Efficacy of prophylactic laxatives against opioid-induced constipation: retrospective propensity score matching analysis

Efficacy of prophylactic laxatives against opioid-induced constipation: retrospective propensity score matching analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy of prophylactic laxatives against opioid-induced constipation: retrospective propensity score matching analysis Yuka Okuda, Toshiyuki Kuriyama, Yoshi Tsukiyama, Toshio Shimokawa, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4851518/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Jan, 2025 Read the published version in Supportive Care in Cancer → Version 1 posted 10 You are reading this latest preprint version Abstract Purpose: Opioid-induced constipation (OIC) is problematic for patients with cancer receiving opioid therapy. Some guidelines recommend initiating regular laxatives at the same time as opioid analgesics. However, the effectiveness of prophylactic laxatives on OIC has not been widely demonstrated. We therefore examined the incidence of OIC among patients with and without prophylactic laxatives within one week after initiating strong opioid analgesics, and the factors associated with the incidence of OIC. Methods: Eligible patients were adults with cancer for whom strong opioid analgesics were initiated after admission and who remained hospitalized for over a week. Propensity score matching analysis was used to compare outcomes after adjusting for patient background. Results: In total, 928 patients were enrolled, from which 536 were selected after propensity score matching analysis. The incidence of OIC in patients with prophylactic laxatives was not significantly different from that without prophylactic laxatives (48.1% vs 48.9%, odds ratio (OR) = 0.97, 95% confidence interval (CI): 0.69-1.36). In multivariable logistic analysis, age ≥65 years (OR = 1.53, 95% CI: 1.07-2.19) and Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥3 (OR = 1.69, 95% CI: 1.04-2.77) were associated with the incidence of OIC. Conclusion: Prophylactic laxatives do not affect the incidence of OIC in our study. Our results suggest that prophylactic laxatives are not necessarily required when initiating opioid therapy. In addition, we found that age ≥65 years and ECOG PS ≥3 were associated in our study with the incidence of OIC. opioid-induced constipation cancer pain prophylactic laxatives ECOG PS Figures Figure 1 Figure 2 Introduction Opioid analgesics are widely used for moderate to severe pain in patients with cancer [ 1 ]. However, constipation is a common side effect of opioid analgesics. Among opioid receptors, µ opioid receptors are related to opioid-induced constipation (OIC). They are mainly found in the stomach and proximal colon, on the membranes of intestinal muscle cells, myenteric and submucosal neurons [ 2 , 3 ]. The activation of these µ opioid receptors reportedly inhibits intestinal movement and intestinal mucosal secretion, promotes intestinal fluid absorption, and increases anal sphincter contraction [ 4 ]. Constipation reportedly occurs in 33–55% in patients with cancer within one week after they initiate strong opioid analgesics [ 5 ]. In addition, OIC could result in avoidance of opioid use, leading to inadequate pain relief, biopsychosocial burden, impaired quality of life (QOL), and subsequently a greater financial burden [ 3 , 6 – 10 ]. However, OIC remains under-recognized and undertreated [ 9 ]. A previous study has shown that healthcare professionals often do not sufficiently inform patients about constipation as a common side effect of opioid use [ 9 ]. In addition, patients often prefer to deal with constipation on their own and do not raise the subject of OIC because of embarrassment [ 10 ]. Therefore, we suggest that OIC requires attention. The use of traditional laxatives (osmotic laxatives and stimulant laxatives) is recommended as first-line therapy [ 11 , 12 ]. In addition, peripherally-acting µ opioid receptor antagonist (PAMORA) including naldemedine is recommended for patients with OIC refractory to traditional laxatives [ 11 , 12 ]. The European Association for Palliative Care [ 13 ] and the National Institute of Clinical Evidence [ 14 ] recommend prescribing prophylactic laxatives to prevent OIC. A clinical guideline of the Japanese Society of Palliative Medicine also recommends initiating regular laxatives at the same time as opioid analgesics; this is based on daily clinical experience but not clinical evidence [ 12 ]. The effectiveness of prophylactic laxatives on OIC has not been sufficiently demonstrated. To our knowledge, only two studies have examined the preventive effects on OIC [ 5 , 15 ]. First, the OIC-J Study prospectively examined the incidence of OIC with or without prophylactic laxatives as a secondary endpoint [ 15 ]. The cumulative incidence of OIC according to the Rome IV diagnostic criteria was 48% in patients who received prophylactic laxatives (constipation agents initiated at the same time of opioid therapy) and 65% of patients who received no prophylactic laxatives. However, the incidence of OIC in patients with prophylactic laxatives was not statistically compared with that of patients without prophylactic laxatives. Therefore, the OIC-J study did not clarify the effectiveness of prophylactic laxatives for OIC. Second, the J-RIGID study retrospectively examined the effectiveness of prophylactic laxatives using the different criteria for OIC from those used in the OIC-J study [ 5 , 15 ]. Prophylactic laxatives administered within 7 days after initiating opioid analgesics statistically significantly decreased the incidence of OIC [ 5 ], but there was no adjustment for confounding bias in patient background. We examined the incidence of OIC as a primary endpoint and made statistical comparisons for the first time. Although retrospective in nature, we used propensity score matching analysis to adjust for comparative bias in patient background as much as possible to enhance the level of evidence. We also investigated risk factors for OIC. Materials and Methods Study Design and Patients Our study was approved by the Wakayama Medical University Certified Review Board (CRB5180004) and was conducted in compliance with the Declaration of Helsinki and Ethical Guidelines for Medical and Health Research Involving Human Subjects. We conducted a retrospective, single-institution observational cohort study to assess the clinical effects of prophylactic laxatives on OIC. All clinical data were obtained from electronic medical records. Eligible patients were adult (≥ 20 years) cancer inpatients who initiated regular administration of strong opioid analgesics after admission to our hospital and who remained hospitalized for over a week between January 2012 and January 2023. We excluded patients with a history of colostomy and those missing description-based data on defecation. Owing to the anonymous nature of the data, informed consent was waived and a disclosure document was posted. Assessments We diagnosed OIC when there was a stool-free interval of ≥ 72-h within one week after initiating strong opioid analgesics, in accordance with a previous study [ 5 ]. We defined prophylactic laxatives as regularly administered laxatives initiated on the same day (day 0) as opioid therapy. Additional laxatives were initiated as needed between the next day (day 1) and seven days (day 7) after initiating opioid therapy. In patients without prophylactic laxatives, laxatives were initiated as needed between day 1 and day 7 after initiating opioid therapy, but the distinction lies in there being no initial administration on the same day like in the prophylactic laxatives. The primary endpoint of this study was the incidence of OIC in patients with and without prophylactic laxatives. In addition, we examined factors associated with the incidence of OIC. Explanatory variables were selected based on previous studies [ 16 – 19 ]. Patient clinical demographics included age (≥ 65 years), sex, body mass index (BMI) (≥ 21 kg/m2), type of cancer (gastrointestinal or not), Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 3, presence of cancerous peritonitis, previous gynecological or abdominal surgery, presence of diabetes, use of benzodiazepine, timing of anti-cancer treatment, use of weak opioid analgesics before initiating strong opioid analgesics, types of laxatives used, use of laxatives before initiating strong opioid analgesics and their types, and the administration route and morphine equivalent daily dose of opioid analgesics. We also examined the effect of the types of laxatives on the incidence of OIC. Laxatives were classified into four types: osmotic laxatives, stimulant laxatives, PAMORA, and others [ 20 ]. ‘Osmotic laxatives’ included magnesium oxide, lactulose and polyethylene glycol, ‘stimulant laxatives’ included sennoside and picosulfate, PAMORA was naldemedine, and then ‘others’ comprised linaclotide, lubiprostone, and elobixibat. In addition, ‘combination therapy’ was the use of more than two types of laxatives. Statistical Analysis Categorical variables, summarized as frequency and proportion, were compared using the Fisher's exact test. Continuous variables, summarized as median (range), were compared using the Wilcoxon test. We used propensity score matching analysis to adjust for comparative bias in patient background as much as possible to enhance the level of evidence. A propensity score was calculated using the multivariate logistic regression with following covariates: age, sex, BMI, type of cancer, ECOG PS, presence of cancerous peritonitis, previous gynecological or abdominal surgery, presence of diabetes, use of benzodiazepine, timing of cancer treatment, use of weak opioid analgesics, use of laxatives before initiating strong opioid analgesics, and the types of opioid analgesics and their administration route. We performed propensity score matching analysis between patients with and without prophylactic laxatives. We used the caliper width of 0.20 for one-to-one matching analysis and the nearest neighbor matching on the logit of the propensity score. The propensity score-matched data were analyzed for the incidence of OIC in patients with and without prophylactic laxatives using the Fisher’s exact test. Multivariable logistic analysis was performed to clarify factors associated with the incidence of OIC. To compare