Predictors for Effectiveness of Naldemedine in Patients with Cancer Pain: A Retrospective, Single-Institution Analysis

Purpose To identify predictors for the effectiveness of naldemedine. Methods Participants comprised 106 advanced cancer patients receiving pain treatment with opioids who were prescribed naldemedine for OIC at Seirei Hamamatsu General Hospital in Japan between November 2016 and June 2021.For the regression analysis of factors associated with OIC, variables were extracted manually from medical charts. The effectiveness of naldemedine was evaluated 3 days after administration, based on whether patients showed OIC. Presence of OIC was dened based on Rome IV diagnostic criteria. Multivariate logistic regression analysis was performed to identify predictors for naldemedine effectiveness. Values of P < 0.05 (two-tailed) were considered signicant.

Naldemedine improves OIC by binding to opioid receptors in the gastrointestinal tract and antagonizing opioid analgesics. The analgesic effects of many opioid analgesics are expressed mainly via the central µ-opioid receptors. Naldemedine is a PAMORA designed so as not to inhibit the action of opioid analgesics in the central nervous system [6,7]. Naldemedine has also been shown to improve patientrated constipation-related symptoms and QOL [6-10]. Previous studies have suggested that no baseline variables affect the e cacy or safety of once-daily oral naldemedine 0.2 mg in patients with OIC [11,12].
On the other hand, in daily clinical practice, some advanced cancer patients have shown insu cient OIC control even while receiving naldemedine [3,12]. This retrospective study was thus undertaken to identify predictors for the effectiveness of naldemedine, to help guide future strategies toward improving QOL in advanced cancer patients receiving pain treatment with opioids.

Extraction of Variables
Variables associated with the effectiveness of naldemedine were extracted from clinical records and used for regression analysis. Variables extracted were factors potentially affecting the effectiveness of naldemedine: demographic data (age, height, weight, body surface area, body mass index [BMI]), Eastern Cooperative Oncology Group performance status, daily dosage of opioid in milligrams of morphineequivalents, types of concomitant laxatives, types of opioids, stage of cancer, anti-cancer drugs administered within 1 month of the evaluation of naldemedine effectiveness, timing of naldemedine administration, and cancer type.
The effectiveness of naldemedine was evaluated 3 days after administration, based on whether the patient had OIC. The presence of OIC was de ned based on Rome IV diagnostic criteria [3]. Details of the Rome IV diagnostic criteria for the diagnosis of OIC used in this study have been published previously [13][14][15].

Statistical Analysis
The analytical procedure employed was logistic regression, with the response = Y being a binary categorical variable (naldemedine effective or naldemedine not effective) and evaluated simultaneously with multiple predictors of effectiveness of naldemedine = X. To improve accuracy, predictors that were not essential to explain the response = Y were excluded.
Independent variables were analysed for multicollinearity (correlation coe cient |r| ≥ 0.7), since correlations among variables can lead to unreliable and unstable results of regression analyses. Independent variables were extracted based on the strength of the correlation with effectiveness of naldemedine or clinical signi cance. First, univariate logistic regression analyses between outcomes and each potential independent variable were performed. Subsequently, a multivariate logistic regression Page 4/12 model was constructed by employing the forward-backward stepwise selection procedure with the resulting candidate variables.
For all statistical analyses, values of P < 0.05 (two-tailed) were considered signi cant. All analyses were conducted using JMP version 14.3.0 (SAS Institute, Cary, NC).

Results
All 139 patients were newly prescribed naldemedine, but 33 patients were excluded from this study due to insu cient data. Table 1 presents the clinical characteristics of the remaining 106 enrolled patients, potential variables related to OIC, and the results of univariate analyses. The forward-backward stepwise selection procedure identi ed the following candidate variables: BMI, chemotherapy with taxane within 1 month of evaluation of naldemedine effectiveness, daily dosage of opioid, use of naldemedine prescription within 2 days of opioid initiation, and addition of or switching to naldemedine due to insu cient prior laxatives.

Discussion
The multivariate logistic regression analysis performed in this study showed that predictors for naldemedine effectiveness included chemotherapy with taxanes within 1 month of evaluation of naldemedine effectiveness and addition of or switching to naldemedine due to insu cient prior laxatives.
The results of this study showed that OIC was poorly controlled when chemotherapy with taxane was given within 1 month of evaluation of naldemedine effectiveness. Taxanes are anticancer drugs that have a side effect of constipation due to neuropathy [16]. Taxane-induced neuropathy persists for a long period in clinical practice. If taxanes was administered within 1 month of evaluation of naldemedine effectiveness, side effects may persist. OIC control may thus be di cult. On the other hand, naldemedine is primarily metabolized by cytochrome P450 3A4 (CYP3A4) to form nor-naldemedine [17]. In this study, some patients were receiving chemotherapy with taxanes at the time of evaluation of naldemedine effectiveness. Molecular species such as CYP3A4 are involved in metabolism of taxanes such as paclitaxel and docetaxel [18,19]. Although there are no reports of drug-drug interactions between naldemedine and taxanes, it is necessary to consider the possibility to reduce naldemedine effectiveness due to drug-drug interactions, especially in patients undergoing chemotherapy with taxanes. This point needs further veri cation in daily clinical practice. In recent years, new opioid prescriptions are often made by oncologists during chemotherapy, rather than by palliative care physicians. Oncologists who prescribe opioids need to consider OIC control during chemotherapy, particularly in patients receiving taxane-based chemotherapy.
Addition of or switching due to insu cient prior laxatives was also extracted as a risk factor for OIC. Naldemedine is a PAMORA, and the mechanism of action clearly suggests that the shorter the period of exposure to opioids, the more likely the effects of naldemedine are to manifest. On the other hand, in the present study, the factor "naldemedine prescription within 2 days of opioid initiation" was not extracted as a signi cant factor. Some of the patients were undergoing chemotherapy at the time of evaluation of naldemedine effectiveness. In other words, the serotonin receptor antagonist may have also acted on serotonin receptors in the intestine and decreased intestinal motility [20]. The guidelines for OIC also suggest that classic laxatives should be used rst, with the use of novel constipation treatments or PAMORA recommended only if the effects prove insu cient [21][22][23]. The appropriate timing of naldemedine administration needs to be veri ed in the future.
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. Second, since this study was performed at a single institute, prospective studies involving multiple centres are needed to con rm the results.
In conclusion, no administration of a chemotherapeutic regimen that included taxanes within one month before the evaluation of naldemedine effectiveness and no addition of or switching to naldemedine due to insu cient prior laxatives were identi ed as predictors of effectiveness of naldemedine in advanced cancer patients with cancer pain. However, our ndings need to be con rmed in further studies. Nevertheless, these results may assist to improve QOL among advanced cancer patients with cancer pain.