Objectives
This is a protocol for a Cochrane Review (intervention). The objectives are as follows:
The primary objective is to examine the efficacy of botulinum toxin therapy in the treatment of provoked vestibulodynia (PVD) compared with placebo or no treatment.
The secondary objectives are to investigate the dose effect of botulinum toxin and the complication rates associated with botulinum toxin.
Background
Description of the condition
Vulvodynia is a common pain disorder among premenopausal women, with an estimated prevalence of 8.3% to 16% among women in the USA [1, 2, 3]. Provoked vestibulodynia (PVD), previously known as vulvar vestibulitis syndrome (VVS), is the most frequently reported subcategory of vulvodynia and the most common reason for sexual pain in young women. According to the 2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia, PVD refers to pain at the openings of the urethra and vagina (the vulvar vestibule) that lasts for more than three months and occurs without the presence of any other identifiable vulvar disease [4]. Although the cause is unclear, various psychosocial and pathophysiological factors are thought to play a role in the onset and persistence of this pain [4, 5].
Societal misconceptions and stigmatization often surround this condition, contributing to the suffering of those affected [6]. Moreover, the historical under‐representation of women's health issues in research and funding exacerbates the challenges faced by those with vestibulodynia [7].
Description of the intervention and how it might work
Non‐pharmacological treatments, pharmacological treatments, and surgical interventions have been tested for vulvodynia, both individually and in combination. Non‐pharmacological options mainly include variations of cognitive behavioral therapy (CBT), pelvic floor physical therapy, and alternative therapies such as acupuncture and transcutaneous electrical nerve stimulation (TENS). Pharmacological treatments include muscle relaxants and agents that target peripheral and central pain mechanisms [5]. However, there is currently no 'gold standard' treatment for women with this condition [8, 9].
Botulinum toxin acts by blocking the release of acetylcholine from the presynaptic terminal of the neuromuscular junction, leading to chemodenervation and temporary muscle paralysis [10]. Only botulinum toxin serotypes A and B (BTX‐A and BTX‐B) are approved by the US Food and Drug Administration (FDA) for neurological conditions.
Examples of pain syndromes successfully treated with botulinum toxin include interstitial cystitis and migraine [11, 12]. Several theories explain how botulinum toxin alters pain perception, including changes in muscle nociceptor sensitivity, reduced gamma motor neuron activity, altered cholinergic control of vascular and autonomic functions, induced neuroplastic changes in afferent somatosensory processing, and direct effects on pain afferents [13].
Why it is important to do this review
There is evidence from observational studies suggesting that botulinum toxin is a potentially effective treatment for PVD.
There are several case reports, observational studies, and clinical trials on the efficacy of BTX‐A in treating vulvodynia with single injections of 10 to 80 units [14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29].
There are also previous systematic reviews that have addressed a similar question. One systematic review – now out of date – focused on chronic pelvic pain [30]. One large systematic review examined all possible interventions for PVD but involved no quantitative pooling of data [8].
Objectives
The primary objective is to examine the efficacy of botulinum toxin therapy in the treatment of provoked vestibulodynia (PVD) compared with placebo or no treatment.
The secondary objectives are to investigate the dose effect of botulinum toxin and the complication rates associated with botulinum toxin.
Methods
We will follow the Methodological Expectations for Cochrane Intervention Reviews (MECIR) when conducting the review [31], and PRISMA 2020 for the reporting [32].
Criteria for considering studies for this review
Types of studies
We will include randomized controlled trials (RCTs) that examine the use of botulinum toxin for the treatment of PVD. We will exclude cross‐over trials, cluster RCTs, quasi‐RCTs, and other observational studies to maintain a higher level of methodological rigor. We will include both published and unpublished studies and apply no language restrictions.
Types of participants
We will include studies in adults (age ≥ 18 years) with a clinical diagnosis of PVD, regardless of race, social and economic status, profession, or place of residence. We will consider a diagnosis of PVD according to the 2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia [4].
We will not include people with the following contraindications to botulinum toxin.
History of hypersensitivity to any component of the product
Disturbances of muscular activity in concomitant treatment with antibiotics aminoglycoside or spectinomycin
Any bleeding disorders
Treatment with anticoagulants
Any reason to avoid injection of intramuscular agents
Pregnancy or breastfeeding
We will include studies with a mixture of eligible and ineligible participants if separate data for eligible participants are available.
Types of interventions
We will include intramuscular injections of any type of botulinum toxin administered into the vaginal muscles or soft tissues of the groin, regardless of dosage regimen. Although only BTX‐A and BTX‐B are FDA‐approved, we will also include other types such as botulinum toxin type F (BTX‐F) to capture exploratory or off‐label studies.
