␣-Blockers in Prostatitis Timothy D. Moon, MBChB
Address Department of Surgery, Division of Urology, G5/341 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792, USA. E-mail:
[email protected] Current Prostate Reports 2004, 2:145–149 Current Science Inc. ISSN 1544-1865 Copyright © 2004 by Current Science Inc.
Chronic prostatitis affects up to 16% of the male population. The pathophysiologic etiology of chronic prostatitis is unclear, but dysfunctional voiding appears to be associated with the problem. The bladder, bladder neck, and prostate are richly innervated with adrenergic fibers (α-1d in the bladder and α-1a at the bladder neck and prostate). αBlockers have been used for more than 20 years with mixed results. Overall, the data support a trial of α-blockers for patients with chronic prostatitis. In addition, if the drug appears to work, continued use for 6 months is warranted. Limited data suggest that 6 months of α-blockers in patients with chronic bacterial prostatitis may have fewer recurrences, again supporting the hypothesis of dysfunctional voiding.
Introduction Chronic prostatitis has been estimated to affect 5% to 16% of the adult male population [1–3]. Prostatitis has been classified into four different categories [4•] (Table 1). Acute bacterial prostatitis (category I) is a severe infection and will not be discussed further in this article. Likewise, category IV prostatitis is asymptomatic and generally is not diagnosed and rarely (if ever) treated. Chronic bacterial prostatitis (category II) and chronic pelvic pain syndrome (CPPS; category III prostatitis) are the subcategories, which will be addressed in this review. They also constitute most of the clinical cases. While the etiology of CPPS is obscure, it has been hypothesized that the symptomatology may be secondary to voiding dysfunction [5–7]. As part of the pathophysiologic process in developing the symptom complex of CPPS, failure to relax the bladder neck during voiding may be key. The bladder neck and prostate are richly innervated with α-adrenergic receptors (α-AR). The α-1a receptor is responsible for bladder neck closure and thus blocking agents will cause bladder neck relaxation. Caine et al. [8] first introduced αblocking agents in the 1970s as a treatment for benign prostatic hyperplasia (BPH)/lower urinary tract symptomatology. Using the same basic mechanism of relaxing the
bladder neck, α-blockers have been used to treat CPPS for more than 20 years. This paper reviews the hypothetical basis for α-blocking agents and their place in the treatment of this syndrome.
Pathophysiology The etiology of CPPS is elusive. It has been hypothesized that dysfunctional voiding [5–7] leads to turbulent flow within the prostatic urethra, which in turn leads to reflux of urine into the prostatic ducts (Fig. 1A and B). Acidic urine then may cause inflammation of the prostatic ducts, which in turn may lead to stimulation of pain fibers [9]. Anatomic studies have demonstrated that the peripheral zone is more susceptible to inflammation because ducts from this area enter the urethra at right angles, making them more susceptible to reflux of urine [10,11]. Kirby et al. [12] demonstrated that the installation of carbon particles into the bladder was followed by their observation within the prostatic tissue within 72 hours (at the time of prostatectomy). Urodynamic studies have demonstrated abnormalities from low pressure-low flow to high pressure-low flow to dyssynergia [5,13]. The postulated effect of αblockers is to relax the bladder neck and relieve the previously mentioned dysfunction and improve flow and symptoms. In addition, all of the α-blockers also block the α-1d receptors, localized in the bladder body (Fig. 2), causing relaxation and relief from irritative voiding symptoms (frequency, urgency, and nocturia).
