Published online Jun 5, 2026. doi: 10.4292/wjgpt.v17.i2.118616
Revised: January 30, 2026
Accepted: March 4, 2026
Published online: June 5, 2026
Processing time: 140 Days and 19 Hours
Gastroparesis, functional dyspepsia, chronic constipation, esophageal motility disorders, and colonic dysmotility are among the gastrointestinal (GI) motility disorders that constitute a significant global health burden. These disorders lead to reduced quality of life, higher healthcare utilization, and substantial socioeconomic costs. Therapeutic options are still scarce despite their prevalence. Prokinetic medications currently on the market offer only modest symptomatic relief, frequently reaching a plateau in efficacy, and their long-term use is limited by safety concerns, especially those related to cardiovascular and neurological side effects, as well as limited regional availability of some agents. The conceptual framework has moved beyond a purely neurocentric model due to recent advances in our understanding of GI motor physiology. The integrated functions of enteric neurobiology, gut-brain axis signaling, smooth muscle contractile pathways, interstitial cells of Cajal as motility pacemakers, and neuromodulatory circuits are highlighted by emerging mechanistic insights. These advancements have made it easier to find new pharmacologic targets and treatment approaches. An overview of new classes of prokinetic and motility-modulating drugs, such as selective receptor agonists and antagonists, hormone-based treatments, neuromodulators, and drugs that target pacemaker cell and smooth muscle function, is given in this review. Lastly, the clinical ramifications of these developing treatments are examined, with a focus on individualized treatment plans and potential future paths to enhance GI motility disorder efficacy, safety, and disease-specific management.
Core Tip: Prokinetic therapy has long been constrained by modest efficacy, tachyphylaxis, and significant cardiovascular and neurological safety concerns, limiting sustained clinical benefit in gastrointestinal motility disorders. This review redefines prokinetic treatment through an integrated pathophysiological framework that extends beyond traditional neuro-centric models to encompass enteric neurobiology, smooth muscle signalling, interstitial cells of Cajal, gut-brain axis modulation, and hormonal regulation. Emerging agents such as selective 5-hydroxytryptamine type 4 agonists, motilin and ghrelin receptor agonists, sodium/hydrogen exchanger-3 inhibitors, and neuromodulatory approaches, which offer improved mechanistic precision and safety. A phenotype-driven, precision-medicine strategy is essential to optimize therapeutic outcomes and guide future drug development in motility disorders.
- Citation: Goyal O, Chowdhary R, Sehgal T, Joshi T, Bhambri A, Rampurawala IM, Sohi GS, Das A, Arora K, Vuthaluru AR, Goyal MK. Evolving prokinetic therapy: New targets and therapeutic opportunities in gastrointestinal motility disorders. World J Gastrointest Pharmacol Ther 2026; 17(2): 118616
- URL: https://www.wjgnet.com/2150-5349/full/v17/i2/118616.htm
- DOI: https://dx.doi.org/10.4292/wjgpt.v17.i2.118616
Prokinetic agents constitute a heterogeneous class of pharmacologic therapies designed to enhance gastrointestinal (GI) smooth muscle contractility and coordination, thereby improving gastric emptying, intestinal and colonic transit[1]. Despite limitations in high-quality evidence for many indications, prokinetics remain widely used across a range of motility disorders, from common disorders of gut-brain interaction (DGBI) like functional dyspepsia (FD), postprandial distress syndrome (PDS), functional constipation (FC), to more severe and disabling entities including gastroparesis and chronic intestinal pseudo-obstruction. Multiple classes of prokinetic agents with distinct mechanisms of action are currently available worldwide, and significant efforts are ongoing to develop novel therapies in response to persistent unmet clinical need. However, the widespread clinical adoption of prokinetics has been profoundly influenced by safety concerns arising from the use of traditional prokinetic agents like cisapride, tegaserod, metoclopramide, domperidone etc. Due to their serious cardiovascular and/or GI adverse effects, many of these molecules have been either withdrawn from the market, or allowed to use under specific conditions and for a limited period of time.
