Efficacy of transcranial direct-current stimulation (tDCS) in women with provoked vestibulodynia: study protocol for a randomized controlled trial

The proposed research design is a triple-blind (physiotherapist assessor, patient, and treatment provider), randomized, placebo-controlled, parallel-group trial. Participants are randomized to receive either active or sham tDCS for ten sessions of 20 minutes of stimulation over a 2-week period. As illustrated in the flow diagram (Fig. 1), the study includes three evaluation points (pretreatment assessment, post-treatment assessment performed at 2 weeks, and follow-up assessment at 3-months post-treatment). This study protocol was written in accordance with the SPIRIT statement (see Additional file 1 for the completed SPIRIT checklist).

Premenopausal women, ages 18–45 years, suffering from pain during intercourse, are being recruited at the Research Center of the Centre Hospitalier Universitaire de Sherbrooke (CHUS). The eligibility criteria are detailed in Table 1. These criteria were selected to ensure recruitment of a homogenous sample of sexually active women with PVD and were based on previous successful studies [13, 50, 51]. In order to confirm the diagnosis of PVD, the eligibility screening comprises a gynecological assessment performed by a gynecologist from our team, following a standardized protocol. The latter consists of a brief anamnesis and a comprehensive gynecological examination of the vulvar region (clitoris, small lips, interlabial furrow, and vestibule), testing for vaginal infection and sexually transmitted disease, and palpation of the uterus and appendices. This evaluation follows the diagnostic criteria defined by Friedrich [2] and more recently modified by Bergeron et al. [52], namely, (1) pain in the vestibule following touch or an attempted vaginal penetration or (2) acute pain during palpation of the vestibule region with a cotton swab. Interevaluator fidelity of this diagnosis method has been demonstrated [52] and used in several RCTs [13, 53, 54]. Therefore, vulvar pain occurring in the absence of an underlying recognizable disease and provoked spontaneously as a result of physical contact can be classified as PVD [55].

Participants are randomized to receive ten sessions of either active or sham anodal tDCS over a period of 14 days. tDCS treatments are given once a day, during weekdays (Monday to Friday). Each session lasts 20 minutes [20, 41, 44, 56, 57] and is administered by a research professional experienced in tDCS. The treatment provider is not involved in the patient assessment and is blinded to the treatment allocation by selecting a preset program of the tDCS device (NeuroConn DC stimulator). Two electrodes are applied to the subject’s scalp; the anode is placed over the motor cortex (M1) [58], and the cathode, over the contralateral supraorbital area [20, 41, 44, 57, 58]. For treatment with active tDCS, the intensity of the stimulation is set at 2 mA for the entire duration of the treatment [20, 41, 42, 44, 49, 56]. The parameters used in our study have been tested with many subjects in several different laboratories without side effects [59], apart from a slight itching, tingling, or burning sensation under the electrode during the first seconds of stimulation; discomfort or erythema (skin reddening) under the active electrode; and possible headache in the hours following the treatment. If the stimulation is switched on or off abruptly, the sensation of a short ocular light flash could also be felt by the participant [60]. For subjects receiving sham tDCS (placebo group), the electrodes are positioned in the same areas as the group receiving active stimulation, and the intensity is set at 2 mA for the first 30 seconds of treatment [57], after which the stimulation stops automatically. Just as for active tDCS, participants are advised that a brief tingling sensation may be felt at the beginning of treatment. This method is effective for preserving subject and investigator blinding [61].

In order to report the participants’ adverse events during tDCS treatment, at each treatment session, the treatment provider notes the participants’ side effects, and the subjects are asked to complete a logbook in which they have to report whether they experience any adverse events or pain in the vulvar region, whether related to intercourse or not. Participants also have to record their experienced vulvar pain in the same logbook between the end-of-treatment period and the 2-week post-treatment assessment.

