Peripherally Acting Mu-opioid Receptor Research Articles

Response Rates to Methylnaltrexone in Hospitalized Cancer Patients.

Context: Methylnaltrexone is a peripherally-acting mu-opioid receptor antagonist studied in both cancer and non-cancer patients with opioid-induced constipation (OIC), but mostly in the outpatient setting. For adult hospitalized cancer patients with OIC, its effectiveness is unknown. Objectives: Describe the efficacy of methylnaltrexone for OIC in the inpatient setting, defined as bowel movement (BM) within 24hours of methylnaltrexone administration. Methods: We performed a single-center, retrospective chart review of all hospitalized, adult patients with a cancer diagnosis who received methylnaltrexone from the palliative care team between January 1st, 2012 and July 1st, 2019. Results: We identified 194 patients. The mean age was 59, 50.5% were male and 88% were white. 192 patients (98%) received the 8mg dose subcutaneously. The median oral morphine equivalent (OME) was 135mg (IQR 70-354mg). 45% (95% confidence interval, 38-53%) had a BM within 24hours. Higher OME was correlated with successful BM, with a response in 93% (86/92) of patients receiving ≥150 OME and 2% (2/102) of patients receiving <150 OME (P < .0001). Prior laxative use did not predict response at 24hours whether these were osmotic laxatives (40.7% vs 47.1%, P = .52), stimulant laxatives (45.7% vs 45.2%, P > .99), or stool softeners (44.7% vs 46.1%, P = .89). Conclusion: Methylnaltrexone has a high response rate when used as treatment for OIC in hospitalized adult cancer patients, especially for patients taking ≥150 OME.

Evaluation of a Pharmacist-Driven Protocol for the Treatment of Opioid-Induced Constipation

Background: Opioid-induced constipation (OIC) treatment guidelines recommend over-the-counter laxatives as first-line therapy, followed by treatment with a peripherally-acting mu-opioid receptor antagonist (PAMORA) in refractory patients. Objective: To evaluate the ability of a pharmacist-driven OIC protocol to promote increased scheduled laxative use prior to escalation to PAMORA therapy. Methods: This retrospective, single-center cohort study evaluated patients 2 years pre- and post-protocol implementation. The primary outcome was the difference in the percentage of patients receiving 2 scheduled laxatives for ≥ 2 days prior to PAMORA therapy pre- and post-protocol. Secondary outcomes included difference in time to first bowel movement after PAMORA initiation, difference in total number of laxative/PAMORA doses administered, and difference in overall estimated total cost. Data was analyzed using chi-squared tests and Student’s t tests. Results: Three-hundred patients were included (150 patients in the pre and post-protocol groups). In the pre-protocol group, 53 patients (35%) received 2 scheduled laxatives for 2 days prior to naloxegol/methylnaltrexone compared to 96 patients (64%) in the postprotocol group (p < 0.0001). One-thousand twenty-one scheduled laxative doses were given pre-protocol versus 1625 doses post-protocol. Average time to first bowel movement was similar between groups (17.7 hours vs 16.0 hours p = 0.441). Estimated total cost of OIC reversal therapy decreased from $20,896.95 to $13,405.47. Conclusion: A pharmacist-driven OIC protocol is associated with an increase in the use of scheduled laxatives prior to PAMORA administration and decreased overall estimated total cost. A larger, prospective study is necessary to assess if this promotes more efficacious OIC.

Prevention and management of diarrhea associated with naldemedine among patients receiving opioids: a retrospective cohort study

