Pharmacological interventions for acute attacks of vestibular migraine

Abstract Background Vestibular migraine is a form of migraine where one of the main features is recurrent attacks of vertigo. These episodes are often associated with other features of migraine, including headache and sensitivity to light or sound. The unpredictable and severe attacks of vertigo can lead to a considerable reduction in quality of life. The condition is estimated to affect just under 1% of the population, although many people remain undiagnosed. A number of pharmacological interventions have been used, or proposed to be used, at the time of a vestibular migraine attack to help reduce the severity or resolve the symptoms. These are predominantly based on treatments that are in use for headache migraine, with the belief that the underlying pathophysiology of these conditions is similar. Objectives To assess the benefits and harms of pharmacological interventions used to relieve acute attacks of vestibular migraine. Search methods The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 23 September 2022. Selection criteria We included randomised controlled trials (RCTs) and quasi‐RCTs in adults with definite or probable vestibular migraine comparing triptans, ergot alkaloids, dopamine antagonists, antihistamines, 5‐HT3 receptor antagonists, gepants (CGRP receptor antagonists), magnesium, paracetamol or non‐steroidal anti‐inflammatory drugs (NSAIDs) with either placebo or no treatment. Data collection and analysis We used standard Cochrane methods. Our primary outcomes were: 1) improvement in vertigo (assessed as a dichotomous outcome ‐ improved or not improved), 2) change in vertigo (assessed as a continuous outcome, with a score on a numerical scale) and 3) serious adverse events. Our secondary outcomes were: 4) disease‐specific health‐related quality of life, 5) improvement in headache, 6) improvement in other migrainous symptoms and 7) other adverse effects. We considered outcomes reported at three time points: < 2 hours, 2 to 12 hours, > 12 to 72 hours. We used GRADE to assess the certainty of evidence for each outcome. Main results We included two RCTs with a total of 133 participants, both of which compared the use of triptans to placebo for an acute attack of vestibular migraine. One study was a parallel‐group RCT (of 114 participants, 75% female). This compared the use of 10 mg rizatriptan to placebo. The second study was a smaller, cross‐over RCT (of 19 participants, 70% female). This compared the use of 2.5 mg zolmitriptan to placebo. Triptans may result in little or no difference in the proportion of people whose vertigo improves at up to two hours after taking the medication. However, the evidence was very uncertain (risk ratio 0.84, 95% confidence interval 0.66 to 1.07; 2 studies; based on 262 attacks of vestibular migraine treated in 124 participants; very low‐certainty evidence). We did not identify any evidence on the change in vertigo using a continuous scale. Only one of the studies assessed serious adverse events. No events were noted in either group, but as the sample size was small we cannot be sure if there are risks associated with taking triptans for this condition (0/75 receiving triptans, 0/39 receiving placebo; 1 study; 114 participants; very low‐certainty evidence). Authors' conclusions The evidence for interventions used to treat acute attacks of vestibular migraine is very sparse. We identified only two studies, both of which assessed the use of triptans. We rated all the evidence as very low‐certainty, meaning that we have little confidence in the effect estimates and cannot be sure if triptans have any effect on the symptoms of vestibular migraine. Although we identified sparse information on potential harms of treatment in this review, the use of triptans for other conditions (such as headache migraine) is known to be associated with some adverse effects. We did not identify any placebo‐controlled randomised trials for other interventions that may be used for this condition. Further research is needed to identify whether any interventions help to improve the symptoms of vestibular migraine attacks and to determine if there are side effects associated with their use.


A B S T R A C T Background
Vestibular migraine is a form of migraine where one of the main features is recurrent attacks of vertigo.These episodes are o en associated with other features of migraine, including headache and sensitivity to light or sound.The unpredictable and severe attacks of vertigo can lead to a considerable reduction in quality of life.The condition is estimated to a ect just under 1% of the population, although many people remain undiagnosed.A number of pharmacological interventions have been used, or proposed to be used, at the time of a vestibular migraine attack to help reduce the severity or resolve the symptoms.These are predominantly based on treatments that are in use for headache migraine, with the belief that the underlying pathophysiology of these conditions is similar.

Objectives
To assess the benefits and harms of pharmacological interventions used to relieve acute attacks of vestibular migraine.

Search methods
The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov;ICTRP and additional sources for published and unpublished trials.The date of the search was 23 September 2022.

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Cochrane Database of Systematic Reviews -whether the treatments might cause any harm.

What did we do?
We searched for studies in adults that compared di erent medications to either no treatment or placebo (dummy) treatment.We used standard methods to assess the quality of the evidence.We rated our confidence in the evidence, based on factors such as study methods, the number of participants in them and the consistency of findings across studies.

What did we find?
We found two studies, which included a total of 133 people (75% female).Both studies looked at a specific type of medication known as triptans.The evidence showed that taking a triptan may make very little di erence to the number of people whose vertigo symptoms improved.However, there are problems with the evidence, which means that we are uncertain about this result.
One of the studies looked at side e ects related to this medication and found that nobody developed serious side e ects.However, as this study only included 114 people, it was too small to assess this properly.Therefore, we are not sure whether there may be a risk of harms from taking these treatments.

What are the limitations of the evidence?
We have very little confidence in the evidence because the studies conducted were small.There were also some problems with the conduct of the studies, which means that the results may be unreliable.We know that triptans may cause some side e ects in people who use them for headache migraine, but we were not able to find out if these side e ects are also common when the medications are used for vestibular migraine.

⊕⊝⊝⊝
Very low 1,2,3   Triptans may have little or no effect on improvement in vertigo at up to 2 hours, but the evidence is very uncertain.

Change in vertigo
No studies reported this outcome.
Study population Serious adverse events 0 per 1000 0 per 1000

⊕⊝⊝⊝
Very low 1,3,4   The evidence is very uncertain about the effect of triptans on serious adverse events.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

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B A C K G R O U N D Description of the condition
Vestibular migraine is a form of migraine in which a prominent symptom, o en the predominant symptom, is recurrent attacks of vertigo (Dieterich 1999;Lempert 2009).These episodes of vertigo are associated with other headache migraine features, such as headache or sensitivity to light or sound.
The diagnosis of vestibular migraine is challenging because of the overlap of some symptoms with both other balance disorders (such as Ménière's disease) and with headache migraine.People su ering from headache migraine may experience occasional vestibular symptoms, but this does not amount to a diagnosis of 'vestibular migraine'.
There is now an agreed international classification system that includes categories for 'definite' and 'probable' vestibular migraine (Lempert 2012; described in Appendix 1).In brief, a definite diagnosis of vestibular migraine requires at least five episodes of vestibular symptoms (of moderate to severe intensity) lasting between five minutes and 72 hours.At least half of the episodes must be associated with migrainous features (such as headache, photophobia, phonophobia or a visual aura) and individuals must also have a history of migraine The pathophysiology of vestibular migraine is still uncertain, but it seems likely to involve similar mechanisms to those of headache migraine.These include activation of the trigeminovascular system (TGVS), which receives nociceptive signals from the large intracranial vessels and the dura (Bernstein 2012).Activation of the TGVS results in neuronal stimulation within parts of the brain involved in pain perception and sensory processing (including the thalamus and the periaqueductal grey) and also causes the release of vasoactive neuropeptides, such as calcitonin gene-related peptide (CGRP).These, in turn, cause dilatation of the meningeal vessels, extravasation of fluid from the vasculature and release of other inflammatory substances in the dura (Pietrobon 2003), creating a cycle of nerve stimulation.Cortical hyperexcitability, and subsequent cortical spreading depolarisation, also occurs.This may account for the aura or visual symptoms experienced by many migraineurs (Hadjikhani 2001).There may be overlap between headache migraine pathways and those of the vestibular system, accounting for the balance symptoms.For example, the trigeminovascular system receives pain signals from nerves of the dura mater and large intracranial blood vessels, but also from vessels of the inner ear (Vass 1998).Abnormal thalamic activation in response to vestibular stimulation has also been identified in patients with vestibular migraine (Russo 2014).CGRP itself is implicated in vestibular migraine, along with headache migraine, and increased CGRP levels have been linked to the development of symptoms in migraine (Villalón 2009).Work is ongoing into the relevance of CGRP in vestibular migraine, and whether pharmacological targeting of this molecule and its receptors will a ect the condition.
The consequences of vestibular migraine for the individual may be considerable.The unpredictable, disabling attacks of spinning sensory disorientation can be distressing and debilitating in equal measure.This has a considerable impact on engagement with dayto-day activities and overall quality of life.