In the aftermath of these highly publicized events, newer prokinetic agents have undergone rigorous pre-marketing safety evaluations. Nevertheless, heightened awareness of prior adverse outcomes continues to limit clinician confidence and utilization of newer therapies, even when appropriately indicated. As DGBIs and GI motility are seldom associated with increased mortality, regulatory agencies have adopted highly conservative safety standards for pharmacologic therapies. As a result, even rare or theoretical serious adverse events have significantly constrained the development, approval, and clinical uptake of prokinetic agents. In this setting, clinicians are often required to balance modest efficacy against safety concerns and limited therapeutic options[2-4]. This review aims to provide a practical, clinically focused overview of the efficacy and safety of currently available and emerging prokinetic therapies across the GI tract, including considerations for use during pregnancy. The goal is to support evidence-based, individualized treatment decisions in routine clinical practice.
Normal gut functioning is a well-coordinated multifactorial process. Earlier prokinetics were predominantly neurocentric, while other factors involved in the normal functioning of the GI tract were underappreciated. Hence a broader pathophysiological framework needs to be taken into consideration while developing next-generation prokinetics[5,6].
The GI motility works through a synchronized network of enteric nervous system (ENS), smooth muscle cells, interstitial cells of Cajal (ICC), GI hormones and gut microbiota. GI motility is carefully regulated by continuous activation and inhibition of these components. Disruption of any individual component can impair this coordination and result in abnormal motility[5,7-9].
The ENS regulates gut motility producing stimulatory or inhibitory signals on the smooth muscles of gut, a mechanism used in old generation prokinetics. In parallel with this, the smooth muscles in the gut is regulated by intracellular signalling that maintain a balance between myosin-light chain kinase and myosin light-chain phosphatase (MLCP). Inhibition of MLCP by Rho-kinase pathway increases calcium concentration producing a more effective contraction. ICC function as pacemaker cells located within the GI wall generating slow electrical waves that determine the frequency and direction of contraction. Regulation of motility is also maintained through interplay of various hormones like ghrelin, motilin, somatostatin and GLP-1. All these mechanisms contribute in producing well coordinated contraction and relaxation in the gut helping in propelling the luminal contents in forward direction[5,7-9] (Figure 1).
Disturbances affecting any of these regulatory mechanisms result in disordered motility. Emotional and environmental stressors activate corticotrophin-releasing hormone signaling leading to a disruption in ENS, increased sympathetic tone and decreased vagal tone thereby suppressing coordinated motor activity. Stress-induced motility dysfunction is also closely associated with visceral hypersensitivity[10,11]. Hypersensitivity produces abnormal sensory reception to luminal contents leading to central malfunctioning. Enteric neurons, ICC, and smooth muscle cells are negatively impacted by altered microbial metabolites and low-grade inflammation in dysbiosis, which results in a cascade of reduced motility[12]. When taken as a whole, these interactions demonstrate the complex causes of GI dysmotility and emphasize the necessity of mechanism-based, next-generation prokinetic techniques.
Prokinetic agent shave been made available in the market since several decades and have played an important role in the management of GI motility disorders (Figure 2). However, due to significant arising from the clinical use to the traditional prokinetic agents like cisapride, tegaserod, metoclopramide, domperidone etc., many of these molecules have been either withdrawn from the market, or allowed to use under specific conditions and for a limited period of time. An integrated overview of traditional and emerging prokinetic therapies including mechanisms of action, therapeutic indications, safety concerns, and limitations (Figure 3).
Dopamine D2 receptor antagonists, such as metoclopramide and domperidone prevent dopamine-mediated inhibition of GI motility, and improve gastric emptying. However, safety issues like extrapyramidal side effects from metoclopramide, and QT interval prolongation from domperidone restrict their clinical use, resulting in strict regulatory controls in many areas[13,14].
Serotonergic drugs that function as 5-hydroxytryptamine type (5-HT) 4 receptor agonists, stimulate the release of acetylcholine from enteric neurons and enhance GI motility. Despite being efficient prokinetics, these medications' limited indications, high cost, and diminished efficacy over time due to tachyphylaxis restrict their use to a limited spectrum of disease[15-17]. Cisapride, a prototype drug of this class, showed efficacy for treatment of gastroparesis. However, due to its poor receptor selectivity and high cardiac adverse effects including ventricular arrhythmias, it has been withdrawn from the market[18].
