PLOS ONE

RESEARCH ARTICLE

Factors associated with non-response to

naldemedine for opioid-induced constipation
in cancer patients: A subgroup analysis
Yuko Kanbayashi ID1*, Mayumi Shimizu2, Yuichi Ishizuka2, Shohei Sawa2,
Katsushige Yabe2, Mayako Uchida3
1 Faculty of Pharmacy, Department of Education and Research Center for Clinical Pharmacy, Osaka Medical
and Pharmaceutical University, Takatsuki, Japan, 2 Department of Pharmacy, Seirei Hamamatsu General
Hospital, Hamamatsu, Japan, 3 Department of Education and Research Center for Pharmacy Practice,
Doshisha Women’s College of Liberal Arts, Kyotanabe, Japan
a1111111111
a1111111111 * [email protected]
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Abstract

Background
OPEN ACCESS
Opioid-induced constipation (OIC) is one of the most common adverse events of opioid ther-
Citation: Kanbayashi Y, Shimizu M, Ishizuka Y, apy and can severely reduce quality of life (QOL). Naldemedine is the orally available
Sawa S, Yabe K, Uchida M (2022) Factors
peripheral-acting μ-opioid receptor antagonist approved for OIC treatment. However in daily
associated with non-response to naldemedine for
opioid-induced constipation in cancer patients: A clinical practice, some cancer patients show insufficient control of OIC even while receiving
subgroup analysis. PLoS ONE 17(12): e0278823. naldemedine.
https://doi.org/10.1371/journal.pone.0278823

Editor: Masahiko Sumitani, University of Tokyo, Objective

JAPAN
To identify factors associated with non-response to naldemedine in cancer patients.
Received: May 21, 2022

Accepted: November 25, 2022

Methods
Published: December 9, 2022
This study retrospectively analyzed 127 cancer patients prescribed naldemedine at Seirei
Copyright: © 2022 Kanbayashi et al. This is an Hamamatsu General Hospital in Japan between November 2016 and June 2021. For the
open access article distributed under the terms of
regression analysis of factors associated with OIC, variables were extracted manually from
the Creative Commons Attribution License, which
permits unrestricted use, distribution, and electronic medical records. Naldemedine had been prescribed by the attending physician
reproduction in any medium, provided the original after the presence of OIC had been defined with reference to Rome IV diagnostic criteria.
author and source are credited.
Naldemedine was evaluated as “effective” in cases where the number of defecations
Data Availability Statement: Data cannot be increased at least once in the first 3 days after starting naldemedine. Multivariate logistic
shared publicly because the data contain potentially
regression analysis was performed to identify factors associated with non-response to nal-
identifying or sensitive patient information.
However, data are available from the institutional demedine. The data used were from the group of patients who received naldemedine in our
medical ethics review committee at Osaka Medical previous study.
Pharmaceutical University (contact via
[email protected]) for researchers who meet the
criteria for access to confidential data. Results
Funding: The author(s) received no specific Factors significantly associated with non-response to naldemedine included chemotherapy
funding for this work. with taxanes within 1 month of evaluation of naldemedine effect (odds ratio [OR] = 0.063;

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PLOS ONE Factors associated with non-response to naldemedine

Competing interests: The authors have declared 95% confidence interval [CI] = 0.007–0.568), and addition of or switching to naldemedine
that no competing interests exist. due to insufficient efficacy of prior laxatives (OR = 0.352, 95% CI = 0.129–0.966).

Conclusion
The identification of factors associated with non-response to naldemedine prescribed for
OIC may help improve QOL among cancer patients.

