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Postoperative ileus (POI) and constipation are common secondary effects of opioids and carry significant clinical and economic impacts. μ-Opioid receptors mediate opioid analgesia in the central nervous system (CNS) and gastrointestinal-related effects in the periphery. Peripherally acting μ-opioid receptor antagonists (PAMORAs) block the peripheral effects of opioids in the gastrointestinal tract, while maintaining opioid analgesia in the CNS. While most are not approved for POI or postoperative opioid-induced constipation (OIC), PAMORAs have a potential role in these settings via their selective effects on the μ-opioid receptor. This review will discuss recent clinical trials evaluating the safety and efficacy of PAMORAs, with a focus on alvimopan (Entereg®) and methylnaltrexone (Relistor®) in patients with POI or postoperative OIC. We will characterize potential factors that may have impacted the efficacy observed in phase 3 trials and discuss future directions for the management and treatment of POI. [ABSTRACT FROM AUTHOR]

Introduction: To determine the benefits of alvimopan and multimodal pain management strategies in men undergoing retroperitoneal lymph node dissection for testicular cancer.Methods: A retrospective cohort study was completed in men undergoing retroperitoneal lymph node dissection from January 2017 to May 2018. Patients were placed into the 3-drug, 2-drug, and control cohorts as a result of a prospectively determined protocol during the study period. Men in the 3-drug group were managed using alvimopan 12 mg PO the morning of surgery then BID until bowel movement, gabapentin 300 mg daily, and acetaminophen 1,000 mg q6H. The 2-drug group was managed with the above regimen excluding alvimopan. Controls were treated per our standard perioperative pathway. Primary outcomes were length of stay, IV narcotic consumption, bowel movement during hospitalization, and time to bowel movement and assessed in multivariate models controlling for operative time, concomitant surgery, chemotherapy receipt, and residual mass size.Results: One-hundred and fifty-two consecutive patients underwent RPLND (42 3-drug, 38 2-drug, and 72 controls). Multivariable models indicated that the 3-drug (IRR 0.89, P < 0.0001) and 2-drug group (IRR 0.87, P = 0.0209) had shorter hospital stays than controls. Men in the 3-drug group required less narcotic pain medication than the 2-drug (β -8.16, P = 0.0405) and the control (β -8.16, P = 0.0302) group. Men receiving alvimopan (3-drug) were almost 6 times more likely than the 2-drug group (odds ratio 5.94, P < 0.0001) and 4 times more likely than the control group (odds ratio 3.86, P = 0.0017) to have a bowel movement during hospitalization. Men in the 3-drug group had the quickest return of bowel movements.Conclusions: Multimodal pain management improves length of stay in men undergoing retroperitoneal lymph node dissection for testis cancer. The addition of alvimopan allows for quicker return of bowel movements and reduces overall narcotic requirements. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Study of stress degradation behaviour of alvimopan under stress conditions. • A total of five degradation products (DP1-DP5) were detected using HPLC. • All the degradation products (DP1-DP5) were identified by LC/MS/MS. • Major degradation products (DP1-DP3) were isolated by prep-HPLC and subjected to NMR analysis. Abstract Alvimopan (ALV), a peripherally acting mu-opioid receptor (PAM-OR) antagonist used for the treatment of postoperative ileus, was examined for its degradation behaviour under different stress conditions. A total of five degradation products (DP1-DP5) were formed and identified using high-performance liquid chromatography (HPLC) method. Primarily, complete fragmentation pathways of the protonated drug and its degradation products (DP1-DP5) were elucidated by using liquid chromatography-mass spectrometry (LC/MS) and high-resolution mass spectrometry (HRMS) studies. Subsequently, three major degradation products (DP1-DP3) formed under acid hydrolytic stress conditions were isolated by preparative-high performance liquid chromatography (prep-HPLC) and subjected to nuclear magnetic resonance (NMR) experiments (1D and 2D NMR) for further confirmation of their structures. All the spectral data from LC/QTOF/MS/MS and NMR studies were used for the identification and structural characterization of degradation products (DP1-DP5). [ABSTRACT FROM AUTHOR]

