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The Cochrane Database of Systematic... Sep 2022Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events... (Review)
Review
BACKGROUND
Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events (AEs) of treatment for pain in cancer and palliative care, resulting in increased morbidity and reduced quality of life. This review is a partial update of a 2008 review, and critiques as previous update (2018) trials only for people with cancer and people receiving palliative care.
OBJECTIVES
To assess for OIBD in people with cancer and people receiving palliative care the effectiveness and safety of mu-opioid antagonists (MOAs) versus different doses of MOAs, alternative pharmacological/non-pharmacological interventions, placebo, or no treatment.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science (December 2021), clinical trial registries and regulatory websites. We sought contact with MOA manufacturers for further data.
SELECTION CRITERIA
Randomised controlled trials (RCTs) assessing the effectiveness and safety of MOAs for OIBD in people with cancer and people at a palliative stage irrespective of the type of terminal disease.
DATA COLLECTION AND ANALYSIS
Two review authors assessed risk of bias and extracted data. The appropriateness of combining data from the trials depended upon sufficient homogeneity across trials. Our primary outcomes were laxation response, effect on analgesia, and AEs. We assessed the certainty of evidence using GRADE and created summary of findings tables.
MAIN RESULTS
We included 10 studies (two new trials) randomising in-total 1343 adults with cancer irrespective of stage, or at palliative care stage of any disease. The MOAs were oral naldemedine and naloxone (alone or in combination with oxycodone), and subcutaneous methylnaltrexone. The trials compared MOAs with placebo, MOAs at different doses, or in combination with other drugs. Two trials of naldemedine and three of naloxone with oxycodone were in people with cancer irrespective of disease stage. The trial on naloxone alone was in people with advanced cancer. Four trials on methylnaltrexone were in palliative care where most participants had advanced cancer. All trials were vulnerable to biases; most commonly, blinding of the outcome assessor was not reported. Oral naldemedine versus placebo Risk (i.e. chance) of spontaneous laxations in the medium term (over two weeks) for naldemedine was over threefold greater risk ratio (RR) 2.00, 95% confidence interval (CI) 1.59 to 2.52, 2 trials, 418 participants, I² = 0%. Number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 3 to 4; moderate-certainty evidence). Earlier risk of spontaneous laxations and patient assessment of bowel change was not reported. Very low-certainty evidence showed naldemedine had little to no effect on opioid withdrawal symptoms. There was little to no difference in the risk of serious (non-fatal) AEs (RR 3.34, 95% CI 0.85 to 13.15: low-certainty evidence). Over double the risk of AEs (non-serious) reported with naldemedine (moderate-certainty evidence). Low-dose oral naldemedine versus higher dose Risk of spontaneous laxations was lower for the lower dose (medium term, 0.1 mg versus 0.4 mg: RR 0.69, 95% CI 0.53 to 0.89, 1 trial, 111 participants (low-certainty evidence)). Earlier risk of spontaneous laxations and patient assessment of bowel change not reported. Low-certainty evidence showed little to no difference on opioid withdrawal symptoms (0.1 mg versus 0.4 mg mean difference (MD) -0.30, 95% CI -0.85 to 0.25), and occurrences of serious AEs (0.1 mg versus 0.4 mg RR 0.25, 95% CI 0.03 to 2.17). Low-certainty evidence showed little to no difference on non-serious AEs. Oral naloxone versus placebo Risk of spontaneous laxations and AEs not reported. Little to no difference in pain intensity (very low-certainty evidence). Full data not given. The trial reported that no serious AEs occurred. Oral naloxone + oxycodone versus oxycodone Risk of spontaneous laxations within 24 hours and in the medium term not reported. Low-certainty evidence showed naloxone with oxycodone reduced the risk of opioid withdrawal symptoms. There was little to no difference in the risk of serious (non-fatal) AEs (RR 0.68, 95% CI 0.44 to 1.06), 3 trials, 362 participants, I² = 55%: very low-certainty evidence). There was little to no difference in risk of AEs (low-certainty evidence). Subcutaneous methylnaltrexone versus placebo Risk of spontaneous laxations within 24 hours with methylnaltrexone was fourfold greater than placebo (RR 2.97, 95% CI 2.13 to 4.13. 