1. health and fitness
2. disease

JOURNAL OF ENDOUROLOGY
Volume 18, Number 3, April 2004
© Mary Ann Liebert, Inc.
Reviews in Endourology
Chronic Prostatitis/Chronic Pelvic Pain Syndrome: Is There a
Role for Local Drug Infiltration Therapy?
ASSAAD EL-HAKIM, M.D., FRCS(C)
ABSTRACT
The clinical syndrome of chronic prostatitis ranges from well-defined chronic bacterial infections to poorly
defined chronic pelvic pain syndrome (CPPS), previously referred to as “prostatodynia” or “abacterial prostatitis.” Faced with the obscure nature of the disease, its protracted course, and the poor response to oral
medication, urologists have considered alternative routes of drug administration. We review the indications
and outcomes of local drug infiltration (intraprostatic antibiotic and zinc, intrasphincteric botulinum toxin
A, pudendal nerve blocks) and discuss their potential use and benefit in the treatment of chronic prostatitis
syndromes.
INTRODUCTION
T
HE CLINICAL SYNDROMES of chronic prostatitis range
from well-defined chronic bacterial infections to poorly defined chronic pelvic pain syndrome (CPPS), previously referred
to as “prostatodynia” or “abacterial prostatitis.” The International Prostatitis Collaborative Network established by the National Institutes of Health (NIH) has evaluated the literature and
clinical practice and established a new definition and classification for prostatitis (Table 1).1 Chronic prostatitis/chronic
pelvic pain syndrome (CP/CPPS) is a multifactorial problem
affecting men of all ages and demographics. The natural history of this syndrome is ill understood. The condition has a severe impact on mental and physical health-related quality of
life, as measured by sickness impact profiles.2
Faced with the obscure nature of the disease and its debilitating and protracted course, urologists have used a large number of oral medications with limited success, including antimicrobials, alpha-blockers, anti-inflammatory agents, muscle
relaxants, immune modulators, hormone therapy, and phytotherapy. More than half of the patients report previous or current use of five or more categories of prostatitis-related treatments.2 Failure of oral therapy may be caused by various
bioavailability problems inherent in the route of administration,
including poor absorption, metabolic degradation, and insuffi-
cient concentration in the targeted tissue. Alternative administration routes may offer an advantage.
Intraprostatic antibiotic injections have been used for more
than two decades. More recently, novel therapeutic approaches
were developed, including intraprostatic zinc injections, intrasphincteric botulinum toxin A injections, and pudendal nerve
blocks. This paper reviews local drug infiltration therapies and
discusses their potential use and benefit in the treatment of
CP/CPPS.
INTRAPROSTATIC ANTIBIOTICS
Although bacteria are cultured in 10% or less of all cases of
prostatitis, most urologists believe that treating chronic prostatitis and related syndromes with antibiotics confers benefit on
a higher percentage of patients. In fact, antibiotics are the most
commonly used treatment for chronic prostatitis, regardless of
culture results.3 Patients with Category IIIA disease may also
respond to antibiotics because of their anti-inflammatory effect,
reduction of cytokine production,4 the neurotoxic effect of some
antimicrobials (i.e., aminoglycosides), effects on bacterial
strains that are not routinely cultured or not yet identified, or
even by a strong placebo effect.
In order for a given antibiotic to be effective, it must reach
Department of Urology, Long Island Jewish Medical Center, New Hyde Park, New York.
