Treatment of Provoked Vulvodynia: A Systematic Review

Background: Treatment recommendations for provoked vulvodynia (PVD) are based on clinical experiences and there is a need for systematically summarizing the controlled trials in this ﬁ eld. Aim: To provide an overview of randomized controlled trials and non-randomized studies of intervention for PVD, and to assess the certainty of the scienti ﬁ c evidence, in order to advance treatment guidelines. Data Sources: The search was conducted in CINAHL (EBSCO), Cochrane Library, Embase (Embase.com), Ovid MEDLINE, PsycINFO (EBSCO) and Scopus. Databases were searched from January 1, 1990 to January 29, 2021. Study Eligibility Criteria: Population: Premenopausal women with PVD. Interventions: Pharmacological, surgical, psychosocial and physiotherapy, either alone or as combined/team-based interventions. Control: No treatment, waiting-list, placebo or other de ﬁ ned treatment. Outcomes: Pain during intercourse, pain upon pressure or touch of the vaginal opening, sexual function/satisfaction, quality of life, psychological distress, adverse events and complications. Study design : Randomized controlled trials and non-randomized studies of interventions with a control group. Study Appraisal and Synthesis Methods: 2 reviewers independently screened citations for eligibility and assessed relevant studies for risk of bias using established tools. The results from each intervention were summarized. Studies were synthesized using a narrative approach, as meta-analyses were not considered appropriate. For each outcome, we assessed the certainty of evidence using grading of recommendations assessment, development, and evaluation (GRADE). Results: Most results of the evaluated studies in this systematic review were found to have very low certainty of evidence, which means that we are unable to draw any conclusions about effects of the interventions. Multimodal physiotherapy compared with lidocaine


INTRODUCTION
Provoked localized vulvodynia (PVD) is a common and debilitating chronic vulvar pain condition, affecting approximately 7 −13% of premenopausal women. 1,2Women with PVD describe a sharp pain or burning sensation, localized at the entry of the vagina during touch, pressure, and attempted or accomplished vaginal intercourse. 3The pain does not only affect sexual function and satisfaction, 4 but is also associated with psychological distress, 5,6 relational dissatisfaction and a lower quality of life. 7et, it is a neglected pain condition, 8 and many women are left without correct diagnosis and treatment. 9cording to the 2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia, PVD conveys pain in the vulvar entry lasting more than 3 months, appearing in the absence of another recognizable vulvar disease. 3Although the etiology is ambiguous, several psychosocial and pathophysiological mechanisms are believed to contribute to pain onset and maintenance 3,10 Numerous treatment approaches, each based on its own assumed mechanism, have been developed and evaluated with varying results (for a review, see Rosen et al, 2019). 11There is however a lack of controlled trials exploring treatment effects, 12 thus current state of evidence remains unclear.
To date there is no "gold standard" treatment for women with PVD. 11Non-pharmacological as well as pharmacological and surgical treatments have been tested, both individually and in combination.Non-pharmacological options have primarily been variations of cognitive-behavioral therapy (CBT), pelvic floor physical therapy, and alternative therapies such as acupuncture and Transcutaneous Electrical Nerve Stimulator (TENS).Pharmacological and medical options include agents targeting peripheral and central pain mechanisms, muscle relaxants and surgical interventions. 10However, most treatment studies have involved heterogeneous samples, and not only women with PVD, despite it being the most common type of vulvar pain in premenopausal women.Yet, as there is no updated systematic review of different treatments' effects on PVD, current state of evidence is still to be determined.
Current treatment recommendations are largely based on clinical experiences. 10,13,14In previous systematic reviews on treatment for provoked vulvodynia, a mixture of study designs and study populations have been included which limits the certainty of evidence. 15,16Thus, there is an urgent need for systematically summarizing the few controlled trials that exist in this field.In Sweden, this need has been noted at a national level, and the current systematic review was initiated as an assignment from the Swedish government with the aim to establish national recommendations for PVD treatment.
The aim was to provide an overview of randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSIs) of the effect of treatment approaches for women with PVD, in order to advance treatment guidelines.Considering the various treatment approaches, we included all identified controlled trials for this selected group.