Pharmacology Overview The neuroanatomy of the autonomic nervous system as it relates to the bladder outlet recently has been reviewed [8]. Adrenergic fibers from the hypogastric nerves densely innervate the prostate and bladder neck. By blocking adrenergic stimulation, the smooth muscle of the bladder neck and prostate will relax, widening the bladder neck and reducing the tendency for turbulent flow within the prostatic urethra (Fig. 1A and B). α-1 Receptors There are three α-1 AR subtypes involved with urinary function (α-1a, α-1b, and α-1d). Alpha-1a-subtype ARs are predominantly found on the smooth muscle of the prostate, bladder neck, and trigone (mesodermal origin) [14••] (Fig. 2). Alpha-1 d -ARs are found predominantly in the
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Table 1. Classification of prostatitis syndromes Category I Category II Category III Category IIIa Category IIIb Category IV
Acute bacterial prostatitis Chronic bacterial prostatitis Chronic prostatitis/chronic pelvic pain syndrome Inflammatory (WBC present in EPS) Non-inflammatory (no WBC present in EPS) Asymptomatic inflammatory prostatitis
EPS—expressed prostatic secretions; WBC—white blood cells.
smooth muscle of the bladder body. The α-1b ARs are predominantly found on the blood vessels of older people (older than 55 years of age) [15]. Younger people generally have a predominance of α-1a in the arteries, while α-1 AR expression generally increases with age and also converts to α-1 b [15]. In the spinal cord, all three α-1 ARs are present, but α-1d is the most common [16]. Alpha-1a is the predominant AR on the smooth muscle of the prostate. Overall ratios of AR subtypes have been found to be in the order of 40:20:1 for α-1a, α-1d, and α-1b, respectively, for normal prostate; in BPH cases, the ratio changes to 6:1:0 [17].
α-Blocking drugs α-Adrenergic blocking agents may be classified as selective or non-selective (Table 2). The non-selective drugs block α1 and α-2 receptors and thus are not clinically useful because of side effects from the α-2 activity (palpitation, tachycardia, nasal congestion, and visual difficulties). The selective drugs bind α-1 receptors over α-2 receptors. The relative binding for each α-1 subtype has been evaluated [18,19]. Most of the long-acting selective agents are quinazoline derivatives and have similar receptor subtype affinities. Alpha-1a affinity actually may be the lowest. Tamsulosin differs from the other drugs in that it is a methoxybenzene sulphonamide and although it has equal affinity for α-1a/α-1d ARs, its affinity for α-1b receptor is approximately one twelfth that of the other two. Overall, its affinity for α-1a receptor is 10 to 200 times greater than the quinazoline drugs.
Clinical Studies
α-Blocking agents were first used in the 1970s by Caine et al. [8] for BPH symptoms. The first study involving patients with prostatitis was performed by Osborn et al. [7] in 1981 using phenoxybenzamine, baclofen, and placebo. This study demonstrated a 48% symptom improvement with phenoxybenzamine, but the study was lacking in defined entry criteria and objective patient response measurement. In 1992, de la Rosette et al. [20] performed a doubleblind, placebo-controlled trial with short-acting alfuzosin versus placebo in 20 patients. Despite the small sample size, statistically significant improvements in maximal flow
rate and reduction in symptom score were found in favor of alfuzosin.
Category III prostatitis studies Neal and Moon [21] performed an open-label study using terazosin for 25 patients with category III prostatitis. Patients were monitored using a newly created symptom score index. Overall, the response rate was 76% at 1 month, with 58% of patients remaining asymptomatic after an additional 2 months. The mean symptom response was 5.2 to 1.9 on a 12-point scale. In another study, patients were randomized to placebo or terazosin and demonstrated a significant reduction in symptoms for the group of patients treated with terazosin over the placebo group [22]. Although this was a placebocontrolled study, the validated symptom questionnaire was not used. In addition, only 2 mg of terazosin was used, which would not be expected to have much effect (in the BPH population). A similar study also was published from Turkey using a single-blind alternate treatment approach with doxazosin (titrated to 4 mg) or placebo [23]. Patients did not enter the trial until after a 3month placebo lead in. The study lasted for 3 months. No validated prostatitis symptom questionnaire was used, but a significant resolution in symptoms in the test group was seen. Surprisingly, there appeared to be no placebo effect with the