- Email: [email protected]
Use of terazosin in prostatodynia and validation of a symptom score questionnaire
USE OF TERAZOSIN IN PROSTATODYNIAAND VALIDATION OF A SYMPTOM SCORE QUESTIONNAIRE DURWOOD E. NEAL, JR., M.D. TIMOTHY D. MOON, M.D. From the University of Texas, Galveston, Texas, and University of Wisconsin Medical School, Madison, Wisconsin
ABSTRACT-Objective. The purpose of this trial was to study the use of terazosin in nonbacterial prostatitis/prostatodynia, and to evaluate a new symptom score sheet for this disease. Methods. Twenty-five patients who presented with lower urinary tract symptoms suggestive of prostatitis were evaluated for evidence of bacterial infection by Meares-Stamey criteria and found to be negative. They were then treated with the alpha-blocking drug terazosin in doses from 1 to 10 mg. A symptom score index for prostatitis was developed, tested in these patients, and validated against patients with benign prostatic hyperplasia. Normal control patients, who presented for vasectomy, were studied as well. Results. Nineteen patients (76%) responded to one month’s therapy, with 11 (58%) remaining asymptomatic three months later. The symptom score index, as measured by Cronbach’s alpha measure of index reliability, was excellent at 0.78 and logistic regression analysis demonstrated each prostatitis question to have independent validity (P < 0.001) but not to the extent of the combined score. Conclusions. Terazosin appears effective in treating patients with nonbacterial prostatitis/prostatodynia. This new symptom score is one way to evaluate and track patients with this disease. A randomized, placebo-controlled clinical trial has been initiated to study this.
Chronic prostatitis is a common condition which affects men of all ages. Data collected during Prostate Cancer Awareness Week suggest the prevalence of lower tract urinary symptoms compatible with prostatitis at 12 percent.’ Another study suggested that there were twenty office visits per 1,000 men per year for prostatitis.* The above figures, however, are based upon questionnaire data and do not necessarily reflect diagnostic accuracy. Data are lacking about the true frequency of prostatitis in the population and about the relative frequency of the various subgroups. A german study involving 600 men in a prostatitis clinic found that 5 percent had chronic bacterial prostatitis, 64 percent had nonbacterial prostatitis, and 31 percent had prostatodynia.7 In a recent study we found that 8/48 patients (17%) with prostatitis-like symptoms had a diagnosis of chronic Submitted: October 1, 1993, accepted: October 29, 1993
460
bacterial prostatitis,’ as diagnosed by the culture of the initial urine (VBl), midstream urine (VB2), expressed prostatic secretions (EPS), and postprostatic massage urine cultures (VB3). The EPS or VB3 had to have bacterial counts at least one log greater than the VBl or VB2 to be considered as documenting bacterial prostatitis. Nonbacterial prostatitis (NBP) and prostatodynia (PD) are similar entities, with the distinction being created by definition of an inflammatory response without identification of an infectious agent in NBP, and no inflammatory response in PD. The symptoms of prostatitis are well known and have been described as irritative voiding symptoms including dysuria, urgency, frequency, and nocturia together with pain in the pelvic region and genitalia. These data, however, have not been collected in a prospective manner to identify true differentiation of patients with prostatitis from other groups with lower tract symptoms. UROLOGY
t APKII. 1994
t VC)LUW 43. NIIMR~K 4
TABLE I.
Prostatitis questions: circle the number that best describes the symptoms you are currently experiencing No Pain
Perineal palnithlgh paln pain In or between legs Orchialgla painful testicles or scrotal sac Abdorrlnal!ingu~nal pain/ pressure: pain or full feeling In the abdomen Urethral discomfort pain in penis
Occurs (Not
/ APRII.
I994
2
3
0
1
3
3
0
I
2
7
0
1
2
.,z--...
AND METHODS
/ VOLUMF
43.
NUMBFR
incapacitating
1
This study was developed out of an antimicrobial study for chronic bacterial prostatitis. As part of their evaluation, the patients underwent the Meares-Stamey urinary regimen for diagnosing bacterial prostatitis.” Urine and expressed prostatic secretion specimens were collected for bacterial culture, and we added cultures for Ureaplasma, Mycoplasma, and L-form bacteria. The VBl, VB2, EPS, and VB3 were submitted to this culture regimen. As a result of this work, if the urinalysis was acellular and VB3 urine was sterile, no infection could be confirmed, and the patients were then eligible for entry into this open-label study.’ In this manner, patients with NBP and prostatodynia may be considered by some urologists to be comingled. Thus, 25 patients who were evaluated for prostatitis using clinical criteria7 and found to have a negative urinalysis and VB3 urine culture were offered participation in this study Patients were asked to complete a Boyarsky symptom scorerO,’ ’ modified with four other questions (Table I> that reflect the symptoms associated with prostatitis. Patients were then started at a dosage of 1 mg terazosin per day for four days, at which time the dosage was advanced to 2 mg, provided there were no side efUROLOGY
Usual But Does Not Stop Activity
0
Pelvic floor tension and other urodynamic abnormalities have been described,i,6 with successful treatment being anecdotally achieved with alphablockade.‘.” With the scientific literature lacking data on the use of current alpha-blocking drugs, we therefore treated men with this constellation of symptoms in a prospective (but open-label) manner with the alpha-blocking agent terazosin. We also tested a questionnaire on this group of patients and provisionally validated it against patients with benign prostatic hyperplasia (BPH) and asymptomatic, normal control patient populations. MATERIAL
Occasionally Every Day)
J
fects. Patients were reviewed at approximately two weeks after starting therapy, and if their symptoms had improved they continued to receive the 2 mg dosage. If their symptoms persisted, this dosage was increased to 5 mg per day and for 1 patient to 10 mg/day. The therapeutic range was therefore from 2 to 10 mg per day Therapy was continued for one month, at which time it was arbitrarily discontinued. Further treatment was individualized based upon the patient’s symptoms. Uroflowmetry was variably collected on patients as this data set was added after the start of the study. Data are available on 18 patients. Most patients had been previously treated with antibiotics and, in many cases, multiple courses of treatment, but all were off therapy with no resolution of their symptoms at the time of entry into this protocol. In an attempt to validate this symptom scoring system, 20 patients who had qualified for enrollment into a medical BPH study (American IJrological Association score > 8, peak uroflow 4 to 15 ml/second) were asked to complete the questionnaire, as were 10 normal control patients. For logistical reasons 10 patients presenting for vasectomy were utilized for the normal control group since they were of similar age to t-he patients with prostatitis but without urinary symptoms. The ability of the symptom score to discriminate between control patients (vasectomy and BPH) and patients with prostatitis was examined with logistic regression. The contributions and optimal weighting for individual questions were also examined with logistic regression. The internal consistency reliability of the symptom score was estimated with Cronbach’s alpha statistic.” Question similarity was examined with Spearman correlations. Prepost-treatment differences in the prostatitis group were tested with the Wilcoxon signed rank test (same patients) and Wilcoxon ranked sum test (between patients). 461
TABLE II.