Tegaserod is a partial 5-HT4 receptor agonist was originally approved for irritable bowel syndrome with constipation (IBS-C). It improves GI motility and visceral sensitivity but was withdrawn due to cardiovascular safety concerns[19,20]. A subsequent analysis found no significant increase in cardiovascular events in low-risk patients[21,22]. Despite Food and Drug Administration reapproval, it is no longer marketed in the United States.
Mosapride is a selective 5-HT4 agonist that enhances acetylcholine release and accelerates gastric emptying, with minimal cardiac ion-channel effects[23]. Clinical trials show modest benefit in FD and constipation, with inconsistent results as adjunctive therapy for gastroesophageal reflux disease. It may improve gastric accommodation and gastroduodenal coordination[24,25]. Mosapride is generally well tolerated, with mild GI side effects and rare cardiac events reported primarily in the presence of electrolyte abnormalities or interacting drugs. Mosapride is safe and may benefit selected patients with FD or constipation, but overall efficacy is modest.
Erythromycin and azithromycin are motilin receptor agonists that cause powerful stomach contractions and quicken stomach emptying. These drugs have short-term advantages, but they are not appropriate for long-term treatment because they increase the risk of cardiac arrhythmias and their effects diminish quickly with continued use[26-30].
Bethanechol was one of the earliest used prokinetics to treat gastroeosphageal reflux disease. Its clinical utility was limited due to adverse effects and comparatively weaker prokinetic efficacy[31-33].
The need for safer and more focused treatments is demonstrated by the variations in dyspepsia types, the emphasis on symptoms rather than actual stomach movement, and regional variations in drug approval[14].
Motilin agonists: Mitemcinal is a non-antibiotic erythromycin derivative developed to overcome acid instability and antimicrobial-induced dysbiosis. It is a selective and full motilin receptor agonist with improved stability in acidic environments[34,35]. Two randomized trials in gastroparesis demonstrated dose-dependent improvements in gastric emptying and symptoms, with the greatest efficacy at 30 mg twice daily. Symptom improvement was more pronounced in diabetic than idiopathic gastroparesis[36-42] (Figure 4 and Table 1).
| Drug class | Agent | Mechanism of action | Initial promise | Major adverse effects | Current status | Efficacy limitations |
| Dopamine antagonists[13,15-19] | Metoclopramide | D2 antagonist, 5-HT4 agonist, 5-HT3 antagonist | First-line therapy for gastroparesis | Tardive dyskinesia, extrapyramidal symptoms | Restricted to < 12 weeks of use | Poor symptom correlation, tolerance |
| Domperidone | D2 antagonist (peripheral) | Alternative without CNS effects | Cardiac arrhythmias, QT prolongation | Limited access in United States, cardiac warnings | Moderate efficacy, safety concerns | |
| Levosulpiride | D2 antagonist, 5-HT4 agonist | Enhanced prokinetic efficacy | Extrapyramidal symptoms, sedation | Limited use | Variable effectiveness | |
| 5-HT4 receptor agonists[17,42] | Cisapride | 5-HT4 agonist, 5-HT3 antagonist | Potent prokinetic for GERD/gastroparesis | Fatal arrhythmias, sudden cardiac death | Withdrawn from market (2000) | Good efficacy but fatal toxicity |
| Tegaserod | 5-HT4 agonist, 5-HT1 and 5-HT2b serotonergic antagonist | Improved transit in IBS-C | Ischemic colitis; Cardiovascular risk | Restricted/withdrawn in many regions | Safety concerns | |
| Prucalopride | 5-HT4 agonist, mild affinity for dopamine D4 receptor σ1 receptor | Effective for constipation; some benefit in gastroparesis | Headache, diarrhea; rare neuropsychiatric AEs | Approved (EU/India) | Colonic > gastric effects | |
| Velusetrag | 5-HT4 agonist | Accelerated GE in gastroparesis (Phase 2) | Nausea, diarrhea; rare palpitations | Investigational (fast track) | Limited long-term data | |
| Motilin agonists[20-25] | Erythromycin | Motilin receptor agonist | Strong gastric motility stimulant | Tachyphylaxis, antibiotic resistance | Off-label use, limited efficacy | Rapid tachyphylaxis (2-3 days) |
