piperidines and methylnaltrexone

To summarize and evaluate the existing literature regarding medications to treat opioid-induced constipation (OIC) in patients with chronic noncancer pain (CNCP).. PubMed, EMBASE, and Web of Science were searched using the following terms: constipation, opioid, chronic, pain, noncancer, nonmalignant, methylnaltrexone, alvimopan, lubiprostone, naloxegol, and naldemedine.. The search was limited to randomized controlled trials reporting human outcomes. Data extracted included the following: study design, population, intervention, control, outcomes related to OIC and safety, and potential biases assessed using Cochrane Collaboration's Risk of Bias Assessment Tool.. After assessment, 16 of the 190 studies were included: methylnaltrexone (n = 4), naloxegol (n = 3), naldemedine (n = 2), lubiprostone (n = 3), and alvimopan (n = 4). Lubiprostone was the only nonperipherally acting µ-opioid receptor antagonist included. Only 1 study (naloxegol) used "usual care" (nonstudy laxative) rather than placebo as a comparator. Placebo-controlled trials demonstrated benefit for methylnaltrexone, naloxegol, naldemedine, and lubiprostone, with conflicting evidence for alvimopan. No data suggest that one agent is better than another. Overall risk of bias across all studies was low to moderate.. With risk of bias determined to be low to moderate, published data to date suggest that methylnaltrexone, naloxegol, and naldemedine may be appropriate to treat OIC in patients with CNCP.

Topics: Analgesics, Opioid; Chronic Pain; Constipation; Evidence-Based Practice; Humans; Laxatives; Lubiprostone; Morphinans; Naltrexone; Narcotic Antagonists; Piperidines; Polyethylene Glycols; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic

Topics: Analgesics, Opioid; Cancer Pain; Constipation; Enema; Gastrointestinal Agents; Gastrostomy; Humans; Laxatives; Morphinans; Naltrexone; Piperidines; Polyethylene Glycols; Practice Guidelines as Topic; Quaternary Ammonium Compounds

Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events of treatment for pain in cancer and in palliative care, resulting in increased morbidity and reduced quality of life.This is an update of two Cochrane reviews. One was published in 2011, Issue 1 on laxatives and methylnaltrexone for the management of constipation in people receiving palliative care; this was updated in 2015 and excluded methylnaltrexone. The other was published in 2008, Issue 4 on mu-opioid antagonists (MOA) for OIBD. In this updated review, we only included trials on MOA (including methylnaltrexone) for OIBD in people with cancer and people receiving palliative care.. To assess the effectiveness and safety of MOA for OIBD in people with cancer and people receiving palliative care.. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, and Web of Science to August 2017. We also searched clinical trial registries and regulatory websites. We contacted manufacturers of MOA to identify further data.. We included randomised controlled trials (RCTs) that assessed the effectiveness and safety of MOA for OIBD in people with cancer and people at a palliative stage irrespective of the type of terminal disease they experienced.. Two review authors assessed risk of bias and extracted data. The appropriateness of combining data from the trials depended upon sufficient homogeneity across the trials. Our primary outcomes were laxation, impact on pain relief, and adverse events. Impact on pain relief was a primary outcome because a possible adverse effect of MOAs is a reduction in pain relief from opioids. We assessed the evidence on these outcomes using GRADE.. We identified four new trials for this update, bringing the total number included in this review to eight. In total, 1022 men and women with cancer irrespective of stage or at a palliative care stage of any disease were randomised across the trials. The MOAs evaluated were oral naldemedine and naloxone (alone or in combination with oxycodone), and subcutaneous methylnaltrexone. The trials compared with MOA with a placebo or with the active intervention administered at different doses or in combination with other drugs. The trial of naldemedine and the two of naloxone in combination with oxycodone were in people with cancer irrespective of disease stage. The trial on naloxone alone was in people with advanced cancer. The four trials on methylnaltrexone were undertaken in palliative care where most participants had cancer. All trials were vulnerable to biases; four were at a high risk as they involved a sample of fewer than 50 participants per arm.In the trial of naldemedine compared to placebo in 225 participants, there were more spontaneous laxations over the two-week treatment for the intervention group (risk ratio (RR) 1.93, 95% confidence intervals (CI) 1.36 to 2.74; moderate-quality evidence). In comparison with higher doses, lower doses resulted in fewer spontaneous laxations (0.1 mg versus 0.2 mg: RR 0.73, 95% CI 0.55 to 0.95; 0.1 mg versus 0.4 mg: RR 0.69, 95% CI 0.53 to 0.89; moderate-quality evidence). There was moderate-quality evidence that naldemedine had no effect on opiate withdrawal. There were five serious adverse events. All were in people taking naldemedine (low-quality evidence). There was an increase in the occurrence of other (non-serious) adverse events in the naldemedine groups (RR 1.36, 95% CI 1.04 to 1.79, moderate-quality evidence). The most common adverse event was diarrhoea.The trials on naloxone taken either on its own, or in combination with oxycodone (an opioid) compared to oxycodone only did not evaluate laxation response over the first two weeks of administration. There was very low-quality evidence that naloxone alone, and moderate-quality evidence that oxycodone/naloxone, had no effect on analgesia. There was low-quality evidence that oxycodone/naloxone did not increase the risk of serious adverse events and moderate-quality evidence that it did not increase risk of adverse events.In combined analysis of two trials of 287 participants, we found methylnaltrexone compared to placebo induced more laxations within 24 hours (. In this update, the conclusions for naldemedine are new. There is moderate-quality evidence to suggest that, taken orally, naldemedine improves bowel function over two weeks in people with cancer and OIBD but increases the risk of adverse events. The conclusions on naloxone and methylnaltrexone have not changed. The trials on naloxone did not assess laxation at 24 hours or over two weeks. There is moderate-quality evidence that methylnaltrexone improves bowel function in people receiving palliative care in the short term and over two weeks, and low-quality evidence that it does not increase adverse events. There is a need for more trials including more evaluation of adverse events. None of the current trials evaluated effects in children.

