Opioid-induced Constipation Symptoms Research Articles

Opioid-Induced Constipation and Associated Symptoms After Orthopedic Trauma

PurposeOpioid-induced constipation is an adverse effect often experienced among patients taking prescription opioid medication. Despite frequent opioid prescribing after orthopedic injury, there is a dearth of research examining opioid-induced constipation presentations in this population. This analysis examines the frequency of opioid-induced constipation manifestations and association with patient-reported outcomes among participants prescribed opioid medication following orthopedic injury. DesignSecondary analysis of 86 clinical trial participants following orthopedic trauma. MethodsParticipants were assessed 2-weeks postoperatively with the following measures: Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference, PROMIS Physical Function, past 24-hour average pain intensity captured on the numeric pain rating scale, and the Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaire. Linear regressions examined the association between PAC-SYM scores and both pain intensity and PROMIS T-scores while accounting for injury severity and opioid medication dosage. ResultsMost participants (69%) reported experiencing opioid-induced constipation symptoms and 7% reported moderate to severe symptoms. Compared to those without symptoms, participants reporting opioid-induced constipation symptoms were found to have a 3-point increase in PROMIS Pain Interference (95% Confidence Interval [CI]: 0.28-5.90; p = .032), a 3-point decline in PROMIS Physical Function (95% CI: -6.57 to -0.02; p = .049), and a 1.7-point increase in average pain scores (95% CI: 0.50-3.01; p = .007) at 2-weeks following surgery. ConclusionsOpioid-induced constipation symptoms are common after orthopedic trauma and linked to increased pain interference and pain intensity as well as reduced physical function. Clinical ImplicationsNurse-led assessments of opioid-induced constipation can support the timely delivery of interventions to alleviate symptoms and potentially improve patient-reported outcomes after injury.

Efficacy and Safety of Naloxegol in Patients with Chronic Non-Cancer Pain Who Experience Opioid-Induced Constipation: A Pooled Analysis of Two Global, Randomized Controlled Studies.

This study evaluates the onset, magnitude, and consistency of improvement of opioid-induced constipation (OIC) symptoms with naloxegol treatment. This was a pooled analysis of two Phase 3, double-blind, randomized, placebo-controlled studies (KODIAC-04/05, NCT01309841/NCT01323790) in patients with chronic non-cancer pain and OIC treated with naloxegol 25mg or 12.5mg daily. This analysis assessed improvements in response rates, frequency of spontaneous bowel movement (SBM) and complete SBMs (CSBM), OIC constipation symptoms (straining, stool consistency), time to first post-dose SBM and CSBM, and onset of adverse events over the 12-week period. The population of 1337 subjects had a mean age of 52 years and mean duration of opioid use of 3.6 years at baseline. Mean SBM frequency was 1.4/week. Naloxegol 25mg and 12.5mg demonstrated significantly higher response rates vs placebo (PBO) [41.9% (P < 0.001), 37.8% (P = 0.008), 29.4% respectively]. Rapid (within 1 week) and sustained (over 12 weeks) symptom improvement was significantly greater for naloxegol vs PBO (P < 0.05). Both doses showed statistically significant and clinically meaningful improvements in straining, stool consistency, number of SBMs and CSBMs/wk. Significantly shorter times to first post-dose SBM and CSBM were observed with naloxegol vs PBO (SBM HR: 25mg = 1.90, 12.5mg= 1.60; CSBM HR: 25mg = 1.42, 12.5mg = 1.36; P < 0.001 for each regimen). Adverse events occurred more frequently in the naloxegol 25mg group and were most frequently reported during the first week. In patients with chronic non-cancer pain, naloxegol 25mg and 12.5mg demonstrated significantly higher response rates and rapid and sustained improvements in OIC symptoms compared with PBO.

