In a logistic regression model with PGI-S (moderate or severe) as the outcome variable and symptoms (stress urinary incontinence and mixed urinary incontinence) and conditions (urodynamic stress incontinence and urodynamic stress incontinence plus detrusor overactivity) as the explanatory variables, mixed symptoms were significantly associated with increased severity (P = .001, odds ratio = 6.4, 95% confidence interval [CI] 2.0, 20.2), whereas mixed conditions were not (P = .80, odds ratio = .87, 95% CI 0.2, 3.2). The tendency for comparable or less severe incontinence in subjects with mixed conditions but for more severe incontinence in subjects with mixed symptoms persisted when data were stratified according to condition and symptom classes (Table 5). Twelve of seventeen women (71%) who had mixed symptoms and pure urodynamic stress incontinence and 6 of 7 (86%) who had mixed symptoms and mixed conditions at baseline reverted to the symptom of pure stress urinary incontinence with treatment. No treatment phase urodynamic studies were performed.
The statistically significant efficacy demonstrated by duloxetine at the 40 and 80 mg per day doses compared with placebo in the overall study population has been reported previously.6 When responses were stratified by symptom type and analyzed with the analysis of variance model on ranked percentage changes, both symptom groups demonstrated significant improvements in incontinence (expressed as the median percentage decrease in pooled weekly incontinent episode frequency) with duloxetine 40 mg per day (stress urinary incontinence: 58%, P < 0.05; mixed urinary incontinence: 62%, P < .004) and with 80 mg per day (stress urinary incontinence: 65%, P < .001; mixed urinary incontinence: 63%, P <.01) compared with placebo (stress urinary incontinence: 44%; mixed urinary incontinence: 33%). The decrease in placebo response in the mixed urinary incontinence group is similar to the decreased placebo response reported with more severely incontinent women in the original report.6 The same analysis of variance model revealed that the significant treatment responses observed were not dependent on the symptom type (interaction P = .47).
The results of this analysis indicate that, for women presenting with predominant stress urinary incontinence symptoms, the major determinant of concurrent urge symptoms is incontinence severity and not the pathophysiologic condition(s) causing the incontinence. A major premise of previous explanations for the increased severity of incontinence symptoms reported by women with mixed incontinence has been that two conditions combine to create two symptoms and that having two conditions results in worse symptoms. In contrast, our findings suggest that, in many cases, it is actually the more severe stress incontinence that leads to mixed symptoms. The data show that women with more severe incontinence are more likely to report mixed symptoms. As the severity of incontinence improves during treatment, mixed symptoms resolve.
One explanation for these observations is probably derived from the fact that more severe incontinence recalled over a long period with a greater number of incontinence episodes tends to compromise a patient's ability to focus on the events related to each episode. As a result, distinctions between symptom types blur. As the number of incontinent episodes and the recall period decrease, the patient is better able to discriminate individual events, and her symptom recall becomes more focused and specific. This scenario is roughly synonymous with the unfocused history offered by a patient with chronic pelvic pain compared with the specific recall of events by a patient with acute pain.
This change in perspective—that symptoms are driven by incontinence severity rather than by conditions—helps reconcile some apparent contradictions observed with the latter paradigm. It helps explain why mixed urinary incontinence patients report more severe incontinence despite the fact that most such patients do not have both urodynamic stress incontinence and detrusor overactivity. Because severity of incontinence is a major impetus for a patient's seeking care for her incontinence,5 it helps explain why mixed symptoms are more common in clinical populations1,3 than in representative epidemiologic populations.2 Finally, it helps explain why a treatment that is felt to be relatively specific for one of the two major incontinence symptoms (for example, continence surgery for stress urinary incontinence or bladder retraining for urge urinary incontinence) may also prove effective for the other symptom.
One potential criticism of our methods was our use of I-QOL responses to identify subjects with urge symptoms in this secondary analysis. We feel that several facts substantiate the validity of this approach, however. First, the index questions were identified a priori by the first author, based on more than 20 years of clinical experience in the management of urinary incontinence, before any analysis was performed. Second, there were clear differences in the distributions of responses between the two symptom groups. Finally, the fact that subjects in the mixed urinary incontinence group were significantly more likely to have detrusor overactivity, had significantly greater urinary frequency, and had significantly more voids associated with severe urge, further support the validity of assigning an urge component to this patient group. However, the wording of the I-QOL questions does not allow us to determine whether these subjects had stress urinary incontinence plus urge incontinence or stress urinary incontinence plus dry overactive bladder symptoms.
Our findings differ somewhat from those reported by Kreder from a single-blind, multicenter tolterodine study of a population whose recruitment was based on a predominant symptom complex of overactive bladder (Kreder KJ. Tolterodine is equally effective in patients with mixed incontinence. International Continence Society 31st Annual Meeting; Seoul, South Korea; September 18–21, 2001). The symptom of stress urinary incontinence was also reported by 26% of the female study subjects (165 of 629) with overactive bladder symptoms. In contrast to the findings from our population, whose recruitment was based on a predominant symptom of stress urinary incontinence, Kreder's stress urinary incontinence–overactive bladder group had similar measures of baseline disease severity (daily incontinent episode frequency and voiding frequency) compared to his overactive bladder–only group. No urodynamic studies were performed in this overactive bladder study, so it is not possible to know whether most of the subjects with mixed symptoms also had mixed conditions. It is plausible that many of the stress incontinence symptoms actually represented stress-induced detrusor overactivity. Nonetheless, we would conclude that incontinence severity is not so important in determining mixed symptoms when urge symptoms predominate compared with when stress symptoms predominate. In both studies, it was the predominant urinary symptom that seemed to be most responsible for predicting treatment response.
