Administration Of Methylnaltrexone Research Articles

Clinical Outcomes of Intravenous Methylnaltrexone in Children: A Single-Arm Retrospective Cohort Study.

Constipation is a common adverse event of opioid use that is often difficult to treat. Methylnaltrexone is a therapeutic option for opioid-induced constipation (OIC) approved for oral and subcutaneous use in adults. These administration routes are not always feasible in the pediatric population. The primary objective of this research was to quantify the response rate of methylnaltrexone in pediatric patients when it was administered via the intravenous (IV) route. This retrospective study evaluated patients ages <18 years who received IV methylnaltrexone between January 1, 2013, and June 30, 2020, for OIC. Efficacy was evaluated through documentation of bowel evacuation within 4 hours of methylnaltrexone administration. Adverse events observed within 24 hours of administration were attributed to methylnaltrexone. Methylnaltrexone was administered to 134 unique patients during the study period. Of these, 46 met exclusion criteria, resulting in 88 patients being included in the study. Patients with an underlying hematology/oncology diagnosis consisted of 77% of the study population, and 23% of patients had an -underlying medical/surgical diagnosis. The response rate to IV methylnaltrexone was 25% (CI, 16-34). The results of this retrospective chart review demonstrate the potential role of IV methylnaltrexone in the pediatric population. Despite the overall lower response rate relative to that reported in adults, IV methylnaltrexone possesses a unique mechanism of action that may serve as an alternative treatment option for patients unable to use the oral and subcutaneous administration routes. There were no significant adverse events seen in the study.

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

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

Methylnaltrexone for Opioid-Induced Dysmotility in Critically Ill Infants and Children: A Pilot Study.

Critically ill pediatric patients commonly experience opioid-induced dysmotility. Methylnaltrexone, a subcutaneously administered, peripherally acting mu-opioid receptor antagonist, is a compelling adjunct to enteral laxatives in patients with opioid-induced dysmotility. Data for methylnaltrexone use in critically ill pediatric patients are limited. The purpose of this study was to determine the effectiveness and safety of methylnaltrexone for opioid-induced dysmotility in critically ill infants and children. Patients younger than 18 years who received subcutaneous methylnaltrexone from January 1, 2013, through September 15, 2020, in the pediatric intensive care units at an academic institution were included in this retrospective analysis. Outcomes included incidence of bowel movement, enteral nutrition feeding volume, and adverse drug events. Twenty-four patients, median age 3.5 years (IQR, 0.58-11.1), received 72 methylnaltrexone doses. The median dose was 0.15 mg/kg (IQR, 0.15-0.15). Patients were receiving a mean ± SD of 7.5 ± 4.5 mg/kg/day of oral morphine milligram equivalents (MMEs) at methylnaltrexone administration and received opioids for median 13 days (IQR, 8.8-21) prior to methylnaltrexone administration. A bowel movement occurred within 4 hours following 43 (60%) administrations and within 24 hours following 58 (81%) administrations. Enteral nutrition volume increased by 81% (p = 0.002) following administration. Three patients had emesis and 2 received anti-nausea medication. No significant changes in sedation or pain scores were observed. Withdrawal scores and daily oral MMEs decreased following administration (p = 0.008 and p = 0.002, respectively). Methylnaltrexone may be an effective treatment for opioid-induced dysmotility in critically ill pediatric patients with low risk of adverse effects.

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.

Naloxone Versus Methylnaltrexone for Opioid-Induced Constipation in Critically Ill Patients.

Opioid-induced constipation (OIC) may occur in up to 81% of critically ill patients and can lead to many complications. Opioid antagonists are a reasonable approach and may be used for managing OIC. The purpose of this study was to assess the efficacy of enteral naloxone (NLX) versus subcutaneous methylnaltrexone (MNTX) for the management of OIC in critically ill patients. A retrospective analysis was conducted on adult patients who received NLX or MNTX and a continuous opioid infusion for at least 48 hours. The primary end point was time to resolution of constipation, defined as hours to first bowel movement (BM) after the first dose of an opioid antagonist. Reversal of analgesia was assessed by comparing the total number of morphine milligram equivalents (MME) 24 hours preopioid and postopioid antagonist administration. Univariate and multivariate analyses were conducted to assess treatment response within 48 hours. Baseline characteristics were similar between patients receiving NTX (n = 89) and MNTX (n = 71). However, the time to the first BM with NLX was 18 hours compared with 41 hours with MNTX (P = 0.004). There was no difference in MME requirements 24 hours pre/post NLX or MNTX administration. Naloxone administration was identified as a statistically significant predictor of BM within 48 hours (odds ratio [OR] = 2.68 [1.33-5.38]). The time to first BM was shorter with enteral NLX. Both NLX and MNTX appear to be effective for the management of OIC without causing reversal of analgesia. Future controlled, prospective trials comparing these agents are warranted.

