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David Foster, MD, MPH
University of Rochester
Vulvar vestibulitis trial: Desipramine-Lidocaine
Abstract: DESCRIPTION (provided by applicant): This application
is submitted in response to RFA:HD-00-008 entitled Pathophysiology,
Epidemiology and Treatment of Vulvodynia. Studies are proposed for
the subtype of vulvodynia known as vulvar vestibulitis. The first
major aim of this application is to conduct a randomized, placebo-controlled,
double-blinded clinical trial to study the clinical efficacy of
four medical regimens: topical lidocaine, oral desipramine, topical
lidocaine combined with oral desipramine and placebo. The efficacy
of standard treatments for vulvar vestibulitis proven by randomized,
placebo-controlled, blinded clinical trials has not been assessed.
The tricyclic class of antidepressants, represented by desipramine,
have gained empiric acceptance for the treatment of vulvar vestibulitis,
although favorable therapeutic results have been reported by only
a few retrospective studies or uncontrolled clinical trials. Although
the precise mechanism of action remains undefined for tricyclic
antidepressants, a "central" action through the dorsal
horn and brain stem has been suggested. In contrast to oral desipramine,
the long-term, topical application of lidocaine may act through
a "local" mechanism. This randomized, placebo-controlled,
double-blinded clinical trial is designed to determine whether "local"
or "centrally-acting" treatments alone, or in combination
are efficacious in treating vulvar vestibulitis. Outcome measures
of success will include reduced overall pain, reduced pain to touch,
reduced pain to standardized mechanical stimuli, increased pain-free
intercourse, improved sexual function, improved quality-of-life
as measured by psychometric tests, and adherence to active drug
regimens. The second major aim of this application is to study the
relationship among genetic polymorphisms of the IL-1 Receptor Antagonist
locus, tissue levels of pro-inflammatory cytokines, and response
to treatment of vulvar vestibulitis. Pro-inflammatory cytokines,
such as interleukin-I beta (IL-1 beta) and tumor necrosis factor
alpha (TNF-alpha), are secreted from a local cellular source and
accumulate above normal levels in the region of the hymeneal ring.
Recent genetic analysis finds a 53% homozygosity for allele 2 IL-1
Receptor Antagonist (IL-1 RA*2) in cases of vulvar vestibulitis,
in contrast to 8.5% homozygosity in asymptomatic women. Furthermore,
the IL-1 RA*2 allele has been linked to increased production of
IL-1 beta in vitro. In our second aim, we will determine whether
these in vitro results can be extrapolated to clinical cases of
vulvar vestibulitis. Using samples from our clinical trial, we will
assess the relationship between homozygosity for IL-1 RA*2, tissue
levels of IL-1 beta, and TNF-alpha, and response to treatment. In
summary, this project will allow us to answer several important
questions about vulvar vestibulitis. Is medical treatment effective?
Is centrally-acting or locally-acting treatment equally effective
or is one superior to the other? Is there any benefit from combined
local and systemic treatments? And finally, do genetic characteristics
and tissue cytokine concentrations influence treatment response?
back to NIH Funding
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