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Urinary tract disorders
URINARY TRACT DISORDERS Clinical Comparison STANLEY
GOULD,
of Flavoxate
and Phenazopyridine
M.D.
Philadelphia, Pennsylvania
ABSTRACT - In nine separate clinical trials, 392 patients having symptoms of either prostatitis, acute cystitis, urethritis, andlor trigonitis were randomly assigned to treatment with jlavoxate or phenazopyridine. Over-all response was evaluated in 384 patients after-five days of therapy. In patients having prostatitis, response was satisfactory in 66 per cent treated with Javoxate and 31 per cent treated with phenazopyridine. In all other patients, satisfactory responses were reported in 80 per cent onfEavoxate compared with 56 per cent on phenazopyridine. Similarly, symptom-severity evaluations at two andjve days of therapy showed most symptoms improved in more of the patients onfEavoxate therapy than on phenazopyridine therapy. Although more adverse effects were reported in patients treated with phenazopyridine than with jlavoxate, the diffmence between medications was not statistically signi$cant.
Anticholinergic antispasmodics and analgesic/ anesthetic dyes have been available for many years for the symptomatic treatment of disorders of the lower urinary tract. Although both types of drugs produce satisfactory relief, the autonomic side effects of the anticholinergic agents and the staining of urine, and consequently, clothing, by the azo dyes are practical limitations to their use. Several years ago flavoxate, a new urinary tract antispasmodic, chemically unrelated to the anticholinergic drugs or azo dyes, became available. Flavoxate is a flavone derivative which has been shown in laboratory animal studies to have pharmacologic properties similar to those of papaverine in its ability to counteract smooth muscle spasm in abdominal viscera through a selective effect on the muscle rather than through a nonselective anticholinergic effect.’ In a double-blind cystometric evaluation in patients having neurogenic bladders2 and in two double-blind clinical studies,3,4 flavoxate compared favorably with the anticholinergic, propantheline, in efficacy and incidence of adverse effects. This multi-investigator study was undertaken to compare flavoxate hydrochloride (Urispas) with phenazopyridine hydrochloride
612
(Pyridium), an azo dye, in the symptomatic treatment of disorders of the lower urinary tract. Methods Nine physicians were asked to follow identical protocols and conduct the individual studies in their private practices. Each was to study 48 patients having urinary frequency, dysuria, nocturia, urgency, incontinence and/or suprapubic pain associated with acute cystitis, prostatitis, urethritis, or trigonitis. The study could not be double-blind, because phenazopyridine colors the urine and because the recommended dosage regimens for the two drugs are different. However, assignment of medication was randomized and double-blind. After a patient was admitted to the study, the investigator opened a sealed envelope to learn which medication the patient would be taking. He gave each patient a five-day supply of medication and asked him to return two and five days later for evaluation. At the pretreatment and subsequent visits the investigator evaluated the patient’s symptoms as absent, mild, moderate, or severe. He also completed a global evaluation
UROLOGY
/ MAY1975
/ VOLUMEV,
NUMBER5
TABLE I. Satisfactory responses in patients having acute cystitis, urethritis, an&or trigonitis
Investigators
Flavoxate Number of Number Patients Satisfactory
A B
15 20
14 18
C D E F G H I
11* 13 15 21 22* 23* 24
3 12 15 18 19 17 12
TOTALS
164 161
-Phenazopyridine--Number of Number Patients Satisfactory 12
7
21 11t 11 18 22* 22* 21 23
11 2 7 8 15 13 15 10
161 156
128
(56 pt: cent)
(80per cent)
*One patient not rated for global efficacy. tThree patients not rated for global efficacy.