Eligible studies will not be restricted based on treatment duration, frequency, or intensity.
We will consider studies with co‐interventions if these are evenly distributed between groups.
Botulinum toxin must be delivered via localized injections by trained physicians, typically in outpatient clinical settings such as gynecology or sexual medicine departments. We will not exclude studies based on the use of anesthetic agents, such as topical creams applied prior to injection, nor based on whether a single or repeated injection strategy was employed. We will also include studies utilizing either submucosal or subcutaneous injection techniques if they are directed to relevant anatomical sites related to PVD.
Eligible comparators will be placebo or no treatment. A placebo is an inactive drug or procedure intended to have no therapeutic effect. The duration, frequency, or intensity of the placebo will not be restricted.
Outcome measures
We will include trials with eligible study design, participants, interventions and comparators, irrespective of whether they report our prespecified outcomes.
Since the effect of botulinum toxin generally lasts for two to three months before gradually wearing off, we will consider outcomes measured up to three months after administration [33].
If an improvement scale is defined in each study, we will assess the appropriateness of data integration by conducting an analysis based on the criteria used in each study.
Economic outcomes are not within the scope of this review.
We found no core outcome set for this review in the Core Outcome Measures in Effectiveness Trials (COMET) database.
We will report all critical and important outcomes in the summary of findings table, abstract, and plain language summary of the review [34].
Critical outcomes
Pain during intercourse: self‐reported pain during intercourse or sexual activity rated on a visual analogue scale (VAS) or a numeric rating scale (NRS) [35]
Pain upon pressure or touch: pain ratings (VAS, NRS) during a gynecological examination, measured using a cotton swab test or a vulvar algesiometer
Adverse events (AEs), complications, and negative treatment effects. If reported, adverse events and complications will be divided into mild or severe. We will first extract the proportion of participants with AEs, and secondly extract data on other descriptions of AEs and complications.
Important outcomes
Sexual function and satisfaction. Our preferred measurement tool is the Female Sexual Function Index (FSFI). Other eligible measures of sexual health include the Index of Sexual Satisfaction (ISS) and Global Sexual Functioning (GSF) score [36, 37].
Quality of life measured on a validated instrument
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Mental distress. We will extract data from validated instruments that assess anxiety and depressive symptoms. The examples below are listed in order of preference.
Search methods for identification of studies
We will develop a search strategy for each database to identify studies for inclusion in the review. The corresponding search strategies will be based on the design for Ovid MEDLINE, with adjustments for differences in vocabulary and syntax guidelines (see Supplementary material 1). This search strategy will utilize the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐maximizing version (2008 revision), as described in the Cochrane Handbook for Systematic Reviews of Interventions [43]. A title and abstract filter will be applied when appropriate to focus the search on relevant textual content. We will not restrict searches by language or publication date, and we will also include unpublished studies.
Electronic searches
We will search the following databases.
Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Library
Ovid MEDLINE (1946 onwards)
Embase via Ovid (1974 onwards)
CINAHL via EBSCOhost (Cumulative Index to Nursing and Allied Health Literature) (1981 onwards)
Searching other resources
We will conduct an additional search for relevant studies in topic‐related reviews and reference lists of retrieved papers. In addition, we will conduct electronic searches of the following sources.
Google Scholar for grey literature
Online abstracts from sexual health‐related congresses, unpublished studies, thesis dissertations, preprint services, and non‐indexed journals
Moreover, we will perform an online search for abstracts and unpublished studies in the indexes of the annual meetings held by the following organizations.
World Association for Sexual Health
International Society for Sexual Medicine
Finally, for unpublished results and ongoing studies, we will search the following trial registries.
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov/)
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (trialsearch.who.int/)
PROSPERO (www.crd.york.ac.uk/prospero/)
We will contact experts in the field for information about any ongoing or unpublished trials as needed.
We will also check for any postpublication amendments (including retractions, errata, and expressions of concern) related to included or potentially eligible studies. We will search the Retraction Watch Database (retractiondatabase.org/) and the websites of the journals in which the studies were published to identify any such amendments.
Data collection and analysis
Selection of studies
To identify eligible studies, two review authors (SK, JS) will screen the titles and abstracts of papers retrieved by the search. They will then evaluate the full‐text articles of potentially eligible studies to determine if they meet the eligibility criteria. A third review author (NW) will resolve any disagreements regarding eligibility by co‐ordinating a group discussion to reach a final decision. We will list all studies excluded at the full‐text review stage along with the main reasons for their exclusion in a 'Characteristics of excluded studies' table.
When unanticipated issues arise, the review authors will make sensible post hoc decisions about study inclusion or exclusion and will document any such decisions in the review.
