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Cancer Treatment Reviews Apr 2024Cancer-related pain often requires opioid treatment with opioid-induced constipation (OIC) as its most frequent gastrointestinal side-effect. Both for prevention and... (Meta-Analysis)
Meta-Analysis Review
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 = 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 = 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 = 0 %; MNTX: RR 3.83, 95 % CI 2.81-5.22, I = 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.
Topics: Humans; Laxatives; Analgesics, Opioid; Narcotic Antagonists; Constipation; Oxycodone; Opioid-Induced Constipation; Magnesium Oxide; Cohort Studies; Naloxone; Polyethylene Glycols; Neoplasms; Drug-Related Side Effects and Adverse Reactions; Quaternary Ammonium Compounds; Naltrexone
PubMed: 38452708
DOI: 10.1016/j.ctrv.2024.102704 -
Neurogastroenterology and Motility Dec 2023Constipation is frequent in critically ill patients, and potentially related to adverse outcomes. Peripherally-active mu-opioid receptor antagonists (PAMORAs) are... (Meta-Analysis)
Meta-Analysis
Peripherally-active mu-opioid receptor antagonists for constipation in critically ill patients receiving opioids: A case-series and a systematic review and meta-analysis of the literature.
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.
Topics: Adult; Humans; Narcotic Antagonists; Analgesics, Opioid; Constipation; Opioid-Induced Constipation; Retrospective Studies; Critical Illness; Naltrexone; Laxatives
PubMed: 37869768
DOI: 10.1111/nmo.14694 -
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 -
Cureus Jul 2021In treating chronic and acute pain, opioids are widely used. Although they do provide analgesia, their usage does come with adverse events (AEs). One of the most... (Review)
Review
In treating chronic and acute pain, opioids are widely used. Although they do provide analgesia, their usage does come with adverse events (AEs). One of the most burdensome is opioid-induced bowel dysfunction, and more specifically opioid-induced constipation (OIC). The pathogenesis of these AEs is well known as the consequence of the action of opioids on m-receptors in the enteric nervous system. In recent years, medicines counteracting this specific action at the receptors have been registered for clinical use: the peripherally acting μ-opioid receptor antagonists (PAMORAs). The knowledge of their comparative efficacy and tolerability is very important for physicians and patients in opioid therapy. This systematic review of the existing literature on PAMORAs aimed to study the relative clinical advantages and disadvantages. The most important data banks, including "PubMed," "Embase," "CT.gov," "ICTRP" and "CINAHL" were used to find the published material on PAMORAs. The selected publications were examined to systematically analyze the efficacy and safety of the four existing PAMORAs. All of the medications are superior to placebo in reducing OIC. There are few published data on alvimopan used to treat OIC, and it is only indicated for the treatment of post-abdominal surgery ileus. Methylnaltrexone is studied mainly in its subcutaneous (SC) formulation. When used in its oral formulation, it seems more rapid than naloxegol and placebo in the reduction of OIC. Naldemedine is able to produce more spontaneous bowel movements (SBMs) when compared to alvimopan and naloxegol. Tolerability was found to be similar for all of them. In particular, they affect the gastrointestinal tract (GI), with flatulence and diarrhea, especially at high dosages. For some of them, nasopharyngitis and abdominal pain were observed as treatment adverse effects (TEAs). Several cardiovascular TEAs were reported after methylnaltrexone use, but it is not clear whether they were consequences of the drug or related to the general conditions of the patients. Considering the existing data, naloxegol and naldemedine seem to be the best choices, with a higher number of spontaneous bowel movements following naldemedine administration.
PubMed: 34367804
DOI: 10.7759/cureus.16201 -
Oncology Nursing Forum Nov 2020A systematic review and meta-analysis was conducted to inform the development of national clinical practice guidelines on the management of cancer constipation. (Meta-Analysis)
Meta-Analysis
PROBLEM IDENTIFICATION
A systematic review and meta-analysis was conducted to inform the development of national clinical practice guidelines on the management of cancer constipation.
LITERATURE SEARCH
PubMed®, Wiley Cochrane Library, and CINAHL® were searched for studies published from May 2009 to May 2019.
DATA EVALUATION
Two investigators independently reviewed and extracted data from eligible studies. The Cochrane Collaboration risk-of-bias tool was used, and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to assess the certainty of the evidence.
SYNTHESIS
For patients with cancer and opioid-induced constipation, moderate benefit was found for osmotic or stimulant laxatives; small benefit was found for methylnaltrexone, naldemedine, and electroacupuncture. For patients with cancer and non-opioid-related constipation, moderate benefit was found for naloxegol, prucalopride, lubiprostone, and linaclotide; trivial benefit was found for acupuncture.
