Risk factors for opioid-induced constipation in cancer patients: a single-institution, retrospective analysis

To identify risk factors for opioid-induced constipation (OIC). This study retrospectively analyzed 175 advanced cancer patients who were receiving pain treatment with opioids and were newly prescribed laxatives for OIC at Seirei Hamamatsu General Hospital between November 2016 and June 2021. For the regression analysis of factors associated with OIC, variables were extracted manually from clinical records. The effect of newly prescribed laxatives for OIC was evaluated as “effective” in cases where the number of spontaneous bowel movements increased at least once in the first 3 days. The OIC was defined based on Rome IV diagnostic criteria. Multivariate logistic regression analysis was performed to identify risk factors for OIC. Optimal cutoff thresholds were determined using receiver operating characteristic analysis. Values of P < 0.05 (two-tailed) were considered significant. Significant factors identified included body mass index (BMI) (odds ratio [OR] = 0.141, 95% confidence interval [CI] = 0.027–0.733; P = 0.020), chemotherapy with taxane within 1 month of evaluation of laxative effect (OR = 0.255, 95% CI = 0.068–0.958; P = 0.043), use of naldemedine (OR = 2.791, 95% CI = 1.220–6.385; P = 0.015), and addition or switching due to insufficient prior laxatives (OR = 0.339, 95% CI = 0.143–0.800; P = 0.014). High BMI, chemotherapy including a taxane within 1 month of evaluation of laxative effect, no use of naldemedine, and addition or switching due to insufficient prior laxatives were identified as risk factors for OIC in advanced cancer patients with cancer pain.


Introduction
Opioid analgesics represent the standard of treatment for moderate-to-severe cancer pain [1,2]. While definitely effective in managing cancer pain, opioid use is often limited by adverse effects, which can lead to their discontinuation following significantly negative impacts on quality of life (QOL) [2,3]. Opioid-induced constipation (OIC) remains the most common adverse event associated with opioid use. OIC is common among advanced cancer patients, with a prevalence of approximately 51-87% in patients taking opioids for pain management [4][5][6]. OIC has a considerable effect on the QOL for cancer patients on opioid treatment [6,7]. Cancer patients tend to discontinue or avoid opioid treatment because of OIC and may sacrifice effective pain control to prevent constipation [6][7][8]. Advanced cancer patients tend to associate constipation with severe distress, and are also likely to experience severe distress, reduced work productivity, poor QOL, and increased healthcare utilization [6][7][8]. Currently in Japan, pharmacological treatments involve the use of traditional laxatives (e.g., stimulants, stool softeners, and osmotic laxatives) and newer agents like chloride channel activators, guanylate cyclase C receptor agonists, ileal bile acid transporter inhibitors, and peripherally acting mu-opioid receptor agonists (PAMORAs), including naldemedine [6,9,10]. On the other hand, some patients have insufficient OIC control even with these laxatives in clinical practice. This retrospective study was thus undertaken to identify risk factors for OIC to help guide future strategies toward improving QOL in cancer patients receiving pain treatment with opioids.

Study period and participants
This study retrospectively analyzed 208 cancer patients newly prescribed laxatives for OIC at Seirei Hamamatsu General Hospital between November 2016 and June 2021. All study protocols were approved by the Medical Ethics Review Committee at Seirei Hamamatsu General Hospital (approval no. 3310) and the Faculty of Pharmacy at Osaka Medical Pharmaceutical University (approval no. 0088).

Extraction of variables
Variables associated with alleviation of OIC were extracted from clinical records when laxatives were newly prescribed for OIC and used for regression analysis. Variables extracted were factors potentially affecting OIC based on previous studies [11][12][13] and clinical significance: demographic data (age, height, weight, body surface area [BSA], body mass index [BMI]), Eastern Cooperative Oncology Group Performance Status (ECOG-PS), stage of cancer, anti-cancer drug administered within 1 month of evaluation of laxative effect, types of opioid, daily dosage of opioid in morphine-equivalents (milligrams), types of laxative, laxative prescription within 2 days of opioid initiation, addition or switching due to insufficient prior laxative as diagnosed by the physician, and cancer type.
A retrospective nature of study failed to extract enough data on stool properties after prescribing laxatives. Thus, the effect of newly prescribed laxatives for OIC was evaluated as "effective" in cases where the number of spontaneous bowel movements increased at least once in the first 3 days after starting laxatives. The OIC was defined based on Rome IV diagnostic criteria [9]. Details of Rome IV diagnostic criteria for the diagnosis of OIC used in this study have been published previously [14][15][16].

Statistical analysis
The analytical procedure employed was logistic regression, with the response = Y being a binary categorical variable (laxative effective or laxative not effective) and evaluated simultaneously with multiple predictors of OIC = X.
Independent variables were analyzed for multicollinearity (correlation coefficient |r|≥ 0.7), since correlations among variables can lead to unreliable and unstable results of regression analyses. Independent variables were extracted based on previous studies [11][12][13] or clinical significance.
First, univariate logistic regression analyses between outcomes and each potential independent variable were performed. Subsequently, a multivariate logistic regression model was constructed by employing with the resulting candidate variables with P < 0.20 in univariate regression or selected based on previous studies [11][12][13]. Optimal cutoff thresholds were determined using receiver operating characteristic (ROC) curve analysis.
For all statistical analyses, values of P < 0.05 (two-tailed) were considered significant. All analyses were performed using JMP version 14.3.0 (SAS Institute, Cary, NC).