Data extraction and management
We will create a standardized data extraction form using Covidence to systematically collect and organize data on study characteristics [44]. This form will be piloted on at least one included study. The information of interest will include details of interventions and comparisons, participants, co‐interventions, and randomization procedures. We will also document definitions used and information required for the risk of bias assessment. Two review authors (SK, JP) will independently extract the data, with a third review author (NW) resolving any disagreements. Additionally, we will record any other information pertinent to the objectives of this review. For studies not written in English, we will employ specialized translation services if needed.
Risk of bias assessment in included studies
We will use the Cochrane RoB 2 tool to evaluate the following sources of bias in included studies [45].
Bias arising from the randomization process
Bias due to deviations from intended interventions
Bias due to missing outcome data
Bias in measurement of the outcome
Bias in selection of the reported result
The outcomes assessed using RoB 2 will be the critical outcomes contributing to the summary of findings table, as follows.
Pain during intercourse
Pain upon pressure or touch
Adverse events
The nature of the effect of interest is the effect of assignment to the interventions at baseline, regardless of whether the interventions were received as intended (the 'intention‐to‐treat effect'). Two review authors (SK, JP) will independently evaluate each domain. The RoB 2 algorithm will categorize risk of bias judgments as 'low risk of bias,' 'some concerns,' or 'high risk of bias,' based on the responses to a set of signaling questions. We will use the RoB 2 Excel tool (available at www.riskofbias.info/) to implement and manage the assessment. Any disagreements will be resolved by a third review author (NW). We will create a graphic to illustrate the proportion of studies in each risk category. Additionally, we will provide a detailed description of the risk of bias for each study in the 'Characteristics of included studies' table. We will contact the corresponding authors or co‐authors of the included studies via email for further information as needed. We will assess the overall risk of bias in each study as low risk of bias (if all domains are low risk), high risk of bias (if one or more domains are high risk), or some concerns (if no domains are high risk but one or more domains are some concerns).
Measures of treatment effect
We will use the mean difference (MD) and its 95% confidence interval (CI) to estimate treatment effects for continuous outcomes measured on the same scale. We will calculate the standardized mean difference (SMD) when different scales are used for the same outcome. For recurrent events, we will employ the rate ratio, as detailed in Section 6.7.1 of the Cochrane Handbook for Systematic Reviews of Interventions [46].
Unit of analysis issues
For studies in which more than two arms are deemed relevant, we will distribute participants from the control group across the other groups (interventions) in any meta‐analysis to avoid double counting. For outcomes reported at multiple time points, we will focus on those reported closest to three months for each study. In all cases, we will consider the participant as the unit of analysis. For events that may recur, we will use the rate ratio as outlined above.
Dealing with missing data
In the case of missing data, we will contact the corresponding authors, provided contact information is available. We will employ the intention‐to‐treat approach if the data are reported accordingly. If missing data cannot be obtained after author contact, we will impute replacement values and treat these as if they were observed. To assess the robustness of our results, we will conduct a sensitivity analysis to evaluate the effect of assumptions made on the findings. We will discuss the potential influence of missing data on our conclusions in the 'Discussion' section of the review.
Reporting bias assessment
We will assess publication bias according to the recommendations in Section 13.3.5 of the Cochrane Handbook for Systematic Reviews of Interventions [47].
Synthesis methods
We will apply the random‐effects model using a restricted maximum likelihood variance estimator for improved performance [48]. We will use Wald‐type CIs by default to calculate the CI for the summary effect; however, if the number of studies is small and between‐study variance is greater than zero, we will apply the Hartung‐Knapp‐Sidik‐Jonkman (HKSJ) method according to the recommendations in Section 10.10.4.4 of the Cochrane Handbook for Systematic Reviews of Interventions [49]. The decision to perform a meta‐analysis will be based on the availability of data and the degree of heterogeneity between studies. We will conduct the meta‐analysis using RevMan software and generate forest plots to illustrate the effects [50]. If meta‐analysis is not feasible, we will present the data according to the Synthesis Without Meta‐analysis (SWiM) guideline [51].
Investigation of heterogeneity and subgroup analysis
If we observe heterogeneity in the data, we will verify whether the data were accurately extracted and entered. Once confirmed, we will visually inspect the graphs and remove studies as needed to restore homogeneity. If this process affects data contributing no more than 10% to the total weighting, we will report it. If substantial heterogeneity persists, especially with inconsistent effect directions, we will not pool these data in a meta‐analysis but will discuss them narratively. For significant unanticipated clinical or methodological heterogeneity, we will suggest hypotheses for future reviews but will not conduct statistical analyses.
We will consider performing subgroup analyses or meta‐regression for the critical outcomes based on the following factors.
