methylnaltrexone and Ileus

Peripherally acting mu-opioid receptor antagonists methylnaltrexone and alvimopan are a new class of drugs designed to reverse opioid-induced side-effects on the gastrointestinal system without compromising pain relief. This article gives an overview of the pharmacology, the efficacy, and adverse effects of these drugs. Both compounds seem to be generally well tolerated and effective for the treatment of opioid-related bowel dysfunction and postoperative ileus. Methylnaltrexone recently received approval by the US Food and Drug Administration (FDA) and the European Medicines Agency for treatment of opioid-related bowel dysfunction in patients with advanced illness. Alvimopan was recently approved by the FDA for treatment of postoperative ileus, but the use of the drug is restricted to inpatients because it has been associated with an increased rate of myocardial infarction. Further research should assess the effectiveness and safety of these drugs in clinical practice.

Topics: Analgesics, Opioid; Blood-Brain Barrier; Drug Approval; Europe; Humans; Ileus; Myocardial Infarction; Naltrexone; Narcotic Antagonists; Patient Selection; Piperidines; Postoperative Complications; Quaternary Ammonium Compounds; Research Design; Safety; United States; United States Food and Drug Administration

The duration of postoperative ileus following abdominal surgery is quite variable, and prolonged postoperative ileus is an iatrogenic phenomenon with important influence on patient morbidity, hospital costs and length of stay in hospital. Adequate treatment for prolonged postoperative ileus is important to improve patient morbidity and clinical efficiency. Both clinical and pharmacological management strategies have improved rapidly over the last decade, and appropriate and timely management using multimodal techniques should be used for optimal care. In this review, we define postoperative ileus, describe the pathogenesis and briefly discuss clinical management before detailing potential pharmacologic management options.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Anti-Inflammatory Agents, Non-Steroidal; Bisacodyl; Cathartics; Cisapride; Dihydroergotamine; Humans; Ileus; Inflammation; Naltrexone; Neostigmine; Parasympathomimetics; Piperidines; Postoperative Complications; Propranolol; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Serotonin Receptor Agonists

Progenics Pharmaceuticals Inc and Wyeth Pharmaceuticals are developing methylnaltrexone, a micro-receptor opioid antagonist derived from naltrexone by the addition of a methyl group. The intravenous formulation of methylnaltrexone is currently in phase III clinical trials for the potential treatment of postoperative ileus.

Topics: Analgesics, Opioid; Gastrointestinal Motility; Humans; Ileus; Naltrexone; Postoperative Complications; Postoperative Nausea and Vomiting; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Urinary Retention

Methylnaltrexone and alvimopan are two new and potentially useful agents in the management of opioid-induced bowel dysfunction and prevention of postoperative ileus. Both agents have promising prokinetic properties and appear to be capable of reversing the effects of opioids on delayed gastrointestinal transit. This article reviews currently available published literature to provide an overview of the clinical trials and to provide insight for the potential use of these agents for patients requiring opioid based analgesia. These compounds represent a new class of compounds that may impact the therapeutics for opioid induced bowel dysfunction as well as postoperative ileus.

Topics: Analgesics, Opioid; Gastrointestinal Transit; Humans; Ileus; Intestinal Diseases; Naltrexone; Narcotic Antagonists; Piperidines; Postoperative Complications; Quaternary Ammonium Compounds

The adverse effects of opioids are well documented. Because opioid receptors have a wide-ranging anatomic distribution, the effects subsequent to opioid binding, both good and bad, occur centrally and in the periphery. Postoperative strategies to reduce opioid burden, therefore, are in the patient's best interest. Multimodal analgesia is the key towards balancing the need for opioids while simultaneously reducing their burden. Alternative anesthesia and analgesia options such as regional anesthesia, nonsteroidal anti-inflammatory drugs, or cyclooxygenase-2 enzyme inhibitors should be considered part of multimodal protocols. Familiarity of where these drugs are active in the body and how they can be employed is imperative for all surgical team members. Optimal implementation of multimodal approaches can reduce hospital stay and improve clinical outcomes, including patient satisfaction. Finally, strategies that may help reduce rates of hospital readmission also contribute to overall improved outcome. New peripherally acting mu-opioid-receptor antagonists represent significant progress in the ability of perianesthesia nurses to play an even greater role in achieving these goals. In contrast to older opioid-receptor antagonists, these agents specifically target an important aspect of the multifactorial etiology of postoperative ileus (POI), mu-opioid-receptor-mediated activity in the GI tract. In addition, they do not pass the blood-brain barrier or diminish opioid-mediated analgesia. Advanced clinical trials have already demonstrated the ability of one of these agents, alvimopan, to reduce POI and improve other postoperative outcomes while maintaining adequate analgesia. Combined with other options aimed at reducing opioid burden, alvimopan and similar drugs in development hold promise as part of multimodal protocols to optimize pain management while minimizing postoperative morbidities.

