Efficacy and Safety of Methylnaltrexone for the Treatment of Opioid-Induced Constipation: A Meta-analysis of Randomized Controlled Trials

Abstract

Background: Opioid-induced constipation (OIC) is a distressing side effect during opioid analgesia and is mainly mediated by gastrointestinal μ opioid receptors. Methylnaltrexone, a peripheral μ opioid receptor antagonist with restricted ability to cross the blood-brain barrier, may alleviate OIC without reversing analgesia. We performed a meta-analysis to assess the efficacy and safety of methylnaltrexone for the treatment of OIC.

Methods: We searched PubMed, Embase, and Cochrane Library for randomized controlled trials that compared methylnaltrexone with placebo for the treatment of OIC. The primary efficacy outcome was rescue-free bowel movement (RFBM) within 4 hours after the first dose. Secondary efficacy outcomes included RFBM within 24 hours after the first dose, RFBM ≥3 times per week, and need take rescue laxatives. The primary safety outcome was any adverse events. Secondary safety outcomes included abdominal pain, diarrhea, nausea, vomiting, and flatulence. Relative risks (RR) and 95% confidence interval (CI) were pooled using random-effects model with the intention-to-treat principle. We used the GRADE approach to assess the certainty of the evidence.

Results: Eight trials with 2,034 participants were included. Compared with placebo, methylnaltrexone significantly increased RFBM within 4 hours after the first dose (8 trials; 1,833 participants; RR 3.74, 95% CI 3.02-4.62; I² = 0%; high-certainty evidence), RFBM within 24 hours after the first dose (2 trials; 614 participants; RR 1.98, 95% CI 1.52-2.58; I² = 9%; moderate-certainty evidence), and RFBM ≥3 times per week (3 trials; 1,396 participants; RR 1.33, 95% CI 1.17-1.52; I² = 0%; moderate-certainty evidence) and decreased need to take rescue laxatives (3 trials; 807 participants; RR 0.73, 95% CI 0.63-0.85; I² = 0%; moderate-certainty evidence). For safety outcomes, there was no difference in any adverse events between the two groups (8 trials; 2,034 participants; RR 1.11, 95% CI 0.99-1.23; I² = 34%; moderate-certainty evidence), including diarrhea, nausea, vomiting, and flatulence; but for the most commonly reported adverse events, the abdominal pain was higher in methylnaltrexone group than that in placebo group (6 trials; 1,813 participants; RR 2.30, 95% CI 1.29-4.08; I² = 62%; moderate-certainty evidence).

Conclusions: Methylnaltrexone is an effective and safe drug for treating OIC. But the safety of abdominal pain should be considered.

Trial registration: PROSPERO (CRD42020187290).

Background

Opioid-induced constipation (OIC) is the most common side effect during opioid analgesia in patients with advanced illness including incurable cancer or other terminal diseases. According to Rome Ⅳ, OIC is defined as new or deteriorating constipation when initiating, changing, or increasing opioid therapy, that must include two or more of the following: straining, lumpy or hard stools, sensation of incomplete evacuation, sensation of anorectal blockage, use of manual maneuvers to facilitate defecation, and fewer than three spontaneous bowel movement per week [1]. >85% of cancer and > 40% of non-cancer patients treated with opioids experience symptoms of OIC [2]. Differ from other complications of opioids, such as nausea or vomiting, tolerance to constipation develops very slowly. In addition to increasing hospitalization and healthcare costs [3], OIC may cause patients to become intolerant to opioids, thus greatly compromising the analgesic effect of opioids and leading to a serious decline in quality of life [4]. The first-line strategy to treat OIC is a prophylactic regimen that involves increased fluid and fiber intake, exercise, stool softeners, and laxatives. However, at present, there is a lack of high-quality evidence to confirm the effectiveness of these treatment regimens [5, 6]. The second-line treatment, which includes peripherally acting µ opioid receptor antagonists, can be considered when patients with recalcitrant symptoms.

