Efficacy of Treatments for Opioid-Induced Constipation: Systematic Review and Meta-analysis

Judy Nee, Mohammed Zakari, Michael A. Sugarman, Julia Whelan, William Hirsch, Shahnaz Sultan, Sarah Ballou, Johanna Iturrino, Anthony Lembo

Research output: Contribution to journalReview article

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1569-1584.e2
JournalClinical Gastroenterology and Hepatology
Volume16
Issue number10
DOIs
StatePublished - Oct 2018

Fingerprint

Constipation
Opioid Analgesics
Meta-Analysis
prucalopride
alvimopan
Placebos
Therapeutics
Numbers Needed To Treat
Laxatives
Naloxone
Opiate Alkaloids
Pharmaceutical Preparations
Second Primary Neoplasms
United States Food and Drug Administration
MEDLINE
Nausea
Abdominal Pain
Vomiting
Prescriptions
Diarrhea

Keywords

  • Comparison
  • Opioid-Induced Bowel Dysfunction
  • Pharmacologic
  • Phase 3 Trial

Cite this

Efficacy of Treatments for Opioid-Induced Constipation : Systematic Review and Meta-analysis. / Nee, Judy; Zakari, Mohammed; Sugarman, Michael A.; Whelan, Julia; Hirsch, William; Sultan, Shahnaz; Ballou, Sarah; Iturrino, Johanna; Lembo, Anthony.

In: Clinical Gastroenterology and Hepatology, Vol. 16, No. 10, 10.2018, p. 1569-1584.e2.

Research output: Contribution to journalReview article

Nee, J, Zakari, M, Sugarman, MA, Whelan, J, Hirsch, W, Sultan, S, Ballou, S, Iturrino, J & Lembo, A 2018, 'Efficacy of Treatments for Opioid-Induced Constipation: Systematic Review and Meta-analysis', Clinical Gastroenterology and Hepatology, vol. 16, no. 10, pp. 1569-1584.e2. https://doi.org/10.1016/j.cgh.2018.01.021
Nee, Judy ; Zakari, Mohammed ; Sugarman, Michael A. ; Whelan, Julia ; Hirsch, William ; Sultan, Shahnaz ; Ballou, Sarah ; Iturrino, Johanna ; Lembo, Anthony. / Efficacy of Treatments for Opioid-Induced Constipation : Systematic Review and Meta-analysis. In: Clinical Gastroenterology and Hepatology. 2018 ; Vol. 16, No. 10. pp. 1569-1584.e2.
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abstract = "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.",
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T1 - Efficacy of Treatments for Opioid-Induced Constipation

T2 - Systematic Review and Meta-analysis

AU - Nee, Judy

AU - Zakari, Mohammed

AU - Sugarman, Michael A.

AU - Whelan, Julia

AU - Hirsch, William

AU - Sultan, Shahnaz

AU - Ballou, Sarah

AU - Iturrino, Johanna

AU - Lembo, Anthony

PY - 2018/10

Y1 - 2018/10

N2 - 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.

AB - 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.

KW - Comparison

KW - Opioid-Induced Bowel Dysfunction

KW - Pharmacologic

KW - Phase 3 Trial

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