Clinical trial NCT04234542: Is Low Level Laser Therapy (LLLT) Effective for Reducing Pain Experienced by Women With Provoked Vestibulodynia?
Official title: Is Low Level Laser Therapy (LLLT) Effective for Reducing Pain Experienced by Women With Provoked Vestibulodynia?
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Provoked Vestibulodynia
Keywords: vulvar pain
pelvic floor
low level laser therapy
laser
transcranial magnetic stimulation
electromyography
Lead sponsor: University of Ottawa
Sponsor class: OTHER
Collaborators: name: BioFlexTM Laser Therapy
First posted: 2020-01-21
Enrollment: 28
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Provoked vestibulodynia (PVD) is one major subtype of vulvar pain, affecting close to one in ten women and resulting in pain during attempts at vaginal intercourse and/or attempts to insert a digit, device or tampon into the vagina. Management involves a multidisciplinary approach, through physicians, psychologists, sex therapists and physiotherapists. Low Level Laser Therapy (LLLT) is a therapeutic modality involving irradiation of injured or diseased tissue with a combination of red and infrared light. This process is thought to initiate a series of physiological reactions within the cells exposed to light at these wavelengths, leading to the restoration of normal cell structure and function. The investigators hypothesize that LLLT will be effective at reducing pain and improving sexual function among women with PVD.

The purpose of this double-blind randomized controlled trial is to assess the feasibility of using a LLLT intervention for the management of PVD in women. The aim is to determine whether there is evidence of a positive effect of LLLT, delivered using a BioFlexTM laser system (Health Canada Licence No. 7931) and a semi-standardized protocol, in terms of self-reported pain and sexual functioning, physiological responses to pressure applied at the vulvar vestibule, tonic and phasic activation of the PFM and/or corticomotor excitability to the PFMs in women with PVD with or without concurrent vaginismus (VAG) when compared to an identical treatment schedule where sham LLLT is delivered.

Women will be recruited from among eighty women with confirmed PVD and PVD+VAG who participate in a cross sectional study investigating pelvic floor muscle involvement in PVD. If they are interested in participating in this intervention study, they will be asked to consent to having their data from the cross sectional study used for the purposes of this concurrent study.

Women will be evaluated before the intervention using a battery of physical assessments and questionnaires, re-evaluated on primary outcome measures 3 weeks after initiating the intervention and then re-evaluated using the complete battery of physical assessment and questionnaires at the end of the intervention period. If we secure further funding, a medium term (12 weeks later) follow-up will be added. Physical assessment will include evaluation of pressure-pain threshold, temporal summation of pain, electromyographic (EMG) evaluation of PFM activity, responses of the PFMs to pressure applied at the vulvar vestibule using a custom electronic vulvalgesiometer, motor evoked potential threshold, amplitude, latency and the duration of cortically mediated silent period recorded from the PFMs following transcranial magnetic stimulation. The questionnaires will include the The Vulvar Pain Assessment Questionnaire (VPAQ), the Female Sexual Functioning Index, the Pain Catastrophizing Scale, the Depression Anxiety Stress Scales and the Central Sensitization Inventory. Three weeks and 12 weeks after the first start of treatment, the Global Perception of Improvement and Global patient satisfaction with treatment questionnaires will be administered. These will be repeated 12 weeks after completing treatment if funding becomes available.

Detailed description: Vulvar pain affects the psychological and sexual health of more than one in five Canadian women, yet its pathophysiology is poorly understood. Provoked vestibulodynia (PVD) is one major subtype of vulvodynia, affecting close one in ten women and resulting in sharp, burning pain during attempts at vaginal intercourse and/or attempts to insert a digit, device or tampon into the vagina. Hypersensitivity of the vulvar vestibule is one of the key defining characteristics of PVD and, while its pathogenesis is unknown, it has been primarily attributed to inflammatory processes and hyperinnervation. Pelvic floor muscle (PFM) dysfunction has also been implicated in many forms of dyspareunia, yet the nature of this involvement also remains largely unknown.

Low Level Laser Therapy (LLLT), or photobiomodulation, is a therapeutic resource involving irradiation of injured or diseased tissue with a combination of red and infrared light. This laser is thought to initiate a series of physiological reactions within the cells exposed to light at these wavelengths, leading to the restoration of normal cell structure and function.

