The research, conducted by a team at Anglia Ruskin University’s School of Medicine in Chelmsford, United Kingdom, pooled data from eight randomised controlled trials involving a total of 1,741 patients. Both palonosetron and ondansetron belong to a class of drugs known as 5-hydroxytryptamine type 3 receptor antagonists, or 5HT3RAs, which block serotonin receptors in the gut and brainstem that trigger the vomiting reflex. Ondansetron, a first-generation agent introduced in the early 1990s, transformed cancer care by dramatically reducing acute vomiting, while palonosetron, approved later, binds to the same receptor with far higher affinity and a much longer half-life of roughly 40 hours compared with ondansetron’s three to six hours.

The researchers set out to address a gap in the evidence base. Although earlier meta-analyses had suggested palonosetron was superior to first-generation 5HT3RAs as a class, direct head-to-head comparisons with ondansetron specifically remained limited, and prior analyses may not have captured the most recent trial data. To fill that void, the team systematically searched PubMed, the Cochrane Library and Scopus, identifying randomised controlled trials that compared the two drugs directly in patients receiving chemotherapy.

The primary outcome was complete response, defined as the absence of vomiting or retching with no use of rescue antiemetic medication. Secondary outcomes included complete control, which additionally requires no significant nausea, and the incidence of adverse events. The meta-analysis employed a statistically rigorous approach, using the Restricted Maximum Likelihood estimator combined with the Hartung-Knapp-Sidik-Jonkman correction, a method designed to produce more reliable confidence intervals in meta-analyses with a small number of trials, a situation where conventional methods can be overly optimistic.

The results were striking in their consistency. Palonosetron was associated with significantly higher complete response rates than ondansetron in all three clinically defined phases of CINV. During the acute phase, the first 24 hours after chemotherapy, the risk ratio was 1.10 with a 95 percent confidence interval of 1.04 to 1.15. In the delayed phase, spanning 24 to 120 hours after treatment, the advantage grew, with a risk ratio of 1.22 and a confidence interval of 1.13 to 1.32. Across the overall phase, the risk ratio reached 1.28 with a confidence interval of 1.20 to 1.36, meaning patients receiving palonosetron were substantially more likely to avoid emesis entirely throughout the full risk window.

The delayed and overall findings are particularly meaningful because delayed CINV has historically proven harder to control than the acute phase. Ondansetron’s short duration of action means its protective effect wanes within hours of administration, whereas palonosetron’s prolonged receptor binding is thought to sustain serotonin blockade through the delayed period. The pharmacology aligns neatly with the pooled clinical data: the largest effect sizes appeared precisely where the drug’s longer half-life would be expected to matter most.

However, the picture changes when the outcome shifts from complete response to complete control. For this stricter measure, which demands freedom from both emesis and significant nausea, the meta-analysis found no statistically significant differences between the two drugs in any phase. The risk ratios were 1.09 in the acute phase, 1.17 in the delayed phase and 1.08 overall, with confidence intervals in each case crossing the threshold of no effect. This divergence highlights a well-recognised challenge in antiemetic research: nausea, a subjective sensation, is considerably harder to suppress than vomiting, and no 5HT3 receptor antagonist has shown robust superiority against it. Nausea is now understood to involve multiple neurotransmitter pathways beyond serotonin, including neurokinin-1 and substance P signalling, which explains why combination regimens incorporating NK1 receptor antagonists and dexamethasone have become standard for highly emetogenic chemotherapy.

On safety, the analysis found no significant differences between the two agents in the most commonly reported adverse events. Headache showed a risk ratio of 0.88 with a confidence interval of 0.68 to 1.14, constipation a risk ratio of 1.47 with a confidence interval of 0.67 to 3.25, and dizziness a risk ratio of 0.71 with a confidence interval of 0.32 to 1.59. Yet the authors are careful to caution against overinterpreting these null findings. The available safety data were limited, and the absence of statistically significant differences should not, they emphasise, be read as proof that the two drugs are equally safe. Underpowered safety comparisons are a persistent weakness of meta-analyses built on trials designed primarily to measure efficacy.