2 trials, 287 participants, I² = 31%. NNTB 3, 95% CI 2 to 3; low-certainty evidence). Risk of spontaneous laxations in the medium term was over tenfold greater with methylnaltrexone (RR 8.15, 95% CI 4.76 to 13.95, 2 trials, 305 participants, I² = 47%. NNTB 2, 95% CI 2 to 2; moderate-certainty evidence). Low-certainty evidence showed methylnaltrexone reduced the risk of opioid withdrawal symptoms, and did not increase risk of a serious AE (RR 0.59, 95% CI 0.38 to 0.93. I² = 0%; 2 trials, 364 participants). The risk of AEs was higher for methylnaltrexone (low-certainty evidence). Lower-dose subcutaneous methylnaltrexone versus higher dose There was little to no difference in risk of spontaneous laxations in the medium-term (1 mg versus 5 mg or greater: RR 2.91, 95% CI 0.82 to 10.39; 1 trial, 26 participants very low-certainty evidence), or in patient assessment of improvement in bowel status (RR 0.98, 95% CI 0.71 to 1.35, 1 trial, 102 participants; low-certainty evidence). Medium-term assessment of spontaneous laxations and serious AEs not reported. There was little to no difference in symptoms of opioid withdrawal (MD -0.25, 95% CI -0.84 to 0.34, 1 trial, 102 participants) or occurrence of AEs (low-certainty evidence).
AUTHORS' CONCLUSIONS
This update's findings for naldemedine and naloxone with oxycodone have been strengthened with two new trials, but conclusions have not changed. Moderate-certainty evidence for oral naldemedine on risk of spontaneous laxations and non-serious AEs suggests in people with cancer that naldemedine may improve bowel function over two weeks and increase the risk of AEs. There was low-certainty evidence on serious AEs. Moderate-certainty evidence for methylnaltrexone on spontaneous laxations over two weeks suggests subcutaneous methylnaltrexone may improve bowel function in people receiving palliative care, but certainty of evidence for AEs was low. More trials are needed, more evaluation of AEs, outcomes patients rate as important, and in children.
Topics: Adult; Analgesics, Opioid; Child; Humans; Naloxone; Naltrexone; Narcotic Antagonists; Neoplasms; Opioid-Induced Constipation; Oxycodone; Palliative Care; Quaternary Ammonium Compounds; Substance Withdrawal Syndrome
PubMed: 36106667
DOI: 10.1002/14651858.CD006332.pub4 -
Journal of Pain and Symptom Management Nov 2007Many patients treated with opioids suffer from constipation. Opiate- or opioid-related constipation is not only a frequent but also a distressing symptom and difficult... (Meta-Analysis)
Meta-Analysis Review
Many patients treated with opioids suffer from constipation. Opiate- or opioid-related constipation is not only a frequent but also a distressing symptom and difficult to treat. There is emerging evidence regarding a novel approach to the management of opiate-related constipation. The aim of this paper is to collect, critically appraise, and summarize the evidence on the effectiveness of recently developed peripherally acting micro-receptor antagonists in the treatment of opiate-related constipation. A comprehensive search of 11 computerized databases was conducted and efforts were made to identify unpublished and ongoing research. Twenty studies were identified; 13 were randomized controlled trials (RCTs) and 7 were Phase II studies assessing toxicity. Studies were mainly executed in healthy volunteers or members of methadone programs with opioid-induced constipation as a model to mimic the condition of patients on opioids. Two RCTs were conducted in hospice patients. Quality of study design and validity of the findings was assessed in all studies. Data show proof of concept but do not allow a definitive answer concerning the effectiveness of the peripherally acting micro-opioid antagonists methylnaltrexone and alvimopan in managing opiate-related constipation. Further research is needed. If future Phase III trials provide supportive data, opioid antagonists may become a standard therapeutic option for the treatment of opiate-related constipation in patients with advanced cancer.