Topics: Constipation; Defecation; Female; Gastrointestinal Agents; Humans; Intestinal Diseases; Male; Nalbuphine; Naloxone; Naltrexone; Narcotic Antagonists; Neoplasms; Opioid-Related Disorders; Oxycodone; Palliative Care; Piperidines; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic; Receptors, Opioid, mu

Constipation is a common adverse effect of opioids. As an example, constipation is reported in 52% of people with advanced malignancy, and this figure rises to 87% in people who are terminally ill and taking opioids. There is no reason to believe that people with chronic non-malignant disease who are prescribed opioids will be any less troubled by this adverse effect.. We conducted a systematic overview and aimed to answer the following clinical question: What are the effects of opioid antagonists for constipation in people prescribed opioids? The population we studied included people with any condition, although most studies were in people with cancer pain. We searched Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review).. At this update, searching of electronic databases retrieved 162 studies. After deduplication and removal of conference abstracts, 84 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 47 studies and the further review of 37 full publications. Of the 37 full articles evaluated, two systematic reviews and one RCT were included at this update. We performed a GRADE evaluation for three PICO combinations.. In this systematic overview we categorised the efficacy for three interventions based on information relating to the effectiveness of alvimopan, methylnaltrexone, and naloxone.

Topics: Analgesics, Opioid; Constipation; Gastrointestinal Agents; Humans; Naloxone; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds; Treatment Outcome

There has been no definitive synthesis of the evidence for any benefit of available pharmacological therapies in opioid-induced constipation (OIC). We conducted a systematic review and meta-analysis to address this deficit.. We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials through to December 2012 to identify placebo-controlled trials of μ-opioid receptor antagonists, prucalopride, lubiprostone, and linaclotide in the treatment of adults with OIC. No minimum duration of therapy was required. Trials had to report a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Effect of pharmacological therapies was reported as relative risk (RR) of failure to respond to therapy, with 95% confidence intervals (CIs).. Fourteen eligible randomized controlled trials (RCTs) of μ-opioid receptor antagonists, containing 4,101 patients, were identified. These were superior to placebo for the treatment of OIC (RR of failure to respond to therapy=0.69; 95% CI 0.63-0.75). Methylnaltrexone (six RCTs, 1,610 patients, RR=0.66; 95% CI 0.54-0.84), naloxone (four trials, 798 patients, RR=0.64; 95% CI 0.56-0.72), and alvimopan (four RCTs, 1,693 patients, RR=0.71; 95% CI 0.65-0.78) were all superior to placebo. Total numbers of adverse events, diarrhea, and abdominal pain were significantly commoner when data from all RCTs were pooled. Reversal of analgesia did not occur more frequently with active therapy. Only one trial of prucalopride was identified, with a nonsignificant trend toward higher responder rates with active therapy. Two RCTs of lubiprostone were found, with significantly higher responder rates with lubiprostone in both, but reporting of data precluded meta-analysis.. μ-Opioid receptor antagonists are safe and effective for the treatment of OIC. More data are required before the role of prucalopride or lubiprostone in the treatment of OIC are clear.

