Supplementary material Methods: Search strategy for MEDLINE Intervention "analgesics, opioid"[mesh Terms] OR codeine OR fentanyl OR hydrocodone OR hydromorphone OR levophanol OR meperidine OR morphine OR oxycodone OR oxymorphone OR pentazocine OR (propoxyphene and sufentanil) OR tramadol OR tapentadol OR buprenorphine OR opioid Population "chronic pain"[mesh Terms] OR neuropathic pain OR osteoarthritis OR arthritis OR rheumatoid OR phantom limb pain OR fibromyalgia OR (diabetic neuropathy and pain*) OR postherpetic neuralgia OR musculoskeletal pain OR "Neuralgia"[Mesh] OR "Osteoarthritis"[Mesh] OR "Arthritis"[Mesh] OR ("Phantom Limb"[Mesh] and pain) OR "Fibromyalgia"[Mesh] OR "Diabetic Neuropathies"[Mesh] OR "Musculoskeletal Pain"[Mesh] Limits random allocation [mh] OR double blind method[mh] OR single blind method[mh] OR random* OR "Clinical Trial" [Publication Type] OR "Clinical Trials as Topic"[Mesh] OR "Placebos"[Mesh] OR placebo OR ((clinical OR controlled) and trial*) OR ((singl* OR doubl* OR trebl* OR tripl*) and (blind* OR mask*)) OR rct OR enriched enrollment randomized withdrawal NOT ("Animals"[Mesh] NOT "Humans"[Mesh]) Search as run (((((random allocation [mh] OR double blind method[mh] OR single blind method[mh] OR random* OR "Clinical Trial" [Publication Type] OR "Clinical Trials as Topic"[Mesh] OR "Placebos"[Mesh] OR placebo OR ((clinical OR controlled) and trial*) OR ((singl* OR doubl* OR trebl* OR tripl*) and (blind* OR mask*)) OR rct OR enriched enrollment randomized withdrawal)) AND ("chronic pain"[mesh Terms] OR neuropathic pain OR osteoarthritis OR arthritis OR rheumatoid OR phantom limb pain OR fibromyalgia OR (diabetic neuropathy and pain*) OR postherpetic neuralgia OR musculoskeletal pain OR "Neuralgia"[Mesh] OR "Osteoarthritis"[Mesh] OR "Arthritis"[Mesh] OR ("Phantom Limb"[Mesh] and pain) OR "Fibromyalgia"[Mesh] OR "Diabetic Neuropathies"[Mesh] OR "Musculoskeletal Pain"[Mesh])) AND ("analgesics, opioid"[mesh Terms] OR codeine OR fentanyl OR hydrocodone OR hydromorphone OR levophanol OR meperidine OR morphine OR oxycodone OR oxymorphone OR pentazocine OR (propoxyphene and sufentanil) OR tramadol OR tapentadol OR buprenorphine OR opioid))) NOT (("Animals"[Mesh] NOT "Humans"[Mesh])
Table S1. Efficacy analysis methodology by study Author Year Cohort Analyzed Primary Outcome Measure Hale 2007 ITT Mean change from baseline in average PI (VAS) to final visit Katz 2007 ITT Mean change from baseline in average PI (VAS) to final visit Vorsanger 2008 ITT Mean change from randomization in PI VAS score since the previous visit averaged over the 12 week RBTP Hale 2010 ITT Mean change from baseline to week 12 or final visit of the RBTP in weekly PI NRS scores Katz 2010 ITT Change in diary BPI average pain score from randomization baseline to last 7 days of RBTP Schwartz Friedman ITT ITT Change from baseline in average PI over the last week (week 12) of the double blind maintenance period. Mean AUC for the change in PI scores from pre randomization baseline to the end of week 12 Steiner ITT Average PI over the last 24 hours score obtained at Week 12 Primary Analysis Method ANOVA Cochran Mantel Haenszel (CMH) Mixed effect repeatedmeasure general linear model was used to analyze the primary efficacy variable Definition of a Achieved stable dose that provided tolerable and adequate analgesia (pain 40 mm on VAS; <3 doses of rescue medication) for 3 of 5 consecutive days. Answered yes to question Has this treatment helped your pain enough so that you would continue to take this medication? Patients receiving 300mg tramadol ER once daily at the end of the run in period who had adequate pain relief and no unacceptable side effects. Patients taking 12 mg and 64 mg of hydromorphone ER per day; remained on the same dose without change for at least 7 consecutive days; took a mean of 2 tablets of rescue medication hydromorphone IR per day; had adequate pain control as indicated by a mean PI score 4 on the PI NRS; patients answered yes to the question Has this medication helped your pain enough so that you would continue to take the medication? ; patients had no sideeffects that were intolerable or that could impact their ability to complete the study. Patients with average PI scores of 4 on the Brief Pain Inventory (BPI) scale over the last 4 days before the clinic visit and whose scores had declined by 2 points from baseline. Patients with a 1 point reduction in pain from the pre titration intensity to the last three days of the titration period were eligible to continue. Patients who tolerated 20mg Remoxy BID and had a 75% or greater compliance with phone diary reports during titration. Defined as having 2 point reduction from screening in average pain over the last 24 hours scores, and an average pain over the last 24 hours score for low back pain of 4. Both criteria had to be met for three consecutive days prior to randomization.