Introduction
Opioid-induced constipation (OIC) is one of the most common adverse events of opioid ther-
apy and can severely reduce quality of life (QOL) [1,2]. OIC is common among patients with
advanced cancers, with a prevalence of approximately 51–87% among patients receiving opioids
for pain management [1–4]. Naldemedine is the newest orally available peripheral-acting μ-opi-
oid receptor antagonist (PAMORA) approved for OIC treatment in adult patients [5–7]. Nalde-
medine improves OIC by binding to opioid receptors in the gastrointestinal tract and
antagonizing opioid analgesics [5]. The analgesic effects of many opioid analgesics are expressed
mainly via the central μ-opioid receptor [1,2,5]. Naldemedine is a PAMORA designed so as not
to inhibit the action of opioid analgesics in the central nervous system [5–7]. In phase III trials,
naldemedine was more effective than placebo for increasing the frequency of spontaneous
bowel movements among patients with OIC and cancer pain [6,7]. Naldemedine has also been
shown to improve patient-rated constipation-related symptoms and QOL [6–8].
However, in daily clinical practice, some advanced cancer patients show insufficient OIC con-
trol even while receiving naldemedine. We showed that in our previous study, OIC was poorly
controlled in 39.6% of patients, even when naldemedine was administered [9]. In addition, direct
evidence remains lacking regarding the comparative efficacy of naldemedine compared with pre-
vious laxative treatments (osmotic laxative [e.g., magnesium and sulfate salts, lactulose and poly-
ethylene glycol], stimulant laxative [e.g., anthranoid plant compounds, bisacodyl] or intestinal
secretagogues [lubiprostone]) and PAMORAs (e.g., methylnaltrexone or naloxegol).
Previous studies have clarified that risk factors for constipation include female sex, advanced
age, medications (e.g., anticholinergics, antipsychotics), diets, comorbidities, and mental states
[10–12]. We also showed that the risk factors of OIC were high body mass index (BMI), chemo-
therapy including a taxane within 1 month of evaluation of laxative effect, no use of naldemedine,
and addition or switching due to insufficient prior laxatives in advanced cancer patients [9].
Lavan et al. clarified in an observational study of an oncological population that constipation
occurred in 20% of patients [13]. In that study, causative medications included systemic antican-
cer therapies (53.3%) and opioids (17.3%) [13]. Although a previous study clarified use of nalde-
medine within 2 days of opioid initiation was a predictor of efficacy of naldemedine, including
patients with chronic pain, information remains limited for cancer patients [14,15]. This sub-
group analysis of our previous study [9] was therefore undertaken to identify predictors of non-
response to naldemedine prescribed for OIC among cancer patients, to help guide future strate-
gies toward improving QOL in advanced cancer patients receiving pain treatment with opioids.

Patients and methods

Study period and participants
This subgroup analysis analyzed 127 cancer patients with cancer pain who were prescribed
naldemedine at Seirei Hamamatsu General Hospital in Japan between November 2016 and

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PLOS ONE Factors associated with non-response to naldemedine

June 2021. Patients who discontinued naldemedine within 2 days, were discharged within 2
days after starting naldemedine, or lacked data on defecation for the first 3 days after naldeme-
dine prescription (missing data) were excluded. The data used were from the group of patients
who received naldemedine in our previous study [9].

Ethics and consent

All study protocols were approved by the Medical Ethics Review Committee at Seirei Hamama-
tsu General Hospital (approval no. 3310) and the Faculty of Pharmacy at Osaka Medical Phar-
maceutical University (approval no. 0088). All procedures were performed in accordance with
the ethical standards of Seirei Hamamatsu General Hospital, the Institutional Medical Ethics
Review Committee at Osaka Medical Pharmaceutical University and the 1964 Declaration of
Helsinki and its later amendments. Given the retrospective nature of this work, the need to
obtain informed consent was waived for the individual participants included in the study, in
accordance with the standards of the Seirei Hamamatsu General Hospital and Osaka Medical
Pharmaceutical University of Medicine Institutional Medical Ethics Review Committee.

Extraction of variables
Variables associated with potential risk factors for OIC were extracted from electronic medical
records and used for regression analysis. Variables extracted were factors considered as poten-
tially affecting OIC based on previous studies [1,9–13] or clinically rational mechanisms,
including demographic data (age, BMI, body surface area [BSA]), clinical data (Eastern Coop-
erative Oncology Group performance status [ECOG-PS], and stage of cancer), medication-
related data (chemotherapy administered within 1 month of the evaluation of naldemedine
effect, anti-cancer drugs administered within 1 month of the evaluation of naldemedine effect,
types of opioids, daily dose of opioid in milligrams of morphine-equivalents, concomitant lax-
ative, concomitant use of the serotonin 5-hydroxytryptamine-3 (5-HT3) receptor antagonists,
naldemedine prescription within 2 days of opioid initiation, and addition of or switching to
naldemedine due to insufficient efficacy of prior laxatives), and cancer type.

Outcomes measured
The presence of OIC was defined based on Rome IV diagnostic criteria [2] by the attending
physician, who then prescribed naldemedine. Details of the Rome IV diagnostic criteria used
for the diagnosis of OIC in this study have been published previously [16,17].
The retrospective nature of this study meant that insufficient data were able to be extracted
regarding stool properties after prescribing naldemedine. Naldemedine was thus evaluated as
“effective” in cases where the number of defecations increased at least once within the first 3
days after starting naldemedine.