patient background, the chi-squared test was used for categorical variables and the Wilcoxon rank sum test for continuous variables. All analyses were carried out using JMP®ฎ version 14.1.0 (SAS Institute, Cary, NC, USA). All statistical tests were performed with a two-sided significance level of 0.05. Results Characteristics of all eligible patients Between January 2012 and January 2023, 1006 patients initiated regular administration of strong opioid analgesics for cancer pain after admission to our hospital and were hospitalized for over a week. We excluded 78 patients: 53 due to a history of colostomy, and 25 because they lacked description about defecation due to missing description-based data on defecation in electronic medical records. Accordingly, 928 patients met the eligibility criteria of our study, 370 (39.9%) of whom received prophylactic laxatives (Fig. 1 ). Characteristics of all eligible patients are shown in Table 1 . There were significant differences between patients with and without prophylactic laxatives in sex, BMI, type of cancer, ECOG PS, timing of anti-cancer treatment, types and administration route of opioid analgesics, and use of laxatives before initiating strong opioid analgesics. Table 1 Characteristics of all eligible patients All (n = 928) With prophylactic laxatives (n = 370) Without prophylactic laxatives (n = 558) P value Age (years) Median (range) ≥ 65 (%) < 65 (%) 67 (22–93) 530 (57.1) 398 (42.9) 68 (29–92) 211 (57.0) 159 (43.0) 67 (22–93) 319 (57.2) 239 (42.8) 0.636 0.967 Sex Male (%) Female (%) 600 (64.7) 328 (35.3) 257 (69.5) 113 (30.5) 343 (61.5) 215 (38.5) 0.014* BMI (kg/m2) Median (range) ≥ 21 (%) < 21 (%) 21 (11.7–37.1) 472 (50.9) 456 (49.1) 21.4 (13.1–37.1) 211 (57.0) 159 (43.0) 20.7 (11.7–36.6) 261 (46.8) 297 (53.2) 0.002* 0.001* Type of cancer Gastrointestinal (%) Others (%) 87 (9.4) 841 (90.6) 25 (6.8) 345 (93.2) 62 (11.1) 496 (88.9) 0.023* ECOG PS ≤ 2 (%) ≥ 3 (%) 623 (67.1) 305 (32.9) 271 (73.2) 99 (26.8) 352 (63.1) 206 (36.9) 0.001* Timing of anti-cancer treatment Anticancer treatment (%) Best Supportive care (%) 619 (66.7) 309 (33.3) 271 (73.2) 99 (26.8) 348 (62.4) 210 (37.6) < .001* Presence of cancerous peritonitis Yes (%) No (%) 174 (18.8) 754 (81.2) 61 (16.5) 309 (83.5) 113 (20.3) 445 (79.7) 0.148 Previous gynecological or abdominal surgery Yes (%) No (%) 263 (28.3) 665 (71.7) 166 (44.9) 204 (55.1) 97 (17.3) 461 (82.6) 0.317 Presence of diabetes Yes (%) No (%) 163 (17.6) 765 (82.4) 68 (18.4) 302 (81.6) 95 (17.0) 463 (83.0) 0.597 Use of benzodiazepine Yes (%) No (%) 246 (26.5) 682 (73.5) 88 (23.8) 282 (76.2) 158 (28.3) 400 (71.7) 0.124 Types of opioid analgesics Morphine (%) Oxycodone (%) Fentanyl (%) Hydromorphone (%) Tapentadol (%) 56 (6.0) 629 (67.8) 212 (22.8) 74 (8.0) 25 (2.7) 20 (5.4) 278 (75.1) 39 (10.5) 44 (11.9) 16 (4.3) 36 (6.5) 351 (62.9) 173 (31.0) 30 (5.4) 9 (1.6) 0.510 < .001* < .001* < .001* 0.014* Administration route of opioid analgesics Oral (%) Not oral (%) 645 (69.5) 283 (30.5) 322 (87.0) 48 (13.0) 323 (57.9) 235 (42.1) < .001* Daily dose of opioid analgesics (morphine equivalent) (mg/day) Median (range) 30 (9.6–210) 30 (9.6–120) 30 (9.6–210) 0.051 Use of weak opioid analgesics Yes (%) No (%) 355 (38.3) 573 (61.7) 138 (37.3) 232 (62.7) 217 (38.9) 341 (61.1) 0.625 Use of laxatives before initiating strong opioid analgesics Yes (%) No (%) 335 (36.1) 593 (63.9) 90 (24.3) 280 (75.7) 245 (43.9) 313 (56.1) < .001* Types of prophylactic laxatives Osmotic laxatives (%) Stimulant Laxatives (%) PAMORA (%) Others (%) Combination therapy (%) 194 (20.9) 53 (5.7) 85 (9.2) 11 (1.2) 27 (2.9) 194 (52.4) 53 (14.3) 85 (23.0) 11 (3.0) 27 (7.3) NA NA BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group Performance Status; BSC, Best Supportive Care; PAMORA, peripherally-acting µ opioid receptor antagonist; NA, not applicable *P < 0.05 Characteristics of after propensity score matching analysis After propensity score matching analysis, 536 patients were selected. Characteristics of patients after propensity score matching analysis are shown in Table 2 . The patients' characteristics were similar between patients with and without prophylactic laxatives. Table 2 Characteristics of the patients after propensity score matching analysis With prophylactic laxatives (n = 268) Without prophylactic laxatives (n = 268) P value Age (years) Median (range) ≥ 65 (%) < 65 (%) 68 (29–92) 157 (58.6) 111 (41.4) 67 (22–93) 150 (56.0) 118 (44.0) 0.389 0.541 Sex Male (%) Female (%) 177 (66.0) 91 (34.0) 177 (66.0) 91 (34.0) 1.000 BMI (kg/m2) Median (range) ≥ 21 (%) < 21 (%) 21.2 (13.1–37.1) 140 (52.2) 128 (47.8) 21.1 (11.7–36.6) 137 (51.1) 131 (48.9) 0.569 0.795 Type of cancer Gastrointestinal (%) Others (%) 22 (8.2) 246 (91.8) 24 (9.0) 244 (91.0) 0.758 ECOG PS ≤ 2 (%) ≥ 3 (%) 192 (71.6) 76 (28.4) 184 (68.7) 84 (31.3) 0.450 Timing of anti-cancer treatment Anticancer treatment (%) Best Supportive care (%) 192 (71.6) 76 (28.4) 179 (66.8) 89 (33.2) 0.224 Presence of cancerous peritonitis Yes (%) No (%) 38 (14.2) 230 (85.8) 44 (16.4) 224 (83.6) 0.471 Previous gynecological or abdominal surgery Yes (%) No (%) 74 (27.6) 194 (72.4) 73 (27.2) 195 (72.8) 0.923 Presence of diabetes Yes (%) No (%) 52 (19.4) 216 (80.6) 50 (18.7) 218 (81.3) 0.826 Use of benzodiazepine Yes (%) No (%) 71 (26.5) 197 (73.5) 63 (23.5) 205 (76.5) 0.425 Types of opioid analgesics Morphine (%) Oxycodone (%) Fentanyl (%) Hydromorphone (%) Tapentadol (%) 15 (5.6) 198 (73.9) 35 (13.1) 30 (11.2) 11 (4.1) 9 (3.4) 210 (78.4) 29 (10.8) 25 (9.3) 8 (3.0) 0.208 0.224 0.424 0.476 0.483 Administration route of opioid analgesics Oral (%) Not oral (%) 239 (89.2) 29 (10.8) 239 (89.2) 29 (10.8) 1.000 Daily dose of opioid analgesics (morphine equivalent) (mg/day) Median (range) 30 (9.6–120) 30 (10–204) 0.293 Use of weak opioid analgesics Yes (%) No (%) 97 (36.2) 171 (63.8) 102 (38.1) 166 (61.9) 0.655 Use of laxatives before initiating strong opioid analgesics Yes (%) No (%) 87 (32.5) 181 (67.5) 80 (29.8) 188 (70.2) 0.514 Types of prophylactic laxatives Osmotic laxatives (%) Stimulant Laxatives (%) PAMORA (%) Others (%) Combination therapy (%) 133 (49.6) 39 (14.6) 66 (24.6) 7 (2.6) 23 (8.6) NA NA BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group Performance Status; BSC, Best Supportive Care; PAMORA, peripherally-acting µ opioid receptor antagonist; NA, not applicable Among patients without prophylactic laxatives, 104 of 268 (38.8%) required laxatives within one week of initiating opioid therapy. The median time from initiating opioid therapy to administering laxatives was 3 days (range: 1–7 days). The remaining 164 patients did not receive any laxatives. Among the patients with prophylactic laxatives, 114 of 268 patients had received additional laxatives, and the median time from initiating opioid therapy to administering additional laxatives was also 3 days (range: 1–7 days). The remaining 154 patients never received any additional laxatives. Primary endpoint The incidence of OIC in patients with and without prophylactic laxatives is shown in Table 3 . Before propensity score matching analysis, there was no statistically significant difference in the incidence of OIC between patients with and without prophylactic laxatives (47.8% vs 49.8%, odds ratio (OR) = 0.92, 95% confidence interval (CI): 0.71–1.21) (Table 3 A). After propensity score matching analysis, the incidence of OIC in patients with prophylactic laxatives was not significantly different from that in patients without prophylactic laxatives (48.1% vs 48.9%, OR = 0.97, 95% CI: 0.69–1.36) (Table 3 B). Table 3 The incidence of OIC in patients with and without prophylactic laxatives (A) Before propensity score matching analysis Prophylactic laxatives OR (95% CI) P value Yes (n = 370) No (n = 558) OIC Yes (n = 455) 177 278 0.92 (0.71-1.21) 0.554 No (n = 473) 193 280 (B) After propensity score matching analysis Prophylactic laxatives OR (95% CI) P value Yes (n = 268) No (n = 268) OIC Yes (n = 260) 129 131 0.97 (0.69-1.36) 0.863 No (n = 276) 139 137 OR, odds ratio; CI, confidence interval; OIC, opioid-induced constipation The types of prophylactic laxatives used are shown in Table 2 . The incidence of OIC for osmotic laxatives, stimulant laxatives, PAMORA, others, and their combinations were 54.9%, 43.6%, 36.4%, 57.1%, and 47.8%, respectively. The p-value in the Fisher's exact test was 0.148, and there was no significant difference in the incidence of OIC according to the types of prophylactic laxatives used. Factors associated with the incidence of OIC Next, we examined the factors associated with the incidence of OIC after propensity score matching analysis (Fig. 2 ). Multivariable logistic analysis showed that age ≥ 65 years (OR = 1.53, 95% CI: 1.07–2.19) and ECOG PS ≥ 3 (OR = 1.69, 95% CI: 1.04–2.77) were associated with the incidence of OIC. Discussion The propensity score matching analysis showed that the incidence of OIC in patients with and without prophylactic laxatives was comparable, suggesting that prophylactic laxatives are not necessarily required when initiating opioid therapy. In addition, age ≥ 65 years and ECOG PS ≥ 3 were shown in multivariate logistic analysis to be significant risk factors in the incidence of OIC. We found that age ≥ 65 years was a risk factor for OIC. Previous studies also showed that age ≥ 50 years [ 19 ] and increased age [ 21 ] were associated with the incidence of OIC. Constipation occurs due to structural and functional changes of the anorectum in elderly people [ 22 ], so elderly patients may be especially prone to constipation. However, the association between OIC and age varies in the studies: one study found no association with age [ 23 ], while another study found that age ≥ 65 years decreased the risk of OIC [ 16 ]. Further investigation of the potential relationship between OIC and age is therefore warranted. We also found that ECOG PS ≥ 3 was another risk factor for OIC. To the best of our knowledge, the previous studies did not examine the association between performance status and the incidence of OIC. Poor general performance status has been associated with the incidence of constipation in patients with cancer and receiving palliative care [ 24 ]. In patients receiving chemotherapy, ECOG PS ≥ 2 has been reported to have an association with higher severity of constipation [ 25 ]. This evidence suggests that the patients with decreased physical performance