| Mitemcinal | Acid-stable erythromycin derivative; full and selective motilin receptor agonist → MMC induction and enhanced antral contractions | Improved gastric emptying and symptom relief in idiopathic and diabetic gastroparesis | Generally well tolerated; nausea, vomiting, diarrhea, tremors | Investigational | Limited clinical data; studied primarily in gastroparesis | |
| Ghrelin receptor agonists | Relamorelin | Ghrelin receptor agonist → ↑ antral contractions, | Symptom and GE improvement in diabetic gastroparesis | Hyperglycemia, headache | Investigational (fast track) | Injectable; metabolic effects |
| Ulimorelin (TZP-102) | Ghrelin receptor agonist | Data scarce/inconclusive | No safety data available | Investigational; ongoing clinical evaluation | Lack of publicly available human efficacy and safety data | |
| Muscarinic agonist[26-28] | Bethanechol | Muscarinic agonist | Early prokinetics for reflux | Cholinergic side effects | Largely abandoned | Weak prokinetic effect |
| Acotiamide | Novel acetylcholinesterase inhibitor | Improved gastric emptying and accommodation in FD | Minimal; headache, diarrhea | Approved in Japan, India and few other countries | Limited availability |
Mitemcinal was well tolerated, with adverse events similar to placebo and no significant cardiac safety concerns. Mild, dose-related elevations in liver enzymes were reported at higher doses[32]. Mitemcinal shows promise as a motilin agonist without antimicrobial effects, but evidence remains limited and larger trials are needed before routine clinical use.
Dopamine antagonists: Trazpiroben is a novel dopamine D2/D3 receptor antagonist under development for the chronic treatment of moderate-to-severe gastroparesis, designed to overcome the central nervous system and cardiovascular safety limitations of metoclopramide and domperidone, respectively. Nonclinical studies demonstrate D2/D3 receptor antagonism comparable to existing agents, with reduced central exposure. In a phase 2a pilot study, twice-daily trazpiroben (5, 25, and 100 mg) was well tolerated, with no cardiovascular or central nervous system adverse events, and showed predictable pharmacokinetics[37]. Unlike metoclopramide and other older dopamine antagonists, trazpiroben is designed to minimize central nervous system penetration, thereby reducing the risk of extrapyramidal symptoms and hyperprolactinemia.
By selectively blocking peripheral D2 receptors in the GI tract, trazpiroben enhances acetylcholine release from enteric neurons, leading to improved gastric contractility and accelerated gastric emptying. Importantly, trazpiroben has shown a favorable safety profile, with no clinically meaningful effects on prolactin levels, QT interval prolongation, or extrapyramidal adverse events[37]. Adverse effects reported in trials were generally mild and comparable to placebo, supporting its suitability for longer-term use. Trazpiroben represents a promising next-generation dopamine D2 antagonist that preserves prokinetic efficacy while addressing the major safety limitations of existing agents. Ongoing late-phase trials will further define its role in the management of gastroparesis and other GI motility disorders.
5-HT4 receptor agonists: Prucalopride, relatively new prokinetic, is a highly selective 5-HT4 receptor agonist that enhances acetylcholine release and promotes coordinated GI motility[38,39]. Unlike earlier agents, it lacks significant off-target cardiac effects. Randomized trials demonstrate improvement in gastric emptying, gastroparesis symptoms, and quality of life, particularly in idiopathic gastroparesis. Its strongest evidence supports treatment of chronic idiopathic constipation, with consistent benefit across multiple large trials[40,41].
Prucalopride is generally well tolerated, the most common adverse effects are headache, nausea, and diarrhea, typically transient. Extensive studies show no increased cardiovascular risk, though rare psychiatric adverse effects warrant monitoring[22,41,42]. Prucalopride has a favorable efficacy, safety profile with growing evidence for use beyond constipation, including gastroparesis and postoperative ileus.
Ghrelin receptor agonists: Ghrelin is a 28-amino acid peptide secreted predominantly by the stomach and plays a key role in gastric motility, appetite regulation, and energy homeostasis. Exogenous ghrelin and synthetic ghrelin receptor agonists accelerate gastric emptying and enhance antral contractility. Among this class, relamorelin and ulimorelin (TZP-102) have demonstrated consistent promotility effects, with relamorelin being the most extensively studied in clinical trials[6-8].
Relamorelin is a synthetic ghrelin receptor agonist with greater potency and longer half-life than native ghrelin and is administered subcutaneously. In multiple phase 2 and 2b randomized trials, relamorelin significantly accelerated gastric emptying and improved key symptoms, including nausea, vomiting, postprandial fullness, abdominal pain, and bloating, in patients with diabetic gastroparesis, and also demonstrated promotility effects throughout the small bowel and colon in chronic idiopathic constipation[8,9,43]. Relamorelin has been well tolerated across trials, with no consistent signal for serious adverse events or clinically significant electrocardiogram abnormalities. However, dose-dependent hypergly
CCK1 receptor antagonists: CCK is a GI peptide secreted predominantly by I-cells in the duodenum and jejunum in response to nutrients, particularly long-chain fatty acids. Through activation of CCK1 receptors on vagal afferents and the pyloric sphincter, CCK inhibits gastric emptying and promotes satiety, and exogenous administration reduces meal size in humans and animal models[14]. Selective CCK1 receptor antagonists, including loxiglumide, dexloxiglumide, devazepide, and A-70104, have been shown in healthy volunteers and patients with IBS to accelerate gastric emptying and, in some studies, colonic transit, without significantly impairing gallbladder function[13]. Clinical trials suggest that prokinetic effects are meal-dependent, reflecting nutrient-stimulated CCK release, and optimal dosing can enhance GI transit while minimizing adverse effects[26]. These findings indicate that CCK1 receptor antagonists may offer therapeutic benefit for patients with FD, IBS, and other disorders of gastric or colonic motility, although further studies are required to clarify their clinical role.
Sodium/hydrogen exchanger inhibitors: Tenapanor is a first-in-class, minimally absorbed inhibitor of the sodium/hydrogen exchanger-3 (NHE3) and represents an important second-line pharmacologic option for IBS-C. Colonic transit acceleration and visceral analgesia. It inhibits the absorption of dietary sodium and phosphate, which increases intestinal fluid volume and transit, with greater efficacy when administered prior to meals[27,28]. In a phase 2 randomized, placebo-controlled study, tenapanor 50 mg twice daily significantly increased complete spontaneous bowel movement responder rates and improved abdominal pain compared with placebo[45]. These findings were supported by subsequent phase 3 trials demonstrating statistically significant, albeit modest, improvements in composite pain and stool frequency endpoints with sustained benefit over 26 weeks[46]. Diarrhea remains the most common treatment-related adverse event and is dose-limiting in a small proportion of patients, though clinically meaningful electrolyte disturbances have not been observed, including in older populations treated for hyperphosphatemia. Clinically, tenapanor offers a mechanistically distinct option for patients with IBS-C or constipation-predominant disorders of gut-brain interaction, particularly in those with prominent bloating and abdominal pain who have failed conventional therapies.
Pharmacologic modulation of bile acid signaling and enterohepatic circulation represents an emerging strategy for the treatment of constipation-predominant motility disorders. Elobixibat (A3309) is a first-in-class ileal bile acid transporter inhibitor that increases delivery of bile acids to the colon, where they stimulate secretion and accelerate colonic transit[41]. In randomized phase 2 and 3 trials involving patients with chronic constipation, elobixibat significantly shortened time to first spontaneous and complete spontaneous bowel movements, increased stool frequency, and improved constipation-related symptoms, with greatest efficacy observed at doses of 10-15 mg daily[22]. Adverse events, primarily mild abdominal pain and diarrhea, were common but generally self-limited; however, overall tolerability concerns have limited regulatory approval outside Japan. In contrast, NGM282, a fibroblast growth factor 19 analog that suppresses bile acid synthesis, has also been shown to enhance gastric and colonic transit and improve stool consistency in FC, despite reducing fecal bile acid concentrations[19]. These paradoxical findings suggest bile acid–dependent and bile acid–independent mechanisms of motility modulation and underscore the need for further physiologic studies to define the clinical role of bile acid–targeted therapies in GI dysmotility.
NK receptor modulators: NK-1 receptor antagonists modulate central and peripheral pathways involved in nausea and vomiting and have been evaluated as symptom-directed therapies in gastroparesis. Aprepitant and the novel agent tradipitant have been evaluated for symptom relief in patients with gastroparesis and FD–gastroparesis overlap[10,12]. In randomized, placebo-controlled trials, these agents improved nausea, vomiting, and associated symptoms, potentially via effects on the brainstem vomiting center and by increasing fasting gastric volume and gastric accommodation without altering gastric emptying[15]. While primarily antiemetic rather than truly prokinetic, NK1 receptor antagonists may serve as adjunctive therapy for patients with nausea-predominant gastroparesis. Clinically, they are considered particularly useful in individuals with persistent nausea despite standard prokinetic therapy, helping to improve symptom burden and quality of life while complementing other promotility interventions.
Cannabinoid receptor modulation: Cannabinoids are increasingly explored for gastroparesis due to their antiemetic, analgesic, prokinetic, and appetite-modulating properties. While delta-9-tetrahydrocannabinol. slows gastric emptying in healthy individuals, patients with diabetic or idiopathic gastroparesis frequently report improvement in nausea, vomiting, and abdominal discomfort, suggesting symptomatic benefit independent of gastric transit[16,17]. Cannabidiol is a CB2 receptor agonist and CB1 receptor antagonist which is non-psychotropic and has significant anti-inflammatory effects. It modulates multiple receptors including being an agonist at 5-HT1A, adenosine A1 and A2A, and TRPV1 receptors, and is an allosteric modulator of μ and δ opioid receptors[18]. It has shown modest reductions in gastroparesis symptom scores and improved caloric intake, though it may slow gastric emptying. Overall, cannabinoids may offer symptomatic relief for select patients, particularly those with nausea-predominant or refractory gastroparesis, but clinical application requires careful risk-benefit assessment and further controlled studies to define efficacy and safety.
Gastric electrical stimulation: Gastric electrical stimulation (GES) is an emerging intervention for the management of severe gastroparesis, aimed primarily at reducing vomiting and GI symptoms rather than directly accelerating gastric emptying. The implantable Enterra system delivers high-frequency, low-energy electrical pulses via electrodes placed in the antral muscle wall and connected to a subcutaneous neurostimulator[20]. In clinical studies, GES has been shown to improve symptom burden and quality of life, though enhancement of gastric emptying is inconsistent and often limited to diabetic gastroparesis[47]. Mechanistically, GES may modulate gastric tone, improve gastric accommodation, and influence afferent neural pathways, with some evidence for central antiemetic effects. Approximately 20% of patients experience device-related complications, including infection, lead migration, erosion, and pain from pacing wires, which restrict its broader use[23]. Overall, GES represents a symptom-directed, neuromodulatory approach to gastroparesis.
Transcutaneous auricular vagus nerve stimulation: Auricular and transcutaneous vagal nerve stimulation represents an emerging neuromodulatory approach for the treatment of DGBIs. Preclinical studies have shown that auricular vagal nerve stimulation reduces visceral hypersensitivity, suppresses pro-inflammatory cytokines [tumor necrosis factor-alpha, interleukin (IL)-6, IL-1β, and accelerates gastric emptying, suggesting combined anti-nociceptive, anti-inflammatory, and prokinetic effects. These effects are mediated via vagal afferent and efferent pathways, with central modulation involving the nucleus tractus solitarius, hypothalamus, and thalamic networks[24,25]. Clinical studies in patients with FD and IBS have demonstrated improved GI symptoms, enhanced parasympathetic activity, and normalization of gastric slow waves, supporting the role of vagal modulation in symptom relief[45]. Despite these promising findings, optimal stimulation parameters, and treatment regimens remain undefined, and further clinical studies are needed to establish efficacy and standardize protocols.
Behavioral and diet-based strategies: Dietary modification and glycemic control form the cornerstone of first-line therapy for gastroparesis. Patients are advised to consume small, frequent meals low in fat and fiber, with liquids preferred when solids are poorly tolerated, as liquid emptying is often preserved even in severe disease[48]. In diabetic gastroparesis, strict glucose management improves antral contractility, reduces dysrhythmias, and accelerates gastric emptying through frequent monitoring and short-acting insulin administration. Behavioral therapies, such as gut-directed cognitive behavioral therapy and hypnotherapy, help modulate maladaptive brain-gut interactions that exacerbate symptoms. In patients with IBS, diets low in FODMAPs are widely recommended, implemented through restriction, reintroduction, and personalization phases[49-52]. Integrated care models combining dietary, behavioral, and pharmacologic strategies have demonstrated improved clinical outcomes, patient satisfaction, and quality of life, though access to specialized psychogastroenterology and dietetic services remains a barrier. Telehealth platforms offer potential for broader dissemination of multidisciplinary care, highlighting the need for further research to optimize imple
GI motility disorders are clinically heterogeneous, and optimal use of prokinetic therapy requires careful alignment between drug mechanism and disease phenotype. Gastroparesis, FD, and chronic constipation represent overlapping yet pathophysiologically distinct entities, with further subdivision within FD into PDS (FD-PDS) and epigastric pain syndrome (FD-EPS). Prokinetic agents are most likely to benefit patients with FD-PDS and gastroparesis, in whom impaired gastric emptying, antral hypomotility, or defective gastric accommodation predominate, whereas FD-EPS is more closely associated with visceral hypersensitivity and central pain processing.
Similarly, constipation phenotypes influence therapeutic response. Patients with slow-transit constipation are more likely to respond to promotility agents targeting colonic transit, whereas those with outlet dysfunction (dyssynergic defecation) derive limited benefit from prokinetics and require pelvic floor–directed therapies. Objective motility assessment including gastric emptying scintigraphy, wireless motility capsule testing, and high-resolution antroduodenal or colonic manometry can refine phenotyping and improve therapeutic precision by identifying the dominant motor abnormality and the most appropriate pharmacologic target[48].
Emerging biomarker strategies aim to further individualize prokinetic therapy by identifying biological signatures associated with dysmotility and treatment response. Circulating neuropeptides such as ghrelin and neuropeptide Y reflect upstream regulatory pathways influencing gastric and intestinal motor function and may help identify patients most likely to benefit from hormone-based promotility agents.
At the tissue level, abnormalities of the ICC have been implicated in gastroparesis and severe motility disorders. Reduced expression of ICC markers, including c-Kit and Ano1, correlates with impaired motor coordination and may explain resistance to conventional prokinetics in some patients. While not yet clinically actionable, these biomarkers highlight the biological diversity of motility disorders and underscore the need for mechanism-specific therapies.
In addition, transcriptomic studies in disorders of gut-brain interaction have demonstrated altered mucosal gene expression involving ion transport, epithelial barrier function, immune regulation, and mast cell activation. These molecular alterations may contribute to variability in motility patterns and therapeutic response, suggesting that future biomarker-driven strategies could identify patients who require combination approaches rather than isolated promotility therapy.
Genetic variability represents an important but underutilized dimension of precision medicine in prokinetic therapy. Pharmacogenomic differences in drug metabolism can influence both efficacy and tolerability of prokinetics and commonly co-prescribed agents. Cytochrome P450 enzymes, particularly CYP2D6, CYP2C19, and CYP3A4, exhibit substantial genetic polymorphism and are responsible for the metabolism of neuromodulators, acid-suppressive therapies, and serotonergic agents frequently used alongside prokinetics[53].
CYP2D6 polymorphisms affect metabolism of tricyclic antidepressants and selective serotonin reuptake inhibitors, which are often prescribed in conjunction with prokinetics for symptom modulation in DGBIs. Variability in enzyme activity may contribute to treatment failure or adverse effects misattributed to prokinetic therapy. Similarly, increased CYP2C19 activity has been associated with reduced response to proton pump inhibitors in FD, indirectly influencing outcomes in FD-PDS patients receiving combination therapy; in such cases, use of proton pump inhibitors with alternative metabolic pathways (e.g., rabeprazole) may improve response.