Methylnaltrexone in the Management of Opioid-Associated Urinary Retention in Children.

To evaluate the association between methylnaltrexone and urine output (UOP) in critically ill children with opioid-associated urinary retention. This retrospective study included patients admitted to the pediatric intensive care unit between December 1, 2019, and November 30, 2020, who received methylnaltrexone for opioid-associated oliguria (spontaneous UOP below 1 mL/kg/hr and at least 1 dose of an opioid within the preceding 6 hours). Twenty-five patients (median age = 5.5 years, IQR 1.7-16.4; median weight = 19 kg, IQR 9-45) were included. Mean methylnaltrexone dose was 0.15 ± 0.006 mg/kg. A statistically significant increase in UOP from baseline to 6 hours following methylnaltrexone was observed (p = 0.001), but not all patients responded. Fourteen patients (56%) had no UOP following methylnaltrexone administration, while 11 (44%) demonstrated a robust increase (median = 0 mL/kg/hr at baseline [IQR 0-0] to 1.96 mL/kg/hr [IQR 1.08-2.22; p = 0.001]) within 6 hours following methylnaltrexone administration. Younger patients responded better than older patients (responder age = 2.5 years [IQR 0.8-7]) versus 11.4 years [IQR 1.75-17.5] for non-responders) (p = 0.04). Both intravenous (IV) and subcutaneous (SQ) routes were associated with an increase in UOP (IV, p = 0.04; SQ, p = 0.02). The effect persisted for up to 24 hours after administration. Sixty-four percent of patients required urinary catheter placement. Pain scores (averaged 6 hours before and after methylnaltrexone) remained unchanged (p = 0.44). Methylnaltrexone may increase spontaneous UOP in some children with opioid-associated urinary retention, but urinary catheterization rates remain high.

The Efficacy and Safety of Methylnaltrexone for the Treatment of Postoperative Ileus.

Postoperative ileus (POI) is a surgical complication resulting in increased morbidity and length of stay (LOS). Usual care for POI includes bowel rest and gastric decompression. It has been questioned if methylnaltrexone (MNTX), a peripheral opioid antagonist, could be used as treatment for POI. The purpose of this study was to determine if MNTX is effective and safe for POI treatment. This single-center, retrospective cohort study included patients ⩾ 18years with a POI. Patients with acute colonic pseudo-obstruction, small bowel obstruction, and gastrointestinal malignancy were excluded. The intervention was MNTX administration. The primary outcome was time to ileus resolution. Secondary outcomes included LOS, duration of nasogastric tube, total parenteral nutrition requirement, and incidence of gastrointestinal perforations. 110 patients were included in the analysis; 28 received MNTX. Time to ileus resolution was 9.9days for the MNTX group and 11.4days for the control group (P = .38). Duration of gastric decompression was 4.6days for the MNTX group and 4.2days for the control group (P = .71). Length of stay was 19.9days for the MNTX group and 19.7days for the control group (P = .96). The percentage of TPN requirement was 17.9% in the MNTX group and 22.0% in the control group (P = .65). No gastrointestinal perforations were observed in either group. For the treatment of POI, MNTX did not significantly reduce time to resolution of ileus, LOS, duration of gastric decompression, or TPN requirements. However, no gastrointestinal perforations were seen, indicating that MNTX may be safely used in these patients.