Methodological transparency was a strength of the review. The team assessed risk of bias in the included trials using the Cochrane Risk of Bias 2.0 tool, the current standard for judging the internal validity of randomised studies, and evaluated the certainty of the evidence using the GRADE framework, which grades confidence in effect estimates from high down to very low based on study limitations, inconsistency, indirectness and imprecision. The review was prospectively registered under CRD420251108042, and the authors declared no funding and no competing interests, factors that reduce the risk of bias in the synthesis itself.

For clinicians and patients, the findings carry practical weight. Ondansetron remains one of the most prescribed antiemetics worldwide, largely because it is inexpensive and available in generic formulations, while palonosetron typically costs more. The evidence that palonosetron delivers significantly better protection against vomiting, particularly in the delayed phase, may prompt oncology teams to reconsider drug selection, especially for moderately emetogenic regimens where the choice between the two agents has often been driven by cost rather than comparative data. At the same time, the authors’ caution about safety data and the lack of a complete-control advantage suggest that palonosetron is not a wholesale replacement but rather a better-performing option within a broader antiemetic strategy. As CINV management continues to evolve toward guideline-driven, risk-adapted combinations, this analysis provides one of the clearest head-to-head syntheses to date of the two most familiar 5HT3 receptor antagonists, and a reminder that even decades-old drug classes still hold questions worth answering.

Subject of Research: Comparative efficacy and safety of palonosetron versus ondansetron for preventing chemotherapy-induced nausea and vomiting

Article Title: Efficacy and safety of palonosetron versus ondansetron for preventing chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomised controlled trials

Article References: Efficacy and safety of palonosetron versus ondansetron for preventing chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomised controlled trials. (n.d.). https://doi.org/10.1186/s40360-026-01206-z

Image Credits: AI Generated

DOI: 10.1186/s40360-026-01206-z

Keywords: palonosetron, ondansetron, chemotherapy-induced nausea and vomiting, 5HT3 receptor antagonists, meta-analysis, systematic review, antiemetics, complete response, drug safety, oncology, randomised controlled trials, pharmacology

The study, led by Xiaoge Zhang, Xiaoyun Wang, Na Li, Qunying Han and Zhengwen Liu, analyzed the records of 1,141 patients with advanced hepatocellular carcinoma who had received best supportive care, meaning treatment aimed at relieving symptoms rather than attacking the tumor directly. Among these patients, 102 had been given 5-HT3 receptor antagonists, drugs that are routinely prescribed to control nausea and vomiting, particularly during chemotherapy or in the course of supportive management of advanced cancer.

Serotonin, chemically known as 5-hydroxytryptamine or 5-HT, is best known as a neurotransmitter that regulates mood, appetite and gut motility. But its influence extends well beyond the brain and digestive tract. Serotonin signaling has been implicated in hepatocarcinogenesis, the process by which normal liver cells transform into cancerous ones. Serotonin receptors on cells can promote proliferation, angiogenesis and tumor progression, which is why drugs that block specific serotonin receptors have long been suspected of having potential anticancer properties.

When the researchers compared overall survival between patients who received 5-HT3 receptor antagonists and those who did not, the difference was striking. Users of the drugs had a significantly reduced risk of death, with a hazard ratio of 0.690, meaning their mortality risk was roughly 31 percent lower than that of nonusers. The 95 percent confidence interval ranged from 0.546 to 0.871, and the result was statistically significant with a p value of 0.002.

Because patients who receive anti-nausea medications may differ systematically from those who do not, in terms of disease severity, performance status or other treatments received, the team employed propensity score matching, a statistical technique designed to mimic the conditions of a randomized controlled trial using observational data. After matching 89 patients who used the drugs with 161 comparable nonusers, the survival advantage persisted. In this matched cohort, the hazard ratio fell to 0.615, with a confidence interval of 0.457 to 0.829 and a p value of 0.001, indicating that the association was unlikely to be explained by imbalances in baseline characteristics alone.