Topics: Analgesics, Opioid; Constipation; Humans; Narcotic Antagonists; Pain, Intractable; Receptors, Opioid, mu
PubMed: 17900855
DOI: 10.1016/j.jpainsymman.2006.12.018 -
Advances in Therapy May 2022Opioid-induced constipation (OIC) prescription medications (OIC-Rx) like methylnaltrexone subcutaneous (SC) have shown efficacy in treating OIC in the emergency...
INTRODUCTION
Opioid-induced constipation (OIC) prescription medications (OIC-Rx) like methylnaltrexone subcutaneous (SC) have shown efficacy in treating OIC in the emergency department (ED). This study aimed to describe and compare healthcare resource utilization (HRU) and healthcare costs in ED patients with OIC receiving OIC-Rx versus those not receiving OIC-Rx.
METHODS
Adult patients with OIC during an ED encounter were identified from a hospital-based ED encounters database (2016-2019) and classified on the basis of receipt of OIC-Rx (OIC-Rx versus No OIC-Rx cohorts). Entropy balancing was used to reweight characteristics of the two cohorts. HRU and healthcare costs were measured and compared during the ED encounter and 30-day post-discharge period.
RESULTS
Among 11,135 patients in the OIC-Rx cohort (21,474 in the No OIC-Rx cohort), 93% received methylnaltrexone SC. Patients in the OIC-Rx cohort had 0.7 fewer inpatient days per OIC ED encounter and 64% decreased odds of being hospitalized versus the No OIC-Rx cohort (both p < 0.001). During the post-discharge period, the OIC-Rx cohort had 35% decreased odds of any re-encounter (p < 0.001). The OIC-Rx cohort had a $732 reduction in costs per OIC ED encounter versus the No OIC-Rx cohort (p < 0.001), driven by larger hospitals and patients with Medicare or Commercial insurance. During the post-discharge period, the OIC-Rx cohort had a $421 reduction in costs associated with any re-encounter versus the No OIC-Rx cohort (p = 0.004).
CONCLUSION
Patients receiving OIC-Rx in the ED had decreased odds of being hospitalized and fewer re-encounters in the 30-day post-discharge period versus patients who did not receive OIC-Rx, resulting in cost savings for insurance agencies and healthcare providers.
Topics: Adult; Aftercare; Aged; Analgesics, Opioid; Constipation; Emergency Service, Hospital; Humans; Medicare; Opioid-Induced Constipation; Patient Discharge; United States
PubMed: 35298784
DOI: 10.1007/s12325-022-02090-9 -
Journal of Pain Research 2020Opioid analgesics remain a treatment option for refractory acute and chronic pain, despite their potential risk for abuse and adverse events (AEs). Opioids are... (Review)
Review
Opioid analgesics remain a treatment option for refractory acute and chronic pain, despite their potential risk for abuse and adverse events (AEs). Opioids are associated with several common AEs, but the most bothersome is opioid-induced constipation (OIC). OIC is often overlooked but has the potential to affect patient quality of life, increase associated symptom burden, and impede long-term opioid compliance. The peripherally acting µ-receptor antagonists (PAMORAs) are a class of drugs that include methylnaltrexone, naloxegol, and naldemedine. Collectively, each is approved for the treatment of OIC. PAMORAs work peripherally in the gastrointestinal tract, without impacting the central analgesic effects of opioids. However, each has unique pharmacokinetic properties that may be impacted by coadministered drugs or food. This review focuses on important metabolic and pharmacokinetic principals that are pertinent to drug interactions involving µ-opioid receptor antagonists prescribed for OIC. It highlights subtle differences among the PAMORAs that may have clinical significance. For example, unlike naloxegol or naldemedine, methylnaltrexone is not a substrate for CYP3A4 or p-glycoprotein; therefore, its plasma concentration is not altered when coadministered with concomitant medications that are CYP3A4 or p-glycoprotein inducers or inhibitors. With a better understanding of pharmacokinetic nuances of each PAMORA, clinicians will be better equipped to identify potential safety and efficacy considerations that may arise when PAMORAs are coadministered with other medications.
PubMed: 32158255
DOI: 10.2147/JPR.S220859 -
The Journal of Pediatric Pharmacology... Jun 2024Constipation is a common adverse event of opioid use that is often difficult to treat. Methylnaltrexone is a therapeutic option for opioid-induced constipation (OIC)...
OBJECTIVES
Constipation is a common adverse event of opioid use that is often difficult to treat. Methylnaltrexone is a therapeutic option for opioid-induced constipation (OIC) approved for oral and subcutaneous use in adults. These administration routes are not always feasible in the pediatric population. The primary objective of this research was to quantify the response rate of methylnaltrexone in pediatric patients when it was administered via the intravenous (IV) route.
METHODS
This retrospective study evaluated patients ages <18 years who received IV methylnaltrexone between January 1, 2013, and June 30, 2020, for OIC. Efficacy was evaluated through documentation of bowel evacuation within 4 hours of methylnaltrexone administration. Adverse events observed within 24 hours of administration were attributed to methylnaltrexone.
RESULTS
Methylnaltrexone was administered to 134 unique patients during the study period. Of these, 46 met exclusion criteria, resulting in 88 patients being included in the study. Patients with an underlying hematology/oncology diagnosis consisted of 77% of the study population, and 23% of patients had an -underlying medical/surgical diagnosis. The response rate to IV methylnaltrexone was 25% (CI, 16-34).
CONCLUSIONS
The results of this retrospective chart review demonstrate the potential role of IV methylnaltrexone in the pediatric population. Despite the overall lower response rate relative to that reported in adults, IV methylnaltrexone possesses a unique mechanism of action that may serve as an alternative treatment option for patients unable to use the oral and subcutaneous administration routes. There were no significant adverse events seen in the study.
PubMed: 38863861
DOI: 10.5863/1551-6776-29.3.292 -
Clinical and Experimental... 2014Opioid-induced bowel dysfunction (OIBD) is a burdensome condition which limits the therapeutic benefit of analgesia. It affects the entire gastrointestinal tract,... (Review)
Review
Opioid-induced bowel dysfunction (OIBD) is a burdensome condition which limits the therapeutic benefit of analgesia. It affects the entire gastrointestinal tract, predominantly by activating opioid receptors in the enteric nervous system, resulting in a wide range of symptoms, such as reflux, bloating, abdominal cramping, hard, dry stools, and incomplete evacuation. The majority of studies evaluating OIBD focus on constipation experienced in approximately 60% of patients. Nevertheless, other presentations of OIBD seem to be equally frequent. Furthermore, laxative treatment is often insufficient, which in many patients results in decreased quality of life and discontinuation of opioid treatment. Novel mechanism-based pharmacological approaches targeting the gastrointestinal opioid receptors have been marketed recently and even more are in the pipeline. One strategy is prolonged release formulation of the opioid antagonist naloxone (which has limited systemic absorption) and oxycodone in a combined tablet. Another approach is peripherally acting, μ-opioid receptor antagonists (PAMORAs) that selectively target μ-opioid receptors in the gastrointestinal tract. However, in Europe the only PAMORA approved for OIBD is the subcutaneously administered methylnaltrexone. Alvimopan is an oral PAMORA, but only approved in the US for postoperative ileus in hospitalized patients. Finally, naloxegol is a novel, oral PAMORA expected to be approved soon. In this review, the prevalence and pathophysiology of OIBD is presented. As PAMORAs seem to be a promising approach, their potential effect is reviewed with special focus on naloxegol's pharmacological properties, data on safety, efficacy, and patient-focused perspectives. In conclusion, as naloxegol is administered orally once daily, has proven efficacious compared to placebo, has an acceptable safety profile, and can be used as add-on to existing pain treatment, it is a welcoming addition to the targeted treatment possibilities for OIBD.
PubMed: 25278772
DOI: 10.2147/CEG.S52097 -
Pain Medicine (Malden, Mass.) Mar 2023Preclinical and clinical studies suggest that activation of the µ-opioid receptor may reduce overall survival and increase the risk for all-cause mortality in patients... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Preclinical and clinical studies suggest that activation of the µ-opioid receptor may reduce overall survival and increase the risk for all-cause mortality in patients with cancer and noncancer pain. Methylnaltrexone, a selective, peripherally acting µ-opioid receptor antagonist, has demonstrated efficacy for the treatment of opioid-induced constipation. This retrospective analysis of 12 randomized, double-blind, placebo-controlled studies of methylnaltrexone evaluated the treatment of opioid-induced bowel disorders in patients with advanced illness or noncancer pain.
METHODS
The risk of all-cause mortality within 30 days after the last dose of study medication during the double-blind phase was compared between methylnaltrexone and placebo groups. The data were further stratified by cancer vs noncancer, age, gender, and acute vs chronic diagnoses.
RESULTS
Pooled data included 2,526 methylnaltrexone-treated patients of which 33 died, and 1,192 placebo-treated patients of which 35 died. The mortality rate was 17.8 deaths/100 person-years of exposure in the methylnaltrexone group and 49.5 deaths/100 person-years of exposure for the placebo group. The all-cause mortality risk was significantly lower among patients receiving methylnaltrexone compared with placebo (hazard ratio: 0.399, 95% confidence interval: 0.25, 0.64; P = .0002), corresponding to a 60% risk reduction. Significant risk reductions were observed for those receiving methylnaltrexone who had cancer or chronic diagnoses. Methylnaltrexone-treated patients had a significantly reduced mortality risk compared with placebo regardless of age or gender.
CONCLUSIONS
Methylnaltrexone reduced all-cause mortality vs placebo treatment across multiple trials, suggesting methylnaltrexone may confer survival benefits in patients with opioid-induced bowel disorders taking opioids for cancer-related or chronic noncancer pain.
Topics: Humans; Analgesics, Opioid; Retrospective Studies; Constipation; Chronic Pain; Naltrexone; Narcotic Antagonists; Double-Blind Method; Randomized Controlled Trials as Topic
PubMed: 36102822
DOI: 10.1093/pm/pnac136 -
Journal of Pain Research 2023Opioid-induced constipation (OIC) is a common side effect of opioid therapy. Methylnaltrexone (MNTX) is a selective, peripherally acting μ-opioid receptor antagonist,... (Clinical Trial)
Clinical Trial
PURPOSE
Opioid-induced constipation (OIC) is a common side effect of opioid therapy. Methylnaltrexone (MNTX) is a selective, peripherally acting μ-opioid receptor antagonist, with demonstrated efficacy in treating OIC. We pooled results from MNTX clinical trials to compare responses to an initial dose in patients with chronic cancer and noncancer pain.
PATIENTS AND METHODS
This post hoc analysis used pooled data from 3 randomized, placebo-controlled studies of MNTX in patients with advanced illness with OIC. Assessments included the proportions of patients achieving rescue-free laxation (RFL) within 4 and 24 hours of the first study drug dose, time to RFL, current and worst pain intensity, and adverse events, stratified by the presence/absence of cancer.