The purpose of this randomized controlled trial is to assess the feasibility of using a comprehensive LLLT intervention for the management of PVD in women with PVD alone (PVD) or with concurrent vaginismus (PVD+VAG). True and sham LLLT will be delivered by the BioFlexTM laser system (Health Canada License No. 7931). The aim is to determine whether there is evidence of a positive effect of LLLT delivered using a semi-standardized protocol delivered by the BioFlexTM laser in terms of primary outcomes including pain, sexual functioning and overall symptoms and secondary outcomes including changes in physiological responses to pressure applied at the vulvar vestibule, corticomotor excitability to the PFMs, and tonic activation and motor control of the PFMs.

Women will be recruited from among eighty women participating in a cross sectional study investigating pelvic floor muscle involvement in PVD. Women will therefore already have been recruited through local physiotherapists and gynecologists who have specific expertise in genital pain disorders and a diagnosis of PVD and PVD+VAG will have been confirmed through screening (Friedrich's Criteria as well as digital palpation assessment) by a gynaecologist, gynaecology resident or pelvic health physiotherapist, all with specific training on the assessment of vulvar pain. Other causes of vulvar pain, including generalized vulvodynia, infection, lichen sclerosis etc. will have been ruled out. Potential participants will be approached by the study protocol officer after they have participated in the cross sectional study and asked if they are interested in participating in this intervention study. If so, they will be asked to consent to having their data from the cross sectional study passed on to the current study.

Women will be evaluated before and after the 12-week intervention on all outcome measures, while primary outcome measures will be also evaluated after 3 weeks of intervention in both groups.

The physical assessment will be conducted by an experienced pelvic floor physiotherapist.

The evaluations will include the completion of five online questionnaires (The Vulvar Pain Assessment Questionnaire (VPAQ), Female Sexual Functioning Index, Pain Catastrophising Scale, Depression Anxiety Stress Scales, the Central Sensitization Index) and the physical assessment.

The physical assessment will involve:

1. Tampon test: participants will be provided with Original Regular Tampax Tampon and will be instructed to insert and then remove it. The participant will be instructed to report the level of pain induced through the entire insertion/removal experience on a 0-10 numeric rating scale for pain (0 meaning no pain and 10 meaning the worst pain imaginable).
2. Pressure pain threshold (PPT) will be determined involving three trials using a custom vulvalgesiometer, and will be defined as the median pressure at which women first report pain when a cotton swab tip is applied at the posterior fourchette of the vaginal introitus.
3. Temporal summation (TS) of pain: The vulvalgesiometer will again be used. A consistent pressure equivalent to the pressure that induced a pain rating of 4/10 will be applied to the posterior vaginal fourchette ten times at a rate of approximately one per second. Participants will rate their pain level on the initial and final application of this pressure using the numeric rating scale (0-10). TS will be defined as the difference in pain rating between the final and first application of the pressure.
4. Responses of the pelvic floor muscles to pressure applied at the vulvar vestibule: Women will be instrumented with electromyography (EMG) electrodes over four muscles. The superficial (bulbocavernosus and external anal sphincter) layer will be instrumented with rectangular self-adhesive gelled electrodes placed in a differential configuration on the participant's right side. The deep (pubovisceralis) PFMs will be instrumented using one custom differential suction electrode (DSE) configuration with one electrode (pole) placed on the vaginal wall overlying the muscle on the right side and the other electrode (pole) located on the anterior vaginal wall superficial to the PFMs (i.e. approx. 1.5 cm from the introitus). A common reference gelled electrode will be adhered to the skin overlying the anterior superior iliac spine on the right side. Additionally, Delsys D.E. 2.1 differential electrodes will be located over the upper trapezius muscle and over the adductor longus muscle on the right side. All EMG electrodes will be interfaced with Delsys Bagnoli-16 amplifiers (overall gain X1000, common mode rejection ratio -120dB at 60Hz; bandpass 20Hz-450Hz) and all EMG data will be sampled at 2000Hz through a 32-bit National Instruments Analog to Digital Converter (NIDAQ USB3086) and stored on a PC using Powerlab Labchart 8 Pro software. Two separate, custom vulvalgesiometers will be instrumented such that a switch that is activated when a low (25 g) or moderate (232 g) pressure is delivered. The switch (on-off) data will be recorded alongside the EMG data through the PowerLab™ software in order to separate out anticipatory activation (i.e. the EMG signal onset is before the switch is activated) from response activation (i.e. the EMG signal onset is after the switch is activated).

