Opioid-induced Constipation In Patients Research Articles

Efficacy and safety of naldemedine for opioid-induced constipation in older patients with cancer: a retrospective study.

Opioids are pain relievers that are often associated with opioid-induced constipation (OIC) that worsens with age. We performed a multicenter, retrospective analysis on the efficacy and safety of naldemedine, an opioid receptor antagonist, in treating OIC in patients with cancer (age >75 years). The electronic medical records of cancer patients who received naldemedine at 10 Japanese institutions between 7 June 2017 and August 31, 2019, were retrieved. Patients aged ≥75 years who were treated with naldemedine for the first time and hospitalized for at least 7 days before and after initiating naldemedine therapy were included in this analysis. Sixty patients were observed for at least 7 days before and after starting naldemedine. The response rate was 68.3%, and the frequency of bowel movements increased significantly after naldemedine administration in the overall population ( P < 0.0001) and among those who defecated <3 times/week before naldemedine administration ( P < 0.0001). Diarrhea was the most frequent adverse event in all grades, observed in 45% of patients, of which 92.6% were Grade 1 or 2. Grade 4 or higher adverse events, including death, were not observed. Naldemedine exhibits significant efficacy and safety in OIC treatment in older patients with cancer.

Efficacy and safety of Naldemedine in the long-term treatment of opioid-induced constipation in patients on methadone agonist therapy monitored for three consecutive months

Efficacy and safety of Naldemedine in the long-term treatment of opioid-induced constipation in patients on methadone agonist therapy monitored for three consecutive months

Impact of Patient Subgroups on the Efficacy and Safety of Methylnaltrexone for Opioid-Induced Constipation in Patients with Advanced Illness.

We evaluated the impact of baseline patient characteristics on safety and efficacy of methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, in patients with advanced illness with opioid-induced constipation (OIC). This analysis pooled data from 2 randomized, double-blind, placebo-controlled studies (study 302: NCT00402038; study 4000: NCT00672477) in patients with advanced illness, including cancer, and OIC. Patients were randomized to receive subcutaneous methylnaltrexone (study 302: 0.15 mg/kg; study 4000: 8 or 12 mg based on weight) or placebo every other day for 2 weeks. The proportions of patients achieving rescue-free laxation within 4 or 24 hours after the first dose of study drug were assessed in patient subgroups stratified by baseline age, Eastern Cooperative Oncology Group (ECOG) performance status, cancer status, laxative type, and opioid requirement. Treatment-emergent adverse events (TEAEs) were evaluated. Overall, 363 patients were included in this analysis (methylnaltrexone, 178; placebo, 185). Mean (SD) age was 66.3 (13.7) years and 48.5% were men overall. A significantly greater proportion of patients receiving methylnaltrexone versus placebo achieved rescue-free laxation within 4 hours (111/178 [62.4%] vs 31/185 [16.8%]; P<0.0001) and 24 hours (135/178 [75.8%] vs 81/185 [43.8%]; P<0.0001) of the first dose. These trends were consistent across all subgroups. Most patients experienced ≥1 TEAE in the overall population (methylnaltrexone, 82.1%; placebo, 76.2%), which remained consistent when stratified by baseline characteristics. More than half of TEAEs were gastrointestinal in nature. Abdominal pain was more common in patients receiving methylnaltrexone than placebo across baseline characteristic subgroups. Methylnaltrexone treatment was superior to placebo in achieving rescue-free laxation within 4 and 24 hours after the first dose, irrespective of patients' cancer status, baseline ECOG performance status, or baseline opioid or laxative use. The methylnaltrexone safety profile remained consistent across baseline characteristic subgroups.

2079P Naloxegol for the treatment of opioid-induced constipation in patients with cancer pain: A pooled analysis of real-world studies (NALOPOOL)

2079P Naloxegol for the treatment of opioid-induced constipation in patients with cancer pain: A pooled analysis of real-world studies (NALOPOOL)

Real-World Evidence for the Safety and Effectiveness of Naldemedine in the Management of Opioid-Induced Constipation in Patients With Cancer Pain: Post-hoc Subgroup Analysis of Post-marketing Surveillance in Japan.