Background: Previous analyses evaluating alvimopan included patients at varying risk for ileus after intestinal resection, which may have precluded its widespread adoption. We assess the early and delayed effects of alvimopan in patients stratified by risk for ileus after intestinal and colon resection.Methods: From the Premier Perspective database, patients with elective small and large bowel resections from 2012 to 2014 were identified. Multivariable analysis identified 14 perioperative risk factors for postoperative ileus. Within low- (0-4 factors), intermediate- (5 factors), and high-risk (6-12 factors) ileus categories, alvimopan and no-alvimopan patients were propensity-score matched for demographics, morbidities, diagnosis, surgery and approach, postoperative complications, surgeon specialty, and hospital features. In-hospital postoperative ileus, length of stay, discharge destination, and ileus-related readmission were compared.Results: Of 52,948 patients, 15,719 (29.7%) received alvimopan. Risk for ileus in low- (18,784), intermediate- (14,370), and high-risk (19,794) categories was 8.9, 13, and 22% (p ≤ .0001) respectively. After matching, alvimopan was associated with significantly reduced in-hospital postoperative ileus in all (low, 6%; intermediate, 9.4%; and high risk, 16.2%) categories. Hospital stay and 30-, 60-, and 90-day postdischarge ileus were also significantly lower with alvimopan. For low-risk patients, alvimopan increased discharge to home, while 90-day emergency readmission was reduced.Conclusions: Alvimopan, regardless of ileus risk, improves ileus, hospital stay, and ileus-related readmission after intestinal resection and these effects are sustained over the long term. Since fewer than a third of patients currently receive alvimopan, its routine adoption with small and large intestinal resection will significantly impact patients and health systems. [ABSTRACT FROM AUTHOR]

BACKGROUND: Alvimopan (Entereg), a peripherally acting muopioid receptor antagonist, has been shown to expedite recovery of bowel function after colon resection surgery. Most data are available from industry-sponsored trials. This study aims to evaluate the clinical impact of this drug on perioperative outcomes and costs in patients undergoing segmental colonic resection for diverticular disease. METHODS: A large administrative database maintained by the University Health System Consortium, an alliance of over 200 academic and affiliate hospitals, was queried from 2008 to 2011. International Classification of Diseases, 9th Revision, Clinical Modification codes for segmental colon resection because of diverticular disease were used to identify 2 matched cohorts of adult patients. University Health System Consortium's clinical resource manager was used to access pharmacy data and compare it with patient outcomes. RESULTS: Five thousand two hundred ninety-nine patients met the above criteria. Four hundred thirty-eight patients received alvimopan and 4,861 did not. Regardless of laparoscopic or open approach, alvimopan significantly improved the postoperative length of stay (4.43 ± 2.02 vs 5.92 ± 3.79, P < .0001), cost (9,974 ± 4,077 vs 11,303 ± 6,968, P < .0001), and intensive care unit admission rate (1.83% vs 7.20%, P < .05), with no significant difference in mortality (.0% vs .19%, P = 1.000), morbidity (5.93% vs 8.39%, P = .08), or 30-day readmission rate (4.40% vs 4.63%, P = .90). CONCLUSIONS: Alvimopan significantly reduced length of stay, days in the intensive care unit, and hospital cost for patients undergoing colonic segmental resections. Unlike some previously reported studies, we also observed a significant reduction in the length of stay in patients undergoing laparoscopic colectomies who received the drug. Alvimopan may reduce total healthcare costs if used as part of a best care practice model for colon resections. [ABSTRACT FROM AUTHOR]