   The vulvalgesiometers will be used at the posterior vaginal fourchette and at the posterior aspect of the thigh. The order of the pressure application sites (vaginal fourchette vs posterior thigh) and the intensity of the pressure stimulus (low vs moderate) will be randomized using a computer generated randomization scheme. Five repetitions will be performed for each location/pressure intensity combination using a consistent inter-stimulus interval of 120 seconds. For each pressure level and site, an anticipatory response will be considered to be present on an EMG channel if, at that site, EMG activity rises two standard deviations above the noise before the pressure is applied on at least two of ten trials; while a behavioral response will be considered to be present on any EMG channel if, at that site, the EMG activity rises two standard deviations above the noise after the pressure is applied on all ten trials. For each pressure level and site, EMG response amplitudes will be recorded based on smoothed (full-wave rectified and low pass filtered using a 4th order dual-pass Butterworth filter with 3dB cut-off of 5Hz).
5. Tonic, phasic and reflex activation of the PFMs: After five minutes of rest, tonic EMG activation will be recorded from all EMG channels for a period of one minute while women are instructed to relax their PFMs as much as possible, then EMG data will be recorded throughout three trials of maximum effort PFM contractions. Next, women will be instructed on a bearing down maneuver (Valsalva) whereby they will use their diaphragm and abdominal muscles to generate an increase in intra-abdominal pressure. EMG data will be recorded from one second before the command to inhale and until 20 seconds after the command to bear down is given; three separate trials will be performed. A rest of two minutes will be given between trials and tasks to minimize the effect of fatigue, activation induced by the tasks, and/or vasovagal symptoms. Raw EMG data will be smoothed (full-wave rectified and low pass filtered using a 4th order dual-pass Butterworth filter with 3dB cut-off of 5Hz) before EMG amplitudes are determined. For tonic activation and activation during the Valsalva, mean smoothed EMG amplitude will be computed across the length over which the task is sustained. For voluntary activation, the peak smoothed EMG amplitude will be retained.
6. Corticomotor excitability of the projections to the PFMs - A Magstim® 200 system coupled with a double cone coil (96 mm loops, P/N 9902) will be used to probe the corticospinal projections to PFMs using transcranial magnetic stimulation (TMS). Participants will be fitted with a Waveguard TMS compatible cap (ANT North America Inc, WI 53719) and the vertex location will be marked at the intersection between the sagittal and coronal bisections of the head. An additional EMG channel will be added to the others already instrumented; a D.E. 2.1 electrode will be placed over the tibialis anterior muscle on the right side. With the coil at a point 2cm ventral to the vertex, magnetic stimulation intensity will be systematically increased until MEPs (50µv) are reliably evoked from the tibialis anterior muscle. The resting motor threshold (rMT) will be established using a software tool (Motor Threshold Assessment Tool 2.0) which allows fast and reliable estimation with 14 to 17 stimulations. After rMT determination, 12-20 MEPs will be recorded with participants at rest and using an intensity equivalent to 1.3 rMT. The intensity will be set at 100% maximum stimulator output in cases where the 1.3 rMT is greater than 90 % maximum stimulator output. Next the cortical silent period (cSP) will be assessed by asking participants to perform 5-10 moderate contractions of their PFMs while the TMS pulse is delivered at the same intensity (1.3 rMT) as above during the contraction. During this contraction. This will conclude the pre-intervention assessment.

After the initial assessment is complete, using concealed allocation, women will be randomized to receive either the LLLT protocol or a sham protocol, for a twelve- week intervention period using a permuted block computer-generated randomization scheme (block size 4) stratified by condition (PVD vs PVD+VAG). The participant, the protocol officer, the physiotherapists delivering the treatment and the PI will remain blinded to participant group assignment throughout the treatments and the follow-up assessment.

