Abstract
Purpose
This study aimed to evaluate the efficacy and potential pharmacological interaction of naldemedine and magnesium oxide (MgO) in the management of opioid-induced constipation (OIC) in cancer patients, with a particular focus on the impact of different MgO doses on treatment outcomes.
Methods
A total of 171 patients who received opioid therapy were included in this study. The outcome variable was defecation. Daily defecation status during the observation period was extracted from electronic medical records. To assess the effects and potential interaction between naldemedine and MgO on defecation, a generalized estimating equations (GEE) model with a logit link function was used to account for within-patient clustering. Predicted probabilities of defecation were calculated based on the fitted GEE model.
Results
The probability of defecation increased with higher doses of MgO. Among patients receiving both MgO and naldemedine, the likelihood of defecation was significantly higher at MgO doses ≤ 1500 mg compared to those receiving MgO alone. However, at doses > 1500 mg, naldemedine did not add further benefit. Naldemedine was independently associated with improved bowel movements, regardless of MgO use. The association between MgO and defecation also strengthened with increasing doses. No significant interaction between naldemedine and MgO was observed at any dose.
Conclusion
The concomitant use of MgO and naldemedine was associated with improved defecation, although no statistically significant interaction was detected. However, the added benefit of naldemedine may be limited at higher MgO doses. Naldemedine may be particularly effective in patients with constipation during opioid therapy that is insufficiently responsive to conventional laxatives, especially when an increase in MgO is difficult due to risks such as hypermagnesemia.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00520-026-10487-3.
Keywords: Constipation, Laxatives, Opioids, PAMORAs, Pharmacological interaction, Antacid
Introduction
Opioid-induced constipation (OIC) represents a critical challenge in cancer pain management, affecting 55%–81% of patients receiving opioid therapy and significantly impairing their quality of life while potentially compromising pain control itself [1–3]. This persistent adverse effect creates a clinical dilemma where effective analgesia must be balanced against gastrointestinal dysfunction, often forcing clinicians to choose between adequate pain relief and acceptable bowel function. Although combination therapy using laxatives with different mechanisms (e.g., osmotic laxatives and peripherally acting μ-opioid receptor antagonists [PAMORAs]) has been reported to improve bowel function in OIC, the extent to which the benefit of adding PAMORAs depends on the dose of concomitant osmotic laxatives in routine practice remains unclear.
Several studies have already reported that combining PAMORAs with conventional laxatives can be more effective than monotherapy. Accordingly, the specific novelty of the present study is not the concept of combination therapy itself but the evaluation of a dose-dependent association across clinically used MgO dose strata and the assessment of whether the association of naldemedine differs by MgO dose and by concomitant antacid use in a real-world inpatient setting [4–6].
Magnesium oxide (MgO), an osmotic laxative, serves as the first-line treatment for OIC in Japan due to its efficacy, safety profile, and cost-effectiveness, with doses of 1000 mg or more demonstrating clinical benefit [7–10]. However, clinical practice reveals substantial variability in MgO dosing due to patient-specific factors, including age, renal function, and concomitant medications, with some patients requiring doses exceeding 2000 mg/day while others develop hypermagnesemia even at standard doses [11–13]. Thus, the optimal approach to managing refractory OIC when MgO monotherapy fails or when dose escalation poses risks remains unclear.
Naldemedine, a PAMORA, offers a mechanistically distinct approach by directly antagonizing peripheral μ-opioid receptors in the gastrointestinal tract without compromising central analgesia [14–16]. While clinical trials have demonstrated naldemedine’s efficacy in both cancer and noncancer patients with OIC, the specific interaction between naldemedine and varying doses of MgO has not been systematically evaluated [4, 17, 18]. Furthermore, the common clinical scenario of concurrent antacid use—which may alter MgO’s efficacy by affecting gastric pH—adds another layer of complexity to optimizing OIC management [13]. Therefore, understanding how naldemedine’s efficacy varies across different MgO doses and whether antacid use modifies these relationships represents a critical knowledge gap with immediate clinical implications.