BackgroundNaldemedine, a novel peripherally-acting mu-opioid receptor antagonist, has improved opioid-induced constipation in randomized controlled trials. The most frequent adverse event of naldemedine is diarrhea, which can cause abdominal pain and often leads to treatment discontinuation. We aimed to identify risk factors and appropriate management strategies for key adverse events including diarrhea associated with naldemedine, since those have not been extensively studied.MethodsWe conducted a multi-center retrospective cohort study. Eligible patients had cancer, had undergone palliative care at participating centers, had been prescribed regular opioids, and had taken at least one dose of naldemedine between June 2017 and March 2018. The primary endpoint was the incidence of diarrhea according to baseline characteristics. Secondary endpoints included the duration of naldemedine administration, daily defecation counts before and after starting naldemedine, duration and severity of diarrhea as an adverse event of naldemedine, other adverse events, and the incidence of constipation within 7 days after recovery from diarrhea. We defined patients who started naldemedine within three days of starting a regularly prescribed opioid as the early group, and the remainder as the late group.ResultsAmong 103 patients who received naldemedine, 98 fulfilled the eligibility criteria. The median age was 68 years and 48% of the patients were female. Median performance status was 3, and the median oral intake was 50%. The median duration of naldemedine administration and overall survival were 25 and 64 days, respectively. The incidence of diarrhea in the early group (n = 26) was significantly lower than in the late group (n = 72) (3.9% vs. 22.2%, p = 0.02). Daily defecation counts increased after late (median 0.43 to 0.88, p < 0.001), but remained stable after early naldemedine administration (median 1.00 to 1.00, p = 0.34). Constipation after the diarrhea was resolved was common (53%), especially among patients who stopped naldemedine (78%). The diarrhea was improved within three days in 92% of patients who stopped other laxatives.ConclusionsThe early administration of naldemedine is beneficial because it reduces adverse events including diarrhea. Diarrhea caused by naldemedine can be effectively managed by stopping other laxatives while continuing naldemedine.

Naldemedine for opioid-induced constipation in patients receiving palliative care: A real-world registry study (Phase-R OIC Study).

11582 Background: Although naldemedine, a new peripherally-acting mu-opioid receptor antagonist, was approved for the management of opioid-induced constipation (OIC), its safety and effectiveness in real world clinical practice is unknown. Methods: We conducted a real world registry study in 14 hospital palliative care teams and inpatient palliative care units in Japan between April and December 2018. Consecutive cancer patients who received naldemedine for OIC were enrolled in a 7-day observational study. All treatment and assessment procedures were performed according to the accepted clinical practice. The primary outcome of the study was the proportion of patients who experienced spontaneous bowel movement within 24 hours after the initial administration of naldemedine. Adverse events, which indicated a possible or stronger causal relationship with naldemedine treatment, were reported according to the Common Terminology Criteria for Adverse Events (CTCAE) ver 4.0. Results: Overall, 204 patients were enrolled in the study. The mean age of the patients was 63±14 years, and 103 (50.5%) were male. The most common primary cancer site was lung (23.5%), followed by gastrointestinal (13.7%), and urological organs (9.3%). The proportion of patients undergoing active cancer treatment was 59.9%. Oxycodone was the most frequently used regular opioid (n = 115, 56.4%), and the median oral morphine-equivalent daily dose of opioids was 30 mg (interquartile range: 20-60 mg). Magnesium oxide (64.2%) and Senna (17.2%) were used as concomitant laxatives. All patients received 0.2 mg of naldemedine orally once daily. Most patients (90.2%) completed the 7-day observation. In 146 patients, spontaneous bowel movement was observed within 24 hour after the first administration of naldemedine (71.6%, 95% confidence interval 65.4-77.8%). Nearly two-thirds of the patients experienced increased frequency of spontaneous bowel movement in the week after naldemedine administration. The most prevalent adverse events were diarrhea (CTCAE grade 1-2, 35 cases; grade 3, 1 case) and abdominal pain (CTCAE grade 1-2, 10 cases; grade 3, 1 case). No serious adverse events including gastrointestinal perforation were reported. Conclusions: Naldemedine for opioid-induced constipation is safe and effective in the real world oncology and palliative care settings. Clinical trial information: UMIN000031381.