The findings held up in subgroup analyses as well. Among patients whose liver cancer was associated with hepatitis B virus infection, the dominant cause of hepatocellular carcinoma in China where the study population was drawn, the survival benefit of 5-HT3 receptor antagonist use remained evident. This consistency across a clinically important subgroup strengthens the case that the observed effect is not an artifact of the broader patient mix.

Perhaps the most intriguing results emerged when the researchers examined individual drugs within the class. Tropisetron, one of the second-generation setrons, showed a particularly pronounced effect. After propensity score matching, the five-year overall survival rate among tropisetron users was 23.7 percent, compared with just 10.9 percent among nonusers, a difference that was statistically significant with a p value of 0.004. For a disease in which five-year survival in the advanced stage is typically measured in single digits, a more than doubling of long-term survival in the matched cohort is a remarkable signal.

When the team applied Cox regression analysis, a statistical method that identifies factors independently associated with prognosis, both ondansetron and tropisetron emerged as independent predictors of improved survival. Ondansetron use carried a hazard ratio of 0.603, with a confidence interval of 0.365 to 0.995 and a p value of 0.048, while tropisetron performed even better, with a hazard ratio of 0.477, a confidence interval of 0.299 to 0.759 and a p value of 0.002. In practical terms, patients receiving either of these drugs had roughly half the mortality risk of comparable patients who did not receive them.

The biological rationale for these findings is grounded in a growing body of laboratory research. Serotonin can stimulate tumor cell proliferation and promote the formation of new blood vessels that feed growing tumors, processes mediated in part through serotonin receptors expressed on tumor and endothelial cells. Blocking the 5-HT3 receptor subtype may therefore interfere with signaling pathways that support tumor growth and spread. Some setrons, including tropisetron, have also been shown in preclinical studies to possess anti-inflammatory and immune-modulating properties, raising the possibility that their benefit in liver cancer may extend beyond simple receptor blockade.

The authors conclude that the use of 5-HT3 receptor antagonists is associated with improved overall survival, and that ondansetron and tropisetron in particular were independently associated with better prognosis in patients with advanced hepatocellular carcinoma. As with any observational study, the results demonstrate association rather than causation, and randomized controlled trials would be needed to confirm whether these drugs can truly extend survival. Nevertheless, the prospect that cheap, well-tolerated anti-nausea medications already in the clinic could improve outcomes in one of the world’s most lethal cancers makes this a finding that oncologists and researchers will be watching closely.

Subject of Research: Association of 5-HT3 receptor antagonist use with survival outcomes in advanced hepatocellular carcinoma

Article Title: Association of 5-hydroxytryptamine 3 receptor antagonists with prognosis in patients with advanced hepatocellular carcinoma: A propensity score-matched study

Article References: Zhang, X., Wang, X., Li, N., Han, Q., & Liu, Z. (2026). Association of 5-hydroxytryptamine 3 receptor antagonists with prognosis in patients with advanced hepatocellular carcinoma: A propensity score-matched study. PLOS One, 21(10), e0359798. https://doi.org/10.1371/journal.pone.0359798

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0359798

Keywords: hepatocellular carcinoma, 5-HT3 receptor antagonists, serotonin, ondansetron, tropisetron, overall survival, propensity score matching, liver cancer, hepatitis B, supportive care, Cox regression, drug repurposing

The research, published in the Journal of Emergency and Disaster Medicine, examined 96 adult encounters for acute peripheral vertigo at Rasool-e-Akram Hospital in Tehran between January and June 2024. Peripheral vertigo, in which the sensation of spinning originates in the inner ear rather than the brain, is most often caused by benign paroxysmal positional vertigo, vestibular neuritis, or Ménière’s disease. Yet because these same symptoms can occasionally signal a stroke, emergency clinicians face a diagnostic tightrope: they must rule out dangerous central causes while relieving distressing symptoms and keeping patients moving through a crowded department.

