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Opioid-induced constipation (OIC) is a rising problem due to the progressive increase in opioid prescription. In contrast to functional constipation, opioid-induced constipation is not a functional gut disorder but a side effect of opioid use. Opioids produce constipation due to a decrease in gastrointestinal motility and a reduction in gastrointestinal secretions. The treatment of OIC focuses on three basic pillars: optimizing opioid drug indication, preventing constipation onset, and treating constipation should it develop. As with any other cause of constipation, lifestyle adjustments and laxatives should be the first-line option in the pharmacological management of OIC. Osmotic laxatives such as polyethylene glycol (PEG) are the agents of choice. PEG is inert and is neither fermented nor absorbed in the gastrointestinal tract. Furthermore, it has broad clinical applicability due to its favourable safety profile. If first-line treatments fail, peripheral μ-opioid receptor antagonists (PAMORA) are the drugs of choice. They reduce the peripheral effects of OIC with a minimal potential to diminish analgesia or induce a centrally mediated withdrawal syndrome. Different PAMORA are available in the market both for oral and subcutaneous administration, with demonstrated efficacy for the management of OIC in different clinical trials.

Introduction: The rise in opioid use for managing chronic and oncologic pain has led to a significant increase in opioid-induced constipation (OIC) that impacts patient quality of life and pain management., Areas Covered: In this study, emerging therapies for OIC were criticized for refining advancements and novel treatment options. Key topics included the efficacy of peripherally acting mu-opioid receptor antagonists (PAMORAs) such as methylnaltrexone, naloxegol, and naldemedine, which specifically target opioid-induced gut dysfunction. Other treatment options, including intestinal secretagogues like lubiprostone and linaclotide, selective 5-HT receptor agonists such as prucalopride, and emerging adjunctive therapies like transcutaneous electrical nerve stimulation (TENS) and electroacupuncture were mentioned. Current guidelines from the American Gastroenterological Association (AGA) and the European consensus were criticized., Expert Opinion: Experts stress the importance of a stepwise approach to managing OIC, considering patient-specific factors and the efficacy of various treatments. While PAMORAs have demonstrated effectiveness in improving bowel function, their high cost and lack of extensive head-to-head comparisons with traditional laxatives are significant concerns. Emerging therapies and adjunctive treatments offer promising results but require further validation through rigorous studies. Future research should focus on long-term outcomes, cost-effectiveness, and comparative effectiveness to better address the complex needs of patients with OIC and refine treatment protocols.