METHODS
This systematic review was conducted at the Swedish Agency for Health Technology Assessment and Assessment of Social Services, SBU, following a protocol preregistered on PROS-PERO (preregistered 01/08/2020, number CRD42020196455; https://www.crd.york.ac.uk/prospero/.The assessment also covered diagnostic methods, but these results are reported elsewhere. 17The systematic review was performed and reported in accordance with the PRISMA guidelines. 18,19igibility Criteria The research question and the inclusion criteria were formulated using the PICO (Population Intervention Comparison Outcome) model for clinical questions with the following definitions 20 : Population.The target population was premenopausal women with provoked vulvodynia (PVD) diagnosed according to 2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia. 3 Study populations with up to 25% postmenopausal woman or with other forms of vulvodynia were accepted.No limit concerning population size was used.
Interventions.Pharmacological (systemic, topical or local), surgical, psychosocial and physiotherapy were considered, either alone or as combined/team-based interventions.No restrictions concerning treatment duration or follow-up time were applied.
Control.The control conditions were no treatment, waitinglist, placebo or other defined control treatment.
Outcomes.Included outcomes were pain during intercourse, pain upon pressure or touch of the mucosa around the vaginal opening, sexual function or satisfaction, quality of life, and psychological distress (anxiety and depressive symptoms), adverse events and complications.
Study Design.Included study designs were randomized controlled trials (RCT) and non-randomized studies of interventions (NRSI) with a control group.
Publication Type.Original studies published in peer-reviewed scientific journals from 1990 and onwards were searched.Accepted languages were English, Swedish, Norwegian, or Danish.Conference abstracts, book chapters and theses were excluded.

Information Sources
The literature search was performed by an information specialist (K.M.) and included the databases CINAHL (EBSCO), Cochrane Library, Embase (Embase.com),Ovid MEDLINE, PsycINFO (EBSCO) and Scopus.In addition, the following sources were searched for systematic reviews that were not included in the review but were used to control for additional primary studies: CADTH publication database, CRD Database (including HTA Database, DARE, NHS EED), Epistemonikos, Evidence search (NICE), KSR Evidence and PROSPERO.Reference lists from published articles were scrutinized for additional inclusion.

Search Strategy
Treatment studies for PVD started to appear in the beginning of 1990s and databases were searched from January 1, 1990 to January 29, 2021.The search strategy is based on the population provoked vulvodynia for which appropriate controlled vocabulary and relevant text word terms have been identified.Duplicates were removed using a deduplication method in EndNote. 21The detailed search strategy is available in Appendix A (Tables Search Strategy).

Study Screening and Selection
2 authors (K.W.R., P.L.) screened the titles and abstracts independently using the web-based screening tool Rayyan. 22ull-text articles were retrieved if 1 or both reviewers considered a study potentially eligible.At least 2 authors (I.F., I.S., B.N., N. B.S.) read the full-text articles independently and checked them for eligibility against the prestated criteria, and any disagreement was resolved by discussion.At least 2 authors (I.F., I.S., B.N., N. B.S., K.W.R., P.L.) independently assessed eligible studies for risk of bias using established tools developed by Cochrane for randomized controlled studies, 23,24 and non-randomized controlled studies of interventions. 25Swedish versions of the tools were used which included an extra question regarding potential conflicts of interests of the study authors.The outcomes of the studies were assessed as having either high risk of bias, some concern, or low risk of bias, based on risks of bias in the following domains: randomization, adherence, missing outcome data, measurement and reporting.Any disagreement was resolved by discussion involving at least 3 authors.Studies with high risk of bias were excluded from the subsequent analysis.