Successful Use of Intravenous Methylnaltrexone for Opioid-Induced Constipation in Critically Ill Pediatric Patients

Abstract Objectives Methylnaltrexone is U.S. Food and Drug Administration (FDA) approved as a subcutaneous injection for adults with opioid-induced constipation (OIC). Case series have described the use of methylnaltrexone for OIC in the pediatric oncology population. There are limited data describing its intravenous use in critically ill pediatric patients. Methods We conducted a retrospective observational study at St. Louis Children's Hospital. Patients less than 18 years old who received at least one dose of intravenous methylnaltrexone while admitted to an intensive care unit between January 2016 and August 2019 were included. The primary outcome was documented laxation within 24 hours of methylnaltrexone administration. Results Sixteen patients received a total of 34 doses of intravenous methylnaltrexone. Patients received a median of 1.69 (interquartile range [IQR], 0.9–4.86) morphine milligram equivalents per kilogram per 24 hours, over a median of 14 days (IQR, 11–30), before methylnaltrexone administration. The median dose of methylnaltrexone was 0.15 mg/kg (IQR, 0.15–0.16). Ten patients (63%) responded to the first dose of methylnaltrexone, and 14 patients (88%) responded to at least one dose. Overall, 26 doses (76%) led to patient response. Four patients (25%) experienced adverse events (emesis, abdominal pain) after methylnaltrexone administration. No signs or symptoms of opioid withdrawal were documented. Conclusions Intravenous methylnaltrexone appears to be safe and effective in treating OIC in critically ill pediatric patients. No serious adverse events or signs of opioid withdrawal were observed after single and repeat dosing. Patients responded to methylnaltrexone with varying opioid dosing and durations prior to administration.

Perioperative subcutaneous methylnaltrexone does not enhance gastrointestinal recovery after posterior short-segment spinal arthrodesis surgery: a randomized controlled trial

BACKGROUND CONTEXTPostoperative ileus is a major barrier to gastrointestinal recovery following surgery. Opioid analgesics likely play an important causative role, particularly in spinal or orthopedic surgeries not involving bowel manipulation. Methylnaltrexone, a peripherally-acting µ-opioid receptor antagonist, is a potential prophylactic treatment. PURPOSETo assess the influence of perioperative subcutaneous methylnaltrexone administration on gastrointestinal recovery following short-segment lumbar arthrodesis surgeries. DESIGNThis is a randomized, double-blind, controlled trial. PATIENT SAMPLEEligible patients undergoing posterior short-segment lumbar arthrodesis surgeries at a single institution between February 2019 and April 2021 were enrolled in this study. OUTCOME MEASURESThe primary outcome measure was time-to-first bowel movement. Secondary outcome measures included time-to-discharge/discharge eligibility. Exploratory outcome measures included daily postoperative opioid consumption and pain scores. METHODSIn this study, eligible patients were enrolled to receive either methylnaltrexone or placebo perioperatively. Time-to-bowel movement, time-to-discharge/discharge eligibility, intra and postoperative analgesic administration, and pain scores were recorded and compared. RESULTSEighty two patients in total were enrolled; 41 to the methylnaltrexone and 41 to the placebo group. Both groups were similar in their baseline characteristics. There was no difference in median (range) time-to-bowel movement between the 2 groups [61.8 hours (35.7–93.6) versus 50.7 hours (17.8–110.8), p = .391]. There was also no difference in time-to-discharge/discharge eligibility [105.0 hours (81.0 – 201.3) versus 90.7 (77.5 – 184.5), p=.784]. Finally, there were no differences in either postoperative opioid consumption or numeric rating scores for back, leg, or abdominal pain on postoperative days 0 to 4 (p>.05). CONCLUSIONSMethylnaltrexone did not accelerate gastrointestinal recovery and did not affect opioid consumption or pain scores following short-segment spinal surgery as compared to placebo. Additional studies will be needed to identify effective opioid receptor antagonist dosing regimens for patients undergoing either short- or long-segment spinal arthrodesis procedures.

Improved Bowel Function With Oral Methylnaltrexone Following Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis.