Naloxegol (Movantik®) Provides Rapid and Sustained Improvement of Opioid-Induced Constipation Symptoms Irrespective of Opioid Dose

AimNaloxegol (Movantik), an oral peripherally acting mu-opioid receptor antagonist has demonstrated rapid relief of opioid-induced constipation (OIC) in patients with chronic non-cancer pain in two phase 3 trials (KODIAC 4/5; NCT01309841/NCT01323790). This analysis aims to characterize the OIC symptom burden and evaluate the efficacy of naloxegol in treating symptoms of OIC based on daily opioid dosages. This is the first naloxegol analysis based on a lower opioid dose cutoff of 100 MEU/day. MethodsData were pooled from the KODIAC 4/5 intent-to-treat populations (N=1337). Subjects treated with placebo (PBO) and naloxegol (12.5mg, 25mg) QD were evaluated based on opioid dose ranges (lower dose, ≤100mg; higher dose, >100mg MEU/day). OIC symptoms assessed include number of spontaneous bowel movements (SBM/wk), complete evacuation (CSBM), straining (scale 1=not at all, 5=extreme) and stool consistency (Bristol Stool Scale: 1=hard, 7=watery). ResultsBaseline OIC symptom burden (SBM/wk, CSBM/wk, straining, stool consistency) was similar between lower (n=764) and higher (n=567) opioid dose subgroups. Naloxegol (12.5mg, 25mg) provided significant improvement vs PBO in SBMs/wk in the lower and higher opioid dose subgroups; ≤100 MEU (mean SBM/wk: 2.41, 2.91 vs 1.99, respectively; p<0.05) and ˃100 MEU (mean SBM/wk: 2.81, 3.53 vs 2.05, respectively; p< 0.05). A significant improvement in CSBMs/wk vs PBO was demonstrated in the lower dose subgroup for naloxegol 25mg (mean CSBM/wk: 1.48, 1.97 vs 1.38; p=0.54 and p<0.05, respectively) and in the higher dose subgroup for both naloxegol regimens (mean CSBM/wk: 1.90, 2.36 vs 1.20, respectively; p<0.05). In both dose subgroups, rapid symptom improvement in SBM, CSBM and stool consistency were seen within the first week with naloxegol (p<0.05). ConclusionsRegardless of opioid dose, naloxegol (12.5mg, 25mg) provided rapid and sustained improvement of clinically relevant OIC symptoms. These data suggest that all patients should routinely be assessed for OIC, as lower opioid doses often induce constipation.

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.

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.

Constipation Severity and Quality of Life among Patients with Cancer Who Received Prophylactic Laxatives: Quasi-Experimental Study.

Prophylactic laxatives were associated with decreasing the incidence of Opioid-induced constipation among patients with cancer. This study aims to evaluate the effectiveness of early prophylactic laxatives therapy on the severity of constipation and quality of life among patients with cancer receiving opioids. Using a quasi-experimental design with 64 patients assigned to control group and 66 patients assigned to intervention group. The final sample was composed from 112 patients (57 in control group and 55 in intervention group), who were selected from an oncology clinic. Patients in the intervention group have received prophylactical laxatives The intervention included an oral colonic stimulant laxative (i.e., Bisacodyl, Dose= 3 tab/ day and/or Senna 6.8 mg twice daily) and an oral colonic osmotic laxative (i.e., Lactulose, Dose = 15 ml three times per day). Patients in the control group continue to receive their routine care without laxatives. Patients in the intervention group have reported a significant reduction in the severity of constipation symptoms at eight weeks post the intervention (p &lt; 0.001). Furthermore, the patients in the intervention group have revealed a significant improvement in their quality of life (QoL) (p&lt; 0.001). Patients with cancer need to use the first line of laxatives as prophylactic alongside with opioids to minimize the severity of Opioid-induced constipation symptoms and to enhance the QoL.

Constipation in Cancer Patients - an Update of Clinical Evidence.

Constipation is one of the most frequent problems in cancer patients, and its etiology is multifactorial. It leads to decreased quality of life and impedes optimal pain treatment. Despite the high prevalence, constipation is frequently underdiagnosed mainly because of lack of validated diagnostic criteria or widely accepted definition of constipation in cancer patients. All cancer patients should be evaluated regularly for constipation, and concomitant causes and risk factors were assessed. Opioids are responsible for a much of the secondary constipation in cancer patients. The management of constipation in cancer patients should be multifaceted, addressing dietary and behavioral issues and optimizing pharmacological interventions. Prevention of opioid-induced constipation (OIC) is pivotal, as treatment is often unsatisfactory or inefficient. Dietary and behavioral interventions should be considered. Non-pharmacological measures include hydration and nutrition, ensuring privacy during defecation, using a commode or footstool, and the availability of a caregiver. Abdominal massage may be of value. Traditional laxatives are recommended in prevention but not in the treatment of OIC. Peripherally acting mu-opioid receptor antagonists (PAMORA) appear the first choice in the treatment and an alternative to laxatives in some recent clinical practice guidelines in preventing OIC. Naldemedine, naloxegol, and methylnaltrexone are supported by quality evidence for OIC management. Naloxone or naltrexone, taken orally in combined formulations with opioids, may be valuable in preventing or reducing OIC symptoms.