status are prone to constipation. Our results suggest that prophylactic laxatives do not affect the incidence of OIC. Despite using the same OIC criteria as the J-RIGID study, our findings were different: the J-RIGID study found significant effectiveness of prophylactic laxatives in preventing OIC. The incidence of OIC with prophylactic laxatives in our study (48.1%) was higher than that in the J-RIGID study (33.7%), although the incidences were comparable between our study and the J-RIGID study in those without prophylactic laxatives (48.9% vs 54.6% respectively) [ 5 ]. Comparing patient background, performance status was different between these studies. While the J-RIGID study did not include ECOG PS ≥ 3 patients [ 5 ], our study included 305 patients (32.9%) with ECOG PS ≥ 3. Our study showed that ECOG PS ≥ 3 is a risk factor for OIC, so difference in performance status may affect the results. In actual clinical settings, performance status of patients receiving strong opioid analgesics vary, from ECOG PS 1 to 4. Therefore, our result is suggested to reflect the real-world clinical practice. Various types of laxatives are currently available for clinical use. In our study, osmotic laxatives, stimulant laxatives, PAMORA, other types, either alone or in combination, were administered, with osmotic laxatives being utilized in approximately 50% of patients. Recently, PAMORA, including naldemedine, has become part of clinical practice and is recommended for patients with OIC refractory to traditional laxative [ 11 , 12 ]. Several studies have demonstrated the effectiveness of PAMORA in treating OIC [ 26 , 27 ], but few studies have investigated the preventive effects of prophylactic laxatives on OIC. Ozaki et al. compared prophylactic naldemedine with prophylactic magnesium oxide in terms of the incidence of OIC. The incidence of OIC was found to be significantly lower in patients receiving naldemedine compared with those receiving prophylactic magnesium oxide. Additionally, they reported that naldemedine significantly prevented the decline in constipation-specific QOL and promoted complete spontaneous bowel movements [ 28 ]. However, there has been no investigation into whether the incidence of OIC is significantly lower in patients receiving prophylactic naldemedine compared with those not receiving it. In our study, PAMORA was used as a prophylactic laxative in 24.6% of patients. Although the incidence of OIC in patients with prophylactic naldemedine (36.4%) tended to be lower than in those receiving other treatments (osmotic laxatives 54.9%, stimulant laxatives 43.6%, others 57.1%, and their combinations 47.8%), no statistical difference was found. Therefore, prospective studies are warranted to investigate the preventive effect of naldemedine on OIC. Several limitations of our study need to be considered. First, it was performed in a single-center, it may be difficult to generalize the findings. Second, our study was a retrospective approach, which may reduce the validity of the data. Although propensity score matching analysis was used to adjust for comparative bias in patient background as much as possible to enhance the level of evidence, an RCT is needed to investigate the more accurate effects of prophylactic laxatives. Third, some studies have reported that transdermal fentanyl and buprenorphine have significantly lower incidence of OIC than slow-release oral morphine [ 29 , 30 ]. Therefore, the type of opioid analgesics used may affect the preventive effect of prophylactic laxatives on OIC. Some patients in our study had a change in the type of opioid analgesics changed during the observation period. Therefore, we did not perform a subgroup analysis based on the type of opioid analgesics. In the future, studies are needed to investigate whether the incidence of OIC with prophylactic laxatives varies depending on the type of opioid analgesics used. Finally, our data were collected from medical records over an 11-year period, during which several types of laxatives, especially naldemedine, were used. Conclusions We retrospectively examined the effect of prophylactic laxatives on OIC using propensity score analysis. Prophylactic laxatives did not affect the incidence of OIC in our study. Our results suggest that prophylactic laxatives are not necessarily required when initiating opioid therapy. In addition, we found that age ≥ 65 years and ECOG PS ≥ 3 were associated with the incidence of OIC. Declarations Acknowledgments: We acknowledge proofreading and editing by Benjamin Phillis at the Clinical Study Support Center at Wakayama Medical University. Author Contributions: Y.O is the first author and responsible for the concept and design of the study, data collection, analysis and interpretation. T.Ku, Y.T. conducted concept and design, and data interpretation. K.W. and T.S. were responsible for the concept and design, data interpretation and statistical analysis of the study data. T.Ka. were responsible for the concept and design, data interpretation, and supervision of the written manuscript. All authors have read and agreed to the final manuscript. Data availability: Due to ethical constraints, data are not available. 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Opin 34:1187-1192 Ducrotté P, Milce J, Soufflet C, Fabry C (2017) Prevalence and clini- cal features of opioid‐induced constipation in the general pop- ulation: A French study of 15,000 individuals. United European Gastroenterol. J 5:588‐600 Higashibata T, Kessoku T, Morioka Y, Koretaka Y, Mishima H, Shibahara H, Masuda Y, Ichikawa Y, Nakajima A, Hisanaga T (2023) A Nationwide Hospital Claims Database Analysis of Real-World Patterns of Laxative Use for Opioid-Induced Constipation in Japanese Patients with Cancer. Pain Ther 12:993-1003 Rosti G, Gatti A, Costantini A, Sabato AF, Zucco F (2010) Opioid-related bowel dysfunction: prevalence and identification of predictive factors in a large sample of Italian patients on chronic treatment. Eur. Rev. Med. Pharmacol. Sci 14:1045-50 Yu SW, Rao SS (2014) Anorectal physiology and pathophysiology in the elderly. Clin. Geriatr. Med 30:95-106 Clark K, Lam LT, Talley NJ, Phillips JL, Currow DC (2017) Identifying Factors That Predict Worse Constipation Symptoms in Palliative Care Patients: A Secondary Analysis. J. Palliat. Med 20:528-532 Dzierżanowski T, Ciałkowska-Rysz A (2015) Behavioral risk factors of constipation in palliative care patients. Support Care Cancer 23:1787-93 Pehlivan Z, Nural N (2022) Prevalence of constipation in patients undergoing chemotherapy and the effect of constipation on quality of life. Support Care Cancer 30:8019-8028 Katakami N, Harada T, Murata T, Shinozaki K, Tsutsumi M, Yokota T, Arai M, Tada Y, Narabayashi M, Boku N (2017) Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid-Induced Constipation and Cancer. J. Clin. Oncol 35:3859-3866 Lacy BE, Cangemi DJ (2024) Opioids and the Gastrointestinal Tract: The Role of Peripherally Active µ-Opioid Receptor Antagonists in Modulating Intestinal Permeability. Am J Gastroenterol Ozaki A, Kessoku T, Tanaka K, Yamamoto A, Takahashi K, Takeda Y, Kasai Y, Iwaki M, Kobayashi T, Yoshihara T, Kato T, Suzuki A, Honda Y, Ogawa Y, Fuyuki A, Imajo K, Higurashi T, Yoneda M, Taguri M, Ishiki H, Kobayashi N, Saito S, Ichikawa Y, Nakajima A (2022) Effectiveness of Naldemedine Compared with Magnesium Oxide in Preventing Opioid-Induced Constipation: A Randomized Controlled Trial. Cancers (Basel) 14:2112 Tassinari D, Sartori S, Tamburini E, Scarpi E, Tombesi P, Santelmo C, Maltoni M (2009) Transdermal fentanyl as a front-line approach to moderate-severe pain: a meta-analysis of randomized clinical trials. J Palliat Care 25:172-80 Tassinari D, Sartori S, Tamburini E, Scarpi E, Raffaeli W, Tombesi P, Maltoni M (2008) Adverse effects of transdermal opiates treating moderate-severe cancer pain in comparison to long-acting morphine: a meta-analysis and systematic review of the literature. J Palliat Med 11:492-501 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 21 Jan, 2025 Read the published version in Supportive Care in Cancer → Version 1 posted Editorial decision: Revision requested 24 Nov, 2024 Reviews received at journal 18 Nov, 2024 Reviewers agreed at journal 04 Nov, 2024 Reviewers agreed at journal 31 Oct, 2024 Reviews received at journal 30 Sep, 2024 Reviewers agreed at journal 28 Sep, 2024 Reviewers invited by journal 23 Sep, 2024 Editor assigned by journal 18 Sep, 2024 Submission checks completed at journal 09 Aug, 2024 First submitted to journal 03 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4851518","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":337983047,"identity":"3f1791b1-5eea-40b7-9bd7-ae75c10a8b9d","order_by":0,"name":"Yuka Okuda","email":"","orcid":"","institution":"Wakayama Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuka","middleName":"","lastName":"Okuda","suffix":""},{"id":337983048,"identity":"35e7616f-9ef1-4391-ba33-e0e7b62cd3f7","order_by":1,"name":"Toshiyuki Kuriyama","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABKklEQVRIiWNgGAWjYBACCSA+AGLwMzAwI4R5wOQB/FokG0jRAgYGBzC1YAeSM3IfHuap2SZvfCP5scHPNrto/gbuxAdvGOzkGRjPYrVGWiLd4DDPsduG226kGSf2tiXnzjjAu9lwDkOyYQPDuQRsWuQk0hgO87DdZtx2O8H4AG8bc27D/bfbpHkYmIHKzxjg1vLvtv3m2emfD/5tq8+df4B3+28ehnqcWqRBWnjbbidukM4xTuZtO5y74QDvNmYehsM4tUj2PGM4OLfvdvKM+2+KjWXOHc/dCPSL5ByD44ZtOPwicTyN+cObb7dt+3uOb5Z8U1adO+8A78YPbyqq5fklsIcYCDDBY4GRDcYCOolN4gwuHQyMP+DMP8ji/D04tYyCUTAKRsGIAgDL7GfyFzBoLAAAAABJRU5ErkJggg==","orcid":"","institution":"Wakayama Medical University","correspondingAuthor":true,"prefix":"","firstName":"Toshiyuki","middleName":"","lastName":"Kuriyama","suffix":""},{"id":337983049,"identity":"10684653-a284-4d1f-943c-0d67905aabf4","order_by":2,"name":"Yoshi Tsukiyama","email":"","orcid":"","institution":"Wakayama Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yoshi","middleName":"","lastName":"Tsukiyama","suffix":""},{"id":337983050,"identity":"18429413-9c68-4b16-a686-a03fe1cb05ef","order_by":3,"name":"Toshio Shimokawa","email":"","orcid":"","institution":"Wakayama Medical University","correspondingAuthor":false,"prefix":"","firstName":"Toshio","middleName":"","lastName":"Shimokawa","suffix":""},{"id":337983051,"identity":"76be7d28-b6a9-48a2-a223-beb9443e59a0","order_by":4,"name":"Ke