Statistical analysis
This study used logistic regression analysis, with the response Y being a binary categorical vari-
able (naldemedine effective = 1; naldemedine not effective = 0) evaluated simultaneously with
multiple predictors for 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. First, univariate logistic regression analyses between outcomes and each potential
independent variable were performed. Subsequently, a multivariate logistic regression model
was constructed by employing those candidate variables showing values of P < 0.20 in

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PLOS ONE Factors associated with non-response to naldemedine

univariate regression or selected based on previous studies. Whether a difference in the effect
of naldemedine was seen according to the concomitant use of opioids or laxatives was also ana-
lyzed. Wilcoxon/Kruskal–Wallis test was used to identify significant differences between
groups.
For all statistical analyses, values of P < 0.05 (two-tailed) were considered significant. All
analyses were conducted using JMP Pro1 version 16.2 (SAS Institute, Cary, NC, USA).

Results
Of the 127 patients extracted, 106 patients were evaluated in this study (Fig 1). A total of 21
patients were excluded from this study due to discontinuation of naldemedine within 2 days
(n = 1), discharge within 2 days (n = 1) or missing data (n = 19). Table 1 presents the clinical
characteristics of the remaining 106 enrolled patients. Potential variables related to OIC and
the results of univariate logistic regression analyses are shown in Table 2. The response rate to
naldemedine was 60.4% (64/106). Univariate analyses only extracted “chemotherapy with tax-
ane within 1 month of evaluation of naldemedine effect” as a significant factor.
Multicollinearity was detected in BMI and BSA. BMI, which was considered the most clini-
cally relevant for constipation, was used for analysis. The selection procedure using factors
showing values of P < 0.20 in univariate regression or selection based on previous studies
identified the following variables: BMI, chemotherapy with taxane within 1 month of evalua-
tion of naldemedine effect, daily dose of opioid, use of naldemedine within 2 days of opioid
initiation, and addition of or switching to naldemedine due to insufficient efficacy of prior

Fig 1. Of the 127 patients extracted, 106 patients were evaluated in this study. A total of 21 patients were excluded from this study due to discontinuation of
naldemedine within 2 days (n = 1), discharge within 2 days (n = 1) or missing data (n = 19).
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PLOS ONE Factors associated with non-response to naldemedine

Table 1. Patient demographics and baseline clinical characteristics.

Patients
(n = 106)
Demographic data
Sex, male, n (%) 69 (65.9)
Age (y), median (range) 69 (42–89)
Height (cm), median (range) 162 (143–180)
Weight (kg), median (range) 51.9 (32.5–84)
Body mass index (kg/m2), median (range) 19.7 (13.0–28.9)
Body surface area (m2), median (range) 1.55 (1.22–2.04)
Clinical data
ECOG PS status
ECOG PS status 0, n (%) 0 (0)
ECOG PS status 1, n (%) 12 (11.3)
ECOG PS status 2, n (%) 46 (43.4)
ECOG PS status 3, n (%) 39 (36.8)
ECOG PS status 4, n (%) 9 (8.5)
Stage of cancer
Cancer stage I, n (%) 0 (0)
Cancer stage II, n (%) 5 (4.7)
Cancer stage III, n (%) 5 (4.7)
Cancer stage IV, n (%) 96 (90.6)
Cancer type
Colon, n (%) 10 (9.4)
Gastric, n (%) 5 (4.7)
Pancreatic, n (%) 28 (26.4)
Esophageal, n (%) 7 (6.6)
Lung, n (%) 16 (15.1)
Breast, n (%) 3 (2.8)
Head and neck, n (%) 19 (17.9)
Urologic, n (%) 8 (7.6)

ECOG PS, Eastern Cooperative Oncology Group performance status.

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laxatives. Neither platinum-based nor fluorouracil-based protocols other than taxanes were
extracted as significant factors in the univariate analysis.
Multivariate logistic regression analysis was performed using these variables. Significant
factors identified included chemotherapy with taxanes within 1 month of evaluation of nalde-
medine effect (odds ratio [OR] = 0.063; 95% confidence interval [CI] = 0.007–0.568), and addi-
tion of or switching to naldemedine due to insufficient efficacy of prior laxatives (OR = 0.352,
95% CI = 0.129–0.966) (Table 3). Since the ORs were less than 1.0, both factors were extracted
as factors associated with non-response to naldemedine.
No differences were evident in the effect of naldemedine among types of concomitant opi-
oids (P = 0.658) or according to the concomitant use of laxatives (P = 0.536).