Methylnaltrexone, a peripheral opioid antagonist, is used to decrease opioid-induced constipation; however, there is limited evidence for its use in children. The primary objective of the study is to assess the efficacy of per os (PO) methylnaltrexone in inducing bowel movements (BMs) in patients with adolescent idiopathic scoliosis who underwent a posterior spinal fusion and instrumentation (PSFI). Secondary outcomes include hospital length of stay, postoperative pain scores, and postoperative opioid usage. Retrospective chart review identified all adolescent idiopathic scoliosis patients above 10 years of age who underwent PSFI with a minimum of 24 hours of postoperative opioid analgesia after the initiation of the new bowel regimen protocol. The bowel regimen included daily administration of PO methylnaltrexone starting on postoperative day 1 until BM is achieved. A case-matched cohort was obtained with patients who did not receive PO methylnaltrexone and otherwise had the same bowel function regimen. Case-matched controls were also matched for age, sex, body mass index, and curve severity. t Tests and Pearson χ2 tests were used for statistical analysis. Fifty-two patients received oral methylnaltrexone (14±2.6 y) and 52 patients were included in the case-matched control group (14±2.1 y). The methylnaltrexone group had a significantly shorter hospital length of stay (3.09±0.66) compared with controls (3.69±0.80) (P<0.01). 59% (31 of 52) of the methylnaltrexone group had a BM by postoperative day postoperative day 2, compared with 30% (16 of 52) of the control group (P<0.01). In the methylnaltrexone group, 44% (23 of 52) of the patients required a Dulcolax (bisacodyl) suppository and 11% (6 of 52) required an enema, compared with 50% (26 of 52) and 33% (12 of 52) of the control group respectively (P=0.43 and 0.12). In addition, significantly less patients had abdominal distension during their postoperative stay in the methylnaltrexone group (17%, 9 of 52) compared with the control group (40%, 21 of 52) (P<0.01). There was no significant difference in self-reported average FACES pain score (P=0.39) or in opioid morphine equivalents required per hour (P=0.18). Patients who received PO methylnaltrexone after PSFI had decreased length of stay and improved bowel function. Administration of methylnaltrexone did not increase maximum self-reported FACES pain values or opioid consumption compared with controls. The use of oral methylnaltrexone after PSFI reduces postoperative constipation, which has implications for reducing hospital length of stay and overall morbidity. Level III-retrospective comparative study.

Methylnaltrexone crosses the blood-brain barrier and attenuates centrally-mediated behavioral effects of morphine and oxycodone in mice

BackgroundAntagonism of peripheral opioid receptors by methylnaltrexone (MNTX) was recently proposed as a potential mechanism to attenuate the development of opioid analgesic tolerance based on experiments conducted in mice. However, reports indicate that MNTX is demethylated to naltrexone (NTX) in mice, and NTX may subsequently cross the blood-brain barrier to antagonize centrally-mediated opioid effects. The goal of this study was to determine whether MNTX alters centrally-mediated behaviors elicited by the opioid analgesics, morphine and oxycodone, and to quantify concentrations of MNTX and NTX in blood and brain following their administration in mice. MethodsCombinations of MNTX and morphine were tested under acute and chronic conditions in thermal nociceptive assays. Effects of MNTX and NTX pretreatment were assessed in an oxycodone discrimination operant procedure. Blood and brain concentrations of these antagonists were quantified after their administration using liquid chromatography-mass spectrometry. ResultsMNTX dose-dependently attenuated acute and chronic morphine antinociception. MNTX and NTX dose-dependently antagonized the discriminative stimulus effects of oxycodone. MNTX and NTX were detected in both blood and brain after administration of MNTX, confirming its demethylation and demonstrating that MNTX itself can cross the blood-brain barrier. ConclusionsThese results provide converging behavioral and analytical evidence that MNTX administration in mice attenuates centrally-mediated effects produced by opioid analgesics and results in functional concentrations of MNTX and NTX in blood and brain. Collectively, these findings indicate that MNTX cannot be administered systemically in mice for making inferences that its effects are peripherally restricted.

Abstract 5027: The mu-opioid receptor antagonist methylnaltrexone can decrease tumorigenesis in head and neck squamous cell carcinoma