Background: Cancer-related pain often requires opioid treatment with opioid-induced constipation (OIC) as its most frequent gastrointestinal side-effect. Both for prevention and treatment of OIC osmotic (e.g. polyethylene glycol) and stimulant (e.g. bisacodyl) laxatives are widely used. Newer drugs such as the peripherally acting µ-opioid receptor antagonists (PAMORAs) and naloxone in a fixed combination with oxycodone have become available for the management of OIC. This systematic review and meta-analysis aims to give an overview of the scientific evidence on pharmacological strategies for the prevention and treatment of OIC in cancer patients., Methods: A systematic search in PubMed, Embase, Web of Science and the Cochrane Library was completed from inception up to 22 October 2022. Randomized and non-randomized studies were systematically selected. Bowel function and adverse drug events were assessed., Results: Twenty trials (prevention: five RCTs and three cohort studies; treatment: ten RCTs and two comparative cohort studies) were included in the review. Regarding the prevention of OIC, three RCTs compared laxatives with other laxatives, finding no clear differences in effectivity of the laxatives used. One cohort study showed a significant benefit of magnesium oxide compared with no laxative. One RCT found a significant benefit for the PAMORA naldemedine compared with magnesium oxide. Preventive use of oxycodone/naloxone did not show a significant difference in two out of three other studies compared to oxycodone or fentanyl. A meta-analysis was not possible. Regarding the treatment of OIC, two RCTs compared laxatives, of which one RCT found that polyethylene glycol was significantly more effective than sennosides. Seven studies compared an opioid antagonist (naloxone, methylnaltrexone or naldemedine) with placebo and three studies compared different dosages of opioid antagonists. These studies with opioid antagonists were used for the meta-analysis. Oxycodone/naloxone showed a significant improvement in Bowel Function Index compared to oxycodone with laxatives (MD -13.68; 95 % CI -18.38 to -8.98; I 2  = 58 %). Adverse drug event rates were similar amongst both groups, except for nausea in favour of oxycodone/naloxone (RR 0.51; 95 % CI 0.31-0.83; I 2  = 0 %). Naldemedine (NAL) and methylnaltrexone (MNTX) demonstrated significantly higher response rates compared to placebo (NAL: RR 2.07, 95 % CI 1.64-2.61, I 2  = 0 %; MNTX: RR 3.83, 95 % CI 2.81-5.22, I 2  = 0 %). With regard to adverse events, abdominal pain was more present in treatment with methylnaltrexone and diarrhea was significantly more present in treatment with naldemedine. Different dosages of methylnaltrexone were not significantly different with regard to both efficacy and adverse drug event rates., Conclusions: Magnesium oxide and naldemedine are most likely effective for prevention of OIC in cancer patients. Naloxone in a fixed combination with oxycodone, naldemedine and methylnaltrexone effectively treat OIC in cancer patients with acceptable adverse events. However, their effect has not been compared to standard (osmotic and stimulant) laxatives. More studies comparing standard laxatives with each other and with opioid antagonists are necessary before recommendations for clinical practice can be made., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Constipation is frequent in critically ill patients, and potentially related to adverse outcomes. Peripherally-active mu-opioid receptor antagonists (PAMORAs) are approved for opioid-induced constipation, but information on their efficacy and safety in critically ill patients is limited. We present a single-center, retrospective, case-series of the use of naldemedine for opioid-associated constipation, and we systematically reviewed the use of PAMORAs in critically ill patients., Methods: Case-series included consecutive mechanically-ventilated patients; constipation was defined as absence of bowel movements for >3 days. Naldemedine was administered after failure of the local laxation protocol. Systematic review: PubMed was searched for studies of PAMORAs to treat opioid-induced constipation in adult critically ill patients., Primary Outcomes: time to laxation, and number of patients laxating at the shortest follow-up., Secondary Outcomes: gastric residual volumes and adverse events., Key Results: A total of 13 patients were included in the case-series; the most common diagnosis was COVID-19 ARDS. Patients had their first bowel movement 1 [0;2] day after naldemedine. Daily gastric residual volume was 725 [405;1805] before vs. 250 [45;1090] mL after naldemedine, p = 0.0078. Systematic review identified nine studies (two RCTs, one prospective case-series, three retrospective case-series and three case-reports). Outcomes were similar between groups, with a trend toward a lower gastric residual volume in PAMORAs group., Conclusions & Inferences: In a highly-selected case-series of patients with refractory, opioid-associated constipation, naldemedine was safe and associated to reduced gastric residuals and promoting laxation. In the systematic review and meta-analysis, the use of PAMORAs (mainly methylnaltrexone) was safe and associated with a reduced intolerance to enteral feeding but no difference in the time to laxation., (© 2023 John Wiley & Sons Ltd.)

Background: When opioid-induced constipation is treated with centrally acting opioid antagonists, there may be opioid withdrawal or aggravation of pain due to inhibition of μ-opioid analgesia. This led to the development of peripherally acting μ-opioid receptor antagonists (PAMORAs)., Aim: To evaluate the efficacy of available PAMORAs and other approved or experimental treatments for relieving constipation in patients with opioid-induced constipation, based on a systematic review and meta-analysis of published studies., Methods: A search of MEDLINE, EMBASE and EBM Reviews Cochrane Central Register of Controlled Trials was completed in July 2019 for randomised trials compared to placebo. FDA approved doses or highest studied dose was evaluated. Efficacy was based on diverse endpoints, including continuous variables (the bowel function index, number of spontaneous bowel movements and stool consistency based on Bristol Stool Form Scale), or responder analysis (combination of >3 spontaneous bowel movements or complete spontaneous bowel movements plus 1 spontaneous bowel movement or complete spontaneous bowel movements, respectively, over baseline [so-called FDA endpoints]). Adverse effects evaluated included central opioid withdrawal, serious adverse events, abdominal pain and diarrhoea., Results: We included 35 trials at low risk of bias enrolling 13 566 patients. All PAMORAs demonstrated efficacy on diverse patient response endpoints. There was greater efficacy with approved doses of the PAMORAs (methylnaltrexone, naloxegol and naldemidine), with lower efficacy or lower efficacy and greater adverse effects with combination oxycodone with naloxone, lubiprostone and linaclotide., Conclusions: Therapeutic response in opioid-induced constipation is best achieved with the PAMORAs, methylnaltrexone, naloxegol and naldemidine, which are associated with low risk of serious adverse events., (© 2020 John Wiley & Sons Ltd.)

