alvimopan-anhydrous and Constipation

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

Opioid-induced constipation (OIC) is a major side effect of opioid use. Centrally acting antagonists result in opioid withdrawal or worsening of pain and lead to use of peripherally acting mu-opioid receptor antagonists (PAMORAs). The required doses of the PAMORAs, methylnaltrexone and naloxegol, in the treatment of OIC are well established in chronic opioid users. OIC may occur after short duration of opioid treatment; the required doses of naloxone, naltrexone, and PAMORAs in opioid-naïve subjects (with no opioid use for at least 3 months) are unclear. The aim of this review was to evaluate the PAMORA dose required for opioid-naïve subjects to achieve similar beneficial effects on symptoms or valid surrogates to those observed in chronic opioid users.. A PubMed search of μ-opioid antagonists to counter μ-opioid effects included terms: naloxone, naltrexone, methylnaltrexone, alvimopan, and naloxegol, as well as OIC and colonic transit.. The approved dose of methylnaltrexone in chronic opioid users, 0.3 mg/kg subcutaneous (SQ), did not affect motility in opioid-naïve subjects. Trials investigating the required dose of alvimopan showed 0.5-1 mg dose was efficacious in treating OIC; a 10-fold higher dose (12 mg) of alvimopan is needed to block effects of codeine on small bowel and colonic transit in opioid-naïve subjects compared to chronic opioid users. Opioid-naïve users need 125 mg of naloxegol to reverse the effects of opioids on transit; this is in contrast to the 12.5 to 25 mg needed to treat OIC in chronic opioid users.. Opioid-naïve subjects require a higher dose of PAMORA than chronic opioid users to achieve μ-opioid antagonist effect.

Topics: Analgesics, Opioid; Constipation; Dose-Response Relationship, Drug; Gastrointestinal Agents; Humans; Morphinans; Narcotic Antagonists; Pain; Piperidines; Polyethylene Glycols; Receptors, Opioid, mu; Treatment Outcome

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

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

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

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

Constipation is a worldwide problem that affects many children. Treatment of constipation is largely based on clinical experience rather than on evidence-based controlled clinical trials. Stool softeners and cathartic agents in combination with behavioral interventions constitute the programs most commonly used to facilitate painless and frequent defecation. Long-term treatment is needed for most patients, and approximately 30% of children beyond puberty continue to struggle with symptoms of constipation, such as infrequent, painful evacuation of stools and fecal incontinence. Not surprisingly, chronicity of these bowel complaints may cause significant interference with the child's emotional growth and development. Development of new therapeutic strategies is necessary in order to treat these challenging patients more effectively. This review provides an overview of novel and alternative therapies, such as new drugs, surgery, and probiotics, that are being proposed for the treatment of childhood chronic constipation.

Topics: Acupuncture Therapy; Alprostadil; Botulinum Toxins; Child; Complementary Therapies; Constipation; Electric Stimulation; Fatty Acids; Humans; Indoles; Lubiprostone; Massage; Piperidines; Probiotics; Serotonin Receptor Agonists

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

Alvimopan is a novel, peripherally acting mu-opioid antagonist that is being developed for the management of acute postoperative ileus and for the reversal of the delayed gastrointestinal and colonic transit that result in symptoms such as constipation, nausea and motility disorders in patients treated with opiate analgesics. There is a clinical need for effective medications for the treatment of postoperative ileus and opiate-induced constipation and other motility disorders. This review addresses the basic and applied pharmacology and current evidence for the use of the medication, alvimopan, in clinical gastroenterology.

Topics: Animals; Constipation; Gastrointestinal Motility; Humans; Ileus; Narcotic Antagonists; Piperidines; Postoperative Complications; Receptors, Opioid, mu

Alvimopan is a synthetic peripherally restricted mu-receptor opioid antagonist. Alvimopan has a greater affinity for the mu-receptor than the kappa- or sigma-opioid receptors (Ki = 0.77 nM). The polarity of the molecule limits gastrointestinal absorption and central nervous system penetration. It has limited systemic bioavailability and higher affinity for the mu-opioid receptor than naloxone (Ki = 3.7 nM). Completed Phase III trials suggest efficacy in accelerating the recovery of gastrointestinal function after abdominal surgery. Adverse events with all doses have been similar to placebo groups. Further efficacy in alleviating opioid-induced bowel dysfunction in patients with chronic opioid usage has also been demonstrated. This evidence-based review assesses this new drug and discusses its potential role in clinical practice.

