Opioid-induced Constipation In Cancer Patients Research Articles

Effect of add-on naldemedine treatment in patients with cancer and opioid-induced constipation insufficiently responding to magnesium oxide: a pooled, subgroup analysis of two randomized controlled trials.

To evaluate the additive effect of naldemedine tosylate (naldemedine) on opioid-induced constipation in cancer patients insufficiently responding to magnesium oxide treatment. We combined two randomized, double-blind, placebo-controlled, phase IIb and III trials of naldemedine and conducted a post hoc subgroup analysis. We evaluated the effect and safety of naldemedine in 116 patients who received naldemedine in addition to magnesium oxide (naldemedine group) and 117 patients who received placebo in addition to magnesium oxide (placebo group). Both groups included patients insufficiently responding to magnesium oxide for opioid-induced constipation. Effect was assessed using spontaneous bowel movement responder rate, complete spontaneous bowel movement responder rate, changes in spontaneous bowel movements and complete spontaneous bowel movements. Safety was also assessed. During the 2-week treatment period, the responder rates for spontaneous bowel movement and complete spontaneous bowel movement were 73.3 and 43.1% in naldemedine group, respectively, which were significantly higher (P<0.0001) than 41.9 and 14.5% in placebo group, respectively. Median time to first spontaneous bowel movement and first complete spontaneous bowel movement was significantly shorter (P<0.0001) in the naldemedine group (4.0 and 21.3h, respectively) than in the placebo group (27.7 and 211.7h, respectively). The incidence of adverse events and diarrhoea was significantly higher (P<0.05) in the naldemedine group than in the placebo group, while the incidence of serious adverse events and severe diarrhoea was not significantly different between the naldemedine and placebo groups. The study suggested the addition of naldemedine as an effective treatment option for opioid-induced constipation in cancer patients insufficiently responding to magnesium oxide treatment.

A Systematic Review of Naldemedine and Naloxegol for the Treatment of Opioid-Induced Constipation in Cancer Patients.

Opioid-induced constipation (OIC) is a pervasive and distressing side effect of chronic opioid therapy in patients with cancer pain, significantly impacting their quality of life. Peripherally acting μ-opioid receptor antagonists (PAMORAS) were developed for treatment-resistant OIC but most studies were conducted with non-cancer patients. to discuss two oral formulations of PAMORAs, naldemedine and naloxegol, and to review available evidence of the effectiveness of these drugs for OIC in cancer patients. a comprehensive search to identify primary literature for either naldemedine or naloxegol for OIC in cancer patients. Only three prospective randomized, double-blind, placebo-controlled clinical trials for naldemedine enrolling cancer patients were identified; the results of a subgroup analysis of two of those studies and two non-interventional post marketing surveillance studies of these trials are also reported here. For naloxegol, only two randomized controlled trials were identified; both were unsuccessful in enrolling sufficient patients. An additional four prospective non-interventional observational studies with naloxegol were found that enrolled cancer patients. There were significantly higher rates of responders in the PAMORA groups than in the placebo groups. The most common side effect for both PAMORAs was diarrhea. All studies were industry-funded, and given that only three trials were randomized controlled studies, the overall quality of the studies was lacking. Naldemedine or naloxegol appeared safe and useful in the treatment of OIC in cancer patients and may improve their quality of life. Larger-scale randomized placebo-controlled studies of PAMORAs in cancer patients would strengthen existing evidence.

Efficacy and Safety of Naldemedine Administration for Opioid-Induced Constipation in Cancer Patients with Poor Performance Status.

Background: Constipation is a concern among patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 3 and 4. Objectives: To assess naldemedine's efficacy and safety in cancer patients on opioids with poor PS. Design: Multicenter, retrospective study. Setting/Subjects: Japanese cancer patients with ECOG performance status 3 or 4 who received naldemedine. Measurements: Frequency of defecations before/after naldemedine use. Responders were patients whose defecation frequency increased to ≥3 times/week, from baseline ≥1 defecations/week over seven days after naldemedine administration. Results: Seventy-one patients were analyzed; 66.1% were responders (95% confidence interval: 54.5%-76.1%). Defecation frequency increased significantly after naldemedine in the overall population (6 vs. 2, p < 0.0001) and among those who defecated <3 times/week before naldemedine (4.5 vs. 1, p < 0.0001). Diarrhea (38.0%) of all grades was the most common adverse event; 23 (85.2%) events were classified as Grade 1 or 2. Conclusion: Naldemedine is effective and safe among cancer patients with poor PS.

