An observational post-authorization safety study (PASS) of naloxegol drug utilization in four European countries.

PURPOSE: Naloxegol has been shown to be an efficient alternative to treat opioid-induced constipation (OIC). This study aimed at describing the characteristics of naloxegol users and assessing patterns of naloxegol use and associated factors. METHODS: This drug utilization cohort study used observational registry data on patients newly prescribed naloxegol in four European countries. Patient characteristics and patterns of naloxegol use and associated factors were described. RESULTS: A total of 17 254 naloxegol users were identified across the countries. Their median age was 56-71 years, and each country had a majority of women (ranging 57.5%-62.9%). Multiple comorbidities, including cancer, were common. Natural opium alkaloids and osmotically acting laxatives (excluding saline) were the most frequently used opioids and laxatives. Overall prior use of opioids ranged from 91.9% to 99.6% and overall prior use of laxatives ranged from 69.9% to 92.4%. Up to 77.7% had prior use of medications with interaction potential, and up to 44.5% used them concurrently with naloxegol. Naloxegol was discontinued by 55.1%-90.9% of users, typically during the first 30 days. Approximately 10%-30% switched to or augmented the treatment with another constipation medication or restarted naloxegol after discontinuation. Augmentation with another constipation medication was relatively common, suggesting that naloxegol was used for multifactorial constipation. CONCLUSION: The present study reflects real-world clinical use of naloxegol, including in vulnerable patient groups. Some naloxegol users lacked laxative or regular opioid use within six months before index date or used naloxegol concomitantly with medications presenting an interaction potential.

Naloxegol versus Methylnaltrexone for Opioid-Induced Constipation in Critically Ill Patients.

BACKGROUND: Constipation impacts 58% to 83% of critically ill patients and is associated with increased time on mechanical ventilation, delirium, and increased length of stay (LOS) in the intensive care unit (ICU). OBJECTIVE: The purpose of this study was to evaluate the efficacy of enteral naloxegol (NGL) versus subcutaneous methylnaltrexone (MNTX) for the management of opioid-induced constipation (OIC) in critically ill patients. METHODS: A retrospective analysis was conducted on adult patients admitted to the ICU who received a parenteral opioid infusion for at least 4 hours and experienced no bowel movement (BM) within the 48-hour period preceding the administration of NGL or MNTX. The primary outcome was time to first BM from the start of NGL or MNTX therapy. Secondary outcomes included number of BMs 72 hours following NGL or MNTX administration, ICU LOS, and cost-effectiveness. RESULTS: After exclusion criteria were applied, 110 and 51 patients were included in the NGL and MNTX groups, respectively. With a 10% noninferiority margin, NGL was noninferior to MNTX (Wald statistic = 1.67; P = 0.047). Median time to first BM was 23.7 hours for NGL and 18.3 hours for MNTX patients. Median LOS was 14 days (NGL) and 12 days (MNTX), and the average number of BMs in 72 hours was 3.9 for NGL and 3.8 for MNTX. Using wholesale acquisition cost (WAC), the cost per BM for NGL and MNTX was $21.74 and $170.00, respectively. CONCLUSION AND RELEVANCE: This study determined that NGL and MNTX had similar time to BM. NGL appears to be a safe and effective alternative with cost-saving potential in treating OIC in critically ill patients.

Effectiveness of naloxegol in patients with cancer pain suffering from opioid-induced constipation.

PURPOSE: Naloxegol, an oral once-daily peripherally acting mu-opioid receptor antagonist, is indicated for the treatment of opioid-induced constipation (OIC) with inadequate response to laxative(s), in cancer and non-cancer patients. This study mainly aimed to assess in real-life conditions the efficacy and safety of naloxegol in cancer pain patients and the evolution of their quality of life. METHODS: A non-interventional, 4-week follow-up study was conducted in 24 French oncology and pain centers between 2018 and 2019. Eligible patients were aged ≥ 18 years, treated with opioids for cancer pain, and started naloxegol for OIC with inadequate response to laxatives. The rate of the response to naloxegol (primary criterion) was assessed at W4. The evolution of quality of life was measured using the Patient Assessment of Constipation Quality of Life (PAC-QOL). RESULTS: A total of 124 patients were included (mean age, 62 ± 12 years; ECOG ≤ 2, 79%; primary cancer, lung 18%, breast 16%, prostate 11%, head and neck 9%, digestive 9%…; metastatic stage, 80%). At inclusion, the median opioid dosage was 60 mg of oral morphine or equivalent. At W4, the response rate was 73.4% (95% CI [63.7-83.2%]), and 62.9% (95% CI [51.5-74.2%]) of patients had a clinically relevant change in quality of life (decrease in PAC-QOL score ≥ 0.5 point). Adverse events related to naloxegol were reported in 8% of patients (7% with gastrointestinal events; one serious diarrhea). CONCLUSION: This real-world study shows that naloxegol is effective and well tolerated in cancer pain patients with OIC and that their quality of life improves under treatment.

