Proton pump inhibitors promote lubiprostone-induced nausea in cancer patients: A Retrospective Study

Chronic idiopathic constipation (CIC) is a frequently encountered problem in cancer patients, occurring in 23–65% of those receiving palliative care [1]. Constipation is caused by various factors; in particular, chemotherapy and opioid use in cancer patients often lead to difficulty in controlling bowel movements.

Lubiprostone is an effective treatment for chronic constipation and acts through a mechanism distinct from that of conventional osmotic or stimulant laxatives. It activates chloride channel 2 in the epithelial membrane of the small intestine, causing chloride ions Cl to flow into the intestinal lumen and sodium ions to be drawn into the intestinal tract to maintain electrical neutrality. This process promotes defecation by stimulating intestinal water secretion, softening stools, and enhancing transport function in the intestinal tract. Although lubiprostone is effective for managing chronic constipation, the incidence of nausea is higher than that associated with other constipation treatments. In Japan, the incidence of nausea with lubiprostone has been reported to be 14.5 % [2].   Although the precise mechanism underlying lubiprostone-induced nausea remains unclear, it has been suggested that delayed gastric emptying, secondary small intestinal dilation due to increased intestinal fluid secretion [3], and altered gastrointestinal sensation [4] may be involved. Lubiprostone-induced changes in gastrointestinal motility—specifically, increased basal pyloric sphincter tone—have been reported to delay gastric emptying and cause nausea in the form of pyloric spasm [4]. In addition, inhibition of defecation [5] has also been reported to induce nausea, suggesting that nausea tends to occur in patients with defecation disorders. Furthermore, based on previous reports, the occurrence of nausea induced by lubiprostone is dose-dependent [6].

 The efficacy of lubiprostone in patients with chronic constipation has been demonstrated by improvements in the weekly frequency of spontaneous bowel movements [2]. Regarding the safety of lubiprostone, the occurrence of nausea following diarrhea is common. The incidence of treatment discontinuation due to nausea after starting lubiprostone has been reported to be 8.7%, 2.1%, and 1.3% in patients with CIC, opioid-induced constipation, and constipation-predominant irritable bowel syndrome, respectively [5].

 Nausea is a factor that can make the continuation of treatment difficult in some cases. However, limited data are available regarding the efficacy and safety of lubiprostone in cancer patients. A study by Sada et al. demonstrated that the effectiveness of lubiprostone in cancer patients was comparable to that in non-cancer patients.[7] However, the incidence of diarrhea and nausea was higher among cancer patients, and the treatment discontinuation rate due to adverse events was significantly elevated [7]

 Previous studies have identified certain risk factors for lubiprostone-induced nausea, such as female sex [5, 8, 9] and younger age (<65 years) [5].However, risk factors for nausea in cancer patients remain unclear. Therefore, this study aimed to investigate the incidence of lubiprostone-induced nausea in cancer patients and explore potential risk factors.

 

Study participants

This study included patients from Shizuoka Cancer Center who began inpatient treatment with lubiprostone between November 2017 and August 2022. Patients with severe constipation, subileus, or organic constipation were excluded. In addition, patients who were discharged during the observation period (33 patients) or whose treatment was discontinued (26 patients) were excluded. A total of 79 patients were analyzed.

 Investigation items

The observation period was set to five days from the initiation of lubiprostone treatment. This period was selected based on the frequent occurrence of nausea and vomiting, as well as treatment interruption, during the first five days of therapy [5]. The primary endpoint was defined as the incidence of nausea. Nausea was assessed using the Common Terminology Criteria for Adverse Events version 5.0, with Grade 1 or higher nausea as the evaluation threshold. Background factors, including age, sex, and cancer type, were examined. Treatment-related factors—such as dosage, concomitant medications (opioids, antiemetics, PPIs or histamine H₂-receptor antagonists, magnesium oxide, naldemedine, stimulant laxatives, anti-cancer drugs with emetogenic risk, and radiation therapy)—were also analyzed. The emetogenic risk of chemotherapy and the risk of radiation-induced nausea were classified according to cancer treatment guidelines [10-12].

 Statistical analysis

Univariate logistic regression analysis was performed on background factors (age, sex) and treatment-related factors (dosage, concomitant medications, anti-cancer drugs, and radiation therapy). Multivariate logistic regression analysis was performed by selecting variables such as PPIs, naldemedine, and anti-cancer drugs, based on clinical relevance and statistical criteria (p < 0.1). Statistical analyses were performed using Microsoft Excel  software, and the significance level was set at 5%.

 Ethical considerations

This study was conducted in accordance with the Ethical Guidelines for Life Science and Medical Research Involving Human Subjects and was approved by the Ethics Committee of Shizuoka Cancer Center (approval number: J2022-142-2022-1-3).