TABLE II. Satisfactory responses in patients having prostatitis
Investigators*
Flavoxate--------Number of Number Satisfactory Patients
A B, D, and Gt C E
5 8 13 9
TOTALS
35
-Phenazopyridine--Number of Number Satisfactory Patients
3 6 6 8
10 6 11 5
23 (66per cent)
7 1 1 1
32
(31 pi:cent)
*No data for investigators F, H, and I. tcombined data from three investigators.
of the patient’s response after the five days of therapy. The dosage of flavoxate was two tablets (100 mg. each), taken four times a day (after meals and at bedtime). The dosage of phenazopyridine was two tablets (100 mg. each), taken three times a day (after meals). Concomitant antibacterial, antibiotic, or general analgesic therapy was given if indicated, but analgesics having a therapeutic effect on the urinary tract, peripheral anticholinergics, and corticosteroids and antibiotics combined with azo dyes were not prescribed. Results A total of 408 patients were included in the nine studies. However, 15 patients failed to return after the pretreatment visit or had received concomitant therapy excluded by the protocol; another refused to continue therapy with phen-
UROLOGY
/ MAY1975 / VOLUMEV,
NUMBER5
azopyridine because it stained her clothing. Subsequently, all of these were dropped from the study. Thus, data adequate for analysis were obtained on 392 patients, 289 women and 103 men, ranging in age from seven to ninety years.* Of these, 199 received flavoxate hydrochloride and 193 phenazopyridine hydrochloride. Global efficacy ratings were reported for only 384 patients. The criteria used were: satisfactory relief of all symptoms within forty-eight hours Good - satisfactory relief of most symptoms after five days Fair - partial relief of symptoms, but persistence of some mild symptoms after five days Poor - little or no relief
Excellent
*One mended
-
investigator treated 3 patients under
the recom-
age limit of twelve years.
613
TABLE III. Symptomatic improvement in patients having acute cystitis, urethritis, andlor trigonitis
Symptoms Frequency Dysuria Nocturia Urgency Incontinence Suprapubic pain
Day 2-------------Flavoxate Phenazopyridine Number Per Cent Number Per Cent Patients Improved Patients Improved 165 160 139 160 116 131
70 63 49 68 31 56
157 149 124 156 110 124
54 60 42 51 20 51
Day C Flavoxate Phenazopyridine Number Per Cent Number Per Cent Patients Improved Patients Improved 158 154 134 155 115 127
84 84 75 87 48 70
148 142 115 148 105 118
85 82 70 72 35 69
TABLE IV. Symptomatic improvement in patients having prostatitis Day 2-----------
Symptoms Frequency Dysuria Nocturia Urgency Incontinence Suprapubic pain
Flavoxate Number Per Cent Patients Improved 35 34 29 34 24 32
60
32
53
71 34 50 25 62
30 25 31 23 29
53 20 42 22 69
All good and excellent ratings were considered satisfactory responses. Since the responses of the patients with prostatitis were of particular interest, the data were divided into two groups on the basis of the primary diagnosis, namely, those patients having prostatitis alone or in combination with other diagnoses formed one group, while those with all other diagnoses formed a second group. In the latter group most patients were diagnosed as having acute cystitis alone or cystitis with an associated diagnosis. The number of satisfactory responses in 317 patients having diagnoses other than prostatitis and in the 67 patients whose diagnoses included prostatitis are shown in Tables I and II, respectively. In both groups flavoxate produced more satisfactory responses than phenazopyridine, and the difference between the two drugs was statistically significant (P < 0.01). Tables III and IV show the efficacy of flavoxate and of phenazopyridine in improving each of the presenting symptoms in the two diagnostic groups after two and five days of therapy. The per cent improved includes all patients whose symptom severity while on therapy indicated there was some degree of improvement over the pretreatment severity. The data account for
614
Day 5-----------
Phenazopyridine Number Per Cent Patients Improved
Flavoxate Number Per Cent Patients Improved 34 33 27 31 23 33
74 85 63 74 48 79
Phenazopyridine Number Per Cent Patients Improved 32 30 25 31 23 29
72 80 52 64 39 86
all patients evaluated at two and/or five days of therapy. Most of the patients had more than one presenting symptom. The data at day 2 indicate that flavoxate had a faster onset of action than phenazopyridine in controlling the symptoms except for suprapubic pain associated with prostatitis. At the end of five days flavoxate produced symptomatic improvement in more patients than phenazopyridine, except for suprapubic pain, in which phenazopyridine was superior. For the symptom of frequency in both diagnostic groups, both drugs were approximately equally effective. The differences between flavoxate and phenazopyridine in per cent of patients showing improvement in individual symptoms are not as marked as the differences found in the global it must be kept in efficacy ratings. However, mind that the tables of symptomatic improvement do not show the differences in degree of improvement recorded by the investigators. Differences in degree of improvement were, however, taken into account in a statistical analysis of total morbidity score averages, which showed a significant difference favoring flavoxate over phenazopyridine in total symptomatic relief in prostatitis (P < 0.05) and again in cystitis,
UROLOGY
/ MAY1975 / VOLUMEV,
NUMBER5
TABLE V. Effects
Adverse effects*
Flavoxate
Backache Diarrhea Dizziness Gastrointestinal distress Headache Nausea Rash Vomiting Miscellaneous Total symptoms Number patients per total treated
3
2 7 0
3 2 5 2
0 3 16 1
1 1
1
1
2f 20
3$ 33
16/199 (8
Phenazopyridine
per cent)
251193
(13 per cent)
*Includes all adverse effects reported whether or not a relationship to the drug was established. t Heart pounding; sick. $Epigastric abdominal pain; burning skin; light-headed.
