Prokinetics for the treatment of functional dyspepsia: Bayesian network meta-analysis

Functional dyspepsia (FD) is a common condition in clinical practice [1]. According to the Rome III and IV criteria, FD is defined as the presence of at least one of the following symptoms; postprandial fullness, early satiation, epigastric pain or burning, without evidence of structural disease to explain the symptoms fulfilling time criteria for the last three months with symptom onset at least six months before diagnosis and a frequency of at least three days per week [2, 3]. FD is subcategorized into two distinct conditions, which are postprandial distress syndrome, associated with meal-induced bothersome fullness or early satiation, and epigastric pain syndrome, showing bothersome epigastric pain or burning [2, 3].

This condition involves complex pathophysiologic mechanisms and shares overlapping symptoms with gastroesophageal reflux disease or other functional gastrointestinal disorders. The mainstay of the treatment of FD has been to target gastric acid secretion and impaired gut motility. The role of acid inhibitory drugs in the treatment of FD is well established [4]. In a subtype of FD, the response rate of epigastric pain syndrome to acid inhibitory therapy is known to be better than that of post-prandial distress syndrome [5].

Excluding acid inhibitory therapy, prokinetics are the mainstay of the treatment of FD. However, the role of prokinetics has not been well established, and inconsistent results have been reported regarding the therapeutic efficacy of each drug [6‐10]. Moreover, previously published pairwise meta-analyses were conducted by examining several drugs with different mechanisms of action as a single group, which cannot present the efficacy of each prokinetic agent [8, 9]. However, head-to-head efficacy comparison of prokinetic agents in the treatment of FD is not easy and pooled comparative efficacy has not been established.

Unlike traditional pair-wise meta-analysis, network meta-analysis enables comparing more than 2 treatments strengthening the precision in the estimate and presenting relative effect sizes in a rank order [11]. Therefore, this study aimed to evaluate the comparative effectiveness of each prokinetic in the treatment of FD using an indirect comparison method.

FD involves complex pathophysiologic mechanisms including visceral hypersensitivity, impaired gastric accommodation, delayed gastric emptying, H. pylori infection, psychosocial disorders, and even an unhealthy lifestyle [39‐41]. The prevalence of gastric emptying delay was reported to be 37–39% in patients with FD. Consequently, prokinetics were developed based on the concept that promoting impaired gut motility could reduce the symptoms of FD [39, 40]. However, improved delayed gastric emptying was not associated with symptomatic relief in patients with gastroparesis [39, 40]. It is apparent that dysmotility cannot be the only target. Multiple other mechanisms should be considered in the treatment of FD.

Proton-pump inhibitors (PPI) and prokinetic agents are the mainstays of the treatment of FD [39], both of which have similar relative efficacy [42]. However, adverse events related to PPI have been reported, and the comparative efficacy of prokinetics has thus far not been evaluated [43, 44]. Because the adverse events associated with PPIs are linked to long-term use of this medication and the recurrence of FD is not infrequent [45], repeated prescriptions of PPI should be re-evaluated and additional focus should be directed toward the role of prokinetic agents in the treatment of FD.

In this analysis, the relative efficacy of prokinetics was based on the SUCRA value. However, there was no significant difference in efficacy between the prokinetics including metoclopramide, trimebutine, mosapride, and domperidone (Table 3). Though the mechanisms of action of these medications are slightly different, the precise reason for the superior or inferior comparative efficacy between these medications could not be evaluated in this analysis. For example, although mosapride, itopride, and acotiamide are all known to modulate gastric accommodation, the statistical effects of these drugs differed in this analysis [46‐48].

The frequency of adverse event must also be considered in selecting prokinetics for the treatment of FD. In the case of metoclopramide, which is a central D₁ and D₂ receptor antagonist, extrapyramidal symptoms including dystonic movement or tardive dyskinesia, which are often irreversible, inhibit the administration of high doses or the long-term use of this medication [49].