N Prostatitis BPH Control
25 20 10
TABLE III.
Patient data
Age WI [Mean *SD) 39&10 66 9 t6.6 38.9 k5.92
TABLE IV.
Peak Uroflow (mUsecond, mean +SD] Baseline
Final
16.9?7 9 10.45k2.84
2Ok8.1
Before Treatment (Mean Score)
Responder
-p 5.000\ p = 0.7202 I
score
After Treatment (Mean Score)
= 0.000l/1
fl1
vp=;Iooo7
Analysis of symptoms Nonresoonder Baseline [Mean
Score *SD)
Prostatitis questions (out of 12) 5.16+1.77 Prostatitis 0.95 i-0 76 BPH Control 0.7+1 06 Boyarsky irritative questions (out of 12) Prostatrtls 484i1.60 BPH 5 7 k I .63 0 9k1.20 Control Boyarsky obstructive questions (out of 151 Prostatitis 2 96+2.67 BPH 5.50*2.42 Control 0 5 kO.97
5 667-
u = 0.0625-
Final Score (Mean ?SD)
1.88+1
64
2.8O-tl
68
1.4452
12
RESULTS
The patient age and uroflowmetry data are shown in Table II. Patients with prostatitis and normal control patients were of equal age (39 years). As is appropriate, the patients with BPH were older (67 years). The symptom scores were organized into three groups: our prostatitis questions (Table I), the Boyarsky irritative questions, and Boyarsky obstructive questions. The results of these scores are shown in Table III. As might be anticipated, the control patients had symptom scores across all categories statistically significantly lower than those for the treatment groups. Because of the age overlap between patients with prostatitis and BPH, we considered that such patients were another important discriminant group for validating the questions. Thus, patients entering another study of medical therapy were chosen since they were well characterized. These patients were merely asked to fill out the questionnaire, having already fulfilled the other studies’ entry criteria. The patients with BPH had mean obstructive and irritative scores of 5.93 and 5.73, respectively This appropriately reflects the BPH symptoms as found in other studies. However, the prostatitis score of 0.95 is completely different from that obtained from our patients with prostatitis: 5.16 + 1.77 (P = 0.0001). The patients with prostatitis had similar irritative scores to the patients with BPH 462
Wilcoxon analysis of symptom changes with treatment
(4.8 + 1.6 vs. 5.7 + 1.63), but lower obstructive scores (2.96 r 2.67 vs 5.50 + 2.42) (P < 0.0025). Comparison of peak uroflowmetries, with minimum voided volumes of 125 mL, showed that patients with BPH had a mean peak flow of 10.45 mUsecond while the baseline prostatitis peak flow was 16.9 ml/second, although with a range of 3 to 29.6 mllsecond. The post-treatment uroflow for the group with prostatitis was statistically insignificantly increased at 20 * 8 ml/second. Changes in flow did not appear to correlate with treatment efficacy Treatment benefit was determined subjectively by asking the patient whether or not he was improved with therapy. Of the 25 patients, 19 (76%) indicated symptomatic improvement and were, therefore, considered responders. We then reanalyzed the data for symptom scores based upon whether or not the patient considered himself a responder or nonresponder, but this did not materially alter the baseline scores obtained. Overall, the prostatitis symptom score decreased after treatment from 5.16 f 1.77 to 1.88 + 1.64 (P < 0.0001). When broken down by patient response or nonresponse, responders decreased from 5.00 + 1.76 to 1.21 + 1.13 while nonresponders decreased from 5.67 + 1.86 to 4.00 f 1.10. A Wilcoxon signed rank and rank sum analyses of these changes (Table IV) demonstrate the significant change from before to after treatment for the responders and between the responders and nonresponders after treatment but not between the before and after scores for the nonresponders. Additionally, both Boyarsky obstructive and irritative scores reduced significantly after treatment (P < 0.0001). Patients who were going to respond to treatment subjectively reported improvement after only a few doses of drug. Finally, we looked at the separation of patient groups by prostatitis question scores. Of a maximum score of twelve only 1 patient with prostatitis UROLOGY
/ APRH 1994
/ VOLC:M~ 4.3. NC~MBFR 4
_TABLE
-~-
V.