Wan","email":"","orcid":"","institution":"Wakayama Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ke","middleName":"","lastName":"Wan","suffix":""},{"id":337983052,"identity":"72128cc5-e6dc-42a1-931e-77ad63a85a74","order_by":5,"name":"Tomoyuki Kawamata","email":"","orcid":"","institution":"Wakayama Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tomoyuki","middleName":"","lastName":"Kawamata","suffix":""}],"badges":[],"createdAt":"2024-08-03 05:38:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4851518/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4851518/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00520-025-09154-w","type":"published","date":"2025-01-21T15:57:50+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":64712713,"identity":"a7174555-cc48-4d9d-87e5-ea6b562029d7","added_by":"auto","created_at":"2024-09-18 02:06:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":15159,"visible":true,"origin":"","legend":"\u003cp\u003ePatient flow diagram\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4851518/v1/f364188164f65128b5dbe04b.png"},{"id":64712712,"identity":"a042663a-e91a-4f9b-bdce-c6cfc1523ecf","added_by":"auto","created_at":"2024-09-18 02:06:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":23007,"visible":true,"origin":"","legend":"\u003cp\u003eFactors associated with the incidence of OIC after propensity score matching analysis using multivariable logistic analysis. Age ≥65 years and ECOG PS ≥3 were associated with the incidence of OIC. BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group Performance Status; BSC, Best Supportive Care\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4851518/v1/10a7ee8246fe8e6518941018.png"},{"id":74858450,"identity":"270d8220-cba0-480b-b4f9-1dfeb557ab59","added_by":"auto","created_at":"2025-01-27 16:09:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":960710,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4851518/v1/485160ef-6e49-426c-8ff5-1b60b9a0e874.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy of prophylactic laxatives against opioid-induced constipation: retrospective propensity score matching analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOpioid analgesics are widely used for moderate to severe pain in patients with cancer [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. However, constipation is a common side effect of opioid analgesics. Among opioid receptors, \u0026micro; opioid receptors are related to opioid-induced constipation (OIC). They are mainly found in the stomach and proximal colon, on the membranes of intestinal muscle cells, myenteric and submucosal neurons [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The activation of these \u0026micro; opioid receptors reportedly inhibits intestinal movement and intestinal mucosal secretion, promotes intestinal fluid absorption, and increases anal sphincter contraction [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Constipation reportedly occurs in 33\u0026ndash;55% in patients with cancer within one week after they initiate strong opioid analgesics [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In addition, OIC could result in avoidance of opioid use, leading to inadequate pain relief, biopsychosocial burden, impaired quality of life (QOL), and subsequently a greater financial burden [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, OIC remains under-recognized and undertreated [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. A previous study has shown that healthcare professionals often do not sufficiently inform patients about constipation as a common side effect of opioid use [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In addition, patients often prefer to deal with constipation on their own and do not raise the subject of OIC because of embarrassment [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Therefore, we suggest that OIC requires attention.\u003c/p\u003e \u003cp\u003eThe use of traditional laxatives (osmotic laxatives and stimulant laxatives) is recommended as first-line therapy [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In addition, peripherally-acting \u0026micro; opioid receptor antagonist (PAMORA) including naldemedine is recommended for patients with OIC refractory to traditional laxatives [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The European Association for Palliative Care [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and the National Institute of Clinical Evidence [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] recommend prescribing prophylactic laxatives to prevent OIC. A clinical guideline of the Japanese Society of Palliative Medicine also recommends initiating regular laxatives at the same time as opioid analgesics; this is based on daily clinical experience but not clinical evidence [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The effectiveness of prophylactic laxatives on OIC has not been sufficiently demonstrated. To our knowledge, only two studies have examined the preventive effects on OIC [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. First, the OIC-J Study prospectively examined the incidence of OIC with or without prophylactic laxatives as a secondary endpoint [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The cumulative incidence of OIC according to the Rome IV diagnostic criteria was 48% in patients who received prophylactic laxatives (constipation agents initiated at the same time of opioid therapy) and 65% of patients who received no prophylactic laxatives. However, the incidence of OIC in patients with prophylactic laxatives was not statistically compared with that of patients without prophylactic laxatives. Therefore, the OIC-J study did not clarify the effectiveness of prophylactic laxatives for OIC. Second, the J-RIGID study retrospectively examined the effectiveness of prophylactic laxatives using the different criteria for OIC from those used in the OIC-J study [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Prophylactic laxatives administered within 7 days after initiating opioid analgesics statistically significantly decreased the incidence of OIC [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], but there was no adjustment for confounding bias in patient background.\u003c/p\u003e \u003cp\u003eWe examined the incidence of OIC as a primary endpoint and made statistical comparisons for the first time. Although retrospective in nature, we used propensity score matching analysis to adjust for comparative bias in patient background as much as possible to enhance the level of evidence. We also investigated risk factors for OIC.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Patients\u003c/h2\u003e \u003cp\u003e Our study was approved by the Wakayama Medical University Certified Review Board (CRB5180004) and was conducted in compliance with the Declaration of Helsinki and Ethical Guidelines for Medical and Health Research Involving Human Subjects. We conducted a retrospective, single-institution observational cohort study to assess the clinical effects of prophylactic laxatives on OIC. All clinical data were obtained from electronic medical records. Eligible patients were adult (\u0026ge;\u0026thinsp;20 years) cancer inpatients who initiated regular administration of strong opioid analgesics after admission to our hospital and who remained hospitalized for over a week between January 2012 and January 2023. We excluded patients with a history of colostomy and those missing description-based data on defecation. Owing to the anonymous nature of the data, informed consent was waived and a disclosure document was posted.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAssessments\u003c/h2\u003e \u003cp\u003eWe diagnosed OIC when there was a stool-free interval of \u0026ge;\u0026thinsp;72-h within one week after initiating strong opioid analgesics, in accordance with a previous study [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. We defined prophylactic laxatives as regularly administered laxatives initiated on the same day (day 0) as opioid therapy. Additional laxatives were initiated as needed between the next day (day 1) and seven days (day 7) after initiating opioid therapy. In patients without prophylactic laxatives, laxatives were initiated as needed between day 1 and day 7 after initiating opioid therapy, but the distinction lies in there being no initial administration on the same day like in the prophylactic laxatives.\u003c/p\u003e \u003cp\u003eThe primary endpoint of this study was the incidence of OIC in patients with and without prophylactic laxatives. In addition, we examined factors associated with the incidence of OIC. Explanatory variables were selected based on previous studies [\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Patient clinical demographics included age (\u0026ge;\u0026thinsp;65 years), sex, body mass index (BMI) (\u0026ge;\u0026thinsp;21 kg/m2), type of cancer (gastrointestinal or not), Eastern Cooperative Oncology Group Performance Status (ECOG PS)\u0026thinsp;\u0026ge;\u0026thinsp;3, presence of cancerous peritonitis, previous gynecological or abdominal surgery, presence of diabetes, use of benzodiazepine, timing of anti-cancer treatment, use of weak opioid analgesics before initiating strong opioid analgesics, types of laxatives used, use of laxatives before initiating strong opioid analgesics and their types, and the administration route and morphine equivalent daily dose of opioid analgesics.\u003c/p\u003e \u003cp\u003eWe also examined the effect of the types of laxatives on the incidence of OIC. Laxatives were classified into four types: osmotic laxatives, stimulant laxatives, PAMORA, and others [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. \u0026lsquo;Osmotic laxatives\u0026rsquo; included magnesium oxide, lactulose and polyethylene glycol, \u0026lsquo;stimulant laxatives\u0026rsquo; included sennoside and picosulfate, PAMORA was naldemedine, and then \u0026lsquo;others\u0026rsquo; comprised linaclotide, lubiprostone, and elobixibat. In addition, \u0026lsquo;combination therapy\u0026rsquo; was the use of more than two types of laxatives.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eCategorical variables, summarized as frequency and proportion, were compared using the Fisher's exact test. Continuous variables, summarized as median (range), were compared using the Wilcoxon test.