Background: Radical cystectomy (RC) for bladder cancer is frequently associated with delayed gastrointestinal (GI) recovery that prolongs hospital length of stay (LOS). Objective: To assess the efficacy of alvimopan to accelerate GI recovery after RC. Design, setting, and participants: We conducted a randomized double-blind placebo-controlled trial in patients undergoing RC and receiving postoperative intravenous patient-controlled opioid analgesics. Intervention: Oral alvimopan 12 mg (maximum: 15 inpatient doses) versus placebo. Outcome measurements and statistical analysis: The two-component primary end point was time to upper (first tolerance of solid food) and lower (first bowel movement) GI recovery (GI-2). Time to discharge order written, postoperative LOS, postoperative ileus (POI)-related morbidity, opioid consumption, and adverse events (AEs) were evaluated. An independent adjudication of cardiovascular AEs was performed. Results and limitations: Patients were randomized to alvimopan (n = 143) or placebo (n = 137); 277 patients were included in the modified intention-to-treat population. The alvimopan cohort experienced quicker GI-2 recovery (5.5 vs 6.8 d; hazard ratio: 1.8; p < 0.0001), shorter mean LOS (7.4 vs 10.1 d; p = 0.0051), and fewer episodes of POI-related morbidity (8.4% vs 29.1%; p < 0.001). The incidence of opioid consumption and AEs or serious AEs (SAEs) was comparable except for POI, which was lower in the alvimopan group (AEs: 7% vs 26%; SAEs: 5% vs 20%, respectively). Cardiovascular AEs occurred in 8.4% (alvimopan) and 15.3% (placebo) of patients (p = 0.09). Generalizability may be limited due to the exclusion of epidural analgesia and the inclusion of mostly high-volume centers utilizing open laparotomy. Conclusions: Alvimopan is a useful addition to a standardized care pathway in patients undergoing RC by accelerating GI recovery and shortening LOS, with a safety profile similar to placebo. Patient summary: This study examined the effects of alvimopan on bowel recovery in patients undergoing radical cystectomy for bladder cancer. Patients receiving alvimopan experienced quicker bowel recovery and had a shorter hospital stay compared with those who received placebo, with comparable safety. Trial registration: ClinicalTrials.gov identifier NCT00708201 Take Home Message: In a randomized double-blind placebo-controlled study, alvimopan significantly decreased time to gastrointestinal recovery, shortened hospital stay, and reduced postoperative ileus-related morbidity in radical cystectomy patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: Alvimopan has been shown to shorten time to return of bowel function (RBF), thereby decreasing length of stay (LOS). The aim of this study was to assess the clinical significance of this effect on actual practice. Metjods: A retrospective and prospective study of elective bowel resection patients was performed. Surgeons were assigned to alvimopan users (treatment) or nonusers (control). Primary outcome measures included LOS, RBF, and total hospital cost (THC). Results: Mean RBF was 2.93 ± 1.22 days in the treatment group and 4.22 ± 1.81 days in the control group (P < .001). Mean LOS was 7 ± 2.6 days in the treatment group and 7.2 ± 2.2 days in the control group. Mean THC was $7,584 ± $4,770 in the treatment group and $7,310 ± $5,471 in the control group (P > .81). LOS decreased by 2.5 days compared with the historical controls, independent of alvimopan use. Conclusions: Alvimopan improved RBF but not LOS or THC. Reductions in average LOS of 1 day for ≤6 doses and 2 days if patients received >6 doses were needed to decrease THC. [Copyright &y& Elsevier]

