Botulinum Toxin A as a Treatment for Provoked Vestibulodynia

NCT ID: NCT04057755

Last Updated: 2019-08-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-05-15
• Study Completion Date: 2019-06-15

Brief Summary

Women with provoked vestibulodynia (PVD) suffer from severe dyspareuni and often present a hyperactivity of the pelvic floor muscles (PFM) which maintain the dyspareunia. The rationale for the study is that for women with PVD who don't succeed to restore the function of the PFM by physiotherapy, Botulinum Toxin A (BTA) could be an optional treatment by decreasing the high muscle tonus and thus possibly reduce the coital pain.

Objectives and outcome Women with PVD will be recruited for a double blind RCT of 2 injection of 50 Allergan-units BTA (3 months apart) or placebo in the bulbocavernous muscles (situated adjacent to the lower part of the vagina).

Primary outcome: The reduction of patient self-reported dyspareunia measured by VAS 0 (no pain) to 100 (worst pain imaginable).

Secondary outcome: Pain at tampon insertion measured by VAS 0-100, functional measurement of dyspareunia (see below), the reduction of pelvic floor hyperactivity/tonus, measured with a vaginal manometer, safety aspects and effect duration of BTA, influence on quality of life and psychosexual evaluation.

Detailed Description

Rationale Dyspareunia is a common pain problem among women. The prevalence has been estimated to be 10-15%. The most common type of dyspareunia among premenopausal women is provoked vestibulodynia (PVD). PVD is characterized by pain upon touch, pressure and stretch of the vestibular tissue in spite of the absence of other gynecological or dermatological disease [4]. The pain and its associated sexual consequences have a severe negative impact on the quality of life of affected women. Currently the etiology, although still not completely clarified, is considered to be multi-factorial involving biomedical and psychosexual causes. Two sub-categories of PVD has been identified; primary PVD, where pain occurs at the first attempt of vaginal entry (intercourse or tampon use) and secondary PVD, where pain occurs after a period of normal functioning. There is evidence of patho-physiological changes in three interdependent systems; the vestibular tissue, the pelvic floor muscles and the pain regulatory pathways of the central nervous system. Signs of a neurogenic inflammation in the vestibular mucosa, with neural hyperplasia of CGRP and Substance P positive C-fibers have been found. Furthermore, recent evidence supports the importance of a pelvic floor muscle (PFM) dysfunction to the etiology of PVD. Women with PVD have been shown to have elevated resting activity, lower maximal strength and poorer control of the PFM compared to healthy controls. Evidence suggests that this hyperactivity, although possibly originating as a protective defense mechanism provoked by pain, is chronic and thus contributes to maintaining and exacerbating the neurogenic inflammation and pain. A circular model has been suggested in which pain during intercourse and fear of pain may decrease sexual arousal and increase PFM tonus, whereby the PFM hyperactivity might act as an initiator of vestibular sensory changes and inflammation. However there is a lack of longitudinal studies to answer the question whether the PFM dysfunction is antecedent to the pain or a result of the pain.

Gentilcore-Saulnier et al. proposed that superficial and deep layers of the PFM may differ in their involvement in PVD as assessed with EMG external surface electrodes and an intravaginal probe, respectively. They found that women with PVD have significantly higher resting activity in the superficial muscle (bulbocaverneous) in comparison with controls. The difference was not significant for the deep layer (puborectalis, pubococcygeus, ileococcygeus and ischiococcygeus muscles).

The treatment guidelines today recommend a multi-modal treatment including topical anesthetic agents, cognitive behavioral therapy and PFM rehabilitation based on physiotherapy. As a second line treatment injections with botulinum toxin A (BTA) in the bulbocavernous muscles bilaterally has been suggested and to a limited extent tested. The main target for BTA is a transient paretic effect on skeletal muscular fibers and it also blocks the release of neuropeptides and neurotransmitters involved in the neuropathic pain and could therefore have additional effect in the treatment of PVD. Previously published reports on the effects of BTA for PVD are few and the methods of injection (different injection sites, use or non-use of an EMG needle for direction of injection sites) and doses used (20, 35, 100 IU) differ as well as methods of measuring treatment outcome. Only one double blind RCT has been published so far where no additional effect of BTA compared to saline could be detected, however the BTA dose used was low (20 IU) and only one treatment was performed. Using BTA in the PFM seems to be safe and only tenderness at the injection site and mild influenza like symptoms have been reported side effects so far.

Hypothesis Our hypothesis is that two treatments (three months apart) of injections with 50 Allergan-units of BTA in the bulbocavernosus muscles in women with PVD will reduce the hyperactivity in the PFM and thus significantly decrease the pain during intercourse.

Conditions

Vulvodynia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Botulinum toxin A vs placebo

50 Allergan units (diluted in 0,5 ml sterile NaCl) or 0,5 ml of sterile NaCl will be injected in the bulbocavernosus muscle just inside the hymenal ring. The injection with the same substance, dose and volume will be repeated after 3 months.

Group Type: EXPERIMENTAL

botulinum toxin A

Intervention Type: DRUG

NaCl

Intervention Type: DRUG

Botulinum toxin A

50 Allergan units (diluted in 0,5 ml sterile NaCl) will be injected in the bulbocavernosus muscle just inside the hymenal ring. The injection with the same substance, dose and volume will be repeated after 3 months.

Group Type: ACTIVE_COMPARATOR

botulinum toxin A

Intervention Type: DRUG

NaCl

0,5 ml of sterile NaCl will be injected in the bulbocavernosus muscle just inside the hymenal ring. The injection with the same substance and volume will be repeated after 3 months.

Group Type: PLACEBO_COMPARATOR

NaCl

Intervention Type: DRUG

Interventions

botulinum toxin A

Intervention Type: DRUG

NaCl

Intervention Type: DRUG

Other Intervention Names

Botox; Saline

Eligibility Criteria

Inclusion Criteria

• Age 18-40 years
• PVD defined as significant pain at vestibular contact and vaginal entry
• VAS ≥ 6 at the tampon test or severe pain, preventing intercourse
• Duration of symptoms of ≥ 3 months
• 0-para
• Patients who are willing to participate in the study after it has been explained orally and in writing will be included.

Exclusion Criteria

• Vulvo-vaginal infection
• Dermatological conditions or other causes to dyspareunia
• Regular medication with analgesics
• Major psychiatric or medical disease
• Known allergy to any components of the active drug (Botox®)
• Medical disease contradictory to treatment with the active drug (Botox®)
• Peripheral motor neurological disease such as myasthenia gravis, amyotrophic lateral sclerosis or Lambert-Eaton syndrome
• Diabetes)
• Pregnancy
• Pelvic floor deficiency with urine and or flatulence incontinence.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Karolinska Institutet

OTHER

Sponsor Role: lead

Responsible Party

Nina Bohm-Starke

MD, associte professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nina Bohm-Starke, MD

Role: PRINCIPAL_INVESTIGATOR

Karolinska Institutet

Locations

Danderyd Hospital, Dep. of Obstetrics and Gynecology

Stockholm, , Sweden

Countries

Sweden

Other Identifiers

2016-000375-25

Identifier Type: -

Identifier Source: org_study_id