Systematic review with meta‐analysis: highly selective 5‐HT4 agonists (prucalopride, velusetrag or naronapride) in chronic constipation

Abstract

Summary Background Highly selective 5‐HT4 agonists have been suggested for the treatment of chronic constipation (CC). Aim To assess the effects of highly selective 5‐HT4 agonists (prucalopride, velusetrag or naronapride) on patient‐important clinical efficacy outcomes and safety in adults with CC. Methods We searched the medical literature in January 2013 using MEDLINE/Pubmed, Embase, Cochrane Library, and Web of Science/Scopus for randomised, controlled trials of highly selective 5‐HT4 agonists in adults with CC, with no minimum duration of therapy (maximum 12 weeks) or date limitations. Data were extracted from intention‐to‐treat analyses, pooled using a random‐effects model, and reported as relative risk (RR), mean differences, or standardised mean differences with 95% confidence intervals (CI). Results Main outcomes included stool frequency, Patient‐Assessment of Constipation Quality of Life (PAC‐QOL), PAC of symptoms (PAC‐SYM) and adverse events. Thirteen eligible trials were identified: 11 prucalopride, 1 velusetrag, 1 naronapride. Relative to control, treatment with highly selective 5‐HT4 agonists was superior for all outcomes: mean ≥3 spontaneous complete bowel movements (SCBM)/week (RR = 1.85; 95% CI 1.23–2.79); mean ≥1 SCBM over baseline (RR = 1.57; 95% CI 1.19, 2.06); ≥1 point improvement in PAC‐QOL and PAC‐SYM scores. The only active comparator trial of prucalopride and PEG3350 suggested PEG3350 is more efficacious for some end points. Adverse events were more common with highly selective 5‐HT4 agonists, but were generally minor; headache was the most frequent. Most trials studied prucalopride. Conclusion Demonstration of efficacy on patient‐important outcomes and a favourable safety profile support the continued use and development of highly selective 5–HT4 agonists in the treatment of chronic constipation.

Use of Prucalopride for Chronic Constipation: A Systematic Review and Meta-analysis of Published Randomized, Controlled Trials

“…However, there are several systematic reviews and meta-analyses evaluating the role of prucalopride [59][60][61][62][63][64][65][66][67][68] in the management of chronic constipation and their findings are consistent with the findings of the current study. Although the scope of the current article is the evaluation of clinical effectiveness and adverse events related to prucalopride only, previously reported systematic reviews [59][60][61][62][63][64][65][66][67][68] have reported its safety, efficacy, pharmacokinetics, and tolerability providing supporting evidence to our conclusions. As reported by Tack et al 69 "Prucalopride is an important addition to the therapeutic abilities for treating chronic constipation, especially in females poorly responding to laxatives.…”

“…[59][60][61][62][63][64][65][66][67] However, this study provides up to date, comprehensive and cumulative evidence on the use of prucalopride that meaningfully reduce symptoms related to chronic constipation. One review 59 reported the combined analysis of 3 trials, 4 reviews 62,64,65,67 reported the combined analysis of 4 trials each, 2 reviews 64,66 reported systematic review of the trials evaluating four 5-HT 4 agonist agents, whereas 3 reviews 60,61,68 were evidence reviews.…”

Diagnosis and Treatment of Dyssynergic Defecation

“…70,71 Prucalopride, a 5-HT 4 receptor agonist, is effective and well-tolerated for treatment of chronic constipation at a dose of 2 mg/day for adults and 1 mg/day for those over 65 years of age. 72 These new drugs have not been assessed in dyssynergic defecation.…”

The serotonergic system in the neurobiology of depression: Relevance for novel antidepressants

“…It is expressed in enteric neurons and smooth-muscle cells. Activation of 5-HT4 receptors are located on myenteric with cholinergic motor neurons which stimulate gut motility through enhanced release of acetylcholine (Shin et al, 2014). 5-HT4 receptors are also found in the central nervous system (CNS), where their functions remain largely unclear.…”