Introduction: Due to the increased use of opioids for pain and their abuse globally, the rate of restrictive side effects is elevating. Opioid-induced constipation (OIC) is probably the most widespread, underdiagnosed, and yet common adverse effect. Naloxegol, as an opioid antagonist, is associated with beneficial impacts in OIC. Indeed, blocking mu (μ)-opioid receptors in the gastrointestinal tract (GI) may lead to neutralization of the GI adverse events of opioids., Areas Covered: This review is based on a PubMed and Clinicaltrials.gov search for studies undertaken over the past 20 years (2000-2020) using the following keywords: Movantik®, Moventig®, Naloxegol, Opioids, Opioid-induced constipation and Opioid antagonists., Expert Opinion: Similar to the management of functional constipation, non-pharmacological therapies are applied as the first step of the procedure. However, in most cases, laxative therpaies with or without stool softeners, which may not result in satisfactory relief are applied. In these instances, administration of prokinetic agents is recommended. Furthermore, studies have shown that the best second-line therapy option is a peripherally acting μ-opioid receptor antagonist (PAMORA), which antagonizes GI adverse events.

Background: Widespread opioid use has led to increase in opioid-related adverse effects like constipation. We examined the impact of study endpoints on reported treatment benefits., Methods: Using MEDLINE, EMBASE, and ClinicalTrials.gov, we searched for randomized control trials targeting chronic opioid-induced constipation (OIC) and subjected them to meta-analysis. Data are given with 95% confidence intervals., Results: Thirty trials met our inclusion criteria. Combining all dichotomous definitions of responders, active drugs were consistently more effective than placebo, with an odds ratio (OR): 2.30 [2.01-2.63; 15 studies], independent of the underlying drug mechanism. The choice of endpoints significantly affected the therapeutic gain. When time from drug administration to defecation was used, the OR decreased from 4.74 [2.71-4.74] at 6 h or less to 2.46 [1.80-3.30] at 24 h (P < 0.05). Using other response definitions, the relative benefit over placebo was 2.10 [1.77-2.50; 12 studies] for weekly bowel frequency, 2.03 [1.39-2.95; 9 studies] for symptom scores, 2.21 [1.25-3.90; 4 studies] for global assessment scales, and 1.27 [0.79-2.03; 7 studies] for rescue laxative use., Conclusion: While treatment of OIC with active drugs is more effective than placebo, the relative gain depends on the choice of endpoints. The commonly used time-dependent response definition is associated with the highest response rate but is of questionable relevance in a chronic disorder. The limited data do not clearly demonstrate a unique advantage of the peripherally restricted opioid antagonists, suggesting that treatment with often cheaper agents should be optimized before shifting to these novel expensive agents.

Opioids have been used for centuries, mostly as a sedative and to treat pain. Currently, they are used on a global scale for the treatment of acute and chronic pain in diseases as osteoarthritis, fibromyalgia, and low back pain. Binding of opioids on opioid receptors can cause a range of different effects such as changes in stress response, analgesia, motor activity and autonomic functions. This review provide a synthetic summary of the most recent literature on the use of drugs acting on mu-receptors to treat two prevalent functional bowel disorders, presenting with opposite bowel habit. Eluxadoline and naloxegol, methylnaltrexone and naldemedine are recently FDA and/or EMA approved drugs demonstrated to be effective and safe for treatment respectively of irritable bowel syndrome subtype diarrhea and opioid induced constipation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