Here, we investigated the dose-dependent interaction between naldemedine and MgO in managing OIC among hospitalized cancer patients receiving opioid therapy. Using real-world clinical data, we examined whether the combination of these mechanistically distinct agents provides additive benefits and how this effect varies across different MgO dose ranges. Additionally, we evaluated the impact of concurrent antacid use on the efficacy of both naldemedine and MgO to provide comprehensive guidance for clinical decision-making in constipation during opioid therapy that is insufficiently responsive to conventional laxative management.
Methods
Study design
This study was conducted in a single-center, retrospective cohort design at the 614-bed Gifu University Hospital. The study period was from April 1, 2017, to September 30, 2022. Data were obtained from electronic patient medical records held in the central database of our hospital and retrospectively analyzed. This study was carried out by the Ethics Committee of Gifu University Graduate School of Medicine and Gifu Pharmaceutical University and was approved by the Gifu University Graduate School of Medicine Review Committee (Institutional Review Approval Number 2023-103) and Gifu Pharmaceutical University (Institutional Review Approval Number 5–17). All procedures involving human participants were consistent with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Consent to participate
The requirement for written informed consent was waived because this study exclusively used anonymized, retrospective data. All patients were provided with an opt-out opportunity in accordance with institutional and national guidelines.
Setting and participants
Patients who were admitted to the hospital and prescribed opioid analgesics were eligible. Patients admitted for surgery were excluded because perioperative bowel management differs from routine care and was outside the scope of this study. Patients who were already prescribed naldemedine at the time of admission were also excluded from the primary analysis to reduce prevalent-user bias.
For each eligible admission, the baseline was defined as the day opioid analgesics were started or, for patients already using opioids before admission, as the day of admission. The observation period lasted from baseline to either discharge or discontinuation of opioid analgesics. In cases where patients were hospitalized two or more times, each hospitalization was considered separately, and the same criteria were applied to define the baseline and observation period.
Variables and data sources
The outcome variable in this study was defecation, as extracted daily from electronic medical record data during the observation period. Defecation status was converted into a binary variable, indicating whether there was at least one defecation during the observation period. Thus, the outcome variable was both binary and longitudinal. Exposure variables were the use of MgO and naldemedine. MgO was categorized according to dosage as follows: none, ≤ 990 mg, > 990–1500 mg, and > 1500 mg/day. Potential confounders were age, gender, use of other laxatives, opioid dosage (oral morphine equivalent), use of transdermal fentanyl, given reports that it causes less constipation [19, 20], and use of antacids. To investigate the effect modification of laxatives, interactions were examined between MgO and naldemedine, MgO and antacids, and naldemedine and antacids.
Outcome definition
The outcome variable in this study was daily defecation status, extracted from electronic medical records during the observation period. Because this was a retrospective study using routinely collected electronic medical records, a formal symptom-based diagnostic definition of opioid-induced constipation (e.g., Rome criteria) was not consistently available. Therefore, we operationalized constipation burden during opioid therapy using daily defecation status as a pragmatic outcome.
Statistical analysis
No a priori sample size calculation was performed because this was a retrospective observational study and we included all eligible patients during the study period.
To evaluate the associations of naldemedine use and MgO dose category with defecation, including their interaction, we fitted generalized estimating equations (GEE) with a logit link to account for within-patient clustering, specifying an exchangeable working correlation structure. The multivariable model included MgO dose category (none, ≤ 990 mg, > 990–1500 mg, and > 1500 mg/day), use of naldemedine, time (days from baseline), age, gender, use of other laxatives, opioid dosage (oral morphine equivalent), use of transdermal fentanyl, and the interaction term between MgO and naldemedine. Furthermore, to assess the impact of antacid use on the efficacy of MgO and naldemedine, antacid use, the interaction term between antacids and MgO, and the interaction term between antacids and naldemedine were added to the model. As a sensitivity analysis, we fit the same GEE model after including patients who were already using naldemedine at baseline to evaluate the impact of excluding these patients on the estimated associations.