placebo group, which raises some questions regarding the study; almost all of the lower urinary tract studies, whether considering BPH or prostatitis, demonstrate a 25% placebo response. Subsequently, the National Institutes of Health (NIH) convened a series of meetings to formally classify prostatitis [4•] and develop a consensus approach to future investigations of prostatitis. These meetings led to the formation of the Chronic Prostatitis Pelvic Pain Research Network (CPPRN). Among other activities, they developed a validated symptom questionnaire, which is routinely used for research studies and permits comparison of one study with another [24••]. Using the new symptom index, a study was performed comparing terazosin with placebo for category III prostatitis [25]. Eighty-six patients were randomized and treated for 14 weeks, titrating terazosin from 1 to 5 mg. The mean chronic prostatitis symptom index (CPSI) score at entry was 25.1 (maximum, 33) for the patients treated with terazosin. This decreased consistently over the treatment period to 10.8 at 14 weeks. Likewise, the quality-of-life index decreased from 8.3 to 3.6. The placebo data was 27.2 to 17.0 for the NIH-CPSI total score and 8.9 to 5.5 for the quality-of-life data. These data were significant at the P = 0.003 level. Overall, although this study showed a statistical improvement for terazosin over placebo, it suggests that longer therapy is beneficial. Continuing the idea that longer is better, Mehik et al. [26] randomized 40 patients to 5 mg of alfuzosin twice daily or placebo. This study demonstrated a mean drop of 10 points for the CPSI score
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Figure 1. The effect of bladder neck relaxation on urine flow through the prostatic urethra. A, Normal flow with relaxation of the bladder neck. B, Turbulent flow in prostatic urethra with non-relaxation of the bladder neck.
from 26 to 16 over 6 months. The fall in CPSI was progressive over this 6-month period. However, after discontinuing therapy, the score approached baseline by 1 year. In comparison, the placebo score fell from a mean of 23 to 19 (P = 0.01 compared with alfuzosin). The placebo scores also returned to baseline at 12 months, having fallen during the active placebo-controlled trial period. The question raised by this study concerns what a truly long-term (multiyear) study would show for effect. This is especially true considering that studies have shown patients with category III prostatitis to be symptomatically remittent. Nickel et al. [27] resurveyed 40 men with prostatitis symptoms 1 year later; 38% have had resolution of their symptoms without any active treatment. A short-term trial of placebo versus tamsulosin for the treatment of category III prostatitis has been reported [28]. Fifty-seven patients were randomized and 50 completed the study. At 45 days of treatment, the tamsulosin group (0.4 mg daily) showed a greater reduction in CPPS score at 3.6 (baseline, 26.3) over placebo (P = 0.04). The patients with the most symptoms experienced the most benefit with tamsulosin (mean score, 31; reduction in score, 8.3 greater than placebo; P < 0.01). Overall, these studies suggest some benefit for α-blockers in the treatment of prostatitis (category III), but demonstrate the need for a large, randomized study, with the study period exceeding 6
months and preferably 1 year. The CPPRN is conducting a fairly large study, but with only a short follow-up (12 weeks) [29]. The study randomized 196 patients to ciprofloxacin, tamsulosin, both, or placebo. No significant drug effects were seen. However, the authors recognized that the patient population was heavily pretreated and refractory to other treatments.
Category II prostatitis studies The use of α-blockers for chronic bacterial prostatitis has received little study. One group, as part of a larger study, randomized 64 patients with chronic bacterial prostatitis to antibiotics with or without α-blockers [30]. Patients were treated for at least 1 month with antibiotics, which were chosen by a sensitivity profile. α-Blockers were titrated to response. Follow-up was a mean of 22 months. In the year after treatment, 6.2% of the patients treated with an α-blocker and 14% of those who were not had culture-positive recurrences. Symptomatically, the recurrence rate was 16.7% for those patients treated with an αblocker and 66.7% for those who were not. These data, although complex and difficult to understand from the article, suggest that dysfunctional voiding is part of the pathology associated with bacterial prostatitis. By improving flow characteristics and reducing turbulent flow, recurrences may be reduced.
