Second- and third-line treatment options for refractory monosymptomatic enuresis in children: a scoping review.

Around one-third of patients with monosymptomatic nocturnal enuresis (MNE) do not respond to conventional first-line treatments. Although international guidelines outline second- and third-line treatment options, these recommendations may not fully address the needs of every case encountered in daily practice. Therefore, the question of which treatment strategy should be used for refractory cases remains unanswered. We conducted a scoping review (PROSPERO CRD420251171197) following PRISMA Extension for Scoping Reviews (PRISMA-ScR), searching the PubMed, Embase, Ovid MEDLINE, Scopus, Web of Science, Google Scholar, CINAHL and the Cochrane Library databases to identify all published reports of treatment for refractory MNE in paediatric patients up to March 2026. Eligible studies included randomized controlled trials and prospective or retrospective observational cohort studies written in English. The primary outcome was the number of wet nights (classified as complete, partial or no response according to the ICCS criteria). Secondary outcomes included a comparison of the efficacy of second- and third-line treatment options if enough data could be found. The Cochrane RoB 2 tool was used to assess the risk of bias in randomized clinical trials, and the Methodological Index for Non-Randomized Studies (MINORS) was used for non-randomized cohort studies. Following screening and eligibility assessment, 17 out of 2578 articles met the PICO inclusion criteria. The included studies enrolled a total of 1348 children and adolescents with mean ages ranging from approximately 8 to 17 years. Many of the second- or third-line treatments described in the literature were excluded due to incorrect methodology, study design or patient population. The results showed that, following first-line treatment, a combination of biofeedback, electrical nerve stimulations, anticholinergics (e.g. oxybutynin, tolterodine, solifenacin), β3-adrenoceptor agonists (e.g. vibegron), tricyclic antidepressants (e.g. imipramine) and selective serotonin reuptake inhibitor (e.g. fluoxetine) improved both partial response (PR) and complete response (CR) at varying rates across highly heterogeneous interventions and study populations. However, the evidence does not strongly support a treatment algorithm. Furthermore, reports on electro-acupuncture, furosemide, onabotulinumtoxin A injections or the herbal medicine 'shokenchuto' were considered unreliable for pure refractory MNE, despite improvements in PR and CR occurring at different rates. Conclusion: The question of which treatment strategy should be used for refractory cases remains unanswered due to a lack of sufficiently unbiased, prospective, randomized, controlled studies involving long-term follow-up. Some second- and third-line treatment options may improve PR and CR rates, despite the limited available evidence to support a treatment algorithm. However, further research is needed to confirm these benefits.