Abstract
Background:
Opioid-induced constipation is a practical bowel-management issue when opioids are started for cancer pain, but real-world naldemedine timing and subsequent laxative needs remain variable.
Objective:
To describe naldemedine initiation timing/context after oxycodone start and early additional laxative adjustment among adults with cancer.
Design:
Single-center retrospective cohort study using routine clinical records.
Setting/Subjects:
Adults with cancer pain in a single-center Japanese cancer-care setting who started oxycodone between June 1, 2017, and December 31, 2018, and subsequently received naldemedine.
Measurements:
Concurrent initiation was naldemedine prescribed as part of the same oxycodone-start prescribing decision; reactive initiation was naldemedine added as a separate prescribing decision after physician-recognized constipation during ongoing oxycodone therapy. The primary outcome was prescription-record-based additional laxative initiation or dose escalation of existing laxatives within 7 days after naldemedine initiation. Secondary outcomes were oxycodone-to-naldemedine interval and diarrhea-related discontinuation within 28 days.
Results:
Among 101 patients, the primary outcome occurred in 6/31 (19.4%) concurrent and 2/70 (2.9%) reactive cases (p = 0.010). The reactive group had a median oxycodone-to-naldemedine interval of 15 days (interquartile range, 5–83); diarrhea-related discontinuation occurred in 2/31 (6.5%) versus 6/70 (8.6%).
Conclusions:
Concurrent naldemedine at oxycodone start did not eliminate early additional laxative initiation or escalation. Naldemedine timing should be understood within individualized bowel-management planning, with conventional or rescue laxatives considered when clinically appropriate.
Keywords: cancer pain, laxatives, naldemedine, oxycodone, opioid-induced constipation, palliative care
Introduction
Oxycodone is commonly used for cancer pain, and opioid-induced constipation (OIC) is a frequent, clinically burdensome adverse effect that can worsen symptoms, daily functioning, quality of life, and adherence to analgesic treatment.1,2 In cancer care, bowel management is therefore part of opioid-initiation planning, and guideline-based care emphasizes assessment, management of contributory factors, treatment, and reassessment of constipation in patients with advanced cancer.3,4 Naldemedine, a peripherally acting μ-opioid receptor antagonist (PAMORA), has demonstrated efficacy and acceptable tolerability for OIC in patients with cancer.5,6 Naldemedine is available beyond Japan, including in the United States and Europe, with jurisdiction-specific indications. 7
However, the practical timing of naldemedine initiation in routine care remains less well defined. Physicians may start naldemedine at oxycodone initiation or add it later after constipation is recognized, and these observed initiation patterns may be associated with different needs for conventional laxative adjustment, follow-up, and diarrhea monitoring. This question is clinically relevant because OIC can occur early after opioid initiation and real-world assessment may be variable.2,8 Although recent studies have supported the clinical relevance of early naldemedine use, short real-world data describing concurrent and later/reactive initiation patterns remain limited.9,10 Takemura et al. examined inpatient naldemedine-laxative combinations. 11
This retrospective cohort study aimed to describe naldemedine initiation timing/context after oxycodone start and early additional laxative adjustment within 7 days as a prescription-record-based measure of bowel management activity. The 2017–2018 cohort provides an early post-approval real-world adoption snapshot, not a test of naldemedine monotherapy efficacy.
Methods
Study design and setting
We conducted a single-center retrospective cohort study at the University of Toyama Hospital (Toyama, Japan), a tertiary academic cancer-care hospital in Japan, using routine electronic medical and prescribing records. The study described observed naldemedine initiation patterns during oxycodone treatment in adults with cancer pain; naldemedine timing reflected routine physician judgment rather than a standardized institutional protocol.
Data source and case identification
We reviewed electronic medical and prescribing records for inpatient and outpatient care. Potentially eligible cases were identified from oxycodone initiation and subsequent naldemedine use, and chart review confirmed eligibility, exposure classification, medication dates, physician-recognized constipation, additional laxative events, and diarrhea-related discontinuation. Physician-recognized constipation was defined by chart documentation of constipation/OIC or constipation-related prescribing; Bristol Stool Form Scale (BSFS), Rome criteria, and standardized severity scores were not routinely available.
Participants
We included adults aged ≥18 years with cancer who started oxycodone for cancer pain between June 1, 2017, and December 31, 2018, and received at least one naldemedine prescription during follow-up. Opioid-naive status was not required. Patients switched to oxycodone from another strong opioid, and those receiving oxycodone for noncancer pain were excluded. The cohort was restricted to the prespecified decision point of oxycodone start.