IMPLICATIONS FOR PRACTICE
Effective strategies for managing opioid-induced and non-opioid-related constipation in patients with cancer include lifestyle, pharmacologic, and complementary approaches.
SUPPLEMENTAL MATERIAL CAN BE FOUND AT HTTPS
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Topics: Analgesics, Opioid; Constipation; Gastrointestinal Agents; Humans; Neoplasms
PubMed: 33063777
DOI: 10.1188/20.ONF.E211-E224 -
Alimentary Pharmacology & Therapeutics Jul 2020When opioid-induced constipation is treated with centrally acting opioid antagonists, there may be opioid withdrawal or aggravation of pain due to inhibition of... (Meta-Analysis)
Meta-Analysis
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.
Topics: Analgesics, Opioid; Constipation; Humans; Laxatives; Narcotic Antagonists; Randomized Controlled Trials as Topic; Receptors, Opioid, mu; Treatment Outcome
PubMed: 32462777
DOI: 10.1111/apt.15791 -
The Cochrane Database of Systematic... Jun 2018Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events of... (Meta-Analysis)
Meta-Analysis 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 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.
OBJECTIVES
To assess the effectiveness and safety of MOA for OIBD in people with cancer and people receiving palliative care.
SEARCH METHODS
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.
SELECTION CRITERIA
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.
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 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.
MAIN RESULTS
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 (RR 2.77, 95% CI 1.91 to 4.04. I² = 0%; moderate-quality evidence). In combined analysis, we found methylnaltrexone induced more laxation responses over two weeks (RR 9.98, 95% CI 4.96 to 20.09. I² = 0%; moderate-quality evidence). The proportion of participants who had a rescue-free laxation response within 24 hours of the first dose was 59.1% in the methylnaltrexone arms and 19.1% in the placebo arm. There was moderate-quality evidence that the rate of opioid withdrawal was not affected. Methylnaltrexone did not increase the likelihood of a serious adverse event; there were fewer in the intervention arm (RR 0.59, 95% CI 0.38 to 0.93; I² = 0%; moderate-quality evidence). There was no difference in the proportion of participants experiencing an adverse event (RR 1.17, 95% CI 0.94 to 1.45; I² = 74%; low-quality evidence). Methylnaltrexone increased the likelihood of abdominal pain and flatulence.Two trials compared differing methylnaltrexone schedules of higher doses with lower doses. For early laxation, there was low-quality evidence of no clear difference between doses on analgesia and adverse events. Both trials measured laxation response within 24 hours of first dose (trial one: RR 0.82, 95% CI 0.41 to 1.66; trial two: RR 1.07, 95% CI 0.81 to 1.42).
AUTHORS' CONCLUSIONS
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
PubMed: 29869799
DOI: 10.1002/14651858.CD006332.pub3 -
Clinical Gastroenterology and... Oct 2018Opioid-induced constipation (OIC) is a common problem in patients on chronic opioid therapy for cancer-related and non-cancer-related pain. Approved treatments for OIC... (Meta-Analysis)
Meta-Analysis
BACKGROUND & AIMS
Opioid-induced constipation (OIC) is a common problem in patients on chronic opioid therapy for cancer-related and non-cancer-related pain. Approved treatments for OIC are methylnaltrexone, naloxone, naloxegol, alvimopan, naldemedine, and lubiprostone. Since a meta-analysis performed in 2014, 2 new agents have been approved by the Food and Drug Administration for treatment of OIC (naloxegol and naldemedine).
METHODS
We conducted a search of the medical literature following the protocol outlined in the Cochrane Handbook for systematic review. We searched MEDLINE, EMBASE, EMBASE Classic, Web of Science, and the Cochrane Central Register of Controlled Trials until March 2017 to identify randomized controlled trials of peripheral μ-opioid-receptor antagonists (methylnaltrexone, naloxone, naloxegol, alvimopan, axelopran, or naldemedine), lubiprostone, or prucalopride. Response to therapy was extracted in a dichotomous assessment as an overall response to therapy. The effect of pharmacologic therapies was pooled and reported as a relative risk (RR) of failure to respond to the treatment drug, with 95% CIs.
RESULTS
We included 27 placebo-controlled trials in our meta-analysis (23 trials evaluated μ-opioid-receptor antagonists, 3 trials evaluated lubiprostone, and 1 trial evaluated prucalopride). In these trials, 5390 patients received a drug and 3491 received a placebo. Overall, μ-opioid-receptor antagonists, lubiprostone, and prucalopride were superior to placebo for the treatment of OIC, with a RR of failure to respond to therapy of 0.70 (95% CI, 0.64-0.75) and an overall number needed to treat of 5 (95% CI, 4-7). When restricted to only Food and Drug Administration-approved medications for OIC, the RR of failure to respond to therapy was 0.69 (95% CI, 0.62-0.77), with a number needed to treat of 5 (95% CI, 4-7). Sensitivity analyses and meta-regression performed to account for heterogeneity showed that treatment was more likely to be effective in study populations taking higher doses of opiates at baseline or refractory to laxatives. Study duration and prespecified primary outcome did not affect the RR of failure. Participants who received μ-opioid-receptor antagonists were significantly more likely to have diarrhea, abdominal pain, nausea, or vomiting than patients who received placebo.
CONCLUSIONS
In a systematic review and meta-analysis, we found μ-opioid-receptor antagonists to be safe and effective for the treatment of OIC. Prescription-strength laxatives (prucalopride, lubiprostone) are slightly better than placebo in reducing OIC.
Topics: Analgesics, Opioid; Constipation; Female; Gastrointestinal Agents; Humans; Male; Narcotic Antagonists; Randomized Controlled Trials as Topic; Receptors, Opioid, mu; Treatment Outcome
PubMed: 29374616
DOI: 10.1016/j.cgh.2018.01.021 -
Regional Anesthesia and Pain Medicine 2017Opioid-induced constipation has a negative impact on quality of life for patients with chronic pain and can affect more than a third of patients. A related but separate... (Review)
Review
Opioid-induced constipation has a negative impact on quality of life for patients with chronic pain and can affect more than a third of patients. A related but separate entity is postoperative ileus, which is an abnormal pattern of gastrointestinal motility after surgery. Nonselective μ-opioid receptor antagonists reverse constipation and opioid-induced ileus but cross the blood-brain barrier and may reverse analgesia. Peripherally acting μ-opioid receptor antagonists target the μ-opioid receptor without reversing analgesia. Three such agents are US Food and Drug Administration approved. We reviewed the literature for randomized controlled trials that studied the efficacy of alvimopan, methylnaltrexone, and naloxegol in treating either opioid-induced constipation or postoperative ileus. Peripherally acting μ-opioid receptor antagonists may be effective in treating both opioid-induced bowel dysfunction and postoperative ileus, but definitive conclusions are not possible because of study inconsistency and the relatively low quality of evidence. Comparisons of agents are difficult because of heterogeneous end points and no head-to-head studies.
Topics: Analgesics, Opioid; Constipation; Humans; Ileus; Narcotic Antagonists; Postoperative Complications; Randomized Controlled Trials as Topic
PubMed: 29016552
DOI: 10.1097/AAP.0000000000000671 -
Journal of Pain and Symptom Management Feb 2018Opioid-induced constipation is a common problem associated with chronic use of opioid analgesics. (Meta-Analysis)
Meta-Analysis
CONTEXT
Opioid-induced constipation is a common problem associated with chronic use of opioid analgesics.
OBJECTIVES
The objective of this study was to compare available interventions for the treatment of opioid-induced constipation, using principles of network meta-analysis.
METHODS
Electronic databases were searched for randomized controlled clinical trials evaluating drugs used in opioid-induced constipation. Number of patients with rescue-free bowel movements (RFBM) was the primary outcome, and time for achieving RFBM, adverse events, and changes in the analgesic activity of the opioid analgesics were the secondary outcomes. Inverse variance heterogeneity model was used for direct and mixed treatment comparison analysis. Odds ratio for categorical outcomes and weighted mean difference for numerical outcomes were the effect estimates.
RESULTS
We included a total of 23 studies in the systematic review and 21 in the network meta-analysis. Lubriprostone, prucalopride, naldemedine, naloxegol, alvimopan, subcutaneous, and oral methyl naltrexone were observed to perform better than placebo in terms of RFBM. Additionally, subcutaneous methyl naltrexone was significantly better than lubiprostone, naloxegol, oral methyl naltrexone, and prucalopride. Lubiprostone and naldemedine were associated with increased risks of adverse events. Subcutaneous methyl naltrexone did not significantly affect the analgesia due to background opioid use. Quality of evidence for the comparisons is either low or very low.
CONCLUSION
Subcutaneous methyl naltrexone was found to perform better than other interventions for managing opioid-induced constipation.
Topics: Analgesics, Opioid; Constipation; Humans; Laxatives; Network Meta-Analysis; Opioid-Related Disorders; Randomized Controlled Trials as Topic
PubMed: 28919541
DOI: 10.1016/j.jpainsymman.2017.08.022