Abstract: The balance between the pain relief provided by opioid analgesics and the side effects caused by such agents is of particular significance to patients who take opioids for the long-term relief of non-cancer pain. The spectrum of signs and symptoms affecting the gastrointestinal (GI) tract associated with opioid use is known as opioid-induced bowel dysfunction. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist, approved in the US for the management of postoperative ileus in patients undergoing bowel resection (short-term, in-hospital use only). Alvimopan was under clinical development for long-term treatment of opioid-induced constipation (OIC) but this program has been discontinued. This double-blind, placebo-controlled trial, part of the former OIC development program, enrolled patients (N = 485) receiving opioids for non-cancer pain. Patients were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo, for 12 weeks. The primary efficacy endpoint was the proportion of patients who experienced ≥3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period, and an average increase from baseline of ≥1 SBM per week. There were greater proportions of SBM responders in both alvimopan treatment groups (63% in both groups) compared with placebo (56%), although these differences were not statistically significant. Secondary efficacy analyses indicated that alvimopan was numerically superior to placebo in improving opioid-induced bowel dysfunction symptoms and patients'' global assessment of opioid-induced bowel dysfunction, and reduced the requirement for rescue laxatives. Active treatment was well tolerated and alvimopan did not antagonize opioid analgesia. Perspective: Although the primary endpoint was not met in this study, the magnitude of alvimopan-induced improvements versus baseline, together with previous study results, suggest that a PAM-OR antagonist has the potential to improve OIC. [Copyright &y& Elsevier]

Abstract: Gastrointestinal (GI) side effects are common with opioid medication, and constipation affects ∼40% of patients. Such symptoms considerably impair patients'' quality of life. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist approved in the US for short-term, in-hospital management of postoperative ileus in patients undergoing bowel resection. This double-blind, placebo-controlled trial was conducted as part of a recently discontinued clinical program, in which alvimopan was being developed for opioid-induced constipation (OIC). Patients (N = 518) receiving opioids for non-cancer pain were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo for 12 weeks. The primary efficacy endpoint was the proportion of patients experiencing ≥3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period and an average increase from baseline of ≥1 SBM per week. A significantly greater proportion of patients in the alvimopan .5 mg twice-daily group met the primary endpoint compared with placebo (72% versus 48%, P < .001). Treatment with alvimopan twice daily improved a number of other symptoms compared with placebo and reduced the requirement for rescue laxative use. The opioid-induced bowel dysfunction Symptoms Improvement Scale (SIS) responder rate was 40.4% in the alvimopan .5 mg twice daily group, versus 18.6% with placebo (P < .001). In general, alvimopan .5 mg once daily produced qualitatively similar but numerically smaller responses than twice-daily treatment. Active treatment did not increase the requirement for opioid medication or increase average pain intensity scores. Over the 12-week treatment period, alvimopan appeared to be well tolerated. Perspective: These results demonstrate the potential for a PAM-OR antagonist to improve the symptoms of OIC without antagonizing opioid analgesia. [Copyright &y& Elsevier]

Abstract: Opium is arguably one of the oldest herbal medicines, being used as analgesic, sedative and antidiarrheal drug for thousands of years. These effects mirror the actions of the endogenous opioid system and are mediated by the principal μ-, κ- and δ-opioid receptors. In the gut, met-enkephalin, leu-enkephalin, β-endorphin and dynorphin occur in both neurons and endocrine cells. When released, opioid peptides activate opioid receptors on the enteric circuitry controlling motility and secretion. As a result, inhibition of gastric emptying, increase in sphincter tone, induction of stationary motor patterns and blockade of peristalsis ensue. Together with inhibition of ion and fluid secretion, these effects cause constipation, one of the most frequent and troublesome adverse reactions of opioid analgesic therapy. Although laxatives are most frequently used to ameliorate opioid-induced bowel dysfunction, their efficacy is unsatisfactory. Specific antagonism of peripheral opioid receptors is a more rational approach. This goal is addressed by the use of opioid receptor antagonists with limited absorption such as oral prolonged-release naloxone and opioid receptor antagonists that do not penetrate the blood-brain barrier such as methylnaltrexone and alvimopan. Preliminary evidence indicates that peripherally restricted opioid receptor antagonists may act as prokinetic drugs in their own right. [Copyright &y& Elsevier]