Discussion
The results of this study showed that OIC was poorly controlled when taxane chemotherapy
was administered within 1 month of evaluation of the naldemedine effect or with addition of
or switching to naldemedine due to insufficient efficacy of prior laxatives. Our results are

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PLOS ONE Factors associated with non-response to naldemedine

Table 2. Extracted variables, and results of univariate logistic regression analyses (n = 106).
Patients Naldemedine not effective Naldemedine effective Odds ratio P value�
(n = 106) (n = 42) (n = 64) (95%CI)
Demographic data
Sex, male, n (%) 69 30 39 0.62 0.269
(65.9) (71.4) (60.9) (0.27–1.44)
Age (y), median (range) 69 69 70 1.01 0.777
(42–89) (42–88) (42–89) (0.97–1.04)
Body mass index (kg/m2), median (range) 19.7 19.7 19.6 0.95 0.434
(13.0–28.9) (13.0–28.9) (14.2–28.8) (0.84–1.08)
Body surface area (m2), median (range) 1.55 1.58 1.55 0.30 0.365
(1.22–2.04) (1.22–1.84) (1.24–2.04) (0.02–4.06)
Clinical data
Eastern Cooperative Oncology Group performance status 0/12/46/39/9 0/4/21/15/2 0/8/25/24/7 1.19 _
(0/1/2/3/4), n (%) (0/11.3/43.4/36.8/8.5) (0/9.5/50/35.7/4.8) (0/12.5/39.1/37.5/10.9) (0.73–1.94)
Eastern Cooperative Oncology Group performance status 48 17 31 2.46 0.278
3 & 4, n (%) (45.3) (40.5) (48.4) (0.48–12.4)
Stage of cancer (I/II/III/IV), 0/5/5/96 0/3/0/39 0/2/5/57 1.01 -
n (%) (0/4.7/4.7/90.6) (0/7.1/0/92.9) (0/3.1/7.8/89.1) (0.37–3.33)
Cancer Stage IV, n (%) 96 39 57 0.63 0.516
(90.6) (92.9) (89.1) (0.15–2.57)
Medication-related data
Chemotherapy given within 1 month of evaluation of 42 19 23 0.68 0.339
naldemedine effect, n (%) (39.6) (45.2) (35.9) (0.31–1.50)
Concomitant use of serotonin 5-HT3 receptor antagonist 33 15 18 0.70 0.410
(31.1) (35.7) (28.1) (0.31–1.62)
Anti-cancer drugs administered within 1 month of the evaluation of naldemedine effect
Taxanes, n (%) 9 7 2 0.16 0.028
(8.5) (16.7) (3.1) (0.03–0.82)
Fluorouracil, n (%) 15 5 10 1.37 0.592
(14.2) (11.9) (15.6) (0.43–4.34)
Platinum, n (%) 24 9 15 1.12 0.809
(22.6) (21.4) (23.4) (0.44–2.86)
Types of opioids
Morphine, n (%) 15 4 11 1.00 0.606
(14.2) (9.5) (17.2) (1.00–1.01)
Fentanyl, n (%) 5 2 3 0.98 0.986
(4.7) (4.8) (4.7) (0.16–6.15)
Oxycodone, n (%) 73 31 42 0.68 0.375
(68.9) (73.8) (65.6) (0.29–1.60)
Daily dose, morphine-equivalents (mg), median (range) 40 45 40 1.00 0.606
(10–576) (10–144) (15–576) (1.00–1.01)
Concomitant laxative
Magnesium oxide, n (%) 18 5 13 1.89 0.265
(17.0) (11.9) (20.3) (0.61–5.75)
Sennoside, n (%) 8 2 6 2.07 0.388
(7.6) (4.8) (9.4) (0.39–10.8)
Lubiprostone, n (%) 3 1 2 1.32 0.822
(2.8) (2.4) (3.1) (0.12–15.1)
Naldemedine prescription within 2 days of opioid initiation, n 10 4 6 0.98 0.980
(%) (9.4) (9.5) (9.4) (0.26–3.71)
Addition of or switching to naldemedine due to insufficient 63 29 34 0.51 0.105
prior laxative, n (%) (59.4) (69.0) (53.1) (0.22–1.15)
Cancer type
Colon, n (%) 10 3 7 1.60 0.516
(9.4) (7.1) (10.9) (0.39–6.56)
(Continued )

