A total of 1450 patients were screened for eligibility at 17 outpatient sites; 221 patients were randomised at 14 sites. To deal with the missing data structure in the longitudinal individual observations, we used a negative binomial, generalised linear mixed effects model (NB GLMM) that not only yields unbiased parameter estimates when missing observations are missing at random (MAR),46 but also provides reasonably stable results even when the assumption of MAR is violated.47 48. Participants were instructed to record acute attacks of vertigo related to Menieres disease, coexisting symptoms (such as aural fullness, changes in tinnitus, changes in hearing) and other characteristics of their vertigo attack. Of 1450 patients, 1229 (85%) did not pass the screening stage. There are no plans to explicitly involve patients in dissemination. Betahistine alleviates benign paroxysmal positional vertigo (BPPV) through inducing production of multiple CTRP family members and activating the ERK1/2-AKT/PPARy pathway. It was designed as an investigator initiated, prospective, longitudinal, multicentre, double blind, randomised, placebo controlled, three arm, parallel group, phase III superiority trial. There's simply no scientific evidence to support its use for . We assessed safety from reports of adverse events as well as laboratory parameters, vital signs (blood pressure, pulse, height, weight, and body mass index), and physical or neurological examinations. Using the GRADE system, we judged the quality of evidence overall to be low for two outcomes (proportion of patients with improvement and proportion with adverse events).Pooled data showed that the proportion of patients reporting an overall reduction in their vertigo symptoms was higher in the group treated with betahistine than the placebo group: risk ratio (RR) 1.30, 95% confidence interval (CI) 1.05 to 1.60; 606 participants; 11 studies). Accessibility All the uncertainty was almost as stressful as a vertigo attack. See: http://creativecommons.org/licenses/by-nc/3.0/. Statistical analyses were performed using the statistical software package R version 3.1.1.54 We used the R packages lme4 (version lme4_1.1-7) to fit frequentist generalised linear mixed effects models,55 56 ordinal to fit cumulative logit models,57 and mice for multiple imputation techniques applied for key secondary efficacy outcomes.52 53 All statistical tests were two sided, and P<0.05 was considered significant. National guidelines support this use. Betahistine | Prescribing information | Mnire's disease - CKS Is betahistine different to antihistamines? The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2015, Issue 8); PubMed; EMBASE; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. Other reasons (for example, a desire for another treatment option such as an operation; or moving abroad) were named in 158 patients. All patients underwent a standardised physical, neurological, and neuro-orthoptic examination; peripheral vestibulocochlear testing; assessment of medical history (for up to five years before enrolment); laboratory examination; and measurement of blood pressure and heart rate. Patients experiencing chronic digestive problems may lower their dose to the minimum effective range and by taking betahistine with meals. Betahistine is generally well tolerated with a low risk of adverse events. The individual study duration was 12 months: nine months of treatment and three months of follow-up. Secondary outcomes assessed during clinic visitsthat is, both the observer-reported outcome and the quality of life scores, were analysed in a descriptive manner. Additional digestive problems may require that patients consult their physician in order to possibly find a suitable alternative. Below, we reconsider these aspects using the PICO approach (patient, intervention, comparison, outcome) to discuss the strengths and limitations of the BEMED trial. For differences between treatment groups, we used an analysis of covariance (ANCOVA) for absolute change scores, with factor for treatment group and the baseline value as covariates. ordinalregression models for ordinal data, R package version 2014.12-22: Please note: your email address is provided to the journal, which may use this information for marketing purposes. To summarise, the limitations of the evidence base for preventive treatment strategies for Menieres disease include: Predominance of trials investigating short term effects (treatment periods of six months or less), Inclusion criteria of enrolled patients (for instance, no differentiation between patients with the disease and patients with other causes of vertigo), High dropout rates35 with potential for considerable attrition bias, Small trials or few placebo controlled trials36, Varying quality of outcome measures for assessing efficacy (including quality of life scores, functional impairment, disability, and the number and severity of acute attacks of vertigo).33. FOIA Li W, Sun J, Zhao Z, Xu J, Wang H, Ding R, Zhang Y. We wanted to examine whether the percentages of patients with attacks of a longer duration and a higher severity, respectively, were reduced by the assigned treatment. This dose increase was supported by an open, uncontrolled, non-masked study without a placebo arm that compared a high dose regimen of 48 mg three times daily with the recommended standard dose of 16 or 24 mg three times daily.36 This non-interventional study showed that the higher dose was superior