227
228
EL-HAKIM
TABLE 1. NIH CLASSIFICATION
Category
OF
PROSTATITIS
Name
Description
I
II
III
Acute bacterial prostatitis
Chronic bacterial prostatitis
Chronic prostatitis/chronic pelvic
pain syndrome (CPPS)
IIIA
IIIB
IV
Inflammatory CPPS
Non-inflammatory CPPS
Asymtomatic inflammatory
prostatitis
Acute infection
Recurrent and chronic infection
Discomfort or pain in pelvic region for at
least 3 months with variable voiding and
sexual symptoms; no demonstrable
infection
Leukocytes in semen, EPS, or VB3
No leukocytes in semen, EPS, or VB3
Evidence of inflammation in biopsy,
semen, EPS, or VB3; no symptoms
Samples are taken during the Stamey localization technique. EPS 5 expressed prostatic secretions; VB3 5 postmassage voided
bladder urine.
adequate concentrations within the prostate. Theoretically, after oral or systemic administration, only weakly acidic and lipidsoluble antimicrobials achieve high intraprostatic concentrations because the prostatic fluid pH increases with infection.5
With intraprostatic injections, on the other hand, therapeutic
drug concentrations may be reached within the prostatic tissue
independent of the pharmacokinetic and pharmacodynamic
properties of the antibiotic. Other advantages of local injection
include the absence of any limitation on the drug concentration
and of inactivation by metabolism in the body. Therefore, the
therapeutic window may be enhanced.
We identified six series of patients with chronic bacterial
prostatitis (Category II) that was refractory to or recurrent despite adequate oral antimicrobials who were treated with intraprostatic injections of various antibiotics (Table 2). All infections were diagnosed using the Meares-Stamey four-glass
TABLE 2. RESULTS
OF
test. Plomp and colleagues6 treated 29 patients with transperineal injection of thiamphenicol glycinate (2 g). Fifty-five percent of the patients achieved a negative culture of the prostatic
fluid at 6 months with one or two infiltrations. An additional
10% required more than two infiltrations. Baert and Leonard7
also used the transperineal route to inject intraprostatic antibiotics in refractory chronic bacterial prostatitis in 24 patients.
Cure was defined as negative prostatic fluid cultures and remission of symptoms for at least 6 months. Seventy-one percent of all patients were cured with one or two infiltrations,
while 25% required several injections to obtain long-term remission. Seven patients (29%) relapsed after remission periods
raging from 13 months to 7 years. Jimenez-Cruz and coworkers8 treated 51 patients with intraprostatic amikacin (N 5 27)
or tobramycin (N 5 24) weekly for 2 to 4 weeks. Injection was
performed transperineally under ultrasound guidance in the
INTRAPROSTATIC ANTIBIOTIC INFILTRATION
Age
(range)
REFRACTORY CHRONIC PROSTATITIS (CATEGORY II)
Series
No.
Plomp et al6
1980
Baert et al7
1983
29
52 (27–64) Thiamphenicol 2 g
24
Jimenz-Cruz
et al8
1988
51
Yamamoto
et al9
1996
25
Yavascaoglu
et al10
1998
Hu et al11
2002
37
45 (29–63) Gentamicin
2 3 80 mg,
cephazolin 3 3 1 g
NA
Amikacin 500 mg
Transperineal, US
(27) or tobramycin
guided
100 mg
(24) for 2–4 weeks
37 (28–57) Amikacin 400 mg
Rectal, US guided
cephazolin 2 g
in 10 mL
lidocaine 1%
42 (24–61) Amikacin 500 mg
Suprapubic
transvesical (19),
transperineal (18)
NA
Amikacin 400 mg
Anal submucosal
QD 10 times
(30), IM (20)
50
Drug, dose
FOR
PF 5prostatic fluid; NA 5 not available.