Description of the intervention
Current pharmacological treatments for people with vestibular migraine may be prophylactic, or used to treat an acute attack.Many are based on interventions that have been widely used to treat headache migraine.This review is focused on pharmacological interventions that are taken to relieve an attack.

How the intervention might work
For many of these interventions, the precise mechanism of action is uncertain.However, the use of these medications for headache migraine attacks has resulted in their uptake for vestibular migraine.Interventions may target the underlying processes that are thought to trigger vestibular migraine, or treat the associated symptoms, including headache, nausea and vomiting.
Triptans are commonly used as a treatment for headache migraine.They act as agonists at serotonergic 5HT1B/D receptors.Their e ects include vasoconstriction of intracranial vessels, as well as altering the release of other neurotransmitters, which may interrupt the early pathways involved in a migraine attack (Tepper 2002).

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Cochrane Database of Systematic Reviews
Ergot alkaloids (such as dihydroergotamine or ergotamine) were the first specific anti-migraine therapy available.Ergot alkaloids target serotonergic receptors, but unlike triptans they also a ect dopamine and norepinephrine receptors (reviewed in Tfelt-Hansen 2000 andBigal 2003).With the emergence of the triptans, ergot alkaloids are used less o en in the treatment of migraine.
Dopamine antagonists have been suggested to have some e icacy in treating acute attacks of migraine, but it is not clear whether this is dependent on their e ects on dopamine receptors, or due to some other mechanism (reviewed in Akerman 2007).
Antihistamines have been used for their well-known antiemetic and anti-vertiginous properties.They are widely used for management of acute vestibular disorders (Hunter 2022).5-HT3 receptor antagonists are also primarily used for their anti-emetic e ects.
CGRP is a neurotransmitter found in numerous locations within the central nervous system and peripheral sensory nerves.Levels of this neurotransmitter have been found to be elevated during headache migraine episodes (Goadsby 1990), and to decrease with the use of triptans (Goadsby 1993).Gepants are novel molecules that target the calcitonin gene-related peptide receptor, and are increasingly used for headache migraine (reviewed in Moreno-Ajona 2020).
Magnesium has also been suggested to be of benefit in acute headache migraine episodes (Bigal 2002), although the mechanism of action is unclear.
A variety of analgesics have been used for migraine attacks, including paracetamol and NSAIDs.They may be e ective for headache symptoms, but it is uncertain whether they have any benefit for vestibular symptoms.Ca eine is sometimes used in conjunction with analgesics to promote pain relief (Derry 2014a).
As well as their analgesic properties, NSAIDs may have additional e ects on the underlying pathophysiology of migraine (reviewed in Pardutz 2010).

Why it is important to do this review
Balance disorders can be di icult to diagnose and treat.There are few specific diagnostic tests, a variety of related disorders and a limited number of interventions that are known to be e ective.
To determine which topics within this area should be addressed with new or updated systematic reviews, we conducted a scoping and prioritisation process, involving stakeholders (https:// ent.cochrane.org/balance-disorders-ent).Vestibular migraine was ranked as one of the highest priority topics during this process (along with persistent postural-perceptual dizziness and Ménière's disease).
The impact of vestibular migraine is considerable, with 40% of su erers reporting sickness from work, and over 70% reporting the impact of their symptoms on daily activities as either moderate or severe (Neuhauser 2006).At present, there are no national or international guidelines to inform the management of this condition, therefore up-to-date, reliable evidence syntheses are required to help patients and healthcare professionals determine the benefits and harms of di erent interventions used for the condition.

O B J E C T I V E S
To assess the benefits and harms of pharmacological interventions used to relieve acute attacks of vestibular migraine.

M E T H O D S
Criteria for considering studies for this review

Types of studies
We included randomised controlled trials (RCTs) and quasirandomised trials (where trials were designed as RCTs, but the sequence generation for allocation of treatment used methods such as alternate allocation, birth dates etc).
We planned to include cross-over RCTs or cluster-RCTs, providing we could appropriately account for the clustering in the data analysis (according to methods described in the Cochrane Handbook for Systematic Reviews of Interventions) (Handbook 2021, also see Unit of analysis issues).

Types of participants
We included studies that recruited participants with a diagnosis of either definite or probable vestibular migraine, according to the International Headache Society (IHS) and Bárány Society criteria (see Appendix 1).We also included studies that used other, established criteria, for example those of Neuhauser 2001 (see Appendix 2).
If studies had recruited participants with a variety of diagnoses (e.g.vestibular migraine and headache migraine) we planned to include the study if either: • the majority of participants (≥ 90%) had a diagnosis of vestibular migraine; or • subgroup data were available that allowed us to identify data relevant specifically to those with vestibular migraine.
However, we did not identify any studies that this applied to -both included studies specifically recruited individuals with a diagnosis of vestibular migraine.
Ca eine is frequently used in combination with analgesics.If we had identified studies where a combination of an analgesic and ca eine were used then we planned to include these as part of the interventions listed above, and to explore whether there may be additional e ects from the ca eine using subgroup analysis.However, this was not necessary.

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Concurrent treatments
There were no limits on the type of concurrent treatments used, providing these were used equally in each arm of the study.We planned to pool studies that included concurrent treatments with those where participants did not receive concurrent treatment, but to conduct subgroup analysis to determine whether the e ect estimates may be di erent in those receiving additional treatment.Again, this was not necessary, as neither study used any concurrent treatments.

Types of outcome measures
We assessed outcomes at the following time points: • up to 2 hours; • > 2 to 12 hours; • > 12 to 72 hours.
An exception was adverse event data, where we used the longest time period of follow-up.
We searched the COMET database for existing core outcome sets of relevance to vestibular migraine and vertigo, but were unable to find any published core outcome sets.We therefore conducted a survey of individuals with experience of (or an interest in) balance disorders to help identify the outcomes that should be prioritised.This online survey was conducted with the support of the Ménière's Society and the Migraine Trust, and included 324 participants, who provided information regarding priority outcomes.The review author team used the results of this survey to inform the choice of outcome measures in this review.
We analysed the following outcomes in the review, but we did not use them as a basis for including or excluding studies.