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PLOS ONE Factors associated with non-response to naldemedine

Table 2. (Continued)

Patients Naldemedine not effective Naldemedine effective Odds ratio P value�

(n = 106) (n = 42) (n = 64) (95%CI)
Gastric, n (%) 5 1 4 2.73 0.376
(4.7) (2.4) (6.3) (0.29–25.3)
Pancreatic, n (%) 28 13 15 0.68 0.392
(26.4) (31.0) (23.4) (0.29–1.64)
Esophageal, n (%) 7 3 4 0.86 0.856
(6.6) (7.1) (6.3) (0.18–4.08)
Lung, n (%) 16 6 10 1.11 0.851
(15.1) (14.3) (15.6) (0.37–3.33)
Breast, n (%) 3 0 3 - -
(2.8) (4.7)
Head and neck, n (%) 19 9 10 0.69 0.47
(17.9) (15.6) (0.25–1.88)
Urologic, n (%) 8 4 4 0.63 0.54
(7.6) (9.5) (6.3) (0.15–2.68)

CI, confidence interval; 5-HT3, 5-hydroxytryptamine-3.

�
P value pulled from univariate logistic regression analyses.

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similar to those of our previous study [9], suggesting that patients prone to developing OIC
may also be non-responsive to naldemedine. This study also showed that the effect of naldeme-
dine was not different types of concomitant opioids or according to the concomitant use of
laxatives.
Taxanes are anticancer drugs that have an adverse effect of constipation due to neuropathy
[18]. Taxane-induced neuropathy persists for a prolonged period in clinical practice. If taxanes
were administered within 1 month of evaluation of naldemedine effect, those adverse effects
may still be present. As naldemedine is a PAMORA, control of constipation caused by taxanes
may be difficult. Taxane-induced neuropathy may also affect the enteric nervous system and
may decrease intestinal motility. Colonic irritant laxatives such as castor oil may thus be pref-
erable. If paralysis of the intestinal tract occurs, intestinal decompression or other measures
may be necessary. This point needs further validation. On the other hand, naldemedine is pri-
marily metabolized by cytochrome P450 3A4 (CYP3A4) to form nor-naldemedine [19]. A pre-
vious study showed that coadministration of a P-glycoprotein inhibitor, CYP3A inhibitors,
and a CYP3A inducer had notable effects on the pharmacokinetics of naldemedine [19]. In
this study, some patients were receiving taxane chemotherapy at the time of evaluation of nal-
demedine effect. Enzyme systems such as CYP3A4 participate in metabolism of taxanes such
as paclitaxel and docetaxel [20,21]. Although no reports have described drug-drug interactions
between naldemedine and taxanes, the possibility of reduced naldemedine effects due to drug-

Table 3. Relative odds of naldemedine effectiveness in a multivariate model (n = 106).

Variable Odds ratio 95% confidence interval P value
Lower endpoint Upper endpoint
Body mass index 0.890 0.776 1.022 0.098
Taxanes 0.063 0.007 0.568 0.014
Daily dose in morphine-equivalents (mg) 1.002 0.995 1.009 0.585
Naldemedine prescription within 2 days of opioid initiation 0.411 0.085 1.981 0.268
Addition of or switching to naldemedine due to insufficient prior laxative 0.352 0.129 0.966 0.043
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PLOS ONE Factors associated with non-response to naldemedine

drug interactions needs to be kept in mind, particularly in patients undergoing chemotherapy

