Testing peripheral and central therapies for provoked vestibulodynia: results from the UPDATe trial

AbstractIntroductionVestibulodynia (VBD) is a common chronic pelvic pain condition with heterogeneous clinical presentation, including subtypes distinguished by the presence (VBD-central; VBD-c) or absence (VBD-peripheral; VBD-p) of comorbid pain conditions. Despite frequent prescribing of topical therapies such as lidocaine/estradiol and centrally-acting agents such as tricyclic antidepressants, high-quality evidence for efficacy, alone or in combination, remains limited. This study evaluated effects of peripheral, central, and combined pharmacologic treatments for two VBD subtypes and whether treatment response varied by subtype.Patients and MethodsWe conducted a multicenter, randomized, double-blind, placebo-controlled, 2 × 2 factorial trial (ClinicalTrials.gov identifier: NCT03844412) at two academic medical centers. Women aged 18–50 with clinician-confirmed VBD were randomized to one of four treatment arms: 1) topical 5% lidocaine + 0.05% estradiol vaginal cream and placebo pill, 2) oral nortriptyline pill and placebo cream, 3) combined active pill and cream, or 4) double placebo for 16 weeks. The primary outcome was provoked vulvovaginal pain by a standardized tampon test (0–10 numeric rating scale).ResultsOf 209 participants, 69 had VBD-p and 140 had VBD-c. Tampon test pain decreased modestly across all arms, with the greatest proportion of decrease in the combined nortriptyline plus lidocaine/estradiol group, but there was no difference between subtypes. In the primary model, baseline pain strongly predicted Week 16 pain (β = 0.68, p < 0.001), and while many participants had a decrease in pain over time, no treatment produced a statistically significant reduction compared with placebo.ConclusionsIn this trial, neither peripheral nor centrally targeted pharmacotherapies demonstrated superiority over placebo in reducing provoked vulvovaginal pain at 16 weeks.KEY MESSAGES In this multicenter, randomized, placebo-controlled factorial trial, neither oral nortriptyline nor topical lidocaine/estradiol, alone or in combination, demonstrated superiority over placebo in reducing provoked vulvovaginal pain at 16 weeks.Despite the absence of significant treatment effects, 33.3% to 61.3% of women in the treatment-compliant population experienced pain improvement across all study arms, highlighting substantial nonspecific and individual-level responses.Heterogeneous, subtype-specific response patterns and baseline differences in psychosocial and functional burden underscore the need for precision-based, phenotype-informed approaches to vestibulodynia treatment.