Data Extraction
For included studies, we extracted country of origin, sample size, mean age of the participants, description of the intervention and the control intervention, length of follow-up, drop-out rate, and outcome data.It was also checked if the study was registered in a clinical trials registry, and whether the registration date was prior to enrollment of the first participants or reported date of study start.For outcomes, the following data were extracted: -Pain during intercourse − self reported pain during intercourse or sexual activity rated on a visual analogue scale (VAS) or a numeric scale (NRS).For some studies, data was extracted from questionnaires using various functional descriptors of coital pain.
-Pain upon pressure or touch − pain ratings (VAS, NRS) during a gynecological examination using a cotton swab test or a vulvar algesiometer.
-Sexual function and satisfaction − data was extracted from the Female Sexual Function Index (FSFI; first choice), or an equivalent questionnaire evaluating sexual health, such as Index of Sexual Satisfaction 0−100 (ISS) or Global Sexual Functioning 0−1, (GSF) (second choice).
-Quality of life − various validated instruments regarding different aspects of QoL.
-Mental distress − data was extracted from various validated instruments assessing anxiety and depressive symptoms such as Beck Depression Inventory, Generalized Anxiety Disorder 7) and State-Trait Anxiety Inventory of Spielberger, state domain.
-Adverse events (AE), complications and negative treatment effects − if reported, adverse events and complications were divided into mild or severe.Firstly, data on the proportion of participants with AEs was extracted and secondly data on other descriptions of AEs and complications.

Synthesis and Statistical Analysis
Our intention was to perform meta-analyses when comparable outcomes were reported from studies with similar comparisons of interventions, but that was not applicable.The results from each intervention were summarized in tables where effectsizes, depending on the type of outcomes, were expressed as mean difference (MD), risk difference (RD) or risk ratio (RR) with 95% confidence intervals (CI), or alternatively, as "significant/non-significant" if no other information was available.If no comparative analysis between study groups was reported in the original study, the effect-size was calculated with 95% CI using Review Manager. 26

Assessment of Evidence
For each outcome, we assessed the certainty of evidence that an intervention was superior, inferior, or equivalent to the control, using grading of recommendations assessment, development, and evaluation (GRADE), where the certainty of evidence is expressed as high (++++, moderate (+++o), low (++oo) or very low (+ooo). 27Thresholds for effect sizes were not integrated in the rating. 28

Search Results and Study Selection
The search of databases yielded 2873 records, from which 72 articles were examined in full text.Of these, 33 articles reporting data from 30 studies fulfilled the eligibility criteria and were assessed for risks of bias.The final sample consisted of 27 articles with low or moderate risk of bias from 22 unique RCTs and 2 non-randomized studies (Figure 1).