Results
All 208 patients were newly prescribed laxatives for OIC, but 33 patients were excluded from this study due to insufficient data. Table 1 presents the clinical characteristics of the remaining 175 enrolled patients, potential variables related to OIC, and the results of univariate analyses. The selection procedure with P < 0.20 in univariate regression or selected based on previous studies identified the following candidate variables: age, BMI, chemotherapy with taxane within 1 month, daily dosage of opioid, use of naldemedine, laxative prescription within 2 days of opioid initiation, and addition or switching due to insufficient prior laxatives.

Discussion
The multivariate logistic regression analysis performed in this study showed that risk factors for OIC included high BMI, chemotherapy with a taxane within 1 month, no use of naldemedine, and addition or switching of laxatives.
BMI was extracted as a significant factor for OIC. Previous studies have reported obesity as a risk factor for constipation [17,18]. Yurtdaş et al. discussed a connection between obesity and constipation, low physical activity, inadequate dietary fiber intake, and poor nutritional habits (fast food, not eating enough fiber, and not drinking enough water) which are reasons for obesity and constipation [17]. The results of this study were also consistent with the results of previous studies. On the other hand, ROC curve analysis revealed a BMI cutoff of ≥ 21.5 kg/ m 2 for the group likely to be poorly OIC-controlled. The World Health Organization has defined obese or overweight patients as individuals with BMI ≥ 25 kg/m 2 [19]. Patients with BMI ≥ 21.5 kg/m 2 do not represent an obese population, so this result seems to be due to the fact that the target population for analysis comprised advanced cancer patients with cancer-related pain, mostly with cachexia and not good ECOG-PS. In fact, in our study, many of the patients were cancer stage 4 or ECOG-PS 2 or higher (Table 1). Furthermore, this might be due to the difference in physique between Japanese and Westerners. Our results only suggested that the higher the BMI, the less effective laxatives were. Further verification is needed in this regard among cancer patients with OIC. The results of this study showed that OIC was poorly controlled when chemotherapy with taxane was given within 1 month. Taxanes are anti-cancer drugs that have an adverse effect of constipation due to neuropathy [20]. Taxane-induced neuropathy persists for a long period in clinical practice. If a taxane was administered within 1 month of evaluation of laxative effect, adverse effects may persist. OIC control may thus be difficult.
The initiation of naldemedine was extracted as a predictor of the effectiveness of OIC control. All were opioid-treated patients in this study, suggesting that naldemedine is the most effective for OIC. Naldemedine is a novel PAMORA being developed for the treatment of OIC without affecting central analgesia. Therefore, this mechanism of action suggests that the use of naldemedine will prove effective in avoiding OIC. However, the guidelines for OIC suggest that classic laxatives should be used first, and if the effects are insufficient, use of novel constipation treatments or PAMORA is recommended [21][22][23]. Further verification of the appropriate timing of naldemedine initiation is needed.
Addition or switching due to insufficient prior laxatives was also extracted as a risk factor for OIC. Poor control of OIC clearly makes sufficient control difficult to obtain, even with the addition of or switching to new laxatives. OIC is less tolerant and requires early control. Clinicians need to make early adjustments to address OIC.
Several limitations to the current study need to be considered. First, the retrospective nature of the study may have decreased the validity of the data obtained. The evaluation of laxative effect depends on the descriptions only due to the number of spontaneous bowel movements increased at least once in the first 3 days after starting laxatives in the chart. Therefore, there is a possibility of misclassification. Second, it was difficult to completely exclude factors affecting constipation, such as medication (e.g., anticholinergics, antipsychotics), diets, comorbidities, and mental states. Third, since this study was performed at a single institute and involved a relatively small number of patients, prospective multicenter studies are needed to confirm the results. Fourth, potential confounding, selection, and information biases cannot be fully excluded in this study.
In conclusion, high BMI, chemotherapy including a taxane within 1 month of evaluation of laxative effect, no use of naldemedine, and addition or switching due to insufficient prior laxatives were identified as risk factors for OIC in advanced cancer patients with cancer pain. However, our findings need to be confirmed in further studies. Nevertheless, these results may assist in developing strategies to improve QOL among patients with OIC. Author contribution YK: concept and design, data analysis, data interpretation, manuscript writing; YI, MS, SS, and KY: concept and design, data acquisition, data interpretation; MU: concept and design, data interpretation, supervision of the manuscript. All authors read and approved the final manuscript.
Data availability Data are not available due to ethical restrictions.
Code availability Not applicable. This study retrospectively analyzed 208 cancer patients newly prescribed laxatives for OIC or OIC prevention at Seirei Hamamatsu General Hospital between November 2016 and June 2021. All study protocols were approved by the Medical Ethics Review Committee at Seirei Hamamatsu General Hospital (approval no. 3310) and the Faculty of Pharmacy at Osaka Medical Pharmaceutical University (approval no. 0088).