to the lower dose, and that the treatment effect of betahistine on the incidence of attacks of vertigo became more prominent over time. An event was defined as end of treatment before day 241 (start of grey region), according to the prespecified minimum exposure to the treatment regimen defined as per protocol and the corresponding definition of a major protocol deviation. Previous and concomitant drug treatments were coded using the World Health Organization Drug Dictionary (version 1 March 2014). The three tinnitus related or vertigo specific quality of life scores remained fairly stable at the end of the treatment period compared with the baseline scores. MS, JW, CSF, CA, and UM contributed to the design of the trial, wrote the study protocol and subsequent amendments, and interpreted the work. Clinical experience and several studies have supported a potential beneficial effect of prophylactic drug treatment with betahistine on the attacks of vertigo as well as on vestibular and, to a lesser degree, audiological symptoms.34 However, according to a Cochrane review of betahistine for Menieres disease or Menieres syndrome,33 there is insufficient evidence to say whether betahistine has any effect. Official answer by Drugs.com Betahistine is used to treat symptoms of Meniere's disease, a condition of the inner ear that can cause symptoms such as dizziness, nausea, vertigo (a spinning sensation), ringing in the ears (tinnitus), and hearing loss. These may include nausea, upset stomach, vomiting, diarrhea and stomach cramping. We used the standard methodological procedures expected by Cochrane. doi: 10.1002/14651858.CD008675.pub2. Christensen RHB. Patients were enrolled in the study from 31 March 2008 (first patient, first visit) to 5 November 2013 (last patient, last visit), including a three month follow-up. On the basis of many years clinical experience, the dose was successively increased to 48 mg three times a day, pointing towards the role of long term treatment (up to 12 months). Typically, attack data were recorded by the patients whenever they experienced vertigo related symptoms. Antihistamine (Oral Route, Parenteral Route, Rectal Route) Treatment can help to ease and prevent symptoms. Even higher doses of up to 480 mg per day have shown benefit for severe cases in a small case series, suggesting a possible effect of high dose regimens in the treatment of Menieres disease.37 The drug seems to retain a good tolerability profile. The package insert for Serc, a trade name for betahistine, states that patients may experience several gastrointestinal side effects 2. Cochrane Database Syst Rev. Some did not meet the inclusion criteria of definite Menieres disease (n=123), fulfilled exclusion criteria (n=173), or could not tolerate or were allergic to betahistine (n=31). Instead, we used the treatment duration (defined as the difference between the end of treatment and the first study drug intake) as a measure of treatment adherence. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. [ ABPI, 2023; BNF, 2023] Hence, patients who prematurely discontinued the study or treatment before month 7 were excluded from the per protocol sample. The package insert for Serc, a trade name for betahistine, states that patients may experience several gastrointestinal side effects 2. We used a closed testing approach to avoid the adjustment of the significance level because of multiple testing. In total, 45 patients were judged ineligible because they fulfilled two of these criteria. NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. government site. Publication RM03/JH17/MK. 2023 Jul 19;14:1175481. doi: 10.3389/fneur.2023.1175481. In particular, these interviews reminded patients to complete their vertigo diary every day and to record any treatment discontinuation, change in relevant concomitant drug treatment, or adverse events they might have experienced in the meantime (which were also documented regularly on the case report forms during each telephone and clinic visit). The majority were at high risk of bias, but in some the risk of bias was unclear. Betahistine (Serc, Betaserc) is used by many people to reduce the frequency and severity of these attacks but there is conflicting evidence relating to its effects. Patients taking betahistine may experience several other side effects ranging from mild to serious. Hence, a sample size of 21 patients in each group would have 80% power to detect the difference between two groups using a two sided Mann-Whitney U test on a 5% significance level. Store below 25 degrees Celsius. Betahistine hydrochloride has been studied extensively in clinical trials and post-marketing research and has proven generally safe and effective, but it may also cause several side effects ranging from mild to serious. How betahistine might have an effect in the prophylactic treatment of Menieres disease is so far unknown. Acute vertigo attacks caused by Menieres disease greatly affect patients quality of life and perceived wellbeing, The diseases natural history is one of remission and recurrence; because participants must first have active vertigo to enrol in a study, spontaneous improvement through regression to the mean is expected, Observational studies or low quality randomised controlled trials of low and moderate betahistine doses have produced contradictory results on treatment efficacy, and have not investigated the effect of an experimental intervention from the patients perspective with