PGI3 INDIRECT TREATMENT COMPARISONS AND NETWORK META-ANALYSES OF NALDEMEDINE FOR THE TREATMENT OF OPIOID-INDUCED CONSTIPATION

Opioid treatment often leads to opioid-induced constipation (OIC). We compared the efficacy and safety of naldemedine 0.2mg (NLD), a peripherally-acting mu-opioid receptor antagonist, to alternative OIC treatments. A systematic literature review identified phase III/IV randomized controlled trials (RCTs) of EU-licensed OIC-indicated treatments in adults via searches of MEDLINE, Embase and the Cochrane Library from database inception to 14-Jun-2017, and of congresses, reference lists and grey literature. Outcomes at 12 and 52 weeks were assessed using indirect treatment comparisons (ITCs) or network meta-analyses (NMAs). Of 26 identified placebo/usual care-controlled RCTs, six reported 12-week outcomes (three NLD; two naloxegol 12.5mg [NLX12.5]-vs-naloxegol 25mg [NLX25]; one oxycodone/naloxone). NMAs suggest that NLD was generally comparable to other treatments at 12 weeks for response rate, mean change from baseline in spontaneous bowel movements (SBMs), patient assessment of constipation-symptoms (PAC-SYM) questionnaire, all-cause discontinuation (ACD) and discontinuation due to adverse events (AEs), except that there was a lower risk of discontinuation due to AEs for oxycodone/naloxone over NLD (risk ratio [RR]: 0.22; 95% credible interval [95%CrI]: 0.07, 0.60), and NMAs of SBMs and PAC-SYM favored NLD over NLX12.5 (SBMs: difference -0.82; 95%CrI: -1.33, -0.32; PAC-SYM: difference 0.16; 95%CrI: 0.01, 0.30). ITCs of the two studies reporting 52-week outcomes showed NLD had a lower risk of total AEs (RR: 0.84; 95% confidence interval [95%CI]: 0.75, 0.94), discontinuation due to AEs (RR: 0.19; 95%CI: 0.07, 0.52) and flatulence (RR: 0.10; 95%CI: 0.03, 0.41) versus NLX25; no statistically significant differences were observed in abdominal pain, ACD, serious AEs, deaths, diarrhea, nausea, vomiting or major adverse cardiac events. Efficacy of NLD and NLX25 was similar for OIC treatment, with an improved longer-term safety profile for NLD versus NLX25. 12-week comparisons suggest NLD is superior to NLX12.5 for the treatment of OIC in terms of SBMs and PAC-SYM.

Identification and structural characterization of hydrolytic degradation products of alvimopan by LC/QTOF/MS/MS and NMR studies

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).

Opioid induced constipation in cancer patients: pathophysiology, diagnosis and treatment

ABSTRACTOpioid-induced constipation (OIC) has emerged as a major contributor to morbidity in cancer patients. OIC is common, difficult to treat and causes significant reductions in the quality-of-life of cancer patients. It results from opioid action on gut mu-receptors, which leads to the disruption of bowel motility, mucosal transport and defecation reflexes. Laxatives are cornerstone in the management of OIC despite their relatively limited effectiveness and lack of strong evidence supporting their use. In the past few years, novel therapeutics have emerged for the management of OIC. These include; prokinetic agents, peripherally-acting mu-opioid receptor antagonists (PAMORAs), secretagogues and opioid receptor agonist/antagonist combination tablets. This article will review the mechanism of OIC in cancer patients and describe the novel therapeutic options for its prevention and management.

A Randomized, Placebo-Controlled Phase 3 Trial (Study SB-767905/012) of Alvimopan for Opioid-Induced Bowel Dysfunction in Patients With Non-Cancer Pain

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. These results demonstrate the potential for a PAM-OR antagonist to improve the symptoms of OIC without antagonizing opioid analgesia.

A Randomized, Placebo-Controlled Phase 3 Trial (Study SB-767905/013) of Alvimopan for Opioid-Induced Bowel Dysfunction in Patients With Non-Cancer Pain

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. 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.

Anesthetic Routines: The Anesthesiologist's Role in GI Recovery and Postoperative Ileus

All patients undergoing bowel resection experience postoperative ileus, a transient cessation of bowel motility that prevents effective transit of intestinal contents or tolerance of oral intake, to varying degrees. An anesthesiologist plays a critical role, not only in the initiation of surgical anesthesia, but also with the selection and transition to effective postoperative analgesia regimens. Attempts to reduce the duration of postoperative ileus have prompted the study of various preoperative, perioperative, and postoperative regimens to facilitate gastrointestinal recovery. These include modifiable variables such as epidural anesthesia and analgesia, opioid-sparing anesthesia and analgesia, fluid restriction, colloid versus crystalloid combinations, prokinetic drugs, and use of the new peripherally acting mu-opioid receptor (PAM-OR) antagonists. Review and appropriate adaptation of these multiple modifiable interventions by anesthesiologists and their surgical colleagues will facilitate implementation of a best-practice management routine for bowel resection procedures that will benefit the patient and the healthcare system.