S497 Naloxegol Accelerates Time to First Spontaneous Bowel Movement (SBM) and Complete SBM (CSBM) With Predictable Efficacy in Patients With Extreme Opioid-Induced Constipation (OIC): A Pooled Analysis of Two Phase 3 Trials

Introduction: In a pooled analysis of two phase 3 trials, naloxegol, a peripherally acting mu-opioid receptor antagonist (PAMORA), demonstrated rapid onset and predictable efficacy in relieving OIC symptoms in subjects taking opioids for chronic non-cancer pain (KODIAC 4/5 [N=1337]; NCT01309841/NCT01323790). For a proportion of patients, symptoms of OIC are severe, resulting in < 1 SBM/week. The objective of this analysis was to characterize the initial onset and maintenance of response in subjects with extreme OIC at baseline. Methods: Data were pooled from the two phase 3 trials; extreme OIC was defined as < 1 SBM and < 1 complete SBM (sense of complete evacuation) (CSBM) per week; 380 subjects (28.4% of the overall population) met these criteria. Data were analyzed to characterize the time to and predictability of initial response within 48 hours of the first dose of naloxegol (12.5mg/25mg). The time to 1st post-dose SBM & CSBM without rescue medication for naloxegol vs placebo (PBO) during the 12-week treatment period was analyzed via the Cox proportional hazard model; treatment effect was analyzed via the hazard ratio (HR). The median time to 1st post-dose SBM & CSBM was derived via the Kaplan-Meier (KM) method. Onset of action was measured by the proportion of patients achieving a SBM and CSBM from 4hrs to 48hrs following the initial dose, which reflects a clinically relevant timeframe. Results: The time to first SBM and CSBM was significantly shorter for naloxegol (12.5mg/25mg) vs PBO (all P< 0.05); the corresponding HRs all favored naloxegol over PBO (all P< 0.001), indicating an approximate twofold reduction in the time to 1 st SBM and CSBM for the naloxegol groups vs PBO (Table). The median times to 1st SBM were 6.3hrs (25mg), 22.9hrs (12.5mg), and 55.8hrs (PBO). The median times to 1st CSBM were 75.8hrs (25mg), 74.0hrs (12.5mg), and 263.8hrs (PBO). The KM curves showed clear separation of naloxegol treatments from PBO for the 1st SBM and CSBM. Higher proportions of patients achieved a SBM and CSBM by ≤4hr, ≤6hr, ≤8hr, ≤12hr, ≤24hr, and ≤48hr for the naloxegol groups vs PBO (Figure). Conclusion: Consistent with the overall phase 3 data, naloxegol (12.5mg/25mg) demonstrates rapid and clinically relevant onset of action and predictable dose-dependent efficacy in subjects with extreme OIC.Figure 1.: Patients with Extreme OIC. A. Kaplan-Meier Curve for Time to the First Post-Dose SBM; B. Kaplan-Meier Curve for Time to the First Post-Dose CSBM; C. Onset of Action Within the First 48 Hours Post-Initial Dose for a SBM. D. Onset of Action within the First 48 Hours Post-Initial Dose for a CSBM.Table 1.: Patients with Extreme OIC: The Median Time To 1st SBM and 1st CSBM During the 12-Wk Treatment Period (KODIAC 4/5 Studies; ITT Population)

Insights into the Use of Peripherally Acting μ-Opioid Receptor Antagonists (PAMORAs) in Oncologic Patients: from Scientific Evidence to Real Clinical Practice.

Management of chronic pain is crucial to improve the quality of life of cancer and palliative care patients. Opioid-based treatments used to control pain can be prolonged over time. Unfortunately, constipation is one of the most disturbing adverse effects of long-term use of opioids. Opioid-induced constipation (OIC) occurs when opioids bind to the specific receptors present in the gastrointestinal (GI) tract, and can affect any patients receiving chronic opioid therapy, including cancer patients. The limited efficacy of laxatives to treat OIC symptoms prompted the search for new therapeutic strategies. Peripherally acting μ-opioid receptor antagonists (PAMORAs) have recently emerged as new effective drugs for OIC management due to their specific binding to enteric μ-receptors. Little information is available on the use of PAMORAs in real-life practice for OIC treatment in cancer patients. In this paper, a panel of experts specializing in cancer and palliative care pools their clinical experience with PAMORAs in cancer patients presenting OIC and highlights the importance of timing and choice of therapy in achieving prompt OIC management and benefitting 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.

