Antifungal Azoles – New Antidote for Chronic Pelvic Pain?

Note the dosage, 800mg fluconazole/day.

Central European Journal of Urology

Antifungal azoles – new antidote for chronic pelvic pain?
Bartosz Dybowski
Department of Urology, Medical University of Warsaw, Warsaw, Poland

Chronic prostatitis/chronic pelvic pain syndrome
(CP/CPPS) is a poorly–defined condition or a group
of conditions in which chronic pain in the genital
area and pain during prostate palpation are the two
most common features. Causative treatment is rarely
available since in most cases the etiology in unknown.
Paradoxically, long–term Antibiotic therapy
is recommended and often relieves symptoms despite
negative cultures of urine, semen or prostate biopsy
samples. Compared to placebo drugs that are used
as first–line therapy, it shows the following advantages:
anti–inflammatories (risk ratio 1.7, 95% CI
1.4–2.1; P <0.001), α–blockers (risk ratio 1.4, 95% CI
1.1–1.8; = 0.013), Antibiotics (risk ratio 1.2, 95% CI
0.7–1.9; P = 0.527) [1]. New forms of therapy are desperately
needed for men after the failure of first–line
therapy. In this issue of CEJU, Dr. Ahmed F. Kotb
and colleagues present their experience with fluconazole
used for treating persistent CP/CPPS symptoms.
Using fluconazole 2x400 mg PO, daily authors
observed response rates at about 70%.

This is a surprisingly good result bearing in mind that these patients failed primary treatment. To my knowledge,
this is the first report in medical literature on such
a form of CP/CPPS therapy. Although mepartricin,
which has been found to improve symptoms for six
or more points in the NIH–CPSI scale, has an antifungal
effect as well, this drug does not absorb from
intestines and its mechanism of action relies on the
hormonal effect. Fungal etiology of CP/CPPS in otherwise
healthy, immunologically non–compromised
men has not been reported yet, thus these observations
have to be considered with caution.

Furthermore, one may find other explanations of the
positive effects of fluconazole therapy in comparison
to antifungals. The placebo effect is strong in chronic
conditions that can spontaneously wane or aggravate.
Systematic review and meta–analysis of trials
on CP/CPPS have found that placebo improves the
total NIH–CPSI score on average of 2.4 points (95%
CI: 1.7–3.2). A positive effect on all specific domains
of the score was also reported–pain: 1.34 (95% CI:
0.88–1.79); voiding: 0.59 (95% CI: 0.33–0.84); quality
of life: 0.95 (95% CI: 0.62–1.27). There was no evidence
of a changing placebo effect over time [2]. For
this reason, only placebo–controlled trials may prove
efficacy of a specific treatment in CP/CPPS.


Chronic pain conditions coexist with increased anxiety,
perceived stress, and a higher profile of global
distress when compared to asymptomatic controls.
Both these disturbances and chronic central sensitization
by nociceptive stimuli affect hypothalamic–
pituitary–adrenal (HPA) axis, causing a decrease of
plasma adrenocorticotropin hormone and blunting
its stress response curve. In patients with CP/CPPS,
cortisol levels remain intact under stress conditions
but the slope of the awakening cortisol is steeper
[3]. Both ketoconazole and, to the lesser extent,
fluconazole also influence this hormonal axis by inhibiting
synthesis of cortisol and other steroids [4].
Hormonal effects of azoles may modulate HPA axis
reversing the vicious circle of pain, stress, and hormonal
dysregulation. Two drugs affecting hormonal
milieu of the prostate, finasteride and mepartricin,
have been proven to improve symptoms in CP/CPPS
patients. Azoles may be a new hormonally–active
group of agents used in this indication.
The most recent possible explanation of fluconazole
efficacy in CP/CPPS comes from the Texas Health
Science Center whose researchers have reported on
potential analgesic effects of ketoconazole [5].This
drug has been used in their experiment as a broad–
spectrum cytochrome P450 (CYP) inhibitor. CYP is involved
in oxidation of linoleic acid into its metabolites
(OLAMs) and OLAMs are agonists of the TRPV1 ion
channel involved in transmitting pain signals from
inflammation or injury involving tissue. In this study
it has also been found that ketoconazole possesses
an unexpected antihyperalgesic effect. Treatment
with ketoconazole inhibited a release of endogenous
TRPV1 agonists from the inflamed tissue. However,
since ketoconazole inhibits multiple oxidative enzymes
including CYPs, the biochemical mechanism
of action requires further evaluation. Fluconazole
does not have the same profile of CYP inhibition, but
both substances share many pharmacologic and biochemical
effects. These results are complimentary to
clinical effects found by urologists from Egypt. All
above hypotheses of antifungal, antisteroid, and antihyperalgesic
effects of azoles deserve scientific attention
before this group of agents can be involved in
the treatment of patients with CP/CPPS.