Pharmacological Treatments
A large variety of pharmacological treatments has been investigated for provoked vulvodynia.In total, 16 articles based on 14 studies (13 RCTs and 1 NRSI) with low or moderate risk of bias were identified, and are presented in Tables 1−3.All results on pharmacological treatments were assessed to have very low certainty of evidence.
Oral Medications.Pain reduction was the main rationale for the various oral medications.Gabapentin, an anticonvulsant, and desipramine, which is a tricyclic antidepressant drug, are often used as first line treatments for neuropathic pain. 29The substances were used in randomized double-blinded placebocontrolled trials.For gabapentin, sexual function improved for the intervention group, and for desipramine, sexual satisfaction improved, both compared to placebo 30−32 (Table 1).The antiinflammatory substance palmitoylethan olamide (PEA) was used in combination with oral transpolydatine for 2 months in 1 small    Limitations in reporting, no intention to treat (ITT) analysis.
x Risk for confounding (not randomized).
{ Other treatment arms from this study are reported in Table 1.RCT. 33 No significant difference in treatment effect compared to placebo was reported (Table 1).
Topical Medications.For topical medications, 5 RCTs and 1 NRSI study were identified, each one investigating the effect of different substances (Table 2).
2 substances with potential anti-inflammatory effect were evaluated in double-blinded RCTs.In 2 separate studies, cutaneous fibroblast lysate and cromolyn sodium creams were applied externally on the vestibule for 3 months.For fibroblast lysate, the intervention group reported significantly less pain during intercourse compared to placebo after 12 weeks' treatment, but no difference was found in pain intensity during cotton-swab test. 34No significant difference in pain during intercourse was obtained for the cromolyn sodium cream compared to placebo (Table 2). 35peated application of topical lidocaine gel or cream is recommended in clinical guidelines to decrease pain sensitivity in the vestibular mucosa. 11However, the treatment effect has only been studied in comparison to placebo in 1 doubleblinded 12-week RCT. 32No differences in pain variables related to pain during intercourse, tampon test, or cotton swab test were observed between the groups.Non-significant differences were neither obtained for depression nor sexual function (Table 2).
The role of local hormonal status has been discussed as a possible etiological factor in PVD. 36The effect of topical conjugated estrogen-or placebo cream was investigated in a double-blinded 8-week RCT without any proven effect for reduction of pain during intercourse or improved sexual function (Table 2). 37udies on other topical treatment included 1 non-randomized but double-blinded study investigating the effect of nifedipine cream that previously has been reported to heal anal fissures. 38The result showed no differences in pain during intercourse or cotton swab test between the groups.Daily application of vaginal diazepam 5 mg tablets for 2 months in combination with TENS was evaluated in a double-blinded placebo-controlled trial. 39The aim of the study was possible improvements in pain and pelvic floor muscle (PFM) function due to muscle relaxing effect of diazepam.The intervention group reported significant less pain during intercourse after 2 months' treatment and 10% experienced a mild drowsiness (Table 2).
Treatment by Injections.The neurotoxin botulinum toxin A (BTA) has been evaluated in 3 double-blinded RCTs with a total of 186 participants.BTA was injected in either PFM, or in the vestibular submucosal tissue. 1 study reported significantly less pain during intercourse or tampon use at 3 months after 1 treatment.The positive effect was no longer present at the 6 months' follow-up, despite repeated treatment. 40For the other 2 studies, no significant favorable effect of BTA was reported compared to placebo for variables related to pain or sexual function. 41,42The results were not combined statistically due to various aspects of study heterogeneity (Table 3).Subcutaneous injections of enoxaparin (low-molecular-weight heparin) with the aim to block the enzyme heparinase and thus hamper potential neuroproliferation in the vestibular mucosa was used in 1 small double-blinded RCT. 43No difference in pain during intercourse was obtained between the study groups, but less pain for vestibular touch and pressure was reported in the intervention group (Table 3).

Physiotherapeutic Treatments
4 randomized controlled trials for physiotherapeutic treatments were included.The results could not be combined for statistical synthesis due to the differences of the various interventions.−47 The study with some proven evidence of effect was an RCT where the intervention group received a combination of physiotherapeutic treatments for 10 weeks. 44The treatment consisted of education and information, exercises for pelvic floor muscles (PFM) using EMG biofeedback, as well as manual physiotherapy.The intervention group was further instructed to perform home exercises for PFM function and vaginal dilation.The control group used topical lidocaine cream every night for the equivalent period of time.There were significantly better results in the intervention group for pain during intercourse and sexual function, when the treatment was completed, but also at 6 months' follow-up (Table 4).
Improvement in pain during intercourse and sexual function was reported in a 20-session RCT using transcutaneous electrical nerve stimulation (TENS). 47Both the intervention and control group used the same device, but the intervention group received higher frequency compared to a simulated treatment with low frequency for the control group (Table 4).
1 RCT evaluating EMG biofeedback for PFM rehabilitation vs topical lidocaine 45 and another RCT comparing traditional acupuncture to sham-procedures, 46 didn't show any significant findings in favor for the intervention group regarding pain or sexual function (Table 4).