Opioid-Induced Constipation in Oncological Patients: New Strategies of Management.

OPINION STATEMENT: Cancer-associated pain has traditionally been treated with opioid analgesics, often in escalating doses. Opioid-induced constipation (OIC) is a common problem associated with chronic use of opioid analgesics. Typical treatment strategies to alleviate constipation are based on dietary changes, exercise, and laxatives. However, laxatives have a nonspecific action and do not target underlying mechanisms of OIC. This article will review prevalent, clinical presentation and recommendations for the treatment of OIC. An independent literature search was carried out by the authors. We reviewed the literature for randomized controlled trials that studied the efficacy of laxatives, naloxone, and naloxegol in treating OIC. Newer strategies addressing the causal pathophysiology of OIC are needed for a more effective assessment and management of OIC. Finally, traditional recommended therapies are appraised and compared with the latest pharmacological developments. Future research should address whether naloxegol is more efficacious by its comparison directly with first-line treatments, including laxatives.

Pharmacological Treatment of Opioid-Induced Constipation Is Effective but Choice of Endpoints Affects the Therapeutic Gain.

BACKGROUND: Widespread opioid use has led to increase in opioid-related adverse effects like constipation. We examined the impact of study endpoints on reported treatment benefits. METHODS: Using MEDLINE, EMBASE, and ClinicalTrials.gov, we searched for randomized control trials targeting chronic opioid-induced constipation (OIC) and subjected them to meta-analysis. Data are given with 95% confidence intervals. RESULTS: Thirty trials met our inclusion criteria. Combining all dichotomous definitions of responders, active drugs were consistently more effective than placebo, with an odds ratio (OR): 2.30 [2.01-2.63; 15 studies], independent of the underlying drug mechanism. The choice of endpoints significantly affected the therapeutic gain. When time from drug administration to defecation was used, the OR decreased from 4.74 [2.71-4.74] at 6 h or less to 2.46 [1.80-3.30] at 24 h (P < 0.05). Using other response definitions, the relative benefit over placebo was 2.10 [1.77-2.50; 12 studies] for weekly bowel frequency, 2.03 [1.39-2.95; 9 studies] for symptom scores, 2.21 [1.25-3.90; 4 studies] for global assessment scales, and 1.27 [0.79-2.03; 7 studies] for rescue laxative use. CONCLUSION: While treatment of OIC with active drugs is more effective than placebo, the relative gain depends on the choice of endpoints. The commonly used time-dependent response definition is associated with the highest response rate but is of questionable relevance in a chronic disorder. The limited data do not clearly demonstrate a unique advantage of the peripherally restricted opioid antagonists, suggesting that treatment with often cheaper agents should be optimized before shifting to these novel expensive agents.

Treatment with Naloxegol Versus Placebo: Pain Assessment in Patients with Noncancer Pain and Opioid-Induced Constipation.

