A Network Meta-Analysis of the Efficacy of Opioid Analgesics for the Management of Breakthrough Cancer Pain Episodes  Giovambattista Zeppetella, FRCP, Andrew Davies, FRCP, Indra Eijgelshoven, BSc, Jeroen P. Jansen, PhD  Journal of Pain and Symptom Management  Volume 47, Issue 4, Pages 772-785.e5 (April 2014) DOI: 10.1016/j.jpainsymman.2013.05.020 Copyright © 2014 U.S. Cancer Pain Relief Committee Terms and Conditions

Fig. 1 Flow chart of study selection. Faded entries represent the process of study selection for the original analysis (Vissers et al.27); the six selected studies also were included in the present analysis. Non-faded entries represent the additional studies selected for the present analysis resulting from the second systematic literature search conducted in 2010. aData included in the network meta-analysis were obtained from a poster presented by Fallon et al. at ESMO congress (2009).44 PID15 from the study (as presented at ESMO) was included in the present network meta-analysis under the remit of the updated search criteria. A full report of the study has been published by Fallon et al.,48 and further results have been published by Davies et al.47 after the systematic literature search was conducted in April 2010. RCT = randomized controlled trial; INFS = intranasal fentanyl spray; ESMO=European Society for Medical Oncology; PID=primary efficacy data. Journal of Pain and Symptom Management 2014 47, 772-785.e5DOI: (10.1016/j.jpainsymman.2013.05.020) Copyright © 2014 U.S. Cancer Pain Relief Committee Terms and Conditions

Fig. 2 Network of RCTs included in the meta-analysis. Faded sections of the network represent the studies that were identified and included in the original analysis (Vissers et al.27) and in the present analysis. Non-faded sections of the network represent the additional studies that were identified during the second systematic literature search and included in the present analysis. aRauck et al. (2009);42 bPortenoy et al. (2006);37 cSlatkin et al. (2007);36 dKress et al. (2009);35 eMercadante et al. (2009);39 fFarrar et al. (1998);38 gColuzzi et al. (2001);40 hFallon et al. (2009);44 iPortenoy et al. (2010);41 jRauck et al. (2010).43 RCTs=randomized controlled trials; FBSF = fentanyl buccal soluble film; FST = fentanyl sublingual tablets; FBT = fentanyl buccal tablets; FPNS = fentanyl pectin nasal spray; OTFC = oral transmucosal fentanyl citrate; INFS = intranasal fentanyl spray; MSIR = morphine sulfate immediate release. Journal of Pain and Symptom Management 2014 47, 772-785.e5DOI: (10.1016/j.jpainsymman.2013.05.020) Copyright © 2014 U.S. Cancer Pain Relief Committee Terms and Conditions

Fig. 3 PID of BTCP medications relative to placebo. PIDs relative to placebo were calculated for each medication by subtracting a pooled reference estimate of PID for placebo (derived from a fixed-effects meta-analysis of the results from the placebo-controlled trials included in the network meta-analysis). Pooled placebo data allow for standardization across studies. PID = pain intensity difference; BTCP = breakthrough cancer pain; CrI = credibility interval; INFS = intranasal fentanyl spray; FPNS = fentanyl pectin nasal spray; FST = fentanyl sublingual tablets; FBSF = fentanyl buccal soluble film; FBT = fentanyl buccal tablets; OTFC = oral transmucosal fentanyl citrate; MSIR = morphine sulfate immediate release. Journal of Pain and Symptom Management 2014 47, 772-785.e5DOI: (10.1016/j.jpainsymman.2013.05.020) Copyright © 2014 U.S. Cancer Pain Relief Committee Terms and Conditions

Fig. 4 Estimate of absolute PID, 15 minutes after intake of BTCP medication. Absolute PID15 was calculated from the relative PID15 of each BTCP medication and a pooled reference estimate of PID15 for placebo (derived from a fixed-effects meta-analysis of the results from the placebo-controlled trials included in the network analysis). Pooled placebo data were included to allow for standardization across studies. The dashed lines represent the pooled reference estimate of PID15 for placebo (0.91) and the threshold for clinical relevance—an absolute PID ≥2 on a numeric rating scale is generally accepted as a clinically important improvement.29,30 PID = pain intensity difference; BTCP = breakthrough cancer pain; INFS = intranasal fentanyl spray; FPNS = fentanyl pectin nasal spray; FST = fentanyl sublingual tablets; FBSF = fentanyl buccal soluble film; FBT = fentanyl buccal tablets; OTFC = oral transmucosal fentanyl citrate; MSIR = morphine sulfate immediate release. Journal of Pain and Symptom Management 2014 47, 772-785.e5DOI: (10.1016/j.jpainsymman.2013.05.020) Copyright © 2014 U.S. Cancer Pain Relief Committee Terms and Conditions

Fig. 5 PID of INFS relative to other BTCP medications. PIDs relative to placebo were calculated for each medication by subtracting a pooled reference estimate of PID for placebo (derived from a fixed-effects meta-analysis of the results from the placebo-controlled trials included in the network meta-analysis). Pooled placebo data allows for standardization across studies. PID = pain intensity difference; CrI = credibility interval; INFS = intranasal fentanyl spray; BTCP = breakthrough cancer pain; FPNS = fentanyl pectin nasal spray; FST = fentanyl sublingual tablets; FBSF = fentanyl buccal soluble film; FBT = fentanyl buccal tablets; OTFC = oral transmucosal fentanyl citrate; MSIR = morphine sulfate immediate release. Journal of Pain and Symptom Management 2014 47, 772-785.e5DOI: (10.1016/j.jpainsymman.2013.05.020) Copyright © 2014 U.S. Cancer Pain Relief Committee Terms and Conditions

Fig. 6 Concept of network meta-analysis: dAB and dAC are basic parameters of the network meta-analysis model that are estimated based on the available RCTs. RCTs=randomized controlled trials. Journal of Pain and Symptom Management 2014 47, 772-785.e5DOI: (10.1016/j.jpainsymman.2013.05.020) Copyright © 2014 U.S. Cancer Pain Relief Committee Terms and Conditions