Opioid-induced constipation is common and greatly affects the quality of life but is often under-recognised and undertreated. This study aimed to investigate the safety and effectiveness of naldemedine for opioid-induced constipation with cancer pain according to specific subgroups of clinical interest. In this exploratory post-hoc subgroup analysis of post-marketing surveillance from Japan (UMIN: 000042851), data were investigated by the subgroups: age (≥75, <75 years), Eastern Cooperative Oncology Group performance status (PS 0-2, 3-4), constipation severity (mild, moderate, severe), brain metastasis (yes, no), anticancer drug treatment (yes, no), opioid at naldemedine initiation (fentanyl only, only strong opioids other than fentanyl, weak opioids only, other), and prior or concomitant use of laxative (only osmotic/saline laxatives, only stimulant laxatives, other, none). Enrolled patients (n = 1184) received naldemedine (0.2 mg once daily) orally for up to 12 weeks. Regarding safety endpoints, the incidence of adverse drug reactions, including diarrhoea, was determined within each subgroup. Regarding effectiveness endpoints, improvement rates in the frequency and condition of bowel movements were investigated by subgroups. The incidence of adverse drug reactions, including diarrhoea, among subgroups ranged from 7.74% to 16.08% (diarrhoea: 5.95% to 13.19%), compared to 11.30% (diarrhoea: 9.09%) in the total population. Through week two to week 12, improvement rates in the frequency and condition of bowel movement among subgroups ranged from 63.6% to 89.7% and 67.6% to 94.9%, compared to 75.0% to 83.2% and 80.0% to 88.0% in the total population, respectively. Naldemedine was well tolerated and effective in patients with opioid-induced constipation and cancer pain regardless of the subgroups investigated.

Evaluating the Safety and Efficacy of Naloxegol in Critically Ill Opioid-Induced Constipation Patients.

Background Opioid-induced constipation (OIC) has become more common in the intensive care unit (ICU) due to increased opioid utilization. Traditional laxatives often prove ineffective against OIC, leading to the increased utilization of naloxegol. However, further research is needed to confirm naloxegol's effectiveness and safety in critical care. This study aimed to explore the safety and efficacy of this intervention in critically ill OIC patients. Methods A single-center retrospective study was conducted on 353 patients who received one or more doses of naloxegol from January 1, 2019, to June 30, 2020, for OIC at a tertiary care center. The primary endpoint of this study was to evaluate serious adverse events such as reduced analgesic effect, gastrointestinal perforation, seizure, acute myocardial infarction (AMI), or ventricular arrhythmias using Naranjo Scale in critically ill patients. The secondary goal was to assess the efficacy of naloxegol, measured by the time of the first bowel movement. Results The average duration of naloxegol use was three days, with the first bowel movement occurring at an average of 11.3 hours. Furthermore, 59.8% of individuals had their first bowel movement within 20 hours of receiving naloxegol. There was a low level of causality between naloxegol use and adverse events such as gastrointestinal perforation, seizures, AMI, cardiovascular mortality, stroke, and ventricular arrhythmia. Additionally, reduction in analgesia showed no strong relationship with naloxegol use indicated by the Naranjo Scale assessment. Conclusion Naloxegol showed promising safety and efficacy profiles in treating OIC amongst critically ill patients, though our findings require further validation through prospective studies. This research paves the way for further investigation into naloxegol's role in OIC management, emphasizing the necessity of personalized treatment strategies in critical care settings.

Naloxegol (Movantik®) Provides Rapid Response and Sustained Improvement of Opioid-Induced Constipation Symptoms in Older Adults

Naloxegol (Movantik®), an oral peripherally acting mu-opioid receptor antagonist (PAMORA) has demonstrated rapid and predictable relief of OIC in patients treated with opioids for chronic non-cancer pain in two phase 3 trials (KODIAC 4/5; NCT01309841/NCT01323790). In subjects ≥65 yrs, naloxegol (25mg, 12.5mg) demonstrated significantly better response rates, clinically relevant early symptom relief, and predictable efficacy compared with PBO. Improvements in SBMs, CSBMs, straining, and stool consistency were rapid and sustained across 12 weeks. Naloxegol is effective and safe in individuals ≥65 yrs with non-cancer pain experiencing OIC.Aim: Naloxegol, an oral peripherally acting mu-opioid receptor antagonist (PAMORA) has demonstrated rapid and predictable relief of opioid-induced constipation (OIC) in patients treated with opioids for chronic non-cancer pain in two phase 3 trials (KODIAC 4/5; NCT01309841/NCT01323790). This analysis evaluates the speed and predictability of response, and the rapid and sustained impact of naloxegol on OIC symptoms in subjects aged ≥65 yrs. Methods: Data were pooled from the KODIAC 4/5 intent-to-treat populations (N=1337). Subjects ≥65 yrs treated once daily with naloxegol 25mg, 12.5mg, or placebo (PBO) were evaluated. Response definition: ≥3 SBM/wk and increase of ≥1 SBM/wk over baseline for ≥9 of 12 weeks, and ≥3 of the final 4 weeks. For each SBM, patients documented complete evacuation (CSBM) (Yes/No), degree of straining (scale 1=not at all, 5=extreme), and stool consistency via the Bristol Stool Scale (1=hard, 7=watery). Results: This analysis evaluated 148 subjects ≥65 yrs (11.1% of the overall population). In these older adults, a significantly higher response rate was achieved with naloxegol (25mg, 50.9%, p=0.037; 12.5mg, 53.3%; p=0.036) vs PBO (32.0%). Corresponding HRs (2.52, p< 0.001; 1.90, p=0.005) indicated significant, ∼two-fold reduction in time to first SBM with naloxegol vs PBO. Time to first CSBM was ∼50% shorter for naloxegol vs PBO for both regimens (Hazard Ratios: 1.66, p=0.019; 1.45, p=0.103). Rapid, statistically significant, and clinically relevant symptom improvement (straining and stool consistency) was generally sustained from weeks 1-12 for naloxegol vs PBO. The most common AEs were GI-related and similar across regimens. Conclusion: In subjects ≥65 yrs, naloxegol (25mg, 12.5mg) demonstrated significantly better response rates, clinically relevant early symptom relief, and predictable efficacy compared with PBO. Improvements in SBMs, CSBMs, straining, and stool consistency were rapid and sustained across 12 weeks. Naloxegol is effective and safe in individuals ≥65 yrs with non-cancer pain experiencing OIC.