OBJECTIVE: To summarize results from pain and opioid use assessments with naloxegol in adults with opioid-induced constipation (OIC) and chronic noncancer pain. METHODS: Two phase 3 randomized, double-blind, 12-week studies evaluated the efficacy and safety of oral naloxegol (12.5 or 25 mg daily) in adults (18 to < 85 years) with confirmed OIC and chronic noncancer pain: KODIAC-04 (NCT01309841) and KODIAC-05 (NCT01323790). Pain level was assessed daily (11-point numeric rating scale [NRS]; 0 = no pain, 10 = worst imaginable pain). Changes from baseline in mean weekly pain scores and opioid dose (weeks 1 through 12) were analyzed using mixed-model repeated measures. RESULTS: At baseline, mean daily NRS average pain scores ranged from 4.5 to 4.8 for all groups in KODIAC-04 (N = 652) and were 4.6 for each group in KODIAC-05 (N = 700). Respective mean ± SD changes from baseline average pain for placebo, naloxegol 12.5 mg, and naloxegol 25 mg were -0.2 ± 1.07, -0.3 ± 1.05 (P = 0.773 vs. placebo), and 0.2 ± 0.95 (P = 0.837 vs. placebo; KODIAC-04) and -0.1 ± 0.94, -0.1 ± 0.87 (P = 0.744), and 0.0 ± 1.18 (P = 0.572; KODIAC-05). At baseline, mean daily opioid doses ranged from 135.6 to 143.2 morphine equivalent units (MEUs)/day in KODIAC-04, and from 119.9 to 151.7 MEUs/day in KODIAC-05. Respective mean ± SD changes from baseline dose were -1.8 ± 30.19, -2.3 ± 20.52 (P = 0.724 vs. placebo), and 0.4 ± 13.01 (P = 0.188 vs. placebo; KODIAC-04) and -0.3 ± 17.14, -1.3 ± 17.11 (P = 0.669 vs. placebo), and 0.1 ± 8.54 (P = 0.863 vs. placebo; KODIAC-05). Changes in maintenance opioid dose were few; reasons for such changes were similar across treatment groups. CONCLUSION: Centrally mediated opioid analgesia was maintained during treatment with naloxegol in patients with noncancer pain and OIC.

Opioid-Related Constipation in Patients With Non-cancer Pain Syndromes: a Review of Evidence-Based Therapies and Justification for a Change in Nomenclature.

PURPOSE OF REVIEW: Opioids are a mainstay in the treatment of chronic non-cancer pain syndromes, but their analgesic benefits come at a cost as opioid-related constipation occurs in 40-80% of individuals taking chronic opioids. Furthermore, as 10-20% of the population suffers from constipation at baseline, it should be expected that while a proportion of individuals will develop constipation as a direct consequence of opioids (OIC), others will experience it as an exacerbation of their baseline constipation (OEC). Herein, we review the evidence-based data for treatments directed at opioid-related constipation focusing on individuals with non-cancer pain syndromes and provide a template for the development of differentiated treatment algorithms for OIC and OEC. RECENT FINDINGS: Historical and current treatment protocols recommend traditional laxatives, but these are ineffective in up to 50%, due in part to the heterogeneous pathogenesis of constipation. Therapeutic decisions must be tailored to account for this overlapping pathogenesis. OIC and OEC are distinct entities. As such, additional research and guidelines should address these as different patient populations.

Population pharmacokinetics of naloxegol in a population of 1247 healthy subjects and patients.

AIMS: Naloxegol, a polyethylene glycol conjugated derivative of the opioid antagonist naloxone, is in clinical development for treatment of opioid-induced constipation (OIC). The aim of the study was to develop a population pharmacokinetic model describing the concentration vs. time profile of orally administered naloxegol, and determine the impact of pre-specified demographic and clinical factors and concomitant medication on population estimates of apparent clearance (CL/F) and apparent central compartment volume of distribution (Vc /F). METHODS: Analysis included 12,844 naloxegol plasma concentrations obtained from 1247 healthy subjects, patients with non-OIC and patients with OIC in 14 phase 1, 2b and 3 clinical studies. Pharmacokinetic analysis used the non-linear mixed effects modelling program. Goodness of fit plots and posterior predictive checks were conducted to confirm concordance with observed data. RESULTS: The final model was a two compartment disposition model with dual absorptions, comprising one first order absorption (ka1 4.56 h(-1) ) and one more complex absorption with a transit compartment (ktr 2.78 h(-1) ). Mean (SE) parameter estimates for CL/F and Vc /F, the parameters assessed for covariate effects, were 115 (3.41) l h(-1) and 160 (27.4) l, respectively. Inter-individual variability was 48% and 51%, respectively. Phase of study, gender, race, concomitant strong or moderate CYP3A4 inhibitors, strong CYP3A4 inducers, P-glycoprotein inhibitors or inducers, naloxegol formulation, baseline creatinine clearance and baseline opioid dose had a significant effect on at least one pharmacokinetic parameter. Simulations indicated concomitant strong CYP3A4 inhibitors or inducers had relevant effects on naloxegol exposure. CONCLUSIONS: Administration of strong CYP3A4 inhibitors or inducers had a clinically relevant influence on naloxegol pharmacokinetics.

