Salman Nusrat1, Taseen Syed2, Rabia Saleem2, Shari Clifton3,4, Klaus Bielefeldt5. 1. Neurogastroenterology and Motility Program, Division of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Andrews Academic Tower, Suite 7400, 800 Stanton L. Young Blvd, Oklahoma City, OK, 73104, USA. Salman-nusrat@ouhsc.edu. 2. Department of Internal Medicine, University of Oklahoma Health Sciences Center, 1200 Children's Ave, Oklahoma City, OK, 73104, USA. 3. Health Sciences Library and Information Management, Graduate College, University of Oklahoma Health Sciences Center, 1105 N. Stonewall Ave, Oklahoma City, OK, 73117, USA. 4. Reference and Instructional Services, Robert M. Bird Health Sciences Library, University of Oklahoma Health Sciences Center, 1105 N. Stonewall Ave, Oklahoma City, OK, 73117, USA. 5. Section of Gastroenterology, George E. Wahlen VAMC, 500 Foothill Dr, Salt Lake City, UT, 84103, USA.
Abstract
BACKGROUND: Widespread opioid use has led to increase in opioid-related adverse effects like constipation. We examined the impact of study endpoints on reported treatment benefits. METHODS: Using MEDLINE, EMBASE, and ClinicalTrials.gov, we searched for randomized control trials targeting chronic opioid-induced constipation (OIC) and subjected them to meta-analysis. Data are given with 95% confidence intervals. RESULTS: Thirty trials met our inclusion criteria. Combining all dichotomous definitions of responders, active drugs were consistently more effective than placebo, with an odds ratio (OR): 2.30 [2.01-2.63; 15 studies], independent of the underlying drug mechanism. The choice of endpoints significantly affected the therapeutic gain. When time from drug administration to defecation was used, the OR decreased from 4.74 [2.71-4.74] at 6 h or less to 2.46 [1.80-3.30] at 24 h (P < 0.05). Using other response definitions, the relative benefit over placebo was 2.10 [1.77-2.50; 12 studies] for weekly bowel frequency, 2.03 [1.39-2.95; 9 studies] for symptom scores, 2.21 [1.25-3.90; 4 studies] for global assessment scales, and 1.27 [0.79-2.03; 7 studies] for rescue laxative use. CONCLUSION: While treatment of OIC with active drugs is more effective than placebo, the relative gain depends on the choice of endpoints. The commonly used time-dependent response definition is associated with the highest response rate but is of questionable relevance in a chronic disorder. The limited data do not clearly demonstrate a unique advantage of the peripherally restricted opioid antagonists, suggesting that treatment with often cheaper agents should be optimized before shifting to these novel expensive agents.
BACKGROUND: Widespread opioid use has led to increase in opioid-related adverse effects like constipation. We examined the impact of study endpoints on reported treatment benefits. METHODS: Using MEDLINE, EMBASE, and ClinicalTrials.gov, we searched for randomized control trials targeting chronic opioid-induced constipation (OIC) and subjected them to meta-analysis. Data are given with 95% confidence intervals. RESULTS: Thirty trials met our inclusion criteria. Combining all dichotomous definitions of responders, active drugs were consistently more effective than placebo, with an odds ratio (OR): 2.30 [2.01-2.63; 15 studies], independent of the underlying drug mechanism. The choice of endpoints significantly affected the therapeutic gain. When time from drug administration to defecation was used, the OR decreased from 4.74 [2.71-4.74] at 6 h or less to 2.46 [1.80-3.30] at 24 h (P < 0.05). Using other response definitions, the relative benefit over placebo was 2.10 [1.77-2.50; 12 studies] for weekly bowel frequency, 2.03 [1.39-2.95; 9 studies] for symptom scores, 2.21 [1.25-3.90; 4 studies] for global assessment scales, and 1.27 [0.79-2.03; 7 studies] for rescue laxative use. CONCLUSION: While treatment of OIC with active drugs is more effective than placebo, the relative gain depends on the choice of endpoints. The commonly used time-dependent response definition is associated with the highest response rate but is of questionable relevance in a chronic disorder. The limited data do not clearly demonstrate a unique advantage of the peripherally restricted opioid antagonists, suggesting that treatment with often cheaper agents should be optimized before shifting to these novel expensive agents.
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