Route
Cure definition
Transperineal, finger Neg. culture PF at
guided
6 months
Transperineal, finger Neg. culture PF
guided
$6 months
Percent
Cure rate requiring .2
with 1–2
cycles to
cycles (%) achieve cure
55
10
71
25
Neg. culture PF at 70 and 59
3 and 6 months
NA
Neg. culture PF
$12 months
56
28
Neg. culture PF
at 12 months
44 v 7
NA
Neg. culture PF
at 3 months
33 v 5
NA
229
LOCAL DRUG INFILTRATION FOR CHRONIC PROSTATITIS
echoic zone or external gland. The microbiologic cure indexes
were 70% and 59% after 3 and 6 months, respectively, with
one or two treatment cycles. The clinical cure rate was 43%,
and 41% of the patients improved. No differences were observed between the two antimicrobials. Yamamoto et al9 reported on 25 patients with refractory chronic prostatitis treated
with ultrasound-guided transrectal injections of amikacin and
documented negative cultures of prostatic fluid beyond 12
months in 56% of the patients with one or two treatments; 28%
of the patients required multiple infiltrations. Interestingly, the
concentration of amikacin in the prostatic fluid 24 hours after
the first intraprostatic injection, which was measured in five patients, exceeded the minimum inhibitory concentration of the
causal organism, E. coli, by 1.3- to 4.7-fold. Yavascaoglu and
associates10 randomized 37 patients with resistant prostatitis to
receive local amikacin injections via a transperineal (N 5 18)
or suprapubic transvesical (N 5 19) approach. The main reason for seeking an alternative route of injection was the pain
and discomfort associated with the transperineal approach. At
1-year follow-up, the overall bacteriologic cure rate was similar for the two approaches (47% v 44%). Patients experienced
less pain during access by the suprapubic route, but considerable difficulty was encountered in directing the needle to the
prostate, and hematuria was observed more often. Hu and colleaugues11 randomized 50 patients with chronic prostatitis to
receive anal submucosal (N 5 20) or intramuscular (N 5 30)
injection of amikacin 400 mg daily for 10 days. This is the only
study that compared intraprostatic with systemic antibiotic. At
3 months, the cure rates were 33% compared with 5%. The authors claimed that this method of local injection is painless. Although the overall cure rate was lower than in previous studies, this controlled trial showed the superiority of local antibiotic
injections to systemic treatment in chronic bacterial prostatitis.
The microorganism cultured most frequently was E. coli, followed by other enterobacteria (Klebsiella spp, Streptococcus
faecalis, etc.). The overall complication rate for local injection
was low. Usually, multiple infiltrations were required to achieve
adequate dispersion of the antibiotic solution in different directions of both prostatic lobes. Although painful, the procedure could be tolerated by most patients, and perineal discomfort usually subsided within 24 hours. Hematuria, dysuria, and
hematospermia generally disappeared within 1 to 2 weeks. Although necrosis at the site of injection is a feared complication,
it has not been reported recently.
Most of the aforementioned studies lacked long-term followup and did not incorporate a placebo arm. The natural history
of the disease therefore could not be accounted for. It is also
questionable whether the results are owing to systemic levels
of the drugs. Hence, this technique did not gain widespread acceptance. Patients’ and physicians’ reluctance also may have
played a role. Although acceptable results are shown initially,
bacteriologic and symptomatic cure rates drop dramatically after 6 months. Local intraprostatic antibiotic injections remain a
limited treatment option for only a subset of patients with
chronic bacterial prostatitis, mainly those with refractory or recurrent disease despite adequate oral antimicrobials.
Mayersak12 explored this modality in 75 patients with “recalcitrant benign painful prostate syndrome” (CPPS; Category
IIIA and B). The symptoms consisted of dysuria, urgency, perineal or suprapubic pain, rectal pain, nocturia, and urinary fre-
quency. Culture of pathogens was not possible from urine or
expressed prostatic secretions in 90% of the patients. A major
criticism of this paper is that it did not document the inclusion
criteria. Transrectal ultrasound-directed injection of gentamicin
160 mg (4 mL) and lidocaine 1% (2 mL) was used. Ninety percent of the patients were free of symptoms after one or two injections and 10% after multiple injections. The mean followup was not mentioned; however, those patients requiring four
or five injections had a mean follow-up of 2.25 years (range
1–4 years). This casts doubt on treatment durability, as multiple injections were needed for those patients followed for more
than 1 year. It also is debatable whether the therapeutic benefit could be attributed to the antibiotic or the anesthetic agent,
as 90% of the patients experienced immediate relief of pain that
the author himself attributed to lidocaine. Gentamicin may have
also acted on the afferent limb of the pain circle by its neurotoxic effect on sensory nerve endings.