Topics: Analgesia; Analgesics, Opioid; Anesthesia; Anesthesiology; Anti-Inflammatory Agents, Non-Steroidal; Attitude of Health Personnel; Blood-Brain Barrier; Clinical Trials, Phase III as Topic; Humans; Ileus; Length of Stay; Naltrexone; Narcotic Antagonists; Nurse's Role; Outcome Assessment, Health Care; Pain, Postoperative; Patient Satisfaction; Piperidines; Postanesthesia Nursing; Postoperative Care; Postoperative Complications; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Risk Factors

Postoperative ileus (POI) is defined as the impairment of bowel motility that occurs almost universally after major open abdominal procedures, as well as other abdominal and nonabdominal procedures. For the majority of affected patients, POI generally lasts approximately three to five days, but longer duration is not uncommon. The causes of POI are multifactorial, but can be broadly categorized into two groups: those related to the surgical procedure and those related to pharmacologic interventions (opioids). The fact that POI is generally transient and therefore self-limited should not deter the surgical team from seeking improved ways to mitigate its associated adverse effects, which can be substantial and immensely uncomfortable for the patient, and can have far-reaching implications regarding overall hospitalization costs for many types of surgeries. Optimization of POI management and prevention efforts is a responsibility of all members of the surgical team and can drastically affect the overall clinical outcome of major abdominal surgery. Depending on the individual team member's role, different perspectives and strategies may be used to achieve improved outcomes, including but not limited to hospitalization costs related to care and length of stay, resource utilization, and, perhaps most critically, patient quality of life not only immediately after surgery but also after discharge. The ability to reliably and significantly decrease the duration of POI should be readily recognized as an important objective in the management of this condition. Opioids will continue to be a mainstay of postoperative care regimens, but new agents such as peripherally acting mu-opioid-receptor antagonists may offer a unique clinical advantage by helping to reduce the adverse gastrointestinal effects of opioids while preserving their desired benefits for postoperative analgesia.

Topics: Analgesics, Opioid; Causality; Cost of Illness; Hospital Costs; Humans; Ileus; Incidence; Laparotomy; Length of Stay; Naltrexone; Narcotic Antagonists; Nurse's Role; Outcome Assessment, Health Care; Pain, Postoperative; Patient Care Team; Patient Satisfaction; Piperidines; Postanesthesia Nursing; Postoperative Care; Postoperative Complications; Professional Role; Quaternary Ammonium Compounds; Time Factors; Total Quality Management

Postoperative ileus (POI) is frequently experienced by many patients undergoing abdominal operations and other surgical procedures. Postoperative ileus causes physical discomfort and may increase risk for prolonged hospital length of stay. Despite its prevalence, there is currently no accepted standard definition of POI and, consequently, no standardized mode of prevention or treatment; it is no wonder that a variety of management approaches for POI have been developed. Some of these include alternative surgical techniques such as laparoscopic or endoscopic procedures to minimize trauma and help lessen the release of endogenous mediators of POI. Others have evaluated alternate analgesic regimens such as thoracic epidural anesthetics to avoid stimulating opioid receptors in the gut. These approaches have had varying results. Other pharmacologic attempts to reduce POI have focused on the blockade of opioid receptors to prevent opioid-induced GI-related adverse effects. A new class of agents, peripherally acting mu-opioid-receptor antagonists such as methylnaltrexone and alvimopan, may improve the pharmacologic management of POI and reshape the current paradigm of multimodal management of POI. Protocols that incorporate these agents may offer yet another avenue to mitigate the adverse effects of POI, and thus help improve surgical outcomes. To date, alvimopan has been shown in phase 3 clinical trials to significantly reduce the duration of POI while maintaining satisfactory analgesia and reducing length of hospital stay. Combinations of strategies with demonstrated effectiveness such as early feeding, epidural analgesia, laparoscopic surgery, and peripherally acting mu-opioid-receptor antagonists may help transform the management of POI into an effective multimodal paradigm that targets the diverse etiologic factors leading to this common clinical problem. Clearly, all surgical team members are crucial in the optimal implementation of such multimodal approaches.