Background and Objectives: Opioid-induced constipation (OIC) is the most common adverse effect reported in patients receiving opioids to manage pain. Initial treatment with laxatives provides inadequate response in some patients. Naloxegol is a peripherally acting µ-opioid receptor antagonist used to treat patients with inadequate response to laxative(s) (laxative inadequate responder [LIR]). A cost-effectiveness model was constructed from the UK payer perspective to compare oral naloxegol 25 mg with placebo in non-cancer LIR patients receiving opioids for chronic pain, and a scenario analysis of naloxegol 25 mg with rescue laxatives compared with placebo with rescue laxatives in the same patient population., Methods: The model comprised a decision tree for the first 4 weeks of treatment, followed by a Markov model with a 4-week cycle length and the following states: 'OIC', 'non-OIC (on treatment)', 'non-OIC (untreated)' and 'death'. Two phase III trials with a follow-up period of 12 weeks provided data on treatment efficacy, transition probabilities, adverse event frequency and patient utility. Resource utilisation data were sourced from a UK-based burden of illness study and physician surveys. A UK National Health Service and Personal Social Service perspective was adopted; costs and health-related quality of life gains were discounted at a rate of 3.5 %. The model was run over a time horizon of 5 years, reflecting the average period of opioid use., Results: Naloxegol has an incremental cost-effectiveness ratio of £10,849 per quality-adjusted life-year gained versus placebo, and £11,179 when rescue laxatives are made available in both arms (2014 values). Model outcomes were only sensitive to variations in utility inputs. However, the probabilistic sensitivity analyses indicate that naloxegol has a 91 % probability of being cost effective at a £20,000 threshold when compared with placebo., Conclusions: Naloxegol is likely a cost-effective treatment option for LIR patients with OIC. This assessment should be supported by further work on the utility of patients with OIC, including how utility varies with more granular measures of OIC.

Introduction: Gastrointestinal dysmotility and constipation are common problems in intensive care patients. The majority of critical care patients are sedated with opioids to facilitate tolerance of endotracheal tubes and mechanical ventilation, which inhibit gastrointestinal motility and lead to adverse outcomes. Methylnaltrexone is a peripheral opioid antagonist that does not cross the blood-brain barrier and can reverse the peripheral side effects of opioids without affecting the desired central properties. This trial will investigate whether methylnaltrexone can reverse opioid-induced constipation and gastrointestinal dysmotility., Methods: This is a single-centre, multisite, double-blind, randomised, placebo-controlled trial. 84 patients will be recruited from 4 intensive care units (ICUs) within Imperial College Healthcare NHS Trust. Patients will receive intravenous methylnaltrexone or placebo on a daily basis if they are receiving opioid infusion to facilitate mechanical ventilation and have not opened their bowels for 48 hours. All patients will receive standard laxatives as per the clinical ICU bowel protocol prior to randomisation. The primary outcome of the trial will be time to significant rescue-free laxation following randomisation. Secondary outcomes will include tolerance of enteral feed, gastric residual volumes, incidence of pneumonia, blood stream and Clostridium difficile infection, and any reversal of central opioid effects., Ethics and Dissemination: The trial protocol, the patient/legal representative information sheets and consent forms have been reviewed and approved by the Harrow Research Ethics Committee (REC Reference 14/LO/2004). An independent Trial Steering Committee and Data Monitoring Committee are in place, with patient representation. On completion, the trial results will be published in peer-reviewed journals and presented at national and international scientific meetings., Trial Registration Number: 2014-004687-37; Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Up to 40% of patients taking opioids develop constipation. Opioid-induced constipation (OIC) may limit the adequate dosing of opioids for pain relief and reduce quality of life. Health professionals must therefore inquire about bowel function in patients receiving opioids. The management of OIC includes carefully re-evaluating the necessity, type and dose of opioids at each visit. Lifestyle modification and alteration of aggravating factors, the use of simple laxatives and, when essential, the addition of newer laxatives or opioid antagonists (naloxone, naloxegol or methylnaltrexone) can be used to treat OIC. This review discusses the recent literature regarding the management of OIC and provides a rational approach to assessing and managing constipation in individuals receiving opioids.

Background: Dutch clinical guidelines recommend that a standard laxative treatment (SLT) should be prescribed concomitantly when starting opioid treatment to prevent opioid-induced constipation (OIC)., Methods: Clinical evidence for SLT in the treatment of OIC is lacking, therefore an observational pilot study was performed to explore the efficacy and tolerability of SLT on OIC in patients treated with the opioid oxycodone., Results: Twenty-four patients (58% female, median (range) age 65 (39-92)) were included in this pilot study. The analysis showed that 9 out of 21 patients (43%) were non-responders to SLT. When also taking into consideration patients tending to develop diarrhea 75% of patients are non-responsive to SLT., Conclusion: This pilot study indicates that optimal laxative therapy (SLT) might not be effective and feasible for the prevention and treatment of OIC.