The research team, led by emergency medicine physicians and researchers affiliated with Iran University of Medical Sciences, conducted a cross-sectional review of patient charts, excluding anyone with a documented central cause of vertigo, incomplete management records, or a history of chronic vertigo. The cohort, with a mean age of 60.3 years and a striking 68.8 percent female majority, was analyzed for five vertigo-specific drugs commonly used in emergency settings: ondansetron, betahistine, promethazine, metoclopramide, and benzodiazepines such as diazepam. The primary outcome was length of stay, measured in minutes from documented arrival to physical departure from the department.

The headline result was stark. Patients who received three or more distinct vertigo medications stayed a median of 652 minutes, compared with 467.5 minutes for those given two or fewer drugs, a difference that held up under non-parametric statistical testing. In a multivariable linear regression adjusted for age, sex, consultation patterns, and self-discharge status, complex regimens were independently associated with an additional 180.9 minutes of department time, with a 95 percent confidence interval of 76.0 to 285.7 minutes and a p-value of 0.0009. The mean stay in the simple-regimen group was 528 minutes, while the complex-regimen group averaged 752.3 minutes, a gap of nearly four hours.

Drug-specific analyses sharpened the picture further. Benzodiazepines, the sedating class often deployed to dampen the anxiety and vestibular storm of acute vertigo, were strongly linked to longer stays, adding an estimated 356.2 minutes even after adjustment for regimen complexity and consultations. The authors suggest this may reflect the sedation burden such drugs impose, which typically mandates prolonged observation before patients can be safely discharged. Promethazine, by contrast, was independently associated with a shorter stay, reducing department time by an estimated 161.3 minutes, possibly because it achieves faster symptom control or because clinicians reserve it for more straightforward presentations. Ondansetron, betahistine, and metoclopramide showed no clear independent association, though the authors caution that small exposed groups and confounding by indication, in which sicker patients receive certain drugs, make these estimates imprecise.

Consultations emerged as the other major lever on throughput. Neurology was the most frequently requested specialty, consulted in 28.1 percent of encounters, followed by cardiology at 15.6 percent. More than half of visits required no consultation at all, but 40.6 percent involved one and 7.3 percent involved two. In the adjusted model, neurology consultation added an estimated 163.9 minutes, while internal medicine and ear, nose, and throat consultations were associated with even larger increases of 501.3 and 476.0 minutes respectively, all statistically significant. The authors interpret these large effects not as evidence that the consultations themselves are wasteful, but as a signal that their involvement flags clinically challenging presentations, such as cardiovascular comorbidity or overlapping otologic disease, that demand additional diagnostic workup.

The prescribing patterns documented in the study reveal a clear hierarchy of practice. Ondansetron, a serotonin-receptor antagonist used to control vertigo-related nausea, was the first drug ordered for nearly half the cohort and was administered at some point to more than 70 percent of patients, consistent with international guideline support for this class. When a second-line agent was needed, betahistine topped the list, reflecting its long-standing track record in peripheral vestibular disease. Diazepam appeared in a smaller number of regimens, hinting at clinicians’ awareness of the anxiety that frequently accompanies acute vertigo, a dimension emphasized in the psychosocial literature on vestibular disorders.

The authors are careful to frame their findings as hypothesis-generating rather than prescriptive. Because the study lacked standardized measures of vertigo severity or clinical acuity at arrival, it is entirely possible that patients who appeared more unwell both received more medications and required longer observation, meaning residual confounding by illness severity may partly explain the association between regimen complexity and longer stays. The single-center design, the absence of data on time to symptom relief, functional outcomes such as safe ambulation at discharge, and unplanned return visits, and the inability to analyze non-pharmacologic interventions like canalith repositioning maneuvers all constrain the conclusions. Rare consultation types produced wide confidence intervals that larger samples would need to tighten.

Even so, the operational message resonates with a broader body of evidence linking polypharmacy and regimen complexity to slower hospital throughput in other acute conditions, from bronchiectasis to sedation-heavy critical care. The findings align with expert recommendations favoring stepwise pharmacotherapy, in which drugs are added sequentially as needed, rather than simultaneous multi-drug administration from the outset. They also echo prior reports that specialty input, while essential when central causes are suspected, can inadvertently lengthen emergency department stays when requested routinely rather than selectively for peripheral vertigo.