Methylnaltrexone, a pure peripheral µ opioid receptor antagonist, is a quaternary compound created by adding a methyl group to the opioid antagonist naltrexone [7]. Since the methyl group restricts its ability to cross the blood-brain barrier, methylnaltrexone can alleviate OIC effectively without weakening centrally mediated analgesia. So far, trials reporting the effect of methylnaltrexone on the treatment of OIC have conveyed conflicting results. Furthermore, due to modest sample size, these individual trails were not adequately powered to detect the true effect. Therefore, we performed a meta-analysis to investigate the efficacy and safety of methylnaltrexone for the treatment of OIC.

Materials

Protocol and registration

The meta-analysis was performed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions [8] and is reported in compliance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement [9]. This meta-analysis was prospectively registered in PROSPERO (CRD42020187290).

Data sources and search strategy

We searched PubMed, Embase, and Cochrane Library from inception to May 19, 2020, without any restrictions. Search terms included: methylnaltrexone, opioid*, opioid-induced constipation, intestinal dysfunction, bowel dysfunction, gut motility, rescue-free bowel movement. The reference lists of included trials were scanned for potential eligible articles. Additionally, we reviewed conference abstracts for unpublished work.

Study selection and eligibility criteria

Two authors (YYZ and WJG) independently carried out the study selection based on predefined inclusion and exclusion criteria. Disagreements were resolved by discussion. We included randomized controlled trials that compared the efficacy and safety of methylnaltrexone with placebo for the treatment of OIC in adults who received opioid therapy. We excluded trails with healthy volunteers as participants.

Data extraction and outcomes assessment

We developed a data extraction sheet in standardized Excel (Microsoft Corporation). Two authors (YYZ and WJG) independently extracted data from included trails. Discrepancies were handled by discussion. The following information was extracted from each trail: author, year, country, population, sample size, drug regimen (route and dosage), and outcomes.

The primary efficacy outcome was rescue-free bowel movement (RFBM) within 4 hours after first dose (RFBM was defined as a bowel movement without use of any rescue medication or procedure within four hours before the bowel movement). The secondary efficacy outcomes included RFBM within 24 hours after the first dose, RFBM ≥ 3 times per week, and need to take rescue laxatives. The primary safety outcome was any adverse events, which was defined as all treatment related adverse events in individual trial. The secondary safety outcomes included abdominal pain, diarrhea, nausea, vomiting, and flatulence.

Quality assessment and certainty of Evidence

We used the Cochrane Collaboration’s tool for assessing risk of bias [10]. We reviewed each trial and scored as high, low, or unclear the risk involving the following domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias. Thus, trials with high risk of bias for ≥ 1 key domains were considered to be at high risk of bias whereas trials with low risk of bias for all key domains were considered to be at low risk of bias; otherwise they were considered to be at unclear risk of bias.

We evaluated the certainty of evidence for primary and secondary outcomes according to Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach for risk of bias, inconsistency, indirectness, imprecision, and publication bias, classified as very low, low, moderate, or high [11]. Summary tables were constructed using the GRADE Profiler (version 3.6, GRADE pro).

Statistical analysis

We calculated relative risks (RRs) with 95% CIs for dichotomous outcomes. Meta-analyses were performed using a random-effects model accounting for clinical heterogeneity. All analyses were performed on an intention-to-treat basis. Statistical heterogeneity across trials was assessed by the Cochrane Q test (with P < 0.1 indicating significance) and quantified by the I² statistic (I² > 50% for a significant heterogeneity) [12, 13]. A two-sided P < 0.05 was considered statistically significant. All statistical analyses were performed using RevMan 5.3 (Nordic Cochrane Centre).