Background: World Health Organization step III opioids are required to relieve moderate-to-severe cancer pain; constipation is one of the most frequent opioid-induced side effects. A fixed combination, prolonged-release oxycodone/naloxone (OXN), was developed with the aim of reducing opioid-related gastrointestinal side effects. The objective of this study was to compare the efficacy and safety of prolonged-release oxycodone (OXY) alone to OXN in opioid-naïve cancer patients with moderate-to-severe pain., Methods: Propensity analysis was utilized in this observational study, which evaluated the efficacy, safety, and quality of life., Results: Out of the 210 patients recruited, 146 were matched using propensity scores and included in the comparative analysis. In both groups, pain intensity decreased by ≈3 points after 60 days, indicating comparable analgesic efficacy. Responder rates were similar between groups. Analgesia was achieved and maintained with similarly low and stable dosages over time (12.0-20.4 mg/d for OXY and 11.5-22.0 mg/d for OXN). Bowel Function Index (BFI) and laxative use per week improved from baseline at 30 days and 60 days in OXN recipients (-16, P<0.0001 and -3.5, P=0.02, respectively); BFI worsened in the OXY group. The overall incidence of drug-related adverse events was 28.9% in the OXY group and 8.2% in the OXN group (P<0.01); nausea and vomiting were two to five times less frequent with OXN. Quality of life improved to a significantly greater extent in patients receiving OXN compared to OXY (increase in Short Form-36 physical component score of 7.1 points vs 3.2 points, respectively; P<0.001)., Conclusion: In patients with chronic cancer pain, OXN provided analgesic effectiveness that is similar to OXY, with early and sustained benefits in tolerability. The relationship between responsiveness to OXN and clinical characteristics is currently being investigated.

Numerous factors, such as changes in gastrointestinal physiology, reduced mobility, decreased liquid and nutritional intake, and certain comorbidities, predispose older adults to constipation. Use of opioid medications further compounds this problem. Unlike other side effects associated with opioid use, patients do not develop tolerance to constipation and other opioid-induced bowel dysfunctions. Although opioid-induced constipation has a prevalence rate of 80% in this population, it remains highly undertreated. Despite this problem, there have been limited therapeutic options available for older adults suffering from opioid-induced constipation. On September 16, 2014, a new oral agent, naloxegol, a peripherally acting muopioid receptor antagonist (PAMORA), approved by the Food and Drug Administration, provides new hope for patients. This paper explores clinical complications associated with opioid-induced constipation in older adults, analyzes the efficacy and safety of laxatives and PAMORAs, and defines the future role of naloxegol in this vulnerable population.

Background: Opioid-induced constipation (OIC) is a common adverse effect of opioid therapy., Aim: To evaluate the long-term safety and tolerability of naloxegol, an oral, peripherally acting μ-opioid receptor antagonist (PAMORA), in patients with noncancer pain and OIC., Methods: A 52-week, multicenter, open-label, randomised, parallel-group phase 3 study was conducted in out-patients taking 30-1000 morphine-equivalent units per day for ≥4 weeks. Patients were randomised 2:1 to receive naloxegol 25 mg/day or usual-care (UC; investigator-chosen laxative regimen) treatment for OIC., Results: The safety set comprised 804 patients (naloxegol, n = 534; UC, n = 270). Mean exposure duration was 268 days with naloxegol and 297 days with UC. Frequency of adverse events (AEs) was 81.8% with naloxegol and 72.2% with UC. Treatment-emergent AEs occurring more frequently for naloxegol vs. UC were abdominal pain (17.8% vs. 3.3%), diarrhoea (12.9% vs. 5.9%), nausea (9.4% vs. 4.1%), headache (9.0% vs. 4.8%), flatulence (6.9% vs. 1.1%) and upper abdominal pain (5.1% vs. 1.1%). Most naloxegol-emergent gastrointestinal AEs occurred early, resolving during or after naloxegol discontinuation and were mild or moderate in severity; 11 patients discontinued due to diarrhoea and nine patients owing to abdominal pain. Pain scores and mean daily opioid doses remained stable throughout the study; no attributable opioid withdrawal AEs were observed. Two patients in each group had an adjudicated major adverse cardiovascular event unrelated to study drug; no AEs were reported nor adjudicated as bowel perforations., Conclusion: In patients with noncancer pain and opioid-induced constipation, naloxegol 25 mg/day up to 52 weeks was generally safe and well tolerated., (© 2014 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

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

Opioid-induced constipation is described, including features, mechanism, and management of the disorder. The role of various categories of laxatives including suppositories and the use of a peripherally acting μ-opioid receptor antagonist are discussed.

