PEDIATRICS Vol. 122 No. 5 November 2008, pp. 1027-1032 (doi:10.1542/peds.2007-3691)
ARTICLE |
Combination Therapy With Desmopressin and an Anticholinergic Medication for Nonresponders to Desmopressin for Monosymptomatic Nocturnal Enuresis: A Randomized, Double-Blind, Placebo-Controlled Trial
a Division of Urology
b Department of Surgery
c Division of Biostatistics, Washington University School of Medicine, St Louis Children's Hospital, St Louis, Missouri
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. Desmopressin is an approved medical therapy for the treatment of monosymptomatic primary nocturnal enuresis. In cases of limited response to desmopressin, we have added anticholinergic therapy to desmopressin (combination therapy). To evaluate this treatment strategy, we examined the efficacy of combination therapy for primary nocturnal enuresis in desmopressin-nonresponders.
METHODS. Only patients with primary nocturnal enuresis refractory to the maximal dosage of desmopressin were enrolled. Children with lower urinary tract symptoms or bowel dysfunction were excluded, on the basis of a 3-day, 24-hour, frequency-volume chart and elimination record. Children continued to take desmopressin and were assigned randomly, in a double-blind manner, to receive either extended-release anticholinergic medication or placebo. Patients were reassessed after 1 month of therapy, with a 1-week nocturnal record.
RESULTS. Forty-one desmopressin-nonresponders were enrolled, and 7 patients were excluded because of noncompliance. The treatment groups were equally matched with respect to age, gender, functional bladder capacity, and number of wet nights per week. After 1 month of treatment, there was a significant reduction in the mean number of wet nights in the combination therapy group, compared with the placebo group. With a generalized estimating equation approach, there was a significant 66% decrease in the risk of a wet episode, compared with the placebo group.
CONCLUSIONS. This study represents the first prospective, placebo-controlled trial examining the effect of desmopressin in combination with long-acting, anticholinergic, bladder-relaxing therapy for monosymptomatic primary nocturnal enuresis.
Key Words: desmopressin • cholinergic antagonists • nocturnal enuresis • placebo-controlled trials
Abbreviations: FBC—functional bladder capacity • LUT—lower urinary tract • OAB—overactive bladder • PNE—primary nocturnal enuresis
There are many treatment approaches for primary nocturnal enuresis (PNE), including behavior modification, alarm therapy, and medications. Medical treatment of PNE consists mainly of administration of either desmopressin or imipramine. Anticholinergic agents such as oxybutynin and tolterodine reduce or abolish detrusor overactivity and may be particularly beneficial for patients who have lower urinary tract (LUT) symptoms or enuresis associated with overactive bladder (OAB).1 In the absence of bladder overactivity, anticholinergic agents are thought to have little effect in the management of monosymptomatic PNE.2
One of the pharmacologic challenges in the management of PNE is predicting who will respond to desmopressin. Functional bladder capacity (FBC) has been demonstrated to be a reliable predictor of response to desmopressin; children with larger capacities are more likely to exhibit successful responses.3–6 Because of this previous research experience, frequently we combine desmopressin with anticholinergic therapy for children who experience failure of or partial response to treatment with desmopressin alone in our pediatric urology practice. The rationale is based on the concept of potentially increasing FBC with anticholinergic therapy, thereby increasing the response to desmopressin. Intuitively, this therapy seems reasonable, in that desmopressin and the anticholinergic agent function through 2 different mechanisms that might be additive in preventing nocturnal enuresis; that is, desmopressin decreases urine production and the anticholinergic agent allows the bladder to store more urine.
Although there have been reports of combination therapy (desmopressin plus anticholinergic agent), this method of treatment has been reported primarily for children with nocturnal enuresis and LUT symptoms or OAB.7 Only a few studies in the literature have examined combination therapy for children with desmopressin-resistant, monosymptomatic secondary nocturnal enuresis.8–11 Limitations of those studies include lack of randomization, lack of a placebo-controlled patient group, use of short-acting anticholinergic agents, and small sample size. Our study attempts to address these issues by examining the efficacy of combination therapy with desmopressin plus a sustained-release, anticholinergic agent in a placebo-controlled trial involving children with enuresis who experienced failure of previous treatment with desmopressin alone.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patient Selection and Assessment
This was a single-institution study, and patients were drawn from among those referred to our pediatric urology clinic for treatment of enuresis. New patients with monosymptomatic PNE refractory to desmopressin were selected prospectively for the study. A minimum of 4 wet nights per week during desmopressin therapy was required for entrance into the study. Patient screening was performed before enrollment and initiation of combination therapy. Screening included a 3-day, 24-hour, frequency-volume chart and elimination record, to rule out LUT dysfunction and to assess any bowel elimination problems. A 1-week nocturnal record was also collected, to document the number of wet nights with desmopressin therapy. All of these records were collected over a 2- to 3-week period before study entry.
