISMA flow diagram

The details of the included studies are listed in Tables 2, 3, and 4 and described in the text.

Table 2 Description of the studies included in the review with a focus on Méniére’s disease

Table 3 Description of the studies included in the review with a focus on benign paroxysmal positional vertigo

Table 4 Description of the studies included in the review with a focus on other causes of vertigo of any cause

Betahistine effect in Ménière’s disease

The effects of betahistine on patients with MD were reported in four studies selected for analysis.

A study carried out by Albu et al. [14] evaluated vertigo control in patients with definite unilateral MD, randomly assigning 66 patients to 2 groups: a group of patients who would receive a combination of intratympanic dexamethasone (ITD) with a high dosage of betahistine (144 mg/day, 48 mg three times daily (t.i.d.)) (n = 33), and another group of patients who received ITD and placebo (n = 33). Of the 62 patients that completed follow-up, combination therapy achieved a significant difference in complete vertigo control (73.3% of patients treated with a combination of ITD and betahistine vs 40.0% of patients treated with ITD alone) and substantial vertigo control (90% of patients treated with a combination of ITD and betahistine vs 65.6% of patients treated with ITD alone), compared to ITD therapy alone, with significance values of p = 0,01 and p = 0.02, respectively. These results indicate that better vertigo control is achieved with a combination of high betahistine dosage and ITD compared to therapy with only ITD alone.

The BEMED trial evaluated the efficacy and safety of betahistine in the treatment of 221 adults with MD [15]. The participants had definite unilateral or bilateral MD in active disease phase and more than 1 monthly attack in the 3 months prior to trial enrolment. After randomization, 74 received placebo, 73 received low-dose betahistine (24 mg twice daily (b.i.d.)), and 74 received high-dose betahistine (48 mg t.i.d.). Over the 9-month treatment period, the monthly attack rate in the placebo group fell significantly by a factor of 0.758 (95% confidence interval [CI] 0.705 to 0.816; p < 0.001) for every additional 30 days on treatment. Although the corresponding decay factors were not reported for the betahistine groups, rate ratios were similar to placebo (rate ratios 1.036 (95% CI 0.942 to 1.140) and 1.012 (95% CI 0.919 to 1.114) for low and high dose respectively, p = 0.759). There was no statistically significant difference between the placebo, low-dose betahistine, and high-dose betahistine groups, neither in the rate of monthly attacks (2.722 (95% CI 1.304 to 6.309), 3.204 (95% CI 1.345 to 7.929), and 3.258 (95% CI 1.685 to 7.266), respectively) nor in the duration (p = 0.348) or severity (p = 0.390) of attacks. The BEMED trial found no favorable effect of betahistine treatment (both low and high dose) with placebo in terms of the time course of vertigo episodes and reduction of attack rates during the study’s 9-month treatment period. Placebo effect was difficult to ascertain and distinguish from spontaneous symptomatic remission and fluctuation because of the lack of a control group (no medication).

A cross-sectional survey conducted by Ward et al. [16] reported that all current treatment approaches were perceived as effective by the patients involved, demonstrating a strong placebo effect in MD treatment. It also highlighted that one of the difficult aspects of studying this disease is the fact that despite debilitating symptoms, recovery is frequent.

Mólnar et al. [17] retrospectively analyzed the frequency, duration, and intensity of vertigo attacks utilizing hospital records, subjective complaints, and vertigo diaries of 105 patients suffering from MD which were subjected to no treatment, betahistine monotherapy, or dual therapy with betahistine plus piracetam (2400 mg a day). Compared with no treatment, the frequency and duration of vertigo attacks significantly decreased from baseline averaging a reduction of 2.1 per month and 2.9 h, respectively. However, there was no significant change in attack intensity with betahistine treatment, and the drug dosage did not affect symptomatic control. Vertigo attacks were less frequent with betahistine treatment compared to no treatment, with an OR of 2.75 (95% CI 1.068 to 4.442), which increased to 4.9 (95% CI 1.2 to 20.02) when comparing combination therapy of betahistine plus piracetam to monotherapy with betahistine.

