Rationale and design of a multicenter randomized clinical trial of extended release gabapentin in provoked vestibulodynia and biological correlates of response

Abstract

Introduction Few randomized controlled trials (RCTs) have been conducted to establish evidence-based management protocols for provoked vestibulodynia (PVD), a chronic vulvar pain condition affecting approximately 14 million women in the U.S. We describe the rationale and design of an NIH funded multicenter clinical trial utilizing an extended release formulation of gabapentin (G-ER), an intervention that preliminary data suggest may be efficacious for this condition. Objectives 1) to determine if pain from tampon insertion (primary outcome measure) is lower in PVD patients when treated with G-ER compared to when treated with placebo and 2) to determine if G-ER reduces vulvar mechanical hyperalgesia, vaginal muscle pain to palpation, the number and intensity of somatic tenderpoints, spontaneous and provoked pain to intradermal capsaicin with an accompanying increase in cardiac beat-to-beat variability and to identify mechanistically-based PVD subtypes. Additional outcomes include subject reported intercourse pain and summative 24-hour pain. Methods This 16-week, randomized, double-blind, placebo-controlled, crossover study will enroll 120 women 18 years and older who report tenderness localized to the vulvar vestibule, pain with tampon insertion, and, when sexually active, insertional dyspareunia. Electronically entered daily diaries will be used to determine if pain is lower in PVD subjects when treated with G-ER (up to 3000 mg/d) compared to when treated with placebo. Psychophysiological measures will be obtained at baseline and after 2 weeks at the maximum tolerated dose. Conclusion We will conduct the first multicenter RCT to confirm efficacy of an agent that is currently used in clinical practice for treating PVD.

A review of the available clinical therapies for vulvodynia management and new data implicating proinflammatory mediators in pain elicitation

“…Nonetheless, gabapentin has other indications for use; double-blind placebo-controlled studies indicate gabapentin is effective in relieving neuropathic pain 26 . Currently, the first multicenter RCT is underway to examine the efficacy of oral gabapentin 38 . Prior studies suggest that gabapentin may improve self-reported symptoms, but these investigations lacked placebo controls 39,40 .…”

“…5,6,25 Another option is the use of oral anticonvulsants (e.g. gabapentin), which may be especially useful for patients with pelvic floor dysfunction; [37][38][39][40] however, pelvic floor dysfunction is likely to be secondary to, and not the cause of, vulvodynia. 1,6 Nonetheless, gabapentin has other indications for use: double-blind placebo-controlled studies indicate that gabapentin is effective in relieving neuropathic pain.…”

“…26 Currently, the first multicentre RCT is underway to examine the efficacy of oral gabapentin. 38 Prior studies suggest that gabapentin may improve self-reported symptoms, but these investigations lacked placebo controls. 39,40 Another confounding factor is that several studies have shown a significant improvement in vulvodynia symptoms with placebo.…”

“…[48][49][50] Multidisciplinary approaches have been most effective and all available evidence suggests that these will continue to make progress; 5,6,25 however, taking into account the limited number of RCTs and the placebo effect, it is difficult to discern what the overall best course of treatment will be for any given woman. 26,36,38 This results in multiple visits to various doctors and therapists, during which time the patient may perceive that her situation is hopeless or is not being adequately addressed. 5,6 This only serves to augment the psychosomatic components of the disease.…”

Vulvar Vestibulodynia

“…2 There are no published prospective placebo-controlled trials regarding the use of anticonvulsants in VVD therapy, 44 but there is a multicenter randomized controlled trial currently underway exploring the efficacy of gabapentin. 47 Data supporting the use of lamotrigine or carbamazepine are likewise limited. 44 Gabapentin is the most commonly prescribed anticonvulsant for this condition and is usually started at a dose of 300 mg/d and increased every 3 days up to a dose of 3600 mg/d.…”