Factors associated with non-response to naldemedine for opioid-induced constipation in cancer patients: A subgroup analysis.

Opioid-induced constipation (OIC) is one of the most common adverse events of opioid therapy and can severely reduce quality of life (QOL). Naldemedine is the orally available peripheral-acting μ-opioid receptor antagonist approved for OIC treatment. However in daily clinical practice, some cancer patients show insufficient control of OIC even while receiving naldemedine. To identify factors associated with non-response to naldemedine in cancer patients. This study retrospectively analyzed 127 cancer patients prescribed naldemedine 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 electronic medical records. Naldemedine had been prescribed by the attending physician after the presence of OIC had been defined with reference to Rome IV diagnostic criteria. Naldemedine was evaluated as "effective" in cases where the number of defecations increased at least once in the first 3 days after starting naldemedine. Multivariate logistic regression analysis was performed to identify factors associated with non-response to naldemedine. The data used were from the group of patients who received naldemedine in our previous study. Factors significantly associated with non-response to naldemedine included chemotherapy with taxanes within 1 month of evaluation of naldemedine effect (odds ratio [OR] = 0.063; 95% confidence interval [CI] = 0.007-0.568), and addition of or switching to naldemedine due to insufficient efficacy of prior laxatives (OR = 0.352, 95% CI = 0.129-0.966). The identification of factors associated with non-response to naldemedine prescribed for OIC may help improve QOL among cancer patients.

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 3days. 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 1month 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 1month 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.

Delphi consensus on strategies in the management of opioid-induced constipation in cancer patients

BackgroundOpioid-induced constipation (OIC) is a frequent and bothersome adverse event related with opioid therapy in cancer patients. Despite the high prevalence, medical management of OIC is often uncertain. The current project aimed to investigate expert opinion on OIC management and provide practical recommendations to improve the clinical approach of OIC in cancer patient.MethodsA modified Delphi method was conducted involving 46 different physicians experts in OIC. Using a structured questionnaire of 67 items this project intended to seek consensus on aspects related to diagnosis, treatment, and quality of life of cancer patients suffering with OIC.ResultsAfter two rounds, a consensus was reached in 91% of the items proposed, all in agreement. Agreement was obtained on OIC definition (95.7%). Objective and patient-reported outcomes included in that definition should be assessed routinely in clinical practice. Responsive to symptom changes and easy-to-use assessment tools were recommended (87.2%). Successful diagnosis of OIC requires increase clinicians awareness of OIC and proactivity to discuss symptoms with their patients (100%). Successful management of OIC requires individualization of the treatment (100%), regular revaluation once is established, and keeping it for the duration of opioid treatment (91.5%). Oral Peripherally Acting μ-Opioid Receptor Agonists (PAMORAs), were considered good alternatives for the treatment of OIC in cancer patients (97.9%). This drugs and laxatives can be co-prescribed if OIC coexist with functional constipation.ConclusionsThe panelists, based on their expert clinical practice, presented a set of recommendations for the management of OIC in cancer patients.

1822P - Consensus on strategies in the management of opioid-induced constipation in cancer patients

