Children with refractory primary monosymptomatic nocturnal enuresis (PMNE) obtained significant short-term symptom relief with the selective serotonin reuptake inhibitor (SSRI) fluoxetine, a small placebo-controlled trial showed.
Two-thirds of patients in the fluoxetine arm had more than a 50% reduction in wet nights by 4 weeks, as compared with 16.7% of the placebo group. By 12 weeks, response rates declined considerably in the fluoxetine arm (32% overall response rate) but remained significantly higher versus placebo. Adverse events were generally minor and rapidly reversible, reported Ahmed Abdelhalim, MD, of Mansoura University in Egypt, and colleagues in the Journal of Urology.
“Although the final success rate seems relatively low, the mean number of wet nights at the study conclusion was significantly less compared to baseline and remained significantly better than placebo,” they wrote. “It should also be kept in mind that patients enrolled in this study have previously failed other lines of treatment of NE [nocturnal enuresis] including desmopressin.”
“To our knowledge, this is the first randomized, placebo-controlled trial testing fluoxetine as a treatment for refractory PMNE in children,” the authors concluded. “We hope that this pilot study will provoke more research to confirm the safety and efficacy of fluoxetine for the treatment of PMNE, compared to other standard treatments for NE, and explore its use in different patient populations and other forms of childhood incontinence.”
Therapeutic Limitations
Though multiple treatment options exist for nocturnal enuresis, the options have notable limitations, and supporting data are limited in some cases, Abdelhalim and colleagues noted. For example, behavioral therapy has a paucity of evidence-based support. Enuresis alarm for PMNE produces more durable results as compared with desmopressin, but alarm failure, false alarms, and interruption of other household members limit effectiveness.
Among medical options for nocturnal enuresis, desmopressin is expensive and not universally available, especially outside the U.S., the authors continued. Additionally, only a third of patients obtain durable responses, and the drug is associated with a risk of hyponatremia. Anticholinergics carry a variety of side effects that lead to lack of compliance and high rates of discontinuation. The tricyclic antidepressant imipramine carries a risk of potentially fatal cardiotoxicity and is associated with a high rate of relapse after discontinuation.
Previous studies of SSRIs for nocturnal enuresis have yielded conflicting results. None of the earlier studies had evaluated fluoxetine, providing a rationale for the current study.
Investigators evaluated children ages 8-18 years with severe PMNE refractory to behavioral treatment, alarm therapy, desmopressin, and anticholinergics. Exclusion criteria included daytime urinary symptoms, untreated constipation, underlying neurologic, renal, endocrinologic, urologic, cardiac, psychiatric, or behavioral disorders.
Subsequently, 110 patients were randomized to fluoxetine 10 mg/d or placebo. The primary outcome was treatment response at 12 weeks, as defined by the International Children’s Continence Society. Complete nighttime dryness was the definition of complete response, and a reduction of 50%-99% in wet nights was partial response. Anything less than a 50% reduction in wet nights was considered nonresponse.
The trial also evaluated nighttime arousal, as fluoxetine is known to stimulate arousal. Nighttime arousal was considered improved if a patient spontaneously awoke to void on 2 or more dry nights over 2 weeks as compared with baseline.
Key Findings
The patients had a mean age of 11.8 and baseline mean number of wet nights per 2 weeks of 11.9. Baseline demographics were similar between the fluoxetine and placebo groups.
The results showed that patients in the fluoxetine arm had significantly fewer wet nights per 2 weeks at evaluations at multiple timepoints:
- 4 weeks: 4.7 vs 9.7 placebo (P<0.001)
- 8 weeks: 5.7 vs 9.9 (P<0.001)
- 12 weeks: 7.5 vs 9.9 (P=0.003)
The reduction from baseline in wet nights was significantly greater with fluoxetine versus placebo at 4, 8, and 12 weeks (P<0.001), but the mean number of wet nights in the fluoxetine arm was significantly worse at 12 weeks versus 4 weeks (P<0.001).
After 4 weeks of treatment, four (7.1%) children in the fluoxetine arm met the definition of complete response and 37 (66.1%) had partial responses. That compared with 0% and 16.7%, respectively, for the placebo arm (P<0.001). At 12 weeks the complete and partial response rates were 10.7% and 21.4% with fluoxetine versus 0% and 14.8% with placebo (P=0.023).
Investigators found no association between response to fluoxetine and patient age, sex, BMI, family history of nocturnal enuresis, or number of wet nights at baseline.
Five (8.9%) patients in the fluoxetine arm had one or more adverse events (AEs) requiring treatment discontinuation. The AEs consisted of two cases of headache/dizziness, and one each of hypersensitivity/skin rash, hair loss, fatigue, depressed mood, and anxiety. All AEs resolved rapidly with treatment discontinuation, the authors reported.
When treatment-refractory PMNE persists into late adolescence and early adulthood, patients experience significant psychological and social stress, said Douglas Husmann, MD, of the Mayo Clinic in Rochester, Minnesota, in an accompanying editorial. Whereas some adult patients often are reluctant to seek treatment, others make large financial investments in advice and or treatment from multiple providers, as well as internet sites.
“Unfortunately, medical treatment recommendations for this difficult-to-treat patient population are based on small treatment numbers,” he wrote. “They are associated with a paucity of data regarding the long-term usage of these medications and the possible drug-drug interactions that might occur if polypharmacy is used for management. Even if the physician can successfully treat these patients, there is almost no information regarding pharmacological withdrawal strategies.”
“In this regard, I greatly appreciate the [authors’] work … . This paper gives us an honest appraisal of fluoxetine’s usefulness for the treatment of refractory PMNE,” Husmann stated. “It exposes the medication’s association with tachyphylaxis and lays the foundation regarding how we may devise treatment plans to use this pharmacologic agent in the future.”
Disclosures
Abdelhalim and co-authors, as well as Husmann, disclosed no relationships with industry.
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