urethritis, and/or trigonitis (P < 0.01) both at day 2 and day 5.5 Hence, the total morbidity score data support the global efficacy data. Adverse
Effects
All adverse effects reported are shown in Table V. Sixteen (8 per cent) of the 199 patients treated with flavoxate reported a total of 20 adverse effects, and 25 (13 per cent) of the 193 treated with phenazopyridine reported a total of 33 adverse effects. Therapy was discontinued in five of the flavoxate patients and eight of the phenazopyridine patients. Although more adverse effects were reported in the phenazopyridine group, there was no statistically significant difference between the two drugs. Comment Ideally, comparative studies of drug efficacy should be double-blind to avoid possible bias. This study could not be double-blind because the recommended dosage schedules for the two drugs differ, and because one drug causes a readily apparent staining of urine. However, the likelihood of bias was diminished by providing for
UROLOGY
/ MAY 1975 / VOLUME
V, NUMBER
5
assignment of medication on a randomized, double-blind basis. If any bias were to occur, the most likely tendency would be to appraise the newer drug, flavoxate, conservatively and underestimate its efficacy. Yet, the results of the study favor flavoxate. The consistency of the results of individual evaluations supports the combined data showing flavoxate to be superior to phenazopyridine to a statistically significant degree. In the global efficacy ratings, a trend favoring flavoxate was seen in the individual data from all 9 investigators in the evaluation of patients having diagnoses other than prostatitis; this same trend was seen in three of four comparisons among patients having prostatitis. The individual symptom relief data favoring flavoxate were consistent with the global efficacy data. Over-all, the results of this study demonstrate the superior action of flavoxate compared with phenazopyridine in terms of faster onset of action and greater relief of most presenting symptoms. 1500 Spring Garden Street Philadelphia, Pennsylvania 19101 ACKNOWLEDGMENT. Our appreciation to the following physicians for participating in this study: Gustave K. Berger, M.D., Wilmington, Delaware; Robert S. Christman, M.D., Harrisburg, Pennsylvania; Walter N. Himmler, M.D., Cumberland, IMaryland; Robert M. Kline, M.D., Lebanon, Pennsylvania; F. W. Kunze, M.D., Los Angeles, California; Benjamin R. Paradee, M.D., Cherry Hill, New Jersey; Jerome J. Schneyer, M.D., Southfield, Michigan; Richard H. Smith, M.D., Downington, Pennsylvania; and Murray Steinberg, M.D., Baltimore, Maryland. References 1. SETNIKAR, I.RAVASI, M. T., and DARE, P.: Pharmacological properties of piperidinoethyl-3-methylflavone8-carboxylate hydrochloride, a smooth-muscle relaxant, J. Pharmacol. Exp. Ther. 130: 356 (1960). 2. KOHLER, F. P., and MORALES, P. A.: Cystometric evaluation of flavoxate hydrochloride in normal and neurogenic bladders, J. Urol. 100: 729 (1968). 3. BRADLEY, D. V., and CAZORT, R. J.: Relief of bladder spasm by flavoxate: a comparative study, J. Clin. Pharmacol. 10: 65 (1970). 4. HERBST, W. P.: Double-blind comparison of flavoxate and propantheline as urologic antispasmodics, Am. J. Clin Res. 1: 65 (1970). 5. Research data: Smith Kline & French Laboratories, December 28, 1973.
615
GOULD,
of Flavoxate
and Phenazopyridine
M.D.
Philadelphia, Pennsylvania
ABSTRACT - In nine separate clinical trials, 392 patients having symptoms of either prostatitis, acute cystitis, urethritis, andlor trigonitis were randomly assigned to treatment with jlavoxate or phenazopyridine. Over-all response was evaluated in 384 patients after-five days of therapy. In patients having prostatitis, response was satisfactory in 66 per cent treated with Javoxate and 31 per cent treated with phenazopyridine. In all other patients, satisfactory responses were reported in 80 per cent onfEavoxate compared with 56 per cent on phenazopyridine. Similarly, symptom-severity evaluations at two andjve days of therapy showed most symptoms improved in more of the patients onfEavoxate therapy than on phenazopyridine therapy. Although more adverse effects were reported in patients treated with phenazopyridine than with jlavoxate, the diffmence between medications was not statistically signi$cant.
Anticholinergic antispasmodics and analgesic/ anesthetic dyes have been available for many years for the symptomatic treatment of disorders of the lower urinary tract. Although both types of drugs produce satisfactory relief, the autonomic side effects of the anticholinergic agents and the staining of urine, and consequently, clothing, by the azo dyes are practical limitations to their use. Several years ago flavoxate, a new urinary tract antispasmodic, chemically unrelated to the anticholinergic drugs or azo dyes, became available. Flavoxate is a flavone derivative which has been shown in laboratory animal studies to have pharmacologic properties similar to those of papaverine in its ability to counteract smooth muscle spasm in abdominal viscera through a selective effect on the muscle rather than through a nonselective anticholinergic effect.’ In a double-blind cystometric evaluation in patients having neurogenic bladders2 and in two double-blind clinical studies,3,4 flavoxate compared favorably with the anticholinergic, propantheline, in efficacy and incidence of adverse effects. This multi-investigator study was undertaken to compare flavoxate hydrochloride (Urispas) with phenazopyridine hydrochloride
612
(Pyridium), an azo dye, in the symptomatic treatment of disorders of the lower urinary tract. Methods Nine physicians were asked to follow identical protocols and conduct the individual studies in their private practices. Each was to study 48 patients having urinary frequency, dysuria, nocturia, urgency, incontinence and/or suprapubic pain associated with acute cystitis, prostatitis, urethritis, or trigonitis. The study could not be double-blind, because phenazopyridine colors the urine and because the recommended dosage regimens for the two drugs are different. However, assignment of medication was randomized and double-blind. After a patient was admitted to the study, the investigator opened a sealed envelope to learn which medication the patient would be taking. He gave each patient a five-day supply of medication and asked him to return two and five days later for evaluation. At the pretreatment and subsequent visits the investigator evaluated the patient’s symptoms as absent, mild, moderate, or severe. He also completed a global evaluation
UROLOGY
/ MAY1975
/ VOLUMEV,
NUMBER5
TABLE I. Satisfactory responses in patients having acute cystitis, urethritis, an&or trigonitis
Investigators
Flavoxate Number of Number Patients Satisfactory
A B
15 20
14 18
C D E F G H I
11* 13 15 21 22* 23* 24
3 12 15 18 19 17 12
TOTALS
164 161
-Phenazopyridine--Number of Number Patients Satisfactory 12
7
21 11t 11 18 22* 22* 21 23
11 2 7 8 15 13 15 10
161 156
128
(56 pt: cent)
(80per cent)
*One patient not rated for global efficacy. tThree patients not rated for global efficacy.
TABLE II. Satisfactory responses in patients having prostatitis
Investigators*
Flavoxate--------Number of Number Satisfactory Patients
A B, D, and Gt C E
5 8 13 9
TOTALS
35
-Phenazopyridine--Number of Number Satisfactory Patients
3 6 6 8
10 6 11 5
23 (66per cent)
7 1 1 1
32
(31 pi:cent)
*No data for investigators F, H, and I. tcombined data from three investigators.
of the patient’s response after the five days of therapy. The dosage of flavoxate was two tablets (100 mg. each), taken four times a day (after meals and at bedtime). The dosage of phenazopyridine was two tablets (100 mg. each), taken three times a day (after meals). Concomitant antibacterial, antibiotic, or general analgesic therapy was given if indicated, but analgesics having a therapeutic effect on the urinary tract, peripheral anticholinergics, and corticosteroids and antibiotics combined with azo dyes were not prescribed. Results A total of 408 patients were included in the nine studies. However, 15 patients failed to return after the pretreatment visit or had received concomitant therapy excluded by the protocol; another refused to continue therapy with phen-
UROLOGY
/ MAY1975 / VOLUMEV,
NUMBER5
azopyridine because it stained her clothing. Subsequently, all of these were dropped from the study. Thus, data adequate for analysis were obtained on 392 patients, 289 women and 103 men, ranging in age from seven to ninety years.* Of these, 199 received flavoxate hydrochloride and 193 phenazopyridine hydrochloride. Global efficacy ratings were reported for only 384 patients. The criteria used were: satisfactory relief of all symptoms within forty-eight hours Good - satisfactory relief of most symptoms after five days Fair - partial relief of symptoms, but persistence of some mild symptoms after five days Poor - little or no relief
Excellent
*One mended
-
investigator treated 3 patients under
the recom-
age limit of twelve years.
613
TABLE III. Symptomatic improvement in patients having acute cystitis, urethritis, andlor trigonitis
Symptoms Frequency Dysuria Nocturia Urgency Incontinence Suprapubic pain
Day 2-------------Flavoxate Phenazopyridine Number Per Cent Number Per Cent Patients Improved Patients Improved 165 160 139 160 116 131
70 63 49 68 31 56
157 149 124 156 110 124
54 60 42 51 20 51
Day C Flavoxate Phenazopyridine Number Per Cent Number Per Cent Patients Improved Patients Improved 158 154 134 155 115 127
84 84 75 87 48 70
148 142 115 148 105 118
85 82 70 72 35 69
TABLE IV. Symptomatic improvement in patients having prostatitis Day 2-----------
Symptoms Frequency Dysuria Nocturia Urgency Incontinence Suprapubic pain
Flavoxate Number Per Cent Patients Improved 35 34 29 34 24 32
60
32
53
71 34 50 25 62
30 25 31 23 29
53 20 42 22 69
All good and excellent ratings were considered satisfactory responses. Since the responses of the patients with prostatitis were of particular interest, the data were divided into two groups on the basis of the primary diagnosis, namely, those patients having prostatitis alone or in combination with other diagnoses formed one group, while those with all other diagnoses formed a second group. In the latter group most patients were diagnosed as having acute cystitis alone or cystitis with an associated diagnosis. The number of satisfactory responses in 317 patients having diagnoses other than prostatitis and in the 67 patients whose diagnoses included prostatitis are shown in Tables I and II, respectively. In both groups flavoxate produced more satisfactory responses than phenazopyridine, and the difference between the two drugs was statistically significant (P < 0.01). Tables III and IV show the efficacy of flavoxate and of phenazopyridine in improving each of the presenting symptoms in the two diagnostic groups after two and five days of therapy. The per cent improved includes all patients whose symptom severity while on therapy indicated there was some degree of improvement over the pretreatment severity. The data account for
614
Day 5-----------
Phenazopyridine Number Per Cent Patients Improved
Flavoxate Number Per Cent Patients Improved 34 33 27 31 23 33
74 85 63 74 48 79
Phenazopyridine Number Per Cent Patients Improved 32 30 25 31 23 29
72 80 52 64 39 86
all patients evaluated at two and/or five days of therapy. Most of the patients had more than one presenting symptom. The data at day 2 indicate that flavoxate had a faster onset of action than phenazopyridine in controlling the symptoms except for suprapubic pain associated with prostatitis. At the end of five days flavoxate produced symptomatic improvement in more patients than phenazopyridine, except for suprapubic pain, in which phenazopyridine was superior. For the symptom of frequency in both diagnostic groups, both drugs were approximately equally effective. The differences between flavoxate and phenazopyridine in per cent of patients showing improvement in individual symptoms are not as marked as the differences found in the global it must be kept in efficacy ratings. However, mind that the tables of symptomatic improvement do not show the differences in degree of improvement recorded by the investigators. Differences in degree of improvement were, however, taken into account in a statistical analysis of total morbidity score averages, which showed a significant difference favoring flavoxate over phenazopyridine in total symptomatic relief in prostatitis (P < 0.05) and again in cystitis,
UROLOGY
/ MAY1975 / VOLUMEV,
NUMBER5
TABLE V. Effects
Adverse effects*
Flavoxate
Backache Diarrhea Dizziness Gastrointestinal distress Headache Nausea Rash Vomiting Miscellaneous Total symptoms Number patients per total treated
3
2 7 0
3 2 5 2
0 3 16 1
1 1
1
1
2f 20
3$ 33
16/199 (8
Phenazopyridine
per cent)
251193
(13 per cent)
*Includes all adverse effects reported whether or not a relationship to the drug was established. t Heart pounding; sick. $Epigastric abdominal pain; burning skin; light-headed.
