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Chun-su Yuan - One of the best experts on this subject based on the ideXlab platform.

  • Methylnaltrexone potentiates body weight and fat reduction with leptin.
    Journal of opioid management, 2018
    Co-Authors: Chun-su Yuan, Chong-zhi Wang, Anoja Attele, Shi Sun, Bs Robin Tong, Robert J. Israel
    Abstract:

    Objective: Leptin increases energy expenditure by enhancing systemic and brown adipose metabolism. In a neonatal rat model, retroperitoneal fat pad weight decreased significantly in leptin-treated animals, which reduced body weight. As opioids increase feeding, opioid antagonists may decrease food intake and body weight. However, interactions between leptin and the activity of peripheral opioids on body weight and fat accumulation have not been investigated. In this study, the authors evaluated the effects of naloxone (a nonselective opioid antagonist) and Methylnaltrexone (a peripherally acting opioid antagonist) on the action of leptin in neonatal rats. Results: Compared with control, the weight gain of pups given a single daily intraperitoneal injection of leptin 0.5 mg/kg, leptin 0.5 mg/kg plus naloxone 0.3 mg/kg, or leptin 0.5 mg/kg plus Methylnaltrexone 3.0 mg/kg for 8 consecutive days was significantly reduced (all p < 0.01). Naloxone or Methylnaltrexone significantly potentiated leptin’s effect on body weight (p < 0.05 or p < 0.01, respectively). After coadministration of leptin plus naloxone or leptin plus Methylnaltrexone, weight reduction in the right retroperitoneal fat pads was also significant compared with the reduction after leptin alone (p < 0.05 or p < 0.01, respectively). Conclusions: The data suggest the existence of a peripheral opioid-related mechanism in leptinactive modulation of body weight.

  • Methylnaltrexone reduced body weight gain in ob/ob mice.
    Journal of opioid management, 2018
    Co-Authors: Chun-su Yuan, Chong-zhi Wang, Anoja Attele, Liu Zhang
    Abstract:

    Objective: Opioids may function to regulate food intake and body weight, an activity that could be predominantly centrally mediated. In this study, the authors evaluated the effects of a peripherally acting opioid receptor antagonist, Methylnaltrexone, on weight changes in adult obese ob/ob mice. Results: After a 12-day treatment with naloxone 0.3 mg/kg, weight was reduced from 63.7 ± 1.1 g in the control group to 59.2 ± 0.9 g in the naloxone group (p < 0.05). After a 12-day treatment with Methylnaltrexone 3.0 mg/kg, weight increase completely ceased. The body weight was 63.9 ± 1.0 g in the control group when compared with 55.9 ± 1.2 g in the drug group (p < 0.01). The effect of Methylnaltrexone (1.0 mg to 3.0 mg/kg) on weight changes was dose-dependent (p < 0.01). Methylnaltrexone significantly reduced daily food intake (p < 0.05), but did not affect body temperature and energy expenditure. Using HPLC analysis, no detectable naltrexone levels were found in association with Methylnaltrexone administration. Whether the observed Methylnaltrexone effects are primarily related to the antagonism of endorphinergic system remains to be investigated. Conclusions: Our results suggest that the peripheral opioid mechanism contributes to modulating food ingestion and Methylnaltrexone may have clinical importance in obesity management.

  • Methylnaltrexone bromide: research update of pharmacokinetics following parenteral administration.
    Expert opinion on drug metabolism & toxicology, 2011
    Co-Authors: Yakov Rotshteyn, Thomas A Boyd, Chun-su Yuan
    Abstract:

    Introduction: Opioid-induced constipation is a major side effect of the use of opioid pain medications in a palliative care population. At present, the only approved treatment for opioid-induced constipation is Methylnaltrexone bromide subcutaneous injection. Methylnaltrexone is a peripherally restricted opioid antagonist with μ-opioid receptor selectivity that can reduce opioid activity in peripheral organs such as the gastrointestinal tract while sparing the pain relief afforded by the pain medications. Areas covered: This article addresses the pharmacokinetics of parenterally administered Methylnaltrexone, including the studies in humans that form the basis for our understanding, and information on the disposition, metabolism and elimination of the drug. From this review, the reader will gain an understanding of the body's handling of Methylnaltrexone following intravenous or subcutaneous administration. Expert opinion: Studies conducted to date indicate that Methylnaltrexone has high bioavailability a...