Psychological Treatments
The effect of psychological treatments was evaluated in 5 different studies, 4 RCTs 48−51 and 1 partly randomized study. 52he treatments were either performed as a single intervention, or in combination with various other interventions.Due to the heterogeneity of the studies, no statistical synthesis of the results could be done.All study results were assessed to have very low certainty of evidence.
All studies evaluated the effect of either cognitive behavior therapy (CBT) or mindfulness-based interventions including  In one 12-weeks RCT, group CBT was compared to either EMG biofeedback for pelvic floor rehabilitation or surgery, where part of the sensitive vestibular mucosa was removed in a standardized procedure (vestibulectomy). 48Variables related to pain and sexual function were measured after completed treatment and at 6 months' follow-up.The results at both occasions showed significantly less pain during intercourse and pain upon touch and pressure (cotton-swab test) for participants who had undergone surgery as compared to CBT and EMG biofeedback (Table 5).Differences in results from the cotton-swab test were in favor for surgery compared to the 2 other interventions at a 2.5 years' follow-up, reported in a separate publication. 53Concerning pain during intercourse, the long-term effect only showed a significant difference between surgery and EMG biofeedback.
Individual or group-based CBT compared to topical hydrocortisone or physiotherapy was investigated in 2 RCTs. 49,50In the first study, the result of 10 sessions group CBT vs application of topical lidocaine during a 13-week RCT showed no significant differences in pain during intercourse or sexual function between the groups. 49In the second study, participants were randomized to either 8 sessions of individual CBT or to physiotherapy with additional home exercises for both groups. 50After treatment, significantly less pain during the cotton-swab test was obtained in the group receiving physiotherapy, but this difference was not found at the 6 months' or 12 months' follow-ups (Table 5).
Mindfulness-based CBT (mCBT) has been evaluated in another 2 studies.In the first study, the allocated interventions were either group mCBT or group CBT for 8 weeks. 51The results showed less pain during intercourse up to 6 months after treatment completion for the mCBT group, but the difference was no longer observed after 12 months.The treatment effect of mCBT in group has also been compared to a therapy consisting of digital PVD education and support. 52The effect on sexual function was in favor for mCBT up to 3 months after completed treatment.For anxiety and depressive symptoms, significantly better results were found up to 6 months after treatment in the mCBT group, but there were no differences in pain upon pressure and touch (Table 5).

Other Treatments
−56 The study results were all assessed to have very low certainty of evidence.
Low level laser therapy or simulated treatment via a vaginal probe with the aim to reduce pain was evaluated in a double-blinded 6-weeks RCT. 55In a 2-week RCT, the effect of transcranial electric stimulation vs sham stimulation for PVD was investigated. 56The intervention is a non-invasive method using direct current towards specific areas of the brain in an attempt to reduce pain during intercourse.None of the studies found any significant differences for variables related to pain, sexual satisfaction, anxiety or depression between the study groups (Table 6).
Low intensity shock-wave treatment via a vaginal probe was evaluated in a small double-blinded RCT over 6 weeks. 54The control group received simulated treatment with the same device.Significant less pain during intercourse was reported in the active treatment group 1 and 3 months' posttreatment, but no effect on sexual function was obtained (Table 6).
Side-Effects.None of the studies reported any serious adverse event, but mild side-effects occurred.In general, data on sideeffects was heterogeneously assessed and reported.