respect to vertigo attack prophylaxis, Long term prophylactic treatment with betahistine dihydrochloride (at daily doses 224 mg or 348 mg) does not change the time course of vertigo episodes related to Menieres disease compared with placebo, Placebo intervention as well as betahistine treatment showed the same reduction of attack rates over the studys nine month treatment period, Reliable and valid instruments that measure subjective vertigo symptoms (in particular, vertigo attacks caused by Menieres disease) are lacking; derivation of definite or probable attacks caused by Menieres disease, on the basis of raw patient recordings in vertigo diaries, is methodologically challenging and requires prespecified rules. Betahistine: a medicine to treat Mnire's disease - NHS The overall decline of attacks over time in the three treatment groups was not significantly affected by whether a patient was recruited in a study centre outside of Munich or not. Missing data in randomised controlled trials - a practical guide. This type of dizziness is thought to originate in the inner ear labyrinth or its neural connections. Capsules containing the active ingredient were refilled from original pharmacy packaging into vials under sterile conditions and relabelled by the pharmacy of the university hospital of the University of Heidelberg. In the control group, an identically appearing capsule filled with mannitol and aerosil but not containing any active ingredient was administered as placebo. To deal with missing items for both the dizziness handicap inventory score and the MiniTF12 questionnaire, we derived the mean total scores for the dizziness handicap inventory and the MiniTF12 as secondary outcome variables, averaging for the number of available answers. Written informed consent was obtained from all patients before initiation of the first study specific procedure. doi: 10.1002/14651858.CD008419.pub2. You should seek medical advice in relation to medicines and use only as directed by a healthcare professional. Histamine can cause itching, sneezing, runny nose, and watery eyes. When it's time for you to stop taking opioids, ask for your doctor's help to develop a medication withdrawal plan (called a taper) that gradually reduces the amount of medication you take. Thirdly, it decreases vestibular input in the peripheral vestibular system, with possible involvement with the H3 and H4 receptors. PMID: 24177346 DOI: 10.3233/VES-130496 Abstract Betahistine dihydrochloride (betahistine) is currently used in the management of vertigo and vestibular pathologies with different aetiologies. Other studies have used quality of life scores, functional impairment, and disability instruments. Patients were excluded if they had known contraindications or sensitivity to betahistine, such as bronchial asthma, pheochromocytoma, treatment with other antihistaminic drugs, ulcer of the stomach or duodendum, or severe dysfunction of liver or kidney. What happens when you stop taking letrozole? - Drugs.com The BEMED trial aimed to determine whether treatment with high or low dose betahistine or placebo differed in effectiveness. The possibility of a patient experiencing an episode free year increases as the disease progresses.60 Therefore, assessment of the efficacy of treatments for Menieres disease needs a randomised approach, including a placebo or no treatment (wait and see) control group. According to the protocol, 270 days was the preplanned treatment duration. Web appendix 1 shows a template of the vertigo diary. The principal model was established by use of data from a previous open non-interventional study36 together with statistical methodology that has been published elsewhere.49. Opioid withdrawal can be dangerous, and symptoms can be severe. 2022 Apr 4;55(1):16. doi: 10.1186/s40659-022-00385-3. We saw no evidence for a treatment by time interaction (global testing, likelihood ratio test P=0.759 for FAS population; P=0.493 for per protocol sample), indicating no significant differences in attack rates across the treatment groups. Betahistine for symptoms of vertigo - PubMed The key findings of the BEMED trial are as follows: A significant decline of attack rates in each treatment arm was observed over the nine month treatment period, The effects of two different doses of betahistine could not be distinguished from a patient reported effect caused by placebo intervention in terms of the incidence of attacks as well as vestibular and audiological function and quality of life. Therefore, determination of sample size focused on a two group comparison based on the U test. Adults aged 21-80 years (mean age 56 years) with definite unilateral or bilateral Menieres disease were recruited from March 2008 to November 2012. This optimistic sample size approach was questioned. Am J Transl Res. The duration of exposure to study treatment was similar across the three treatment groups and ranged between a mean of 214 and 224 days for the intention to treat population. A simulation study was performed to calculate a model based proposal for the probability to achieve a better result on betahistine than on placebo. This finding was confirmed when pooling small investigator sites with fewer than 15 randomised patients (P=0.080, global likelihood ratio test). General exclusion criteria were participation in another trial with an investigational drug or device within the past 30 days, previous participation in the present study, or planned participation in another