A Retrospective Study of the Efficacy and Safety of Naldemedine for Treatment of Opioid-Induced Constipation in Patients with Hepatobiliary Pancreatic Cancer.

Background and Objectives: Opioid analgesics, which are used for cancer-related pain management, cause opioid-induced constipation (OIC). Naldemedine, a peripheral opioid receptor antagonist, is an OIC-modifying agent, but no focused efficacy and safety analysis has been conducted for its use in hepatobiliary pancreatic cancers. We performed a multi-institutional study on the efficacy and safety of naldemedine in patients with hepatobiliary pancreatic cancer using opioids in clinical practice. Materials and Methods: We retrospectively evaluated patients with hepatobiliary pancreatic cancer (including liver, biliary tract, and pancreatic cancers) treated with opioids and naldemedine during hospitalization at ten institutions in Japan from June 2017 to August 2019. We assessed the frequency of bowel movements before and after the initiation of naldemedine therapy. Responders were defined as patients who defecated ≥3 times/week, with an increase from a baseline of ≥1 defecations/week over seven days after the initiation of naldemedine administration. Results: Thirty-four patients were observed for one week before and one week after starting naldemedine. The frequency of bowel movements increased by one over the baseline frequency or to at least thrice per week in 21 patients. The response rate was 61.7% (95% confidence interval: 45.4-78.0%). The median number of weekly bowel movements before and after naldemedine treatment was 2 (range: 0-9) and 6 (range: 1-17), respectively, in the overall population (n = 34); the increase in the number of bowel movements following naldemedine administration was statistically significant (Wilcoxon signed-rank test, p < 0.0001). Diarrhea was the predominant gastrointestinal symptom, and 10 (29.4%) patients experienced grade 1, grade 2, or grade 3 adverse events. The only other adverse event included fatigue in one patient; grade 2-4 adverse events were absent. Conclusions: Naldemedine is effective, and its use may be safe in clinical practice for patients with hepatobiliary pancreatic cancer receiving opioid analgesics.

Effects of Electroacupuncture for Opioid-Induced Constipation in Patients With Cancer in China

Opioid-induced constipation (OIC) is prevalent among patients treated with opioids for cancer pain. Safe and effective therapies for OIC in patients with cancer remain an unmet need. To determine the efficacy of electroacupuncture (EA) for OIC in patients with cancer. This randomized clinical trial was conducted at 6 tertiary hospitals in China among 100 adult patients with cancer who were screened for OIC and enrolled between May 1, 2019, and December 11, 2021. Patients were randomized to receive 24 sessions of EA or sham electroacupuncture (SA) over 8 weeks and then were followed up for 8 weeks after treatment. The primary outcome was the proportion of overall responders, defined as patients who had at least 3 spontaneous bowel movements (SBMs) per week and an increase of at least 1 SBM from baseline in the same week for at least 6 of the 8 weeks of the treatment period. All statistical analyses were based on the intention-to-treat principle. A total of 100 patients (mean [SD] age, 64.4 [10.5] years; 56 men [56.0%]) underwent randomization; 50 were randomly assigned to each group. Among them, 44 of 50 patients (88.0%) in the EA group and 42 of 50 patients (84.0%) in the SA group received at least 20 (≥83.3%) sessions of treatment. The proportion of overall responders at week 8 was 40.1% (95% CI, 26.1%-54.1%) in the EA group and 9.0% (95% CI, 0.5%-17.4%) in the SA group (difference between groups, 31.1 percentage points [95% CI, 14.8-47.6 percentage points]; P < .001). Compared with SA, EA provided greater relief for most OIC symptoms and improved quality of life among patients with OIC. Electroacupuncture had no effects on cancer pain and its opioid treatment dosage. Electroacupuncture-related adverse events were rare, and, if any, all were mild and transient. This randomized clinical trial found that 8-week EA treatment could increase weekly SBMs with a good safety profile and improve quality of life for the treatment of OIC. Electroacupuncture thus provided an alternative option for OIC in adult patients with cancer. ClinicalTrials.gov Identifier: NCT03797586.