Primary outcomes
• Improvement in vertigo • Measured as a dichotomous outcome (improved/not improved), according to self-report, or according to a change of a specified score (as described by the study authors) on a vertigo rating scale.

• Change in vertigo
• Measured as a continuous outcome, to identify the extent of change in vertigo symptoms.

• Serious adverse events
• Including any event that caused death, was life-threatening, required hospitalisation, resulted in disability or permanent damage, or in congenital abnormality.Measured as the number of participants who experienced at least one serious adverse event during the follow-up period.

Secondary outcomes
• Disease-specific health-related quality of life

Search methods for identification of studies
The Cochrane ENT Information Specialist conducted systematic searches for randomised controlled trials and controlled clinical trials.There were no language, publication year or publication status restrictions.The date of the search was 23 September 2022.

Electronic searches
The Information Specialist searched:

Searching other resources
We scanned the reference lists of identified publications for additional trials and contacted trial authors if necessary.In addition, the Information Specialist searched Ovid MEDLINE to retrieve existing systematic reviews relevant to this systematic review, so that we could scan their reference lists for additional trials.The Information Specialist also ran non-systematic searches of Google Scholar to identify trials not published in mainstream journals.
We did not perform a separate search for adverse e ects.We considered adverse e ects described in included studies only.

Selection of studies
At least two review authors or coworkers (of SC, AD, KG, LHK, KW) independently screened the titles and abstracts using Covidence to identify studies that may be relevant for this review.Any discrepancies were resolved by consensus, or by retrieving the full text of the study for further assessment.
We obtained the full text for any study that may have been relevant and two authors (of AD, KG, LHK, KW) again independently checked this to determine whether it met the inclusion criteria for the review.Any di erences were resolved by discussion and consensus, or through recourse to a third author if necessary.
We have listed as excluded any studies that were retrieved in full text but subsequently deemed to be inappropriate for the review (according to the inclusion/exclusion criteria), according to the main reason for exclusion.
The unit of interest for the review was the study, therefore multiple papers or reports of a single study were planned to be grouped together under a single reference identification.We recorded the study selection process in su icient detail to complete a PRISMA flow diagram (see Figure 1) and the Characteristics of excluded studies table.

Screening eligible studies for trustworthiness
We assessed all studies meeting our inclusion criteria for trustworthiness using a screening tool developed by Cochrane Pregnancy and Childbirth.This tool includes specified criteria to identify studies that are considered su iciently trustworthy to be included in the review (see Appendix 4).If any studies were assessed as being potentially 'high risk', we planned to contact the study authors to obtain further information or address any concerns.We planned to exclude 'high risk' studies from the main analyses of the review if we were unable to contact the authors, or there was persisting uncertainty about the study, and only include studies with concerns as part of a sensitivity analysis (see Sensitivity analysis).The process is outlined in Figure 2.

Figure 2. The Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool
The studies included in this review were not considered to be at high risk when using the trustworthiness tool.We did not identify any additional studies that we excluded on this basis.

Data extraction and management
At least two review authors (of AD, LHK, KW) independently extracted outcome data from each study using a standardised data collection form.Any discrepancies in the data extracted by the two authors was checked against the original reports, and di erences were resolved through discussion and consensus, with recourse to a third author where necessary.
We included key characteristics of the studies, including the following information: • study design, duration of the study, number of study centres and location, study setting and dates of the study; • information on the participants, including the number randomised, those lost to follow-up or withdrawn, the number analysed, the age of participants, gender, features of the condition (e.g.probable or definite vestibular migraine), diagnostic criteria used, inclusion and exclusion criteria for the individual studies; • details of the intervention, comparator, and concomitant treatments or excluded medications; • the outcomes specified and reported by the study authors, including the time points; • funding for the study and any conflicts of interest for the study authors; • information required to assess the risk of bias in the study, and to enable GRADE assessment of the evidence.
Once the extracted data were checked and any discrepancies were resolved, a single author (KW) transferred the information to Review Manager 5 (RevMan 2020).
The primary e ect of interest for this review was the e ect of treatment assignment (which reflects the outcomes of treatment for people who were assigned to the intervention) rather than a per protocol analysis (the outcomes of treatment only for those

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Cochrane Database of Systematic Reviews who completed the full course of treatment as planned).For the outcomes of interest in this review, we extracted the findings from the studies on an available case basis, i.e. all available data from all participants at each time point, based on the treatment to which they were randomised.This was irrespective of adherence, or whether participants had received the intervention as planned.
In addition to extracting pre-specified information about study characteristics and aspects of methodology relevant to risk of bias, we extracted the following summary statistics for each study and outcome: • For binary data: we extracted information on the number of participants experiencing an event, and the number of participants assessed at that time point.• For ordinal scale data: some data were collected by the study authors with an ordinal scale (a symptom rating scale of 0 to 3).However, the authors of both studies presented the results as binary data (improved/not improved), therefore we extracted the results as above.• We did not identify any continuous data or time-to-event data for this review.
If necessary, we converted data found in the studies to a format appropriate for meta-analysis, according to the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2021).
We pre-specified time points of interest for the outcomes in this review.Where studies reported data at multiple time points, we took the longest available follow-up point within each of the specific time frames.For example, if a study reported an outcome at three hours and five hours of follow-up then the five-hour data would have been included for the time point more than two to six hours.

Assessment of risk of bias in included studies
Two authors (of AD, LHK, KW) undertook assessment of the risk of bias of the included studies independently, with the following taken into consideration, as guided by the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011).
We used the Cochrane risk of bias tool (Handbook 2011), which involves describing each of these domains as reported in the study and then assigning a judgement about the adequacy of each entry: 'low', 'high' or 'unclear' risk of bias.

Measures of treatment e ect
We summarised the e ects of binary outcomes (e.g.serious adverse e ects) as risk ratios (RR) with 95% confidence intervals (CIs).For the key outcomes that we present in the summary of findings tables, we have also expressed the results as absolute numbers based on the pooled results, and compared to the assumed risk.

Unit of analysis issues
The studies included in this review both had unit of analysis issues.
The first study involved participants taking medication up to three times (for three separate attacks of vestibular migraine) over the course of the study (NCT02447991).The response to treatment was recorded for each attack.This led to two concerns with the data.Firstly, the data from di erent attacks in the same individual are not independent -an individual who responds to treatment for one attack may be more likely to respond again.Secondly, individuals experienced di erent numbers of attacks over the course of the study.A participant who experienced just one attack would only contribute one data point to the results, whilst an individual who experienced three attacks would contribute three (correlated) data points.This skews the overall result towards the outcome for people who su ered more frequent attacks, which may not be relevant for the whole population of people with vestibular migraine.
The second study was a cross-over trial (Neuhauser 2003).Data were reported as the response to treatment per attack, and this study included a total of 17 attacks experienced by 10 participants.Attacks experienced by the same individual cannot be regarded as independent.Ideally, results from this study would be analysed using a paired analysis (where each participant acts as their own control) according to the methods stated in the Handbook 2021.However, insu icient data were reported to allow this.We have therefore analysed the data as if they were independent, but acknowledge that this may lead to some inaccuracy in the results.
We took advice from the Cochrane Methods Support Unit regarding these issues.Given that the data available for this review were sparse, they considered it acceptable to include these data in the review, but highlight the limitations of the analysis, and take this into account when using GRADE to assess the certainty of the analysis.