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some form of urodynamic evaluation becomes appropriate. The lowest level of study would be uroflow and postvoid residual measurements. If there is any abnormality with this, then complex urodynamics with or without fluoroscopy may be appropriate. Kaplan et al. [5] observed 34 men with chronic prostatitis and found bladder neck obstruction in 31 of them. The mean detrusor pressure was 77 mL of water. These patients underwent transurethral incision of their bladder neck. Symptomatic improvement was seen in 30 patients and an increase in flow was seen in all of the patients (mean flow preoperatively, 9.2 mL/s; mean flow postoperatively, 16.4 mL/s). These data suggest that some men may have a fixed deformity at the bladder neck that is unresponsive to medical manipulation by αblocker therapy. Overall, these data demonstrate a place for α-blocker therapy in the treatment of categories II and III chronic prostatitis. However, until the precise etiology is understood, the precise patient group who may benefit from αblockers likely will not be truly defined.
References and Recommended Reading
Figure 2. Localization of adrenoceptors in the bladder and prostate.
Table 2. ␣-Adrenergic blocking agents for lower urinary tract symptoms Non-selective drugs Phentolamine Phenoxybenzamine Selective drugs Short-acting Prazosin Long-acting Alfuzosin Doxazosin Terazosin Uroselective Tamsulosin
Conclusions Unfortunately, the classification and symptom score measurement tools provide little if any information about the etiology or pathophysiology of the process. For that reason, α-blockers have had mixed results in clinical practice and also in the various studies published. Conversely, a therapeutic trial of α-blockers is relatively cheap and thus appropriate for most patients with category III prostatitis. The use of α-blockers for chronic bacterial prostatitis is less well established, although the hypothetical mechanism for their use is reasonable. However, if one accepts this, then 6 months of use appears appropriate. If α-blockers fail, then
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
Moon TD, Hagen L, Heisey DM: Urinary symptomatology in younger men. Urology 1997, 50:700–703. 2. Roberts RO, Lieber MM, Rhodes T, et al.: Prevalence of a physician-assigned diagnosis of prostatitis: the Olmsted County study of urinary symptoms and health status among men. Urology 1998, 51:578–584. 3. McNaughton Collins M, Meigs JB, Barry MJ, et al.: Prevalence and correlates of prostatitis in the health professionals follow-up study cohort. J Urol 2002, 167:1363–1366. 4.• Krieger JN, Nyberg LJ, Nickel JC: NIH consensus definition and classification of prostatitis. JAMA 1999, 282:236–237. This paper provides the background for and the classification of prostatitis. 5. Kaplan SA, Te AE, Jacobs BZ: Urodynamic evidence of vesical neck obstruction in men with misdiagnosed chronic nonbacterial prostatitis and the therapeutic role of endoscopic incision of the bladder neck. J Urol 1994, 152:2063–2065. 6. Hellstrom WJ, Schmidt RA, Lue TF, et al.: Neuromuscular dysfunction in nonbacterial prostatitis. Urology 1987, 30:183–188. 7. Osborn DE, George NJ, Rao PN, et al.: Prostatodynia: physiological characteristics and rational management with muscle relaxants. Br J Urol 1981, 53:621–623. 8. Caine M, Pfau A, Perlberg S: The use of alpha adrenergic blockers in benign prostatic obstruction. Br J Urol 1976, 48:255–263. 9. Weiss SG II, Moon TD: α-Blocker Therapy. Textbook of Prostatitis. Oxford: Isis Medical Media Ltd; 1999:319–328. 10. Blaylock NJ: Anatomical factors in prostatitis. Br J Urol 1974, 46:47–54. 11. McNeal JE: Regional morphology and pathology of the prostate. Am J Clin Path 1962, 49:347–357. 12. Kirby RS, Lowe D, Bultitude MI, et al.: Intraprostatic urinary reflux: an aeteological factor in abacterial Prostatitis. Br J Urol 1982, 54:729–731. 13. Meares EM Jr, Barbalias GA: Clinical and video-urodynamic findings in prostatodynia. Semin Urol 1983, 1:146.