  • Protease inhibitor-induced nausea and vomiting is attenuated by a peripherally acting, opioid-receptor antagonist in a rat model
    AIDS Research and Therapy, 2009
    Co-Authors: Chun-su Yuan, Han H. Aung, Sangeeta R. Mehendale, Chong-zhi Wang, Robert J. Israel
    Abstract:

    Background Protease inhibitors such as ritonavir can cause nausea and vomiting which is the most common reason for discontinuation. Rats react to nauseous and emetic stimuli by increasing their oral intake of non-nutritive substances like kaolin, known as pica behavior. In this study, we evaluated the effects of Methylnaltrexone, a peripherally acting mu -opioid receptor antagonist that does not affect analgesia, on ritonavir-induced nausea and vomiting in a rat pica model. Results We observed that 24 to 48 hr after administration of oral ritonavir 20 mg/kg, kaolin consumption increased significantly in rats ( P < 0.01). This increase was attenuated by pretreatment with an intraperitoneal injection of Methylnaltrexone (0.3–3.0 mg/kg) in a dose dependent manner ( P < 0.01) and also with naloxone (0.1–0.3 mg/kg) ( P < 0.01). The areas under the curve for kaolin intake from time 0 to 120 hr were significantly reduced after administration of the opioid antagonists. Food intake was not significantly affected. Plasma naltrexone levels were measured after Methylnaltrexone injection, and no detectable levels were found, indicating that Methylnaltrexone was not demethylated in our experimental paradigm. Conclusion These results suggest that Methylnaltrexone may have potential clinical utility in reducing nausea and vomiting in HIV patients who take ritonavir.

  • Methylnaltrexone a peripherally acting opioid receptor antagonist enhances tumoricidal effects of 5 fu on human carcinoma cells
    Anticancer Research, 2009
    Co-Authors: Chong-zhi Wang, Han H. Aung, Jing-tian Xie, Shi Sun, Robin Tong, Eryn Mcentee, Chun-su Yuan
    Abstract:

    Background: Methylnaltrexone, a novel peripherally acting opioid receptor antagonist, is used to treat opiate-induced constipation in cancer patients. Its effects on the activities of chemotherapeutic agents, however, have not been evaluated. In this study, the effect of Methylnaltrexone on the action of 5-fluorouracil (5-FU) was tested in three human cancer cell lines. Materials and Methods: Treatment was for 72 h and the effects on cell proliferation were measured in human SW-480 colorectal cancer cells, MCF-7 breast cancer cells and non-small cell lung cancer cells in vitro. The apoptotic effect was analyzed by using flow cytometry. The cell cycle and expression of cyclin A were assayed after staining with propidium iodide and cyclin A-fluorescein isothiocyanate. Results: 5-FU decreased the cancer cell growth significantly in all three cancer cell lines in a concentration-dependent manner and Methylnaltrexone enhanced the actions of 5-FU. Compared to 5-FU 10 μM alone on SW-480 cells (63.5±1.1% ), on MCF-7 cells (58.3±3.1% ), or on non-small cell lung cancer cells (81.3±1.6% ), 5-FU 10 μM plus Methylnaltrexone 1.0 μM reduced cancer cell growth in all three cell lines to 50.2±2.9% for SW-480 cells (p<0.05), 50.0±1.7% for MCF- 7 cells (p<0.05) and 68.7±2.2% for lung cancer cells (p<0.01). Methylnaltrexone alone also showed anti- proliferative activity in the three cell lines. Methylnaltrexone at 1.0 μM, reduced SW-480 cell growth to 81.9±3.7% (p<0.01), MCF-7 cell growth to 85.9±2.4% (p<0.01) and lung cancer cell growth to 85.5±2.2% (p<0.01). Apoptosis was not induced by treatment of SW-480 cells with 1.0 or 10 μM Methylnaltrexone for 48 h. However, Methylnaltrexone increased the number of cells in the G 1 -phase and decreased the expression of cyclin A. Conclusion: At its therapeutic concentrations for opioid-induced constipation, methyl- naltrexone does not attenuate and in fact may enhance the tumoricidal activity of 5-FU. Enhanced 5-FU activity may be attributed to the distinct pathways of 5-FU and Methylnaltrexone, an effect that could give Methylnaltrexone a complementary role in the treatment of cancer with chemotherapeutic agents.