INTRAPROSTATIC ZINC INJECTION
Secretory dysfunction of the prostate, characterized by an alteration in the composition of prostatic secretions, can be diagnostic of prostatitis; that is, a decrease in the zinc-containing
prostatic antimicrobial factor among others. Zinc was one of
the first antimicrobial factors identified in the seminal fluid.13
The finding that men with prostatitis had low levels of seminal
fluid zinc prompted the recommendation of oral zinc supplements. However, oral intake of zinc does not seem to increase
zinc levels in the seminal fluid.14 There are no clinical trials
supporting the use of oral zinc in the prevention or treatment
of chronic prostatitis.
Recently, intraprostatic injection of zinc has been studied in
a rat model of infectious prostatitis.15 Microbiologic culture of
the prostates demonstrated bacterial growth inhibition, and
histopathologic study showed resolving prostatitis in the zinctreated group but not in the control animals. Further studies
from the same institution demonstrated that intraprostatic injection of zinc in normal rats increased and maintained prostatic zinc concentrations for 4 weeks and did not affect serum
levels.16 No human studies are yet available, but it would be
interesting to see if there is any synergistic effect between zinc
and potent antimicrobials.
PERIPROSTATIC BOTOX
Botulinum toxin A has been used for relief of voiding symptoms related to CPPS. Interrupting the efferent somatomotor
branch of this central pain circle may offer an opportunity to
treat chronic pelvic pain. Botox is an inhibitor of acetylcholine
release at the neuromuscular junction of somatic nerves with
striated muscle. Its has been successful in relieving a variety of
conditions, including skeletal muscle spasms and spasticity, focal dystonia, wrinkles, detrusor-sphincter dyssynergia, and lowcompliance neurogenic bladders.
Dysfunctional voiding whereby neurophysiologic obstruction results in high-pressure flow patterns has been implicated
in the pathogenesis of CP/CPPS. Decreasing functional obstruction may reverse the pain circle. Maria and associates17
230
EL-HAKIM
treated four patients with transperineal botulinum toxin A infiltration (30 U). These patients suffered from chronic nonbacterial prostatitis and poor bladder emptying because of a spastic external urethral sphincter and had failed to respond to
tamsulosin 0.4 mg once daily. Three patients showed continued improvement in their voiding at 8 weeks, as defined by a
decrease in times to urinary flow (TQ) and maximum urinary
flow rate (Qmax ). Zermann and coworkers18 treated 11 patients
having “chronic prostatic pain” with transurethral perisphincteric injection of 200 U of botulinum toxin type A. Patients had
suffered from pelvic floor tenderness, decreased conscious
pelvic-floor control, urethral hyperalgesia, and urethral sphincter hyperactivity, as assessed by clinical evaluation, urodynamic
studies, and cystoscopy to exclude other pathologies. The injection was followed by pelvic floor muscle weakening and relief of prostatic pain and urethral hypersensitivity/hyperalgesia.
Decreases in functional urethral length, urethral sphincter closure pressure, and postvoiding residual volume and increases
in peak and average uroflow rates were documented.
Similarly, Phelan et al19 treated 21 patients having a variety
of bladder outlet obstructions, including 12 with neurogenic detrusor-sphincter dyssynergia. After botulinum A injection, all
but one of the patients were able to void without catheterization.
Sixty-seven percent of the patients reported significant subjective improvement in voiding at 3- to 16-months’ follow-up.
A potential side effect of Botox is spread to nearby muscles,
particularly when large volumes are injected. Distant effects can
occur, but generalized weakness is rare. Botox use should be
well monitored in patients with neuromuscular junction disturbances or during treatment with aminoglycosides.20 Larger
prospective controlled studies with long-term follow-up are
warranted before conclusions are drawn on the value of this
modality for the treatment of CP/CPPS. Botox injection may
provide real improvement of some voiding symptoms and pain
in patients with pelvic spasm in CP/CPPS or in patients with
pseudodyssynergia of the external urethral sphincter misdiagnosed as CPPS. Nevertheless, a trial of biofeedback should be
offered first.