DISCUSSION
The main finding of this systematic review is the evident lack of methodologically sound trials evaluating treatment effects for women with PVD.A diversity of treatment approaches was identified, but in most cases only 1 single study fulfilled the selection criteria.Consequently, our conclusions rely on a very restricted research basis, and data could not be merged into meta-analyses due to the heterogeneity in interventions as well as in outcome measures.This does not mean that effective treatments for PVD do not exist, but it underscores the need of stringent trials and defined core outcome sets.
Most results had a very low certainty of evidence, which means that we are unable to conclude on the effects of the interventions.The only intervention where some evidence could be proven (with low certainty) was multimodal physiotherapy, when compared with lidocaine treatment. 44It is worth noting that the more extensive physiotherapeutic intervention that included various pelvic floor muscle exercises but also information and education, resulted in improvements in both intercourse pain and in sexual function, compared to the less complex, yet commonly used, topical lidocaine treatment.Although based on findings from only 1 study, this indicates that women with PVD benefit from more complex interventions, where several components are combined to manage pain and its consequences.
The lack of controlled studies on this group has repeatedly been pointed out in literature. 11,13,14,16,57Yet, a recent systematic review of treatment effects has been warranted to enable evidence-based treatment recommendations.Unfortunately, our findings do not serve this purpose, instead the need of rigorous treatment studies can once more be stated.
The results demonstrate that even studies evaluating effects of frequently used treatment options for PVD are missing.For instance, we cannot draw any conclusions about the effects of   Calculation was made since no analysis of differences between groups were reported in the study.Some uncertainty exists regarding the correct number of participants for the various outcomes.
z Small study population, only 1 study, no statistical significant results.neither surgical interventions, nor multimodal or team-based interventions.Noticeable, not a single study of the effect of vestibulectomy surgery fulfilled the selection criteria, despite its long tradition as a treatment for severe cases of PVD.There have been non-controlled cohort studies of vestibulectomy indicating positive effects, 16 including on long term follow-ups. 58Yet, considering the lack of control groups in these studies, the effects of placebo or spontaneous recovery cannot be ruled out.Multimodal interventions are well-established treatment options for PVD, often recommended by specialists and in treatment guidelines.A combination of pain management, pelvic floor exercises and psychosocial interventions intuitively make sense, and corresponds with treatment for other chronic pain conditions. 51,59,60evertheless, controlled studies are needed to document the effects.
Women with PVD is a heterogeneous group and there might be subgroups who would benefit from different types of interventions.Preferred treatment option might for instance depend on whether the condition is primary or secondary, the age of the woman, and if she is able to engage in intercourse or not.These characteristics should ideally be well described in clinical studies, and it is desirable that strict adherence to the Consensus guidelines from 2015 is maintained regarding definition of PVD and method of diagnosis. 3Indeed, the effect of psychological treatments has been found to depend on individual characteristics. 52o explore this further, future studies should preferably include analyses of potential predictors and moderators of treatment effects.
In this evaluation, standard procedures and tools for systematic reviews were used, and the research question as well as the inclusion criteria were formulated and preregistered using the PICO (Population Intervention Comparison Outcome) model for clinical questions.Hence, our results present a state-of-art overview of current evidence for treatment options for women with PVD, following the golden standard for systematic reviews.
Yet, there are some inevitable shortcomings.The strict eligibility criteria resulted in a very limited number of studies.Only studies of premenopausal women with specifically PVD were included, excluding samples with predominantly generalized vulvodynia, and other age groups.In a few cases, specific information about the study sample was missing, and if this information could not be achieved (eg, by contacting the authors), these studies were excluded.Similarly, all trials without a defined control group were excluded, which might be questioned considering the increasing critique of controlled group designs as the only way of assuring high internal validity in intervention studies. 61eplicated single-case experimental designs is a promising alternative, recently gaining recognition as being able to provide a strong basis for establishing intervention effects. 61,62However, studies with non-traditional designs were outside the scope of the current review.On the one hand, our strict eligibility criteria might have resulted in a loss of important information.Further more, this review provides an up-to-date picture of current evidence.Besides our meticulous selection of studies, conclusions were further complicated by the wide range of outcome measures used in the included trials.This underscores the need of joint defined core outcome sets for intervention trials in this field, pointed out by several earlier reviews. 63,64Conjoint agreements on which outcomes to focus on is a prerequisite for advancing the knowledge about effective treatments for women with PVD.

CONCLUSIONS
This systematic review, aiming at summarizing existing controlled trials of the effects of different treatments for women with PVD, underlines the need for more research in this field, in particular trials evaluating multimodal treatment approaches.Specifically, methodologically rigorous studies of treatment effects, using joint core outcome sets are demanded.This is a key for enabling evidence-based treatment guidelines and enhanced health care for women with PVD.("genito pelvic pain*" or "genitopelvic pain*" or "primary VVS" OR "secondary VVS" or "sexual pain disorder*" or vestibulitis or vestibulodynia or "vulva pain" or "vulvar pain" or " vulvovaginal pain" or vulvodynia)

Figure 1 .
Figure 1.Flow-chart from the literature search.Number of articles are larger than the number of studies since data from the same study are reported in separated publications.RCT = randomized controlled trial; NRSI = non-randomized studies of interventions.