trial. The first drug intake started as soon as possible after receipt of the study medication kits containing the vials during the baseline visit. Table 7 summarises adverse events deemed clinically important. The 15 undocumented days out of the prespecified 90 day assessment period (starting day 181, ending day 270) were considered as missing at random.41. Primary efficacy analysis on full analysis set, plus use of two varying definitions of Menieres attacks as supportive efficacy analyses. According to the consensus document, the variable duration was necessary and sufficient for a Menieres attack to be defined on the basis of the raw diary recordings. Most TEAEs were of mild or moderate intensity. Disclaimer. TEAEs of severe intensity were reported for 20 (27%), 20 (28%), and 19 (26%) patients in the placebo, low dose betahistine, and high dose betahistine groups, respectively. The treatment groups were well balanced for demographics; clinical factors; and tinnitus related, dizziness, and self-assessment scores. It is a commonly experienced symptom and can cause significant problems with carrying out normal activities. Forty treatment emergent serious adverse events (TESAEs) were reported for 15%, 14%, and 14% of patients in the placebo, low dose betahistine, and high dose betahistine groups, respectively. In this figure, an event indicating treatment dropout was defined as end of treatment before day 241 (according to the definition for per protocol). We report the prespecified efficacy and safety analyses at nine months for the BEMED trial. The figure also indicates that about 77% of low dose patients (versus 72% of high dose patients and 70% of placebo patients) were on treatment for at least eight months (241 days). The diagram shows enrolment and primary efficacy endpoints based on patient diaries, from prescreening to data collection; and the extent of exclusions, loss to follow-up, and completeness of diary documentation available across months one to nine. A dose of 24 mg, which is the highest clinically admitted dose, was administered orally two times each day to the low dose group, and 224 mg three times each day were given to the high dose group; both groups received treatment for nine months. The studies varied considerably in terms of types of participants, their diagnoses, the dose of betahistine and the length of time it was taken for, the study methods and the way any improvement in vertigo symptoms was measured. Store in Original Container. "Drug Safety"; Betahistine: A Retrospective Synopsis of Safety Data; Dr. Sabine Jeck-Thole and Dr. Wolfgang Wagner; November 2006. If symptoms persist see your healthcare professional. R: A language and environment for statistical computing. Effects of vestibular rehabilitation, with or without betahistine, on managing residual dizziness after successful repositioning manoeuvres in patients with benign paroxysmal positional vertigo: a protocol for a randomised controlled trial - PMC Journal List BMJ Open v.9 (6); 2019 PMC6589014 Effective at controlling symptoms such as sneezing, itching, watery eyes, and runny nose. The Epley (canalith repositioning) manoeuvre for benign paroxysmal positional vertigo. // Leaf Group Lifestyle. These include a low salt diet and diuretics,8 intratympanic steroid application,9 10 or minimal invasive interventions (such as insertion of a ventilation tube into the tympanic membrane,11 12 endolymphatic sac surgery,13 or pulsed low pressure delivery (using Meniett devices)).14 15 16 17 For patients who do not respond to these treatments, more aggressive procedures can be considered, such as intratympanic application of gentamycin,18 19 plugging of the semicircular canal, labyrinthectomy, or neurectomy.20 21 22 23 However, these interventions are irreversible and could damage the cochlear and vestibular organ; furthermore, a recent Cochrane review could not show any evidence of benefit in a surgical approach.24 25. Re: Efficacy and safety of betahistine treatment in patients with Betahistine is a strong H3 antagonist and a weak H1 agonist26 with three sites of action. Pharmacokinetic Profile of Betahistine With and Without Selegiline in Healthy Volunteers (PK-BesT) The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Wegner I, Hall DA, Smit AL, McFerran D, Stegeman I. Cochrane Database Syst Rev. PMID: 15587054 Abstract A 73-year-old man was admitted because of delirium that had already persisted for 5 days. The main result of no treatment induced changes in attack rates was therefore confirmed. Firstly, it increases dose-dependent cochlear blood flow,27 mainly via the H3 receptor as an inverse agonist.28 Because betahistine has a strong first pass effect and is metabolised in the liver into three metabolites, not only betahistine but also its major metabolite aminoethylpyridine increases cochlear blood flow.29 Secondly, betahistine increases histamine turnover in the central nervous and vestibular system, also mainly via the H3 receptor. These may include nausea, upset stomach, vomiting, diarrhea and stomach cramping. Of these evaluated vertigo episodes, 1833 (37%) could be classified at least as an attack of postural vertigo (P attack); 2633 (53%) were classified as an attack of rotatory vertigo (R attack) and were interpreted as the most severe type of vertigo attack. CSF and CA evaluated the original patient ratings provided by paper based vertigo diaries. Study participants were recruited by the outpatient dizziness