Prostatitis
Prostatitis
----
BPH + Normal Control
1 0 24
<2 1 >L
TABLE
No. of Patients
Score Max = 12)
questions
-.
23 6 1
UROLOC‘I
Question ~2 03 Q4
had a score of less than three (Table V), while only I of the patients with BPH and normal control had a score above two. The single outlier in the patients with prostatitis had marked irritative urinary symptoms. However, he also responded to terazosin therapy, perhaps reflecting the efficacy of terazosin on lower tract urinary symptoms in general. The control patient with a score of three denied urinary symptoms and perhaps reflects poor questionnaire separation between mild, occasional symptoms and recurrent symptoms in patients with problems. Overall the symptom score was very successful at differentiating controls and prostatitis cases. The distribution of scores is shown in Table V If a symptom score cutoff of three or greater is classified as a case of prostatitis, the observed sensitivity is 24/25 = 0.96 and the observed specificity is 29130 = 0.97. Consistent with this, the logistic regression of subject classification on symptom score was highly significant (odds ratio = 10.6, likelihood ratio chisquare = 59.6, P = 0.0001). To examine whether the unweighted score could be improved by differential weightings, a logistic regression was performed that included each of the four individual questions. The coefficient estimates were similar, ranging from 2.35 to 3.45 and the improvement in fit over the unweighted symptom score was negligible (likelihood ratio chi-square = 0.56). This suggests that the unweighted score could not be improved upon by weighting. A Cronbach’s alpha of 0.77 indicates a high level of internal consistency. This suggests high repeatability and also suggests that the questions are not measuring radically different concepts. This was also examined with Spearman correlations of the individual questions, shown in Table VI. All correlations are significant at the individual 5 percent level. Question 3’s correlations with the others were consistently the lowest; this suggests that this question is measuring a somewhat different aspect. This was also suggested by the logistic regression using the individual questions; even after the other three questions were adjusted for, question 3 still seemed to have discriminatory power (P = 0.064).
/ APRIL
I994
/ VOLUMF
43, NUMBI.R
4
VI. Spearman correlation coefficients of prostatitis questions (p values) ___-____ 0 661 10 0001) 0.342 rO.O106] 0 546 10 0001)
1
Question
0 48h IO 002) 13612 ,O.OOOl
S’
)
Question
3
Cl 299 IO 326141
This indicates that question 3 should be retained despite the lower correlations with, the other questions. Logistic regressions were performed separately for each of the individual questions. All four questions had significant discriminatory power, but not to the extent of the combined symptom score. COMMENT The use of alpha-blockade in this disease process has its basis in the anatomic studies by Donker et aI. in 1972.13 They showed that urethral wall tension was under alpha-adrenergic control. This was confirmed by Awad et al. l4 in showing that sympathetic activity was present in the proximal urethra and was higher than in the bladder neck area. In patients with bacteriologically negative prostates and symptoms of prostatitis, markedly elevated urethral pressure profiles were documented by Osborn et al.” Urodynamics in patients with abacterial prostatitis likewise showed an incomplete funneling of the bladder neck and tlarrowing of the external urethral sphincter. These conditions are all consistent with observations by other researchers that pelvic floor muscle spasm or smooth muscle spasm may be operative in this disease.5,h Reflux of urine into the intraprostatic ducts secondary to urethral spasm as well as urethral stricture has been described.” It is possible that this particular event may result in an intraprostatic inflammatory process, resulting in the subsequent symptoms of nonbacterial prostatitis along with evidence of a nonspecific inflammatory response in the EPS. Not all patients have ejaculatory ducts susceptible to the reflux of urine and may have the symptoms of prostatodynia due to smooth muscle spasm itself along with turbulent flow in the proximal urethra, but without the inflammatory response. These data suggest why, at least in some cases, NBP and prostatodynia may be the same disease and why we treated them similarly. Research continues on the causes of nonbacterial prostatitis. Nickel and Costerton’h have shown that organisms may exist in the prostatic ductal 463
system in a glycoprotein matrix that prevents access of the body’s immune system as well as access of antimicrobial chemotherapy Low levels of bacteria have been described on nrostatic needle biopsy specimens, but the current data are conflicting. i’ Chlamydia and other fastidious microorganisms have been implicated, but they may also be found in patients who are without symptoms. In that sense, a cause and effect relationship is somewhat difficult to prove. It seems logical to assume that irrespective of the cause of the inflammatory condition, smooth muscle spasm could be operative in this disease process. In that sense, alpha-blockade therapy may be important in the treatment. This has its basis in previous work that showed a favorable clinical response in nonbacterial prostatitis to the nonspecific alpha-blocking agent phenoxybenzamine. Osborn et aI8 showed a symptomatic response to phenoxybenzamine in 13 of 27 patients. This is especially important because of the placebo control that showed response of only 7 percent. In a review article in 1985, Orland et al’s also showed that alpha-blockage empirically improved voiding symptoms. Contrary to other authors,l’ we have found that after one month’s therapy many patients remain asymptomatic for long periods, while some will require repetitive or continuous therapy for long periods. Of the 19 responders, 11 (58%) had remained well without further therapy for more than three months. Six patients (32%) had required intermittent use of terazosin to maintain symptomatic improvement, while only 2 patients (10%) required continuous therapy for symptomatic relief. Our data have shown for the first time that the symptoms of men with prostatitis can be quantified and differentiated from those of normal controls and patients with BPH. This study was started prior to the publication of the AUA symptoms score and thus requires revalidation of the information together with reworking of the prostatitis questions into the six-point AUA score format (zero to five). Likewise, because of the major placebo response demonstrated in all the literature on medical therapy for the treatment of BPH, it is essential that a placebo-controlled study be performed to confirm the validity of this work. In conclusion, we have shown that patients with prostatitis can be differentiated from patients with BPH and normal controls by the use of a provisionally validated symptom score questionnaire and that terazosin therapy appears effective in the treatment of patients with prostatodynia, warranting a larger Phase III trial to determine efficacy, 464