Inclusion and Exclusion Criteria
Patients 6 to 17 years of age were eligible for enrollment. All patients were required to have monosymptomatic PNE and to have experienced failure of treatment with orally administered desmopressin alone, at the maximal dosage of 0.6 mg per night (three 0.2-mg tablets per night). Failure was defined as partial response or nonresponse to desmopressin therapy. Nonresponse was defined as a 0% to 49% decrease and partial response as a 50% to 89% decrease in the number of wet nights per week.12
Patients were excluded from the study if any LUT symptoms or bowel elimination problems (eg, encopresis or constipation) were noted in the history or elimination records or during the physical examination. Specifically, patients were excluded if there were any episodes of daytime incontinence, increased or decreased voiding frequency (voiding 
8 times per day or 
3 times per day, respectively), encopresis, or constipation. Constipation was defined by using combined definitions from the Rome II criteria and the Paris Consensus on Childhood Constipation Terminology Group.13,14 Constipation was considered if any of the following were present: pebble-like, hard stools, <3 bowel movements per week, >1 episode of fecal incontinence per week, large stools in the rectum or palpable on abdominal examination, passing of stools so large that they might obstruct the toilet, displays of retentive posturing and withholding behaviors, and/or history of painful defecation. Patients also were excluded if they were receiving any anticholinergic therapy during enrollment screening, had any known allergy toward anticholinergic medications used for bladder relaxation or any history of gastric retention, or had uncontrolled, narrow-angle glaucoma.
Study Design
A stratified randomization procedure was used to allocate patients into 2 treatment groups, that is, desmopressin plus long-acting tolterodine or desmopressin plus placebo (Fig 1). The strata formed were based on the initial degree of failure of desmopressin single therapy, and patients were assigned as nonresponders or partial responders, which were thought to be confounding variables in the study. With randomization within each stratum, we ensured that the distributions of nonresponders and partial responders were balanced within the 2 treatment arms. Computer-generated random numbers were used to assign patients to the 2 treatment arms within each stratum.
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Patients received an unlabeled bottle of either tolterodine extended-release capsules or matching placebo capsules. Patients were asked to take 1 capsule each night, with their full dose of desmopressin therapy (0.6 mg total per night), for 4 weeks. A master file list identifying the treatment received was kept by the study coordinator, who did not have direct patient contact during the distribution of the unlabeled treatment bottles. A 4-mg dose of the long-acting tolterodine capsules was arbitrarily chosen because it is the recommended starting dose for the treatment of OAB. All patients were informed that the usage of long-acting tolterodine was off-label, and they received informed consent information approved by the Washington University Human Research Protection Office.
Caregivers for the patients were instructed to report, at the end of the 1-month treatment period, the number of days and doses of medications given. Bottles of medicine were collected to verify the tablets taken during the treatment period. Patient noncompliance or a serious allergic reaction to combination therapy resulted in removal from the study.
Outcome Measurements
By using the information from the preentry, 3-day, 24-hour, frequency-volume charts and the 1-week nocturnal record, the randomly assigned treatment groups were assessed with regard to age, gender, FBC, and entry number of wet nights per week. Comparisons of the number of wet nights in the precombination treatment nocturnal records and during the last week of combination therapy were used to determine the efficacy of combination therapy. Specifically, comparisons were made regarding any response differences between placebo and anticholinergic agent in combination with desmopressin.
Treatment outcomes were categorized as either "success" or "no success" on the basis of the 1-week nocturnal records at the end of treatment. Successful outcomes included the following responses, as defined by the Standardization Committee of the International Children's Continence Society12: full response, no wet nights; response, 90% reduction in the number of wet nights; partial response, 50% to 89% reduction in the number of wet nights. An unsuccessful outcome was defined as nonresponse (<50% reduction in the number of wet nights).