Karim Chamie - One of the best experts on this subject based on the ideXlab platform.

  • The association between N-Methylnaltrexone, a peripherally acting mu-opioid receptor antagonist, and clinical outcomes in patients undergoing robotic-assisted radical cystectomy
    World Journal of Urology, 2020
    Co-Authors: Andrew T. Lenis, Vishnukamal Golla, David C. Johnson, Izak Faiena, Siamak Rahman, Karim Chamie
    Abstract:

    Purpose To assess the impact of N -Methylnaltrexone, a peripherally acting mu-opioid receptor antagonist, on the post-operative recovery of patients undergoing robotic-assisted radical cystectomy for bladder cancer. Methods We retrospectively reviewed patients undergoing robotic-assisted radical cystectomy by a single surgeon (KC) prior to (control group) and after (treatment group) the routine use of N -Methylnaltrexone. Kaplan–Meier curves and the log-rank test were used to quantify time to flatus, bowel movement, and discharge. Daily mean opioid use, daily pain assessment rating, and episodes of severe pain (7–10/10) were compared. Gastrointestinal-related complications, including ileus, emesis, and/or need for post-op nasogastric tube placement, and 30-day readmissions were also compared between groups. Charge capture data were compared between groups to analyze cost impact. Results 29 patients each in the control and treatment group met inclusion criteria. Patients receiving N -Methylnaltrexone had reduced length of stay compared with no N -Methylnaltrexone (median 4 vs. 7 days, p  

  • the association between n Methylnaltrexone a peripherally acting mu opioid receptor antagonist and clinical outcomes in patients undergoing robotic assisted radical cystectomy
    World Journal of Urology, 2020
    Co-Authors: Andrew T. Lenis, Vishnukamal Golla, Izak Faiena, Siamak Rahman, Patrick M Lec, David W Johnson, Carol Lee, Karim Chamie
    Abstract:

    PURPOSE To assess the impact of N-Methylnaltrexone, a peripherally acting mu-opioid receptor antagonist, on the post-operative recovery of patients undergoing robotic-assisted radical cystectomy for bladder cancer. METHODS We retrospectively reviewed patients undergoing robotic-assisted radical cystectomy by a single surgeon (KC) prior to (control group) and after (treatment group) the routine use of N-Methylnaltrexone. Kaplan-Meier curves and the log-rank test were used to quantify time to flatus, bowel movement, and discharge. Daily mean opioid use, daily pain assessment rating, and episodes of severe pain (7-10/10) were compared. Gastrointestinal-related complications, including ileus, emesis, and/or need for post-op nasogastric tube placement, and 30-day readmissions were also compared between groups. Charge capture data were compared between groups to analyze cost impact. RESULTS 29 patients each in the control and treatment group met inclusion criteria. Patients receiving N-Methylnaltrexone had reduced length of stay compared with no N-Methylnaltrexone (median 4 vs. 7 days, p < 0.01). Time to flatus and bowel movement, however, were similar. In a multivariable analysis controlling for possible confounders, however, the improvement in length of stay associated with N-Methylnaltrexone use did not reach statistical significance (p = 0.11). Episodes of severe pain and composite gastrointestinal-related complications were reduced in the N-Methylnaltrexone group (44.8% vs. 10.3%, p < 0.01). The reduction in length of stay was associated with approximately $10,500 in cost savings per patient. CONCLUSIONS In this study, N-Methylnaltrexone was associated with reduced length of stay, fewer episodes of severe pain, and reduced costs. These results provide the impetus for further study.