Results

Trial selection

A total of 630 articles were found from electronic database. After duplicates were removed, 419 articles had been screened for titles and abstracts. Then, 27 articles were identified for full-text review. Of these, 18 articles were excluded: 7 articles were excluded because their participants were healthy volunteers; 2 articles were excluded because there was no relevant data; 6 articles were excluded because they did not use a placebo as a control group; 4 articles were excluded because of duplicate data. Finally, 8 trials (7 full texts and 1 abstract) were included (Fig. 1) [14–21].

Trial characteristics

The characteristics of the included trials are presented in Table 1. These trials were published between 2008 and 2020. The sample size of the individual trial ranges from 33 to 803. The population mainly involved patients with advanced illness (incurable cancer or other terminal diseases) and chronic noncancer pain. The administrated route in all trials is subcutaneous except oral in one trail and intravenous one trail. All trials reported the efficacy and safety outcomes. The details of risk-of-bias assessment for each included trial are summarized in Fig. 2. Overall, two trails were categorized as being at low risk of bias and six as being unclear risk of bias.

Efficacy of methylnaltrexone for treating OIC

GRADE evidence profiles for the primary and secondary outcomes are shown in Table 2. The certainty of evidence is high for RFBM within 4 hours after the first dose, moderate for RFBM within 24 hours after the first dose, RFBM ≥ 3 times per week, need to take rescue laxatives, any adverse events, abdominal pain, diarrhea, nausea, vomiting, and flatulence.

Discussion

Main findings

Our meta-analysis comprehensively and systematically reviewed the current available literature that compared methylnaltrexone with placebo for treating OIC. We found that compared with placebo, methylnaltrexone significantly increased RFBM within 4 hours after the first dose, RFBM within 24 hours after the first dose, and RFBM ≥3 times per week and decreased need to take rescue laxatives; there was no difference in any adverse events (including diarrhea, nausea, vomiting, and flatulence) between the two groups except for abdominal pain.

Comparison with existing literature

Several previous reviews on the similar topic have been published [22-29]. Six of them evaluated the treatment of OIC with different pharmacological therapies, mainly μ opioid receptor antagonists, including methylnaltrexone [22-27]. These meta-analyses consistently found that methylnaltrexone is effective and safe for the treatment of OIC. Two of them specifically evaluated the effect of methylnaltrexone on the treatment of OIC and found that methylnaltrexone increased RFBM within 4 hours after the first dose [28, 29]. In line with these two reviews, our meta-analysis also found that methylnaltrexone increased RFBM within 4 hours after the first dose. Besides, we found that methylnaltrexone increased RFBM within 24 hours after the first dose and RFBM ≥3 times per week and decreased need to take rescue laxatives. For safety outcomes, we found that there was no difference in any adverse events (including diarrhea, nausea, vomiting, and flatulence) between the methylnaltrexone and placebo groups. Notably, the occurrence of abdominal pain is higher in methylnaltrexone group than that in placebo group. In summary, our meta-analysis further confirmed that methylnaltrexone is an effective and safe drug for the treatment OIC. But some differences also should be noted. First, previous meta-analyses included less than 1,500 patients. In comparison, our meta-analysis identified another two recent trials and included more than 2,000 patients. With added statistical power of at least 500 cases, our meta-analysis was the latest and the most comprehensive, which further reinforces earlier results of previous meta-analyses. Second, we used an intention-to-treat principle and pooled data with a random-effects model accounting for clinical heterogeneity to ensure a more conservative estimate of the efficacy and safety of methylnaltrexone for the treatment of OIC. Third, we evaluated the certainty of evidence using GRADE approach to facilitate clinical decisions making.

Implication for clinical practice

The European expert consensus statement for the management of OIC recommended that peripheral μ opioid receptor antagonists can be considered as second-line treatment when prophylactics and laxatives are not effective in relieving OIC [30]. The most well-known example is naloxone, commonly used as an intravenous reversal agent in the context of opioid over-dosing. Methylnaltrexone, a quaternary ammonium derivative of naltrexone, has been approved for the treatment of OIC as subcutaneous injection since 2008. In our meta-analysis, methylnaltrexone was administrated as subcutaneous injection in most trials. The results suggested that methylnaltrexone is effective and safe for the treatment of OIC. But one important thing to note is that methylnaltrexone may increase the risk of abdominal pain. Thus, methylnaltrexone should be used cautiously, especially, in those patients with pre-existing gastrointestinal disorders.