Materials and Methods: To evaluate the evidence for clinically established pharmacological therapies for constipation in palliative care, a systematic literature review was performed in different databases (Cochrane Library, Embase, PubMed, Ovid MEDLINE, CINAHL), textbooks, and publications., Results: Whereas 130 randomized controlled trials were found with patients outside of palliative care settings, only 10 controlled studies with patients in end-of-life situations were identified: three RCTs with methylnaltrexone and one with the combination of oxycodone and naloxone showed the effect and safety of opiate antagonists for patients who are not at risk of gastrointestinal perforation. There have been no studies which test methylnaltrexone against the optimization of therapy with conventional laxatives. Six other controlled studies of limited quality in design and execution and with only few participants tested naloxone, senna, lactulose, Co-danthramer, an Ayurvedic preparation (Misrakasneham), magnesium hydroxide, fluid paraffin, sodium picosulfate and docusate without finding statistically significant differences in efficacy or side effects. Most patients in these studies had cancer. Only case studies with few patients in palliative care were found for meglumine, neostigmine, and other substances mentioned above., Conclusion: Evidence on medical treatment of constipation in palliative care is sparse and guidelines have to refer to evidence from outside the palliative care setting and to expert opinions. Results from studies with other patient groups can only be transferred with limitations to very ill patients at the end of life who might have a higher risk for potential side effects such as gastrointestinal perforation in case of abdominal tumor manifestation. Therefore further studies are required to evaluate the medical treatment of multiple reasons for constipation in these patients. These studies should focus on feasibility, clinical relevance and quality of life. The English full text version of this article will be available in SpringerLink as of November 2012 (under "Supplemental").

Gastrointestinal dysmotility and constipation are common problems in critical care patients. The majority of critical care patients are treated with opioids, which inhibit gastrointestinal (GI) motility and lead to adverse outcomes. We reasoned that methylnaltrexone (MNTX), a peripheral opioid antagonist approved for the treatment of opioid-induced constipation in patients with advanced illness receiving palliative care when response to laxative therapy has not been sufficient, could improve GI function in critically ill patients. The present study included all patients in our intensive care unit who required rescue medication for GI stasis during the 10-week period from September 1 to November 15, 2009. We compared conventional rescue therapy with subcutaneous MNTX. We performed a retrospective chart review of the 88 nonsurgical critical care patients receiving fentanyl infusions, 15 (17%) of whom met the criteria of absence of laxation within 72 hours of intensive care unit admission despite treatment with senna and sodium docusate. Eight of these 15 patients subsequently received conventional rescue therapy (combination of sodium picosulfate [5 mg] and 2 glycerin suppositories [4-g mold]), and 7 patients received MNTX (subcutaneous injection, 0.15 mg/kg). Laxation occurred within 24 hours in 6 of the 7 MNTX patients (86%) but in none of the 8 patients receiving conventional rescue therapy (P=.001). The median difference in time to laxation between the 2 groups was 3.5 days (P<.001). Although not statistically significant, all 7 patients treated with MNTX, but only 4 of 8 (50%) who received conventional rescue therapy, progressed to full target enteral feeding (P=.08). Intensive care unit mortality was 2 of 7 MNTX patients (29%) vs 4 of 8 (50%) in the standard therapy group (P=.61). We hypothesize that MNTX may play an important role in restoration of bowel function in critically ill patients., (Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

The therapeutic action of opioid analgesics is compromised by peripheral adverse effects among which opioid-induced constipation (OIC) is the most disabling, with a prevalence reported to vary between 15 and 90 %. Although OIC is usually treated with laxatives, there is insufficient clinical evidence that laxatives are efficacious in this indication. In contrast, there is ample evidence from double- blind, randomized and placebo-controlled trials that peripheral opioid receptor antagonists (PORAs) counteract OIC. This specific treatment modality is currently based on subcutaneous methylnaltrexone for the interruption of OIC in patients with advanced illness, and a fixed combination of oral prolonged-release naloxone with prolonged-release oxycodone for the prevention of OIC in the treatment of non-cancer and cancer pain. Both drugs counteract OIC while the analgesic effect of opioids remains unabated. The clinical studies show that more than 50 % of the patients with constipation under opioid therapy may benefit from the use of PORAs, while PORA-resistant patients are likely to suffer from non-opioid-induced constipation, the prevalence of which increases with age. While the addition of naloxone to oxycodone seems to act by preventing OIC, the intermittent dosing of methylnaltrexone every other day seems to stimulate defaecation by provoking an intestinal withdrawal response. The availability of PORAs provides a novel opportunity to specifically control OIC and other peripheral adverse effects of opioid analgesics (e.g., urinary retention and pruritus). The continuous dosing of a PORA has the advantage of few adverse effects, while intermittent dosing of a PORA can be associated with abdominal cramp-like pain.