Dealing with missing data
We planned to contact study authors via email whenever the outcome of interest was not reported, if the methods of the study suggested that the outcome had been measured.We did the same if not all data required for meta-analysis were reported (for example, standard deviations), unless we were able to calculate them from other data reported by the study authors.

Assessment of heterogeneity
We assessed clinical heterogeneity by examining the included studies for potential di erences between them in the types of participants recruited, interventions or controls used and the outcomes measured.
We used the I 2 statistic to quantify inconsistency among the studies in each analysis.We also considered the P value from the Chi 2 test.

Assessment of reporting biases
We assessed reporting bias as within-study outcome reporting bias and between-study publication bias.

Outcome reporting bias (within-study reporting bias)
We assessed within-study reporting bias by comparing the outcomes reported in the published report against the study Cochrane Database of Systematic Reviews protocol or trial registry, whenever this could be obtained.If the protocol or trial registry entry was not available, we compared the outcomes reported to those listed in the methods section.If results are mentioned but not reported adequately in a way that allows analysis (e.g. the report only mentions whether the results were statistically significant or not), bias in a meta-analysis is likely to occur.We then sought further information from the study authors.
If no further information could be found, we noted this as being a 'high' risk of bias with the risk of bias tool.If there was insu icient information to judge the risk of bias we noted this as an 'unclear' risk of bias (Handbook 2011).

Publication bias (between-study reporting bias)
We planned to assess funnel plots to identify the likelihood of unpublished data, however we did not identify su icient studies to be able to do this.We also planned to report on whether there were any studies identified through trial registries and other sources (Searching other resources), with unpublished reports.However, we did not identify any unpublished trials.

Meta-analysis of numerical data
Where possible and appropriate (where participants, interventions, comparisons and outcomes were su iciently similar in the studies identified) we conducted a quantitative synthesis of results, using RevMan 2020.We anticipated that the underlying e ect of the intervention may vary between studies, as there were likely to be di erences between participants, settings and the interventions used for each study.We therefore used a random-e ects method for meta-analysis.We explored whether the use of a fixed-e ect model substantially altered the e ect estimates (see Sensitivity analysis).
For dichotomous data, we analysed treatment di erences as a risk ratio (RR) calculated using the Mantel-Haenszel methods.

Synthesis using other methods
If we were unable to pool numerical data in a meta-analysis for one or more outcomes we planned to provide a synthesis of the results using alternative methods, following the guidance in Chapter 12 of the Handbook 2021.However, this was not necessary.

Subgroup analysis and investigation of heterogeneity
If statistical heterogeneity was identified for any comparisons, we planned to assess this considering the following subgroups: • Di erent types of intervention, within a specific group.
• Use of any concomitant treatment.
• Diagnosis of vestibular migraine.
• Age of the participants.
• Sex of the participants.
However, due to the paucity of data available, and the few metaanalyses included in this review, we did not carry out any subgroup analysis.
For the outcome 'improvement of other migrainous symptoms' we planned to pool di erent symptoms (such as nausea and vomiting, photophobia and phonophobia, visual aura) and assess this as a composite measure.However, as we only identified a single study that assessed these outcomes, we have presented them as separate measures.

Sensitivity analysis
As few studies were identified for meta-analysis, the randome ects model may provide an inaccurate measure of the betweenstudies variance.Therefore, we explored the impact of using a fixede ect model using a sensitivity analysis.
If there was uncertainty over the diagnostic criteria used for participants in the studies (for example, if it was not clear whether participants were diagnosed using criteria analogous to the IHS-Bárány Society criteria) then we planned to explore this by including/excluding those studies from the analysis.However, this was not necessary.
We used the Cochrane Pregnancy and Childbirth Screening Tool to identify any studies where there were concerns over the data available.We planned to exclude any studies that we identified as high risk with this tool from the main analyses in the review, but we intended to explore the impact of including the data from these studies through a sensitivity analysis.Again, as we did not exclude any studies on the basis of this tool, no sensitivity analysis was required.

Summary of findings and assessment of the certainty of the evidence
Two independent authors (KG, KW) used the GRADE approach to rate the overall certainty of evidence using GRADEpro GDT (https:// gradepro.org/)and the guidance in Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2021).Disagreements were resolved through discussion and consensus.The certainty of evidence reflects the extent to which we are confident that an estimate of e ect is correct, and we applied this in the interpretation of results.There are four possible ratings: high, moderate, low and very low.A rating of high certainty of evidence implies that we are confident in our estimate of e ect and that further research is very unlikely to change our confidence in the estimate of e ect.A rating of very low certainty implies that any estimate of e ect obtained is very uncertain.
The GRADE approach rates evidence from RCTs that do not have serious limitations as high certainty.However, several factors can lead to the downgrading of the evidence to moderate, low or very low.The degree of downgrading is determined by the seriousness of these factors: • Study limitations (risk of bias): • This was assessed using the rating from the Cochrane risk of bias tool for the study or studies included in the analysis.
We rated down either one or two levels, depending on the number of domains that had been rated at high or unclear risk of bias.• Inconsistency: • This was assessed using the I 2 statistic and the P value for heterogeneity for all meta-analyses, as well as by visual inspection of the forest plot.For results based on a single study we rated this domain as no serious inconsistency.• Indirectness of evidence: • We took into account whether there were concerns over the population included in the study or studies for each Cochrane Database of Systematic Reviews outcome, as well as whether additional treatments were o ered that may impact on the e icacy of the intervention under consideration.• Imprecision: • We took into account the sample size and the width of the confidence interval for each outcome.If the sample size did not meet the optimal information size (i.e.< 400 people for continuous outcomes or < 300 events for dichotomous outcomes), or the confidence interval crossed the small e ect threshold we rated down one level.If the sample size did not meet the optimal information size and the confidence interval included both potential harm and potential benefit we rated down twice.We also rated down twice for very tiny studies (e.g. 10 to 15 participants in each arm), regardless of the estimated confidence interval.• Publication bias: • We considered whether there were likely to be unpublished studies that may impact on our confidence in the results obtained.
We used a minimally contextualised approach, and rated the certainty in the interventions having an important e ect (Zeng 2021).Where possible, we used agreed minimally important di erences (MIDs) for continuous outcomes as the threshold for an important di erence.Where no MID was identified, we provide an assumed MID based on agreement between the authors.For dichotomous outcomes, we looked at the absolute e ects when rating imprecision, but also took into consideration the GRADE default approach (rating down when a RR crosses 1.25 or 0.80).
We have justified all decisions to downgrade the certainty of the evidence using footnotes, and added comments to aid the interpretation of the findings, where necessary.
We prepared a separate summary of findings table for the main comparison: • triptans versus no intervention/placebo.
We included all primary outcomes in the summary of findings table.
We prioritised outcomes at the time point 'up to two hours' for presentation in the table.We have also included a full GRADE profile for all results (Table 1).