Exposure definition
Patients were classified by chart review. Here, “initiation pattern” denotes observed timing and clinical context in routine prescribing, not a formal institutional workflow. Concurrent initiation was defined as naldemedine prescribed as part of the same opioid-start prescribing decision when oxycodone was initiated. Reactive initiation was defined as naldemedine added as a separate prescribing decision after the initial oxycodone-prescribing decision during ongoing oxycodone therapy in the setting of physician-recognized constipation. Classification used the chart-reviewed prescribing sequence and clinical context rather than elapsed calendar days alone. A same-calendar-day interval could still be reactive when naldemedine was added after the initial oxycodone-start decision on that date.
Outcome definitions
The primary outcome was additional laxative initiation or dose escalation of existing laxatives within 7 days after naldemedine initiation. This prescription-record-based outcome was used to describe early bowel-management activity after naldemedine initiation. Laxative events were identified from prescribing records and documented chart entries. Secondary outcomes were days from oxycodone initiation to naldemedine initiation and diarrhea-related discontinuation of naldemedine within 28 days. We calculated the oxycodone-to-naldemedine interval when both dates were available and summarized values after chronology checks. Diarrhea-related discontinuation was defined as naldemedine discontinuation with diarrhea documented as the reason in the medical record.
Baseline variables and concomitant medications
We abstracted age, sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS), care setting at naldemedine initiation, primary cancer site, anticancer treatment status, starting oxycodone dose, oxycodone dose at naldemedine initiation, and maximum oxycodone dose. Concomitant medication variables included the presence and number of laxatives, magnesium oxide, sennosides, other documented laxatives, and antiemetic use at naldemedine initiation. Medication variables were based on prescribing records. Antiemetics were recorded as a broad concomitant medication category; subclasses were not analyzed. Variables were summarized descriptively and not used for adjusted modeling.
Statistical analysis
Continuous variables were summarized as medians with interquartile ranges or ranges, and categorical variables as counts and percentages. Between-group comparisons used Fisher’s exact test for categorical variables and the Mann–Whitney U test for continuous variables in R. Because initiation timing was physician-selected and groups differed at baseline, p values were interpreted descriptively, not causally. We did not perform multivariable adjustment or imputation; patients missing endpoint-specific data were excluded from that analysis.
Ethics
The institutional review board of Toyama University Hospital approved the study (approval no. Rin 29-117). Given the retrospective design, written informed consent was waived, and study information was disclosed via an opt-out approach per institutional policy.
Results
Among 101 patients who received naldemedine after oxycodone initiation, 31 were classified as concurrent and 70 as reactive (Table 1). Demographic and broad disease-related variables were generally similar, but bowel-management intensity and supportive-care context differed between groups. The reactive group more often had concomitant laxatives at naldemedine start, including more frequent magnesium oxide use and a greater proportion receiving two or more laxatives, and it also had higher oxycodone doses at naldemedine start; concomitant antiemetic use was more frequent in the concurrent group (Table 1).
Table 1.