Dutwood E. Neal, Jr., M.D. Universiry of Texas Medical Branch 301 University Blvd., 6.310 0J.S E40 Galveston,
Texas
77550
ACKNOWLEDGMENT. To William Underwood and Jean Tschampa of Abbott Laboratories for their support of this study. Statistical analysis was performed by Dennis Heisey, University of Wisconsin Academic Computing Center, REFERENCES 1. Crawford ED, Blum DS, Becker M, Berger ER, Clejan S, DeAntoni EP, Eisenberger M, Gambert S, Moon T, Staggers FE, and Stone NN: Prostate cancer awareness and recognition: initial report of a nationwide screening campaign. Unpublished data. 2. Koch HK: Office visits for male genitourinary conditions: National Ambulatory Medical Care Survey: United States, 1977-78. Hyattsville, Maryland, U.S. Dept. of Health and Human Services, Public Health Service, Office of Health Research, Statistics, and Technology, National Center for Health Statistics, 1980, pp l-10. 3. Brunner H, Weidner W, and Schiefer HG: Studies of the role of Ureaplasma urealyticum and Mycoplasma hominis in prostatitis. J Infect Dis 147: 807-813, 1983. 4. Neal DE Jr, and Dominigue GJ: Absence of unusual organisms in nonbacterial prostatitis. Manuscript in preparation. 5. Segura JW, Opitz JL, and Greene LF: Prostatosis, prostatitis or pelvic floor tension myalgia? J Urol 122: 168169, 1979. 6. Barbalias GA: Prostatodynia or painful male urethral syndrome? Urology 36: 146-153, 1990. 7. Barbalias GA, Meares EM Jr, and Sant GR: Prostatodynia: clinical and urodynamic characteristics. J Urol 130: 514-517, 1983. 8. Osborn DE, George NJ, Rao PN, Barnard RJ, Reading C, Marklow C, and Blacklock NJ: Prostatodynia-physiological characteristics and rational management with muscle relaxants. Br J Uro153: 621-623, 1981. 9. Meares EM, and Stamey TA: Bacteriologic localization patterns in bacterial prostatitis and urethritis. Invest Urol 5: 492-518,1968. 10. Boyarsky S, Jones G, Paulson DE and Prout GR Jr: A new look at bladder neck obstruction by the Food and Drug Administration regulators: guidelines for investigation of benign prostatic hypertrophy Trans Am Assoc Genitourin Surg 68: 29-32,1976. 11. Lepor H, Auerbach S, Puras-Baez A, Narayan P, Soloway M, Lowe E Moon T, Leifer G, and Madsen P: A randomized, placebo-controlled multicenter study of the efficacy and safety of terazosin in the treatment of benign prostatic hyperplasia. J Urol 148: 1467-1474, 1992. 12. Cronbach LJ: Coefficient alpha and the internal structure of tests. Psychometrika 16: 297-334, 1951. 13. Donker PJ, Ivanovici E Noach EL: Analyses of the urethral pressure profile by means of electromyography and the administration of drugs. Br J Uro144: 180-193, 1972. 14. Awad SA, and Downie JW: Sympathetic dyssynergia in the region of the external sphincter: a possible source of lower urinary tract obstruction. J Urol 118: 636-640, 1977. 15. Hellstrom WJ, Schmidt RA, Lue TE and Tanagho EA: Neuromuscular dysfunction in nonbacterial prostatitis. Urology 30: 183%188,1987. 16. Nickel JC, and Costerton JW: Coagulase-negative staphylococcus in chronic prostatitis. J Urol 147: 398-401, 1992.
UROLOGY
/ APRIL 1994 / VOLLJME~~. NUMBERS
17. Doble A, Thomas BJ, Furr PM, Walker MM, Harris JR, Witherow RO, and Taylor-Robinson D: A search for infectious agents in chronic abacterial prostatitis using ultrasound guided biopsy. Br J Uro164: 297-301, 1989. 18. Orland SM, Hanno PM, and Wein AJ: Prostatitis, prostatosis, and prostatodynia. Urology 25: 439-459. 1985. 19. Meares EM Jr: Prostatitis and related disorders, in Walsh PC, Retik AB, Stamey TA, and Vaughan ED Jr (Eds): Campbelli Urology, Philadelphia, WB Saunders Co, ed 6, 1992, pp 807-822. EDITORlAL COMMENT This study is in two parts, which are linked by the common bond of a condition diagnosed by the absence of objective findings. Nonbacterial prostatitis or prostatodynia refers to a symptom complex affecting the lower urinary tract, but without the bacteriological finding of chronic bacterial prostatitis. It is therefore important to remember that when testing a drug in patients with this condition, the absence of objective findings introduces a placebo possibility that is probably highly significant. The authors address this in an
UROLOGY
/ APRIL 1994
/ VOLUME 43, NUMBER
4
interesting way; realizing that this is the case, they introduce a symptom score that might be of value in the future when considering this condition. This is subjected to a rigorous statistical analysis and seems sound. The one shght criticism one might have is that the authors, although referring to a score that would be useful in nonbacterial prostatitis and prostatodynia, consistently refer to one of the groups as the “prostatitis group.” Anything that helps in prostatodynia is of value; this is an open study and so the possible weakness of a potentially strong placebo effect is not excluded. The authors point out the possible rationale for the use of terazosin in this condition, and this is helpful to the clinician. It is of help to the clinician that another agent can be offered to patients with this condition, but I would agree with the authors that a randomized placebo-controlled trial should be performed. John Fitzpatrick, M.D. Surgical Pro/&sorial 47 Eccles Street Dublin 7, Ireland
465
ABSTRACT-Objective. The purpose of this trial was to study the use of terazosin in nonbacterial prostatitis/prostatodynia, and to evaluate a new symptom score sheet for this disease. Methods. Twenty-five patients who presented with lower urinary tract symptoms suggestive of prostatitis were evaluated for evidence of bacterial infection by Meares-Stamey criteria and found to be negative. They were then treated with the alpha-blocking drug terazosin in doses from 1 to 10 mg. A symptom score index for prostatitis was developed, tested in these patients, and validated against patients with benign prostatic hyperplasia. Normal control patients, who presented for vasectomy, were studied as well. Results. Nineteen patients (76%) responded to one month’s therapy, with 11 (58%) remaining asymptomatic three months later. The symptom score index, as measured by Cronbach’s alpha measure of index reliability, was excellent at 0.78 and logistic regression analysis demonstrated each prostatitis question to have independent validity (P < 0.001) but not to the extent of the combined score. Conclusions. Terazosin appears effective in treating patients with nonbacterial prostatitis/prostatodynia. This new symptom score is one way to evaluate and track patients with this disease. A randomized, placebo-controlled clinical trial has been initiated to study this.