Robert J. Israel - One of the best experts on this subject based on the ideXlab platform.

  • Subcutaneous Methylnaltrexone for opioid-induced constipation in advanced-illness patients with or without active cancer.
    Pain management, 2020
    Co-Authors: Bruce H. Chamberlain, Neal E Slatkin, Nancy Stambler, Michelle Rhiner, Robert J. Israel
    Abstract:

    Aim: To evaluate Methylnaltrexone for opioid-induced constipation in patients with and without cancer. Methods: This post hoc analysis comprises two Phase III, multicenter, double-blind, randomized studies of advanced-illness patients who received Methylnaltrexone subcutaneous injection or placebo. Results: Significantly more patients treated with Methylnaltrexone than placebo experienced laxation within 4 (cancer = 55.5 vs 15.5%; noncancer = 55.6 vs 12.8%) and 24 (cancer = 64.7 vs 29.8%; noncancer = 64.4 vs 30.8%) h after the first dose (p < 0.01 vs placebo). Regardless of cancer status, Methylnaltrexone reduced median time to laxation and improved constipation relief without impacting opioid analgesia or withdrawal symptoms. Conclusion: Methylnaltrexone provided significant improvements in opioid-induced constipation over placebo in advanced-illness patients with and without cancer. Clinical trial registration numbers: study 301: NCT00401362; study 302: NCT00402038.

  • safety of oral Methylnaltrexone for opioid induced constipation in patients with chronic noncancer pain
    Journal of Pain Research, 2018
    Co-Authors: Richard Rauck, Neal E Slatkin, Nancy Stambler, Robert J. Israel
    Abstract:

    Purpose Oral Methylnaltrexone was shown to be effective in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain in a Phase III randomized controlled trial. This report provides a detailed safety analysis from that study. Methods Adults (n=803) with chronic noncancer pain for ≥2 months and confirmed OIC while receiving opioid doses ≥50 mg morphine equivalent per day for ≥14 days were randomized 1:1:1:1 to oral Methylnaltrexone (150, 300, or 450 mg) or placebo once daily for 4 weeks, followed by as-needed use for 8 weeks. Safety was evaluated by examining treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, electrocardiography, rescue-laxative and opioid use, Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS), and pain-intensity scores. Results TEAEs occurred at a similar incidence in the Methylnaltrexone groups (59.0%) and placebo group (63.0%). The most common TEAEs with Methylnaltrexone were abdominal pain (8.0% vs 8.5% with placebo), nausea (6.8% vs 9.0%), and diarrhea (6.0% vs 3.5%). Cardiac-related TEAEs occurred in 1.8% and 1.0% of patients, respectively, and no major adverse cardiovascular events were reported. No patient had a cluster of TEAEs associated with opioid withdrawal after excluding gastrointestinal TEAEs. Changes in laboratory parameters, vital signs, and electrocardiography were generally small and similar across treatment groups. Rescue-laxative use was more common with placebo than Methylnaltrexone 450 mg (6.20% vs 4.27% of study days, P=0.024). Changes in opioid dose, OOWS and SOWS scores, and pain-intensity scores during treatment were minimal. Conclusion Oral Methylnaltrexone had a safety profile comparable with placebo in the treatment of OIC in patients with chronic noncancer pain, with no evidence of cardiac toxicity or opioid withdrawal.

  • Oral Methylnaltrexone is efficacious and well tolerated for the treatment of opioid-induced constipation in patients with chronic noncancer pain receiving concomitant methadone.
    Journal of pain research, 2018
    Co-Authors: Lynn R. Webster, Robert J. Israel
    Abstract:

    Purpose To evaluate the safety and efficacy of oral Methylnaltrexone for opioid-induced constipation (OIC). Patients and methods This was a post hoc analysis of patients receiving methadone in a randomized, double-blind, placebo-controlled, Phase 3 trial. The trial included adults with chronic noncancer pain for ≥2 months receiving opioid doses ≥50 mg/day of oral morphine equivalents for ≥14 days and with a history of OIC. Patients were assigned to oral Methylnaltrexone (150, 300, or 450 mg) or placebo once daily (QD) for 4 weeks followed by 8 weeks as needed. Percentage of dosing days that resulted in a rescue-free bowel movement (RFBM) within 4 hours of dosing was assessed during QD dosing (primary efficacy endpoint). Other endpoints included percentage of responders (ie, ≥3 RFBMs/week, with an increase of ≥1 RFBM/week from baseline for ≥3 of the 4 weeks) during QD dosing and change in weekly number of RFBMs. Adverse events were assessed. Results Concomitant methadone was reported in 120 patients (oral Methylnaltrexone: 150 mg [n=33], 300 mg [n=30], and 450 mg [n=31]; placebo [n=26]). Oral Methylnaltrexone-treated patients had significant increases in mean percentage of dosing days with RFBMs within 4 hours of dosing during weeks 1-4 with 300 mg (33.6%; P

  • Oral Methylnaltrexone does not negatively impact analgesia in patients with opioid-induced constipation and chronic noncancer pain.
    Journal of pain research, 2018
    Co-Authors: Lynn R. Webster, Robert J. Israel
    Abstract:

    Purpose An oral formulation of Methylnaltrexone has been developed for treating opioid-induced constipation (OIC). This manuscript examines the impact of oral Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, on opioid analgesia. Methods This Phase III, randomized, double-blind, placebo-controlled trial, evaluated changes in pain intensity scores (0= no pain to 10= worst possible pain) and opioid use in adults with chronic noncancer pain. Patients taking ≥50 mg/day oral morphine equivalent dose (MED) for ≥14 days before screening with less than three rescue-free bowel movements/week received oral Methylnaltrexone 150 mg/day (n=201), 300 mg/day (n=201), 450 mg/day (n=200), or placebo (n=201) once daily for 4 weeks followed by 8 weeks of oral Methylnaltrexone as needed. Results The primary condition requiring opioid use was back pain (68.2% of 803 patients). Baseline pain intensity scores were similar among treatment groups (mean range, 6.2-6.4) and remained stable throughout the 4-week double-blind (mean range, 6.1-6.5) and 8-week as needed (mean range, 6.3-6.5) periods. Baseline mean MED was comparable between oral Methylnaltrexone 150 mg (200.0 mg/day), Methylnaltrexone 450 mg (218.0 mg/day), and placebo (209.7 mg/day), but was slightly higher in the oral Methylnaltrexone 300-mg group (252.6 mg/day). Nonsignificant, minimal changes in mean MED were observed after 4 weeks of treatment (214.5-235.6 mg/day) and at the end of the as needed phase (202.3-234.9 mg/day). The percentage of patients who initiated new opioid medications during the 4-week, once-daily dosing period was generally similar among the oral Methylnaltrexone 150-mg, 300-mg, and 450-mg groups (44.8%, 43.3%, and 35.0%, respectively), the oral Methylnaltrexone combined group (41.0%), and the placebo group (39.8%). The most common newly initiated opioid medications during this once-daily period were oxycodone (oral Methylnaltrexone groups combined, 14.6%; placebo, 12.4%) and morphine (oral Methylnaltrexone combined, 10.1%; placebo, 7.0%). Conclusion Oral Methylnaltrexone does not elicit opioid withdrawal or interfere with opioid analgesia.

  • Methylnaltrexone potentiates body weight and fat reduction with leptin.
    Journal of opioid management, 2018
    Co-Authors: Chun-su Yuan, Chong-zhi Wang, Anoja Attele, Shi Sun, Bs Robin Tong, Robert J. Israel
    Abstract:

    Objective: Leptin increases energy expenditure by enhancing systemic and brown adipose metabolism. In a neonatal rat model, retroperitoneal fat pad weight decreased significantly in leptin-treated animals, which reduced body weight. As opioids increase feeding, opioid antagonists may decrease food intake and body weight. However, interactions between leptin and the activity of peripheral opioids on body weight and fat accumulation have not been investigated. In this study, the authors evaluated the effects of naloxone (a nonselective opioid antagonist) and Methylnaltrexone (a peripherally acting opioid antagonist) on the action of leptin in neonatal rats. Results: Compared with control, the weight gain of pups given a single daily intraperitoneal injection of leptin 0.5 mg/kg, leptin 0.5 mg/kg plus naloxone 0.3 mg/kg, or leptin 0.5 mg/kg plus Methylnaltrexone 3.0 mg/kg for 8 consecutive days was significantly reduced (all p < 0.01). Naloxone or Methylnaltrexone significantly potentiated leptin’s effect on body weight (p < 0.05 or p < 0.01, respectively). After coadministration of leptin plus naloxone or leptin plus Methylnaltrexone, weight reduction in the right retroperitoneal fat pads was also significant compared with the reduction after leptin alone (p < 0.05 or p < 0.01, respectively). Conclusions: The data suggest the existence of a peripheral opioid-related mechanism in leptinactive modulation of body weight.

Jonathan Moss - One of the best experts on this subject based on the ideXlab platform.

  • Reversal of Opioid-Induced Gastric Dysfunction in a Critically Ill Burn Patient After Methylnaltrexone
    Anesthesia and analgesia, 2008
    Co-Authors: Michael Woo, Michael O'connor, Chun-su Yuan, Jonathan Moss
    Abstract:

    Peripheral-acting mu opiate receptor antagonists have been extensively studied for the treatment of opiate-induced constipation in advanced illness for the prophylaxis of postoperative ileus. We document the first intensive care patient to receive Methylnaltrexone in an attempt to facilitate enteral nutrition. Gastric residuals markedly decreased and enteral feeding increased after administration of IV Methylnaltrexone. The patient's ileus resolved coincident with the first injection.

  • Tolerability, Gut Effects, and Pharmacokinetics of Methylnaltrexone Following Repeated Intravenous Administration in Humans
    Journal of clinical pharmacology, 2005
    Co-Authors: Chun-su Yuan, Robert J. Israel, Michael O'connor, Theodore Karrison, Harold Doshan, Martha R. Charney, Spring Maleckar, Jonathan Moss
    Abstract:

    Previous studies have shown that a single dose of Methylnaltrexone, a unique peripheral opioid antagonist, reverses opioid-induced gut hypomotility in humans. Because repeated drug doses are likely to be needed to treat patients with opioid-induced or postsurgical bowel dysfunction, the authors have now examined the safety, pharmacological activity, and pharmacokinetics of a multiple-dose regimen of Methylnaltrexone, administered as 12 consecutive intravenous doses (0.3 mg/kg every 6 hours) in 12 healthy subjects. Steady state was achieved rapidly, and after repeated dosing for 3 days, Methylnaltrexone decreased oral-cecal transit time from a pretreatment baseline value of 101.3 +/- 29.4 min (mean +/- SD) to 82.5 +/- 20.7 min. Maximum observed plasma concentrations, measured 5 minutes postdose, were 538 +/- 237 and 675 +/- 180 ng/mL after doses 1 and 2, respectively. Based on 6-hour sampling periods, the plasma half-life, 2.5 +/- 0.5 and 2.9 +/- 0.9 hours following the 1st and 12th doses, respectively, was unchanged at steady state. There was essentially no accumulation of Methylnaltrexone, based on the ratio of AUC values after doses 12 and 1. This study showed that repeated administration of intravenous Methylnaltrexone is well tolerated in humans, with no significant adverse events or changes in opioid subjective ratings and no clinically noteworthy alterations in pharmacokinetics. The observation of a significant reduction in the gut transit time after repeated administration of Methylnaltrexone to these opioid-naive volunteers suggests that endogenous opioids modulate human gut motility.