Strengths and limitations

The strength of this meta-analysis lies in compliance with the PRISMA statement, registration on PROSPERO with protocol, and applying GRADE approach to assess the certainty of the evidence. Our meta-analysis has some limitations that may affect the interpretation of the results. First, it is hard to rule out the existence of publication bias since only 8 trials were included in our meta-analysis. Second, although no statistical heterogeneity was observed for main outcomes, differences in included population and drug regimen may introduce clinical heterogeneity and could affect the results.

Conclusions

Methylnaltrexone is an effective and safe drug for treating OIC. But the safety of abdominal pain should be considered.

Abbreviations

CI = confidence interval;

GRADE = Grading of Recommendations Assessment, Development, and Evaluation;

OIC = opioid-induced constipation;

PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses;

RFBM = rescue-free bowel movement;

RR = Relative risk.

Declarations

• Ethics approval and consent to participate: Not applicable

• Consent for publication: Not applicable

• Availability of data and materials: Not applicable

• Competing interests: The authors declare that they have no competing interests

• Funding: None

• Authors' contributions:

Ying-Ying Zhang: Conception and design of the study, acquisition of data, analysis and interpretation of data, drafting the article, final approval of the version to be published.

Rong Zhou: Acquisition of data, analysis and interpretation of data, drafting the article, final approval of the version to be published.

Wan-Jie Gu: Conception and design of the study, analysis and interpretation of data, drafting and revising the article, final approval of the version to be published.

• Acknowledgements: Not applicable.