Abstract Head and neck cancer (HNC) is the sixth leading cause of cancer in the world, and the third most common neoplasia in developing countries [1]. Patients with HNC may suffer significant pain, for which opioids are commonly given. However, recent reports suggest that opioids may promote cancer progression by action on the mu-opioid receptor (MOR) [2, 3]. The goal of this research was to test the hypothesis that the MOR antagonist methylnaltrexone (MTNX) can decrease tumorigenesis in HN squamous cell carcinoma (SCC). First, we confirmed via RNAseq and western blot analyses that FaDu cells (a HNSCC line) express MOR. Then, we performed cyclic adenosine monophosphate (cAMP) activation enzyme-linked immunosorbent assay to evaluate the activity of MOR after activation with [D-Ala2N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO), a selective MOR agonist. Short term (1hr) treatment with DAMGO decreased cAMP levels, suggesting full activity of the receptor. We conducted similar cAMP activity assays using MNTX. Our dose-dependent (10nM-1µM) experiments revealed that 1hr exposure of cells to MTNX inhibited cAMP activity, but not after 48 hrs of treatment, consistent with an inverse or partial agonist effect at low doses. To assess the impact of our findings on FaDu cell behaviors, we conducted in vitro proliferation, colony formation, and migration assays. MTNX at different concentrations (0.1nM, 1nM, 10nM, 100nM and 1µM) inhibited FaDu cell proliferative and metastatic cell behaviors (p&amp;lt;0.05). To translate our results to in vivo, we inoculated the tongue of athymic nude mice with FaDu cells (200,000 cells/30 mL). Starting the day of cell inoculation, we randomly treated the animals with MNTX (subcutaneously, 1µg/kg, 10 µg/kg, and 100µg/kg) versus placebo (saline only) for 17 consecutive days. In vivo experiments demonstrated that administration of MTNX at three different concentrations delayed tumor progression and reduced tumor growth and formation compared to placebo (p&amp;lt;0.0001). Overall, our results suggest that MTNX inhibits tumorigenesis of HNSCC, possibly by acting on MOR. 1. Siegel, R.L. et al, Cancer statistics, 2018. CA Cancer J Clin, 2018. 68(1): p. 7-30. 2. Lennon, F.E., et al, The mu-opioid receptor in cancer progression: is there a direct effect? Anesthesiology, 2012. 116(4): p. 940-5. 3. Patino, M.A., et al., The impact of intraoperative opioid use on survival after oral cancer surgery. Oral Oncol, 2017. 74: p. 1-7. Citation Format: Aysegul Gorur, Miguel Patino, Ted Shi, Hideaki Takahashi, Jeffrey N. Myers, Juan P. Cata. The mu-opioid receptor antagonist methylnaltrexone can decrease tumorigenesis in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5027.

The MOVEMENT Trial

BackgroundMorphine administration is a strong predictor of delayed onset of action of orally administered ticagrelor in patients with ST‐segment–elevation myocardial infarction, likely because of impaired gastrointestinal motility. The aim of this study was to evaluate whether the peripheral opioid antagonist methylnaltrexone could improve pharmacodynamics and pharmacokinetics of orally administered ticagrelor in patients with ST‐segment–elevation myocardial infarction receiving morphine.Methods and ResultsThe MOVEMENT (Methylnaltrexone to Improve Platelet Inhibition of Ticagrelor in Morphine‐Treated Patients With ST‐Segment Elevation Myocardial Infarction) trial was a multicenter, prospective, randomized, controlled trial in patients with ST‐segment–elevation myocardial infarction treated with morphine and ticagrelor. Upon arrival to the catheterization laboratory, patients were randomized to a blinded intravenous injection of either methylnaltrexone (8 or 12 mg according to weight) or 0.9% sodium chloride. The proportion of patients with high on‐treatment platelet reactivity and plasma concentrations of ticagrelor and AR‐C124910XX were assessed at baseline (arrival in the catheterization laboratory) and 1 and 2 hours later. A total of 82 patients received either methylnaltrexone (n=43) or placebo (n=39). Median (interquartile range) time from ticagrelor administration to randomization was 41 (31–50) versus 45.5 (37–60) minutes (P=0.16). Intravenous methylnaltrexone administration did not significantly affect prevalence of high on‐treatment platelet reactivity at 2 hours after inclusion, the primary end point, when compared with placebo (54% versus 51%, P=0.84). Plasma concentrations of ticagrelor and its active metabolite, the prespecified secondary end points, did not differ significantly between the groups over time. There was no significant difference in patient self‐estimated pain between the groups.ConclusionsMethylnaltrexone did not significantly improve platelet reactivity or plasma concentrations of orally administered ticagrelor in patients with ST‐segment–elevation myocardial infarction receiving morphine.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02942550.

Identifying and Treating Opioid Side Effects: The Development of Methylnaltrexone.

Constipation 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. To evaluate the efficacy of methylnaltrexone, the first peripheral opioid receptor antagonist, in treating chronic methadone-induced constipation. Double-blind, randomized, placebo-controlled trial conducted between May 1997 and December 1998. Clinical research center of a university hospital. Twenty-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. Laxation response, oral-cecal transit time, and central opioid withdrawal symptoms were compared between the 2 groups. The 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. Our 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.

391 First Reported Use of Methylnaltrexone to Treat Opioid-Induced Constipation in a Pediatric Burn Patient

Pain in critically ill pediatric burn patients is a complex and challenging issue whose adequate control is further complicated by anticipative fear and anxiety. Undertreated pain increases risk for post-burn PTSD and other psychosocial impairments, so it is aggressively managed with regimens often including high-dose opiates. This often results in Opioid-Induced Constipation (OIC) and first line laxative treatments have high recurrence rates due to the continuous, direct gastrointestinal effects of μ-opioid antagonism. Methylnaltrexone (MLTX), an FDA-approved injectable µ-opioid receptor antagonist, selectively acts on the myenteric plexus to reverse OIC without crossing the blood-brain-barrier to impair systemic analgesia. MLTX is safe and highly efficacious at treating OIC in adult and pediatric oncologic patients with recent data showing great effect in adult burn patients. Here we report the first case of the safe and efficacious reversal of OIC in a critically ill pediatric burn patient who failed standard laxative therapies. A retrospective case review was performed on a pediatric burn patient who was treated with MLTX for OIC in the setting of high-dose intravenous opiates. In our unit, MLTX is reserved for patients who remain without a bowel movement for 3 or more consecutive days on escalating regimens of traditional laxatives, particularly if they have worsening abdominal pain, distension, bladder pressures, or intolerance to enteral feeding. Following approval by a pediatric gastroenterologist and pharmacist, subcutaneous MLTX was administered at a dose of 0.15 mg/kg. Any complications related to drug administration (e.g. new abdominal pain, nausea, or bowel perforation) were tracked for risk analysis. Patient was an 11-year-old female with 18% TBSA partial and full thickness burns to face, trunk, and all four extremities with inhalation injury from a house fire. She was intubated prior to arrival, averaged 114 mg morphine equivalents per day, and stopped responding to first line laxation therapy after 12 days, subsequently going 4 days without laxation. She was given 8 mg MLTX with laxation 19 hours after administration. There were no adverse events associated with MLTX administration. MLTX administered as a single dose of 0.15 mg/kg subcutaneously was safely used to induce laxation in a critically ill pediatric burn patient with no observed adverse effects. To our knowledge, this is the first reported case of treating OIC with MLTX in a pediatric burn patient. Larger studies are indicated to further elucidate the safety and efficacy profile of MLTX in pediatric burn patients. MLTX may be a safe and efficacious treatment for OIC in pediatric burn patients requiring high-dose opiates.

Methylnaltrexone reduced body weight gain in ob/ob mice

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. 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. Our results suggest that the peripheral opioid mechanism contributes to modulating food ingestion and methylnaltrexone may have clinical importance in obesity management.

Fixed-Dose Subcutaneous Methylnaltrexone in Patients with Advanced Illness and Opioid-Induced Constipation: Results of a Randomized, Placebo-Controlled Study and Open-Label Extension.

Background: Subcutaneous methylnaltrexone (MNTX), dosed based on body weight, is efficacious and well tolerated in inducing bowel movements in patients with advanced illness and opioid-induced constipation (OIC); however, fixed-dose administration of MNTX may improve ease of administration.Objective: The study objective was to assess safety and efficacy of fixed-dose MNTX in two phase 4 trials.Methods: In a double-blind, randomized, placebo-controlled trial (RCT), patients with advanced illness and OIC received MNTX (8 mg or 12 mg by body weight [38 kg to <62 kg or ≥62 kg, respectively]) or placebo every other day (QOD) for two weeks. Patients completing the RCT could enroll in an open-label extension (OLE) study with MNTX administered as needed (PRN). The primary endpoint was percentage of patients with a rescue-free bowel movement (RFBM) within four hours after ≥2 of the first 4 doses in the first week.Results: In the RCT, 116 and 114 patients received MNTX and placebo, respectively, and 149 patients continued to the OLE study. The percentage of patients achieving primary endpoint was 62.9% and 9.6% for MNTX and placebo groups, respectively (p<0.0001). Median time to RFBM after the first dose was 0.8 hour and 23.6 hours in MNTX and placebo groups, respectively (p<0.0001). Efficacy results during the OLE study were consistent with the RCT. MNTX demonstrated a favorable safety profile in the RCT and OLE study.Conclusion: Fixed-dose MNTX administered QOD in the RCT and PRN in the OLE study demonstrated robust efficacy and was well tolerated in treating OIC in patients with advanced illness.