Subcutaneous Methylnaltrexone as Treatment for Opioid-Induced Constipation in Patients with Advanced Cancer and Noncancer Illnesses: A Post Hoc Analysis of Two Clinical Trials.

To evaluate the efficacy and safety of subcutaneous (SC) methylnaltrexone for opioid-induced constipation (OIC) in patients with and without active cancer. We analyzed two randomized, double-blind, placebo-controlled, Phase 3/4 trials (NCT00402038, NCT00672477). Patients received SC methylnaltrexone (study 302, 0.15 mg/kg; study 4000, 8 mg or 12 mg based on body weight) or placebo every other day for 2 weeks. Patients were stratified by cancer status. Primary efficacy endpoints included proportion of patients achieving rescue-free laxation (RFL); secondary endpoints included time to RFL, pain intensity scores, and safety/tolerability. Trial results were evaluated separately. The safety population (patients receiving ≥1 study drug dose) included 364 patients (study 302, n=134; study 4000, n=230). Study 302 had 78 patients with active cancer (methylnaltrexone, n=37; placebo, n=41) and 56 without cancer (methylnaltrexone, n=26; placebo, n=30); study 4000 had 152 patients with active cancer (methylnaltrexone, n=79; placebo, n=73) and 78 without cancer (methylnaltrexone, n=37; placebo, n=41). A significantly greater proportion of patients treated with methylnaltrexone achieved a laxation response within 4 hours after at least 2 of the first 4 doses versus placebo, dosed by body weight (cancer, 54.1% [methylnaltrexone] vs 7.3% [placebo], P<0.0001; noncancer, 48.0% vs 10.0%; P<0.005) or given as a weight-adjusted fixed dose (cancer, 59.5% vs 6.8%; noncancer, 70.3% vs 14.6%; P<0.0001 each). With fixed-dose methylnaltrexone, average time to RFL for patients with and without cancer was <1 hour of the first dose; with methylnaltrexone dosed by body weight, the first RFL occurred in <4 and <7 hours of treatment in patients with and without cancer, respectively. No significant differences were found in pain scores. SC methylnaltrexone was well tolerated at all doses in all patient cohorts. SC methylnaltrexone was efficacious in inducing rapid RFL and safe among patients with and without active cancer suffering from OIC.

S165 Impact of Patient Subgroups on the Efficacy and Safety of Methylnaltrexone for Opioid-Induced Constipation in Patients With Advanced Illness