Chronic prostatitis is a common condition which affects men of all ages. Data collected during Prostate Cancer Awareness Week suggest the prevalence of lower tract urinary symptoms compatible with prostatitis at 12 percent.’ Another study suggested that there were twenty office visits per 1,000 men per year for prostatitis.* The above figures, however, are based upon questionnaire data and do not necessarily reflect diagnostic accuracy. Data are lacking about the true frequency of prostatitis in the population and about the relative frequency of the various subgroups. A german study involving 600 men in a prostatitis clinic found that 5 percent had chronic bacterial prostatitis, 64 percent had nonbacterial prostatitis, and 31 percent had prostatodynia.7 In a recent study we found that 8/48 patients (17%) with prostatitis-like symptoms had a diagnosis of chronic Submitted: October 1, 1993, accepted: October 29, 1993
460
bacterial prostatitis,’ as diagnosed by the culture of the initial urine (VBl), midstream urine (VB2), expressed prostatic secretions (EPS), and postprostatic massage urine cultures (VB3). The EPS or VB3 had to have bacterial counts at least one log greater than the VBl or VB2 to be considered as documenting bacterial prostatitis. Nonbacterial prostatitis (NBP) and prostatodynia (PD) are similar entities, with the distinction being created by definition of an inflammatory response without identification of an infectious agent in NBP, and no inflammatory response in PD. The symptoms of prostatitis are well known and have been described as irritative voiding symptoms including dysuria, urgency, frequency, and nocturia together with pain in the pelvic region and genitalia. These data, however, have not been collected in a prospective manner to identify true differentiation of patients with prostatitis from other groups with lower tract symptoms. UROLOGY
t APKII. 1994
t VC)LUW 43. NIIMR~K 4
TABLE I.
Prostatitis questions: circle the number that best describes the symptoms you are currently experiencing No Pain
Perineal palnithlgh paln pain In or between legs Orchialgla painful testicles or scrotal sac Abdorrlnal!ingu~nal pain/ pressure: pain or full feeling In the abdomen Urethral discomfort pain in penis
Occurs (Not
/ APRII.
I994
2
3
0
1
3
3
0
I
2
7
0
1
2
.,z--...
AND METHODS
/ VOLUMF
43.
NUMBFR
incapacitating
1
This study was developed out of an antimicrobial study for chronic bacterial prostatitis. As part of their evaluation, the patients underwent the Meares-Stamey urinary regimen for diagnosing bacterial prostatitis.” Urine and expressed prostatic secretion specimens were collected for bacterial culture, and we added cultures for Ureaplasma, Mycoplasma, and L-form bacteria. The VBl, VB2, EPS, and VB3 were submitted to this culture regimen. As a result of this work, if the urinalysis was acellular and VB3 urine was sterile, no infection could be confirmed, and the patients were then eligible for entry into this open-label study.’ In this manner, patients with NBP and prostatodynia may be considered by some urologists to be comingled. Thus, 25 patients who were evaluated for prostatitis using clinical criteria7 and found to have a negative urinalysis and VB3 urine culture were offered participation in this study Patients were asked to complete a Boyarsky symptom scorerO,’ ’ modified with four other questions (Table I> that reflect the symptoms associated with prostatitis. Patients were then started at a dosage of 1 mg terazosin per day for four days, at which time the dosage was advanced to 2 mg, provided there were no side efUROLOGY
Usual But Does Not Stop Activity
0
Pelvic floor tension and other urodynamic abnormalities have been described,i,6 with successful treatment being anecdotally achieved with alphablockade.‘.” With the scientific literature lacking data on the use of current alpha-blocking drugs, we therefore treated men with this constellation of symptoms in a prospective (but open-label) manner with the alpha-blocking agent terazosin. We also tested a questionnaire on this group of patients and provisionally validated it against patients with benign prostatic hyperplasia (BPH) and asymptomatic, normal control patient populations. MATERIAL
Occasionally Every Day)
J
fects. Patients were reviewed at approximately two weeks after starting therapy, and if their symptoms had improved they continued to receive the 2 mg dosage. If their symptoms persisted, this dosage was increased to 5 mg per day and for 1 patient to 10 mg/day. The therapeutic range was therefore from 2 to 10 mg per day Therapy was continued for one month, at which time it was arbitrarily discontinued. Further treatment was individualized based upon the patient’s symptoms. Uroflowmetry was variably collected on patients as this data set was added after the start of the study. Data are available on 18 patients. Most patients had been previously treated with antibiotics and, in many cases, multiple courses of treatment, but all were off therapy with no resolution of their symptoms at the time of entry into this protocol. In an attempt to validate this symptom scoring system, 20 patients who had qualified for enrollment into a medical BPH study (American IJrological Association score > 8, peak uroflow 4 to 15 ml/second) were asked to complete the questionnaire, as were 10 normal control patients. For logistical reasons 10 patients presenting for vasectomy were utilized for the normal control group since they were of similar age to t-he patients with prostatitis but without urinary symptoms. The ability of the symptom score to discriminate between control patients (vasectomy and BPH) and patients with prostatitis was examined with logistic regression. The contributions and optimal weighting for individual questions were also examined with logistic regression. The internal consistency reliability of the symptom score was estimated with Cronbach’s alpha statistic.” Question similarity was examined with Spearman correlations. Prepost-treatment differences in the prostatitis group were tested with the Wilcoxon signed rank test (same patients) and Wilcoxon ranked sum test (between patients). 461
TABLE II.