BackgroundPatients with cancer under opioid treatment often develop opioid-induced constipation (OIC). Despite the high prevalence, medical management of OIC is often uncertain. This study sought to gather the opinion of experts in opioid use and OIC to reach a consensus on diagnosis and treatment strategies. MethodsA modified Delphi method was conducted involving multidisciplinary experts. The resulting questionnaire addressed OIC diagnosis, OIC treatment, and quality of life of patients with cancer and OIC. ResultsA consensus in agreement was reached in almost all items (91%). Most of the panelists agreed that, although common (87.2%), the diagnosis of OIC in patients with cancer is difficult because of the limited knowledge of its pathophysiological features (80%). In patients with cancer, OIC control improves pain treatment adherence, which in turn improves their quality of life (95.7%). For effective diagnosis, experts recommend healthcare professionals to proactively ask patients under opioid treatment about the symptoms of OIC (100%). Occasionally, patients only report symptoms of OIC when these are severe (85.1%). Additionally, the experts recommended a complete patient’s clinical history (95.7%) with special focus on previous functional constipation (93.6%) that should be treated before opioid therapy begins (76.6%). For the specific treatment of OIC in patients with cancer most of the panelists agree that laxatives are not often effective (78.7%) and, according to clinical practice, it is recommended to take oral Peripherally Acting µ-Opioid Receptor Antagonists (PAMORAs; e.g. naloxegol) along with the prescribed laxative (80%). Furthermore, the management of OIC should start as soon as possible since the treatment is more complicated with stablished OIC and severe symptoms (95.7%). Regarding hygienic-dietary recommendations the panel agreed that, although necessary, they are not sufficiently effective (91.5%). ConclusionsOIC needs to be specifically managed to improve the quality of life of patients with cancer. This modified Delphi consensus considered expert opinions in the search of therapeutic strategies. Legal entity responsible for the studyKyowa Kirin Farmaceutica. FundingKyowa Farmaceutica S.L.U. Spain. DisclosureR. Girones Sarrio: Advisory / Consultancy: Kyowa Kirin Farmaceutica; Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD. E. Falcó: Advisory / Consultancy: Kyowa Kirin Farmaceutica. A. Gozalvo: Advisory / Consultancy: Kyowa Kirin Farmaceutica. J.M. Esparza Miñana: Advisory / Consultancy: Kyowa Kirin Farmaceutica. A. Calsina-Berna: Advisory / Consultancy: Kyowa Kirin Farmaceutica. J. Porta Sales: Advisory / Consultancy: Kyowa Kirin Farmaceutica.

Methylnaltrexone is safe in cancer patients with peritoneal carcinomatosis

Opioid-induced constipation (OIC) has become increasingly prevalent with the rise of prescription opioid use and can significantly impact quality of life, especially in patients with advanced illness. Methylnaltrexone has proven effective in treating cancer patients with OIC who have not responded adequately to conventional laxative therapy, though use is relatively contraindicated in those with peritoneal carcinomatosis due to theoretical risk and reported cases of perforation. The aim of this study was to evaluate the safety of methylnaltrexone in patients with carcinomatosis. We performed a retrospective review of 3058 pediatric and adult patients who received methylnaltrexone at Memorial Sloan Kettering Cancer Center from 2009–2016. Data collected included age, cancer diagnosis, history of abdominal surgery, prior radiation therapy, evidence of peritoneal carcinomatosis, and complications. Charts were reviewed for any complications at 24 hours, 72 hours, and one week following drug administration, as well as at present. We identified 3058 patients (median age 56, range 1–95) who received a total of 3995 doses of methylnaltrexone. Three hundred thirty three (median age 55, range 4–88) had peritoneal carcinomatosis. The most common primary malignancies included pancreatic (17.7%), ovarian (13.5%), colon (7.2%), and lung (6.6%). 228/333 (68.4%) had a history of abdominal surgery and 85/333 (25.5%) underwent prior radiation therapy. Three patients had adverse outcomes or complications, with only one (0.3%) thought to be related to methylnaltrexone use. To our knowledge, this is the largest study to evaluate the outcomes of patients with carcinomatosis receiving methylnaltrexone and the first to include pediatric patients. We found one perforation attributed to methylnaltrexone. Methylnaltrexone should be considered for treatment of refractory OIC in cancer patients with peritoneal carcinomatosis due to low risk of complications.

Chinese herbal medicine for opioid induced constipation in cancer patients

Opioid induced constipation (OIC) is a symptom that is commonly encountered in cancer pain management. Chinese herbal medicine (CHM) has been widely used to improve OIC in China. Many clinical trials indicate that CHM could improve OIC. In this systematic review, we aim to evaluate the effectiveness and safety of CHM for OIC in cancer patients. We will search the following electronic databases for randomized controlled trials to evaluate the effectiveness and safety of CHM for OIC in cancer patients: CENTRAL, EMBASE, MEDILINE, CINAHL and China National Knowledge Infrastructure. Each database will be searched from inception to June 2018. The entire process will include study selection, data extraction, risk of bias assessment and meta-analyses. This proposed study will evaluate the effectiveness and safety of CHM for OIC. The outcomes will include change in bowel movements, quality of life and adverse events. This proposed systematic review will evaluate the existing evidence on the effectiveness and safety of CHM for OIC in cancer patients. The results of this review will be disseminated through peer-reviewed publication. Because all of the data used in this systematic review and meta-analysis has been published, this review does not require ethical approval. Furthermore, all data will be analyzed anonymously during the review process.