\u003c/p\u003e \u003cp\u003eWe used propensity score matching analysis to adjust for comparative bias in patient background as much as possible to enhance the level of evidence. A propensity score was calculated using the multivariate logistic regression with following covariates: age, sex, BMI, type of cancer, ECOG PS, presence of cancerous peritonitis, previous gynecological or abdominal surgery, presence of diabetes, use of benzodiazepine, timing of cancer treatment, use of weak opioid analgesics, use of laxatives before initiating strong opioid analgesics, and the types of opioid analgesics and their administration route. We performed propensity score matching analysis between patients with and without prophylactic laxatives. We used the caliper width of 0.20 for one-to-one matching analysis and the nearest neighbor matching on the logit of the propensity score. The propensity score-matched data were analyzed for the incidence of OIC in patients with and without prophylactic laxatives using the Fisher\u0026rsquo;s exact test. Multivariable logistic analysis was performed to clarify factors associated with the incidence of OIC. To compare patient background, the chi-squared test was used for categorical variables and the Wilcoxon rank sum test for continuous variables. All analyses were carried out using JMP\u0026reg;ฎ version 14.1.0 (SAS Institute, Cary, NC, USA). All statistical tests were performed with a two-sided significance level of 0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eCharacteristics of all eligible patients\u003c/h2\u003e\n \u003cp\u003eBetween January 2012 and January 2023, 1006 patients initiated regular administration of strong opioid analgesics for cancer pain after admission to our hospital and were hospitalized for over a week. We excluded 78 patients: 53 due to a history of colostomy, and 25 because they lacked description about defecation due to missing description-based data on defecation in electronic medical records. Accordingly, 928 patients met the eligibility criteria of our study, 370 (39.9%) of whom received prophylactic laxatives (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Characteristics of all eligible patients are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. There were significant differences between patients with and without prophylactic laxatives in sex, BMI, type of cancer, ECOG PS, timing of anti-cancer treatment, types and administration route of opioid analgesics, and use of laxatives before initiating strong opioid analgesics.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCharacteristics of all eligible patients\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAll\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;928)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eWith prophylactic laxatives\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;370)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eWithout prophylactic laxatives\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;558)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;65 (%)\u003c/p\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;65 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e67 (22\u0026ndash;93)\u003c/p\u003e\n \u003cp\u003e530 (57.1)\u003c/p\u003e\n \u003cp\u003e398 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e68 (29\u0026ndash;92)\u003c/p\u003e\n \u003cp\u003e211 (57.0)\u003c/p\u003e\n \u003cp\u003e159 (43.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e67 (22\u0026ndash;93)\u003c/p\u003e\n \u003cp\u003e319 (57.2)\u003c/p\u003e\n \u003cp\u003e239 (42.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.636\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.967\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale (%)\u003c/p\u003e\n \u003cp\u003eFemale (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e600 (64.7)\u003c/p\u003e\n \u003cp\u003e328 (35.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e257 (69.5)\u003c/p\u003e\n \u003cp\u003e113 (30.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e343 (61.5)\u003c/p\u003e\n \u003cp\u003e215 (38.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.014*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eBMI (kg/m2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;21 (%)\u003c/p\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;21 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e21 (11.7\u0026ndash;37.1)\u003c/p\u003e\n \u003cp\u003e472 (50.9)\u003c/p\u003e\n \u003cp\u003e456 (49.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e21.4 (13.1\u0026ndash;37.1)\u003c/p\u003e\n \u003cp\u003e211 (57.0)\u003c/p\u003e\n \u003cp\u003e159 (43.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e20.7 (11.7\u0026ndash;36.6)\u003c/p\u003e\n \u003cp\u003e261 (46.8)\u003c/p\u003e\n \u003cp\u003e297 (53.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.002*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eType of cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGastrointestinal (%)\u003c/p\u003e\n \u003cp\u003eOthers (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87 (9.4)\u003c/p\u003e\n \u003cp\u003e841 (90.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 (6.8)\u003c/p\u003e\n \u003cp\u003e345 (93.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e62 (11.1)\u003c/p\u003e\n \u003cp\u003e496 (88.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.023*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECOG PS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;2 (%)\u003c/p\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;3 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e623 (67.1)\u003c/p\u003e\n \u003cp\u003e305 (32.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e271 (73.2)\u003c/p\u003e\n \u003cp\u003e99 (26.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e352 (63.1)\u003c/p\u003e\n \u003cp\u003e206 (36.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTiming of anti-cancer treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnticancer treatment (%)\u003c/p\u003e\n \u003cp\u003eBest Supportive care (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e619 (66.7)\u003c/p\u003e\n \u003cp\u003e309 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e271 (73.2)\u003c/p\u003e\n \u003cp\u003e99 (26.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e348 (62.4)\u003c/p\u003e\n \u003cp\u003e210 (37.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePresence of cancerous peritonitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (%)\u003c/p\u003e\n \u003cp\u003eNo (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e174 (18.8)\u003c/p\u003e\n \u003cp\u003e754 (81.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61 (16.5)\u003c/p\u003e\n \u003cp\u003e309 (83.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e113 (20.3)\u003c/p\u003e\n \u003cp\u003e445 (79.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.148\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrevious gynecological or abdominal surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (%)\u003c/p\u003e\n \u003cp\u003eNo (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e263 (28.3)\u003c/p\u003e\n \u003cp\u003e665 (71.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e166 (44.9)\u003c/p\u003e\n \u003cp\u003e204 (55.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97 (17.3)\u003c/p\u003e\n \u003cp\u003e461 (82.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.317\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePresence of diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (%)\u003c/p\u003e\n \u003cp\u003eNo (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e163 (17.6)\u003c/p\u003e\n \u003cp\u003e765 (82.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68 (18.4)\u003c/p\u003e\n \u003cp\u003e302 (81.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95 (17.0)\u003c/p\u003e\n \u003cp\u003e463 (83.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.597\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUse of benzodiazepine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (%)\u003c/p\u003e\n \u003cp\u003eNo (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e246 (26.5)\u003c/p\u003e\n \u003cp\u003e682 (73.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88 (23.8)\u003c/p\u003e\n \u003cp\u003e282 (76.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e158 (28.3)\u003c/p\u003e\n \u003cp\u003e400 (71.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.124\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTypes of opioid analgesics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMorphine (%)\u003c/p\u003e\n \u003cp\u003eOxycodone (%)\u003c/p\u003e\n \u003cp\u003eFentanyl (%)\u003c/p\u003e\n \u003cp\u003eHydromorphone (%)\u003c/p\u003e\n \u003cp\u003eTapentadol (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e56 (6.0)\u003c/p\u003e\n \u003cp\u003e629 (67.8)\u003c/p\u003e\n \u003cp\u003e212 (22.8)\u003c/p\u003e\n \u003cp\u003e74 (8.0)\u003c/p\u003e\n \u003cp\u003e25 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (5.4)\u003c/p\u003e\n \u003cp\u003e278 (75.1)\u003c/p\u003e\n \u003cp\u003e39 (10.5)\u003c/p\u003e\n \u003cp\u003e44 (11.9)\u003c/p\u003e\n \u003cp\u003e16 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36 (6.5)\u003c/p\u003e\n \u003cp\u003e351 (62.9)\u003c/p\u003e\n \u003cp\u003e173 (31.0)\u003c/p\u003e\n \u003cp\u003e30 (5.4)\u003c/p\u003e\n \u003cp\u003e9 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.510\u003c/p\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;.001*\u003c/p\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;.001*\u003c/p\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;.001*\u003c/p\u003e\n \u003cp\u003e0.014*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdministration route of opioid analgesics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOral (%)\u003c/p\u003e\n \u003cp\u003eNot oral (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e645 (69.5)\u003c/p\u003e\n \u003cp\u003e283 (30.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e322 (87.0)\u003c/p\u003e\n \u003cp\u003e48 (13.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e323 (57.9)\u003c/p\u003e\n \u003cp\u003e235 (42.