Topics: Abdomen; Administration, Oral; Adult; Analgesics, Opioid; Constipation; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Ileus; Male; Middle Aged; Narcotic Antagonists; Piperidines; Postoperative Complications; Randomized Controlled Trials as Topic; Receptors, Opioid, mu

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

Pain management following major spine surgery requires high doses of opioids and is associated with a risk of opioid-induced constipation. Peripheral mu-receptor antagonists decrease the gastrointestinal complications of perioperative systemic opioid administration without antagonizing the analgesic benefits of these drugs.. To investigate the impact of alvimopan in opioid-naive patients undergoing major spine surgery.. Patients undergoing >3 levels of thoracic and/or lumbar spine surgery were enrolled in this prospective, randomized, double-blind study to receive either alvimopan or placebo prior to and following surgery. Opioid consumption; pain scores; and time of first oral intake, flatus, and bowel movement were recorded.. A total of 24 patients were assigned to the active group and 25 were assigned to the placebo group. There was no significant difference in demographics between the groups. Postoperatively, the alvimopan group reported earlier time to first solid intake [median (range): alvimopan: 15 h (3-25) vs placebo: 17 h (3-46), P < .001], passing of flatus [median (range): alvimopan: 22 h (7-63) vs placebo: 28 h (10-58), P < .001], and first bowel movement [median (range): alvimopan: 50 h (22-80) vs placebo: 64 h (40-114), P < .001]. The alvimopan group had higher pain scores (maximum, minimum, and median); however, there was no significant difference between the groups with postoperative opioid use.. This study shows that the perioperative use of alvimopan significantly reduced the time to return of bowel function with no increase in postoperative opioid use despite a slight increase in pain scores.

Topics: Adult; Analgesics, Opioid; Constipation; Double-Blind Method; Female; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Middle Aged; Pain; Piperidines; Prospective Studies; Receptors, Opioid, mu; Recovery of Function; Spinal Diseases; Young Adult

Gastrointestinal (GI) side effects are common with opioid medication, and constipation affects ∼40% of patients. Such symptoms considerably impair patients' quality of life. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist approved in the US for short-term, in-hospital management of postoperative ileus in patients undergoing bowel resection. This double-blind, placebo-controlled trial was conducted as part of a recently discontinued clinical program, in which alvimopan was being developed for opioid-induced constipation (OIC). Patients (N = 518) receiving opioids for non-cancer pain were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo for 12 weeks. The primary efficacy endpoint was the proportion of patients experiencing ≥ 3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period and an average increase from baseline of ≥ 1 SBM per week. A significantly greater proportion of patients in the alvimopan .5 mg twice-daily group met the primary endpoint compared with placebo (72% versus 48%, P < .001). Treatment with alvimopan twice daily improved a number of other symptoms compared with placebo and reduced the requirement for rescue laxative use. The opioid-induced bowel dysfunction Symptoms Improvement Scale (SIS) responder rate was 40.4% in the alvimopan .5 mg twice daily group, versus 18.6% with placebo (P < .001). In general, alvimopan .5 mg once daily produced qualitatively similar but numerically smaller responses than twice-daily treatment. Active treatment did not increase the requirement for opioid medication or increase average pain intensity scores. Over the 12-week treatment period, alvimopan appeared to be well tolerated.. These results demonstrate the potential for a PAM-OR antagonist to improve the symptoms of OIC without antagonizing opioid analgesia.