References

1. Tokoro A, Imai H, Fumita S, Harada T, Noriyuki T, Gamoh M, Akashi Y, Sato H, Kizawa Incidence of opioid-induced constipation in Japanese patients with cancer pain: A prospective observational cohort study. Cancer Med 2019;8:4883-91
2. Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain 2004;112:372-80
3. Fine PG, Chen YW, Wittbrodt E, Datto C. Impact of opioid-induced constipation on healthcare resource utilization and costs for cancer pain patients receiving continuous opioid therapy. Support Care Cancer 2019;27:687-96
4. Wittbrodt ET, Gan TJ, Datto C, McLeskey C, Sinha M. Resource use and costs associated with opioid-induced constipation following total hip or total knee replacement surgery. J Pain Res 2018;11:1017-25
5. Argoff CE, Brennan MJ, Camilleri M, Davies A, Fudin J, Galluzzi KE, Gudin J, Lembo A, Stanos SP, Webster LR. Consensus Recommendations on Initiating Prescription Therapies for Opioid-Induced Constipation. Pain Med 2015;16:2324-37
6. Candy B, Jones L, Larkin PJ, Vickerstaff V, Tookman A, Stone P. Laxatives for the management of constipation in people receiving palliative care. Cochrane Database Syst Rev 2015;2015:CD003448
7. Nelson AD, Camilleri M. Opioid-induced constipation: advances and clinical guidance. Ther Adv Chronic Dis 2016;7:121-34
8. Higgins JPT, Altman DG, editors. Cochrane handbook for systematic reviews of interventions. Version 5.0.1. The Cochrane Collaboration; 2008
9. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535
10. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928
11. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924-6
12. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60
13. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539-58
14. Thomas J, Karver S, Cooney GA, Chamberlain BH, Watt CK, Slatkin NE, Stambler N, Kremer AB, Israel RJ. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 2008;358:2332-43
15. Slatkin N, Thomas J, Lipman AG, Wilson G, Boatwright ML, Wellman C, Zhukovsky DS, Stephenson R, Portenoy R, Stambler N, Israel R. Methylnaltrexone for treatment of opioid-induced constipation in advanced illness patients. J Support Oncol 2009;7:39-46
16. Michna E, Blonsky ER, Schulman S, Tzanis E, Manley A, Zhang H, Iyer S, Randazzo B. Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study. J Pain 2011;12:554-62
17. Anissian L, Schwartz HW, Vincent K, Vincent HK, Carpenito J, Stambler N, Ramakrishna T. Subcutaneous methylnaltrexone for treatment of acute opioid-induced constipation: phase 2 study in rehabilitation after orthopedic surgery. J Hosp Med 2012;7:67-72
18. Bull J, Wellman CV, Israel RJ, Barrett AC, Paterson C, Forbes WP. Fixed-Dose Subcutaneous Methylnaltrexone in Patients with Advanced Illness and Opioid-Induced Constipation: Results of a Randomized, Placebo-Controlled Study and Open-Label Extension. J Palliat Med 2015;18:593-600
19. Rauck R, Slatkin NE, Stambler N, Harper JR, Israel RJ. Randomized, Double-Blind Trial of Oral Methylnaltrexone for the Treatment of Opioid-Induced Constipation in Patients with Chronic Noncancer Pain. Pain Pract 2017;17:820-8
20. Dimitroulis I, Peristeris P, Toumbis M. Effectiveness of methylnaltrexone bromide in opioid-induced constipation in advanced NSCLC patients. J Thorac Oncol 2017;12:S2232
21. Patel PB, Brett SJ, O'Callaghan D, Anjum A, Cross M, Warwick J, Gordon AC. Methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients. Results from the MOTION trial. Intensive Care Med 2020;46:747-55
22. McNicol E, Boyce DB, Schumann R, Carr D. Efficacy and safety of mu-opioid antagonists in the treatment of opioid-induced bowel dysfunction: systematic review and meta-analysis of randomized controlled trials. Pain Med 2008;9:634-59
23. Ford AC, Brenner DM, Schoenfeld PS. Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: systematic review and meta-analysis. Am J Gastroenterol 2013;108:1566-74
24. Candy B, Jones L, Vickerstaff V, Larkin PJ, Stone P. Mu-opioid antagonists for opioid-induced bowel dysfunction in people with cancer and people receiving palliative care. Cochrane Database Syst Rev 2018;6:CD006332
25. Nee J, Zakari M, Sugarman MA, Whelan J, Hirsch W, Sultan S, Ballou S, Iturrino J, Lembo A. Efficacy of Treatments for Opioid-Induced Constipation: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2018;16:1569-84
26. Vijayvargiya P, Camilleri M, Vijayvargiya P, Erwin P, Murad MH. Systematic review with meta-analysis: efficacy and safety of treatments for opioid-induced constipation. Aliment Pharmacol Ther 2020;52:37-53
27. Ouyang R, Li Z, Huang S, Liu J, Huang J. Efficacy and Safety of Peripherally Acting Mu-Opioid Receptor Antagonists for the Treatment of Opioid-Induced Constipation: A Bayesian Network Meta-analysis. Pain Med 2020; doi: 10.1093/pm/pnaa152
28. Mehta N, O'Connell K, Giambrone GP, Baqai A, Diwan S. Efficacy of methylnaltrexone for the treatment of opiod-induced constipation: a meta-analysis and systematic review. Postgrad Med 2016;128:282-9
29. Siemens W, Becker G. Methylnaltrexone for opioid-induced constipation: review and meta-analyses for objective plus subjective efficacy and safety outcomes. Ther Clin Risk Manag 2016;12:401-12
30. Farmer AD, Drewes AM, Chiarioni G, De Giorgio R, O'Brien T, Morlion B, Tack J. Pathophysiology and management of opioid-induced constipation: European expert consensus statement. United European Gastroenterol J 2019;7:7-20