Topics: Alprostadil; Analgesics, Opioid; Benzofurans; Constipation; Female; Gastrointestinal Agents; Humans; Lubiprostone; Male; Naloxone; Naltrexone; Narcotic Antagonists; Peptides; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid, mu

Topics: Analgesics, Opioid; Combined Modality Therapy; Constipation; Delayed-Action Preparations; Diet Therapy; Humans; Laxatives; Life Style; Naloxone; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds

Symptoms associated with disorders of the motility of colon and rectum are common problems in clinical practice. Advances in this field continue to expand our understanding of these disorders and provide new and different treatments with promising results.. This article reviews new advances in the past year on the measurement and diagnosis of colonic transit. Recently published data question the importance of dietary fiber in the prevention of colonic diverticulosis and diverticulitis, and support the efficacy of a number of different therapies aimed at improving colonic motility and visceral sensation in constipation and reversing the effects of opioid induced constipation with peripherally acting opioid antagonists.. The articles referenced in this review help inform the reader on new developments in the diagnosis and management of patients with colonic and rectal motility disorders.

Topics: Constipation; Diet; Dipeptides; Diverticulosis, Colonic; Gastrointestinal Agents; Gastrointestinal Transit; Humans; Naltrexone; Narcotic Antagonists; Peptides; Piperidines; Quaternary Ammonium Compounds; Rectal Diseases; Thiazepines; Tryptophan Hydroxylase

Gastrointestinal motility disorders (GMDs) are common in the ICU. When encountering these problems, one typically thinks of prokinetics. This review summarizes current evidence of treatments.. Prokinetics are not the first-line therapy for GMDs. In fact, the clinical implications of using prokinetic agents are rather controversial. Current evidence on alternative treatment modalities such as fluid and electrolyte management, laxatives, opioid antagonists, purgative enemas, acupuncture, physical therapies and probiotics is growing.. Current state of the art to treat GMDs is primarily focused at the elimination of underlying trigger factors. Fluid and electrolyte management as well as laxatives and peripherally acting μ-opioid receptor antagonists are the recommended first-line therapies that can be complemented with prokinetics. Acupuncture as well as physical modalities, such as massage or warming of the abdomen, is promising with few side-effects and should be considered as well.

Topics: Acupuncture Therapy; Animals; Colon; Complementary Therapies; Enema; Gastrointestinal Agents; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Laxatives; Naltrexone; Narcotic Antagonists; Piperidines; Probiotics; Pylorus; Quaternary Ammonium Compounds

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

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

Topics: Animals; Constipation; Gastrointestinal Tract; Humans; Naloxone; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid

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

Constipation and other gastrointestinal symptoms are frequent adverse effects of either short-term postoperative or chronic opioid therapy. The review authors have identified 23 studies to evaluate the efficacy of micro-opioid antagonists for the prevention and treatment of these complications. The data on safety and efficacy of the traditional antagonists naloxone and nalbuphine are insufficient. The results of studies with the newer, peripherally-acting antagonists alvimopan and methylnaltrexone are promising. Methylnaltrexone resulted in four studies with healthy probands in a significant shortening of the gastrointestinal transit time (-52 min). In the postoperative setting, five studies showed a significant improvement of the hazard ratios for different outcomes (e. g., bowel movement, tolerance of solid food) in the alvimopan group. Future studies will be needed to show whether these results can be reproduced in different patient groups on a larger scale. Also, with regard to other pharmacological (e. g., lactulose) and non-pharmacological interventions, the role of the above-mentioned not yet approved medications needs to be defined.