Abstract: Opioid-induced bowel dysfunction is a distressing condition that may persist indefinitely in the clinical setting. As we understand more about normal gastrointestinal (GI) physiology, we are also beginning to understand more fully how opioids cause bowel dysfunction. Current therapeutic interventions for opioid-induced bowel dysfunction can be burdensome and sometimes lack efficacy. Systemic opioid antagonists administered orally can induce laxation, but can unpredictably induce systemic or local GI tract withdrawal symptoms. Two new investigational agents, alvimopan and methylnaltrexone, are peripherally acting opioid antagonists that do not cross the blood-brain barrier. Studies to date show promise that these agents may relieve opioid-induced bowel dysfunction in a well-tolerated manner without reversing central analgesia. [Copyright &y& Elsevier]

Abstract: The localization of opioid receptors and their endogenous peptide ligands within the gastrointestinal (GI) tract and their role in the coordination of propulsion and secretion underscores the importance of opioid receptors in the maintenance of GI homeostasis. The peripherally acting μ-opioid receptor antagonists alvimopan and methylnaltrexone (MNTX) are currently under investigation as therapeutic agents to treat the deleterious GI side effects associated with opioid administration. These compounds have demonstrated efficacy in numerous animal models of GI function, and clinical studies have revealed their efficacy in the treatment of postoperative ileus (POI) and opioid-induced bowel dysfunction. Preservation of opioid-mediated analgesia has been demonstrated for these compounds in both the preclinical and clinical settings. Future studies exploring the benefits of selective antagonism of the peripheral μ-opioid receptor in the treatment of other GI conditions may open new therapeutic opportunities for alvimopan and MNTX. [Copyright &y& Elsevier]

Abstract: Many patients treated with opioids suffer from constipation. Opiate- or opioid-related constipation is not only a frequent but also a distressing symptom and difficult to treat. There is emerging evidence regarding a novel approach to the management of opiate-related constipation. The aim of this paper is to collect, critically appraise, and summarize the evidence on the effectiveness of recently developed peripherally acting μ-receptor antagonists in the treatment of opiate-related constipation. A comprehensive search of 11 computerized databases was conducted and efforts were made to identify unpublished and ongoing research. Twenty studies were identified; 13 were randomized controlled trials (RCTs) and 7 were Phase II studies assessing toxicity. Studies were mainly executed in healthy volunteers or members of methadone programs with opioid-induced constipation as a model to mimic the condition of patients on opioids. Two RCTs were conducted in hospice patients. Quality of study design and validity of the findings was assessed in all studies. Data show proof of concept but do not allow a definitive answer concerning the effectiveness of the peripherally acting μ-opioid antagonists methylnaltrexone and alvimopan in managing opiate-related constipation. Further research is needed. If future Phase III trials provide supportive data, opioid antagonists may become a standard therapeutic option for the treatment of opiate-related constipation in patients with advanced cancer. [Copyright &y& Elsevier]

Two new opioid antagonists, methylnaltrexone and alvimopan, are currently in late-stage clinical trials. With limited ability to cross the blood-brain barrier due to polar chemical structures, they act as peripherally active μ-opioid receptor antagonists, reversing many of the undesired effects of opioids without affecting centrally mediated analgesia or precipitating withdrawal. One of the most common and troubling side effects of opioids is inhibition of gastrointestinal (GI) motility, which increases pain, decreases patient satisfaction, and delays hospital discharge following abdominal surgery. In this article, we review the effectiveness of these new agents, particularly with respect to GI function, in postoperative as well as chronic pain patients. We also consider several novel effects these drugs have in wound healing, cancer growth, and HIV infectivity. [Copyright &y& Elsevier]