Predicted probabilities of defecation were obtained from the fitted GEE model and displayed in three sets of bar charts: (i) for each MgO dose category, stratified by naldemedine use (yes or no); (ii) for each MgO dose category, stratified by antacid use (yes or no); and (iii) within each antacid stratum (with or without antacid), stratified by naldemedine use (yes or no). In every chart, vertical error bars represent 95% confidence intervals. All analyses were performed using R version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria). Multiple imputation was performed to replace missing outcome values using the mice function in the mice package for R [21].
Results
Patient demographics
Of the 361 eligible patients, 9 were excluded because they were admitted for scheduled surgery, and 181 were excluded due to naldemedine use at the time of baseline assessment. Finally, 171 patients were included in this analysis (Fig. 1). Patient demographics are shown in Table 1. The most common cancer was head and neck cancer (19.9%), followed by stomach and esophagus cancer (14.6%), pancreatic cancer (9.4%), and lung cancer (10.5%). Among patients, 95 patients (55.6%) were hospitalized once, and 76 patients (44.4%) were hospitalized twice or more.
Fig. 1.
Patient flow diagram. Three hundred sixty-one inpatients who received opioid analgesics were initially identified. Of these, 9 were excluded due to scheduled surgery and 181 were excluded for receiving naldemedine at the start of the observation period. The remaining 171 patients were included in the final analysis
Table 1.
Patient characteristics. Baseline characteristics of patients stratified by naldemedine use during the observation period. Continuous variables are presented as medians (interquartile range) and categorical variables as numbers (percentage)
| Variable | Patients (n = 171) |
|---|---|
| Age, median (IQR) | 66 (54–73) |
| Sex | |
| Male | 98 (57.3%) |
| Female | 73 (42.7%) |
| Primary disease | |
| Head and neck cancer | 34 (19.9%) |
| Gastric cancer, esophageal cancer | 25 (14.6%) |
| Lung cancer | 18 (10.5%) |
| Pancreatic cancer | 16 (9.4%) |
| Soft tissue tumor, osteosarcoma | 15 (8.8%) |
| Gynecological cancer | 13 (7.6%) |
| Colorectal cancer | 13 (7.6%) |
| Liver/biliary tract cancer | 7 (4.1%) |
| Hematological cancer | 6 (3.5%) |
| Breast cancer | 5 (2.9%) |
| Prostate cancer | 3 (1.8%) |
| Urinary cancer | 3 (1.8%) |
| Noncancer | 13 (7.6%) |
| Number of hospitalizations | |
| 1 time | 95 (55.6%) |
| 2 times | 55 (32.2%) |
| 3 times | 14 (8.2%) |
| 4 or more times | 7 (4.0%) |
The total number of days that any opioid analgesic was administered during hospitalization was 3169 patient days. The number of days that MgO was administered by dose was 1062 days for no administration, 1325 days for ≤ 990 mg/day, 602 days for > 990–1500 mg/day, and 180 days for > 1500 mg/day. Naldemedine was used for 1208 days and not used for 1961 days. Antacids were used for 570 days and not used for 2599 days. Median opioid dose (oral morphine equivalent, mg/day) was 21 mg (interquartile range [IQR]: 15–45 mg) (Supplemental Table 1).
Associations of MgO dose category and naldemedine use with defecation and their interaction
Figure 2 shows the predicted probability of defecation occurring once a day based on the administered dose of MgO and its concomitant use with naldemedine. In the naldemedine nonadministration group, the probability of defecation increased with increasing dose of MgO, at 36.2% (95% confidence interval [95% CI]: 30.3%–42.5%) in the MgO nonadministration group, 41.9% (95% CI: 35.8%–48.2%) for ≤ 990 mg/day, 48.6% (95% CI: 39.9%–57.3%) for > 990–1500 mg/day, and 55.6% (95% CI: 44.2%–66.5%) for > 1500 mg/day. On the other hand, in the group of concomitant use with naldemedine, the probability of defecation increased at MgO doses ≤ 1500 mg/day compared with the naldemedine nonadministration group, at 46.4% (95% CI: 40.6%–52.4%) in the MgO nonadministration group, 58.3% (95% CI: 50.6%–65.5%) for ≤ 990 mg/day, and 62.6% (95% CI: 51.6%–72.5%) for > 990–1500 mg/day.