1819P - Clinical practice evaluation of opioids induced constipation management in cancer patients: The EIO-Praxis project

BackgroundIn 2017, the ECO Foundation (Excellence and Quality in Oncology) completed the EIO-50 project to learn about the diagnostic and treatment criteria of opioid-induced constipation (OIC) in cancer patients. The EIO-Praxis project was designed as a continuation of EIO-50, to learn about the current clinical practice of oncology professionals for the management of patients with OIC (process, follow-up and results). Methods77 health care professionals (HCP) from oncology units participated in the study. Each investigator collected information from 10 medical records of cancer patients who received OIC treatment, with a total of 770 records. In each center, 6 indicators of its structure were collected and the completion of a questionnaire with 15 questions regarding patient’s follow-up and treatment process was conducted. ResultsAccording to healthcare professionals (HCP), an average proportion of 47.5% of cancer patients received treatment with opioids. From these, an average of 44.9% developed OIC. 51.9% of the investigators didn’t follow any guidelines for the management of patients with OIC. The mean age of the patients of the study was 61.6 years old. The mean duration of opioid treatment was 4.9 months, with an average time of 16.5 days from the start of opioid treatment to the appearance of the first symptoms of OIC. Only in 55.1% of the patients, the presence of functional constipation before starting opioid treatment was assessed. Patients of the study presented the following Rome IV criteria symptoms: 82.6% reduced bowel frequency, 52.9% fewer than three spontaneous bowel movements per week, 54.4% development or worsening of straining and stool consistency (54.2%). The majority of the patients were treated with laxatives (76.0%). Oral Peripherally Active µ-Opioid Receptor Antagonist (PAMORA) was also used in 54.8% of the patients. ConclusionsDespite new guidelines for the management of constipation in cancer patients were published in 2018, the management of OIC is still insufficient. After laxative failures, the use of PAMORA drugs should be taken into consideration for the management of OIC. Legal entity responsible for the studyECO Foundation. FundingKyowa Kirin. DisclosureE. Aranda Aguilar: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celgene; Advisory / Consultancy: Merck; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi. J. Garcia Foncillas: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Research grant / Funding (institution): Merck. E. Diaz Rubio: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Genomica; Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Speaker Bureau / Expert testimony: MSD; Research grant / Funding (institution): Roche; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Sysmex. R. López: Shareholder / Stockholder / Stock options, Licensing / Royalties: Nasasbiotech; Shareholder / Stockholder / Stock options: Mtrap Inc; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: Janssen; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer; Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Pierre Fabre. All other authors have declared no conflicts of interest.

The efficacy of abdominal massage in managing opioid-induced constipation.

This study was conducted to determine the effects of abdominal massage in managing opioid-induced constipation. Designed as a randomized controlled trial, this study was conducted between February 2017 and January 2018 with the participation of 204 patients who had complaints of opioid-induced constipation. The experimental and control group, each of which included 102 patients, were randomised using a previously prepared randomization checklist. Patients in the experimental group were given a 15-min video-guided abdominal massage training by the researcher, and the patients in this group were asked to perform abdominal massage for 4 weeks, twice a day, 30 min after breakfast and dinner. In the control group, the standard approach of the clinic was applied. A patient data form, the Defecation Diary, Visual Analogue Scale, and Patient Assessment of Constipation Quality of Life Questionnaire were used to the study. The data from the study showed that abdominal massage decreased the severity of constipation, the feeling of incomplete bowel emptying, the severity of straining, the severity of anal pain, and bloating (p < 0.05), provided better stool consistency (p < 0.05) and increased the number of defecations as well as quality of life scores (p < 0.05). The abdominal massage application increased the number of defecations by 13% and was an effective approach for managing opioid-induced constipation symptoms.