  • Methylnaltrexone prevents morphine-induced kaolin intake in the rat
    Life sciences, 2004
    Co-Authors: Han H. Aung, Jonathan Moss, Sangeeta R. Mehendale, Jing-tian Xie, Chun-su Yuan
    Abstract:

    Opioids are frequently used analgesics, and emesis is a common opioid-induced adverse effect. Methylnaltrexone, a peripheral opioid antagonist, has the potential to block the undesired effects of opioids that are mediated by peripheral receptors while sparing the analgesic effect. We used a rat model of simulated emesis or pica to study if Methylnaltrexone decreases morphine induced-kaolin consumption. We observed that after morphine administration, kaolin intake increased significantly compared to intake in the vehicle group, and the increase could be attenuated by ondansetron administration. Methylnaltrexone dose-dependently reduced kaolin ingestion induced by morphine. Morphine and Methylnaltrexone did not significantly affect food intake and body weight in the experimental animals. Our data suggest that Methylnaltrexone has therapeutic value in treating opioid-induced nausea and vomiting.

  • Methylnaltrexone for reversal of constipation due to chronic methadone use a randomized controlled trial
    JAMA, 2000
    Co-Authors: Chun-su Yuan, Joseph F. Foss, Jonathan Moss, Joachim Osinski, Michael Oconnor, Theodore Karrison, Michael F. Roizen
    Abstract:

    ContextConstipation is the most common chronic adverse effect of opioid pain medications in patients who require long-term opioid administration, such as patients with advanced cancer, but conventional measures for ameliorating constipation often are insufficient.ObjectiveTo evaluate the efficacy of Methylnaltrexone, the first peripheral opioid receptor antagonist, in treating chronic methadone-induced constipation.DesignDouble-blind, randomized, placebo-controlled trial conducted between May 1997 and December 1998.SettingClinical research center of a university hospital.ParticipantsTwenty-two subjects (9 men and 13 women; mean [SD] age, 43.2 [5.5] years) enrolled in a methadone maintenance program and having methadone-induced constipation.Main Outcome MeasuresLaxation response, oral-cecal transit time, and central opioid withdrawal symptoms were compared between the 2 groups.ResultsThe 11 subjects in the placebo group showed no laxation response, and all 11 subjects in the intervention group had laxation response after intravenous Methylnaltrexone administration (P<.001). The oral-cecal transit times at baseline for subjects in the Methylnaltrexone and placebo groups averaged 132.3 and 126.8 minutes, respectively. The average (SD) change in the Methylnaltrexone-treated group was −77.7 (37.2) minutes, significantly greater than the average change in the placebo group (−1.4 [12.0] minutes; P<.001). No opioid withdrawal was observed in any subject, and no significant adverse effects were reported by the subjects during the study.ConclusionsOur data demonstrate that intravenous Methylnaltrexone can induce laxation and reverse slowing of oral cecal-transit time in subjects taking high opioid dosages. Low-dosage Methylnaltrexone may have clinical utility in managing opioid-induced constipation.

  • Effects of enteric-coated Methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time.
    Clinical pharmacology and therapeutics, 2000
    Co-Authors: Chun-su Yuan, Joseph F. Foss, Michael O'connor, Michael F. Roizen, Joachim Osinski, Theodore Karrison, Jonathan Moss
    Abstract:

    BACKGROUND Methylnaltrexone is the first peripheral opioid receptor antagonist. It has the potential to prevent or reverse the peripherally mediated gastrointestinal effects of opioids. In previous human volunteer trials, we demonstrated that oral uncoated Methylnaltrexone prevented morphine-induced delay in gastrointestinal transit time. METHODS This trial consisted of two studies: a pilot study and a controlled study. The lactulose hydrogen breath test was used to measure the oral-cecal transit time. RESULTS In the pilot study with three subjects, an oral dose of 6.4 mg/kg enteric-coated Methylnaltrexone effectively reversed the effects of morphine, producing transit times shorter than baseline levels. Subsequently, in the controlled study with another nine subjects, the transit time increased after intravenous morphine administration in all nine subjects, and the lower dose (3.2 mg/kg) of enteric-coated Methylnaltrexone completely prevented the morphine-induced change in oral-cecal transit time in all nine subjects. Morphine significantly increased oral-cecal transit time from baseline level of 96.7 +/- 54.1 minutes (mean +/- SD) to 155.0 +/- 53.6 minutes (P = .014). After enteric-coated Methylnaltrexone and morphine, the transit time returned to the baseline level (93.3 +/- 56.0 minutes; P = .55 compared with placebo). Plasma concentrations after 6.4 mg/kg and 3.2 mg/kg enteric-coated Methylnaltrexone were substantially lower compared with those after 6.4 mg/kg of the uncoated formulation. CONCLUSION Our results suggest that there is a prevailing direct and local luminal effect of enteric-coated Methylnaltrexone and that the enteric-coated formulation exerts its gut pharmacologic actions more efficiently than the uncoated formulation.