N Prostatitis BPH Control
25 20 10
TABLE III.
Patient data
Age WI [Mean *SD) 39&10 66 9 t6.6 38.9 k5.92
TABLE IV.
Peak Uroflow (mUsecond, mean +SD] Baseline
Final
16.9?7 9 10.45k2.84
2Ok8.1
Before Treatment (Mean Score)
Responder
-p 5.000\ p = 0.7202 I
score
After Treatment (Mean Score)
= 0.000l/1
fl1
vp=;Iooo7
Analysis of symptoms Nonresoonder Baseline [Mean
Score *SD)
Prostatitis questions (out of 12) 5.16+1.77 Prostatitis 0.95 i-0 76 BPH Control 0.7+1 06 Boyarsky irritative questions (out of 12) Prostatrtls 484i1.60 BPH 5 7 k I .63 0 9k1.20 Control Boyarsky obstructive questions (out of 151 Prostatitis 2 96+2.67 BPH 5.50*2.42 Control 0 5 kO.97
5 667-
u = 0.0625-
Final Score (Mean ?SD)
1.88+1
64
2.8O-tl
68
1.4452
12
RESULTS
The patient age and uroflowmetry data are shown in Table II. Patients with prostatitis and normal control patients were of equal age (39 years). As is appropriate, the patients with BPH were older (67 years). The symptom scores were organized into three groups: our prostatitis questions (Table I), the Boyarsky irritative questions, and Boyarsky obstructive questions. The results of these scores are shown in Table III. As might be anticipated, the control patients had symptom scores across all categories statistically significantly lower than those for the treatment groups. Because of the age overlap between patients with prostatitis and BPH, we considered that such patients were another important discriminant group for validating the questions. Thus, patients entering another study of medical therapy were chosen since they were well characterized. These patients were merely asked to fill out the questionnaire, having already fulfilled the other studies’ entry criteria. The patients with BPH had mean obstructive and irritative scores of 5.93 and 5.73, respectively This appropriately reflects the BPH symptoms as found in other studies. However, the prostatitis score of 0.95 is completely different from that obtained from our patients with prostatitis: 5.16 + 1.77 (P = 0.0001). The patients with prostatitis had similar irritative scores to the patients with BPH 462
Wilcoxon analysis of symptom changes with treatment
(4.8 + 1.6 vs. 5.7 + 1.63), but lower obstructive scores (2.96 r 2.67 vs 5.50 + 2.42) (P < 0.0025). Comparison of peak uroflowmetries, with minimum voided volumes of 125 mL, showed that patients with BPH had a mean peak flow of 10.45 mUsecond while the baseline prostatitis peak flow was 16.9 ml/second, although with a range of 3 to 29.6 mllsecond. The post-treatment uroflow for the group with prostatitis was statistically insignificantly increased at 20 * 8 ml/second. Changes in flow did not appear to correlate with treatment efficacy Treatment benefit was determined subjectively by asking the patient whether or not he was improved with therapy. Of the 25 patients, 19 (76%) indicated symptomatic improvement and were, therefore, considered responders. We then reanalyzed the data for symptom scores based upon whether or not the patient considered himself a responder or nonresponder, but this did not materially alter the baseline scores obtained. Overall, the prostatitis symptom score decreased after treatment from 5.16 f 1.77 to 1.88 + 1.64 (P < 0.0001). When broken down by patient response or nonresponse, responders decreased from 5.00 + 1.76 to 1.21 + 1.13 while nonresponders decreased from 5.67 + 1.86 to 4.00 f 1.10. A Wilcoxon signed rank and rank sum analyses of these changes (Table IV) demonstrate the significant change from before to after treatment for the responders and between the responders and nonresponders after treatment but not between the before and after scores for the nonresponders. Additionally, both Boyarsky obstructive and irritative scores reduced significantly after treatment (P < 0.0001). Patients who were going to respond to treatment subjectively reported improvement after only a few doses of drug. Finally, we looked at the separation of patient groups by prostatitis question scores. Of a maximum score of twelve only 1 patient with prostatitis UROLOGY
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_TABLE
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Prostatitis
Prostatitis
----
BPH + Normal Control
1 0 24
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TABLE
No. of Patients
Score Max = 12)
questions
-.