Betahistine effect in benign paroxysmal positional vertigo

Kaur and Shamanna [19] conducted a RCT where they evaluated the efficacy of Epley’s maneuver plus 1 week of betahistine (16 mg/day) versus 1 week of betahistine (16 mg/day) alone versus Epley’s maneuver alone in the treatment of patients with BPPV. Upon reevaluation of patients 1 month after treatment initiation, both VAS and DHI scores had improved significantly in all three groups. Mean VAS scores were significantly higher with Epley’s maneuver plus betahistine after 1 and 4 weeks of treatment when compared to monotherapy with either Epley’s maneuver or betahistine. Symptomatic patients treated with Epley’s maneuver plus betahistine improved more than those treated with only betahistine (94.8% vs 87.1%, respectively). Besides, combination treatment also showed earlier vertigo resolution and prolonged symptom relief without relapse or recurrence.

A double-blind RCT conducted by Jalali et al. [21] compared the efficacy of betahistine and dimenhydrinate for residual dizziness in patients with posterior semicircular canal BPPV. Adult patients with residual dizziness after successful Epley’s maneuver and without vertigo or nystagmus were randomly and blindly allocated to one of three groups: a group was given betahistine 16 mg t.i.d., another group was given dimenhydrinate 50 mg t.i.d., and another group received placebo. After being submitted to Epley’s maneuver, 75.2% of participants had residual dizziness. After 1 week of treatment, 43.2% of patients exhibited an improvement in residual dizziness after Dix-Hallpike’s maneuver, with patients treated with betahistine showing significant improvement on unsteadiness (p < 0.008) and dizziness (p = 0.02). Betahistine was responsible for a decrease in DHI scores of 13.0 ± 6.7, though not statistically significant, as well as a decrease in the percentage of patients with mild to moderate vertigo from 79.5 to 46.5%. In the dimenhydrinate group, there was a 10.2 ± 5.4 decrease in DHI scores, and the percentage of patients with mild to moderate vertigo decreased from 61.5 to 43.6%, though not statistically significant. An improvement in residual dizziness was shown to be 3.18 times more likely with betahistine treatment compared to placebo while only 1.01 times more likely with dimenhydrinate compared to placebo.

A recent RCT by Sayin et al. [22] evaluated 100 patients with BPPV, who were randomized into two groups: one group was subjected to Epley’s maneuver and betahistine 24 mg b.i.d., while the other received Epley’s maneuver alone. Epley’s maneuver was successful in 95% of patients, and no differences were observed between patients on combination treatment (96%) and patients subjected to Epley’s maneuver alone (94%) (p = 0.024). Betahistine add-on treatment in posterior BPPV led to improvements from baseline in VAS when compared with Epley’s maneuver alone (6.24 ± 2.01 vs. 4.34 ± 2.32, respectively, p = 0.000), the same being observed in DHI scores (52.44 ± 21.42 vs. 35.71 ± 13.51, respectively, p = 0.000).

On the other hand, a study by Acar et al. [18] found no statistically significant differences in DHI scores of patients with BPPV that were subjected to repositioning maneuvers followed by 1-week treatment with betahistine, trimetazidine, ginkgo biloba extract, or no medication.

The same was true for a quasi-experimental study by Inan and Kıraç [20], in which the effects of betahistine and dimenhydrinate therapies in addition to Epley’s maneuver were evaluated in 64 patients suffering from BPPV. The participants were divided into an Epley’s maneuver alone group and an Epley’s maneuver plus medication group based on their medical records, the latter being further divided into two groups: a group which received betahistine 24 mg b.i.d. for 10 days and another which received dimenhydrinate 50 mg b.i.d. for 5 days. The DHI score was monitored at baseline and on the 10th day after treatment initiation. In patients subjected to Epley’s maneuver followed by betahistine, there was a statistically significant decrease of 70.83% in mean DHI scores (from 53.33 ± 21.59 to 18.16 ± 16.59, p < 0.001). The 69.45% decrease in mean DHI scores was also statistically significant in the Epley’s maneuver alone group (47.75 ± 21.47 vs 15.83 ± 19.87, p < 0.01), as was the 70.52% decrease in mean DHI scores of the Epley’s maneuver followed by dimenhydrinate group. However, the decrease percentage was not statistically different among the interventions (p = 0.971), and thus, pharmacotherapy in combination with repositioning maneuver was not found to be superior to Epley’s maneuver alone.

Betahistine effect in peripheral vertigo from other causes

We found a few studies regarding betahistine effect on peripheral vertigo caused by any disease other than MD or BPPV or with an unknown cause.

Scholtz et al. [23] conducted a RCT to compare the efficacy of combination of cinnarizine 20 mg and dimenhydrinate 40 mg to betahistine 16 mg in vertigo reduction in 294 patients with peripheral VV. Treatment lasted for 4 weeks, at the end of which mean vertigo score (MVS) was assessed. Vertigo symptoms in both intervention groups significantly decreased throughout the 4-week treatment (p < 0.001), with a decrease in MVS of 25.6% after 1 week and 59.5% after 4 weeks of treatment in the betahistine group. However, treatment with cinnarizine/dimenhydrinate led to a higher reduction in MVS score and was thus considered superior to betahistine.