The intervention protocol will consist of 15 sessions provided over a 12- week period, applied by two experienced pelvic floor physiotherapists (\>5 years) who have received specialized training on the application of LLLT using the Bioflex Laser system. The intervention protocol was developed in collaboration with the Clinical Director of Meditech International Rehabilitation Centers, who is also a scientific advisor to BioFlexTM Laser. Each treatment will last approximately 45 minutes and will be scheduled at the participant's convenience. During the 12- week treatment period, each participant will progress through 5 stages of treatment parameters at their own rate. The sham group will follow the same treatment steps, but the output of the laser will be at a sub-clinical intensity of 1% power. All of the steps will first include laser arrays (red and infrared light) applied to the skin overlying the sacral spine in both a horizontal and oblique placement bilaterally and the laser probe applied over the base of the spine (red and infrared light). Next, the array will be applied to the surface of the perineum (red and infrared light) followed by red light delivered by the probe at specific sites along the perineum, including the vulvar vestibule. Finally, infrared light will be applied using the probe applied to the skin overlying the branches of the pudendal nerve. Women will progress through treatment stages whereby at each stage, the same array positions and probe placement will be used but the dosage of light will be increased according to the BioFlex protocol. The laser arrays and probes will be protected with a low density polyethylene plastic cover that is compliant with the Food and Drug Administration (FDA) and United States Department of Health and Human Services (USDA) regulations. Each cover will be discarded after a single use. A mindfulness-based meditation will be provided during each assessment through noise cancelling headphones interfaced to a PC playing an audio CD. To ensure that the physiotherapists delivering the treatment remain blinded to the treatment being delivered, the real and sham (A and B) protocols have been entered into the Bioflex Laser system by the supplier and verified by a physiotherapist who is not involved in the study to ensure that they are correct. In this way none of the investigators will know which protocol (A or B) is the real treatment, and black towels will be used to cover the arrays while the treatment is delivered such that any differences in light intensity will not be visible.

Three weeks after initiating the intervention, women will repeat the five on-line questionnaires, the tampon test, PPT testing, TS testing as well as Global Perception of Improvement and Global satisfaction with treatment questionnaires, reporting to a research assistant who will remain blinded to treatment assignment. After the final treatment session (12 weeks), women will repeat these on-line questionnaires as well as the tampon test, PPT testing, TS testing, tonic and voluntary activation, anticipatory and behavioural responses, and the TMS protocol, administered by the same, blinded physiotherapist who performed the initial assessment.

After all follow-up visits are complete, women, and the research assistants, will learn whether they received the real or sham LLLT therapy, and those who received sham therapy will be invited to begin the real intervention. If follow-on funding becomes available, all women will be re-evaluated at 12 weeks following the initial therapy on all outcomes.

All outcomes will first be tested for normality using the Shapiro-Wilks test. If all outcomes are normally distributed, they will be compared between the using repeated measures (RM) ANOVA models. The Global perception of improvement will be compared between group (intervention vs control) and time (3 weeks after beginning the intervention, 12 weeks after beginning the intervention, 12 weeks after completing the intervention if available) using a three-way RM ANOVA and including condition (PVD, PVD+VAG) as a nested effect. The other outcomes will be compared between groups using three-way RM ANOVAs including group (intervention, control) and time (pre-intervention, post-intervention, 12 weeks later if available) as main effects, and including condition (PVD, PVD+VAG) as a nested effect. Alpha=0.05 will be used for all tests and effect sizes will be computed based on group means and standard deviations. Adherence rates will be recorded and intent to treat analyses are planned for participants who drop out or are lost to follow-up. For outcomes that are not normally distributed, equivalent non-parametric tests will be used wherever possible.