Opioid-induced constipation (OIC) is associated with negative impact of opioid analgesics on opioid receptors located in the gut wall. Until recently, OIC was treated symptomatically only, with different laxatives which did not target the pathophysiology of OIC. Recently, several opioid receptor antagonists have been introduced in the treatment of OIC. Methylnaltrexone (MNTX) is a peripheral mu-opioid receptor antagonist for subcutaneous administration, which does not evoke symptoms of opioid abstinence. MNTX is indicated for patients with OIC who are not amenable to therapy with oral laxatives. In clinical trials, the effectiveness of MNTX assessed as its ability to induce spontaneous bowel movement, is 50%-60% of treated patients; MNTX demonstrates significant superiority over placebo. Another product is combination of oral formulation of prolonged release oxycodone and prolonged release naloxone (PR oxycodone/PR naloxone), indicated for patients who require opioid administration for chronic pain and have already developed OIC, and for those who need opioid therapy and take the drug to prevent OIC. Naloxone administered orally displays local, antagonist effects on opioid receptors in the gut wall, negligible systemic bioavailability, and significantly reduces the oxycodone constipating effect. PR oxycodone/PR naloxone has similar analgesic efficacy, but causes less constipation and less laxative consumption in comparison with patients treated with oxycodone alone. Both products are expensive, therefore their administration should be carefully considered. On the other hand, uncontrolled OIC and the necessity to perform rectal invasive procedures (enema, manual evacuation) lead not only to increased health care costs, but most importantly, cause severe patient suffering.

Background: Opioid-induced constipation is a common adverse event in patients with advanced illness and has a significant negative impact on patients' quality of life and costs., Aim: To examine the cost-effectiveness of treating opioid-induced constipation with methylnaltrexone bromide (MNTX) plus standard care compared with standard care alone in patients with advanced illness who receive long-term opioid therapy from a third-party payer perspective in the Netherlands., Methods: A decision-analytical model was created in which advanced-illness patients with constipation were treated with MNTX plus standard care or standard care alone. Clinical efficacy in terms of percentage of patients with rescue-free laxation and time to rescue-free laxation were obtained from a randomized, controlled clinical study. Resource use, costs, utilities and mortality were obtained from published literature and supplemented with data from clinical experts., Results: Treatment with MNTX plus standard care results in more days without constipation symptoms. Cost of MNTX was mostly offset by reduction in other constipation-related costs. Thus, treating with MNTX plus standard care is cost-effective, with an incremental cost per QALY of 40,865 euro. Results were robust to changes in all parameters., Conclusions: Although using MNTX may increase total costs, MNTX plus standard care is cost-effective in treating advanced-illness patients with opioid-induced constipation.

Opioid-induced constipation is common in palliative care and causes considerable distress to patients taking opioids. Opioid-induced constipation can be difficult to manage with conventional laxatives, often requiring invasive rectal interventions. A unique bowel intervention linked specifically to opioid-induced constipation in the form of a subcutaneous injection is now available for the management of opioid-induced constipation. This article will examine all aspects of opioid-induced constipation with particular reference to this new management option, methylnaltrexone bromide (Relistor).

Methylnaltrexone, a peripherally acting mu-opioid receptor antagonist with restricted ability to cross the blood-brain barrier, reverses opioid-induced constipation (OIC) without affecting analgesia. A double-blind study in patients with advanced illness and OIC demonstrated that methylnaltrexone significantly induced laxation within four hours after the first dose compared with placebo. In this study, patients with advanced illness and OIC on stable doses of opioids and laxatives were randomized to methylnaltrexone 0.15mg/kg (n=62) or placebo (n=71) subcutaneously every other day for two weeks. Laxation was assessed daily. Constipation distress, bowel status change, pain, laxative use, and opioid withdrawal symptoms were assessed weekly using standardized scales. Additional analyses to further characterize response to methylnaltrexone revealed that among patients with a bowel movement within four hours following the first dose, the median time to response was 0.5 hours for methylnaltrexone. Response rates among methylnaltrexone-treated patients who had responded to all previous doses were 57%-100% for doses two to seven. Among methylnaltrexone-treated patients who did not respond to the first or to the first two consecutive doses, 35% and 26% responded to the second and third dose, respectively. Higher percentages of patients and clinicians rated bowel status as improved in the methylnaltrexone than the placebo group. Fewer methylnaltrexone than placebo patients reported use of common laxative types, particularly enemas, during the study. Subcutaneous methylnaltrexone promptly and predictably induced laxation, improved constipation distress, and was associated with less laxative use in patients with advanced illness and OIC.