Management of opioid-induced constipation.

Up to 40% of patients taking opioids develop constipation. Opioid-induced constipation (OIC) may limit the adequate dosing of opioids for pain relief and reduce quality of life. Health professionals must therefore inquire about bowel function in patients receiving opioids. The management of OIC includes carefully re-evaluating the necessity, type and dose of opioids at each visit. Lifestyle modification and alteration of aggravating factors, the use of simple laxatives and, when essential, the addition of newer laxatives or opioid antagonists (naloxone, naloxegol or methylnaltrexone) can be used to treat OIC. This review discusses the recent literature regarding the management of OIC and provides a rational approach to assessing and managing constipation in individuals receiving opioids.

Naloxegol: treatment for opioid-induced constipation in chronic non-cancer pain.

OBJECTIVE: To describe the effectiveness of naloxegol for the treatment of opioid-induced constipation (OIC) in chronic non-cancer pain patients. DATA SOURCES: Citations in PubMed, Google Scholar, Cochrane Library, CINAHL, ScienceDirect, and ProQuest were obtained. Reference lists from individual articles obtained were reviewed for additional sources. STUDY SELECTION AND DATA EXTRACTION: All English-language publications available as poster presentations, abstracts, and peer-reviewed articles ranging from preclinical to phase III trials and published between 2007 and September 14, 2014, were reviewed and summarized. DATA SYNTHESIS: Naloxegol was shown to be effective for increasing the average weekly number of spontaneous bowel movements (SBMs) in a single phase II trial enrolling 208 patients. Phase III trials (KODIAC-04/-05) enrolling a total of 1352 patients developed a new primary end point with a more strict responder criteria. This entailed a mean increase in SBMs, at least 3 SBMs per week, efficacy in 9 of 12 weeks, and efficacy in 3 of the final 4 weeks of the study period. Both groups receiving naloxegol 25 mg had significant improvement over the placebo group. The improvement was similar in patients who reported failure with laxatives in the past and regardless of daily opioid dose. A long-term trial (KODIAC-08) showed safety over 52 weeks. CONCLUSION: OIC affects many individuals treated with opioids for chronic non-cancer pain. Previous over-the-counter or prescription treatment options were limited by a lack of adequate and well-controlled studies, multiple daily dosing, or need for injections. Cost issues may limit therapy with naloxegol to select patients.

Consensus Recommendations on Initiating Prescription Therapies for Opioid-Induced Constipation.

OBJECTIVE: Aims of this consensus panel were to determine (1) an optimal symptom-based method for assessing opioid-induced constipation in clinical practice and (2) a threshold of symptom severity to prompt consideration of prescription therapy. METHODS: A multidisciplinary panel of 10 experts with extensive knowledge/experience with opioid-associated adverse events convened to discuss the literature on assessment methods used for opioid-induced constipation and reach consensus on each objective using the nominal group technique. RESULTS: Five validated assessment tools were evaluated: the Patient Assessment of Constipation-Symptoms (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL), Stool Symptom Screener (SSS), Bowel Function Index (BFI), and Bowel Function Diary (BF-Diary). The 3-item BFI and 4-item SSS, both clinician administered, are the shortest tools. In published trials, the BFI and 12-item PAC-SYM are most commonly used. The 11-item BF-Diary is highly relevant in opioid-induced constipation and was developed and validated in accordance with US Food and Drug Administration guidelines. However, the panel believes that the complex scoring for this tool and the SSS, PAC-SYM, and 28-item PAC-QOL may be unfeasible for clinical practice. The BFI is psychometrically validated and responsive to changes in symptom severity; scores range from 0 to 100, with higher scores indicating greater severity and scores >28.8 points indicating constipation. CONCLUSIONS: The BFI is a simple assessment tool with a validated threshold of clinically significant constipation. Prescription treatments for opioid-induced constipation should be considered for patients who have a BFI score of ≥30 points and an inadequate response to first-line interventions.