Statistical and Analytical Plan
On the basis of the definitions above, our outcome of interest was binary in nature (wet or dry; success or no success). For the primary objective, that is, assessment of the efficacy of combination therapy for children who experienced failure of desmopressin single therapy for PNE, a 
2 test was used to compare the proportions of success in the 2 treatment arms. Although this study was a randomized, clinical trial, some potential confounding variables might not have been balanced in the 2 treatment arms. Therefore, a logistic regression model was used to compare the probability of success in the 2 treatment arms, with adjustment for potential confounding effects. By using a generalized estimating equation approach, we compared the risk of repeated measurements of wet episodes per night over 7 nights between the 2 treatment groups, with adjustment for pretreatment propensity for wet episodes and age. By using generalized estimating equations, we first examined the possible interaction of treatment and time. When there was evidence of the presence of such an interaction, we summarized the treatment effect as the average effect over time. In addition, a 2-sided, paired t test was used to compare the mean weekly frequency of nocturnal enuresis in the pretreatment and posttreatment groups. To assess the various International Children's Continence Society response criteria, we estimated a sample size of 65 patients for each group, based on the following assumptions: (1) a single primary end point of treatment success, (2) 1 primary comparison (success rate with desmopressin plus placebo versus desmopressin plus long-acting tolterodine), (3) a 2-sided, continuity-corrected, 2 test of statistical significance, (4) a probability of type I error associated with the 2-sided test of .05, (5) a probability of type II error associated with the test of .2 (ie, the power of the test is 80%), and (6) an expected treatment success rate with desmopressin plus placebo of 50% and a clinically relevant difference in success rates of 25%.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Originally, we planned to examine 2 subgroups with monosymptomatic PNE refractory to desmopressin, that is, nonresponders and partial responders to desmopressin treatment. During the study enrollment period, only patients who were categorized as nonresponders were seen in the outpatient pediatric urology clinic. The study was closed after 3 years, and a total 48 patients met the inclusion entry criteria. Seven patients elected not to participate in the study. Of the 41 participants, 7 patients were excluded because of noncompliance issues, that is, incomplete documentation of the 1-week nocturnal records or poor adherence in taking the medicine. The entry characteristics of the study subjects are presented in Table 1. There were no adverse events seen during the study period.
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After 1 month of therapy, we found a significant reduction in the mean number of wet nights in the combination therapy group receiving long-acting tolterodine, compared with placebo (Fig 2). Successful and unsuccessful treatment outcomes are presented in Table 2. When we examined the treatment outcomes categorized according to the degree of response, we noted that the long-acting tolterodine group had a higher rate of full and partial responses (44% success), compared with the placebo group (31% success). In addition, when we examined the nonresponse rates, there was a much larger proportion of patients who exhibited a complete lack of response (0% change) in the placebo group (44%), compared with the long-acting tolterodine group (16.5%). By using a generalized estimating equation approach, we then compared the risk of wet episodes per night between the 2 groups and adjusted for pretreatment propensity for wet episodes and age (Fig 3). We did not observe any time-treatment interaction, and we noted a significant decrease of 66% in the risk of a wet episode in the long-acting tolterodine group, compared with the placebo group (odds ratio: 0.33; 95% confidence interval: 0.12–0.98).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Oxybutynin is one of the most common anticholinergic medications used to treat OAB in children, and there is no question that anticholinergic therapy results in a decrease in nocturnal enuresis when there are concomitant LUT symptoms.7,10,15,16 When no LUT symptoms are present, however, anticholinergic treatment does not seem to be an effective single therapy for PNE. This was supported by the only placebo-controlled trial reported in the literature that examined the efficacy of oxybutynin in treating monosymptomatic PNE. Lovering et al2 observed that oxybutynin was no more effective than placebo in treating nocturnal enuresis without LUT symptoms.
Anticholinergic agents may play a role for a subset of children with enuresis who do not have LUT symptoms during the day but have a restricted bladder capacity because of detrusor overactivity at night. This pattern of latent OAB during the night is found with nocturnal cystometry for 
35% of children with enuresis.17,18 In addition, the FBC may change during the night for a subset of children with enuresis who have normal expected FBC during the day.18,19 We reported, with others, that FBC is predictive of the response to desmopressin.3,5,6 Together, these findings suggest a role for using combination therapy (desmopressin plus anticholinergic) to treat children with monosymptomatic PNE that is refractory to treatment with desmopressin alone.
Combination therapy using an anticholinergic agent with desmopressin was reported to be effective in treating monosymptomatic nocturnal enuresis in older children who had no success with other treatment modalities.8–11 One of the earliest reports of combination therapy for treatment of enuresis used the anticholinergic agent hyoscyamine with desmopressin.8 Cendron and Klauber8 reported a 78% rate of complete or partial response (80% dry nights) with combination therapy with desmopressin nasal spray and time-release hyoscyamine. Hyoscyamine has not been used routinely in pediatric urology since the development of more-selective and longer-lasting anticholinergic agents (eg, extended-released formulations of oxybutynin or tolterodine), and desmopressin is currently dosed orally rather than nasally, to improve dose delivery.8,20,21 Although it is not known whether combination therapy with a long-acting formulation of an anticholinergic agent, compared with an immediate-release form, is more efficacious in treating nocturnal enuresis, we elected to use a long-acting anticholinergic agent to maintain continuous serum levels throughout the night and to minimize the side effect profile found with immediate-release formulations. We hypothesized that this would improve our response rate, compared with immediate-release anticholinergic agents.