In April 2008, the US FDA granted approval to methylnaltrexone (Relistor), the first peripheral micro-opioid-receptor antagonist for the treatment of opioid-induced constipation in advanced-illness patients receiving palliative care and for whom other laxative therapies failed to achieve adequate results. Methylnaltrexone, a quaternary derivative of naltrexone, introduces a novel mechanism of action that selectively antagonizes the peripheral micro-receptors in the GI tract without effects on the CNS. In clinical trials, subcutaneous methylnaltrexone reversed opioid-induced constipation after the first dose in approximately 50-60% of the patients. In most of the cases, effective laxation occurred within 1 h. The therapeutic benefit was sustained in multiple-dose studies. Owing to the nature of the population studied, safety data are available for approximately 4 months of use. Although it is not the focus of this article, methylnaltrexone's mechanism of action suggests it could be beneficial for other peripheral, opioid-induced adverse effects, such as opioid-related nausea, vomiting, urinary retention, pruritus or postoperative ileus.

Constipation is a common problem associated with opiates and opioid compounds used for the treatment of pain and other medical conditions, and can influence patient quality of life. Methylnaltrexone appears effective in the therapy of opioid-induced constipation and will be useful for patients failing to respond to traditional laxative regimens.

Background: Constipation is a distressing side effect of opioid treatment. As a quaternary amine, methylnaltrexone, a mu-opioid-receptor antagonist, has restricted ability to cross the blood-brain barrier. We investigated the safety and efficacy of subcutaneous methylnaltrexone for treating opioid-induced constipation in patients with advanced illness., Methods: A total of 133 patients who had received opioids for 2 or more weeks and who had received stable doses of opioids and laxatives for 3 or more days without relief of opioid-induced constipation were randomly assigned to receive subcutaneous methylnaltrexone (at a dose of 0.15 mg per kilogram of body weight) or placebo every other day for 2 weeks. Coprimary outcomes were laxation (defecation) within 4 hours after the first dose of the study drug and laxation within 4 hours after two or more of the first four doses. Patients who completed this phase were eligible to enter a 3-month, open-label extension trial., Results: In the methylnaltrexone group, 48% of patients had laxation within 4 hours after the first study dose, as compared with 15% in the placebo group, and 52% had laxation without the use of a rescue laxative within 4 hours after two or more of the first four doses, as compared with 8% in the placebo group (P<0.001 for both comparisons). The response rate remained consistent throughout the extension trial. The median time to laxation was significantly shorter in the methylnaltrexone group than in the placebo group. Evidence of withdrawal mediated by central nervous system opioid receptors or changes in pain scores was not observed. Abdominal pain and flatulence were the most common adverse events., Conclusions: Subcutaneous methylnaltrexone rapidly induced laxation in patients with advanced illness and opioid-induced constipation. Treatment did not appear to affect central analgesia or precipitate opioid withdrawal. (Clinical Trials.gov number, NCT00402038 [ClinicalTrials.gov].)., (Copyright 2008 Massachusetts Medical Society.)

Bowel dysfunction is a frequent and serious side effect of opioid analgetics. In spite of its common occurrence, in the course of clinical routine, it is frequently ignored or underestimated. Authors of the analysed literature widely agree that a prophylactic and routine pharmacotherapy is necessary. For this purpose, laxatives, enemas and suppositories, prokinetic agents and opioid antagonists can be considered. Bulk-forming laxatives did not prove to be effective, since the quantity of fluid intake required for the action usually cannot be provided. Furthermore, the benefit of emollient agents is doubted. As a monotherapy they are not sufficient. By contrast, stimulant and osmotic laxatives proved to be active. Prokinetic drugs are not recommended because of their serious side effects. Effective abatement of opioid-induced obstipation by opioid antagonists has been proven in numerous studies. However, the loss of analgesia and opioid withdrawal symptoms were described as adverse effects. Development of quaternary opioid antagonists such as methylnaltrexone was allowed for mitigating these adverse effects.