Topics: Analgesia, Epidural; Analgesics, Opioid; Attitude of Health Personnel; Choice Behavior; Enteral Nutrition; Evidence-Based Medicine; General Surgery; Humans; Ileus; Intubation, Gastrointestinal; Laparoscopy; Laparotomy; Length of Stay; Naltrexone; Narcotic Antagonists; Outcome Assessment, Health Care; Patient Care Team; Patient Selection; Piperidines; Postoperative Care; Postoperative Complications; Practice Guidelines as Topic; Quaternary Ammonium Compounds; Risk Factors

Postoperative ileus (POI) is a common complication with no proven prophylactic measures in place. While perioperative opioid use has been implicated in POI development, current treatments fail to target this disease mechanism. Methylnaltrexone (MNTX) has been used to prevent the effects of opioids on the bowel and could reduce the incidence of POI when administered preoperatively.. In this phase IIb randomized controlled trial, we assessed the effect of perioperative MNTX on time-to-first-bowel movement following spinal arthrodesis surgeries.. 82 patients were randomly selected in a 1:1 ratio to be included in either the treatment or placebo groups. Comparison of relevant factors of included patients to patients who refused to participate (n = 21) and to a prior retrospective series (n = 241) revealed no differences in age, male sex, liver disease, and number of surgical levels. Overall treatment fidelity (98% adherence) and retention (100% at one-month follow-up) were high. The predicted POI incidence (9.3-11.1%) was also equivalent to a prior retrospective series. However, the overall observed POI incidence (3.7%) was lower than expected, which could reflect a superimposed 'trial effect' related to standardized care in a research setting.. Since exposure to significant opioid doses represents a barrier to enhanced recovery after surgery, the results of this innovative trial may provide further guidance for the peri-operative use of opioid-receptor blockers. Here, we show that MNTX can be effectively administered in the peri-operative period with appropriate follow-up achieved in a representative population of patients undergoing spinal surgery.. Clinicaltrials.gov - NCT03852524 and Institutional Review Board - 2018H0260.

Topics: Adult; Arthrodesis; Feasibility Studies; Humans; Ileus; Male; Naltrexone; Postoperative Complications; Quaternary Ammonium Compounds; Retrospective Studies

Postoperative ileus contributes to surgical morbidity and is associated with prolonged hospitalization and increased health care costs. The efficacy and safety of the peripherally acting μ-opioid receptor antagonist methylnaltrexone in shortening the duration of postoperative ileus following segmental colectomy was evaluated.. Two identically designed, multicenter, double-blind, parallel-group, placebo-controlled studies randomly assigned patients undergoing segmental colectomy (study 1, N = 515; study 2, N = 533) to receive 12 or 24 mg of methylnaltrexone intravenously or placebo every 6 hours starting within 90 minutes of surgery completion, continuing for up to 10 days or up to 24 hours after gastrointestinal recovery. The primary efficacy end point was the time from the end of surgery to the first bowel movement. Safety was evaluated via standard assessments (ie, adverse events and related withdrawals, physical examinations, laboratory tests, vital signs, electrocardiograms) and assessment of surgical complications.. The primary and secondary efficacy outcomes (time to discharge eligibility, time to hospital discharge, and clinically meaningful events of nausea and vomiting following segmental colectomy) did not differ significantly between patients treated with either a dose of methylnaltrexone or with placebo. Rates of adverse events and serious adverse events were comparable across all treatment groups in both studies. The most commonly observed adverse events were nausea, pyrexia, and vomiting.. Although the efficacy of methylnaltrexone in reducing the duration of postoperative ileus was not demonstrated in these studies, intravenous methylnaltrexone at doses of 12 mg and 24 mg was safe, in general, and well tolerated in postcolectomy patients. The utility of intravenous methylnaltrexone in treating postoperative ileus remains unproven.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Colectomy; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Ileus; Injections, Intravenous; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Postoperative Complications; Quaternary Ammonium Compounds; Retrospective Studies; Treatment Outcome; Young Adult

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 ⩾ 18 years 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 9.9 days for the MNTX group and 11.4 days for the control 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.

Topics: Female; Humans; Ileus; Intestinal Perforation; Intubation, Gastrointestinal; Length of Stay; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Parenteral Nutrition; Postoperative Complications; Quaternary Ammonium Compounds; Retrospective Studies; Time Factors; Treatment Outcome