The role of oxycodone/naloxone in the management of patients with pain and opioid-induced constipation

ABSTRACTIntroduction: Common opioid adverse effects (AE) of the gastrointestinal tract include opioid-induced constipation (OIC) and opioid-induced bowel dysfunction (OIBD) with traditional laxatives being of limited efficacy, having AEs and not addressing the pathophysiology of OIC or OIBD. Targeted treatment comprises of PAMORA (peripherally acting mu-opioid receptor antagonists) and a combination of an opioid receptor agonist with its antagonist, namely prolonged-release oxycodone with prolonged-release naloxone (OXN) tablets at a fixed ratio of 2:1. Oxycodone provides analgesia, whereas naloxone prevents binding or displaces it from opioid receptors located in the gut wall.Areas covered: The authors review the role of OXN in the management of patients with pain and OIC. A literature search was performed using the search terms ‘oxycodone/naloxone’ and ‘opioid-induced constipation’ using the PubMed database up to October 2018.Expert opinion: OXN delivers analgesia comparable (or superior versus placebo and in observational studies) to oxycodone alone and other opioids with a limited or decreased disturbing effect on bowel function. OXN in daily doses of up to 160 mg/80 mg provides effective analgesia with little negative impact on bowel function. OXN may be successfully used in patients with chronic pain, to prevent or treat symptoms of OIC and OIBD.

The Burden of Opioid-Induced Constipation in Younger Patients with Chronic Noncancer Pain.

The purpose of this analysis was to evaluate the experience of opioid-induced constipation in younger patients and identify differences in the experience of opioid-induced constipation and its symptoms between younger patients (<50 years) and older patients (50-64 years). Post hoc analysis of data from a 24-week prospective, multinational, longitudinal observational cohort study (NCT01928953). Outpatient clinics in the United States, Canada, Germany, and United Kingdom. Two age-based subgroups of adult patients with chronic noncancer pain receiving four or more weeks of daily opioid therapy and experiencing opioid-induced constipation within the previous two weeks. The number of spontaneous bowel movements, frequency of constipation symptoms, amount of bother associated with symptoms, Patient Assessment of Constipation-Symptoms questionnaire, and health-related quality of life and function outcomes. Overall, 419 patients were included in this analysis (younger patients, N = 184; older patients, N = 235). Among younger and older patients, respectively, constipation occurred within the first week after initiating opioid therapy for 32.8% and 35.9%. At baseline, the mean numbers of spontaneous bowel movements/week were 1.3 and 1.5, and moderate opioid-induced constipation-related interference with pain management was reported by 46.6% and 44.5%. Younger patients generally reported that opioid-induced constipation symptoms were more bothersome than did older patients. The impact of opioid-induced constipation on health-related quality of life, work productivity, and day-to-day activities was comparable. In these patients receiving opioid therapy for chronic noncancer pain, the burden of opioid-induced constipation was comparable or greater for patients aged <50 years compared with that for patients aged 50-64 years.

Colorectal Transit and Volume During Treatment With Prolonged-release Oxycodone/Naloxone Versus Oxycodone Plus Macrogol 3350.

Background/AimsOpioid-induced constipation (OIC) is the most common gastrointestinal (GI) side effect to opioid treatment. Opioid receptor antagonists against OIC have been introduced, but their efficacy has not been directly compared to conventional laxatives. Our aim was to compare symptoms and objective parameters of gut function in an experimental model of OIC during treatment with the opioid antagonist naloxone and oxycodone in prolonged-release (PR) formulation versus oxycodone plus macrogol 3350.MethodsIn this randomized, double-blind, crossover trial 20 healthy men received a 5-day treatment of combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350. Regional GI transit times and segmental colorectal transit were assessed with the Motilis 3D-Transit electromagnetic capsule system. Colorectal volumes were determined by MRI. OIC symptoms were assessed with validated questionnaires, along with stool frequency and consistency.ResultsTotal colorectal volume did not change after 5 days’ treatment with PR oxycodone/naloxone (941 vs 1036 mL; P = 0.091), but increased significantly after PR oxycodone plus macrogol treatment (912 vs 1123 mL; P < 0.001). Neither regional GI transit times nor segmental colorectal transit differed between the treatments (all P > 0.05). The Patient Assessment of Constipation Symptom Questionnaire abdominal symptoms score was lower during PR oxycodone/naloxone compared to PR oxycodone plus macrogol (0.2 vs 3.2; P = 0.002). Stool frequency was lower during PR oxycodone/naloxone compared to PR oxycodone plus macrogol (4.2 vs 5.4; P = 0.035).ConclusionsPR oxycodone plus macrogol increases colorectal volume, but does not improve GI transit compared to PR oxycodone/naloxone. However, PR oxycodone/naloxone results in a lower abdominal symptom burden, despite higher stool frequency during macrogol treatment.