Introduction: Methylnaltrexone (MNTX) is a peripherally acting µ-opioid receptor antagonist indicated for opioid-induced constipation (OIC) in patients with advanced illness who are receiving palliative care and in patients with chronic noncancer pain. We investigated if baseline patient characteristics impact the safety and efficacy of MNTX in those with advanced illness and OIC. Methods: This analysis pooled data from 2 randomized, double-blind, placebo (PBO)-controlled studies (study 302–NCT00402038; study 4000‒NCT00672477) in patients with advanced illness, including cancer. Study 302: Patients were randomized to receive subcutaneous (SC) MNTX 0.15 mg/kg or PBO every other day (QOD) for 2 weeks, with possible dose escalation to 0.30 mg/kg at week 2. Study 4000: Patients received weight-based SC MNTX 8 mg or 12 mg QOD or PBO for 2 weeks. The proportion of patients achieving a rescue-free laxation within 4 or 24 hours after the first dose of study drug was assessed in patient subgroups stratified by baseline age (< 65 vs ≥ 65), Eastern Cooperative Oncology Group (ECOG) status (≤ 2 vs > 2), cancer status, laxative type (osmotic agents, stimulants, stool softeners), and opioid requirement (oral morphine equivalent dose < 80 mg/d, 80 ‒ < 150 mg/d, and ≥ 150 mg/d). Treatment-emergent AEs (TEAEs), gastrointestinal (GI) TEAEs, and abdominal pain were evaluated. Results: Overall, 363 patients were included in this analysis (MNTX = 178; PBO = 185). Mean age was 67.8 years in the MNTX group and 66.7 years in the PBO group; 46.8% were men across all groups. A significantly greater proportion of patients receiving MNTX achieved rescue-free laxation within 4 hours (n = 111/178, 62.4% vs n = 31/185, 16.8%, P < .0001) and 24 hours (n = 135/178, 75.8% vs n = 81/185, 43.8%, P < .0001) of the first dose vs PBO. These trends were consistent across all subgroups (Table). Most patients experienced ≥ 1 TEAE in the overall population (MNTX 82.1%; PBO 76.2%); results were similar when stratified by baseline cancer, ECOG, opioid, or laxative group (Table). More than half of TEAEs were GI in nature; abdominal pain was more common in patients receiving MNTX across subgroups. Conclusion: MNTX treatment was superior to PBO in achieving RFL within 4 and 24 hours after the first dose, irrespective of patients’ cancer status, baseline ECOG status, or baseline opioid or laxative use. MNTX remained consistently safe across different baseline clinical and demographic characteristics. Table 1. - Rescue-free laxation response and treatment-emergent events by demographic and clinical characteristics subgroup Rescue-free laxation TEAEs Within 4 hours of the first dose Within 24 hours of the first dose Patients with ≥ 1TEAE Patients with gastrointestinal TEAE Patients with abdominal pain MNTX PBO MNTX PBO MNTX PBO MNTX PBO MNTX PBO Age, n (%) < 65 years 53 (63.9) 13 (14.6) 66 (79.5) 36 (40.4) 70 (84.3) 65 (73.0) 48 (57.8) 37 (41.6) 21 (25.3) 8 (9.0) ≥ 65 years 58 (61.1) 18 (18.8) 69 (72.6) 45 (46.9) 77 (80.2) 76 (79.2) 43 (44.8) 47 (49.0) 18 (18.8) 11 (11.5) Cancer status, n (%) Cancer 74 (63.8) 17 (14.9) 88 (75.9) 53 (46.5) 102 (87.9) 91 (79.8) 67 (57.8) 57 (50.0) 28 (24.1) 11 (9.6) Noncancer 37 (59.7) 14 (19.7) 47 (75.8) 28 (39.4) 44 (69.8) 50 (70.4) 24 (38.1) 27 (38.0) 11 (17.5) 8 (11.3) Functional status, n (%) ECOG ≤ 2 52 (66.7) 18 (22.5) 60 (76.9) 42 (52.5) 67 (85.9) 58 (72.5) 43 (55.1) 37 (46.3) 23 (29.5) 8 (10.0) ECOG > 2 59 (59.0) 13 (12.4) 75 (75.0) 39 (37.1) 80 (79.2) 83 (79.0) 48 (47.5) 47 (44.8) 16 (15.8) 11 (10.5) Baseline opioid dose in OME, n (%) < 80 mg/d 24 (57.1) 7 (12.3) 29 (69.0) 24 (42.1) 30 (71.4) 42 (73.7) 16 (38.1) 26 (45.6) 7 (16.7) 5 (8.8) 80 to < 150 mg/d 24 (61.5) 8 (19.0) 29 (74.4) 22 (52.4) 37 (94.9) 31 (73.8) 22 (56.4) 17 (40.5) 8 (20.5) 6 (14.3) ≥ 150 mg/d 63 (64.9) 16 (18.6) 77 (79.4) 35 (40.7) 80 (81.6) 68 (79.1) 53 (54.1) 41 (47.7) 24 (24.5) 8 (9.3) Baseline laxative regimen, n (%) Stimulants 86 (63.2) 21 (14.1) 104 (76.5) 64 (43.0) 113 (82.5) 118 (79.2) 73 (53.3) 68 (45.6) 29 (21.2) 17 (11.4) Osmotic agents 56 (65.9) 17 (20.7) 64 (75.3) 38 (46.3) 75 (88.2) 63 (76.8) 53 (62.4) 38 (46.3) 25 (29.4) 12 (14.6) Stool softeners 58 (63.0) 15 (15.3) 69 (75.0) 46 (46.9) 72 (78.3) 78 (79.6) 42 (45.7) 46 (46.9) 18 (19.6) 12 (12.2) ECOG = Eastern Cooperative Oncology Group; OME = oral morphine equivalent dose; MNTX = methylnaltrexone; PBO = placebo; TEAE = treatment-emergent adverse event.

S179 Naloxegol Provides Clinically Meaningful Symptom Improvement (PAC-SYM) in Patients With Opioid-Induced Constipation (OIC): A Pooled Analysis of Two Global Phase 3 Studies of Naloxegol