Alvimopan for the Management of Postoperative Ileus After Bowel Resection: Characterization of Clinical Benefit by Pooled Responder Analysis

BackgroundA pooled post hoc responder analysis was performed to assess the clinical benefit of alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, for the management of postoperative ileus after bowel resection.MethodsAdult patients who underwent laparotomy for bowel resection scheduled for opioid-based intravenous patient-controlled analgesia received oral alvimopan or placebo preoperatively and twice daily postoperatively until hospital discharge or for 7 postoperative days. The proportion of responders and numbers needed to treat (NNT) were examined on postoperative days (POD) 3–8 for GI-2 recovery (first bowel movement, toleration of solid food) and hospital discharge order (DCO) written.ResultsAlvimopan significantly increased the proportion of patients with GI-2 recovery and DCO written by each POD (P < 0.001 for all). More patients who received alvimopan achieved GI-2 recovery on or before POD 5 (alvimopan, 80%; placebo, 66%) and DCO written before POD 7 (alvimopan, 87%; placebo, 72%), with corresponding NNTs equal to 7.ConclusionsOn each POD analyzed, alvimopan significantly increased the proportion of patients who achieved GI-2 recovery and DCO written versus placebo and was associated with relatively low NNTs. The results of these analyses provide additional characterization and support for the overall clinical benefit of alvimopan in patients undergoing bowel resection.

The Effects of a Short Course of Antibiotics on Alvimopan and Metabolite Pharmacokinetics

Alvimopan is a novel, oral, peripherally acting mu-opioid receptor (PAM-OR) antagonist that blocks the effects of opioids on the gastrointestinal tract, without blocking opioid-induced analgesic effects. It is metabolized by gut microflora to an active amide-hydrolysis metabolite, which is equipotent to alvimopan. The objective of this study was to characterize the pharmacokinetics of alvimopan and metabolite before, during, and after administration of a short course of antibiotics in healthy adult participants. Simulations were conducted to determine the feasibility for this study. An open-label, sequential drug interaction study was conducted in 45 participants who received twice-daily dosing of alvimopan with and without ciprofloxacin. Metabolite concentrations were reduced by 99.2% (90% confidence interval: 98.8-99.5) in the presence of ciprofloxacin. The interaction occurred rapidly, and recovery was slow. The interaction may be of relevance for patients with relatively high metabolite plasma concentrations prior to antibiotic administration but of little relevance for patients with little or no plasma metabolite exposure initially. Administration of ciprofloxacin decreased alvimopan C(max) by 24%, which is of no clinical relevance. There was no effect of ciprofloxacin on alvimopan trough concentrations or AUC. Alvimopan was well tolerated.

Peripherally Acting Mu-Opioid Receptor Antagonists and Postoperative Ileus: Mechanisms of Action and Clinical Applicability

Postoperative ileus (POI), a transient cessation of coordinated bowel function after surgery, is an important health care problem. The etiology of POI is multifactorial and related to both the surgical and anesthetic pathways chosen. Opioids used to manage surgical pain can exacerbate POI, delaying gastrointestinal (GI) recovery. Peripherally acting mu-opioid receptor (PAM-OR) antagonists are designed to mitigate the deleterious effects of opioids on GI motility. This new class is investigational for POI management with the goal of accelerating the recovery of upper and lower GI tract function after bowel resection. In this review, we summarize the mechanisms by which POI occurs and the role of opioids and opioid receptors in the enteric nervous system, discuss the mechanism of action of PAM-OR antagonists, and review clinical pharmacology and Phase II/III POI trial results of methylnaltrexone and alvimopan. Finally, the role of anesthesiologists in managing POI in the context of a multimodal approach is discussed.

Alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist for the treatment of opioid-induced bowel dysfunction: Results from a randomized, double-blind, placebo-controlled, dose-finding study in subjects taking opioids for chronic non-cancer pain

Our objective was to investigate the efficacy and safety of alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, in subjects with non-cancer pain and opioid-induced bowel dysfunction (OBD), and to identify at least one treatment regimen that improves OBD. Following a 2-week baseline period, 522 subjects reporting <3 spontaneous bowel movements (SBMs)/week (with ⩾25% accompanied by a sensation of incomplete evacuation, straining, or lumpy hard stools), requiring analgesia equivalent to ⩾30 mg oral morphine/day were randomized to alvimopan 0.5 mg twice daily (BID), 1 mg once daily (QD), 1 mg BID, or placebo for 6 weeks. Compared with placebo, there was a statistically and clinically significant increase in mean weekly SBM frequency over the initial 3 weeks of treatment (primary endpoint) with alvimopan 0.5 mg BID (+1.71 mean SBMs/week), alvimopan 1 mg QD (+1.64) and alvimopan 1 mg BID (+2.52); P < 0.001 for all comparisons. Increased SBM frequency and additional treatment effects, including improvements in symptoms such as straining, stool consistency, incomplete evacuation, abdominal bloating/discomfort, and decreased appetite, were sustained over 6 weeks. The most frequently reported adverse events were abdominal pain, nausea, and diarrhea, occurring more frequently in the higher dosage groups. The alvimopan 0.5 mg BID regimen demonstrated the best benefit-to-risk profile for managing OBD with alvimopan in this study population, with a side effect profile similar to that of placebo. There was no evidence of opioid analgesia antagonism. Competitive peripheral antagonism of opioids with alvimopan can restore GI function and relieve OBD without compromising analgesia.

Effect of alvimopan (ALV) on gastrointestinal (GI) recovery, length of hospital stay (LOS), and postoperative ileus (POI)-related morbidity in patients (PTS) undergoing bowel resection (BR) for colon or rectal cancer (CRC)

4014 Background: POI, an interruption of bowel motility, occurs universally after BR and is exacerbated by exogenous opioid analgesia. ALV, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, accelerated GI recovery after BR in multicenter, randomized phase III efficacy trials. CRC is the most common reason for BR in the US, and in the ALV trials CRC was the primary reason for BR for 723 of 1,409 (51%) PTS. This abstract examines GI recovery, LOS, POI-related morbidity, and safety in only this subset of PTS. Methods: This pooled ad hoc analysis assessed the subset of PTS in phase III ALV trials who underwent BR via laparotomy because of CRC and received ALV 12 mg or placebo (PLA) (N = 723). All PTS were scheduled for postoperative intravenous patient-controlled opioid analgesia and received oral ALV or PLA preoperatively and BID postoperatively until hospital discharge or for = 7 postoperative days. Efficacy endpoints included GI-2 recovery (first bowel movement and tolerance of solid food) and postoperative LOS (calendar day after surgery to hospital discharge order written). Treatment effect on GI-2 recovery was analyzed using Cox proportional hazards models, and magnitude of effect was expressed with Kaplan-Meier means. POI-related morbidity included nasogastric tube insertion or complications of POI resulting in prolonged hospital stay or readmission. Safety was monitored by adverse event reports. Conclusions: ALV significantly accelerated GI recovery, reduced postoperative LOS, and reduced the proportion of PTS with POI-related morbidity compared with PLA in PTS undergoing BR for CRC. ALV was well tolerated with a lower incidence of nausea and vomiting in the ALV group than in the PLA group. [Table: see text] No significant financial relationships to disclose.

Alvimopan, a Peripherally Acting Mu-Opioid Receptor (PAM-OR) Antagonist – A Study in Patients with Chronic Idiopathic Constipation (CIC) Not Taking Opioid Medication