A qualitative study to explore psychological distress and illness burden associated with opioid-induced constipation in cancer patients with advanced disease

Background: Constipation affects many patients receiving long-term opioid therapy for cancer pain. Little is known about the nature of psychological distress and the burden associated with this problem. This information may inform the development of effective treatment strategies and ameliorate distress. Aim: The objective was to use qualitative research methods to better understand psychological distress and the burden associated with opioid-induced constipation and its treatment in advanced cancer patients. Design: In this qualitative study, semi-structured interviews explored perceptions of psychological distress and burden from opioid-induced constipation. Interviews were analyzed using a thematic content analysis approach involving descriptive and interpretive coding and identification of recurring themes. Setting/participants: Twelve advanced cancer patients with opioid-induced constipation were recruited from a large urban hospital. Results: Patients experienced various types of negative affect and cognitions associated with opioid-induced constipation. Analyses indicated three major themes: (1) irrational thoughts and educational needs; (2) psychological distress from constipation and (3) the effects of constipation on the decision to use opioid analgesics. Irrational thoughts and educational needs included beliefs that nutrition could improve constipation, the supposition that constipation indicated deteriorating health, and catastrophic beliefs. Psychological distress included depressive symptoms and anticipatory anxiety related to constipation. Decision-making revealed cognitive dissonance about using opioids and conflicting preferences about continuing use. Conclusions: Future investigation of the multiple components of cognitive and affective burden from opioid-induced constipation is warranted. Understanding the varied nature of this burden may improve clinical recognition and assessment and promote more intensive management consistent with the distress it produces.

Management of Opioid-Induced Constipation in Cancer Patients

Opioids are one of the most widely used therapies for the palliative treatment of cancer pain; however, despite their proven analgesic efficacy, they are associated with several adverse effects. Associated with psychological distress and multiple concomitant clinical concerns, constipation is the most commonly occurring adverse effect of chronic opioid therapy in cancer patients. Whilst prophylaxis remains the first-line management option, methylnaltrexone is a recommended treatment option for opioid-related constipation if administration of laxatives is ineffective. Due to its inability to cross the blood-brain barrier, methylnaltrexone exerts a peripheral inhibition of opioid-related effects without influencing the opioid-induced central effects; as a result, the analgesic effect of opioids is unaffected. Moreover, multiple clinical trials, albeit not always conducted specifically in cancer patients, have demonstrated that up to 4 months' treatment with either intravenous or subcutaneous methylnaltrexone provides effective relief from opioid-related constipation and is well tolerated. Preliminary evidence indicates that the addition of methylnaltrexone to standard care for opioid-related constipation may also be advantageous from a pharmacoeconomic perspective. In addition, preliminary data suggest that methylnaltrexone could be associated with some further clinical benefits other than the treatment of opioid-related constipation, such as the improvement of gastric emptying, the relief of nausea/vomiting, and the reduction of the risk of regurgitation and pulmonary aspiration. This narrative review examines the most recent evidence and evaluates the current role of methylnaltrexone in the management of opioid-related constipation, and its potential efficacy in cancer patients. The pharmacokinetics, pharmacodynamics, efficacy and tolerability of methylnaltrexone are discussed.

Phase II trial of subcutaneous methylnaltrexone in the treatment of severe opioid-induced constipation in cancer patients.