Patient Characteristics
| Variable | Concurrent (n = 31) | Reactive (n = 70) | p Value |
|---|---|---|---|
| Age, years, median (IQR) | 69 (66–74) | 67 (59–73) | 0.221 |
| Male sex, n (%) | 20/31 (64.5%) | 45/70 (64.3%) | 1.000 |
| ECOG PS 0–2/3–4, n | 24/7 | 52/18 | 0.807 |
| Inpatient/Outpatient at naldemedine start, n | 24/7 | 63/7 | 0.120 |
| Primary site: Lung/Gastrointestinal/Other, n | 12/13/6 | 21/25/24 | 0.312 |
| On active anticancer treatment/Best supportive care, n | 23/8 | 40/30 | 0.123 |
| Starting oxycodone dose, mg/day, median (IQR) | 10 (10–12) | 10 (10–20) | 0.492 |
| Oxycodone dose at naldemedine start, mg/day, median (IQR) | 10 (10–18) | 20 (10–40) | <0.001 |
| Maximum oxycodone dose during follow-up, mg/day, median (IQR) | 20 (10–40) | 40 (20–75) | 0.008 |
| Any concomitant laxative at naldemedine start, n (%) | 17/31 (54.8%) | 58/70 (82.9%) | 0.006 |
| Number of concomitant laxatives, median (IQR) | 1 (0–1) | 1 (1–2) | 0.001 |
| Number of concomitant laxatives: 0/1/≥2, n | 13/14/4 | 9/39/22 | 0.003 |
| Concomitant magnesium oxide, n (%) | 11/31 (35.5%) | 51/70 (72.9%) | <0.001 |
| Magnesium oxide dose among users, mg/day, median (range) | 990 (660–2000) | 1320 (330–2000) | — |
| Concomitant sennosides, n (%) | 7/31 (22.6%) | 17/70 (24.3%) | 1.000 |
| Sennosides dose among users, mg/day, median (range) | 24 (24–36) | 24 (12–36) | — |
| Other concomitant laxative documented, n (%) | 4/31 (12.9%) | 17/70 (24.3%) | 0.288 |
| Concomitant antiemetic use, n (%) | 20/31 (64.5%) | 21/70 (30.0%) | 0.002 |
Concurrent indicates naldemedine prescribed as part of the same oxycodone-start prescribing decision; reactive indicates naldemedine added as a separate prescribing decision after the initial oxycodone-start decision during ongoing oxycodone therapy in the setting of physician-recognized constipation. Classification was based on the chart-reviewed prescribing sequence and clinical context rather than elapsed calendar days alone. These terms describe observed initiation patterns in routine care, not standardized institutional protocols. Values are presented as median (IQR), median (range), n, or n (%), as shown. p Values are descriptive between-group comparisons and were calculated using the Mann–Whitney U test for continuous variables and Fisher’s exact test for categorical variables. Magnesium oxide and sennosides doses are summarized descriptively among users; corresponding between-group p values were not calculated for these restricted rows.
ECOG PS, Eastern Cooperative Oncology Group performance status; IQR, interquartile range.
Additional laxative initiation or dose escalation of existing laxatives within seven days after naldemedine initiation occurred more frequently in the concurrent group than in the reactive group (6/31 [19.4%] vs. 2/70 [2.9%]; p = 0.010; Table 2).
Table 2.
Early Operational Outcomes
| Outcome | Concurrent (n = 31) | Reactive (n = 70) | p Value |
|---|---|---|---|
| Primary endpoint: additional laxative initiation or dose escalation of existing laxatives within 7 days after naldemedine initiation, n/N (%) | 6/31 (19.4%) | 2/70 (2.9%) | 0.010 |
| Diarrhea-related discontinuation within 28 days, n/N (%) | 2/31 (6.5%) | 6/70 (8.6%) | 1.000 |
| Days from oxycodone start to naldemedine start, median (IQR) | By definition, 0 | 15 (5–83) | — |
| Range of oxycodone-to-naldemedine interval days | — | 0–801 (n = 69) | — |
| Reactive-group interval distribution, n | — | ≤7 days 23 (33.3%); 8–14 days 11 (15.9%); 15–30 days 9 (13.0%); >30 days 26 (37.7%) | — |
Concurrent indicates naldemedine prescribed as part of the same oxycodone-start prescribing decision; reactive indicates naldemedine added as a separate prescribing decision after the initial oxycodone-start decision during ongoing oxycodone therapy in the setting of physician-recognized constipation. Classification was based on the chart-reviewed prescribing sequence and clinical context rather than elapsed calendar days alone. Thus, a reactive interval could be 0 days when naldemedine was added after the initial oxycodone-start decision on the same calendar date; this differed from concurrent initiation, in which naldemedine was part of the same initial prescribing decision. The primary endpoint captured prescription-record-based early additional laxative initiation or dose escalation of existing laxatives within 7 days after naldemedine initiation. Values are presented as n/N (%), median (IQR), range, or n, as shown. p Values are descriptive between-group comparisons and were calculated using Fisher’s exact test for categorical variables. “By definition, 0” indicates that the oxycodone-to-naldemedine interval was necessarily 0 days in the concurrent group because of the exposure definition. Em dashes indicate not applicable. Reactive-group interval values were summarized among 69 evaluable patients with both dates available after chronology checks.
IQR, interquartile range.
In the reactive initiation pattern, the interval from oxycodone start to naldemedine initiation was variable after chronology checks, with a median interval of 15 days (interquartile range, 5–83) and a range of 0–801 days among 69 evaluable patients. Twenty-six patients started naldemedine more than 30 days after oxycodone initiation (Table 2).
Diarrhea-related discontinuation within 28 days was uncommon and did not appear to differ between groups (2/31 [6.5%] vs. 6/70 [8.6%]; p = 1.000; Table 2).