Fig. 2.
Predicted probability of daily defecation by magnesium oxide dose with or without naldemedine. Predicted probability of experiencing daily defecation according to categorized magnesium oxide (MgO) dose, stratified by concomitant use of naldemedine. MgO dose was categorized as follows: none, ≤ 990 mg, > 990–1500 mg, and > 1500 mg/day. Error bars represent 95% confidence intervals
In contrast, when MgO was administered at a dose of > 1500 mg/day, the defecation rate was 55.9% (95% CI: 38.6%–71.9%), and even when naldemedine was added, there was no increase in the defecation rate compared to when MgO was used alone.
Table 2 shows the relationship between the dose of MgO, the use of naldemedine, and their interaction with defecation. Use of naldemedine was associated with defecation regardless of the use of MgO (odds ratio [OR]: 1.527, 95% CI: 1.083–2.153, p = 0.016). In addition, the association with defecation became significantly stronger as MgO dose increased (≤ 990 mg/day: OR: 1.269, 95% CI: 0.880–1.829, p = 0.202; > 990–1500 mg/day: OR: 1.665, 95% CI: 1.073–2.583, p = 0.023; > 1500 mg/day: OR: 2.209, 95% CI: 1.256–3.888, p = 0.006). In contrast, there was no interaction between naldemedine and MgO at any dose of MgO. In a sensitivity analysis including patients with baseline naldemedine use, the estimated associations were similar to those of the primary analysis (Supplementary Tables 2–5 and Figs. 1, 2, 3, and 4).
Table 2.
Association of naldemedine and magnesium oxide dose with the occurrence of defecation. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using generalized estimating equations (GEE) with a logit link to account for within-patient clustering. The model included magnesium oxide (MgO) dose categories (none, ≤ 990 mg, > 990–1500 mg, and > 1500 mg/day), naldemedine use, time (days from baseline), age, gender, use of other laxatives, opioid dose (oral morphine equivalent), use of transdermal fentanyl, and an interaction term between MgO and naldemedine. p values for interaction were also derived from this model
| Variable | Odds ratio | 95% CI | p value | p value for interaction |
|---|---|---|---|---|
| Naldemedine | 1.527 | 1.083–2.153 | 0.016 | - |
| Magnesium oxide | ||||
| 0 < MgO ≤ 990 | 1.269 | 0.880–1.829 | 0.202 | 0.328 |
| 990 < MgO ≤ 1500 | 1.665 | 1.073–2.583 | 0.023 | 0.644 |
| 1500 < MgO | 2.209 | 1.256–3.888 | 0.006 | 0.298 |
Fig. 3.
Predicted probability of daily defecation by magnesium oxide dose with or without antacids. Predicted probability of daily defecation stratified by both MgO dose and the presence or absence of antacid use. MgO dose was categorized as follows: none, ≤ 990 mg, > 990–1500 mg, and > 1500 mg/day. Bar graphs indicate probability estimates, with error bars denoting 95% confidence intervals
Fig. 4.
Predicted probability of defecation by antacid use with and without naldemedine. Predicted probability of defecation stratified by naldemedine and antacid use. Four groups are shown: (1) no antacid/no naldemedine, (2) no antacid/with naldemedine, (3) with antacid/no naldemedine, and (4) with antacid/with naldemedine. Probabilities were derived from the fitted model. Error bars represent 95% confidence intervals
Associations of MgO dose category and naldemedine use with defecation, stratified by antacid use
The predicted probability of defecation under the concomitant use of MgO and antacid is shown in Fig. 3. In the absence of antacids, the probability of defecation was 38.7% (95% CI: 33.7%–43.9%) in the MgO nonadministration group, 48.9% (95% CI: 43.4%–54.5%) for ≤ 990 mg/day, 53.2% (95% CI: 45.7%–60.5%) for > 990–1500 mg/day, and 54.0% (95% CI: 41.9%–65.7%) for > 1500 mg/day. With concomitant use of antacids, the probability of defecation was 47.0% (95% CI: 37.9%–56.2%) in the MgO nonadministration group, 43.4% (95% CI: 35.6%–51.5%) for ≤ 990 mg/day, 59.7% (95% CI: 49.5%–69.2%) for > 990–1500 mg/day, and 56.8% (95% CI: 40.4%–71.8%) for > 1500 mg/day.