Introduction: OIC affects 40-80% of patients taking chronic opioid therapy. Naloxegol (Movantik®), a peripherally acting mu-opioid receptor antagonist (PAMORA) is effective in treating OIC symptoms in adults with chronic non-cancer pain as shown in two pivotal phase 3 trials (KODIAC 4/5; NCT01309841/NCT01323790). This pooled analysis evaluated symptom improvement utilizing the Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM) in these two randomized, placebo-controlled trials. Methods: PAC-SYM scores were collected during KODIAC 4/5 as supportive efficacy measures. Scores range from 0 (absence of symptoms) to 4 (very severe) for each domain (abdominal, rectal, and stool symptoms). Minimal clinically important difference (MCID) thresholds of 0.5 based on literature and naloxegol real world studies, and 0.8 based on anchor method assessment were used to identify responders and non-responders. Results: 1337 patients (naloxegol (25mg, 12.5mg) or placebo (PBO)) were assessed in this analysis. The overall mean baseline values for PAC-SYM total, abdominal, rectal, and stool symptoms scores were 1.8, 1.7, 1.3, and 2.3, respectively, and were similar across groups. For MCID ≥0.5, there was a significantly higher proportion of PAC-SYM responders with naloxegol (25 mg: 69.49%; 12.5 mg: 65.63%) vs PBO (57.66%) at week 12. Odds ratios (OR) were 1.776 (p=0.0010) for 25mg and 1.501 (p=0.0143) for 12.5mg vs PBO. For MCID ≥0.8, higher proportions of PAC-SYM responders were also observed for naloxegol (25mg: 53.47%; 12.5mg: 45.74%) vs PBO (42.34%) at week 12. ORs were 1.709 (p=0.002) for 25mg and 1.217 (p=0.2368) for 12.5mg vs PBO ORs were generally consistent between MCID >0.8 and 0.5 (Table). At 12 weeks for both MCID thresholds, patients receiving naloxegol 25mg were >70% more likely to achieve clinically meaningful symptom improvement than with PBO.Subdomain analyses revealed dose-dependent responses; significantly greater responses in rectal and stool symptoms were achieved for 25mg vs. PBO (p< 0.05) at both MCID cut-offs (Figure 1a-d). Conclusion: OIC patients achieved clinically meaningful, constipation-related symptom improvement with naloxegol. These changes were dose dependent, with significant gains noted for 25mg at both MCID thresholds. Rectal and stool symptoms appear to drive these improvements consistent with the known effects of PAMORAs.Figure 1.: a-d. Likelihood of Achieving PAC-SYM MCID at Week 12: Naloxegol vs. Placebo (KODIAC 4/5; ITT Population) Table 1. - PAC-SYM Total Score: Proportion of Responders Achieving MCID at Week 12 (KODIAC 4/5; ITT Population) Placebo(N=359) a n(%) Naloxegol 12.5 mg(N=352) a n(%) Naloxegol 25 mg(N=331) a n(%) Naloxegol 12 mg vs. PlaceboOR(95% CI)p-value Naloxegol 25 mg vs. PlaceboOR(95% CI)p-value Proportion of PAC-SYM Responders Achieving MCID ≥ 0.5 207 (57.66%) 231 (65.63%) 230 (69.49%) 1.501(1.085, 2.078)0.0143 1.776(1.263, 2.497)0.0010 Proportion of PAC-SYM Responders Achieving MCID ≥ 0.8 152 (42.34%) 161 (45.74%) 177 (53.47%) 1.217(0.879, 1.687)0.2368 1.709(1.216, 2.401)0.0020 aNumber of analyzable subjects with complete PAC-SYM data for 12-wks.PAC-SYM, Patient Assessment of Constipation Symptoms questionnaire; MCID, minimal clinically important difference; OR, odds ratio; CI, confidence interval.

Rationale and design of a multicenter, double-blinded, randomized, placebo-controlled trial to investigate the effects of naldemedine on opioid-induced constipation for patients with cancer pain: A study protocol

BackgroundIt is unclear which laxatives are appropriate to prevent opioid-induced constipation (OIC). This study will evaluate whether prophylactic use of naldemedine prevents OIC in patients with cancer who start opioid administration. MethodsThis study is a multicenter, double-blinded, randomized, placebo-controlled trial. Patients who meet the eligibility criteria and give consent will be randomly assigned to the naldemedine or placebo group. Both groups will take each drug once a day after breakfast for 14 days. ResultsThe primary endpoint is the proportion of patients with a Bowel Function Index of less than 28.8 on Day 14. The secondary endpoints include assessment scales of the impact of constipation on comprehensive quality of life. ConclusionsThis is the first study proposed to assess the superiority of naldemedine over placebo in the prevention of OIC. If naldemedine is found to be effective in reducing OIC compared with the placebo, it will be regarded as a new standard for OIC prophylaxis at opioid initiation. Trial registrationjRCT identifier: jRCTs031200397. Registered March 5, 2021, https://rctportal.niph.go.jp/en/detail?trial_id=jRCTs031200397.

A Case Report on Opioid-Induced Constipation in a Patient with Cancer Treated by &lt;italic&gt;Jowiseunggi-tang&lt;/italic&gt;

Objective: &lt;i&gt;Jowiseunggi-tang&lt;/i&gt; (JWSGT) is a traditional herbal medicine commonly used for purgative activity in constipation. This study evaluates JWSGT for the treatment of opioid-induced constipation (OIC), the most common and debilitating gastrointestinal effect of opioid use.Methods: A 64-year-old man with floor of mouth cancer was hospitalized for OIC, and JWSGT was administered orally twice a day for 10 days, along with acupuncture, moxibustion, and cupping. The primary outcome measures were defecation type according to the Bristol Stool Form Scale (BSFS) and the frequency of bowel movements. The Brief Fatigue Inventory (BFI) and the Functional Assessment of Cancer Therapy-General (FACT-G) were used as secondary measures.Results: After three days of JWSGT administration, spontaneous bowel movements were observed two to three times per week with improved BSFS from type 2 to 4. A reduction in BFI score (8.7 to 2.0) and an increase in FACT-G score (44.3 to 59.0) suggested an improvement in fatigue level and quality of life.Conclusion: This is the first report to assess the efficacy of JWSGT for the management of OIC in patients with cancer, and JWSGT may be an effective option to improve symptoms and quality of life in this group.