The sample size is based on the only pilot study that tested the therapeutic effect of LLLT on women with PVD, this study reported a significant, positive effect on pain reported during attempts at sexual intercourse among women with PVD (n=18) treated using LLLT when compared to controls (n=16) who received sham LLLT. They found that participants who received the treatment were more likely than controls to report significant or complete improvement in their pain (p=0.042) on verbal report at follow-up, a scale similar to the "Global Perception of Improvement" scale as described in this proposal. Using this result, a post-hoc power analysis (Minitab, V. 18) suggested that a sample size of 16 per group will be adequate to see a significant difference in treatment outcomes between women who receive the LLLT intervention and those who receive the sham intervention. The results of the pilot study did not demonstrate a significant treatment effect in any of their objective parameters. For example, post-hoc power analysis (MinitabTM v. 18) estimates that 154 participants per group would be required to detect a difference between treatment and control using the tampon test as the primary outcome. Given that the LLLT intervention proposed here is far more comprehensive than that used in the only pilot study published so far, there may be a greater effect associated with the proposed protocol as compared to the effect seen in the published pilot study.

Eligibility criteria: Inclusion Criteria

* Biologically born female older than eighteen years
* Premenopausal
* Not currently pregnant or pregnancy in the past six months
* No metal or electronic implants near neck or head
* No neurological condition such as stroke, multiple sclerosis, spinal cord injury, epilepsy or history of epilepsy in the family
* No tendency to faint
* Signs and symptoms consistent with provoked vestibulodynia alone or provoked vestibulodynia plus vaginismus

Exclusion Criteria

* gynaecologist cannot insert a single digit intravaginally and thus the participant would be unlikely able to tolerate the assessment procedures
* other evidence of conditions that may cause vulvar pain such as active lichen sclerosis, fissures, or infection