y
Small study population, only 1 study.zNon-blinded study, risk for anticipated effects could have affected the outcome.x Small study population, only 1 study, no statistical significant results.{ Large drop-out rate.C = control; CI = confidence interval; FSFI = Female Sexual Function Index (2−36); I = intervention; ISS = Index of Sexual Satisfaction (0−100); MD = mean difference; MDS = Marinoff Dyspareunia Scale (0−3); NRS = Numeric Rating Scale; NS = non-statistical significant difference; RCT = randomized controlled trial; VAS = Visual analogue scale.CBT-techniques, with various potentially active treatment arms for the control groups.CBT for PVD aims at facilitating pain management through systematic work with behaviors and cognitions related to pain and sexual arousal.Several techniques are applied, such as pelvic floor relaxation, cognitive strategies, and communication skills training.Mindfulness-based interventions add the component of acceptance and mindfulness training to these basic CBT-techniques.

Table 1 .
Pharmacological oral medications * 2 treatment arms from the same study(Foster 2010).y Small study population, only 1 study, no statistical significant difference.

Table 2 .
Pharmacological topical treatments *Small study population, only 1 study.y Small study population, only 1 study, no statistical significant difference.z

Table 3 .
Pharmacological treatments by injections *Unknown questionnaire.y Small study population, no statistical significant difference.z Small study population, only 1 study, no statistical significant results.

Table 4 .
Physiotherapeutic treatmentsCalculation of mean difference (MD) was done from study data, since no differences between groups were presented in the study. *

Table 5 .
Psychological treatments *Large drop-out rate, no blinding.y Small study population, only 1 study.z Small study population, only 1 study, no statistical significance.

Table 6 .
Other treatments *Burning sensation, erythema, itch.y The search result, usually found at the end of the documentation, forms the list of abstracts.AB = Abstract AU = Author DE = Term from the thesaurus MM = Major Concept TI = Title TX = All Text.Performs a keyword search of all the database's searchable fields ZC = Methodology Index * = Truncation " " = Citation Marks; searches for an exact phrase Term from the Medline controlled vocabulary, including terms found below this term in the MeSH hierarchy this term only = Does not include terms found below this term in the MeSH hierarchy :ti = title :ab = abstract :kw = keyword * = Truncation " " = Citation Marks; searches for an exact phrase CDSR = Cochrane Database of Systematic Review CENTRAL = Cochrane Central Register of Controlled Trials, "trials"The search result, usually found at the end of the documentation, forms the list of abstracts./de= Term from the EMTREE controlled vocabulary /exp = Includes terms found below this term in the EMTREE hierarchy /mj = Major Topic :ab = Abstract : au = Author :ti = Article Title :ti:ab = Title or abstract * = Truncation " " = Citation Marks; searches for an exact phrase The final search result, usually found at the end of the documentation, forms the list of abstracts..ab. = Abstract .ab,ti.= Abstract or title .af. = All fields Exp = Term from the Medline controlled vocabulary, including terms found below this term in the MeSH hierarchy .kf. = Keyword heading word .sh. = Term from the Medline controlled vocabulary ti.= Title / = Term from the Medline controlled vocabulary, but does not include terms found below this term in the MeSH hierarchy * = Focus (if found in front of a MeSH-term) * or $ = Truncation (if found at the end of a free text term) .mp= text, heading word, subject area node, title " " = Citation Marks; searches for an exact phrase ADJn = positional operator that lets you retrieve records that contain your terms (in any order) within a specified number (n) of words of each other.
*" or "genitopelvic pain*") OR AB ("genito-pelvic pain*" or "genitopelvic pain*") OR KW ("genito-pelvic pain*" or "genitopelvic pain*") 54 2TI "primary VVS" OR AB "primary VVS" OR KW "primary VVS" 0 The search result, usually found at the end of the documentation, forms the list of abstracts.Appendix B Risk of bias in randomized studies, assessed with the ROB-2 tool *Follow-up study with complementary results to a primary study Risk of bias in non-randomized studies, assessed with the ROBINS-I tool