␣-Blockers in Prostatitis • Moon 14.•• Schwinn DA: The role of α1-adrenergic receptor subtypes in lower urinary tract symptoms. BJU Int 2001, 88(suppl 2):27–34. This paper provides an excellent summary of α receptors in the lower urinary tract. 15. Gregorini L, Marco J, Kozakova M, et al.: Alpha-adrenergic blockade improves recovery of myocardial perfusion and function after coronary stenting in patients with acute myocardial infarction. Circulation 1999, 99:482–490. 16. Stafford-Smith M, Shambra U, Wilson K, et al.: α1-adrenergic receptors in human spinal cord: specific localized expression of mRNA encoding α1-adrenergic subtypes at four distinct levels. Mol Brain Res 1999, 63:254–261. 17. Nasu K, Moriyama N, Kawabe K, et al.: Quantification and distribution of alpha1-adrenoreceptor subtype mRNAs in human prostate: comparison of benign hypertrophied tissue and non hypertrophied tissue. Br J Pharmacol 1996, 119:797–803. 18. Richardson CD, Donatucci CF, Page SO, et al.: Pharmacology of tamsulosin: saturation-binding isotherms and competition analysis using cloned α1-adrenergic receptor subtypes. Prostate 1997, 33:55–59. 19. Foglar R, Shibata K, Horie K, et al.: Use of recombinant α1adrenoceptors to characterize subtype selectivity of drugs for the treatment of prostatic hypertrophy. Eur J Pharmacol 1995, 288:201–207. 20. de la Rosette JJ, Karthaus HF, van Kerrebroeck PH, et al.: Research in ‘prostatitis syndromes:’ the use of alfuzosin (a new alpha-1 receptor blocking agent) in patient mainly presenting with micturition complaints of an irritative nature and confirmed urodynamic abnormalities. Eur Urol 1992, 22:222–227. 21. Neal DE Jr, Moon TD: Use of terazosin in prostatodynia and validation of a symptom score questionnaire. Urology 1994, 43:460–465.
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Gul O, Eroglu M, Ozok U: Use of terazosine in patients with chronic pelvic pain syndrome and evaluation by prostatitis symptom score index. Int Urol Nephrol 2001, 32:433–436. 23. Evliyaoglu Y, Burgut R: Lower urinary tract symptoms, pain, and quality of life assessment in chronic non-bacterial prostatitis patients treated with α-blocking agent doxazosin versus placebo. Int Urol Nephrol 2002, 34:351–356. 24.•• Litwin MS, Mcnaughton-Collins M, Fowler FJ Jr, et al.: The national institutes of health chronic prostatitis symptoms index: development and validation of a new outcome measure. J Urol 1999, 162:369–375. This paper provides the background for the prostatitis symptom index used universally for prostatitis studies. 25. Cheah PY, Liong ML, Yuen KH, et al.: Terazosin therapy for chronic prostatitis/chronic pelvic pain syndrome: a randomized, placebo-controlled trial. J Urol 2003, 169:592–598. 26. Mehik A, Alas P, Nickel JC, et al.: Alfuzosin treatment for chronic prostatitis/chronic pelvic pain syndrome: a prospective, randomized, double-blind, placebo-controlled, pilot study. Urology 2003, 62:425–429. 27. Nickel JC, Downey JA, Nickel KR, Clark JM: Prostatitis-like symptoms: 1 year later. BJU Int 2002, 90:678–681. 28. Nickel JC, Narayan P, Mckay J, Doyle C: Treatment of chronic prostatitis/chronic pain syndrome with tamsulosin: a randomized, double-blind trial. J Urol 2004, 171:1594–1597. 29. Alexander RB, Propert KJ, Schaeffer AJ, et al.: A randomized trial of ciprofloxacin and tamsulosin in men with chronic prostatitis/chronic pelvic pain syndrome [Abstract 232]. J Urol 2004, 171(suppl 4):61. 30. Barbalias GA, Nikiforidis G, Liatsikos EN: α-Blockers for the treatment of chronic prostatitis in combination with antibiotics. J Urol 1998, 159:883–887.