Topics: Analgesics, Opioid; Clinical Trials as Topic; Constipation; Gastrointestinal Transit; Humans; Nalbuphine; Naloxone; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid, mu

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

Topics: Analgesics, Opioid; Animals; Clinical Trials as Topic; Drug Evaluation, Preclinical; Gastrointestinal Diseases; Gastrointestinal Tract; Humans; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid, mu

Opioid-induced bowel dysfunction (OBD) is characterized by constipation, incomplete evacuation, bloating, and increased gastric reflux. OBD occurs both acutely and chronically, in multiple disease states, resulting in increased morbidity and reduced quality of life.. To compare the efficacy and safety of traditional and peripherally active opioid antagonists versus conventional interventions for OBD.. We searched MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE in January 2007. Additional reports were identified from the reference lists of retrieved papers.. Studies were included if they were randomized controlled trials that investigated the efficacy of mu-opioid antagonists for OBD.. Data were extracted by two independent review authors and included demographic variables, diagnoses, interventions, efficacy, and adverse events.. Twenty-three studies met inclusion criteria and provided data on 2871 opioid antagonist-treated patients. The opioid antagonists investigated were alvimopan (nine studies), methylnaltrexone (six), naloxone (seven), and nalbuphine (one). Meta-analysis demonstrated that methylnaltrexone and alvimopan were better than placebo in reversing opioid-induced increased gastrointestinal transit time and constipation, and that alvimopan appears to be safe and efficacious in treating postoperative ileus. The incidence of adverse events with opioid antagonists was similar to placebo and generally reported as mild-to-moderate.. Insufficient evidence exists for the safety or efficacy of naloxone or nalbuphine in the treatment of OBD. Long-term efficacy and safety of any of the opioid antagonists is unknown, as is the incidence or nature of rare adverse events. Alvimopan and methylnaltrexone both show promise in treating OBD, but further data will be required to fully assess their place in therapy.

Topics: Constipation; Defecation; Gastrointestinal Agents; Humans; Intestinal Diseases; Nalbuphine; Naloxone; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid, mu

Cancer-related constipation is common and a significant detractor from patient quality of life. It has many possible causes and is still not well understood. Information is lacking on therapies for cancer-related constipation among current medications approved by the US Food and Drug Administration (FDA). Most agents have only been formally tested in comparison with placebo in chronic idiopathic constipation if at all. Few comparative studies of laxatives have been performed to establish superiority or synergy. As we understand more about the physiology of the gastrointestinal tract, new targeted therapies have become available. These include a selective chloride channel activator, lubiprostone, and a selective 5HT4 serotonin receptor agonist, tegaserod, both of which have been FDA approved for chronic idiopathic constipation. The role of these agents in cancer-related constipation remains to be seen. On the horizon are two investigational peripherally acting opioid receptor antagonists, alvimopan and methylnaltrexone. Preliminary results in cancer-related constipation suggest that these agents may be important additions to our treatment repertoire.

Topics: Alprostadil; Constipation; Fatty Acids; Gastrointestinal Agents; Humans; Indoles; Lubiprostone; Naltrexone; Narcotic Antagonists; Neoplasms; Piperidines; Quaternary Ammonium Compounds; Serotonin Receptor Agonists

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

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

Topics: Analgesics, Opioid; Animals; Constipation; Enteric Nervous System; Gastrointestinal Motility; Humans; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid

A recent study demonstrated that reflux is associated with impaired pressure augmentation in the esophagogastric junction (EGJ), caused by diaphragmal contractions during inspiration. It is unknown whether this augmentation is influenced by opioids. Swallowing difficulties can be a poorly recognised side effect of remifentanil. Here, we investigated whether remifentanil influences inspiratory EGJ augmentation and evaluated subjective swallowing difficulties induced by remifentanil. We also used the peripheral opioid receptor antagonist methylnaltrexone to evaluate whether these effects are centrally or peripherally mediated.. Ten healthy volunteers participated in a double-blind, randomised, cross-over trial at the University Hospital in Örebro, Sweden. They were studied on two different occasions, during which they were randomly assigned to receive either methylnaltrexone 0.15 mg/kg or saline subcutaneously 30 min before the target-controlled infusion of remifentanil of 3 ng/mL. EGJ pressures were measured by high-resolution manometry. Swallowing difficulties were assessed when volunteers performed dry swallows. The outcomes were the differences in EGJ pressures at baseline and during remifentanil infusion and with methylnaltrexone vs. placebo. Differences in swallowing difficulties before and during remifentanil, and with methylnaltrexone vs. placebo were also recorded.. Remifentanil decreased the inspiratory EGJ augmentation and induced swallowing difficulties. No statistically significant differences between methylnaltrexone and placebo occasions were found.. Remifentanil may increase risk for gastroesophageal reflux by decreasing the inspiratory EGJ augmentation. The clinical significance of remifentanil-induced swallowing difficulties is to be studied further. Given the limited sample size, it cannot be concluded whether these effects are centrally or peripherally mediated.