The study’s authors propose that emphasizing focused bedside assessment, tools such as the head-impulse, nystagmus, test-of-skew examination, stepwise rather than simultaneous drug therapy, and judicious specialty consultation could improve both the quality and the pace of vertigo care. Prospective, multi-center interventional studies will be needed to determine whether pathways built on these principles can safely shorten emergency department stays without compromising diagnostic safety, particularly given the stakes of missing a stroke masquerading as benign dizziness. For now, the study offers emergency departments a concrete, testable target: fewer drugs, chosen deliberately, may be the fastest route to getting dizzy patients back on their feet and out the door.

Subject of Research: The association between pharmacological treatment complexity, specialty consultations, and emergency department length of stay in adults with acute peripheral vertigo.

Article Title: Therapeutic approaches and their association with hospitalization duration in patients with peripheral vertigo presenting to the emergency department

Article References: Therapeutic approaches and their association with hospitalization duration in patients with peripheral vertigo presenting to the emergency department. (n.d.). https://doi.org/10.1007/s44467-025-00007-4

Image Credits: AI Generated

DOI: 10.1007/s44467-025-00007-4

Keywords: peripheral vertigo, emergency department, length of stay, polypharmacy, benzodiazepines, promethazine, betahistine, ondansetron, neurology consultation, vestibular disorders, regimen complexity, emergency medicine

Acute gastroenteritis remains one of the most common reasons young children end up in emergency departments worldwide. The illness, usually viral, produces vomiting and diarrhea that can rapidly dehydrate a small body. The cornerstone of treatment is oral rehydration therapy, a carefully balanced solution of salts and sugars. The problem is that persistent vomiting often defeats oral rehydration before it can work, forcing clinicians toward intravenous lines, hospital admission, and prolonged distress. Ondansetron, a selective serotonin 5-HT3 receptor antagonist originally developed for chemotherapy-induced nausea, blocks the signaling pathway that triggers the vomiting reflex at the level of the gut and the brain’s vomiting center. Its adoption in pediatric emergency care has grown steadily, but the evidence base has needed updating.

The previous comprehensive meta-analysis on the question was published in 2020, and the research team identified three specific gaps it left open. It could not incorporate a subsequently published trial of multidose ondansetron given after hospital discharge, it did not evaluate the volume of oral rehydration solution children actually tolerated, and it did not formally explore sources of statistical heterogeneity through meta-regression. The new analysis, conducted and reported according to the PRISMA 2020 statement and guided by the AMSTAR 2 appraisal tool, set out to close those gaps. The researchers searched PubMed, CENTRAL, ScienceDirect, Google Scholar, and ClinicalTrials.gov through June 2026, and assessed risk of bias with the Cochrane RoB 2 tool and certainty of evidence with GRADE.

The headline results are striking in their consistency across measures of vomiting morbidity. Compared with placebo, ondansetron reduced the risk of ongoing vomiting by more than half, with a pooled risk ratio of 0.48. Children given the drug experienced on average 0.73 fewer vomiting episodes. Failure of oral rehydration therapy fell dramatically, with a risk ratio of 0.39, and the use of intravenous fluids dropped to 0.57 times the rate seen with placebo. Perhaps most tellingly for frontline practice, children who received ondansetron tolerated significantly more oral rehydration solution, a mean difference of nearly 48 milliliters more than placebo recipients. For a therapy whose entire purpose is to keep fluids going in by mouth rather than through a needle, that volume difference is clinically meaningful.

The picture darkens somewhat around the outcomes that matter most for health systems and families over longer horizons. The analysis found no significant difference between ondansetron and placebo in hospitalization rates, repeat healthcare visits, ongoing diarrhea, diarrheal episodes, or adverse events. Moreover, the hospitalization result proved fragile: it reached statistical significance only when a single large trial was omitted from the pooling, a sensitivity finding that undermines confidence in any true effect on admissions. Reassuringly for safety, the drug did not appear to worsen diarrhea, a concern sometimes raised because intestinal motility is partly serotonin-mediated. But the authors emphasize that the safety comparison rests on very few estimable comparisons and very few adverse events, meaning the analysis simply cannot rule out uncommon or delayed harms.