Discussion
Among adults with cancer who received naldemedine after starting oxycodone, the key finding was that the prescription-record-based early bowel-management endpoint occurred in 6 of 31 patients (19.4%) even with concurrent naldemedine. This endpoint may reflect symptom burden, physician prescribing behavior, and supportive-care intensity, rather than direct patient-reported constipation severity. Diarrhea-related discontinuation was uncommon in both groups.
This finding is clinically relevant because OIC is common after opioid initiation and can affect symptoms, function, and adherence to analgesic treatment.1,2 PAMORAs such as naldemedine can improve OIC, but their use does not eliminate the need for baseline bowel assessment, conventional laxative planning, and early reassessment.3,4,8 In routine care, a rescue or additional laxative strategy may remain reasonable when bowel function remains uncertain.
Reactive initiation was heterogeneous, with a median oxycodone-to-naldemedine interval of 15 days and more than one-third of evaluable reactive cases starting naldemedine more than 30 days after oxycodone initiation. This likely reflects individualized prescribing, including early symptom-management cases and later bowel-regimen restructuring in patients initially managed with conventional laxatives before naldemedine was added. The absence of an apparent increase in diarrhea-related discontinuation in the reactive group may be consistent with ongoing adjustment of background bowel management, although this interpretation remains exploratory.
Concomitant antiemetic use was more frequent in the concurrent group. Because antiemetics were recorded as a broad category that could include both prophylactic and symptom-triggered use, this variable should not be interpreted simply as nausea burden or as exposure to specific constipation-associated antiemetic classes, including 5-HT3 receptor antagonists. It may partly reflect an anticipatory supportive-care prescribing style among physicians who started naldemedine concurrently and also prescribed antiemetics at opioid initiation.
Limitations include the single-center retrospective design, physician-selected initiation timing, baseline differences in concomitant laxative use and oxycodone dose, and no adjusted modeling; therefore, no causal, comparative efficacy, or superiority inference can be made. The primary outcome was based on prescribing records and chart entries, not standardized patient-reported constipation severity; BSFS/Rome criteria were not routinely available. Outpatient adherence, over-the-counter laxative use, and self-titration could not be verified. Prior opioid exposure beyond strong-opioid switches, antiemetic subclasses/5-HT3 use, proton-pump inhibitor/histamine-2 (PPI/H2) use among magnesium oxide users, gastrointestinal obstruction/carcinomatous peritonitis, prescriber-level variation, laxative de-escalation, and reactive-interval heterogeneity were not systematically investigated or analyzed.
In summary, early additional laxative initiation or dose escalation was needed in approximately one fifth of patients who started naldemedine concurrently with oxycodone. Concurrent naldemedine should, therefore, be accompanied by baseline bowel assessment, early reassessment, and conventional or rescue laxative planning rather than being viewed as a stand-alone solution. Prospective studies using standardized bowel-symptom assessment and predefined reassessment or escalation triggers may refine how concurrent and later/reactive naldemedine initiation should be selected and monitored.2,4 Medication review should accompany these decisions.
Authors’ Contributions
S.K. conceived the study. S.K. curated data. S.K., S.C., Y.Y., N.R., Y.N., M.S., Y.U., I.M., and T.A. contributed to data acquisition and interpretation. S.K. performed the analyses and drafted the article. I.Y., A.K., and R.H. critically revised the article. All authors have read and approved the final version of the article.
Ethical Considerations
The study was conducted according to the principles of the Declaration of Helsinki. The protocol was approved by the Institutional Review Board of Toyama University Hospital (approval no. Rin 29-117).
Consent to Participate
The requirement for informed consent was waived by the Institutional Review Board of Toyama University Hospital under an opt-out policy for retrospective research.
Data Availability
The de-identified dataset supporting the findings of this study is stored on secure institutional servers and is not publicly available due to concerns regarding patient privacy and institutional policies. Additional data may be shared by the corresponding author upon reasonable request, pending institutional approval and data-sharing agreements.
Declaration of Generative AI
During the preparation of this article, the authors used ChatGPT (OpenAI) as an AI-assisted tool to improve language and readability. After using this tool, the authors reviewed and edited the content as required. The authors have full responsibility for the content of the published article.
Declaration of Conflicting Interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding Statement
No external funding or grants were received for this study.