Genetic variation in serotonergic signaling has direct implications for prokinetic efficacy. Polymorphisms in the serotonin transporter gene (5-HTTLPR) alter serotonin reuptake and downstream receptor activation, influencing baseline transit and drug responsiveness. Reduced serotonin transporter expression is associated with accelerated colonic transit, diminished response to 5-HT3 antagonists, and enhanced responsiveness to 5-HT4 agonists, supporting the concept of genotype-informed selection of serotonergic prokinetics[54].
Relamorelin, elobixibat, and tenapanor are examples of more recent prokinetic and gut-targeted medications that have been developed to enhance GI motility without the cardiac and neurological side effects of previous treatments[17]. In short-term clinical trials, these agents have demonstrated generally good safety and tolerability and act through more selective mechanisms[55-57]. However, there are still questions about long-term safety with chronic use, cumulative exposure, and use in elderly or comorbid patients because the majority of the data that is currently available comes from short-term studies in controlled populations. Extended follow-up and post-marketing surveillance are necessary because the current lack of strong real-world evidence (RWE) limits the detection of uncommon or delayed adverse events[17,55-57].
Due to variations in regulatory frameworks, pharmacovigilance systems, and benefit-risk assessment, prokinetic agents’ clinical availability and regulatory approval differ significantly between regions[58]. While some agents are still in use in India and other Asian nations under regulatory supervision, others have been withdrawn or restricted in the United States and Europe due to safety concerns, particularly those pertaining to QT prolongation[59,60]. Japan has a unique regulatory system that frequently depends on clinical data unique to a given area. This regional difference affects prescribing practices globally, restricts cross-regional safety comparisons, and makes global standardization difficult[61,62].
Contemporary management of GI motility disorders increasingly emphasizes an integrative approach that addresses motor dysfunction, visceral sensory abnormalities, and psychosocial factors, recognizing that symptom generation often reflects multifactorial pathophysiology rather than isolated impaired motility. Combining prokinetic agents with neuromodulators and behavioral interventions has shown greater symptomatic improvement than prokinetics alone, highlighting the value of multimodal strategies in disorders such as gastroparesis and FD[63]. Emerging evidence suggests that mechanism-driven therapy tailored to specific pathophysiologic domains such as impaired accommodation, visceral hypersensitivity, and brain-gut axis dysregulation may be more effective than traditional symptom-guided prescriptions alone, especially in overlapping disorders like FD with constipation or nausea-dominant gastroparesis phenotype[64]. A shift toward phenotype-specific management may reduce healthcare utilization by decreasing trial-and-error medication use, improving quality of life, and fostering personalized clinical pathways that integrate dietary, psychological, and pharmacologic domains.
Despite advances in understanding motility disorders, significant gaps remain, including the lack of standardized, harmonized motility testing protocols that can be applied across clinical trials to reliably stratify patients and measure treatment effects[58]. Future research should prioritize phenotype-specific randomized controlled trials rather than broad umbrella studies, enabling clearer evaluation of targeted therapies for distinct clinical presentations. Long-term safety data and RWE are urgently needed for emerging agents and neuromodulatory therapies, as current evidence is limited and heterogeneous. Exploration of the gut microbiome’s role in motility regulation underscores a potential frontier for microbiome-based interventions, with altered microbial pathways implicated in disorders such as IBS[59]. Integration of artificial intelligence–based predictive modeling may enhance identification of responders to specific prokinetic strategies and refine personalized treatment plans. Moreover, combined pharmacologic and neuromodulation approaches leveraging both drug targets and neural modulation of the gut–brain axis, represent a promising multidisciplinary avenue that requires rigorous clinical evaluation[65].
Prokinetic agents are a diverse class of pharmacological treatments. These are known to enhance GI motility by increasing coordination and contractility of smooth muscles. Although the limitations of transit-centered therapeutic regimes are highlighted by various evidences. These evidences showcase that improvement in motility does not correlate with symptomatic improvement, hence a change is observed from traditional prokinetic agents to multimodal treatment options including targeted biologic and microbiome-modulating therapies, behavioral interventions and neuromodulators. Hence an integrated and precision based approach aligned with mechanistic drivers of gastroparesis, is likely to define the next era of prokinetic therapy and optimize clinical outcomes.
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