In an effort to elucidate the role of the pudendal nerve in
pelvic pain syndrome, Robert and colleagues23 led anatomic
and clinical studies for more than 15 years. They defined three
possible entrapment sites along the course of the pudendal
nerve: between the sacrotuberous and sacrospinous ligaments,
in the pudendal canal of Alcock, and during the straddling of
the falciform process of the sacrotuberous ligament by the pudendal nerve and its branches. More than 200 patients received
a pudendal nerve neurolysis with “70% good results” (cure rate
of 45%, and 22% significant improvement).23,24 Other reports
indirectly support the theory of pudendal nerve entrapment. For
example, chronic anoperineal and gynecologic pudendal neuropathy have been treated successfully with pudendal blocks
with anesthetics and corticosteroids using CT guidance.22,25 Ultrasound-guided infiltration can also be performed with direct
monitoring of the nerve or the pudendal artery.
Evaluation consists of applying intrarectal digital pressure at
the ischial spines bilaterally to reproduce pain (Tinel’s sign).
Pudendal neuropathy can be confirmed by evoked nerve potentials. Nerve block inhibits sensory input and has the potential to break the circle of pain. On the other hand, taking advantage of the motor division of the nerve, detrusor-sphincter
dyssynergia in patients with spinal cord injury has been treated
with pudendal block with 5% or 7% phenol solutions.26 A decrease in postvoiding residual volume, leak-point pressure, and
maximal detrusor pressure have been reported, with improvement in quality of life. The motor branch block may also play
a role similar to Botox injections in reducing dyssynergia-like
prostatitis symptoms.
Patients believed to have CP/CPPS may benefit from an evaluation for extraprostatic causes of their pain. Pudendal nerve
entrapment syndrome may play a causative or synergistic role
among other etiologic factors. Greater awareness of this entity
will broaden our therapeutic arsenal. If the diagnosis is confirmed, infiltrations should be considered first. Surgical neurolysis may come to play an extended role in the future after
general acceptance of this entity and more clinical experience
is gained.
PUDENDAL NERVE BLOCK
CONCLUSION
Possible pudendal nerve involvement in anorectal and pelvic
pain dysfunction has received more attention in the proctology
and gynecology literature than in urology. Pudendal neuropathy has been recognized as an etiologic factor in idiopathic vulvodynia, idiopathic proctalgia, and chronic constipation.21,22
Likewise, prostatic pathology might not be the principal source
of urogenital, perineal, and anorectal pain in men believed to
have CP/CPPS. Extraprostatic processes such as pudendal nerve
compression deserve more attention from urologists.
The pudendal nerve (S2, S3, S4) originates from the lumbosacral plexus and follows the pudendal artery to the perineum. It leaves the pelvic cavity through the lesser sciatic
foramen (between the sacrospinous and sacrotuberous ligaments) and runs on the internal surface of the obturator muscle, in Alcock’s canal. The pudendal nerve carries sensory
neurons to the penis, perineum, and posterior scrotum and motor neurons to the muscles of the superficial perineal pouch
and the external sphincter.
Intraprostatic infiltration of antimicrobials for chronic prostatitis has shown acceptable cure rates only in nonrandomized
and uncontrolled studies. It is to be emphasized that the level
of current evidence is at best poor. Intraprostatic antibiotic infiltrations may therefore be used for chronic bacterial prostatitis refractory to oral medication, bearing in mind that long-term
follow-up is not available. There are few data supporting its use
in Category III CP/CPPS. Botox injections and pudendal nerve
blocks are newer and interesting conceptual treatments for a
subset of patients with refractory CPPS. More research and clinical experience are required, however, before their addition to
today’s armamentarium of CPPS treatment options.
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Address reprint requests to:
Assaad El-Hakim, M.D., FRCS(C)
Dept. of Urology
Long Island Jewish Medical Center
270-05 76th Avenue
New Hyde Park, NY, 11040-1496
E-mail: [email protected]