Results of the search
The searches in September 2022 retrieved a total of 1186 records.This reduced to 558 a er the removal of duplicates.We screened the titles and abstracts of these 558 records.We discarded 548 records and assessed 10 full-text records, which were linked to nine studies.
We excluded seven studies (eight records) with reasons recorded in the review (see Excluded studies).We included two completed studies (two records) where results were available.We did not identify any ongoing studies for this review.
A flow chart of study retrieval and selection is provided in Figure 1.

Included studies
We included two RCTs in this review (NCT02447991; Neuhauser 2003).Details of the individual studies can be found in the Characteristics of included studies.

Study design
Both studies were described as randomised controlled trials and included two arms, comparing an active medication to a placebo.
One study used a cross-over method, where participants received the alternate intervention a er their first attack (Neuhauser 2003).
The duration of treatment and follow-up was not reported.Although 19 participants were recruited into this study, only 10 participants experienced a vestibular migraine attack during the course of the study.
The NCT02447991 study aimed to follow up participants until they had experienced three attacks of vestibular migraine (over a period of up to four years).Participants were randomised to use either triptan or placebo, but were asked to treat up to three attacks with the same medication.NCT02447991 was also the largest study, although there was a discrepancy in the reported numbers of participants from two versions of the results (the trial registry states 134 participants; the accompanying statistical analysis plan, which includes the results, states 114 participants).
Further details on the analysis of data from these studies, to account for the cross-over design and multiple data points from the same individual, are described in Unit of analysis issues, above.

Participants
Both studies recruited adult participants with a diagnosis of vestibular migraine.

Diagnosis of vestibular migraine
NCT02447991 used the IHS criteria for the diagnosis of definite vestibular migraine (see Appendix 1 for details).Neuhauser 2003 used the criteria for definite vestibular migraine outlined in Neuhauser 2001 (see Appendix 2 for details).

Features of vestibular migraine
Neither of the included studies gave details on the duration of the disease.All participants had to have experienced at least two attacks of vestibular migraine in the 12 months prior to entry to the study, but no additional information was provided on the frequency of attacks at baseline.

Interventions and comparisons
Both studies evaluated triptans.One evaluated zolmitriptan (Neuhauser 2003) and the other evaluated rizatriptan (NCT02447991).

Comparison 1: Triptans versus placebo
Neuhauser 2003 used 2.5 mg zolmitriptan to be taken orally when symptoms of vestibular migraine were moderate or severe.
A second dose of study medication (either triptan or placebo, accordingly) or a rescue medication (dimenhydrinate 150 mg for vertigo and paracetamol 500 mg for headache) could be taken a er two hours, if required.NCT02447991 used one capsule of 10 mg rizatriptan to be taken orally during an acute episode.

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Improvement in vertigo
This was assessed by both of the studies, with the same scoring system, which appeared to be a global score of vertigo symptoms.Participants in the included studies were asked to rate their vertigo symptoms at the time of an attack using a four-point scale, where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms.The same scale was used to assess the severity of symptoms a er receiving treatment.Both studies reported on the number of migraine attacks in which the severity of vertigo symptoms changed from moderate/severe down to mild/ no symptoms.

Change in vertigo
Neither study considered the change in vertigo using a continuous scale.

Serious adverse events
Only one of the included studies appeared to systematically assess and report serious adverse events (NCT02447991).

Disease-specific health-related quality of life
This outcome was not assessed or reported by either study.

Improvement in headache
Both studies assessed the improvement in headache, using the same four-point scale that had been used to assess severity of vertigo.

Improvement in other migrainous symptoms
One study also considered other migrainous symptoms, again using the same four-point scale, including nausea and vomiting, and photo-and phonophobia (NCT02447991).

Other adverse e ects
One study reported on a number of adverse e ects that were of interest in this review, including gastrointestinal disturbance, sleep disturbance, cardiovascular side e ects, paraesthesia/flushing/ warm or hot sensations, and headache.

Excluded studies
A er assessing the full text, we excluded seven studies (linked to eight records) from this review.The main reason for exclusion for each study is listed below.
Two articles were systematic reviews (Byun 2021;Hou 2020).We checked the reference lists of these to ensure that any relevant studies were included in this review.
The three remaining studies did not consider treatment of acute attacks of vestibular migraine (Furman 2009;Furman 2011;Marcus 2006).Although they were RCTs of people with vestibular migraine, they aimed to assess whether prophylactic treatment with triptans would prevent the onset of motion sickness symptoms (when participants were subjected to a vestibular stimulus).Therefore, the aims, conduct and outcomes reported in these studies were not of relevance to this review.

Risk of bias in included studies
See Figure 3 for the risk of bias graph (our judgements about each risk of bias item presented as percentages across all included studies) and Figure 4 for the risk of bias summary (our judgements about each risk of bias item for each included study).Both of the studies included in this review received a rating of high risk of bias in at least one domain.

Allocation
Neither study provided any information about the generation of the random sequence, or methods used to conceal allocation to each group.Therefore, we rated this domain at unclear risk of bias for both studies.

Blinding
Both studies reported the use of a placebo and indicated that study participants were blinded to their treatment allocation.NCT02447991 also described study personnel as blinded, therefore we rated this at low risk of performance and detection bias.It was unclear whether study personnel in the Neuhauser 2003 study were also blinded.Therefore, we rated

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Cochrane Database of Systematic Reviews this study at unclear risk of performance bias, but low risk of detection bias.

Incomplete outcome data
We rated both studies at high risk of attrition bias.A high level of dropout occurred in the NCT02447991 study and this was not balanced across the two groups (22.2% in the placebo arm, 33.7% in the intervention arm).Although only three participants dropped out of the study Neuhauser 2003, this was a very small study (19 participants in total), therefore even this small number of missing data points may influence the conclusions of this study.

Selective reporting
We rated the NCT02447991 study at low risk of selective reporting bias, as outcomes were reported in accordance with the trial registry details.No protocol or trial registration was available for Neuhauser 2003.In addition, the results of this cross-over trial were not reported in a way that correctly accounted for the paired nature of the data.We therefore rated this study at high risk of selective reporting bias.

Other potential sources of bias
We did not have any additional concerns regarding the studies.

E ects of interventions
See: Summary of findings 1 Triptans compared to placebo for acute attacks of vestibular migraine

Improvement in vertigo
Both studies considered the improvement in vertigo using a fourpoint scale (0 = no vertigo, 1 = mild vertigo, 2 = moderate vertigo and 3 = severe vertigo).Improvement was considered a reduction from moderate or severe vertigo to mild or no vertigo.Both studies assessed this by considering individual attacks of vertigo, therefore the denominator in the analysis is the total number of attacks, rather than the total number of participants.As described above, this causes a unit of analysis error in the results, which we were unable to account for with the data reported.Therefore, these analyses are shown for completeness, but the results should be interpreted with caution.This is reflected in the GRADE certainty rating for these outcomes.

At up to 2 hours
The risk ratio for improvement in vertigo at up to two hours with triptans was 0.84 (95% confidence interval (CI) 0.66 to 1.07; 2 studies; 262 events; 124 participants; I 2 = 0%; Analysis 1.1; very lowcertainty evidence).A sensitivity analysis using a fixed-e ect model caused very little change in this estimate (see Table 2).

At 2 to 12 hours
No results were reported at this duration of follow-up.

Improvement in vertigo frequency
This outcome was not assessed by either study.

Change in vertigo
This outcome was not assessed by either study.