The durability of the antiemetic effect emerged as another key nuance. On subgroup analysis by follow-up duration, the benefit for ongoing vomiting was statistically significant through the first twenty-four hours but attenuated at forty-eight hours and beyond. This time-limited effect provides what the authors call a plausible rationale, though not direct evidence from the synthesis itself, for the extended multidose post-discharge regimen evaluated in the largest included trial. That trial, which the 2020 meta-analysis could not include, tested whether continued ondansetron after children left the emergency department could sustain the protection that a single dose evidently cannot. The updated evidence base now incorporates those findings, strengthening the argument that duration of action is a central design question rather than an afterthought.

Beneath the pooled estimates lies a more uncomfortable statistical story. The trials showed substantial heterogeneity, meaning their results varied far more than chance alone would predict. Exploratory meta-regression, introduced during revision and notably not specified in the registered protocol, suggested that the baseline proportion of male participants, baseline vomiting-episode frequency, and baseline diarrheal-episode frequency acted as study-level moderators of the effect on ongoing vomiting, while mean age did not. More concerning, Egger’s test indicated statistically significant funnel-plot asymmetry for both outcomes where publication bias could be assessed: ongoing vomiting, with a p-value of 0.03070, and number of vomiting episodes, with a p-value of 0.04627. Begg and Mazumdar’s rank correlation test was significant for neither, leaving the signal equivocal but sufficient for the authors to rate certainty of evidence as low for ongoing vomiting and very low for the number of vomiting episodes.

What does funnel-plot asymmetry mean in practical terms? Small trials with favorable results tend to be published more readily than small trials with null findings, so when the smaller studies in a meta-analysis cluster at one extreme of the funnel plot, it suggests the literature may be missing negative results. If so, the pooled effect sizes that look so impressive in the forest plots may overstate what a typical child would experience. The authors state this directly: the pooled magnitude of benefit on vomiting may be overstated. This kind of self-critical transparency is increasingly expected of high-quality systematic reviews, and it distinguishes this update from simpler aggregations that report point estimates without interrogating the shape of the evidence behind them.

The research team, which also included authors from Hawassa University in Ethiopia and Ad Diriyah Hospital in Riyadh, concludes that ondansetron significantly reduces vomiting morbidity in children with acute gastroenteritis, with no statistically significant difference versus placebo in adverse events or diarrhea. Their prescription for future research is precise: further randomized trials directly comparing single-dose and multidose regimens, particularly in high-burden, low-resource settings where gastroenteritis still kills, along with individual patient-data analyses that can resolve the heterogeneity that study-level meta-regression only glimpses. The review was registered prospectively on PROSPERO under identifier CRD420261447906, received no extramural funding, and is published open access. For emergency clinicians deciding whether a dose of ondansetron is worth offering a vomiting, dehydrated child, the accumulated evidence now points, with acknowledged caveats, toward yes.

Subject of Research: Efficacy and safety of ondansetron versus placebo for acute gastroenteritis-associated vomiting in children

Article Title: Updated evidence on efficacy and safety of ondansetron compared with placebo for acute gastroenteritis-associated vomiting in children: a systematic review and meta-analysis of randomized controlled trials

Article References: Althunayyan, B. S., Alhoushani, R. A., Alhesayani, L. M., Alsallal, S. A., Aldakhil, L. N., Alharbi, S. J., Alharbi, M. M., Aldaher, Y. J., Aljumah, Y. S., Alharbi, W. A., Yusuf, S. A., & Alrashidi, S. H. (2026). Updated evidence on efficacy and safety of ondansetron compared with placebo for acute gastroenteritis-associated vomiting in children: a systematic review and meta-analysis of randomized controlled trials. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07694-6

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07694-6

Keywords: ondansetron, acute gastroenteritis, vomiting, children, oral rehydration therapy, meta-analysis, randomized controlled trials, pediatrics, emergency care, intravenous fluids, publication bias, GRADE