The use of combination therapy with desmopressin and oxybutynin in treating desmopressin-resistant monosymptomatic PNE has been reported and has shown promising results.9–11 In their initial study, Nevéus et al10 reported that 71% of 28 patients who were nonresponsive to desmopressin single therapy experienced 50% reduction in the number of wet nights with combination therapy. In our study, the response rate for combination therapy also showed improvement over single-treatment desmopressin but was not as striking (44%), which may reflect differences in the study designs. The most noticeable difference in the response rates for our treatment groups was the larger proportion of children in the placebo group who exhibited no change, compared with the desmopressin plus long-acting tolterodine group (44% and 17%, respectively). In a recent study examining combination therapy for desmopressin-nonresponders, Radvanska et al11 found a 43% reduction in the mean number of wet nights per week after treatment with desmopressin and oxybutynin. This finding was similar to our results, as indicated by the 45% reduction in the mean number of wet nights per week for our patients receiving desmopressin and long-acting tolterodine (6.22–2.83 wet nights per week).
In the treatment of children with enuresis, there may be different degrees of response to treatment. The International Children's Continence Society has recommended that children be grouped together in subgroups with varying degrees of treatment response (eg, full response, response, partial response, and nonresponse) for reasons of comparison.12 Our sample size prevented us from drawing any conclusions with regard to these subcategory response rates; however, we were able to analyze the response to treatment significantly with regard to changes in the mean number of wet nights and the propensity for wet nights. We observed a significant reduction in the number of wet nights per week and a 66% reduction in the propensity for wet nights after combination therapy, compared with desmopressin plus placebo. It should be emphasized that our patients were highly selected to avoid any confounding impact of obvious or latent LUT symptoms. The vast majority of patients referred to our clinic had enuresis with features of LUT symptoms, which limited our pool of monosymptomatic patients over the 3-year period. It is not clear whether the subcategory response rates might have been more significant if we had been able to accrue more patients.
It is noteworthy that our study did not attempt to define or to identify a mechanism that would predict a response to combination therapy for monosymptomatic desmopressin-nonresponders. There are relatively few studies that have explored potential mechanisms that would predict a favorable response to combination therapy for desmopressin-nonresponders, and no definitive mechanism has been identified. In a small group of selected patients who received combination therapy and achieved dryness, Nevéus9 observed that the children tended to have small bladders, as well as high levels of urine production and low renal-concentrating capacity. In another study, Radvanska et al11 examined different methods of estimating bladder capacity that might predict the response to desmopressin and combination therapy in a similar enuretic population. Specifically, the authors examined the maximal voided volume during free access to fluid intake and after water load and found that alterations in maximal voided volume during free access to fluid intake were predictive of desmopressin response, but they did not find results from either method of estimating bladder capacity to be predictive of a response to combination therapy. Additional studies are warranted to identify characteristics to predict which children are best treated with combination therapy.
Although these mechanistic studies are important, the need for a placebo-controlled trial has been emphasized, to validate this regimen of combination therapy for monosymptomatic PNE resistant to desmopressin.9,11 It is important to note the "placebo effect" in our treatment groups. Although there was a statistically significant difference in the mean number of wet nights and a 66% reduction in the propensity for wet nights after treatment in the desmopressin plus long-acting tolterodine group, there was also an overall trend of decreased wet nights in the placebo group. An interesting finding was that our study subjects included a set of twins who were assigned randomly to different treatment arms but had full responses to the different therapies. Together, these findings stress the need for placebo-controlled trials to evaluate critically the effectiveness of a treatment modality.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Our study represents the first prospective, randomized, placebo-controlled trial comparing the effect of desmopressin in combination with a long-acting anticholinergic bladder-relaxing therapy for monosymptomatic PNE. Our results help validate a treatment strategy using combination therapy for children with monosymptomatic PNE refractory to desmopressin.
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ACKNOWLEDGMENTS |
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This study was supported by a grant from the National Kidney Foundation.
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FOOTNOTES |
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Accepted Feb 22, 2008.
Address correspondence to Paul F. Austin, MD, Pediatric Urology, 4990 Children's Place, Suite 1120, Campus Box 8242, St Louis, MO 63110. E-mail: austinp{at}wustl.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Nocturnal enuresis is a global pediatric problem that is frequently treated with desmopressin. A subset of children have enuresis that is refractory to desmopressin treatment.
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| What This Study Adds We examined the rationale for using anticholinergic therapy with desmopressin in cases refractory to desmopressin alone. This study represents the first prospective, placebo-controlled trial examining this treatment approach for children with monosymptomatic nocturnal enuresis.
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REFERENCES |
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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