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDaily dose of opioid analgesics (morphine equivalent) (mg/day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (9.6\u0026ndash;210)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (9.6\u0026ndash;120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (9.6\u0026ndash;210)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.051\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUse of weak opioid analgesics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (%)\u003c/p\u003e\n \u003cp\u003eNo (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e355 (38.3)\u003c/p\u003e\n \u003cp\u003e573 (61.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e138 (37.3)\u003c/p\u003e\n \u003cp\u003e232 (62.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e217 (38.9)\u003c/p\u003e\n \u003cp\u003e341 (61.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.625\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUse of laxatives before initiating strong opioid analgesics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (%)\u003c/p\u003e\n \u003cp\u003eNo (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e335 (36.1)\u003c/p\u003e\n \u003cp\u003e593 (63.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90 (24.3)\u003c/p\u003e\n \u003cp\u003e280 (75.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e245 (43.9)\u003c/p\u003e\n \u003cp\u003e313 (56.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTypes of prophylactic laxatives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOsmotic laxatives (%)\u003c/p\u003e\n \u003cp\u003eStimulant Laxatives (%)\u003c/p\u003e\n \u003cp\u003ePAMORA (%)\u003c/p\u003e\n \u003cp\u003eOthers (%)\u003c/p\u003e\n \u003cp\u003eCombination therapy (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e194 (20.9)\u003c/p\u003e\n \u003cp\u003e53 (5.7)\u003c/p\u003e\n \u003cp\u003e85 (9.2)\u003c/p\u003e\n \u003cp\u003e11 (1.2)\u003c/p\u003e\n \u003cp\u003e27 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e194 (52.4)\u003c/p\u003e\n \u003cp\u003e53 (14.3)\u003c/p\u003e\n \u003cp\u003e85 (23.0)\u003c/p\u003e\n \u003cp\u003e11 (3.0)\u003c/p\u003e\n \u003cp\u003e27 (7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eBMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group Performance Status; BSC, Best Supportive Care; PAMORA, peripherally-acting \u0026micro; opioid receptor antagonist; NA, not applicable\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003e*P\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eCharacteristics of after propensity score matching analysis\u003c/h2\u003e\n \u003cp\u003eAfter propensity score matching analysis, 536 patients were selected. Characteristics of patients after propensity score matching analysis are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The patients\u0026apos; characteristics were similar between patients with and without prophylactic laxatives.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCharacteristics of the patients after propensity score matching analysis\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eWith prophylactic laxatives\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;268)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eWithout prophylactic laxatives (n\u0026thinsp;=\u0026thinsp;268)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;65 (%)\u003c/p\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;65 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e68 (29\u0026ndash;92)\u003c/p\u003e\n \u003cp\u003e157 (58.6)\u003c/p\u003e\n \u003cp\u003e111 (41.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e67 (22\u0026ndash;93)\u003c/p\u003e\n \u003cp\u003e150 (56.0)\u003c/p\u003e\n \u003cp\u003e118 (44.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.389\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.541\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale (%)\u003c/p\u003e\n \u003cp\u003eFemale (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e177 (66.0)\u003c/p\u003e\n \u003cp\u003e91 (34.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e177 (66.0)\u003c/p\u003e\n \u003cp\u003e91 (34.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eBMI (kg/m2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;21 (%)\u003c/p\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;21 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e21.2 (13.1\u0026ndash;37.1)\u003c/p\u003e\n \u003cp\u003e140 (52.2)\u003c/p\u003e\n \u003cp\u003e128 (47.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e21.1 (11.7\u0026ndash;36.6)\u003c/p\u003e\n \u003cp\u003e137 (51.1)\u003c/p\u003e\n \u003cp\u003e131 (48.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.569\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.795\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eType of cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGastrointestinal (%)\u003c/p\u003e\n \u003cp\u003eOthers (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (8.2)\u003c/p\u003e\n \u003cp\u003e246 (91.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (9.0)\u003c/p\u003e\n \u003cp\u003e244 (91.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.758\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECOG PS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;2 (%)\u003c/p\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;3 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e192 (71.6)\u003c/p\u003e\n \u003cp\u003e76 (28.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e184 (68.7)\u003c/p\u003e\n \u003cp\u003e84 (31.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.450\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTiming of anti-cancer treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnticancer treatment (%)\u003c/p\u003e\n \u003cp\u003eBest Supportive care (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e192 (71.6)\u003c/p\u003e\n \u003cp\u003e76 (28.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e179 (66.8)\u003c/p\u003e\n \u003cp\u003e89 (33.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.224\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePresence of cancerous peritonitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (%)\u003c/p\u003e\n \u003cp\u003eNo (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38 (14.2)\u003c/p\u003e\n \u003cp\u003e230 (85.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44 (16.4)\u003c/p\u003e\n \u003cp\u003e224 (83.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.471\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrevious gynecological or abdominal surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (%)\u003c/p\u003e\n \u003cp\u003eNo (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e74 (27.6)\u003c/p\u003e\n \u003cp\u003e194 (72.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73 (27.2)\u003c/p\u003e\n \u003cp\u003e195 (72.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.923\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePresence of diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (%)\u003c/p\u003e\n \u003cp\u003eNo (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52 (19.4)\u003c/p\u003e\n \u003cp\u003e216 (80.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50 (18.7)\u003c/p\u003e\n \u003cp\u003e218 (81.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.826\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUse of benzodiazepine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (%)\u003c/p\u003e\n \u003cp\u003eNo (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71 (26.5)\u003c/p\u003e\n \u003cp\u003e197 (73.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63 (23.5)\u003c/p\u003e\n \u003cp\u003e205 (76.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.425\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTypes of opioid analgesics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMorphine (%)\u003c/p\u003e\n \u003cp\u003eOxycodone (%)\u003c/p\u003e\n \u003cp\u003eFentanyl (%)\u003c/p\u003e\n \u003cp\u003eHydromorphone (%)\u003c/p\u003e\n \u003cp\u003eTapentadol (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (5.6)\u003c/p\u003e\n \u003cp\u003e198 (73.9)\u003c/p\u003e\n \u003cp\u003e35 (13.1)\u003c/p\u003e\n \u003cp\u003e30 (11.2)\u003c/p\u003e\n \u003cp\u003e11 (4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (3.4)\u003c/p\u003e\n \u003cp\u003e210 (78.4)\u003c/p\u003e\n \u003cp\u003e29 (10.8)\u003c/p\u003e\n \u003cp\u003e25 (9.3)\u003c/p\u003e\n \u003cp\u003e8 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.208\u003c/p\u003e\n \u003cp\u003e0.224\u003c/p\u003e\n \u003cp\u003e0.424\u003c/p\u003e\n \u003cp\u003e0.476\u003c/p\u003e\n \u003cp\u003e0.483\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdministration route of opioid analgesics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOral (%)\u003c/p\u003e\n \u003cp\u003eNot oral (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e239 (89.2)\u003c/p\u003e\n \u003cp\u003e29 (10.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e239 (89.2)\u003c/p\u003e\n \u003cp\u003e29 (10.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDaily dose of opioid analgesics\u003c/p\u003e\n \u003cp\u003e(morphine equivalent) (mg/day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (9.6\u0026ndash;120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (10\u0026ndash;204)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.293\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUse of weak opioid analgesics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (%)\u003c/p\u003e\n \u003cp\u003eNo (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97 (36.2)\u003c/p\u003e\n \u003cp\u003e171 (63.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e102 (38.1)\u003c/p\u003e\n \u003cp\u003e166 (61.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.655\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUse of laxatives before initiating strong opioid analgesics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (%)\u003c/p\u003e\n \u003cp\u003eNo (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87 (32.5)\u003c/p\u003e\n \u003cp\u003e181 (67.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e80 (29.8)\u003c/p\u003e\n \u003cp\u003e188 (70.