The probability of defecation decreased with concomitant use of antacids compared to nonconcomitant use at MgO doses ≤ 990 mg/day. On the other hand, no clear difference was observed at MgO doses > 990 mg/day. With concomitant use of naldemedine and antacid, the probability of defecation was 54.9% (95% CI: 49.0%–60.6%) without antacid and 58.9% (95% CI: 49.4%–67.8%) with antacid, showing that the increase in the probability of defecation due to naldemedine was not affected by antacid (Fig. 4).
Table 3 shows the interaction between antacids use and administration of naldemedine and MgO on defecation probability. The interaction between naldemedine and antacid use was not statistically significant (OR: 1.067, 95% CI: 0.681–1.672, p = 0.776). Regarding the interaction between MgO and antacid use, a significant negative interaction was observed only in the group receiving a low dose of MgO (≤ 990 mg/day: OR: 0.570, 95% CI: 0.326–0.995, p = 0.048). In contrast, no significant interaction was found in the medium- or high-dose MgO group (> 990–1500 mg/day: OR: 0.930, 95% CI: 0.483–1.793, p = 0.829; > 1500 mg/day: OR: 0.796, 95% CI: 0.325–1.948, p = 0.617).
Table 3.
Interaction of antacid use with naldemedine and magnesium oxide on defecation probability. Results of the GEE model stratified by magnesium oxide dose. The association of naldemedine with defecation is reported separately for each dose category. Odds ratios (ORs) and 95% confidence intervals (CIs) are shown
| Variable | Odds ratio | 95% CI | p value for interaction |
|---|---|---|---|
| Naldemedine: antacid | 1.067 | 0.681–1.627 | 0.776 |
| Magnesium oxide: antacid | |||
| 0 < MgO ≤ 990 | 0.570 | 0.326–0.995 | 0.048 |
| 990 < MgO ≤ 1500 | 0.930 | 0.483–1.793 | 0.829 |
| 1500 < MgO | 0.796 | 0.325–1.948 | 0.617 |
Discussion
In this study, we examined the associations of naldemedine and MgO with defecation in patients undergoing opioid therapy, together with potential interactions between the two medications. The results suggested that both naldemedine and MgO independently enhanced defecation in patients receiving opioids and that MgO showed a dose–response pattern. Notably, the improvement in defecation with the concurrent use of MgO and naldemedine was particularly significant at MgO doses of 1500 mg/day or less. These findings suggest that naldemedine combined with MgO may be a viable treatment option for patients with constipation during opioid therapy that is insufficiently responsive to conventional laxatives.
Both international and Japanese guidelines recommend osmotic and colonic stimulant laxatives as first-line treatment for OIC and suggest using naldemedine in insufficiently responsive cases [9, 22]. In Japan, MgO is widely used as a first-line agent for OIC because of its safety, convenience, and low cost [8]. Our previous study demonstrated that the prophylactic use of MgO reduced the incidence of constipation in cancer patients receiving opioid analgesics, with particularly notable effects at doses ≥ 1000 mg/day [10, 23]. In this study, MgO also demonstrated a positive effect on defecation, consistent with this earlier finding.
The mechanism of OIC involves the activation of µ-opioid receptors (MORs) in the enteric nervous system, leading to decreased gastrointestinal motility and fluid secretion [14, 24]. Osmotic laxatives such as MgO do not directly target this mechanism but instead exert their effects indirectly [1, 25]. In contrast, naldemedine works directly by antagonizing peripheral MORs [15, 16]. Due to its distinct mechanism, naldemedine demonstrated superior efficacy in improving bowel function in several clinical trials [18, 26], making it particularly useful in cases of constipation during opioid therapy that is insufficiently responsive to conventional laxatives.