Andrew T. Lenis - One of the best experts on this subject based on the ideXlab platform.

  • The association between N-Methylnaltrexone, a peripherally acting mu-opioid receptor antagonist, and clinical outcomes in patients undergoing robotic-assisted radical cystectomy
    World Journal of Urology, 2020
    Co-Authors: Andrew T. Lenis, Vishnukamal Golla, David C. Johnson, Izak Faiena, Siamak Rahman, Karim Chamie
    Abstract:

    Purpose To assess the impact of N -Methylnaltrexone, a peripherally acting mu-opioid receptor antagonist, on the post-operative recovery of patients undergoing robotic-assisted radical cystectomy for bladder cancer. Methods We retrospectively reviewed patients undergoing robotic-assisted radical cystectomy by a single surgeon (KC) prior to (control group) and after (treatment group) the routine use of N -Methylnaltrexone. Kaplan–Meier curves and the log-rank test were used to quantify time to flatus, bowel movement, and discharge. Daily mean opioid use, daily pain assessment rating, and episodes of severe pain (7–10/10) were compared. Gastrointestinal-related complications, including ileus, emesis, and/or need for post-op nasogastric tube placement, and 30-day readmissions were also compared between groups. Charge capture data were compared between groups to analyze cost impact. Results 29 patients each in the control and treatment group met inclusion criteria. Patients receiving N -Methylnaltrexone had reduced length of stay compared with no N -Methylnaltrexone (median 4 vs. 7 days, p  

  • the association between n Methylnaltrexone a peripherally acting mu opioid receptor antagonist and clinical outcomes in patients undergoing robotic assisted radical cystectomy
    World Journal of Urology, 2020
    Co-Authors: Andrew T. Lenis, Vishnukamal Golla, Izak Faiena, Siamak Rahman, Patrick M Lec, David W Johnson, Carol Lee, Karim Chamie
    Abstract:

    PURPOSE To assess the impact of N-Methylnaltrexone, a peripherally acting mu-opioid receptor antagonist, on the post-operative recovery of patients undergoing robotic-assisted radical cystectomy for bladder cancer. METHODS We retrospectively reviewed patients undergoing robotic-assisted radical cystectomy by a single surgeon (KC) prior to (control group) and after (treatment group) the routine use of N-Methylnaltrexone. Kaplan-Meier curves and the log-rank test were used to quantify time to flatus, bowel movement, and discharge. Daily mean opioid use, daily pain assessment rating, and episodes of severe pain (7-10/10) were compared. Gastrointestinal-related complications, including ileus, emesis, and/or need for post-op nasogastric tube placement, and 30-day readmissions were also compared between groups. Charge capture data were compared between groups to analyze cost impact. RESULTS 29 patients each in the control and treatment group met inclusion criteria. Patients receiving N-Methylnaltrexone had reduced length of stay compared with no N-Methylnaltrexone (median 4 vs. 7 days, p < 0.01). Time to flatus and bowel movement, however, were similar. In a multivariable analysis controlling for possible confounders, however, the improvement in length of stay associated with N-Methylnaltrexone use did not reach statistical significance (p = 0.11). Episodes of severe pain and composite gastrointestinal-related complications were reduced in the N-Methylnaltrexone group (44.8% vs. 10.3%, p < 0.01). The reduction in length of stay was associated with approximately $10,500 in cost savings per patient. CONCLUSIONS In this study, N-Methylnaltrexone was associated with reduced length of stay, fewer episodes of severe pain, and reduced costs. These results provide the impetus for further study.