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Candy B, Jones L, Vickerstaff V, et al. Mu-opioid antagonists for opioid-induced bowel dysfunction in people with cancer and people receiving palliative care. Cochrane Database Syst Rev. 2022 Sep 15;9:CD006332. doi: 10.1002/14651858.CD006332.pub4. (Systematic review)
Abstract

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.

Ratings
Discipline Area Score
Physician 5 / 7
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Comments from MORE raters

Physician rater

A huge flaw in the published research of all of these drugs is that the comparator should be PEG or a similar laxative with some evidence. Optimal comparisons would be placebo vs. PEG vs. mu-opioid antagonist vs. PEG plus mu-opioid antagonist. These mu-opioid antagonists are much more expensive and should not be funded until the appropriate trials are completed.

Physician rater

Opioid-induced bowel dysfunction is a serious concern for patients with a need for chronic opioid use. Mu-antagonists are an attractive therapy for this problem, but good data are still lacking on their true effectiveness. More studies are needed.

Physician rater

Well-done systematic review showing that mu-opioid antagonists show some benefit for opioid-induced bowel dysfunction in people with cancer and people receiving palliative care. Probably not terribly relevant for public health but definitely relevant for internal medicine and palliative care.

Physician rater

Results and conclusion are not relevant to clinical practice.

Physician rater

Some new data, although most were included in the previous Cochrane review on this topic. Overall, better quality, longer trials are needed.

Physician rater

Opioid-induced bowel dysfunction is a frequent occurrence among my inpatient population. In general, I am familiar and comfortable with the use of methylnaltrexone but less familiar with other agents, including oral naldemedine. This manuscript confirmed my preconceived understanding that opioid antagonists were effective, with relatively well-tolerated side effects in relieving constipation.

Physician rater

These results are what we have expected.

Physician rater

This systematic review serves as a good reminder of the usefulness of mu-opioid antagonists to improve opioid-induced constipation. It also highlights that methylnaltrexone is probably the most effective option to use.

Physician rater

Expanded evidence on the activity of mu-opioid antagonists for opioid-induced bowel dysfunction in advanced cancer patients receiving palliative care.

Physician rater

This study is a good reminder of the option of Mu antagonists, but I suspect most people in palliative care already know this. What is needed is more robust studies, which is really the conclusion of the review.

Physician rater

Extensive Cochrane review of the use of mu-opioid antagonists for opioid-induced bowel dysfunction concludes that better trials are needed, with soft evidence favoring their use.

Physician rater

The study proves that not much has changed in our knowledge base since the prior review. It is a pity because opioid-induced constipation is a significant problem in oncology, which limits the patient's QoL.
Comments from PAIN+ CPN subscribers

Ms. Sandy Ketler (9/28/2022 6:45 AM)

I agree with the physician rater that comparison to PEG products would be helpful. For people near end of life incontinence may be of less concern than comfort?