Participants are recruited using different promotion strategies: (1) referrals from health professionals (gynecologist, general practitioner, sexologist, psychologist, or physiotherapist); (2) posters and leaflets distributed to women in clinics, universities, professional schools, restaurants, gyms, etc.; (3) Facebook advertisement; and 4) advertisements in local newspapers. Women interested in participating are invited to contact the research coordinator for a detailed explanation of the study and verification of their eligibility. Thereafter, participants undergo a gynecologist’s examination for confirmation of their diagnoses. Once a diagnosis of PVD has been confirmed, the research assistant contacts the participants to confirm their admissibility into the study. Upon doing so, she provides the participants with instructions to follow before the assessment and, then, fixes the appointments. To avoid effects on the vestibular pain sensitivity measurements prior to each assessment, participants will be asked to refrain from smoking and consuming caffeine (coffee, tea, and energy drinks) 4 hours prior to the evaluation [62], to refrain from taking painkillers (Advil®, Motrin®, Tylenol®, etc.) 24 hours before the evaluation [63], and to not have or attempt vaginal intercourse in the 24 hours before the evaluation [64]. After signing the informed consent, the eligible women are invited to undertake a 1-hour pretreatment assessment (baseline) with a physiotherapist specialized in pelvic-floor rehabilitation and pain assessment. During the pretreatment assessment, a structured interview is conducted to collect the patient’s baseline characteristics, and standardized questionnaires are completed. Approximately 30 minutes are required to complete all questionnaires. These questionnaires have been successfully used in our previous studies, without hindering data quality [65]. A vestibular pain sensitivity assessment is also undertaken using the algometer [66]. The participants are then randomized to receive either active or sham tDCS. The same procedures are repeated at the 2-week post-treatment and 3-month follow-up assessments.

As for other clinical trials, the greatest challenges pertain to participant retention. Strategies implemented to minimize attrition are as follows: (1) each participant is required to supply her contact information, such as phone number(s) and e-mail address; 2) a research assistant makes sure to remind participants of their appointments, as well as of the importance of their continuous participation; 3) all appointments are flexible to fit in with the participants’ schedule (i.e., early morning, late in the evening, etc.); and 4) participants receive a $20 compensation at three different stages of the study (the assessments) to cover travel expenses and their participation in the study. Adherence to the study protocol is also promoted throughout the trial. The physiotherapist-evaluator has received a standardized training to ensure homogeneity of procedures and reduce bias due to the evaluator. This physiotherapist-evaluator also has access to a detailed written assessment protocol Version 4 (Nov. 2, 2015). The research professional in charge of treatment is not involved in patient assessment and similarly has received proper training for the application of tDCS. The PI also carries out a weekly supervision of the physiotherapist’s and professional’s adherence to protocols. Moreover, the effectiveness of blinding for all physiotherapists and patients is evaluated with a questionnaire. Participants are also asked to abstain from the following PVD-related treatments (i.e., pelvic floor physical therapy, topical lidocaine application, vestibulectomy, and psychotherapeutic and systemic interventions) during their enrollment in the study, and this is monitored at the 2-week post-treatment and 3-month follow-up assessments. In order to avoid missing data, at the end of each assessment, the physiotherapist-evaluator revises all completed questionnaires before the participant leaves.

After the pretreatment assessment, the participants are randomized into either the active or sham tDCS treatment (ratio 1:1) using permuted blocks of two and four. The allocation is managed by an individual independent from our research team who follows a computer-generated randomization list drawn up by an independent statistician. Participants, investigators, physiotherapist assessors, and the treatment provider remain blinded to group allocation and, therefore, cannot influence the process in any way.

The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) has recently recommended several outcome domains for use in evaluating the effectiveness of treatment in chronic pain conditions [67]. The current protocol adheres to these recommendations, with outcomes focusing on the multiple dimensions of PVD, such as pain, sexual function, psychological distress, participant ratings of improvement and satisfaction with treatment, and the need to assess the potential impact of treatment on these different dimensions.

The study has received ethical approval from the comité d’éthique de la recherche en santé chez l’humain du CHUS (14-169). Every potential participant is made aware that there will be no impact on her medical care if she decides not to participate in the study. Women who refuse to participate in the study or who do not fulfill the eligibility criteria are followed by the clinical staff using the most recently proposed vulvodynia guidelines. In order to minimize privacy risks, all participants are identified by an alpha-numeric code. Informed consent is obtained from all participants prior to trial inclusion. This trial is registered at clinicaltrials.gov NCT02543593.

The recruitment of participants is ongoing at the Research Center of the CHUS. Forty women with PVD are planned to be recruited and randomized from December 2014 to May 2016.