Purpose: Alvimopan is an investigational oral PAM-OR antagonist, which has been shown to block the effects of exogenous opioids in the gut. Binding of opioids to mu-opioid receptors in the GI tract results in decreased GI motility and gastric secretions, causing a constellation of GI side effects, particularly constipation. Results from study SB-767905/011 (011) in opioid-treated subjects (n = 522) with persistent non-cancer pain showed a significant increase in mean spontaneous bowel movement (BM) frequency ranging from 3.39 to 4.34 in all alvimopan treatment groups during the 6 wk treatment period vs 1.71 in the placebo group (p < 0.001). Additional bowel symptoms, such as straining, stool consistency, and incomplete evacuation were also improved, while opioid-induced analgesia was unaffected. Study SB-767905/007 (007), presented here, tested the hypothesis that alvimopan relieves bowel symptoms in subjects with CIC by antagonizing endogenous opioids. Methods: This randomized, double-blind, placebo-controlled study evaluated alvimopan 1mg BID, 3mg BID or 8mg BID for 8 wks in 217 subjects ≥18 yrs old with ≥6-month history of CIC (<3 spontaneous complete (SC) BMs per wk plus straining and/or hard stool consistency associated with ≥25% of all BMs) not taking opioids. Primary endpoint was change in mean weekly SCBM frequency from baseline during the first 4 wks of treatment. Results: At baseline, mean weekly SCBM frequency was 0.5–0.7 throughout the treatment groups. During wks 1–4 there were no significant differences in mean weekly SCBM frequency between any alvimopan dose and placebo (Table). Alvimopan did not affect other bowel symptoms including degree of straining or stool consistency. Alvimopan was generally well tolerated, with a safety profile similar to placebo.TableConclusions: Alvimopan provided clinical relief of constipation and associated BM symptoms in subjects receiving opioids (study 011), but no clinical effect was seen in subjects with CIC not taking opioids (study 007). Although endogenous opioids may play a role in modulation of GI function, antagonism of this pathway with alvimopan does not relieve constipation unrelated to exogenous opioids.

The peripherally-acting mu-opioid receptor antagonist alvimopan* effectively reduces the time to recovery of GI function after bowel resection,

The peripherally-acting mu-opioid receptor antagonist alvimopan* effectively reduces the time to recovery of GI function after bowel resection,

Alvimopan, a peripherally acting mu-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery

Alvimopan is a peripherally acting mu-opioid receptor (PAM-OR) antagonist for accelerating gastrointestinal recovery after surgery. Patients undergoing open laparotomy (bowel resection, n = 418; hysterectomy, n = 197) were randomized to receive alvimopan 6 or 12 mg or placebo orally > or = 2 h before surgery and then b.i.d. until hospital discharge (up to 7 days). The primary efficacy endpoint was time to gastrointestinal (GI) recovery (measured by toleration of solid food and passage of flatus/stool; GI-3). Secondary endpoints included time to GI-2 recovery (toleration of solid food and passage of stool) and hospital discharge order written (DCO). Alvimopan did not significantly accelerate GI-3 compared with placebo [6 mg: hazard ratio (HR) = 1.20, p = 0.080; 12 mg: HR = 1.24, p = 0.038). However, after adjustment for significant covariates (sex/surgical duration), benefits were significant for both doses (6 mg: HR = 1.24, p = 0.037; 12 mg: HR = 1.26, p = 0.028). Alvimopan also significantly accelerated time to GI-2 (6 mg: HR = 1.37, p = 0.008; 12 mg: HR = 1.33, p = 0.018) and DCO (6 mg: HR = 1.31, p = 0.008; 12 mg: HR = 1.28, p = 0.015). Adverse events were similar between groups. Alvimopan (6 or 12 mg) accelerates GI recovery and is well tolerated in patients undergoing open laparotomy.

Novel therapeutic agents: Alvimopan, a novel, peripherally-acting, mu-opioid receptor antagonist for the management of opioid-induced bowel dysfunction (OBD): Positive results from a phase III randomized, placebo-controlled, 21-day trial

