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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 -
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