Primary outcomes:
measure: Global perception of improvement
timeFrame: 3 weeks (during intervention)
measure: Global perception of improvement
timeFrame: 12 weeks (following intervention)
measure: Global perception of improvement
timeFrame: 12 weeks after intervention (if funding becomes available)
measure: The Vulvar Pain Assessment Questionnaire (VPAQ)Inventory:COMPREHENSIVE (FULL) VERSION
timeFrame: Baseline
measure: The Vulvar Pain Assessment Questionnaire (VPAQ)Inventory:COMPREHENSIVE (FULL) VERSION
timeFrame: 3 weeks (during intervention)
measure: The Vulvar Pain Assessment Questionnaire (VPAQ)Inventory:COMPREHENSIVE (FULL) VERSION
timeFrame: 12 weeks (following intervention)
measure: The Vulvar Pain Assessment Questionnaire (VPAQ) Inventory:COMPREHENSIVE (FULL) VERSION
timeFrame: 12 weeks after intervention (if funding becomes available)
measure: Pain rating during the tampon test
timeFrame: Baseline
measure: Pain rating during the tampon test
timeFrame: 3 weeks (during the intervention)
measure: Pain rating during the tampon test
timeFrame: 12 weeks (immediately after the intervention)
measure: Pain rating during the tampon test
timeFrame: 12 weeks later (if funding becomes available)
measure: Pressure pain threshold (PPT) at the posterior vaginal fourchette
timeFrame: Baseline
measure: Pressure pain threshold (PPT) at the posterior vaginal fourchette
timeFrame: 3 weeks (during the intervention)
measure: Pressure pain threshold (PPT) at the posterior vaginal fourchette
timeFrame: 12 weeks (following intervention)
measure: Pressure pain threshold (PPT) at the posterior vaginal fourchette
timeFrame: 12 weeks after intervention (if funding becomes available)
measure: Temporal summation of pain
timeFrame: Baseline
measure: Temporal summation of pain
timeFrame: 3 weeks (during the intervention)
measure: Temporal summation of pain
timeFrame: 12 weeks (after the intervention)
measure: Temporal summation of pain
timeFrame: 12 weeks later (if funding becomes available)
Secondary outcomes:
measure: Global Patient satisfaction with treatment
timeFrame: 3 weeks (during intervention)
measure: Global Patient satisfaction with treatment
timeFrame: 12 weeks (following intervention)
measure: Global Patient satisfaction with treatment
timeFrame: 12 weeks after intervention (if funding becomes available)
measure: Female Sexual Function Index (FSFI)
timeFrame: Baseline
measure: Female Sexual Function Index (FSFI)
timeFrame: 12 weeks (following intervention)
measure: Female Sexual Function Index (FSFI)
timeFrame: 12 weeks after intervention (if funding becomes available)
measure: Motor evoked potential (MEP) peak to peak amplitude (µV)
timeFrame: Baseline
measure: Motor evoked potential (MEP) peak to peak amplitude (µV)
timeFrame: 12 weeks (immediately after the intervention)
measure: Motor evoked potential (MEP) peak to peak amplitude (µV)
timeFrame: 12 weeks later (if funding becomes available)
measure: Cortical silent period (ms)
timeFrame: Baseline
measure: Cortical silent period (ms)
timeFrame: 12 weeks (immediately after the intervention)
measure: Cortical silent period (ms)
timeFrame: 12 weeks later (if funding becomes available)
measure: Pain Catastrophizing Scale
timeFrame: Baseline
measure: Pain Catastrophizing Scale
timeFrame: 12 weeks (after the intervention)
measure: Pain Catastrophizing Scale
timeFrame: 12 weeks later (if funding becomes available)
measure: Depression Anxiety Stress Scale (DASS)
timeFrame: Baseline
measure: Depression Anxiety Stress Scale (DASS)
timeFrame: 3 weeks (during the intervention)
measure: Depression Anxiety Stress Scale (DASS)
timeFrame: 12 weeks (after the intervention)
measure: Depression Anxiety Stress Scale (DASS)
timeFrame: 12 weeks later (if funding becomes available)
measure: Central sensitization index
timeFrame: Baseline
measure: Central sensitization index
timeFrame: 12 weeks (after the intervention)
measure: Central sensitization index
timeFrame: 12 weeks later (if funding becomes available)
measure: The Vulvar Pain Assessment Questionnaire - Supplemental Domains
timeFrame: Baseline
measure: The Vulvar Pain Assessment Questionnaire - Supplemental Domains
timeFrame: 3 weeks (during intervention)
measure: The Vulvar Pain Assessment Questionnaire - Supplemental Domains
timeFrame: 12 weeks (following intervention)
measure: The Vulvar Pain Assessment Questionnaire - Supplemental Domains
timeFrame: 12 weeks after intervention (if funding becomes available)
Other outcomes:
measure: Tonic activation of the pelvic floor muscles (PFMs)
timeFrame: Baseline
measure: Tonic activation of the pelvic floor muscles (PFMs)
timeFrame: 12 weeks (after intervention)
measure: Tonic activation of the pelvic floor muscles (PFMs)
timeFrame: 12 weeks later (if funding becomes available)
measure: Maximum voluntary activation of the pelvic floor muscles (PFMs)
timeFrame: Baseline
measure: Maximum voluntary activation of the pelvic floor muscles (PFMs)
timeFrame: 12 weeks (after intervention)
measure: Maximum voluntary activation of the pelvic floor muscles (PFMs)
timeFrame: 12 weeks later (if funding becomes available)
measure: Activation of the pelvic floor muscles (PFMs) during a bearing down maneuver
timeFrame: Baseline
measure: Activation of the pelvic floor muscles (PFMs) during a bearing down maneuver
timeFrame: 12 weeks (after intervention)
measure: Activation of the pelvic floor muscles (PFMs) during a bearing down maneuver
timeFrame: 12 weeks later (if funding becomes available)
measure: Anticipatory responses (ms) to pressure applied at the vulvar vestibule
timeFrame: Baseline
measure: Anticipatory responses (ms) to pressure applied at the vulvar vestibule
timeFrame: 12 weeks (after the intervention)
measure: Anticipatory responses (ms) to pressure applied at the vulvar vestibule
timeFrame: 12 weeks later (if funding becomes available)
measure: Behavioural responses (µV) to pressure applied at the vulvar vestibule
timeFrame: Baseline
measure: Behavioural responses (µV) to pressure applied at the vulvar vestibule
timeFrame: 12 weeks (after the intervention)
measure: Behavioural responses (µV) to pressure applied at the vulvar vestibule
timeFrame: 12 weeks later (if funding becomes available)
measure: Adherence to the intervention protocol
timeFrame: 12 weeks (after the intervention)
Locations:
city: Ottawa
country: Canada
facility: McLean Function Measurement Lab
state: Ontario
Study officials:
affiliation: University of Ottawa
name: Linda McLean
role: PRINCIPAL_INVESTIGATOR
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