Topics: Adult; Anesthetics, Intravenous; Cross-Over Studies; Data Interpretation, Statistical; Deglutition; Double-Blind Method; Esophagogastric Junction; Female; Humans; Male; Manometry; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Remifentanil; Stomach; Young Adult

Peripheral mechanisms may be involved in opioid actions on the urinary bladder. This double-blind study investigated whether opioid inhibition of bladder function is reversed by methylnaltrexone, a peripheral opioid antagonist. Thirteen healthy male volunteers received an intravenous (i.v.) infusion of remifentanil, 0.15 mcg/kg/min, then a single i.v. dose of study medication (methylnaltrexone 0.3 mg/kg, naloxone 0.01 mg/kg, or saline). Urodynamics were measured with indwelling bladder and rectal catheters, and pupil size was assessed with infrared pupillometry. Remifentanil decreased detrusor pressure in 21/25 sessions and caused complete urinary retention in 18/25. Voiding was possible in 7/7, 5/12, and 0/6 sessions after naloxone, methylnaltrexone, and saline, respectively (P=0.0013). Remifentanil caused marked miosis that was reversed by naloxone, but not methylnaltrexone or placebo (P<0.0001). The pupil data confirm that methylnaltrexone did not reverse central opioid effects. Reversal of urinary retention by methylnaltrexone indicates that peripheral mechanisms may play a role in opioid-induced bladder dysfunction.

Topics: Adult; Analgesics, Opioid; Cross-Over Studies; Double-Blind Method; Humans; Infusions, Intravenous; Male; Middle Aged; Miosis; Muscle Contraction; Naloxone; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds; Remifentanil; Treatment Outcome; Urinary Bladder; Urinary Retention; Urination

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

The clinical efficacy of opioid receptor antagonists for the treatment of opioid-induced constipation (OIC) is established. Peripherally selective antagonists are intended to provide OIC symptom relief without compromising the analgesic effects of centrally penetrant opioid agonists. We describe the in vitro profile of a novel opioid receptor antagonist, TD-1211, at recombinant (human μ and δ, and guinea pig κ) and rodent native opioid receptors. TD-1211 bound with high affinity to human recombinant μ and δ, and guinea pig κ receptors expressed in CHO-K1 cells (pK d = 9.7, 8.6, and 9.9, respectively). The in vitro receptor selectivity of TD-1211 (μ ≈ κ > δ) is similar to that for the peripherally-selective opioid receptor antagonist methylnaltrexone, but contrasts with the μ selectivity of alvimopan. Functionally, TD-1211 behaved as an antagonist at all three receptor types in both recombinant expression systems (pK b = 9.6, 8.8 and 9.5, at μ, δ, and κ, respectively) and rodent native tissue preparations (μ and κ pA2s = 10.1 and 8.8, respectively (guinea pig ileum), and δ pK b = 8.4 (hamster vas deferens)). TD-1211 displayed a high degree of selectivity for opioid receptors over a broad panel of cellular targets. These in vitro data justified investigation of the preclinical in vivo activity of TD-1211 (Armstrong et al., Naunyn-Schmiedeberg's Arch Pharm, 2013).