Serious adverse events
One study assessed serious adverse events (NCT02447991), and reported that no events occurred in either group (1 study; 114 participants; very low-certainty evidence).

Improvement in headache
Both studies also considered an improvement in headache using the same four-point scale as was used for vertigo.

At up to 2 hours
The risk ratio for improvement in headache at up to two hours with triptans was 0.69 (95% CI 0.49 to 0.96; 2 studies; 248 events; 124 participants; I 2 = 0%; Analysis 1.2; very low-certainty evidence).
A sensitivity analysis using a fixed-e ect model caused very little change in this estimate (see Table 2).

At 2 to 12 hours
No results were reported at this duration of follow-up.

At > 12 to 72 hours
The risk ratio for improvement in headache at 24 hours with triptans was 1.16 (95% CI 0.99 to 1.37; 1 study; 171 events; 114 participants; Analysis 1.2; very low-certainty evidence).This analysis only included events in which participants did not take additional medication over the 24-hour follow-up period.

Improvement in other migrainous symptoms
One study assessed this outcome (NCT02447991).Again, a fourpoint scale was used to assess improvement in symptoms, as described above.

At up to 2 hours
The risk ratio for improvement in nausea and vomiting at up to two hours with triptans was 0.80 (95% CI 0.62 to 1.03; 1 study; 239 events; 114 participants; Analysis 1.3; very low-certainty evidence).

At 2 to 12 hours
No results were reported at this duration of follow-up.

At > 12 to 72 hours
The risk ratio for improvement in nausea and vomiting at 24 hours with triptans was 1.02 (95% CI 0.93 to 1.11; 1 study; 170 events; 114 participants; Analysis 1.3; very low-certainty evidence).This analysis only included events in which participants did not take additional medication over the 24-hour follow-up period.

At up to 2 hours
The risk ratio for improvement in photophobia and phonophobia at up to two hours with triptans was 1.05 (95% CI 0.75 to 1.47; 1

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At 2 to 12 hours
No results were reported at this duration of follow-up.

At >12 to 72 hours
The risk ratio for improvement in nausea and vomiting at 24 hours with triptans was 1.20 (95% CI 1.01 to 1.42; 1 study; 171 events; 114 participants; Analysis 1.3; very low-certainty evidence).This analysis only included events in which participants did not take additional medication over the 24-hour follow-up period.

Other adverse e ects
One study reported on the adverse e ects that had been prespecified as of interest in this review (NCT02447991).

Cardiovascular side e ects
The risk ratio for cardiovascular side e ects (including heart rhythm problems or chest pain) with triptans was 1.24 (95% CI 0.60 to 2.56; 1 study; 114 participants; Analysis 1.4; very low-certainty evidence).

Paraesthesia, flushing, warm or hot sensations
No studies reported specifically on flushing, warm or hot sensations.One study reported on weakness of the arms, legs or face or loss of sensation (NCT02447991).We considered that this may include paraesthesia, therefore for completeness we have included the data here.The risk ratio for this outcome was 0.73 (95% CI 0.25 to 2.14; 1 study; 114 participants; Analysis 1.4; very lowcertainty evidence).

Headache
One study reported on the worsening of headache (NCT02447991).

Summary of main results
This review included two studies, both of which compared the use of triptans (either rizatriptan or zolmitriptan) to placebo, for the treatment of acute attacks of vestibular migraine.Triptans may make little or no di erence to the proportion of people who experience an improvement in their vertigo symptoms at up to two hours, or between 12 and 72 hours, but the evidence was very uncertain.We did not identify any evidence on change in vertigo symptoms using a continuous scale for this review.
When considering headache symptoms, the evidence was also very uncertain.However, fewer people reported an improvement in headache at up to two hours a er taking triptans than those who took a placebo.At 12 to 72 hours there was little or no di erence between the two groups.There was also little or no di erence in other migrainous symptoms (including nausea and vomiting, photo-and phonophobia) at both up to two hours, and 12 to 72 hours, but the evidence was all very uncertain.
One study assessed the occurrence of serious adverse events, but only reported that no events occurred in either group.This evidence is also very uncertain.When considering other (less serious) adverse e ects, triptans may increase the proportion of people who experience sleep disturbance.Results for other side e ects were all very uncertain, but indicated little or no di erence in the proportion of people who experienced gastrointestinal disturbance, cardiovascular side e ects, paraesthesia (including flushing and warm or hot sensations) or headache.

Overall completeness and applicability of evidence
The only evidence we identified for this review related to a single intervention: triptans.One study considered the use of rizatriptan, and the other considered zolmitriptan, so the evidence available is based on these two drugs alone.
We did not find any evidence for some of our outcomes of interest, including the change in vertigo (using a continuous score) and disease-specific health-related quality of life.We also found very limited information on potential harms associated with the use of triptans.However, when triptans are used in equivalent doses to treat other conditions (such as headache migraine or cluster headache) they have been associated with side e ects (Derry 2014b;Tepper 2003).
We also did not identify any randomised controlled trials (RCTs) that compared other interventions (as listed in Types of interventions) to either placebo or no treatment.Therefore, we do not have any information on the e icacy or harms of any other medications used to treat acute attacks of vestibular migraine.
Both studies used the same method to assess improvement in symptoms -the change in a four-point scale of symptom severity was converted to a dichotomous outcome (where "improvement" meant a change from severity of 3 or 2 down to 0 or 1).We could not find any information on whether this scale has been validated for used in this context.However, we note that some people may also regard a change in symptoms from 'severe' to 'moderate' as improvement.More work is needed to identify the best ways to measure symptoms of vestibular migraine, and assess what change in symptoms is meaningful and important to people with this condition.
For the outcome 'improvement in vertigo', people with 'mild' attacks of vestibular migraine were not included.Only attacks classed as moderate or severe were assessed for improvement.In addition, one of the included studies allowed participants to treat up to three attacks of vestibular migraine with the same medication (NCT02447991).Consequently, people who su ered more frequent attacks of vestibular migraine will have contributed more outcome data to the analysis than those who su ered only one attack over the course of the trial.The overall e ect of these study features means that the outcome data may be skewed towards the e ect for

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Cochrane Database of Systematic Reviews people with more severe or frequent attacks of vestibular migraine.As a consequence, the results may not be applicable to those with less frequent, or less severe attacks.
Triptans are widely used to treat headache migraine, where there is stronger evidence of their e icacy (Derry 2014b), in contrast to the results of this review of their use in vestibular migraine.It is unclear whether this is because the underlying pathophysiology of the two conditions may di er, or simply because the studies of vestibular migraine are too small or inadequately designed to detect an e ect of triptans.

Quality of the evidence
We rated all of the evidence in this review as either very low-or very low-certainty, showing that we have little confidence in the e ect estimates.Several factors contributed to this assessment.
Firstly, the total number of participants in these studies was relatively small, meaning that the calculated e ect estimates had wide confidence intervals, leading to imprecision.In addition, the number of participants dropping out during the trials was quite considerable.
We also had concerns about the analysis methods in both studies.
One study was a cross-over trial, where participants received either the triptan, or a placebo, and then switched to the alternative treatment for their next attack (Neuhauser 2003).Ideally, these data would be analysed as 'paired data', comparing the results on each treatment for an individual person.However, the information reported in the study did not allow us to analyse the data in that way.There were also concerns with the analysis in the second study (NCT02447991), where participants received one medication and used this repeatedly to treat several attacks.We were unable to account for the correlation between data points from the same individual.Therefore, many of the analyses presented in this review must be viewed as approximate.

Potential biases in the review process
This review only included studies that compared an active intervention to no treatment or placebo.This may mean that we omitted studies that compared one active treatment to another.However, as there is currently no 'gold standard' treatment for acute attacks of vestibular migraine, we considered that this was an appropriate decision.

Agreements and disagreements with other studies or reviews
A recent systematic review evaluated the use of pharmacological (and non-pharmacological) interventions for both the prophylaxis and acute treatment of vestibular migraine (Smyth 2022).The authors of this review included both randomised and non-randomised studies, therefore the results are not directly comparable with our own review.However, their conclusions are similar to our own -that the overall evidence base for the treatment of vestibular migraine is of low certainty and that well-designed clinical trials are required in this area.

Implications for practice
Currently, we have identified only two randomised controlled trials (RCTs) that assessed interventions used for acute attacks of vestibular migraine.The evidence from these studies shows great uncertainty in the e ects of triptans, and limited information on the possibility of harms from these medications.The lack of robust evidence in this area should be recognised by people with vestibular migraine and healthcare professionals, when deciding on possible treatments for this condition.

Implications for research
This review was conducted as part of a suite, which evaluates di erent interventions for the prophylaxis or acute treatment of vestibular migraine (Webster 2022a; Webster 2022b; Webster 2022c).The conclusions below relate to evidence from across the entire suite: • There is a paucity of RCTs in this field, where active interventions are compared to no treatment or a placebo.Given the subjective nature of symptoms of vestibular migraine, the fluctuating severity of the condition and the lack of a 'gold standard' treatment, we consider that comparison with a placebo arm is vital to allow conclusions to be drawn on the e icacy and harms of di erent interventions.• Wherever possible, trialists should ensure that participants, study personnel and outcome assessors are appropriately blinded to the intervention, to reduce the risk of performance and detection bias a ecting the results of studies.• Small, underpowered studies do little to improve the evidence base for these interventions.We would advocate the conduct of large, adequately powered, multicentre trials to ensure that more robust conclusions can be drawn from the study results.
In addition, trialists need to be aware that there is considerable attrition over the course of these studies and should be prepared to make additional e orts to improve follow-up.• Future studies should also aim to follow up participants for longer periods of time, to identify whether interventions have lasting e ects.• There needs to be consensus on the appropriate outcomes to measure in trials that evaluate interventions for vestibular migraine, with input from di erent stakeholders, especially including those with the condition.As well as agreeing the types of outcomes that are important, the methods with which these are measured should be considered, including the use of validated scales to assess more subjective outcomes.This would be best achieved with the development of a core outcome set, analogous to that developed for use in trials of headache migraine (Haywood 2021).
In addition, if study designs are used that include correlated data (such as cross-over or cluster designs, or where multiple outcomes may be reported by a single individual), trialists must ensure that results are reported in a way that accounts for this correlation, or the evidence arising from these studies is likely to be at risk of bias.

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Cochrane Database of Systematic Reviews or Cochrane Incentive funding to Cochrane ENT, as well as an Evidence Synthesis Programme grant (NIHR132217).The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Evidence Synthesis Programme, NIHR, NHS or the Department of Health.
The development of the protocol (including the prioritisation of outcomes) for this review was informed by responses to a survey to encourage patient and public involvement in the review process.
The development and distribution of this survey would not have been possible without the support of the Ménière's Society and the Migraine Trust, and the authors wish to thank them for their help.
The authors would like to thank Lee Yee Chong for her work on generic text that has been used and adapted (with permission) in the methods section of the review protocol.We would also like to extend our thanks to Frances Kellie and Cochrane Pregnancy and Childbirth for their permission to use and reproduce the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool in this review.
The authors are grateful to Professor Malcolm Hilton for clinical peer review of this systematic review, and to Stella O'Brien for her consumer review.Thanks to John P Carey MD and Pavan S Krishnan for clinical peer review of the protocol, and Iris Gordon, Information Specialist with Cochrane Eyes and Vision, for providing peer review comments on the dra search methods.Our thanks also to Professor Stephen O'Leary for editorial sign-o of the protocol and review.
We would also like to thank Yuan Chi, who provided help with translation.
Finally, our grateful thanks to Jenny Bellorini, Managing Editor for Cochrane ENT, and Samantha Cox, Information Specialist, without whom the development of this review would not have been possible.

Editorial and peer reviewer contributions
Cochrane ENT supported the authors in the development of this review.

Inclusion criteria:
Age ≥ 18 years and ≤ 65 years.A history that fulfils all criteria for vestibular migraine.Episodes must have a spontaneous onset and resolution without associated hearing loss or interictal neurotologic deficits.Other causes of vestibular symptoms ruled out by appropriate clinical investigations.Current medication list compatible with concomitant medications.Able to maintain a vestibular symptom diary and complete all other study procedures.At least 2 vestibular migraine attacks during the 12month observation period.

Exclusion criteria:
Ménière's disease.Migraine with brainstem aura (formerly basilar-type migraine) by ICHD-3 criteria.Ischaemic heart disease, coronary artery vasospasm, uncontrolled hypertension.History of stroke or transient ischaemic attack.History of using rizatriptan specifically to treat vestibular attacks.History of adverse response to triptans.Women who are pregnant or breastfeeding.Unable or unwilling to comply with study requirements for any reason.

Diagnosis of vestibular migraine:
International Headache Society criteria for definite vestibular migraine (see Appendix Placebo capsules (contents not stated) to be taken orally during 1 acute episode, until 3 episodes had been treated with the study drug

None reported
Additional treatments (for migraine prophylaxis or other conditions) were permitted if they had been taken during the run-in period to the trial and participants were on a stable dose

Outcomes
Primary outcomes relevant to this review: • Improvement in vertigo • Participants reported symptoms using a patient self-report of the severity of vestibular symptoms (vertigo and unsteadiness/dizziness) where: ▪ 0 = no symptoms ▪ 1 = mild symptoms (no interference with activities) ▪ 2 = moderate symptoms (had to alter some activities) ▪ 3 = severe symptoms (had to stop most or all activities) • Improvement was considered a reduction in symptoms from moderate/severe to none/mild Cochrane Database of Systematic Reviews is sufficient to impact the results of the trial, and may introduce the potential for bias in the results.

Low risk
Comment: outcomes are fully reported on the trial registry website according to the pre-specified plan.

Other bias Low risk
Comment: no other concerns identified.

Study characteristics
Methods Randomised, double-blind, placebo-controlled, cross-over (after one attack) trial Total duration of treatment and follow-up not reported Participants Setting: Specialist dizziness neurology clinic, hospital outpatient management in Germany (single-centre).
Study dates not reported.

Participant baseline characteristics
Only reported for those who completed the trial • Age: • Zolmitriptan group: range 29 to 57 years • Placebo group: range 29 to 57 years • Gender: • Zolmitriptan group: 7 females: 1 male • Placebo group: 7 females: 2 males • Probable/definite vestibular migraine: • Not reported (study was published before the IHS criteria were defined) • Attack frequency at baseline: • At least 2 attacks in the preceding 12 months; no other information provided • Duration of disease: • Not reported

Inclusion criteria:
A diagnosis of vestibular migraine.At least 2 episodes of migrainous vertigo lasting longer than 2 hours within 12 months before enrollment.Aged between 18 and 65 years.