Topics: Analgesics, Opioid; Constipation; Double-Blind Method; Humans; Intestines; Narcotic Antagonists; Pain; Piperidines; Placebos

The balance between the pain relief provided by opioid analgesics and the side effects caused by such agents is of particular significance to patients who take opioids for the long-term relief of non-cancer pain. The spectrum of signs and symptoms affecting the gastrointestinal (GI) tract associated with opioid use is known as opioid-induced bowel dysfunction. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist, approved in the US for the management of postoperative ileus in patients undergoing bowel resection (short-term, in-hospital use only). Alvimopan was under clinical development for long-term treatment of opioid-induced constipation (OIC) but this program has been discontinued. This double-blind, placebo-controlled trial, part of the former OIC development program, enrolled patients (N = 485) receiving opioids for non-cancer pain. Patients were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo, for 12 weeks. The primary efficacy endpoint was the proportion of patients who experienced ≥ 3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period, and an average increase from baseline of ≥ 1 SBM per week. There were greater proportions of SBM responders in both alvimopan treatment groups (63% in both groups) compared with placebo (56%), although these differences were not statistically significant. Secondary efficacy analyses indicated that alvimopan was numerically superior to placebo in improving opioid-induced bowel dysfunction symptoms and patients' global assessment of opioid-induced bowel dysfunction, and reduced the requirement for rescue laxatives. Active treatment was well tolerated and alvimopan did not antagonize opioid analgesia.. Although the primary endpoint was not met in this study, the magnitude of alvimopan-induced improvements versus baseline, together with previous study results, suggest that a PAM-OR antagonist has the potential to improve OIC.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Constipation; Double-Blind Method; Female; Humans; Intestines; Male; Middle Aged; Narcotic Antagonists; Pain; Piperidines; Placebos; Young Adult

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

Topics: Adult; Analgesics, Opioid; Colic; Constipation; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Enteric Nervous System; Female; Gastrointestinal Motility; Humans; Intestines; Male; Middle Aged; Narcotic Antagonists; Pain; Piperidines; Placebos; Receptors, Opioid, mu; Risk Assessment; Treatment Outcome

Alvimopan has been shown to reverse the inhibitory effect of opioids on gastrointestinal transit without affecting analgesia. We evaluated oral alvimopan, 0.5 or 1 mg, versus placebo, once daily for 21 days, in 168 patients with opioid-induced bowel dysfunction (OBD) who were receiving chronic opioid therapy (minimum, 1 month) for nonmalignant pain (n = 148) or opioid dependence (n = 20). The primary outcome was the proportion of patients having at least one bowel movement (BM) within 8 hours of study drug on each day during the 21-day treatment period. Averaged over the 21-day treatment period, 54%, 43%, and 29% of patients had a BM within 8 hours after alvimopan 1 mg, 0.5 mg, or placebo, respectively (P < .001). Secondary outcomes of median times to first BM were 3, 7, and 21 hours after initial doses of 1 mg, 0.5 mg, and placebo, respectively (P < .001; 1 mg vs placebo). Weekly BMs and overall patient satisfaction were increased after the 1-mg dose (P < .001 at weeks 1 and 2 vs placebo, and P = .046, respectively). Treatment-emergent adverse events were primarily bowel-related, occurred during the first week of treatment, and were of mild to moderate severity. Alvimopan was generally well tolerated and did not antagonize opioid analgesia. Patients treated with chronic opioid therapy often experience opioid-induced bowel dysfunction as a result of undesirable effects on peripheral opioid receptors located in the gastrointestinal tract. Alvimopan, a novel peripheral opioid mu-receptor antagonist, has demonstrated significant efficacy for the management of opioid-induced bowel dysfunction without compromise of centrally mediated opioid-induced analgesia.

Topics: Administration, Oral; Analgesics, Opioid; Cathartics; Chronic Disease; Constipation; Female; Follow-Up Studies; Gastrointestinal Motility; Humans; Male; Middle Aged; Pain; Piperidines; Receptors, Opioid, mu; 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

Topics: Cisapride; Constipation; Domperidone; Gastrointestinal Agents; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Indoles; Piperidines; Risk Assessment

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

Topics: Abdomen; Clinical Trials as Topic; Constipation; Digestive System Surgical Procedures; Humans; Ileus; Irritable Bowel Syndrome; Narcotic Antagonists; Piperidines; Postoperative Complications; Receptors, Opioid, mu