Topics: Animals; Benzamides; CHO Cells; Cricetinae; Cricetulus; Guinea Pigs; Humans; In Vitro Techniques; Male; Mesocricetus; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Tropanes

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

Topics: Analgesics, Opioid; Anesthetics; Gastrointestinal Agents; Humans; Intestinal Pseudo-Obstruction; Intubation, Gastrointestinal; Naltrexone; Piperidines; Postoperative Complications; Preoperative Care; Quaternary Ammonium Compounds

This study characterized the pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, its metabolite, ADL 08-0011, and methylnaltrexone. The activities of the compounds were investigated with respect to human or guinea pig opioid receptor binding and function in recombinant cell lines and mechanical responsiveness of the guinea pig ileum. Alvimopan and ADL 08-0011 had higher binding affinity than methylnaltrexone at human mu opioid receptors (pK (i) values of 9.6, 9.6, and 8.0, respectively). The compounds had different selectivities for the mu receptor over human delta and guinea pig kappa opioid receptors. ADL 08-0011 had the highest mu receptor selectivity. With respect to their mu opioid receptor functional activity ([(35)S]GTPgammaS incorporation), methylnaltrexone had a positive intrinsic activity, consistent with partial agonism, unlike alvimopan and ADL 08-0011, which had negative intrinsic activities. Alvimopan, ADL 08-0011, and methylnaltrexone antagonized inhibitory responses mediated by the mu opioid agonist, endomorphin-1 (pA (2) values of 9.6, 9.4, and 7.6, respectively) and by U69593, a kappa opioid agonist (pA (2) values of 8.4, 7.2, and 6.7, respectively). In morphine-naive guinea pig ileum, methylnaltrexone reduced, while alvimopan and ADL 08-0011 increased, the amplitude of electrically evoked contractions and spontaneous mechanical activity. In tissue from morphine-dependent animals, alvimopan and ADL 08-0011 increased spontaneous activity to a greater degree than methylnaltrexone. The data suggested that alvimopan-induced contractions resulted predominantly from an interaction with kappa opioid receptors. It is concluded that alvimopan, ADL 08-0011, and methylnaltrexone differ in their in vitro pharmacological properties, particularly with respect to opioid receptor subtype selectivity and intrinsic activity. The clinical significance of the data from this study remains to be determined.

Topics: Analgesics, Opioid; Animals; Benzeneacetamides; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Humans; Ileum; In Vitro Techniques; Male; Morphine; Muscle Contraction; Naltrexone; Narcotic Antagonists; Oligopeptides; Piperidines; Pyrrolidines; Quaternary Ammonium Compounds; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Recombinant Proteins; Transfection

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

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents; Constipation; Humans; Naltrexone; Narcotic Antagonists; Pain; Piperidines; Pyridines; Quaternary Ammonium Compounds; Receptors, Opioid, mu

Although there is considerable evidence that pretreatment with low doses of opioid agonists can enhance, and opioid antagonists can reduce alcohol consumption in rats, little is known about the locus or mechanism of these effects. As a first approximation as to where the effect may occur, we compared the effects of an opioid agonist morphine (1, 3 and 10 mg/kg) and antagonist naltrexone (1, 3 and 10 mg/kg) that are known to act within the brain as well as the periphery, to those of an agonist-like drug loperamide (0.3, 1 and 3 mg/kg) and an antagonist methylnaltrexone (3, 10 and 30 mg/kg) that are known to act peripherally only. Free-feeding rats were initially trained to drink alcohol using a limited access paradigm, and when animals were drinking asymptotic amounts of 12% (w/v) alcohol, increasing doses of one of the four drugs or saline were administered IP to separate groups of rats 30 min prior to the hour-long daily drinking session. The results confirmed that the effects of the opioids on alcohol consumption are indeed mediated within the central nervous system in that morphine enhanced alcohol consumption but loperamide did not, naltrexone reduced alcohol consumption but methylnaltrexone did not, and naltrexone was able to block the morphine effect but methylnaltrexone failed to do so. An unexpected finding was that methylnaltrexone alone also increased alcohol consumption. Possible means by which this could occur, also supporting the idea of a central locus for the effect, as well as possible mechanisms by which opioids could influence alcohol consumption generally, are discussed.

Topics: Alcohol Drinking; Animals; Dose-Response Relationship, Drug; Drinking Behavior; Drug Interactions; Loperamide; Male; Morphine; Naltrexone; Narcotic Antagonists; Piperidines; Polysorbates; Quaternary Ammonium Compounds; Rats; Rats, Inbred Strains; Time Factors