urethritis, and/or trigonitis (P < 0.01) both at day 2 and day 5.5 Hence, the total morbidity score data support the global efficacy data. Adverse
Effects
All adverse effects reported are shown in Table V. Sixteen (8 per cent) of the 199 patients treated with flavoxate reported a total of 20 adverse effects, and 25 (13 per cent) of the 193 treated with phenazopyridine reported a total of 33 adverse effects. Therapy was discontinued in five of the flavoxate patients and eight of the phenazopyridine patients. Although more adverse effects were reported in the phenazopyridine group, there was no statistically significant difference between the two drugs. Comment Ideally, comparative studies of drug efficacy should be double-blind to avoid possible bias. This study could not be double-blind because the recommended dosage schedules for the two drugs differ, and because one drug causes a readily apparent staining of urine. However, the likelihood of bias was diminished by providing for
UROLOGY
/ MAY 1975 / VOLUME
V, NUMBER
5
assignment of medication on a randomized, double-blind basis. If any bias were to occur, the most likely tendency would be to appraise the newer drug, flavoxate, conservatively and underestimate its efficacy. Yet, the results of the study favor flavoxate. The consistency of the results of individual evaluations supports the combined data showing flavoxate to be superior to phenazopyridine to a statistically significant degree. In the global efficacy ratings, a trend favoring flavoxate was seen in the individual data from all 9 investigators in the evaluation of patients having diagnoses other than prostatitis; this same trend was seen in three of four comparisons among patients having prostatitis. The individual symptom relief data favoring flavoxate were consistent with the global efficacy data. Over-all, the results of this study demonstrate the superior action of flavoxate compared with phenazopyridine in terms of faster onset of action and greater relief of most presenting symptoms. 1500 Spring Garden Street Philadelphia, Pennsylvania 19101 ACKNOWLEDGMENT. Our appreciation to the following physicians for participating in this study: Gustave K. Berger, M.D., Wilmington, Delaware; Robert S. Christman, M.D., Harrisburg, Pennsylvania; Walter N. Himmler, M.D., Cumberland, IMaryland; Robert M. Kline, M.D., Lebanon, Pennsylvania; F. W. Kunze, M.D., Los Angeles, California; Benjamin R. Paradee, M.D., Cherry Hill, New Jersey; Jerome J. Schneyer, M.D., Southfield, Michigan; Richard H. Smith, M.D., Downington, Pennsylvania; and Murray Steinberg, M.D., Baltimore, Maryland. References 1. SETNIKAR, I.RAVASI, M. T., and DARE, P.: Pharmacological properties of piperidinoethyl-3-methylflavone8-carboxylate hydrochloride, a smooth-muscle relaxant, J. Pharmacol. Exp. Ther. 130: 356 (1960). 2. KOHLER, F. P., and MORALES, P. A.: Cystometric evaluation of flavoxate hydrochloride in normal and neurogenic bladders, J. Urol. 100: 729 (1968). 3. BRADLEY, D. V., and CAZORT, R. J.: Relief of bladder spasm by flavoxate: a comparative study, J. Clin. Pharmacol. 10: 65 (1970). 4. HERBST, W. P.: Double-blind comparison of flavoxate and propantheline as urologic antispasmodics, Am. J. Clin Res. 1: 65 (1970). 5. Research data: Smith Kline & French Laboratories, December 28, 1973.
615