Dose of intervention. The intervention can be administered in different doses. Due to the lack of official dose equivalence across various brands of botulinum toxin, we will consider this parameter for subgroup analysis.
Botulinum toxin type. Although BTX‐A is most commonly used for intervention in PVD, if studies evaluate the use of other botulinum toxin types for the same purpose, we will conduct a subgroup analysis based on this parameter.
We will compare subgroups using the formal test for subgroup differences in RevMan [50].
Equity‐related assessment
We will report any relevant characteristics covered by the PROGRESS‐Plus acronym (place of residence, race/ethnicity/culture/language, occupation, gender/sex, religion, education, socio‐economic status, social capital, age, sexual orientation, and disability) [52]. Additionally, we will examine whether the interventions we assess could lead to health inequities within our female population.
Sensitivity analysis
We will conduct a sensitivity analysis for our critical outcomes to assess the validity and strength of our conclusions. This analysis will involve evaluating the impact of excluding studies with a high risk of bias and addressing any missing data.
Certainty of the evidence assessment
We will use the GRADE approach and the summary of findings table format to assess our certainty in the retrieved evidence [34]. With the GRADE method, evidence from RCTs is initially ranked as high certainty but can be downgraded by one level (to 'moderate'), two levels (to 'low'), or three levels (to 'very low'), depending on the presence of risk of bias, inconsistency, indirectness, imprecision, and publication bias [34]. Two review authors (SK, JP) will evaluate the certainty of the evidence independently and in duplicate, with a third review author (NW) resolving any conflicts.
We will create summary of findings tables to summarize the results and our confidence in the evidence [34]. These tables will present two comparisons: botulinum toxin intramuscular injection (in the musculus bulbospongiosus, or the dorsal vulvar vestibulum) versus placebo or no treatment.
We will present results for our prespecified outcomes at three months.
Consumer involvement
This review will not involve direct consumer participation in the development or conduct of the research. However, the findings of the review will be disseminated in a format that is accessible and understandable to consumers, ensuring that the results can inform healthcare decisions at the patient level. Future updates of the review may consider involving consumer representatives to ensure that the perspectives and priorities of end‐users are adequately reflected.
Supporting Information
Supplementary materials are available with the online version of this article: 10.1002/14651858.CD016202.
Supplementary materials are published alongside the article and contain additional data and information that support or enhance the article. Supplementary materials may not be subject to the same editorial scrutiny as the content of the article and Cochrane has not copyedited, typeset or proofread these materials. The material in these sections has been supplied by the author(s) for publication under a Licence for Publication and the author(s) are solely responsible for the material. Cochrane accordingly gives no representations or warranties of any kind in relation to, and accepts no liability for any reliance on or use of, such material.
Supplementary material 1 Search strategies
New
Additional information
Acknowledgements
Cochrane Japan supported the authors in the development of this review. Special thanks to Takaaki Suzuki for his assistance in developing the search strategies and conducting the electronic searches. We are grateful to all the authors who contributed to the development of the review protocol.
The following people conducted the editorial process for this review: Norio Watanabe.
We would like to thank Julia Turner from Cochrane Central Production Service for her support in the production process.
Contributions of authors
SK: screening and study selection, data extraction, synthesis, risk of bias assessment, GRADE assessment, and write‐up. JP: data extraction, synthesis, risk of bias assessment, and GRADE assessment. JS: screening and study selection NW: contribution to write‐up and manuscript review.
Declarations of interest
SK: no commercial or non‐commercial conflicts of interest relevant to this review JP: no commercial or non‐commercial conflicts of interest relevant to this review JS: no commercial or non‐commercial conflicts of interest relevant to this review NW: no commercial or non‐commercial conflicts of interest relevant to this review
Sources of support
Internal sources
-
Example internal funding, Other
Describe the role of funders or sponsors, for example, 'V had no involvement in the development of the protocol or in conducting the review. The views and opinions expressed therein are those of the review authors and do not necessarily reflect those of the V.' OR 'No internal sources of support received.' See Cochrane's editorial policy on conflict of interest for more information.
External sources
-
Example external funding, Other
Describe the role of funders or sponsors, for example, 'V had no involvement in the development of the protocol or in conducting the review. The views and opinions expressed therein are those of the review authors and do not necessarily reflect those of the V.' OR 'No external sources of support received.' See Cochrane's editorial policy on conflict of interest for more information.
Registration and protocol
Cochrane approved the proposal for this review in June 2024.
Data, code and other materials
Data sharing is not applicable to this article as it is a protocol, so no datasets were generated or analyzed.
Notes
Published notes in RevMan are for editor use only. Authors should leave this section blank.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary material 1 Search strategies
Data Availability Statement
Data sharing is not applicable to this article as it is a protocol, so no datasets were generated or analyzed.