Opioid-induced Constipation: Old and New Concepts in Diagnosis and Treatment.

Daily use of opioid analgesics has significantly increased in recent years due to an increasing prevalence of conditions associated with chronic pain. Opioid-induced constipation (OIC) is one of the most common, under-recognized, and under-treated side effects of opioid analgesics. OIC significantly reduces the quality of life by causing psychological distress, lowering work productivity, and increasing access to healthcare facilities. The economic and social burden of OIC led to the development of precise strategies for daily clinical practice. Key aspects are the prevention of constipation through adequate water intake and fiber support, avoidance of sedentariness, and early recognition and treatment of cofactors that could worsen constipation. Recommended first-line therapy includes osmotic (preferably polyethylene glycol) and stimulant laxatives. Peripherally acting µ-opioid receptor antagonists, such as methylnaltrexone, naloxegol, or naldemedine, should be used in patients that have not responded to the first-line treatments. The bowel functional index is the main tool for assessing the severity of OIC and for monitoring the response. The paper discusses the recent literature on the pathophysiology, clinical evaluation, and management of OIC and provides a pragmatic approach for its assessment and treatment.

Population Pharmacokinetics of Naloxegol in Pediatric Subjects Receiving Opioids.

The pharmacokinetics (PK) of naloxegol were characterized in pediatric subjects, aged 6 months or older to less than 18 years who either have or are at risk of developing opioid-induced constipation following single dose administration. Subjects grouped as aged 12 years or older to less than 18 years, 6 months or older to less than 12 years, and 6 months or older to less than 6 years, received a single oral dose of naloxegol at doses that were estimated to achieve plasma exposures comparable to adult 12.5- or 25-mg doses. Intensive and sparse plasma naloxegol samples were collected to assess naloxegol concentrations. Data were combined with previously collected adult PK data and used to estimate PK parameters using population PK analyses. Naloxegol PK was described using a 2-compartment model with Weibull-type absorption. Neither age nor body weight was identified as a significant covariate indicating similar PK properties in adult and pediatric subjects. PK estimates in the youngest age group were approximately 80% less than those in adults (12.5-mg equivalent dose). Exposures in the other pediatric groups were similar to those in adult equivalent doses. The PK of naloxegol were characterized as linear over the dose range, with no clinically significant covariates and comparable PK characteristics in adults and pediatric subjects aged 6 months or older.

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

BACKGROUND: 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. OBJECTIVE: 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. METHODS: a comprehensive search to identify primary literature for either naldemedine or naloxegol for OIC in cancer patients. RESULTS: 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. LIMITATIONS: All studies were industry-funded, and given that only three trials were randomized controlled studies, the overall quality of the studies was lacking. CONCLUSION: 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 Naloxegol in Patients with Chronic Non-Cancer Pain Who Experience Opioid-Induced Constipation: A Pooled Analysis of Two Global, Randomized Controlled Studies.

Objective: This study evaluates the onset, magnitude, and consistency of improvement of opioid-induced constipation (OIC) symptoms with naloxegol treatment. Methods: 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. Subjects: 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. Results: 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. Conclusion: 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 for Treatment of Opioid-Induced Constipation in the Pediatric Intensive Care Unit.

Opioid-induced constipation is a common problem in critically ill children requiring sedation. Naloxegol is an oral U.S. Food and Drug Administration (FDA)-approved peripherally acting mu-opioid receptor antagonist for chronic opioid-induced constipation use in adults, but data on its use in children are lacking. We performed a retrospective analysis of critically ill children that had received naloxegol for opioid-induced constipation at our institution. Of the 45 patients studied, mean stool frequency increased significantly from 0.63 ± 0.12 stools per day to 1.71 ± 0.13 stools per day after starting naloxegol (95% confidence interval [CI]: [0.75, 1.4], P < .001). There was no significant difference in the mean Withdrawal Assessment Tool 1 (WAT-1) score in the 24 hours before and after receiving the first dose (95% CI: [-0.25, 0.40], P = .63). This suggests naloxegol is effective in increasing stool output in critically ill children receiving opioids without an increase in opioid-withdrawal symptoms. It may be an effective adjunctive therapy for this population.

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.

An update on the use of pharmacotherapy for opioid-induced bowel dysfunction.