Abstract: Postoperative ileus (POI) is often exacerbated by opioid analgesic use during and following surgery, since mu opioid receptor activation results in a further delay of gastrointestinal (GI) transit. The effects of alvimopan, a novel, selective, and peripherally acting mu opioid receptor antagonist, and the reference compound methylnaltrexone, upon POI were investigated in rats. Under isoflurane anesthesia, POI was induced by laparotomy with intestinal manipulation. Immediately after the surgery, the rats received 51Cr by gavage. Three hours after the surgery, the rats were sacrificed and GI transit was estimated using the geometric center (GC) of 51Cr. Alvimopan (0.1–3 mg/kg) or methylnaltrexone (100 mg/kg) were administered by gavage either before or after the surgery, with or without morphine administration (1 mg/kg). GI transit was delayed by intestinal manipulation (GC = 2.92 ± 0.17). Alvimopan (1 and 3 mg/kg) significantly reversed this delayed GI transit when administered 45 min prior to surgery. However, the effects of alvimopan were less pronounced when administered following surgery. Morphine administration further delayed GI transit induced by intestinal manipulation (GC = 1.97 ± 0.11). Under these conditions, alvimopan (1 and 3 mg/kg) also significantly improved delayed GI transit when administered before surgery. Methylnaltrexone was inactive under all experimental conditions. These data suggest that mu opioid receptors play a role in the pathogenesis of POI, and that the clinical benefit reported to be afforded by alvimopan may be in part mediated via inhibition of an endogenous opioid release as well as blockade of the unwanted GI actions of analgesic agents. [Copyright &y& Elsevier]

Objective: The purpose of this study was to investigate the safety and efficacy of alvimopan, a novel peripherally acting mu-opioid receptor antagonist, in patients who undergo simple total abdominal hysterectomy. Study design: Women (n = 519) were randomized (4:1) to receive alvimopan 12 mg (n = 413) or placebo (n = 106) ≥ 2 hours before the operation then twice daily for 7 days (hospital and home). Adverse events were monitored up to 30 days after the last dose of study drug was administered. Efficacy was assessed for 7 postoperative days. Results: Overall, the most common adverse events were nausea, vomiting, and constipation; < 5% of patients discontinued use because of adverse events. Alvimopan significantly accelerated the time to first bowel movement (hazard ratio, 2.33; P <.001). Average time to first bowel movement was reduced by 22 hours, with more frequent bowel movement and better bowel movement quality found in the treatment cohort. Conclusion: Alvimopan has a safety profile that is similar to that of placebo and provides significantly improved lower gastrointestinal recovery in women who undergo simple total abdominal hysterectomy. [ABSTRACT FROM AUTHOR]

Abstract: Background: This analysis examines gastrointestinal recovery in patients who underwent bowel resection (BR) in 3 recent trials. Methods: Patients who underwent BR in the placebo groups of 3 randomized, double-blind, phase III, parallel-group, multicenter alvimopan efficacy trials were analyzed. Results: Most patients tolerated solid food and had a bowel movement by postoperative day 4. The majority of patients were discharged from the hospital by day 6, but 24.4% required a prolonged hospital stay or readmission. The incidence of nausea was highest on the day of surgery and decreased thereafter, whereas vomiting was uncommon on the day of surgery but increased slightly on postoperative days 1 to 6. The incidence of postoperative nasogastric tube insertion was highest (12%) on day 2. Conclusions: This analysis provides valuable clinical insight into gastrointestinal recovery after BR in a large homogenous patient population receiving multimodal care. [Copyright &y& Elsevier]

Abstract: Alvimopan is a novel peripheral μ opioid antagonist in clinical development for the management of post-operative ileus and opioid-induced bowel dysfunction. We hypothesized that the long duration of action of alvimopan might be related to a slower dissociation rate from the μ opioid receptor compared to other shorter acting antagonists. The dissociation rate of alvimopan from the μ opioid receptor (t 1/2 =30–44 min) was comparable to that of the long acting partial agonist buprenorphine (t 1/2 =44 min), but was slower than those of the antagonists naloxone (t 1/2 =0.82 min) and N-methylnaltrexone (t 1/2 =0.46 min). Also, increases in the apparent affinities and potencies of buprenorphine and alvimopan, but not of naloxone and methylnaltrexone, were observed upon preincubation with the μ opioid receptor. Consistent with its long duration of action, alvimopan has a slow dissociation rate from the μ opioid receptor compared to other shorter acting antagonists and may be more potent if administered prior to dosing with exogenous opioids. [Copyright &y& Elsevier]