Efficacy of Lubiprostone for the Treatment of Opioid-Induced Constipation, Analyzed by Opioid Class

To examine the efficacy and safety of lubiprostone for the treatment of opioid-induced constipation (OIC) in patients by opioid class received. Data were pooled from three phase III, randomized, double-blind, placebo-controlled studies. Adults with chronic noncancer pain receiving opioid therapy for 30 or more days and diagnosed with OIC. Overall mean change from baseline in spontaneous bowel movement (SBM) frequency, overall treatment response (≥1 SBM/week improvement over baseline SBM frequency in all treatment weeks with available data and ≥3 SBMs/week for ≥9 of the 12 weeks of treatment), and OIC-related symptoms were examined in patients taking opioids. Data were pooled and analyzed by opioid group. In patients receiving phenanthrene opioids (e.g., oxycodone; N = 1,159), lubiprostone significantly increased overall mean changes in SBM frequency from baseline (P = 0.0001), increased overall response rate (P = 0.0024), and improved OIC symptoms (P ≤ 0.0229) vs placebo. Patients receiving phenylpiperidine opioids (e.g., fentanyl; N = 137) had significant improvement in SBM frequency (P = 0.0129) and favorable trends in response rates (21.4% vs 9.8%; P = 0.0723) and OIC symptoms vs placebo. Efficacy was not observed in overall analyses of patients receiving diphenylheptane opioids (e.g., methadone), although an increase in SBM frequency was observed in patients who received a morphine-equivalent daily dose of 200 or fewer mg, suggesting a dose-dependent negative interference of this opioid class on lubiprostone effects. For all groups, the lubiprostone adverse event profile was similar; the most common treatment-emergent adverse events were nausea and diarrhea. In patients using commonly prescribed opioids, lubiprostone is effective and generally well tolerated for the treatment of OIC.

Interrogating Social Media Sources to Gain Insight on Opioid-Induced Constipation Symptoms as Reported By Patients

Opioid-induced constipation (OIC) is the most common adverse effect associated with prolonged use of opioids, and it can have a major impact on patient’s lives. This exploratory project employed text mining techniques to gather information from a range of social media sources, including patient forums, to better understand which symptoms are associated with OIC. A web crawler was seeded with the URLs of websites likely to contain the content we were looking for; this was then run to retrieve web-pages containing mentions of OIC. A machine-learning application was developed to extract patient-reported symptoms relating to OIC from the web-pages. The performance of the model was evaluated and tuned using standard cross-validation techniques. The narrative content of the posts was anonymised and analysed manually. Of the 42,000 web-pages retrieved, we found 128 posts that described symptoms of OIC as reported by patients. Some posts mentioned more than one symptom. The most common symptoms were having pain (39 posts), feeling blocked (37 posts), evacuation issues (22 posts) and bloating (22 posts). There were a range of other symptoms which included: anal spasm, weight change, cramps, nausea/sickness, tenderness, stomach pressure, headache, urge, stitch, leakage, anus not closing, gassy, brain fog, bleeding and feeling tired. Patients also reported a fear of rupture (4 posts) and of piles (1 post). A range of symptoms were reported by patients with OIC. More generally, this research project shows that social media can be an important source of insight on patient symptoms; which could be invaluable when designing further qualitative or quantitative research or in better understanding the burden of a condition.

Effect of Naldemedine on Frequency of Spontaneous Bowel Movements and Associated Symptoms