with taxanes. This point needs further verification using data from daily clinical practice. In
recent years, new opioid prescriptions are often made by oncologists during chemotherapy.
Thus, this information is useful for physicians who examine patients with breast, ovarian, or
lung cancers who are often prescribed taxanes, and may help to improve QOL for patients. In
particular, since these cancer patients are often treated on an outpatient basis, patients need to
receive explanations that they should carefully monitor their own bowel movements at home.
This information will also prove useful for pharmacists in providing medication guidance.
However, the number of patients treated with taxanes in this study was small (9 patients).
Therefore, further studies with larger numbers of patients are needed to establish evidence.
Addition of or switching due to insufficient prior laxatives was also extracted as a factor
associated with non-response to naldemedine being prescribed for OIC. Naldemedine is a
PAMORA, and the mechanism of action suggests that efficacy may be greater for a shorter
duration of opioid exposure. Administration of naldemedine from the initiation of opioids
may also reduce the risk of developing the opioid-withdrawal symptoms that can be seen
when naldemedine is started during opioid administration [22,23]. On the other hand, the fac-
tor “naldemedine prescription within 2 days of opioid initiation” was not extracted as a signifi-
cant factor in the present study. Some patients were undergoing chemotherapy at the time of
evaluation of naldemedine effect. Recently, the serotonin 5-HT3 receptor antagonists have
been commonly used in preventing chemotherapy-induced nausea and vomiting. However,
the serotonin 5-HT3 receptor antagonist may have also acted on serotonin receptors in the
intestine and decreased intestinal motility [24]. Thus, laxative therapy is often indicated.
Although not significant in this study, it has been suggested that concomitant use of the seroto-
nin 5-HT3 receptor antagonists is a nonresponding factor of naldemedine. The guidelines for
OIC also suggest that classic laxatives should be used first, with the use of novel constipation
treatments or PAMORA recommended only if the effects prove insufficient [25,26]. The
appropriate timing of naldemedine administration needs to be verified in the future.
Although BMI was not a significant factor, our results showed that naldemedine tended to
be ineffective for patients with higher BMI. Previous studies have reported obesity as a risk fac-
tor for constipation [27]. The results of this study were thus consistent with previous findings,
and further study of this issue is warranted.
Daily dose of opioid was also not extracted as a significant factor. Roeland et al. showed a
weak to absent association between total daily opioid dose and constipation in patients with
cancer [28]. This result was again consistent with our findings. Our results suggest that OIC
can be controlled with naldemedine regardless of the opioid dose.
OIC has a considerable effect on QOL for cancer patients receiving opioids. Cancer patients
may occasionally discontinue opioid use due to OIC and endure pain. Patients with advanced
cancer are also likely to experience severe distress, reduced work productivity, poor QOL, and
increased healthcare utilization [1,29]. Several studies have reported improved QOL for cancer
patients with improvements in constipation [30,31]. Clinicians should thus be alert to the
occurrence of OIC and work to improve this symptom. The identification of factors associated
with non-response to naldemedine being administered for OIC in this study may therefore
help improve QOL for cancer patients.
In the present study, no difference in the effect of naldemedine was seen among types of
concomitantly used opioids or laxatives. Among opioids, fentanyl has been reported to have a
lower risk of constipation as a side effect [32]. However, the type of concomitantly used opi-
oids in this study did not appear to affect the efficacy of naldemedine. Concomitant use of lax-
atives was also not found to have any effect on the efficacy of naldemedine.

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PLOS ONE Factors associated with non-response to naldemedine

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. That is, potential confound-
ing, selection, and information biases could not be fully excluded in this study. Second,
completely controlling for factors affecting constipation was difficult, given the wide variety of
such factors, including medications (e.g., anticholinergics and antipsychotics), diet, comorbid-
ities (e.g., cerebrovascular diseases), and mental state. Third, since this study was performed at
a single institute, and it only examined a relatively small number of patients, some degree of
selection bias would have been present. The present findings therefore need to be confirmed
in further studies. Nevertheless, these results may help improve QOL among patients with
advanced cancer and cancer pain.
In conclusion, administration of a chemotherapeutic regimen that included taxanes within
one month before the evaluation of naldemedine effect and addition of or switching to nalde-
medine due to insufficient efficacy of prior laxatives were identified as factors associated with
non-response to naldemedine being administered for OIC in cancer patients.

Acknowledgments
We wish to thank all the patients and medical staff at Seirei Hamamatsu General Hospital who
participated in this study.

Author Contributions
Conceptualization: Yuko Kanbayashi, Mayumi Shimizu, Yuichi Ishizuka, Shohei Sawa, Kat-
sushige Yabe, Mayako Uchida.
Data curation: Mayumi Shimizu, Yuichi Ishizuka, Shohei Sawa, Katsushige Yabe.
Formal analysis: Yuko Kanbayashi.
Investigation: Yuko Kanbayashi.
Methodology: Yuko Kanbayashi.
Supervision: Yuko Kanbayashi, Mayako Uchida.
Validation: Yuko Kanbayashi, Mayumi Shimizu, Yuichi Ishizuka, Shohei Sawa, Katsushige
Yabe, Mayako Uchida.
Visualization: Yuko Kanbayashi, Mayumi Shimizu, Yuichi Ishizuka, Shohei Sawa, Katsushige
Yabe, Mayako Uchida.
Writing – original draft: Yuko Kanbayashi.
Writing – review & editing: Yuko Kanbayashi, Mayumi Shimizu, Mayako Uchida.

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