INTRODUCTION: With the growing rate of aging and the incidence of chronic diseases, there has been an upsurge in opioid prescription and abuse worldwide. This has been associated with increased reports of opioid-related adverse events, particularly opioid-induced bowel dysfunction (OIBD), calling for a rational clinical management strategy. AREAS COVERED: Through searching PubMed, Scopus, Cochrane Library, and Web of Science, English literature was gathered as of 1 January 2017. Furthermore, the USFDA, EMA, TGA, Clinicaltrials.Gov, WHO-ICTRP databases, and the latest guidelines were reviewed to extract ongoing clinical studies and provide an evidence-based expert opinion with detailed information on efficacy, safety, approval status, and pharmacokinetics of the currently used medications. EXPERT OPINION: Despite the significant burden of OIBD, the clinical development of agents lags behind disease progress. Although in most places, management of opioid-induced constipation (OIC) is initiated by lifestyle modifications followed by laxatives, opioid antagonists, and secretagogue agents, there are still major conflicts among global guidelines. The fundamental reason is the lack of head-to-head clinical trials providing inter- and intragroup comparisons between PAMORAs, laxatives, and secretagogue agents. These investigations must be accompanied by further valid biopharmaceutical and economic evaluations, paving the way for rational clinical judgment in each context.

Molecular dynamics analysis predicts ritonavir and naloxegol strongly block the SARS-CoV-2 spike protein-hACE2 binding.

The rapid emergence of COVID-19 pandemics has posed humans particularly vulnerable to the novel SARS-CoV-2 virus. Since de novo drug discovery is both expensive and time-consuming, drug repurposing approaches are believed to be of particular help. The SARS-CoV-2 spike (S) protein is known to attach human angiotensin-converting enzyme-2 (hACE2) through its receptor-binding domain (RBD). We screened 1930 FDA-approved ligands for the selection of optimal ones blocking this interaction. Virtual screening predicted top 25 ligands docking to any of the reported binding sites. After exclusion of those ligands which were unsuitable for systemic use, the remaining 69 RBD-ligand complexes were screened based on the masking capacity of the amino acid residues engaged in RBD-hACE2 interaction, excluding 47 RBD-ligand complexes. A short molecular dynamics (MD) simulation analysis identified 11 globally stable complexes with the lowest RMSD (root-mean-square deviation). Next, a moderately long MD analysis revealed those six RBD-ligand complexes with the lowest RMSD variation, as a measure of global stability. Finally, a long MD analysis revealed two select candidate ligands, including ritonavir and naloxegol, highly stabilizing those key residues engaged in RBD-hACE2 interaction. A similar MD analysis of a few antiviral drugs which are under clinical trials or approved for COVID-19 treatment showed them inferior to both select ligands in terms of stabilizing the RBD globally and locally at binding sites. Because of the crucial role of the S protein in virus virulence, our results highly propose ritonavir and naloxegol as the potentially helpful therapeutics against COVID-19, mandating appropriate clinical trials.Communicated by Ramaswamy H. Sarma.

Naloxegol and Postoperative Urinary Retention: A Randomized Trial.

BACKGROUND: Naloxegol antagonizes peripheral opioid-related side effects without preventing opioid-related analgesia. However, the effect of naloxegol on opioid-induced bladder dysfunction remains unknown. HYPOTHESIS: patients given naloxegol have lower residual bladder urine volume than those given placebo. METHODS: 136 patients scheduled for elective hip and knee surgery were randomized to oral naloxegol or placebo given the morning of surgery, and on the first two postoperative mornings. Residual urine volume was measured ultrasonographically within 30 min after voiding once in the morning and once in the afternoon for two postoperative days. Opioid-related Symptom Distress Scale (ORSDS), the need for indwelling urinary catheterization, and quality of recovery (QoR) score were secondary outcomes. RESULTS: 67 were randomized to naloxegol and 64 to placebo. We did not identify a significant effect on urine residual volume, with an estimated ratio of geometric means of 0.9 (0.3, 2.6), p = 0.84. There were no significant differences in ORSDS or QoR. There were 19 (29%) patients assigned to naloxegol who needed indwelling urination catheterization versus 7 (11%) patients in the placebo group, p = 0.012. CONCLUSIONS: Our results do not support use of naloxegol for postoperative urinary retention after hip and knee surgery.