23 6 1
UROLOC‘I
Question ~2 03 Q4
had a score of less than three (Table V), while only I of the patients with BPH and normal control had a score above two. The single outlier in the patients with prostatitis had marked irritative urinary symptoms. However, he also responded to terazosin therapy, perhaps reflecting the efficacy of terazosin on lower tract urinary symptoms in general. The control patient with a score of three denied urinary symptoms and perhaps reflects poor questionnaire separation between mild, occasional symptoms and recurrent symptoms in patients with problems. Overall the symptom score was very successful at differentiating controls and prostatitis cases. The distribution of scores is shown in Table V If a symptom score cutoff of three or greater is classified as a case of prostatitis, the observed sensitivity is 24/25 = 0.96 and the observed specificity is 29130 = 0.97. Consistent with this, the logistic regression of subject classification on symptom score was highly significant (odds ratio = 10.6, likelihood ratio chisquare = 59.6, P = 0.0001). To examine whether the unweighted score could be improved by differential weightings, a logistic regression was performed that included each of the four individual questions. The coefficient estimates were similar, ranging from 2.35 to 3.45 and the improvement in fit over the unweighted symptom score was negligible (likelihood ratio chi-square = 0.56). This suggests that the unweighted score could not be improved upon by weighting. A Cronbach’s alpha of 0.77 indicates a high level of internal consistency. This suggests high repeatability and also suggests that the questions are not measuring radically different concepts. This was also examined with Spearman correlations of the individual questions, shown in Table VI. All correlations are significant at the individual 5 percent level. Question 3’s correlations with the others were consistently the lowest; this suggests that this question is measuring a somewhat different aspect. This was also suggested by the logistic regression using the individual questions; even after the other three questions were adjusted for, question 3 still seemed to have discriminatory power (P = 0.064).
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VI. Spearman correlation coefficients of prostatitis questions (p values) ___-____ 0 661 10 0001) 0.342 rO.O106] 0 546 10 0001)
1
Question
0 48h IO 002) 13612 ,O.OOOl
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)
Question
3
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This indicates that question 3 should be retained despite the lower correlations with, the other questions. Logistic regressions were performed separately for each of the individual questions. All four questions had significant discriminatory power, but not to the extent of the combined symptom score. COMMENT The use of alpha-blockade in this disease process has its basis in the anatomic studies by Donker et aI. in 1972.13 They showed that urethral wall tension was under alpha-adrenergic control. This was confirmed by Awad et al. l4 in showing that sympathetic activity was present in the proximal urethra and was higher than in the bladder neck area. In patients with bacteriologically negative prostates and symptoms of prostatitis, markedly elevated urethral pressure profiles were documented by Osborn et al.” Urodynamics in patients with abacterial prostatitis likewise showed an incomplete funneling of the bladder neck and tlarrowing of the external urethral sphincter. These conditions are all consistent with observations by other researchers that pelvic floor muscle spasm or smooth muscle spasm may be operative in this disease.5,h Reflux of urine into the intraprostatic ducts secondary to urethral spasm as well as urethral stricture has been described.” It is possible that this particular event may result in an intraprostatic inflammatory process, resulting in the subsequent symptoms of nonbacterial prostatitis along with evidence of a nonspecific inflammatory response in the EPS. Not all patients have ejaculatory ducts susceptible to the reflux of urine and may have the symptoms of prostatodynia due to smooth muscle spasm itself along with turbulent flow in the proximal urethra, but without the inflammatory response. These data suggest why, at least in some cases, NBP and prostatodynia may be the same disease and why we treated them similarly. Research continues on the causes of nonbacterial prostatitis. Nickel and Costerton’h have shown that organisms may exist in the prostatic ductal 463
system in a glycoprotein matrix that prevents access of the body’s immune system as well as access of antimicrobial chemotherapy Low levels of bacteria have been described on nrostatic needle biopsy specimens, but the current data are conflicting. i’ Chlamydia and other fastidious microorganisms have been implicated, but they may also be found in patients who are without symptoms. In that sense, a cause and effect relationship is somewhat difficult to prove. It seems logical to assume that irrespective of the cause of the inflammatory condition, smooth muscle spasm could be operative in this disease process. In that sense, alpha-blockade therapy may be important in the treatment. This has its basis in previous work that showed a favorable clinical response in nonbacterial prostatitis to the nonspecific alpha-blocking agent phenoxybenzamine. Osborn et aI8 showed a symptomatic response to phenoxybenzamine in 13 of 27 patients. This is especially important because of the placebo control that showed response of only 7 percent. In a review article in 1985, Orland et al’s also showed that alpha-blockage empirically improved voiding symptoms. Contrary to other authors,l’ we have found that after one month’s therapy many patients remain asymptomatic for long periods, while some will require repetitive or continuous therapy for long periods. Of the 19 responders, 11 (58%) had remained well without further therapy for more than three months. Six patients (32%) had required intermittent use of terazosin to maintain symptomatic improvement, while only 2 patients (10%) required continuous therapy for symptomatic relief. Our data