TPS236 Background: Opioid-induced constipation (OIC) is mainly caused by binding of opioids to mu-opioid receptors in the gastrointestinal system, which affects gastrointestinal motility, secretion, fluid absorption and blood flow, and causes delayed colonic transit and inhibited defecation. Methylnaltrexone bromide is a peripherally-acting antagonist of the mu-opioid receptor. It has recently been approved by the U.S. Food and Drug Administration for treatment of OIC in patients with advanced disease receiving palliative care. However, its clinical utility has not been documented in cancer patients at earlier stages of disease. Methods: The objective of this prospective, single-arm, phase II trial is to evaluate the efficacy of methylnaltrexone in relieving OIC in cancer patients at earlier stages of disease. The primary endpoint is a rescue-free laxation ≤ 4 hours after the dose. Eligible for enrollment are cancer patients at earlier stages of disease with life expectancy ≥ 6 months and OIC with < 3 laxations during the preceding week and no clinically meaningful laxation (as determined by the investigators) ≤ 24 hours before the study entry. A single dose of methylnaltrexone will be administered subcutaneously to eligible patients. The efficacy and adverse events will be evaluated for 48 hours. Patients will complete questionnaires on laxation (frequency, consistency and difficulty), constipation (severity and distress), pain score, symptoms of opioid withdrawal, and satisfaction with the response at 4, 24 and 48 hours following the dose. 17 subjects are required assuming a baseline response rate of 15% against an alternative value of 50% using an exact binomial test with a two-tailed Type I error level of 10% and a power level of 90%. To date 5 patients have been enrolled. Obstacles to enrollment have included the multi-factorial nature of constipation in cancer patients which makes the detection of OIC difficult, initiation of various empirical treatments for OIC in patients who would otherwise be eligible, and lack of timely referral of potentially eligible patients because of poor awareness of supportive care trials. (NCT01004393)

Methylnaltrexone in the Treatment of Opioid-Induced Constipation in Cancer Patients Receiving Palliative Care: Willingness-to-Pay and Cost-Benefit Analysis

When laxative regimens have failed, methylnaltrexone may be indicated for the relief of opioid-induced constipation (OIC) in patients with advanced illness receiving palliative care. A cost-benefit analysis (CBA), based on a willingness-to-pay (WTP) approach, was performed to determine if methylnaltrexone should be added to the formulary list of drugs being reimbursed by third-party payers in Canada for the treatment of cancer patients in palliative care suffering from OIC. The WTP study had two components: a decision board explaining treatment options (Component A) and a questionnaire to measure individual WTP using a bidding game approach (Component B). Component A had two options: Option 1 (laxatives only) and Option 2 (laxatives+methylnaltrexone injection). Only participants choosing Option 2 were invited to complete Component B. The results of the WTP survey were then incorporated into a CBA. Within a hypothetical cohort, additional monthly premiums that individuals were willing to pay for methylnaltrexone were compared with the monthly costs to the insurer for providing methylnaltrexone to all patients who would potentially be using it. Four hundred one Canadians, of age 18 years and older, were surveyed and yielded a WTP in additional monthly insurance premiums of Canadian dollar (CAD) $8.65 (95% confidence interval: CAD$6.17-CAD$11.13). The CBA resulted in additional CAD$89,307 with a cost of CAD$139,840 and benefits of CAD$229,147. A set of 10,000 Monte Carlo simulations resulted in average CBA savings of CAD$145,011 with a 99.86% probability of dominance. The present CBA provides pharmacoeconomic evidence for theadoption of methylnaltrexone for treating OIC in terminally ill cancer patients.

Methylnaltrexone treatment of opioid-induced constipation in cancer patients

9081 Background: Constipation is a common and distressing side effect of opioid treatment particularly in patients with cancer. Two phase 3 trials (Studies 301 and 302) reported that subcutaneous (SC) methylnaltrexone was well tolerated and effective in inducing laxation in patients with advanced illness with opioid-induced constipation (OIC) while maintaining central analgesia. Aims: To evaluate improvement in constipation in cancer patients treated with methylnaltrexone in the above studies. Methods: In Study 301, 124 cancer patients received a single dose of methylnaltrexone (SC 0.15mg/kg, 0.30mg/kg) or placebo. In Study 302, 78 cancer patients received either 0.15mg/kg SC QOD methylnaltrexone for 2 weeks (total of 7 doses) or placebo. Patients had a life expectancy of 1–6 months, no laxation within 48 hours, and were maintained on stable opioids and baseline laxatives. The primary efficacy endpoints were laxation within 4 hours after a single or first dose of study drug and laxation within 4 hours for at least 2 of the first 4 doses (Study 302). The secondary endpoints were laxation within 24 hours, pain scores, and opioid withdrawal symptoms. Results: A majority of the methylnaltrexone-treated cancer patients had a laxation within the first 4 hours of study drug administration ( Table ). There were no clinically significant changes in pain scores or opioid withdrawal symptoms. Conclusions: Our results demonstrate that in cancer patients with advanced illness and OIC, methylnaltrexone significantly improved constipation, without loss of pain control or opioid withdrawal. [Table: see text] No significant financial relationships to disclose.