RESULTS
A total of 355 patients with cancer (MNTX n = 198, placebo n = 157) and 163 without active cancer (MNTX n = 83; placebo n = 80) were included. More patients treated with MNTX compared with those who received placebo achieved an RFL within 4 (cancer: MNTX, 61.1% vs placebo,15.3%, <0.0001; noncancer: MNTX, 62.2% vs placebo, 17.5%, <0.0001) and 24 hours (cancer: MNTX, 71.2% vs placebo, 41.4%, <0.0001; noncancer: MNTX, 74.4% vs placebo, 37.5%, <0.0001) of the initial dose. Cumulative RFL response rates within 4 hours of the first, second, or third dose of study drug were also higher in MNTX-treated patients. The estimated time to RFL was shorter among those who received MNTX and similar in cancer and noncancer patients. Mean pain scores declined similarly in all groups. The most common adverse events in both cancer and noncancer patients were abdominal pain, flatulence, and nausea.
CONCLUSION
After the first dose, MNTX rapidly induced a laxation response in the majority of both cancer and noncancer patients with advanced illness. Opioid-induced analgesia was not compromised, and adverse events were primarily gastrointestinal in nature. Methylnaltrexone is a well-tolerated and effective treatment for OIC in both cancer and noncancer patients.
PubMed: 37533563
DOI: 10.2147/JPR.S405825 -
Patient Preference and Adherence 2017Opioid-induced constipation (OIC), a prevalent and distressing side effect of opioid therapy, does not reliably respond to treatment with conventional laxatives. OIC can... (Review)
Review
Opioid-induced constipation (OIC), a prevalent and distressing side effect of opioid therapy, does not reliably respond to treatment with conventional laxatives. OIC can be a treatment-limiting adverse event. Recent advances in medications with peripherally acting μ-opioid receptor antagonists, such as methylnaltrexone, naloxegol, and alvimopan, hold promise for treating OIC and thus extending the benefits of opioid analgesia to more chronic pain patients. Peripherally acting μ-opioid receptor antagonists have been clinically tested to improve bowel symptoms without compromise to pain relief, although there are associated side effects, including abdominal pain. Other treatment options include fixed-dose combination products of oxycodone analgesic together with naloxone.
PubMed: 28176913
DOI: 10.2147/PPA.S78042 -
Journal of the American Association For... Mar 2017Among the many analgesic agents available, buprenorphine appears to be the analgesic used most often in rabbits. Unfortunately, deleterious side effects of opioids, such... (Clinical Trial)
Clinical Trial
Among the many analgesic agents available, buprenorphine appears to be the analgesic used most often in rabbits. Unfortunately, deleterious side effects of opioids, such as gastrointestinal stasis and anorexia, may discourage the use of these agents. Methylnaltrexone is a peripheral opioid antagonist that ameliorates opioid-induced gastrointestinal stasis in others species yet preserves the analgesic effects of buprenorphine. We evaluated whether methylnaltrexone reversed buprenorphine-induced gastrointestinal stasis in 8 healthy male New Zealand White rabbits. To measure gastrointestinal transit time, each rabbit received 20 barium-filled spheres through an orogastric tube. Rabbits then received 4 treatments in random order: buprenorphine (0.05 mg/kg SC), methylnaltrexone (1 mg/kg SC), both agents combined (B+M), or normal saline (control) every 12 h for 2 d. Fecal production was measured every 6 h, and water and food consumption, and body weight, were measured daily, for 5 d after each treatment. The time to appearance of the first sphere was significantly longer for buprenorphine group than for control and methylnaltrexone groups. Daily fecal output was lowest for buprenorphine and B+M, intermediate for control, and highest for methylnaltrexone. Water and food consumption were lower for groups buprenorphine and B+M than for control and methylnaltrexone. Body weight was not affected. In conclusion, treatment with buprenorphine 0.05 mg/kg BID for 2 d in healthy rabbits decreased food and water consumption, prolonged gastrointestinal transit time and decreased the fecal output. Coadministration of methylnaltrexone at 1 mg/kg did not alleviate these negative side effects.
Topics: Analgesics, Opioid; Animals; Body Weight; Buprenorphine; Drug Therapy, Combination; Feces; Gastrointestinal Transit; Laboratory Animal Science; Male; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Rabbits
PubMed: 28315644
DOI: No ID Found