In this study, the incidence of nausea in patients receiving lubiprostone along with PPIs was as high as 79%, compared to 24% in those not receiving PPIs. This trend was also confirmed by logistic regression analysis. The high incidence of nausea associated with concomitant PPI use should be acknowledged in clinical practice. Although this finding suggests a clinically significant emetogenic effect of lubiprostone in patients receiving PPIs, it has not been widely recognized.

 While previous reports have suggested that female sex [5, 8, 9], and younger age (under 65 years) [5] are risk factors for lubiprostone-induced nausea, this study is the first to identify an association between PPI use and nausea. We hypothesize that the following mechanisms may underlie the PPI-related effect: structural changes in lubiprostone, a prostaglandin E1 analog, and its agonistic activity at prostaglandin receptors (EP1, EP2, EP3, and FP). Although the prostaglandin activity of lubiprostone has been reported to be limited in smooth muscle tissues expressing these receptors [13], Walter W. Chan et al. reported that lubiprostone increased contraction of the mouse pyloric sphincter in a dose-dependent manner. Furthermore, they noted that EP1 receptors may be present in pyloric tissues and that lubiprostone may induce pyloric sphincter contraction via the EP1-mediated pathway.

 It has also been reported that lubiprostone exists as monocyclic (prostaglandin-like structure) and bicyclic (prostaglandin-dissimilar structure) ring–chain tautomers [14]. Prostaglandinergic activity is thought to be exerted by the monocyclic form; however, the extent to which the equilibrium shifts toward the monocyclic form with changes in intragastric pH remains unclear. Nevertheless, because similar ring–chain tautomeric compounds have shown pH-dependent equilibrium shifts [15], it is possible that prostaglandinergic activity is enhanced by PPI-induced alterations in intragastric pH. Further basic research is needed to verify these hypotheses by examining structural and pharmacological correlations.

 The involvement of sex hormones may partially explain why female sex and younger age have been identified as risk factors for lubiprostone-induced nausea in previous studies. Premenopausal women are affected by hormonal changes related to menstruation. Prostaglandins, which increase in the early phase of menstruation, may irritate smooth muscle and cause gastrointestinal disturbances [16], potentially contributing to nausea. The monocyclic form of lubiprostone may amplify prostaglandinergic activity in gastrointestinal tissues and thereby induce nausea. Although there was a tendency for higher nausea incidence in younger and female patients, no significant difference was observed in this study. The reason for this discrepancy is unknown but may be attributed to differences in patient backgrounds, as the previous study was conducted in non-cancer patients with chronic constipation.

 Histamine H₂-receptor antagonists (H₂RAs), which are gastric acid secretion inhibitors like PPIs, did not significantly increase the incidence of nausea. This may be due to differences in acid-suppressing potency between PPIs and H₂RAs. A previous study reported that PPIs significantly increased intragastric pH compared to H₂RAs, and the duration of intragastric pH ≥ 3 was significantly longer with PPIs than with H₂RAs [17]. The elevation in intragastric pH caused by PPIs may promote the conversion of lubiprostone to its monocyclic form, which may contribute to nausea. Furthermore, in this study, no chemotherapy regimens included H₂RAs as part of the premedication.

 This study has several limitations. It employed a retrospective design and relied on the accuracy and completeness of medical records. It was also conducted at a single institution with a relatively small patient sample. In addition, although the emetogenic risk of anticancer agents was classified, individual risk factors for chemotherapy-induced nausea and vomiting were not assessed. It should also be noted that PPI users often have conditions such as gastric ulcers, duodenal ulcers, or reflux esophagitis, or are at high risk for these diseases. As the incidence of nausea in patients with peptic ulcer disease has been reported to be 13.6% [18], nausea in this population may reflect underlying disease in addition to the effects of lubiprostone .

Despite some limitations, our findings suggest that PPI use may be a risk factor for  lubiprostone-induced nausea—an observation that represents a novel contribution to the field.

 Lubiprostone has been reported to cause pyloric constriction and delayed gastric emptying. It may induce nausea by increasing gastric volume and promoting gastric distention. To prevent treatment discontinuation due to lubiprostone-induced nausea, several management strategies may be considered, including the concomitant use of prokinetic agents such as domperidone or metoclopramide, dose reduction of lubiprostone, or switching to alternative constipation treatments such as linaclotide (an epithelial modifier) or elobixibat (a bile acid transporter inhibitor). Changing from a PPI to another therapy may also be appropriate. For patients who can discontinue PPI therapy, substituting a gastric mucosal protective agent such as rebamipide may be a clinically suitable alternative. Future studies involving larger populations and rigorous methodological design are needed to further validate these findings.

 Data Availability

The dataset supporting the conclusions of this article is included within the article.

 

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