Efficacy and Safety of Naldemedine for Patients with Cancer with Opioid-Induced Constipation in Clinical Practice: A Real-World Retrospective Study.

The efficacy and safety of naldemedine for opioid-induced constipation in patients with cancer has not been investigated in clinical practice. We conducted a multicenter, retrospective study to assess the effects of naldemedine among 10 Japanese institutions between June 2017 and August 2019. We evaluated the number of defecations 7 days before and after naldemedine administration. A total of 149 patients (89 male) with a median age of 72 years (range, 38–96) were included. The performance status was 0–1, 2, and ≥3 in 40, 38, and 71 patients, respectively. The median opioid dose in oral morphine equivalents was 30 mg/day (range: 7.5–800 mg). We observed 98 responders and 51 non-responders. The median number of defecations increased significantly in the 7 days following naldemedine administration from three to six (p < 0.0001). Multivariate analysis revealed that an opioid dose <30 mg/day [odds ratio, 2.08; 95% confidence interval, 1.01–4.32; p = 0.042] was significantly correlated with the effect of naldemedine. Diarrhea was the most common adverse event (38.2%) among all grades. The efficacy and safety of naldemedine in clinical practice are comparable to those of prospective studies, suggesting that it is effective in most patients.

Effects of Electroacupuncture on Opioid-Induced Constipation in Patients With Cancer: Study Protocol for a Multicenter Randomized Controlled Trial.

BackgroundOpioid-induced constipation (OIC) is one of the most prevalent adverse events associated with cancer patients who receive opioid analgesics for moderate to severe pain. Acupuncture may be an effective treatment for OIC. We designed this trial to assess the efficacy and safety of electroacupuncture for OIC in cancer patients.MethodsThis is a multicenter, sham-controlled, parallel-group, subject- and assessor-blinded randomized trial. A total of 100 cancer patients with OIC will be randomly assigned to either the electroacupuncture group or the sham electroacupuncture group at a ratio of 1:1. Patients in each group will receive a total of 24-session treatment over 8 weeks, three sessions a week and 30 min each session. Thereafter, patients will be followed up for another 8 weeks. The primary outcome will be the proportion of responders, defined as a patient who has ≥3 spontaneous bowel movements (SBMs)/wk and ≥ increase of 1 SBM from baseline simultaneously for at least 6 out of 8 weeks of the treatment period. The secondary outcomes will include the mean weekly SBMs and complete spontaneous bowel movements, the mean Bristol Stool Form Scale score for stool consistency, the mean score for straining of SBM, the total and subscale scores of Patient Assessment of Constipation-Symptom questionnaires, and the total and subscale scores of Patient Assessment of Constipation-Quality of Life questionnaire. Patients' global assessment of treatment effectiveness, patients' expectation toward the effectiveness of acupuncture and safety of acupuncture will also be assessed. All efficacy analyses will be performed in the intention-to-treat population.DiscussionTo improve the adherence to intervention protocols, the majority of the participants will be recruited from an inpatient setting. The results will help to determine the clinical effects and safety of electroacupuncture for the treatment of OIC among patients with cancer.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier: NCT03797586, registered on 4 January 2019, https://clinicaltrials.gov/ct2/show/NCT03797586.

The efficacy of acupressure in managing opioid-induced constipation in patients with cancer: A single-blind randomized controlled trial.

Opioid-induced constipation is one of the heath problems with a negative impact on the quality of life. This randomized-controlled trial aimed to investigate the effects of acupressure therapy on the management of opioid-induced constipation in patients with cancer. The trial was conducted on 140 cancer patients, who were assigned to the acupressure (n = 70) and the control groups (n = 70). In addition to routine care, patients in the acupressure group received 8-min acupressure from the Zhongwan (CV12), Guanyuan (CV4), and Tianshu (ST25) acupoints once a day for 4weeks. The outcomes included Defecation Diary (DD), Visual Analog Scale Questionnaire (VASQ), and Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL). We found a statistically significant difference between the acupressure and control groups in terms of stool consistency (2.22 ± 0.49 vs 1.80 ± 0.55) (p = 0.001), straining (1.98 ± 0.71 vs 2.91 ± 0.37) (p = 0.001), incomplete evacuation (0.37 ± 0.29 vs 0.61 ± 0.43) (p = 0.001), stool amount (0.93 ± 0.14 vs 0.95 ± 0.20) (p = 0.001), and the number of defecations (0.70 ± 0.22 vs 0.46 ± 0.29), (p = 0.001) measured at the fifth week. Besides, with the exception of stool amount, the DD scores obtained by the acupressure group significantly increased in the fifth week. Inter-group comparison of the pre-test and post-test scores showed that acupressure group obtained statistically significantly lower scores from the PAC-QOL (p = 0.0001). Findings of this trial suggested that a 4-week acupressure was an effective way to improve the quality of life and to reduce both the subjective and the objective constipation symptoms in patients with opioid-induced constipations. NCT04876508.