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.514\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTypes of prophylactic laxatives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOsmotic laxatives (%)\u003c/p\u003e\n \u003cp\u003eStimulant Laxatives (%)\u003c/p\u003e\n \u003cp\u003ePAMORA (%)\u003c/p\u003e\n \u003cp\u003eOthers (%)\u003c/p\u003e\n \u003cp\u003eCombination therapy (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e133 (49.6)\u003c/p\u003e\n \u003cp\u003e39 (14.6)\u003c/p\u003e\n \u003cp\u003e66 (24.6)\u003c/p\u003e\n \u003cp\u003e7 (2.6)\u003c/p\u003e\n \u003cp\u003e23 (8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eBMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group Performance Status; BSC, Best Supportive Care; PAMORA, peripherally-acting \u0026micro; opioid receptor antagonist; NA, not applicable\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eAmong patients without prophylactic laxatives, 104 of 268 (38.8%) required laxatives within one week of initiating opioid therapy. The median time from initiating opioid therapy to administering laxatives was 3 days (range: 1\u0026ndash;7 days). The remaining 164 patients did not receive any laxatives. Among the patients with prophylactic laxatives, 114 of 268 patients had received additional laxatives, and the median time from initiating opioid therapy to administering additional laxatives was also 3 days (range: 1\u0026ndash;7 days). The remaining 154 patients never received any additional laxatives.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003ePrimary endpoint\u003c/h2\u003e\n \u003cp\u003eThe incidence of OIC in patients with and without prophylactic laxatives is shown in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. Before propensity score matching analysis, there was no statistically significant difference in the incidence of OIC between patients with and without prophylactic laxatives (47.8% vs 49.8%, odds ratio (OR)\u0026thinsp;=\u0026thinsp;0.92, 95% confidence interval (CI): 0.71\u0026ndash;1.21) (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA). After propensity score matching analysis, the incidence of OIC in patients with prophylactic laxatives was not significantly different from that in patients without prophylactic laxatives (48.1% vs 48.9%, OR\u0026thinsp;=\u0026thinsp;0.97, 95% CI: 0.69\u0026ndash;1.36) (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e The incidence of OIC in patients with and without prophylactic laxatives\u003c/p\u003e\n \u003cp\u003e(A) Before propensity score matching analysis\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"513\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.586744639376217%\" colspan=\"2\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.57115009746589%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eProphylactic laxatives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.05263157894737%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.789473684210526%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60.09852216748769%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003e(n = 370)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.90147783251231%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003e(n = 558)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.822612085769981%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eOIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.764132553606238%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003e(n = 455)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.78167641325536%\"\u003e\n \u003cp\u003e177\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.789473684210526%\"\u003e\n \u003cp\u003e278\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.05263157894737%\" rowspan=\"2\"\u003e\n \u003cp\u003e0.92\u003c/p\u003e\n \u003cp\u003e(0.71-1.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.789473684210526%\" rowspan=\"2\"\u003e\n \u003cp\u003e0.554\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.757785467128027%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003e(n = 473)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.21453287197232%\"\u003e\n \u003cp\u003e193\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.027681660899653%\"\u003e\n \u003cp\u003e280\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e(B) After propensity score matching analysis\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"513\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.586744639376217%\" colspan=\"2\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.57115009746589%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eProphylactic laxatives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.05263157894737%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.789473684210526%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.79802955665025%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003e(n = 268)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"53.20197044334975%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003e(n = 268)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.822612085769981%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eOIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.764132553606238%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003e(n = 260)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.51851851851852%\"\u003e\n \u003cp\u003e129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.05263157894737%\"\u003e\n \u003cp\u003e131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.05263157894737%\" rowspan=\"2\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003cp\u003e(0.69-1.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.789473684210526%\" rowspan=\"2\"\u003e\n \u003cp\u003e0.863\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.757785467128027%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003e(n = 276)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.8719723183391%\"\u003e\n \u003cp\u003e139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.37024221453287%\"\u003e\n \u003cp\u003e137\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003eOR, odds ratio; CI, confidence interval; OIC, opioid-induced constipation\u003c/p\u003e\n \u003cp\u003eThe types of prophylactic laxatives used are shown in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The incidence of OIC for osmotic laxatives, stimulant laxatives, PAMORA, others, and their combinations were 54.9%, 43.6%, 36.4%, 57.1%, and 47.8%, respectively. The p-value in the Fisher\u0026apos;s exact test was 0.148, and there was no significant difference in the incidence of OIC according to the types of prophylactic laxatives used.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003eFactors associated with the incidence of OIC\u003c/h2\u003e\n \u003cp\u003eNext, we examined the factors associated with the incidence of OIC after propensity score matching analysis (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Multivariable logistic analysis showed that age\u0026thinsp;\u0026ge;\u0026thinsp;65 years (OR\u0026thinsp;=\u0026thinsp;1.53, 95% CI: 1.07\u0026ndash;2.19) and ECOG PS\u0026thinsp;\u0026ge;\u0026thinsp;3 (OR\u0026thinsp;=\u0026thinsp;1.69, 95% CI: 1.04\u0026ndash;2.77) were associated with the incidence of OIC.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe propensity score matching analysis showed that the incidence of OIC in patients with and without prophylactic laxatives was comparable, suggesting that prophylactic laxatives are not necessarily required when initiating opioid therapy. In addition, age\u0026thinsp;\u0026ge;\u0026thinsp;65 years and ECOG PS\u0026thinsp;\u0026ge;\u0026thinsp;3 were shown in multivariate logistic analysis to be significant risk factors in the incidence of OIC.\u003c/p\u003e \u003cp\u003eWe found that age\u0026thinsp;\u0026ge;\u0026thinsp;65 years was a risk factor for OIC. Previous studies also showed that age\u0026thinsp;\u0026ge;\u0026thinsp;50 years [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and increased age [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] were associated with the incidence of OIC. Constipation occurs due to structural and functional changes of the anorectum in elderly people [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], so elderly patients may be especially prone to constipation. However, the association between OIC and age varies in the studies: one study found no association with age [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], while another study found that age\u0026thinsp;\u0026ge;\u0026thinsp;65 years decreased the risk of OIC [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Further investigation of the potential relationship between OIC and age is therefore warranted. We also found that ECOG PS\u0026thinsp;\u0026ge;\u0026thinsp;3 was another risk factor for OIC. To the best of our knowledge, the previous studies did not examine the association between performance status and the incidence of OIC. Poor general performance status has been associated with the incidence of constipation in patients with cancer and receiving palliative care [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In patients receiving chemotherapy, ECOG PS\u0026thinsp;\u0026ge;\u0026thinsp;2 has been reported to have an association with higher severity of constipation [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This evidence suggests that the patients with decreased physical performance status are prone to constipation.\u003c/p\u003e \u003cp\u003eOur results suggest that prophylactic laxatives do not affect the incidence of OIC. Despite using the same OIC criteria as the J-RIGID study, our findings were different: the J-RIGID study found significant effectiveness of prophylactic laxatives in preventing OIC. The incidence of OIC with prophylactic laxatives in our study (48.1%) was higher than that in the J-RIGID study (33.7%), although the incidences were comparable between our study and the J-RIGID study in those without prophylactic laxatives (48.9% vs 54.6% respectively) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Comparing patient background, performance status was different between these studies. While the J-RIGID study did not include ECOG PS\u0026thinsp;\u0026ge;\u0026thinsp;3 patients [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], our study included 305 patients (32.9%) with ECOG PS\u0026thinsp;\u0026ge;\u0026thinsp;3. Our study showed that ECOG PS\u0026thinsp;\u0026ge;\u0026thinsp;3 is a risk factor for OIC, so difference in performance status may affect the results. In actual clinical settings, performance status of patients receiving strong opioid analgesics vary, from ECOG PS 1 to 4. Therefore, our result is suggested to reflect the real-world clinical practice.