Botulinum Toxin A as a Treatment for Provoked Vestibulodynia
Condition: Vulvodynia
MeSH terms: Vulvodynia; Vulvar Vestibulitis
Study type: Interventional
Phase: Phase 3

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.
    

Intervention name(s): botulinum toxin A; NaCl
Intervention type(s): Drug; Drug
Other intervention name(s): Botox; Saline
Intervention MeSH terms: Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: botulinum toxin A; treatment