In addition to the occurrence of adverse events, drug incompatibility due to drug interactions from a combination of prokinetics or other drugs should be considered in selecting prokinetics. Because domperidone, which is a peripheral D₂ and D₃ receptor antagonist is associated with ventricular arrhythmia, concomitant use of drugs that prolong the QTc interval, and potent CYP3A4 inhibitors should be avoided [50].

With respect to serotonergic agonists, targeting multiple receptors with non-selective inhibition can potentially lead to adverse events. Cardiac arrhythmia or QTc prolongation was most commonly associated with cisapride and tegaserod [51]. 5HT₁ receptor subtypes have been suggested to account for adverse events due to interactions with HERG cardiac potassium channel and 5-hydroxytryptamine [52]. Mosapride, which is a nonselective 5-HT₄ agonist with no HERG or 5HT₁ affinity, could be substituted for metoclopramide or domperidone for the specific subset of patients who need long-term treatment.

Trimebutine, which is an enkephalin agonist, has a dual action on both of hyperkinetic and hypokinetic motility disorders [53]. This medication accelerates gastric emptying by inducing premature phase III activity of the migrating motor complex in gut [9]. Although most studies are focused on the treatment of irritable bowel syndrome, this medication could be substituted for other prokinetics that potentially have serious adverse effects.

In this study, we could not investigate the reason for the relatively lower efficacy of itopride, a mixed D₂ receptor antagonist, and acetylcholinesterase inhibitor or acotiamide, an M₁/M₂ muscarinic receptor antagonist and acetylcholinesterase inhibitor. Given the probability of inconsistencies in the enrolled studies and the superior efficacy of prokinetics that have a relatively small number of enrolled population, there could be an overestimation of efficacy drawn from the pairwise indirect comparison.

This study is the first meta-analysis evaluating the comparative effectiveness of prokinetic agents. The strength of this study is the rigorous searching of the literature without language limitations and the use of an indirect comparative method to address the challenge of performing head-to-head analyses in clinical practice. Nonetheless, there are several limitations that impact the generalizability of the main results. All of the available prokinetic drugs could not be included in this study. These omitted agents include levosulpiride, a selective D₂ receptor antagonist, erythromycin, a motilin receptor agonist, tandospirone, a 5HT_1A agonist, prucalopride, a selective 5HT₄ agonist or DA-9701, a 5HT₄ agonist, D₂ receptor and 5HT₃ antagonist. These medications are not available in some countries. Furthermore, levosulpiride is associated with drug-induced parkinsonism, inhibiting its wide application in clinical practice [54]. Prucalopride was developed and licensed for the treatment of constipation. Therefore, these drugs were excluded from the beginning of this study. Another limitation was the lack of data for some prokinetic agents in this analysis. The relatively small number of studies evaluating metoclopramide and trimebutine may in part explain the inconsistencies as well as the overestimation of the comparative effectiveness of some medications. In addition, most enrolled studies did not discriminate between epigastric pain and postprandial distress syndromes, which are subtypes of FD or post-infectious FD. Moreover, H. pylori infection, which is closely associated with the pathogenesis of FD, was not considered in most of the studies [39]. Overlap syndrome (FD + gastroesophageal reflux disease or FD + irritable bowel syndrome) which is frequently encountered in clinical practice, was also not considered [39]. A further limitation was the absence of a no common validated outcome measurement scale for all the enrolled studies. As we have noted in a previous study, there is no definite and unanimous way of defining symptomatic improvement in patients with FD [6]. Further studies that include newer prokinetics and control for the above-mentioned limitations are needed to confirm the results of this study.

In conclusion, metoclopramide, trimebutine, mosapride, and domperidone showed better efficacy for the treatment of FD than that of itopride or acotiamide. Considering the adverse events related to metoclopramide or domperidone, the short-term use of these agents or the alternative use of trimebutine or mosapride could be recommended for the symptomatic relief of FD.