The gut is a neurological organ, which implies that many neuroactive drugs such as opioid analgesics can seriously disturb gastrointestinal function, because many of the transmitters and transmitter receptors present in the brain are also found in the enteric nervous system. One of the most common manifestations of opioid-induced bowel dysfunction is constipation which results from blockade of peristalsis and intestinal fluid secretion. The discovery of opioid receptor antagonists with a peripherally restricted site of action, such as N-methylnaltrexone and alvimopan, makes it possible to normalize bowel function in opiate-treated patients without compromising central opioid analgesia. There is emerging evidence that opioid receptor antagonists may also have prokinetic actions, reversing pathological states of gastrointestinal hypomotility that are due to overactivity of the enteric opioid system. [Copyright &y& Elsevier]

Selective antagonists for the kappa opioid receptor (KOP) have the potential to treat opiate and alcohol addiction, as well as depression and other CNS disorders. Over the years, the development of KOP-selective antagonists yielded very few successful compounds. Recently, N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have emerged as a novel class of pure opioid receptor antagonists, including the marketed Mu opioid receptor (MOP) peripheral antagonist Alvimopan and the potent KOP antagonist JDTic. However, the selectivity determinants of this class of compounds towards the opioid receptor subtypes are still vague and understudied. In this work, we have performed Molecular Dynamics (MD) simulation to gain insights into the differential binding of this class of compounds into KOP, as exemplified by Alvimopan and JDTic. Our study indicated that the selectivity largely depends on ligands interaction with the selectivity pocket formed by Val108, Thr111, and Val118, supported by two additional polar and hydrophobic contacts with Asp138 and Trp287, respectively. Our results also demonstrate, for the first time, that non-morphinan ligands can still adopt the "message-address model" for KOP efficacy and selectivity by binding to Glu297. [Display omitted] • Selective antagonists for the kappa opioid receptor (KOP) have the potential to treat opiate and alcohol addiction. • N-substituted (3-hydroxyphenyl)piperidines have emerged as a novel class of opioid antagonists. • MD) simulation has been performed to gain insights into the differential binding of this class of compounds into KOP. • The selectivity for KOP depends on ligands interaction with the pocket formed by Val108, Thr111, and Val118. • Non-morphinan ligands can still adopt the "message-address model" for KOP efficacy by binding to Glu297. [ABSTRACT FROM AUTHOR]

Context: Opioid-induced constipation is a common problem associated with chronic use of opioid analgesics.Objectives: The objective of this study was to compare available interventions for the treatment of opioid-induced constipation, using principles of network meta-analysis.Methods: Electronic databases were searched for randomized controlled clinical trials evaluating drugs used in opioid-induced constipation. Number of patients with rescue-free bowel movements (RFBM) was the primary outcome, and time for achieving RFBM, adverse events, and changes in the analgesic activity of the opioid analgesics were the secondary outcomes. Inverse variance heterogeneity model was used for direct and mixed treatment comparison analysis. Odds ratio for categorical outcomes and weighted mean difference for numerical outcomes were the effect estimates.Results: We included a total of 23 studies in the systematic review and 21 in the network meta-analysis. Lubriprostone, prucalopride, naldemedine, naloxegol, alvimopan, subcutaneous, and oral methyl naltrexone were observed to perform better than placebo in terms of RFBM. Additionally, subcutaneous methyl naltrexone was significantly better than lubiprostone, naloxegol, oral methyl naltrexone, and prucalopride. Lubiprostone and naldemedine were associated with increased risks of adverse events. Subcutaneous methyl naltrexone did not significantly affect the analgesia due to background opioid use. Quality of evidence for the comparisons is either low or very low.Conclusion: Subcutaneous methyl naltrexone was found to perform better than other interventions for managing opioid-induced constipation. [ABSTRACT FROM AUTHOR]