Methylnaltrexone for Opioid-Induced Constipation in Children and Adolescents and Young Adults with Progressive Incurable Cancer at the End of Life.

Opioid-induced constipation (OIC) is common among children and adolescents and young adults (AYA) with progressive incurable cancer. Although methylnaltrexone is a successful treatment for OIC in adult cancer patients, no case series has established its safety and efficacy in pediatric cancer patients. The aim of the study was to describe the safety and efficacy of methylnaltrexone use for OIC in children and AYA with progressive incurable cancer at the end of life in the inpatient and outpatient settings. We conducted a retrospective review of medical records of children and AYA with progressive incurable cancer who received methylnaltrexone at our institution from May 2008 to June 2013. Pharmacy data were reviewed for each patient and a chart review was performed for documentation of laxation and side effects. Of the 9 patients (age range: 17 months to 21 years) with progressive incurable cancer who developed OIC, 7 (78%) had laxation after methylnaltrexone administration (0.15 mg/kg/dose). Of these 7 patients, 5 (71%) had laxation with the first dose, and 5 (71%) who responded had a continued response to repeated doses. The longest a patient regularly received methylnaltrexone was 9 months. Of 5 patients with intraabdominal disease, 4 (80%) had laxation. There were no negative side effects in any of the patients. Also, there was no increase in pain either qualitatively or by pain score. Methylnaltrexone appears to be safe and efficacious in treating OIC in children and AYA with progressive incurable cancer. Methylnaltrexone was tolerated in both the inpatient and outpatient settings and with repeated dosing.

The Effect of Methylnaltrexone on the Side Effects of Intrathecal Morphine after Orthopedic Surgery under Spinal Anesthesia

Methylnaltrexone is a peripheral opioid receptor antagonist that does not cross the blood-brain barrier; so without interference with pain relief, it could reverse the peripheral opioid side effects such as constipation, pruritus, postoperative ileus, and urinary retention. This study has been designed to evaluate the effect of methylnaltrexone on postoperative side effects of intrathecal morphine. In seventy-two 18- to 55-year-old patients scheduled for elective orthopedic operations under spinal anesthesia, neuraxial blockade was achieved using 10mg 0.5% hyperbaric bupivacaine and 0.1mg preservative-free morphine sulfate. The first group (M) received 12mg methylnaltrexone, while the second group (P) received normal saline, subcutaneously, immediately after spinal block in a randomized, double-blind fashion. There was a significant decrease in the rate of nausea and vomiting in group M, but there was no significant difference in the rate of pruritus or urinary retention between the two groups. Pain score was significantly lower in group M. Respiratory depression or decreased level of consciousness was not reported in any patient. Subcutaneous administration of methylnaltrexone was not effective in decreasing postoperative urinary retention and pruritus, but lowered the rate of nausea and vomiting and pain score after intrathecal bupivacaine and morphine.

Use of Methylnaltrexone to Induce Laxation in Acutely Injured Patients With Burns and Necrotizing Soft-Tissue Infections

The routine use of high-dose opioids for analgesia in patients with acute burns and soft-tissue injuries often leads to the development of opioid-induced constipation. The opioid antagonist methylnaltrexone (MLTX) reverses narcotic-related ileus without affecting systemic pain treatment. The authors' burn center developed a bowel protocol that included administration of MLTX for relief of opioid-induced constipation after other methods failed. The authors performed a retrospective review of patients with acute burns or necrotizing soft-tissue infections, who had been given subcutaneous MLTX to induce laxation. All patients who received MLTX were included and all administrations of the drug were included in the analysis. The primary outcome examined was time to laxation from drug administration. Forty-eight patients received MLTX a total of 112 times. Six patients were admitted with soft-tissue injuries and the rest suffered burns with an average TBSA of 17%. The median patient age was 41 years and the majority (75%) were men. Administration of a single dose of MLTX resulted in laxation within 4 hours in 38% of cases, and within 24 hours in 68%. Patients given MLTX received an average of 174 mg morphine equivalents daily for pain control. MLTX was given after an average of 52 hours since the last bowel movement. As this experience has evolved, it has been incorporated into an organized bowel protocol, which includes MLTX administration after other laxatives have failed. MLTX is an effective laxation agent in patients with burn and soft-tissue injuries, who have failed conventional agents.