Kessoku et al. analyzed the efficacy of naldemedine in combination with MgO in a post hoc subgroup analysis of phase II and III clinical trials [4]. They found that adding naldemedine to MgO significantly increased the number of spontaneous and complete bowel movements compared to placebo. However, the dosage of MgO was not examined. In our study, we observed an improvement in defecation rates with the concurrent use of MgO and naldemedine, although no significant interaction was detected. These findings are consistent with these previous reports. Furthermore, the benefit of concurrent use over MgO monotherapy was most notable at MgO doses ≤ 1500 mg/day, suggesting that the magnitude of the association may vary with the dose of MgO.
In our previous study, we also reported that the laxative effect of MgO was reduced when combined with antacid at doses ≤ 2000 mg/day [13]. The mechanism involves the neutralization of gastric acid: MgO + 2HCl → MgCl2 + H2O. In the duodenum, MgCl2 is further converted: MgCl2 + 2NaHCO3 → Mg(HCO3)2 + 2NaCl. Yamasaki et al. reported that magnesium bicarbonate increases intestinal osmotic pressure, promoting water secretion and stool softening, thus contributing to the laxative effect of MgO [27]. However, antacids such as proton pump inhibitors and H2-receptor antagonists can attenuate this effect, especially at MgO doses ≤ 2000 mg/day. In our study, concomitant use of MgO ≤ 990 mg/day and antacids was associated with reduced defecation. In contrast, naldemedine combined with antacids did not affect defecation, likely due to its mechanism of action. This observation supports the hypothesis that naldemedine’s effect is independent of gastric pH.
This study has several limitations. First, this was a retrospective observational study, making it difficult to establish a causal relationship; in addition, the single-institution setting may limit the generalizability of the findings. Second, due to the retrospective nature of the data collection, it was not possible to accurately document the timing and dosing of other laxatives, such as sennosides, which limits our ability to adjust for their potential confounding effects; thus, residual confounding cannot be excluded. Third, some patients were already using MgO prior to the observation period for indications other than OIC. However, to reduce prevalent-user bias, patients with a prior naldemedine prescription were excluded, and only newly initiated naldemedine users were included in the interaction analysis. Fourth, because the outcome was common, odds ratios may overstate the magnitude of the association compared with risk ratios. Finally, the distribution of cancer types was biased, with most patients having head and neck cancer, followed by gastric and esophageal cancer. Therefore, caution should be exercised when generalizing these findings to broader cancer populations.
In addition, our cohort consisted of hospitalized patients, who may have lower physical activity and different dietary intake compared with outpatients, which can influence bowel function. Moreover, the median opioid dose in this cohort was relatively low, and the findings may not generalize to patients receiving higher opioid doses or to outpatient settings.
In clinical practice, MgO dosing is frequently adjusted based on individual factors. A baseline dose of approximately 2000 mg/day is typically recommended for OIC; however, lower doses may be necessary for elderly patients or those with impaired renal function to avoid hypermagnesemia. Antacids are also often co-prescribed, and in such cases, dose reduction or discontinuation of MgO may be necessary. This study showed that both higher MgO dose categories and naldemedine use were associated with higher predicted probabilities of defecation; however, we did not detect a statistically significant MgO-by-naldemedine interaction, suggesting that the association of naldemedine with defecation did not materially differ across the evaluated MgO dose strata in this dataset. These results suggest that naldemedine combined with MgO may be a viable treatment option for patients with constipation during opioid therapy that is insufficiently responsive to conventional laxatives.
Conclusion
The addition of naldemedine may improve opioid-induced constipation (OIC) in patients with insufficiently responsive symptoms. Specifically, it may be effective in cases where increasing the magnesium oxide (MgO) dose is not feasible due to concerns such as hypermagnesemia.
Supplementary Information
Below is the link to the electronic supplementary material.
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Acknowledgements
The authors wish to express their sincere gratitude to all medical personnel who contributed to patient management and data collection in this study.
Author contribution
RH, MI, RK, and AS contributed to the study design. RH, DW, and AS analyzed and interpreted the raw data. RH and MI drafted the manuscript. DW, SG, HN, RK, and AS critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.
Funding
Open Access funding provided by Gifu University.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Declarations
Competing interests
The authors declare no competing interests.
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Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.