services in the neurology department or the ear, nose, and throat department of 14 German university hospitals. Betahistine for Mnire's disease or syndrome - PMC Opiates come from opium, which can be produced naturally from poppy plants; opioids are chemically synthesized opiate-like drugs. During the trial, it became apparent that dropouts and incomplete diary documentation created missing data that could not be adequately handled by the intended robust comparison. It could lead to an improvement of labyrinthine microcirculation, thereby rebalancing the production and resorption of endolymph. Her institution has received a grant from GSK for a study on the microbiology of acute tympanostomy tube otorrhoea. A total of 221 eligible patients at 14 study sites were randomly assigned in a 1:1:1 ratio to receive either high dose or low dose betahistine, or placebo for nine months (fig 1). Patients aged 18-80 years were eligible for enrolment if they presented with two or more definitive spontaneous episodes of vertigo of at least 20 minutes duration, had audiometrically documented hearing loss on at least one occasion, and tinnitus or aural fullness in the treated ear, excluding other possible causes of vertigo. Treatment was well tolerated with no unexpected safety findings. At the end . The dose of betahistine in these studies varied between 16 and 72 mg per day, which might explain the differences in symptom relief observed. We assumed a dropout rate of about 37%. Main results: Mnire's disease is characterized by recurrent episodes of vertigo, hearing loss, and tinnitus, often with a feeling of fullness in the ear. Carpenter JR, Kenward MG. The largest site was the sponsors site located at the Department of Neurology, University Hospital and German Center of Vertigo and Balance Disorders (DSGZ) in Munich, Germany. On the one hand, non-randomised studies tend to show larger treatment effects compared to randomised controlled trials, and tend to overestimate the magnitude of a potential treatment effect.63 On the other hand, there is the question of whether bias alone can explain the large effect differences between observational and experimental studies. In previous trials, the frequency of vertigo spells was mainly documented by a symptom report card using a Likert scale of 0 (no vertigo) to 4 (worst vertigo attack ever) to characterise a vertigo symptom and to perform a vertigo control categorisation as a simple and convenient summary statistic of a patients vertigo experience.15. Betahistine dihydrochloride tablets were over-encapsulated with mannitol and aerosil as filling material. Leave 6 to 8 hours between doses. Ten patients (n=5 placebo; n=2 low dose betahistine; n=3 high dose betahistine) submitted no diary for the entire study period for various reasons (no specific reasons (n=1), loss to follow-up (n=3), informed consent withdrawn (n=4), analysis dropout due to adverse events (n=2)). Figure 1 shows the flow of participants through the trial together with the completeness of diary information over the entire nine month treatment period. Before Treatment compliance based on drug accountability was not calculated owing to insufficient data quality and a high proportion of missing data. Will it affect my contraception? This review examines whether betahistine is more effective than a placebo at treating symptoms of vertigo from different causes. Eye irritation and palpitations were more commonly reported with high dose betahistine than with low dose betahistine and placebo. Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat. Kiran Hussain has no interests to declare. MethodsThe BEMED trial is a multicentre, double blind, randomised, placebo controlled, three arm, parallel group, phase III, dose defining superiority trial conducted in 14 German tertiary referral centres (for neurology or ear, nose, and throat). Overall, about half of the randomised patients were female; the total age range was 21-80 years. If you are unable to import citations, please contact The study was supported by grants from the German Federal Ministry of Education and Research (Bundesministerium fr Bildung und Forschung (BMBF), support code 01KG0708; sponsors protocol code no 04T-617). To approximate the robust comparison as mentioned at the beginning of this section, we averaged the individual attack rates over the prespecified assessment period (months seven to nine) to derive a (marginal) population based, mean attack rate per 30 days for each treatment arm. The package insert for Serc states that patients may experience nervous system side effects, including convulsions, daytime sleepiness, confusion and hallucinations 2. Patients experiencing chronic digestive problems may lower their dose to the minimum effective range and by taking betahistine with meals. Copyright 2023 Leaf Group Ltd., all rights reserved. A random intercept with a standard deviation of 0.8 and a measurement error of 0.5 was assumed. In figure 3, the upper panels show the observed individual profiles of monthly incidences of attacks caused by Menieres disease during the nine month treatment period, stratified by treatment group. Selection criteria: Betahistine in Mnire's Disease or Syndrome: A Systematic Review About betahistine Who can and cannot take it How and when to take it Side effects Pregnancy, breastfeeding and fertility Taking betahistine with other medicines and herbal supplements Common questions
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