Introduction: Opioid-induced constipation (OIC) is a well-known side effect of opioid therapy. Naldemedine (NAL) is a peripherally-acting μ-opioid receptor antagonist approved for the treatment of OIC in patients with chronic non-cancer pain. Methods: Two randomized, double-blind placebo (PBO) controlled 12-week studies (NCT01965158 and NCT01993940), assessed the effect over time of NAL 0.2 mg once daily vs PBO in the frequency of spontaneous bowel movements (SBMs), complete SBMs (CSBMs, defined as SBMs with a perception of complete evacuation), SBMs without straining, and SBMs with a Bristol Stool Scale (BSS) Score of 3 or 4 in adult (age 18-80 years) subjects with chronic non-cancer pain and OIC. Subjects were required to not be on laxatives at screening or to agree to discontinue laxatives upon signing informed consent. The mean changes in the frequency per week from baseline to each week was compared between NAL and PBO, with a mixed-effects model repeated measures which opioid dose strata and study as a covariate and treatment group, time, time-by-treatment group interaction as fixed effects. Safety was assessed based on the incidence of adverse events (AEs). Results: In the two studies pooled, 1095 subjects were randomized 1:1 to NAL (N=549) or PBO (N=546) for 12 weeks. In all four endpoints, NAL was associated with a significantly (P≤0.0001) greater improvement from baseline at each week relative to PBO, starting at Week 1 and up to Week 12 (Figure). The overall incidence of AEs was generally similar between groups. Treatment with NAL was associated with a greater incidence of gastrointestinal AEs (abdominal pain, diarrhea, nausea) compared with PBO (Table).Figure: Change from Baseline* to Each Week (LS Mean ± SE) in Assessed Endpoints.Table: Table. Overall Summary of Treatment Emergent Adverse Events (Safety Population)Conclusion: Treatment with NAL over 12 weeks compared with placebo improved the frequency of bowel movements as well as the signs and symptoms of OIC frequently reported with bowel movements including perception of incomplete evacuation, need for straining, and hard stools,. NAL was generally well tolerated.

Translating Clinical Findings into the Patient’s Perspective: Post-hoc Pooled Analysis of Bowel Movement Changes as a Predictor of Improvement in Patients’ Opioid-induced Constipation Symptoms and Outcomes

PurposeOpioid-induced constipation (OIC) is a bothersome side effect of opioid use for the management of noncancer pain, affecting patients’ health-related quality of life and chronic-pain management. The objective of this study was to examine the relationship between changes in the frequency of spontaneous bowel movements (SBMs) and changes in patient-reported outcomes (PROs) among patients with OIC treated with naloxegol. MethodsPost hoc analyses were conducted using pooled data from two Phase III 12-week, placebo-controlled trials of naloxegol for the treatment of OIC (NCT01309841 and NCT01323790). Patients completed the Patient Assessment of Constipation–Quality of Life (PAC-QOL) and PAC–Symptoms (PAC-SYM) at each study visit, and the Straining Scale and Bristol Stool Scale (BSS) with each bowel movement for the study duration. Four subgroups were created based on improvements from baseline in mean frequency of SBMs per week: 0 or worse (no change), +1 SBM, +2 SBMs, and +≥3 SBMs. Spearman correlations assessed the association between mean SBM changes from baseline and mean changes from baseline in PROs; analysis of covariance was used to compare changes from baseline. FindingsA total of 1337 patients with mean (SD) age of 52.2 (11.0) years were included in this analysis. The patient population was predominantly white (79.0%) and female (62.4%). At baseline, mean SBM frequency was 1.4 (1.0) per week. At study end, all 4 SBM-change subgroups experienced improvements in PAC-QOL, PAC-SYM, Straining Scale, and BSS scores, and these changes were significantly correlated with mean changes from baseline in SBMs per week. The subgroup of patients with an increase in SBMs of ≥3 per week experienced the greatest improvements in PROs. ImplicationsIn these patients with OIC, an improvement in the frequency of SBMs by ≥3 per week was associated with consistent improvements in PROs, providing support for the use of improvements in SBMs as a clinical outcome surrogate for managing patients with OIC. Further research is needed to determine a threshold for change in SBMs that is clinically meaningful in both research and clinical settings. A key limitation was the post hoc nature of the study, which was not powered prospectively to examine these relationships.

Nanoconjugated NAP as a Potent and Periphery Selective Mu Opioid Receptor Modulator To Treat Opioid-Induced Constipation.

Opioids are the mainstay for cancer and noncancer pain management. However, their use is often associated with multiple adverse effects. Among them, the most common and persistent one is probably opioid-induced constipation (OIC). Periphery selective opioid antagonists may alleviate the symptoms of OIC without compromising the analgesic effects of opioids. Recently our laboratories have identified one novel lead compound, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)acetamido]morphinan (NAP), as a peripherally selective mu opioid receptor ligand carrying subnanomolar affinity to the mu opioid receptor and over 100-folds of selectivity over both the delta and kappa opioid receptors, with reasonable oral availability and half-life, and potential to treat OIC. Nanoparticle-based drug delivery systems are now widely considered due to their technological advantages such as good stability, high carrier capacity, low therapeutic side effects, etc. Herein we report nanoparticle supported NAP as a potential candidate for OIC treatment with improved peripheral selectivity over the original lead compound NAP.