Asadi et al. [24] carried out an RCT with 162 patients to compare the efficacy of cinnarizine/betahistine combination with the respective monotherapies in individuals with acute peripheral vertigo (APV) and found that the effect of cinnarizine and betahistine in combination on APV was greater than the effect of each drug separately. The patients were allocated to one of three groups: betahistine 8 mg and placebo, cinnarizine 25 mg and placebo, and betahistine 8 mg plus cinnarizine 25 mg, all given three times a day for a week. Follow-up at 3 days and 1 week after starting treatment evaluated changes in vertigo severity as measured by VAS, MVS, and mean concomitant symptom score (MCSS). The three groups showed notable disparity in VAS score after 1 week of follow-up, being significantly lower in the cinnarizine plus betahistine group (p = 0.001). Scores for MCSS and MVS were significantly different between the groups after both 3 days and 1 week of follow-up, where the respective value was lower in the betahistine group at day 3 (p = 0.0001) and in the combination group at 1 week (p = 0.0001).

Sanchez-Vanegas et al. [1] conducted a prospective observational cohort study with the goal of establishing betahistine’s clinical effect and safety in the management of peripheral VV. It included 150 adult patients treated with betahistine 48 mg daily, with a 12-week follow-up period, evaluating rotatory movement sensation, loss of balance, and a score of 0 to 100 points on a global improvement scale. By the end of the follow-up period, 73% of patients reported complete control of rotatory movement perception (p = 0.000), while only 8% experienced instability or loss of balance (p = 0.000). The observed symptom improvement ranged from 60 to 100 points, with an average of 89.3 points (95% CI 86.5 to 92.2), indicating a beneficial effect of betahistine on BPPV symptom control.

Discussion

In MD, the analyzed studies showed both betahistine therapy benefit but also a possible placebo effect given that the disease itself is characterized by recurrent symptomatic episodes with spontaneous recovery.

This duality is also shown in previous systematic reviews which included meta-analysis, most of which highlight that the significant heterogeneity in the methodology used between the different studies and the high risk of bias makes it impossible to obtain the mensurable impact of betahistine in vertigo in patients with MD. For instance, a systematic Cochrane review by Webster et al. [25] assessed the benefits and harms of systemic pharmacological treatment in patients with MD, including 548 patients treated with betahistine. The data showed that the RR for vertigo frequency improvement with betahistine compared with placebo or no treatment was 1.50 (95% CI 0.98 to 2.29) at 6 to 12 months and 1.11 (95% CI 0.93 to 1.32) beyond 12 months. With betahistine treatment, the vertigo frequency at 6 to 12 months was 1.90 attacks per month lower (95% CI 3.05 lower to 0.74 lower), but beyond 12 months, it was 0.63 attacks per 30 days higher (95% CI 4.07 lower to 5.33 higher). Using Epistemonikos, Rosenbaum and Winter [26] carried out a meta-analysis from 327 patients with MD, which showed that patients treated with betahistine had on average 2.74 less vertigo crisis (mean difference 95% CI 0.61 to 4.87) and 0.55 less severe vertigo (mean difference 0.55 less; 95% CI 0.18 to 0.92). Ahmadzai et al. [27] performed a systematic review and network meta-analysis of 1020 patients with MD and determined that the probability of high-dose betahistine (144 mg/day) performing better than placebo in complete vertigo control was 0.904 (odds ratio [OR] 13.45; 95% CI 0.10 to 1571.00), increasing to 0.960 (OR 61.45; 95% CI 0.43 to 7304.05) when high-dose betahistine was associated with intratympanic (IT) steroid. Betahistine treatment in MD was also evaluated in a systematic review and meta-analysis by Van Esch et al. [28] which 402 patients diagnosed with MD and highlighted that while one study showed a risk ratio (RR) of 3.0 (95% CI 0.97 to 9.30) in vertigo improvement at short-term follow-up (< 3 months) in favor of betahistine, two others found no beneficial effect of betahistine compared with placebo. Devantier et al. [29] conducted a systematic review and meta-analysis which ultimately based its evidence on 1 RCT (the BEMED trial, already mentioned in the above text), highlighting a deep lack of robust evidence concerning the effect of betahistine.