have shown for the first time that the symptoms of men with prostatitis can be quantified and differentiated from those of normal controls and patients with BPH. This study was started prior to the publication of the AUA symptoms score and thus requires revalidation of the information together with reworking of the prostatitis questions into the six-point AUA score format (zero to five). Likewise, because of the major placebo response demonstrated in all the literature on medical therapy for the treatment of BPH, it is essential that a placebo-controlled study be performed to confirm the validity of this work. In conclusion, we have shown that patients with prostatitis can be differentiated from patients with BPH and normal controls by the use of a provisionally validated symptom score questionnaire and that terazosin therapy appears effective in the treatment of patients with prostatodynia, warranting a larger Phase III trial to determine efficacy, 464
Dutwood E. Neal, Jr., M.D. Universiry of Texas Medical Branch 301 University Blvd., 6.310 0J.S E40 Galveston,
Texas
77550
ACKNOWLEDGMENT. To William Underwood and Jean Tschampa of Abbott Laboratories for their support of this study. Statistical analysis was performed by Dennis Heisey, University of Wisconsin Academic Computing Center, REFERENCES 1. Crawford ED, Blum DS, Becker M, Berger ER, Clejan S, DeAntoni EP, Eisenberger M, Gambert S, Moon T, Staggers FE, and Stone NN: Prostate cancer awareness and recognition: initial report of a nationwide screening campaign. Unpublished data. 2. Koch HK: Office visits for male genitourinary conditions: National Ambulatory Medical Care Survey: United States, 1977-78. Hyattsville, Maryland, U.S. Dept. of Health and Human Services, Public Health Service, Office of Health Research, Statistics, and Technology, National Center for Health Statistics, 1980, pp l-10. 3. Brunner H, Weidner W, and Schiefer HG: Studies of the role of Ureaplasma urealyticum and Mycoplasma hominis in prostatitis. J Infect Dis 147: 807-813, 1983. 4. Neal DE Jr, and Dominigue GJ: Absence of unusual organisms in nonbacterial prostatitis. Manuscript in preparation. 5. Segura JW, Opitz JL, and Greene LF: Prostatosis, prostatitis or pelvic floor tension myalgia? J Urol 122: 168169, 1979. 6. Barbalias GA: Prostatodynia or painful male urethral syndrome? Urology 36: 146-153, 1990. 7. Barbalias GA, Meares EM Jr, and Sant GR: Prostatodynia: clinical and urodynamic characteristics. J Urol 130: 514-517, 1983. 8. Osborn DE, George NJ, Rao PN, Barnard RJ, Reading C, Marklow C, and Blacklock NJ: Prostatodynia-physiological characteristics and rational management with muscle relaxants. Br J Uro153: 621-623, 1981. 9. Meares EM, and Stamey TA: Bacteriologic localization patterns in bacterial prostatitis and urethritis. Invest Urol 5: 492-518,1968. 10. Boyarsky S, Jones G, Paulson DE and Prout GR Jr: A new look at bladder neck obstruction by the Food and Drug Administration regulators: guidelines for investigation of benign prostatic hypertrophy Trans Am Assoc Genitourin Surg 68: 29-32,1976. 11. Lepor H, Auerbach S, Puras-Baez A, Narayan P, Soloway M, Lowe E Moon T, Leifer G, and Madsen P: A randomized, placebo-controlled multicenter study of the efficacy and safety of terazosin in the treatment of benign prostatic hyperplasia. J Urol 148: 1467-1474, 1992. 12. Cronbach LJ: Coefficient alpha and the internal structure of tests. Psychometrika 16: 297-334, 1951. 13. Donker PJ, Ivanovici E Noach EL: Analyses of the urethral pressure profile by means of electromyography and the administration of drugs. Br J Uro144: 180-193, 1972. 14. Awad SA, and Downie JW: Sympathetic dyssynergia in the region of the external sphincter: a possible source of lower urinary tract obstruction. J Urol 118: 636-640, 1977. 15. Hellstrom WJ, Schmidt RA, Lue TE and Tanagho EA: Neuromuscular dysfunction in nonbacterial prostatitis. Urology 30: 183%188,1987. 16. Nickel JC, and Costerton JW: Coagulase-negative staphylococcus in chronic prostatitis. J Urol 147: 398-401, 1992.
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17. Doble A, Thomas BJ, Furr PM, Walker MM, Harris JR, Witherow RO, and Taylor-Robinson D: A search for infectious agents in chronic abacterial prostatitis using ultrasound guided biopsy. Br J Uro164: 297-301, 1989. 18. Orland SM, Hanno PM, and Wein AJ: Prostatitis, prostatosis, and prostatodynia. Urology 25: 439-459. 1985. 19. Meares EM Jr: Prostatitis and related disorders, in Walsh PC, Retik AB, Stamey TA, and Vaughan ED Jr (Eds): Campbelli Urology, Philadelphia, WB Saunders Co, ed 6, 1992, pp 807-822. EDITORlAL COMMENT This study is in two parts, which are linked by the common bond of a condition diagnosed by the absence of objective findings. Nonbacterial prostatitis or prostatodynia refers to a symptom complex affecting the lower urinary tract, but without the bacteriological finding of chronic bacterial prostatitis. It is therefore important to remember that when testing a drug in patients with this condition, the absence of objective findings introduces a placebo possibility that is probably highly significant. The authors address this in an
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interesting way; realizing that this is the case, they introduce a symptom score that might be of value in the future when considering this condition. This is subjected to a rigorous statistical analysis and seems sound. The one shght criticism one might have is that the authors, although referring to a score that would be useful in nonbacterial prostatitis and prostatodynia, consistently refer to one of the groups as the “prostatitis group.” Anything that helps in prostatodynia is of value; this is an open study and so the possible weakness of a potentially strong placebo effect is not excluded. The authors point out the possible rationale for the use of terazosin in this condition, and this is helpful to the clinician. It is of help to the clinician that another agent can be offered to patients with this condition, but I would agree with the authors that a randomized placebo-controlled trial should be performed. John Fitzpatrick, M.D. Surgical Pro/&sorial 47 Eccles Street Dublin 7, Ireland
465