Post-marketing surveillance of the safety and effectiveness of naldemedine in the management of opioid-induced constipation in patients with cancer pain in Japan

PurposeThis prospective post-marketing surveillance (PMS) was designed to collect data on the safety and effectiveness of naldemedine in routine clinical practice in patients with opioid-induced constipation (OIC) and cancer pain in Japan and explore the characteristics of patients prone to diarrhea.MethodsThe enrolled patients received naldemedine (0.2 mg, once a day) orally for up to 12 weeks. In the safety analysis, adverse drug reactions (ADRs), including diarrhea as a special interest, were assessed. Effectiveness was evaluated, especially regarding the frequency and condition of bowel movement.ResultsIn the safety analysis set (n = 1177), 145 ADRs occurred in 133 (11.30%) patients, and diarrhea was the most frequent event (n = 107, 9.09%). Most cases of diarrhea were non-serious (98.1%). Most ADRs were non-serious (93.8%), and they resolved within 2 weeks (75.9%). No patient characteristics influenced the risk of diarrhea development or aggravation. Both the frequency (75.0% and 83.2%) and condition of bowel movement (80.0% and 88.0%) were improved at 2 and 12 weeks, respectively in the effectiveness analysis set (n = 953). Frequency and condition of bowel movement were also improved in patients excluded (e.g., Eastern Cooperative Oncology Group performance status was ≥ 3) or with very small numbers (e.g., received weak opioid) in the clinical trials.ConclusionsThis PMS indicates that naldemedine is well tolerated and effective in patients of various backgrounds in routine clinical practice who have OIC and cancer pain.Trial registrationUMIN000042851.

An Evaluation of Docusate Monotherapy and the Prevention of Opioid-Induced Constipation after Surgery

Our purpose was to determine if docusate monotherapy is effective in preventing opioid-induced constipation in patients receiving opioids following orthopedic surgery. Our single-center, retrospective, cohort study evaluated 212 orthopedic patients who received opioids between May 1, 2018, and December 31, 2018. All patients were aged 18 years and older, hospitalized for more than 48 hours, and received docusate for primary prevention of constipation post-operatively. The primary outcome was the proportion of patients taking opioid medications who experienced docusate failure, defined as patients who did not have a bowel movement within 5 days of starting docusate after surgery or those patients who required the use of additional laxative agents to produce a bowel movement. After excluding patients which did not meet the inclusion criteria, 79.9% (n = 159/199) experienced docusate treatment failure. Of these patients, 42.8% (68/159) failed to have a bowel movement or had a bowel movement greater than 5 days post-surgery. The remaining 57.2% (91/159) of patients required an additional laxative to produce a bowel movement. Docusate monotherapy was not effective in preventing constipation in patients receiving opioids following elective orthopedic surgery. Based on these findings, we propose utilization of stimulant bowel products with proven efficacy as primary therapy after surgery to prevent constipation. Future multi-centered, randomized controlled trials are necessary to evaluate the differences in efficacy and safety between common bowel regimens in treating opioid-induced constipation in patients who undergo elective orthopedic surgery.

Update on the role of naldemedine in opioid-induced constipation in patients with chronic noncancer pain.

Chronic noncancer pain (CNCP) affects up to 20% of adults and can interfere with activities of daily living. Up to 4% of adults in the United States receive chronic opioid therapy and up to 57% of patients on long-term opioids for CNCP report opioid-induced constipation (OIC). OIC is essentially constipation occurring after starting opioid treatment. While laxatives are traditionally the first-line therapy for OIC, 81% of patients taking daily laxatives and opioids still reported OIC and considered that it negatively affected their quality of life. Naldemedine is a peripherally acting µ-opioid receptor antagonists (PAMORA) approved for the treatment of OIC in patients with CNCP. This article reviews the mechanism of action, efficacy, and safety of naldemedine in CNCP patients. Naldemedine improves OIC in patients with CNCP by acting as an opioid receptor antagonist in the gastrointestinal tract. It does not interfere with the analgesic properties of opioids or cause withdrawal symptoms since these effects are centrally mediated, and naldemedine does not cross the blood brain barrier. Naldemedine showed significant and sustained improvement in frequency of bowel movements, quality of life, and constipation-related symptoms. It is generally well tolerated with a higher incidence of gastrointestinal adverse events of mild or moderate severity such as diarrhea, abdominal pain, or vomiting compared to placebo. While there are no randomized, controlled trials that compare head-to-head pharmacological therapies used for treatment of OIC, network meta-analysis shows that naldemedine has an overall good benefit-risk profile compared to the other approved medications.