Off-label uses of the peripheral μ-opioid receptor antagonists alvimopan and methylnaltrexone are reviewed.. Alvimopan is approved by the Food and Drug Administration (FDA) for postoperative ileus after surgeries that include partial bowel resection with primary anastomosis, while methylnaltrexone is approved for the treatment of opioid-induced constipation (OIC) in patients with advanced illness who are receiving palliative care. Literature describing the off-label use of alvimopan in the treatment of OIC and of methylnaltrexone in postoperative ileus was reviewed and included retrospective studies and prospective Phase II-IV trials. Randomized controlled trials did not demonstrate consistent benefit of alvimopan in OIC nor of methylnaltrexone in postoperative ileus. A greater proportion of patients receiving alvimopan for OIC experienced severe adverse cardiovascular events, leading to a risk evaluation and mitigation strategy and discontinuation of its study in this condition. Data are limited and unreplicated for the off-label use of alvimopan for postoperative ileus in patients undergoing abdominal hysterectomy. Individual studies suggest benefit with methylnaltrexone for OIC in unlabeled populations, including patients with non-cancer-related pain, opioid dependence, opioid sedation, and opioid use after orthopedic surgery; however, confirmatory evaluations have not been performed.. Trials of alvimopan in the FDA-approved use of methylnaltrexone (OIC) indicate potentially serious cardiovascular safety concerns and conflicting findings of efficacy. Similarly, trials of methylnaltrexone in the FDA-approved use of alvimopan (postoperative ileus) consistently showed no benefit. Evaluations of both drugs in their labeled conditions in populations not endorsed in their product labeling have been limited and largely unreplicated.

Topics: Analgesics, Opioid; Constipation; Gastrointestinal Agents; Humans; Ileus; Naltrexone; Narcotic Antagonists; Off-Label Use; Piperidines; Postoperative Complications; Quaternary Ammonium Compounds

Postoperative ileus, a temporary cessation in bowel motility, is a common and significant complication of major surgery. Consequences of postoperative ileus include increased patient discomfort, delayed time to adequate nutrition, prolonged length of stay, and increased cost to the patient and healthcare system. The traditional, multi-modal approach to the resolution of postoperative ileus includes opioid minimization, early ambulation, and early feeding. Newer medications, such as methlynaltrexone and alvimopan (which are peripherally acting mu opioid receptor antagonists), have become available and have proven beneficial for use with postoperative ileus.

Topics: Combined Modality Therapy; Exercise Therapy; Gastrointestinal Agents; Humans; Ileus; Naltrexone; Narcotic Antagonists; Piperidines; Postoperative Complications; Quaternary Ammonium Compounds

One of the most common undesired effects of analgesic opioid use and addiction is constipation. Numerous pharmacologic agents have been used to treat opioid-induced bowel hypomotility with limited success. Methylnaltrexone bromide (MNTX) selectively targets the peripheral adverse effects of opioids while preserving the central analgesic effects of opioid agonist treatment.. While it is indicated for use in nonsurgical patients in the palliative care setting, here we report the use of MNTX for the alleviation of postoperative ileus in a heroin user with recurrent cervical cancer undergoing diverting colostomy and urinary conduit placement.. Results suggest that MNTX may accelerate postoperative gastrointestinal recovery in opioid-dependent patients. Further studies are warranted to evaluate its role in the pharmacologic management of postoperative ileus.

Topics: Analgesics, Opioid; Female; Heroin Dependence; Humans; Ileus; Injections, Subcutaneous; Middle Aged; Naltrexone; Narcotic Antagonists; Postoperative Complications; Quaternary Ammonium Compounds

Postoperative ileus (POI), a transient impairment of bowel function, is considered an inevitable response after open abdominal surgery. It leads to significant patient morbidity and increased hospital costs and length of stay. The pathophysiology is multifactorial, involving neurogenic, hormonal, inflammatory and pharmacologic mediators. Several treatments have been shown to reduce the duration of POI, and a multimodal approach combining several of these interventions seems to be the most effective treatment option. Various drug therapies have been evaluated for the treatment of POI, although most have not shown any benefit. Peripherally active mu-opioid receptor antagonists are a new class of compounds that selectively block the peripheral (i.e., gastrointestinal [GI]) effects of opioids while preserving centrally mediated analgesia. Recently, alvimopan was approved in the US for the treatment of POI after abdominal surgery with bowel resection. Methylnaltrexone is a peripherally active mu-opioid receptor antagonist that has been shown to antagonize the inhibitory effects of opioids on GI transit without impairing analgesia. Phase II data indicated that methylnaltrexone was effective for improving GI recovery, reducing POI and shortening the time to discharge readiness in patients who underwent segmental colectomy. Two Phase III trials have been completed, and one is underway at present. Preliminary results from the two completed trials indicate that methylnaltrexone was not better than placebo for the primary or secondary outcomes. Further analyses of these data, clinical trial designs and the various dosage forms are necessary to determine the potential role of methylnaltrexone in the treatment of POI.

Topics: Animals; Clinical Trials as Topic; Drug Evaluation; Humans; Ileus; Naltrexone; Postoperative Complications; Quaternary Ammonium Compounds; Receptors, Opioid, mu

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

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Gastrointestinal Transit; Ileus; Laparotomy; Male; Naltrexone; Narcotic Antagonists; Piperidines; Postoperative Complications; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley