Opioid-Induced Constipation Relief From Fixed-Ratio Combination Prolonged-Release Oxycodone/Naloxone Compared With Oxycodone and Morphine for Chronic Nonmalignant Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials  Lang Huang, MD, Jian-Guo Zhou, MD, Yu Zhang, MM, Fei Wang, MM, Yi Wang, MM, Da-Hai Liu, MM, Xin-Juan Li, MM, Shui-Ping Lv, MM, Su-Han Jin, MM, Yu-Ju Bai, MD, Hu Ma, MD, PhD  Journal of Pain and Symptom Management  Volume 54, Issue 5, Pages 737-748.e3 (November 2017) DOI: 10.1016/j.jpainsymman.2017.07.025 Copyright © 2017 American Academy of Hospice and Palliative Medicine Terms and Conditions

Fig. 1 Flow chart of the systematic review process. Journal of Pain and Symptom Management 2017 54, 737-748.e3DOI: (10.1016/j.jpainsymman.2017.07.025) Copyright © 2017 American Academy of Hospice and Palliative Medicine Terms and Conditions

Fig. 2 Appraisal of risk of bias of the included trials using the Cochrane risk-of-bias tool. Low risk = bias, if present, is unlikely to alter the results seriously, unclear risk = bias raises some doubt about the results, and high risk = bias may alter the results seriously. Journal of Pain and Symptom Management 2017 54, 737-748.e3DOI: (10.1016/j.jpainsymman.2017.07.025) Copyright © 2017 American Academy of Hospice and Palliative Medicine Terms and Conditions

Fig. 3 Meta-analysis result of the RR of constipation at the end of double-blind trial phase. A lower incidence of constipation was found in the OXN PR treatment group compared with OXY PR or MOR PR. OXY = oxycodone; OXN = OXY:naloxone PR = 2:1; PR = prolonged release; RR = relative risk. Journal of Pain and Symptom Management 2017 54, 737-748.e3DOI: (10.1016/j.jpainsymman.2017.07.025) Copyright © 2017 American Academy of Hospice and Palliative Medicine Terms and Conditions

Fig. 4 Meta-analysis result of the MD of BFI change from baseline to the end of double-blind trial. a) The BFI of included patients had lower BFI in baseline and at the end of the treatment (12 weeks) of the BFI became higher; b) The BFI of involved patients had higher BFI in baseline, and BFI was decreased after 12 weeks double-blind trial. The BFI change of (b) was significantly lower in treatment group, and clinical meaningful was found. A change in BFI score of ≥12 points is considered to be clinically meaningful difference. BFI = bowel function index; MD = mean difference. Journal of Pain and Symptom Management 2017 54, 737-748.e3DOI: (10.1016/j.jpainsymman.2017.07.025) Copyright © 2017 American Academy of Hospice and Palliative Medicine Terms and Conditions

Fig. 5 The BFI of included studies at the end of double-blind trial phase. A lower BFI was found in treatment group. BFI score of 0–28.8 is the reference range for nonconstipated patients with chronic pain, and VAS from 0 = freedom from the symptom to 100 = maximum difficulty or most severe symptom. BFI = bowel function index; VAS = Visual Analog Scale. Journal of Pain and Symptom Management 2017 54, 737-748.e3DOI: (10.1016/j.jpainsymman.2017.07.025) Copyright © 2017 American Academy of Hospice and Palliative Medicine Terms and Conditions

Fig. 6 Meta-analysis result of the MD of BFI at end of double-blind trial phase. The BFI of was significantly lower in treatment group, and clinically meaningful difference was found. A change in BFI score of ≥12 points is considered to be clinically meaningful. BFI = bowel function index; MD = mean difference. Journal of Pain and Symptom Management 2017 54, 737-748.e3DOI: (10.1016/j.jpainsymman.2017.07.025) Copyright © 2017 American Academy of Hospice and Palliative Medicine Terms and Conditions

Fig. 7 Meta-analysis result of the MD of pain intensity at end of double-blind trial phase. The pain intensity was significant lower in treatment group, whereas the pain relief was not of clinically meaningful difference. We reported a 10-point difference on this 0- to 100-point scale as a “minimal” difference and a 20-point difference as a “clinically important” difference. MD = mean difference. Journal of Pain and Symptom Management 2017 54, 737-748.e3DOI: (10.1016/j.jpainsymman.2017.07.025) Copyright © 2017 American Academy of Hospice and Palliative Medicine Terms and Conditions

Fig. 8 Percentage of trial participants receiving an opioid analgesic who left the trial and the percentage who completed the double-blind trial. Loss to follow-up includes patients withdrawn from trial owing to loss of follow-up, lack of efficacy, insufficient efficacy, and for other reasons. AE = adverse event; PR = prolonged release; OXY = oxycodone; OXN = OXY:naloxone PR = 2:1. Journal of Pain and Symptom Management 2017 54, 737-748.e3DOI: (10.1016/j.jpainsymman.2017.07.025) Copyright © 2017 American Academy of Hospice and Palliative Medicine Terms and Conditions

Fig. 9 Meta-analysis result of the RR of total AEs at end of double-blind trial phase. The incidence of adverse effects was lower in treatment group. AE = adverse effect; RR = relative risk. Journal of Pain and Symptom Management 2017 54, 737-748.e3DOI: (10.1016/j.jpainsymman.2017.07.025) Copyright © 2017 American Academy of Hospice and Palliative Medicine Terms and Conditions

Supplementary Data 3 Meta-analysis result of the mean difference (MD) of pain intensity between OXY PR vs. MOR PR. RR = relative risk; PR = prolonged-release; OXY = oxycodone; OXN = OXY:naloxone; PR = 2:1. Journal of Pain and Symptom Management 2017 54, 737-748.e3DOI: (10.1016/j.jpainsymman.2017.07.025) Copyright © 2017 American Academy of Hospice and Palliative Medicine Terms and Conditions