It has been hypothesized previously that women with mixed urinary incontinence symptoms have urodynamic stress incontinence as their primary problem and that the detrusor overactivity results secondarily when the incompetent bladder neck allows urine to be forced into the proximal urethra during physical activity, eliciting urethrodetrusor facilitative reflexes that trigger an involuntary detrusor contraction.11 The potential for the entry of fluid into the urethra to reflexively initiate a bladder contraction has been a matter of controversy for most of the 20th century. There is evidence that this reflex is species-dependent, being observed in anesthetized cats,12–14 dogs,15 and rats11 but not being demonstrated convincingly in humans.16–18 The current study does not provide direct evidence for or against this facilitative reflex. However, the fact that most women in the current study with mixed symptoms did not have mixed conditions would seem to suggest that such facilitative reflexes play a minor role in determining mixed urinary incontinence symptoms.
In summary, in women with a predominant symptom of stress urinary incontinence, incontinence severity seems to be the driver of mixed urinary incontinence symptoms rather than conditions being the driver of symptoms and severity. As incontinence severity improves, mixed symptoms resolve. The majority of women with mixed symptoms do not have mixed conditions, and conservative therapy can be directed toward the predominant symptom based on the events (stress or urge) associated with the majority of incontinent episodes.
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The Duloxetine Urinary Incontinence Study Group included the following principal investigators and their staffs: Joseph S. Sanfilippo, MD, Allegheny General Hospital, Pittsburgh, Pennsylvania; Hillary Browne, MD, Alpine Clinical Research Center, Boulder, Colorado; Ronald L. Young, MD, Baylor College of Medicine, Houston, Texas; Harvey E. Armel, MD, Clinical Research Consultants Inc., Trumbull, Connecticut; Guillermo Davila, MD, Colorado Gynecology and Continence Center, Denver, Colorado; Simon Chung, MD, Dominion Urological Associates, Fairfax, Virginia; Jay M. Baker, MD, Eastern Virginia Medical School, Norfolk, Virginia; Mickey M. Karram, MD, Good Samaritan Hospital, Cincinnati, Ohio; Ronald Tutrone, MD, Greater Baltimore Medical Center, Baltimore, Maryland; Edward J. Durbin, MD, PhD, Health Advance Institute, South Bend, Indiana; Warren O. Kessler, MD, Hillcrest Urological Medical Group, San Diego, California; Veronica T. Mallett, MD, Hutzel Hospital, Detroit, Michigan; Christopher Carey, MD, Milton S. Hershey Medical Center, Hershey, Pennsylvania; Lewis F. Russell, Jr, MD, PA, Institute of Clinical Research, San Antonio, Texas; Vincent Lucente, MD, Lehigh Valley Hospital, Allentown, Pennsylvania; Martin Conway, MD, Lovelace Scientific Resources Inc., Albuquerque, New Mexico; Aaron Kirkemo, MD, Metropolitan Urologic Specialists, Detroit, Michigan; James Schoeck, MD, Orlando Clinical Research Center, Orlando, Florida; Alan D. Garely, MD, North Shore University Hospital, Great Neck, New York; Karny Jacoby, MD, Northwest Outpatient Medical Center, Seattle, Washington; Enrique M. deCastro, MD, Northwest Women's Clinic, Portland, Oregon; Roger D. Fincher, MD, PC3 Inc., Spokane, Washington; Brenda Williams, MD, PC3 Inc., Boise, Idaho; John P. Lenihan, Jr, MD, Pacific Coast Clinical Coordinators, Tacoma, Washington; Thomas Melchione, MD, Pacific Coast Clinical Coordinators, Sacramento, California; Stuart A. Sarshik, MD, Pennridge Urological Associates PC, Sellersville, Pennsylvania; David C. Reed, MD, Pacific Coast Clinical Coordinators, Bellevue, Washington; Mark M. Blatter, MD, Primary Physicians Research, Pittsburgh, Pennsylvania; Jaroslava Zoubek, MD, Portland Clinic, Portland, Oregon; Martha C. Storrie, MD, Research Across America, Dallas, Texas; Wulf H. Utian, MD, PhD, Rapid Medical Research, Cleveland, Ohio; David F. Mobley, MD, Research for Health Inc., Houston, Texas; Linda Brubaker, MD, Rush Presbyterian-St. Luke's Medical Center, Chicago, Illinois; William E. Friedel, MD, San Diego Urology Center, San Diego, California; Kandasamychetty Perumal, MD, Seton Health Incontinence Center, Troy, New York; Don I. Boychuk, MD, Sharp Rees – Stealy Medical Center, San Diego, California; Gamal Ghoniem, MD, Tulane Medical School, New Orleans, Louisiana; David Ellis, MD, URO Rehab, Bryn Mawr, Pennsylvania; Larry I. Gilderman, MD, University Clinical Research Associates Inc., Pembroke Pines, Florida; Sandra Culbertson, MD, University of Chicago Hospital, Chicago, Illinois; Ellen Wells, MD, University of North Carolina Hospitals, Chapel Hill, North Carolina; Peggy A. Norton, MD, University of Utah, Salt Lake City, Utah; Anne L. Viselli, MD, University of Vermont Women's Center, Williston, Vermont; J. Thomas Benson, MD, Urogynecology Associates, Indianapolis, Indiana; John R. Miklos, MD, Urogynecology, P.C., Alpharetta, Georgia; Peter Knapp, MD, Urology of Indiana, Indianapolis, Indiana; Norman R. Zinner, MD, Western Clinical Research Inc., Torrance, California; and Ananias Diokno, MD, William Beaumont Hospital, Royal Oak, Michigan.