Opioids remain the “gold standard” for management of moderate to severe pain. With long-term use, patients commonly experience OBD resulting in decreased bowel movements (BMs), abdominal pain, incomplete evacuation, cramping, abdominal distension, and hard, dry stools. Patients do not develop tolerance to OBD and current treatment strategies can have limited efficacy. Alvimopan is a novel, oral, peripherally-acting mu-opioid receptor antagonist. This randomized, placebo-controlled trial (13C304) evaluated the efficacy and safety of 0.5 or 1 mg once-daily alvimopan for 21 days in 168 patients with OBD (defined as history of <3 BMs/week and at least one associated symptom: hard stools, straining, sensation of anorectal obstruction, or incomplete evacuation) who had been treated with opioids long-term (≥1 month). The primary endpoint was the proportion of patients who had ≥1 BM within 8 hours of each study dose across the 21-day treatment period. On average, significantly more patients treated with alvimopan reached this endpoint compared with placebo: 54% for 1 mg alvimopan (P<0.001 vs placebo), 43% for 0.5 mg alvimopan (P<0.001 vs placebo), and 29% for placebo. The alvimopan 1 mg group reported improved bowel evacuation (P=0.002) and improved satisfaction with the quality of BMs during treatment compared with the placebo group (70% vs 50%, P=0.046). Alvimopan was well tolerated; the most common adverse events (range 5%-13% following 1 mg) were nausea, diarrhea, abdominal cramping, vomiting, and headache. Importantly, opioid consumption and pain intensity scores were unchanged with alvimopan dosing. In conclusion, this study provides evidence that daily dosing with alvimopan improves BM frequency and satisfaction in patients with OBD without compromising pain relief. The support of Adolor Corporation is gratefully acknowledged for this project.

Renal effects of TAPP, a highly selective μ‐opioid agonist

1. The effect of i.v. administration of TAPP, a highly selective and exclusively peripherally-acting mu-opioid receptor agonist, on urine output, urinary sodium, potassium and cyclic GMP, and on plasma immunoreactive atrial natriuretic factor (IR-ANF) levels was studied in conscious normally hydrated female rats (200-250 g). 2. TAPP treatment produced a significant dose-dependent increase of urine output and urinary sodium, potassium and cyclic GMP excretion during the first hour. The highest TAPP dose used (2.5 mg kg-1. body weight) elicited a 10 fold elevation of urine output from 0.23 +/- 0.06 ml h-1 to 2.5 +/- 0.3 ml h-1 (n = 18) accompanied by augmented sodium [from 17.0 +/- 4.7 mu Eq h-1 to 79 +/- 12.7 mu Eq h-1, n = 18 (P < 0.001)], potassium [from 9.5 +/- 2.5 mu Eq h-1 to 39.4 +/- 6.6 mu Eq h-1, n = 18 (P < 0.005)], and cyclic GMP excretion [from 191 +/- 21 pmol h-1 to 1340 +/- 322 pmol h-1, n = 18 (P < 0.001)]. Plasma IR-ANF rose from 22 +/- 4 pg ml-1 to 508 +/- 22 pg ml-1 (n = 18) (P < 0.001) 5 min after administration of TAPP (2500 micrograms kg-1). 3. TAPP lowered systemic blood pressure, also in a dose-related manner, 1-5 min after injection. This decrease in blood pressure was transient and did not last more than 10 min. 4. Pretreatment with the opioid antagonist naloxone (0.8 mg per rat) abolished the diuretic, natriuretic and kaliuretic effect of TAPP (250 micrograms kg-1); urine output dropped from 1.16 +/- 0.15 ml h-1, n = 12, to the control value of 0.15 +/- 0.06 ml h-1, n = 12 (P < 0.001), sodium excretion fell from 57.5 +/- 11 mu Eq h-1, to 21.3 +/- 8.5 mu Eq h-1, n = 12 (P < 0.001), and potassium excretion decreased from 45.4 +/- 9.7 mu Eq h-1, n = 12, to 16.1 +/- 7.0 mu Eq h-1, (P < 0.001). 5. Pretreatment with anti-ANF serum (0.4 ml) abolished the diuretic effect of TAPP: urine output diminished significantly from 1.93 +/- 0.28 to 0.88 +/- 0.29 ml h-1 (P < 0.01) (n = 6). The TAPP-induced diuretic action, increased sodium/potassium excretion and elevated urinary cyclic GMP levels were also reversed by anti-ANF antibodies. 6. Since TAPP is totally unable to cross the blood-brain barrier, the ensemble of these observations led to the conclusion that the diuretic, natriuretic, kaliuretic and hypotensive effects produced by this mu-opioid agonist through interaction with peripheral mu-opioid receptors occur via ANF release.