Acknowledgments
The authors thank the clinicians, pharmacists, nurses, and other health care professionals at the Toyama University Hospital who contributed to the routine care of the patients included in this study. The authors also acknowledge the staff involved in clinical documentation and data management, which made this retrospective analysis possible.
Abbreviations Used
- 5-HT3
5-hydroxytryptamine 3
- BSFS
Bristol Stool Form Scale
- ECOG PS
Eastern Cooperative Oncology Group performance status
- H2
histamine-2
- IQR
nterquartile range
- OIC
opioid-induced constipation
- PAMORA
peripherally acting μ-opioid receptor antagonist
- PPI
proton-pump inhibitor
Cite this article as: Kajiura S, Chikaoka S, Yagi Y, Ryu N, Nakayama Y, Sakumura M, Ueda Y, Motoo I, Ando T, Yasuda I, Kato A, Hayashi R (2026) Naldemedine initiation timing after oxycodone start and early laxative adjustment in cancer care: a retrospective cohort study, Palliative Medicine Reports, 2026, 7, 26892820261469733, DOI: 10.1177/26892820261469733.
References
- 1.Bell TJ, Panchal SJ, Miaskowski C, et al. The prevalence, severity, and impact of opioid-induced bowel dysfunction: Results of a US and European Patient Survey (PROBE 1). Pain Med 2009;10(1):35–42; doi: 10.1111/j.1526-4637.2008.00495.x [DOI] [PubMed] [Google Scholar]
- 2.Tokoro A, Imai H, Fumita S, et al. Incidence of opioid-induced constipation in Japanese patients with cancer pain: A prospective observational cohort study. Cancer Med 2019;8(10):4883–4891; doi: 10.1002/cam4.2341 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Hisanaga T, Shinjo T, Imai K, et al. Clinical guidelines for management of gastrointestinal symptoms in cancer patients: The Japanese society of palliative medicine recommendations. J Palliat Med 2019;22(8):986–997; doi: 10.1089/jpm.2018.0595 [DOI] [PubMed] [Google Scholar]
- 4.Davies A, Leach C, Caponero R, et al. MASCC recommendations on the management of constipation in patients with advanced cancer. Support Care Cancer 2020;28(1):23–33; doi: 10.1007/s00520-019-05016-4 [DOI] [PubMed] [Google Scholar]
- 5.Katakami N, Harada T, Murata T, et al. Randomized phase III and extension studies of naldemedine in patients with opioid-induced constipation and cancer. JCO 2017;35(34):3859–3866; doi: 10.1200/jco.2017.73.0853 [DOI] [PubMed] [Google Scholar]
- 6.Candy B, Jones L, Vickerstaff V, et al. Mu-opioid antagonists for opioid-induced bowel dysfunction in people with cancer and people receiving palliative care. Cochrane Database Syst Rev 2022;9(9):Cd006332; doi: 10.1002/14651858.CD006332.pub4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Blair HA. Naldemedine: A review in opioid-induced constipation. Drugs 2019;79(11):1241–1247; doi: 10.1007/s40265-019-01160-7 [DOI] [PubMed] [Google Scholar]
- 8.Alvaro D, Caraceni AT, Coluzzi F, et al. What to do and what not to do in the management of opioid-induced constipation: A choosing Wisely Report. Pain Ther 2020;9(2):657–667; doi: 10.1007/s40122-020-00195-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Hamano J, Higashibata T, Kessoku T, et al. Naldemedine for opioid-induced constipation in patients with cancer: A multicenter, double-blind, randomized, placebo-controlled trial. JCO 2024;42(35):4206–4217; doi: 10.1200/jco.24.00381 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Yamada M, Jimaru Y, Torii S, et al. A retrospective observational study of factors affecting the efficacy of concurrent prescription of naldemedine for opioid-induced constipation caused by oxycodone tablets. Biological & Pharmaceutical Bulletin 2023;46(12):1826–1831; doi: 10.1248/bpb.b23-00487 [DOI] [PubMed] [Google Scholar]
- 11.Takemura M, Niki K, Miyaguchi S, Ueda M. Naldemedine-laxative combination: Retrospective inpatient study. BMJ Support Palliat Care 2024;13(e3):e816–e819; doi: 10.1136/spcare-2022-003685 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The de-identified dataset supporting the findings of this study is stored on secure institutional servers and is not publicly available due to concerns regarding patient privacy and institutional policies. Additional data may be shared by the corresponding author upon reasonable request, pending institutional approval and data-sharing agreements.