Exclusion criteria:
Vestibular disorders other than vestibular migraine.Non-vertiginous dizziness (e.g.orthostatic or due to panic disorder) unless it could be clearly differentiated from attacks of VM by the patient.Cochrane Database of Systematic Reviews and take any other anti-vertiginous drugs or pain medication within 6 hours before taking study medication.

Diagnosis of vestibular migraine:
Criteria were: 1) episodic vestibular symptoms of at least moderate severity (rotational vertigo, other illusory self-or object-motion, positional vertigo or head motion intolerance, i.e. sensation of imbalance or illusory motion provoked by head movements).Vestibular symptoms were "moderate" if they interfered with but did not prohibit daily activities, "severe" if patients could not continue daily activities; 2) current or previous history of migraine according to the 1988 criteria of the International Headache Society; 3) one of the following migrainous symptoms during at least 2 vertiginous attacks: migrainous headache, photophobia, phonophobia, visual or other auras; and 4) other causes ruled out by appropriate investigations.

Interventions
Intervention (n = 11 randomised, number completed not reported) Zolmitriptan 2.5 mg to be taken orally when symptoms of vestibular migraine were moderate or severe Comparator (n = 8 randomised, number completed not reported) A placebo of identical appearance and taste was to be taken when symptoms of vestibular migraine were moderate or severe

Background interventions administered to all participants
A second dose of study medication (either triptan or placebo, accordingly) or a rescue medication (dimenhydrinate 150 mg for vertigo and paracetamol 500 mg for headache) could be taken after 2 hours

Outcomes
Primary outcomes relevant to this review: • Improvement in vertigo • Vertigo was measured as mild, moderate, severe or no vertigo.Improvement was counted as vertigo severity changing from moderate or severe to mild or no vertigo.Patients reported symptoms in a structured diary.

• Change in vertigo
• Not reported • Serious adverse events • Not reported Secondary outcomes relevant to this review: • Disease-specific health-related quality of life

Reason for exclusion
Hou 2020 This is a systematic review, not an RCT.The reference list has been checked to ensure that any relevant articles have been included in this review.

Marcus 2006
This study is not an assessment of medications used to treat acute attacks of vestibular migraine.Instead, it aimed to assess whether prophylactic treatment with triptans might improve motion sickness symptoms in those with vestibular migraine, when subjected to a vestibular stimulus.
RCT: randomised controlled trial  (2) Analysis only includes people who did not take additional medication.Total events: Heterogeneity: Tau² = 0.00; Chi² = 0.09, df = 1 (P = 0.76); I² = 0% Test for overall effect: Z = 2.17 (P = 0.03)     CI: confidence interval; RR: risk ratio * Numerator and denominator for this analysis are the number of events with improvement, compared to the total number of events (as opposed to the number of participants).

Imprecision
a Serious risk of attrition bias.Multiple domains rated at unclear risk of bias.
b Analysis method fails to account for correlation between outcomes reported by the same individual.c Sample size fails to meet the optimal information size, taken to be 300 events for a dichotomous outcome or 400 participants for a continuous outcome, as a rule of thumb.
d No events in either arm, therefore cannot calculate an e ect estimate.
e Confidence interval includes the potential for either substantial benefit or substantial harm from the intervention.

Figure 4 .
Figure 4. Risk of bias summary (our judgements about each risk of bias item for each included study).
capsule to be taken orally during 1 acute episode, until 3 episodes had been treated with the study drug Comparator (n = 45 randomised, n = 35 completed) Denominator is the number of attacks, not the number of participants.
(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) ( Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (applicable Test for overall effect: Z = 0.20 (P = 0.84) Upset stomach, nausea or vomiting (2) Sleepiness or drowsiness (3) Heart rhythm problems or chest pain (4) Weakness of arms, legs or face or loss of sensation (5) Worsening of headache Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias Pharmacological interventions for acute attacks of vestibular migraine (Review) Copyright © 2023 The Authors.Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.
randomisation OR randomisation OR placebo* OR (random* AND (allocat* OR assign*) ) OR (blind* AND (single OR double OR treble OR triple) ))Pharmacological interventions for acute attacks of vestibular migraine (Review) Copyright © 2023 The Authors.Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

Pharmacological interventions for acute attacks of vestibular migraine (Review)
Copyright © 2023 The Authors.Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

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the Cochrane Handbook for Systematic Reviews of Interventions version 6.1) (Lefebvre 2020).Search strategies for major databases including CENTRAL are provided in Appendix 3.

Flow chart of study retrieval and selection.
Cochrane Database of Systematic Reviews Figure 1.
Sign-o Editor (final editorial decision): Professor Stephen O'Leary, Department of Otolaryngology, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne (Cochrane ENT Editor).• Managing Editor (selected peer reviewers, collated peer reviewer comments, provided editorial guidance to authors, edited the article): Jenny Bellorini, Cochrane ENT.• Copy Editor (copy editing and production): Jenny Bellorini, Cochrane ENT.• Peer reviewers: Professor Malcolm Hilton, Department of ENT, Royal Devon University Foundation Trust (clinical/content review), Stella O'Brien (consumer review).

Pharmacological interventions for acute attacks of vestibular migraine (Review)
Copyright © 2023 The Authors.Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

Neuhauser 2003 Pharmacological interventions for acute attacks of vestibular migraine (Review)
History of basilar, ophthalmoplegic or hemiplegic migraine.Severe impairment of hepatic or renal function.Symptoms suggestive of ischaemic heart disease.History of stroke or transitory ischaemic attacks.Alcohol or drug abuse.Diastolic blood pressure more than 95 mmHg or systolic more than 160 mmHg.No contraception for women of childbearing age.Hypersensitivity to the study medication.In addition, patients should not use a triptan or ergot derivative within 24 hours before and after taking study medication; change or start any prophylactic migraine treatment 3 months before taking study medication; Copyright © 2023 The Authors.Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

Pharmacological interventions for acute attacks of vestibular migraine (Review)
Assessed using the same score as vertigo.Improvement was counted as headache changing from moderate or severe to mild or no headache.Patients reported symptoms in a structured diary.Copyright © 2023 The Authors.Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

Comparison 1: Triptans versus placebo, Outcome 1: Improvement in vertigo (global score)
Pharmacological interventions for acute attacks of vestibular migraine (Review)Copyright © 2023 The Authors.Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

3. Comparison 1: Triptans versus placebo, Outcome 3: Improvement in other migrainous symptoms Study or Subgroup 1.3.1 Nausea and vomiting at up to 2 hours
Denominator is the number of attacks, not the number of participants.(2)Analysis only includes people who did not take additional medication.

Pharmacological interventions for acute attacks of vestibular migraine (Review)
Copyright © 2023 The Authors.Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

Table 1 . GRADE profile: Triptans versus placebo for acute attacks of vestibular migraine
(Continued)

Pharmacological interventions for acute attacks of vestibular migraine (Review)
Copyright © 2023 The Authors.Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

Table 1 . GRADE profile: Triptans versus placebo for acute attacks of vestibular migraine (
Continued)