However, patients themselves consider this drug effective, as well as healthcare professionals versed in this subject and with extensive experience managing this disease, as reported by Casani et al. [30] in a study that evaluated statements concerning the use and efficacy of betahistine in MD submitted to a consensus conference (CC) comprised of 78 Italian experts on vestibular disorder. The CC showed 87% agreement for betahistine’s usefulness as a preventive therapy for vertigo attacks, in a dosage between 32 and 48 mg per day, with 71% agreement in using it as a first-choice therapy between attacks. Still, there was 77% agreement that betahistine had lower effectiveness during the acute phase and ought to be combined with other medications. Duration of treatment varies depending on the frequency of MD crises, with experts agreeing on a course of betahistine for 3 months if the number of crises was less than 4 in half a year (82% agreement), 6 months if 4 to 10 crises in half a year (74% agreement), and either 6 months (69% agreement) or 1 year in cases of more than 10 crises in half a year (66% agreement).

Additionally, most of the available clinical guidelines recommend a trial of betahistine in patients with symptomatic MD, especially in the context of maintenance therapy. A commentary provided by the National Institute for Health and Care Excellence (NICE) [31] reinforces that despite a possible powerful placebo effect, in view of betahistine’s low cost, the generally favorable adverse effect profile, and the lack of other interventions with proven benefit, a trial of betahistine may be attempted. This is in line with recommendations by the Triological Society Best Practice [32]. The clinical practice guideline concerning MD diagnosis and treatment by the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) Foundation [33] suggests that diuretics and/or betahistine may be offered as maintenance therapy both for symptomatic control and MD attack prevention, in combination with patient education and diet/lifestyle modification. A position paper by the European Academy of Otology and Neurotology Vertigo Guidelines Study Group states that betahistine 48 mg b.i.d. for 3 to 6 months to prevent MD attacks can be advised [34]. Nonetheless, in case of no clinical benefit or recurrent attacks of MD despite treatment, referral to a specialist should be considered [31].

In BPPV, the significant role of replacement maneuvers in crisis treatment is well established, such as Epley’s maneuver for the posterior semicircular canal. These maneuvers are associated with symptom resolution within just a few days. In general, the studies analyzed presented compelling evidence on the benefit of betahistine when associated with replacement maneuvers to control symptomatic vertigo and reduce episode recurrence which underlines the important role of betahistine in the control of BPPV. A recent systematic review with meta-analysis by Li et al. [35] reviewed the effect of combining betahistine and Epley’s maneuver compared to Epley’s maneuver monotherapy in 860 patients with posterior semicircular canal BPPV, of which 432 were subjected to treatment with betahistine plus Epley’s maneuver and 428 treated with only Epley’s maneuver. Dual therapy was superior in DHI score improvement, with a standardized mean difference of − 0.61 (95% CI − 0.96 to − 0.26 p < 0.001) when compared to Epley’s maneuver monotherapy. However, efficacy rates and recurrence rates did not show statistically significant differences between these groups.

Despite this, the AAO-HNS Foundation Clinical Practice Guideline on BPPV management [36], which was updated in 2017, recommends against the use of betahistine to avoid adverse effects, medication interactions, and altering the diagnostic accuracy during Dix-Hallpike maneuvers due to vestibular suppression.

In peripheral vertigo conditions other than MD or BPPV, most of the studies analyzed demonstrated a positive effect of betahistine in controlling symptoms and frequency of attacks. However, trials with histaminergic drugs such as cinnarizine and dimenhydrinate have shown superiority to betahistine. The combination of such drugs with betahistine has also shown superiority to betahistine alone.

The evidence reviewed in this study seems to indicate that the effect of betahistine on vertigo remains contradictory. While some RCTs show a clear benefit of betahistine in symptomatic vertigo, others show no superiority when compared to other drugs or to placebo/no treatment, which highlights the lack of certainty and heterogeneity of the available evidence. Still, betahistine is a low-cost drug commonly used in clinical practice with minimal side effects (< 10%) [30]; thus, its use may be beneficial and should be considered in the presence of symptomatic vertigo to improve not only symptom control but also the patient’s quality of life, which is of high importance since a vertigo crisis is highly debilitating.

Conclusion

The authors conclude that the available evidence on this subject suggests a potential benefit for betahistine prescription for various peripheral vertigo etiologies (strength of recommendation B). However, additional large-scale studies with validated instruments for vertigo measurement are needed to build robust evidence that establishes a clear effect of betahistine on vertigo.