\u003c/p\u003e \u003cp\u003eVarious types of laxatives are currently available for clinical use. In our study, osmotic laxatives, stimulant laxatives, PAMORA, other types, either alone or in combination, were administered, with osmotic laxatives being utilized in approximately 50% of patients. Recently, PAMORA, including naldemedine, has become part of clinical practice and is recommended for patients with OIC refractory to traditional laxative [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Several studies have demonstrated the effectiveness of PAMORA in treating OIC [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], but few studies have investigated the preventive effects of prophylactic laxatives on OIC. Ozaki et al. compared prophylactic naldemedine with prophylactic magnesium oxide in terms of the incidence of OIC. The incidence of OIC was found to be significantly lower in patients receiving naldemedine compared with those receiving prophylactic magnesium oxide. Additionally, they reported that naldemedine significantly prevented the decline in constipation-specific QOL and promoted complete spontaneous bowel movements [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, there has been no investigation into whether the incidence of OIC is significantly lower in patients receiving prophylactic naldemedine compared with those not receiving it. In our study, PAMORA was used as a prophylactic laxative in 24.6% of patients. Although the incidence of OIC in patients with prophylactic naldemedine (36.4%) tended to be lower than in those receiving other treatments (osmotic laxatives 54.9%, stimulant laxatives 43.6%, others 57.1%, and their combinations 47.8%), no statistical difference was found. Therefore, prospective studies are warranted to investigate the preventive effect of naldemedine on OIC.\u003c/p\u003e \u003cp\u003eSeveral limitations of our study need to be considered. First, it was performed in a single-center, it may be difficult to generalize the findings. Second, our study was a retrospective approach, which may reduce the validity of the data. Although propensity score matching analysis was used to adjust for comparative bias in patient background as much as possible to enhance the level of evidence, an RCT is needed to investigate the more accurate effects of prophylactic laxatives. Third, some studies have reported that transdermal fentanyl and buprenorphine have significantly lower incidence of OIC than slow-release oral morphine [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Therefore, the type of opioid analgesics used may affect the preventive effect of prophylactic laxatives on OIC. Some patients in our study had a change in the type of opioid analgesics changed during the observation period. Therefore, we did not perform a subgroup analysis based on the type of opioid analgesics. In the future, studies are needed to investigate whether the incidence of OIC with prophylactic laxatives varies depending on the type of opioid analgesics used. Finally, our data were collected from medical records over an 11-year period, during which several types of laxatives, especially naldemedine, were used.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWe retrospectively examined the effect of prophylactic laxatives on OIC using propensity score analysis. Prophylactic laxatives did not affect the incidence of OIC in our study. Our results suggest that prophylactic laxatives are not necessarily required when initiating opioid therapy. In addition, we found that age\u0026thinsp;\u0026ge;\u0026thinsp;65 years and ECOG PS\u0026thinsp;\u0026ge;\u0026thinsp;3 were associated with the incidence of OIC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eWe acknowledge proofreading and editing by Benjamin Phillis at the Clinical Study Support Center at Wakayama Medical University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eY.O is the first author and responsible for the concept and design of the study, data collection, analysis and interpretation. T.Ku, Y.T. conducted concept and design, and data interpretation. K.W. and T.S. were responsible for the concept and design, data interpretation and statistical analysis of the study data. T.Ka. were responsible for the concept and design, data interpretation, and supervision of the written manuscript. All authors have read and agreed to the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eDue to ethical constraints, data are not available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement:\u0026nbsp;\u003c/strong\u003eOwing to the anonymous nature of the data, informed consent was waived and a disclosure document was posted.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e No external funding was received in relation to this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWiffen PJ, Wee B, Moore RA (2016) Oral morphine for cancer pain. Cochrane Database Syst. 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Oncol 35:3859-3866\u003c/li\u003e\n\u003cli\u003eLacy BE, Cangemi DJ (2024) Opioids and the Gastrointestinal Tract: The Role of Peripherally Active \u0026micro;-Opioid Receptor Antagonists in Modulating Intestinal Permeability. Am J Gastroenterol\u003c/li\u003e\n\u003cli\u003eOzaki A, Kessoku T, Tanaka K, Yamamoto A, Takahashi K, Takeda Y, Kasai Y, Iwaki M, Kobayashi T, Yoshihara T, Kato T, Suzuki A, Honda Y, Ogawa Y, Fuyuki A, Imajo K, Higurashi T, Yoneda M, Taguri M, Ishiki H, Kobayashi N, Saito S, Ichikawa Y, Nakajima A (2022) Effectiveness of Naldemedine Compared with Magnesium Oxide in Preventing Opioid-Induced Constipation: A Randomized Controlled Trial. Cancers (Basel) 14:2112\u003c/li\u003e\n\u003cli\u003eTassinari D, Sartori S, Tamburini E, Scarpi E, Tombesi P, Santelmo C, Maltoni M (2009) Transdermal fentanyl as a front-line approach to moderate-severe pain: a meta-analysis of randomized clinical trials. J Palliat Care 25:172-80 \u003c/li\u003e\n\u003cli\u003eTassinari D, Sartori S, Tamburini E, Scarpi E, Raffaeli W, Tombesi P, Maltoni M (2008) Adverse effects of transdermal opiates treating moderate-severe cancer pain in comparison to long-acting morphine: a meta-analysis and systematic review of the literature. J Palliat Med 11:492-501 \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"opioid-induced constipation, cancer pain, prophylactic laxatives, ECOG PS","lastPublishedDoi":"10.21203/rs.3.rs-4851518/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4851518/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e Opioid-induced constipation (OIC) is problematic for patients with cancer receiving opioid therapy. Some guidelines recommend initiating regular laxatives at the same time as opioid analgesics. However, the effectiveness of prophylactic laxatives on OIC has not been widely demonstrated. We therefore examined the incidence of OIC among patients with and without prophylactic laxatives within one week after initiating strong opioid analgesics, and the factors associated with the incidence of OIC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Eligible patients were adults with cancer for whom strong opioid analgesics were initiated after admission and who remained hospitalized for over a week. Propensity score matching analysis was used to compare outcomes after adjusting for patient background.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eIn total, 928 patients were enrolled, from which 536 were selected after propensity score matching analysis. The incidence of OIC in patients with prophylactic laxatives was not significantly different from that without prophylactic laxatives (48.1% vs 48.9%, odds ratio (OR) = 0.97, 95% confidence interval (CI): 0.69-1.36). In multivariable logistic analysis, age ≥65 years (OR = 1.53, 95% CI: 1.07-2.19) and Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥3 (OR = 1.69, 95% CI: 1.04-2.77) were associated with the incidence of OIC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Prophylactic laxatives do not affect the incidence of OIC in our study. Our results suggest that prophylactic laxatives are not necessarily required when initiating opioid therapy. In addition, we found that age ≥65 years and ECOG PS ≥3 were associated in our study with the incidence of OIC.\u003c/p\u003e","manuscriptTitle":"Efficacy of prophylactic laxatives against opioid-induced constipation: retrospective propensity score matching analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-18 02:06:40","doi":"10.21203/rs.3.rs-4851518/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-24T07:07:18+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-18T13:26:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"22131203622561679803860684420968171350","date":"2024-11-04T10:14:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"141274287238452882607137261097428876257","date":"2024-10-31T09:45:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-30T19:59:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"136842373460647575258791295163530493139","date":"2024-09-28T13:25:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-23T05:52:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-18T18:34:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-09T06:08:08+00:00","index":"","fulltext":""},{"type":"submitted","content":"Supportive Care in Cancer","date":"2024-08-03T05:36:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"20868201-b860-4b12-909d-137f6a902277","owner":[],"postedDate":"September 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-27T16:03:00+00:00","versionOfRecord":{"articleIdentity":"rs-4851518","link":"https://doi.org/10.1007/s00520-025-09154-w","journal":{"identity":"supportive-care-in-cancer","isVorOnly":false,"title":"Supportive Care in Cancer"},"publishedOn":"2025-01-21 15:57:50","publishedOnDateReadable":"January 21st, 2025"},"versionCreatedAt":"2024-09-18 02:06:40","video":"","vorDoi":"10.1007/s00520-025-09154-w","vorDoiUrl":"https://doi.org/10.1007/s00520-025-09154-w","workflowStages":[]},"version":"v1","identity":"rs-4851518","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4851518","identity":"rs-4851518","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}