Rauck 2014 ITT Change in average PI score from baseline (randomization) to day 85 (end of treatment) on the 11 point NRS as recorded daily in an electronic diary. Vinik 2014 ITT Mean change in average PI from baseline to week 12 on 11 point NRS Wen 2015 ITT Mean weekly PI during the RBTP Katz 2015 ITT Change in average pain intensity measured by the change in PI NRS scores from randomization baseline to week 12 of the RBTP Hale 2015a ITT Change from baseline (final visit of the OLP) to week 12 in the mean weekly API Hale 2015b ITT Change from baseline (end of open label titration) to week 12 in the weekly average of WPI scores Rauck 2016 ITT Change from baseline to week 12 in the primary efficacy end point of NRS average daily pain intensity scores Mixed effect model with repeated measures Two piece linear regression mixed model Patients who tolerated a stabilized dose for at least 7 days, with an average 24 hour daily average pain score of 4 on the NRS during the past 7 days; reduction of two points on the NRS compared with screening; and required no more than two tablets of rescue medication (see treatment section) on any day. Patients who tolerated tapentadol ER and had 1 point improvement in average PI from the pre titration evaluation period to the last 3 days of the OLP. Patient received the same dose for 7 ± 2 consecutive days; and if, for 3 consecutive days before randomization, patient had both an average pain over the last 24 h score that was 4 with a 2 point reduction in screening mean pain score, and also did not take more than the maximum daily dose of supplemental pain medication. Remained on a stable (i.e., unchanged) dose of Xtampza ER for the last 7 consecutive days, (2) had a 24 hour pain intensity score 4 for 6 of the last 7 days, (3) had an average 24 hour PI score 4 for the last 7 days, (4) had a reduction of at least 2 points in the average 24 hour pain intensity score for the last 7 days, and (5) had taken #2000 mg of APAP daily during the last 7 days. Patients who achieved an API score of 4 within the past 24 hours for 3 consecutive days or for at least 3 of 5 consecutive days. API score of 4 within the past 24 hours and WPI score of 6 for 4 consecutive days or at least 4 of 7 consecutive days, while the same study drug dose was maintained for up to 7 days /MMRM Patients with a mean of average daily pain intensity score 4 for the last 3 days before randomization and at least two points lower than the score at screening were eligible for randomization. Patient had to be titrated to a BBUP dose 150 µg BID, had to have received their stable optimal dose of BBUP for 2 weeks and had to have taken no more than one dose per day of rescue acetaminophen during the last 7 days.
Table S2. Risk of bias Random Sequence Generation (Selection Bias) Allocation Concealment (Selection Bias) Blinding (Performance and Detection Bias) all outcomes Blinding (Performance and Detection Bias) all outcomes Blinding (Performance and Detection Bias) all outcomes Incomplete Outcome Data (Attrition Bias) All Outcomes Selective Reporting (Reporting Bias) Group Similarity at Baseline Influence of Cointerventions Compliance with interventions Timing of Outcome Assessment Hale 2007 Katz 2007 Vorsanger 2008 Hale 2010 Katz 2010 Schwartz Friedmann Steiner Rauck 2014 Vinik 2014 Wen 2015 Katz 2015 Hale 2015a Hale 2015b?? + + +? + + + + + +? + + + + + + + + +?? + + + + + + + + +? + + + + + + + + + + + +? + + + + +?? + +? +? + + + +? + +???? + +?? + +? +?? + + + + + + + + +? + +? + + + +? + + + + + + +? + + + + + +? + + + +? + + + +? + + + + + + + + + + +? + +??? + + + + +? + Rauck 2016 Studies marked with a (+) clearly demonstrated that the particular type of bias was not present. Those marked with a ( ) clearly demonstrated that the particular type of bias was present in the study. In studies marked with a (?) it was unclear as to whether the particular bias was accounted for.
Table S3. Primary and Secondary endpoint data Author Year Hale 2007 Katz 2007 Drug / Placebo Change PI Score from BL to Week 12 8.7 (25.1) 30% 50% PGIC or PGASM* 40 (58.0) * Placebo: 31.6 (24.6) 15 (22) * 10.9 (24.53) 66 (93) 61 (85.9) 57 (55.4) * Placebo: 26.0 (27.9) 34 (72.3) 26 (55.3) 26 (28.9) * Change in Function Life PCS Life MCS Vorsanger 2008 5.2 (24.82) Placebo: 12.2 (26.25) Hale 2010 x Katz 2010 Schwartz x Friedmann Steiner Rauck, 2014 Vinik 2014 Wen 2015 x Katz 2015 0.6 (1.29) 80 (60.6) 56 (42.4) 107 (80.5) * Placebo: 1.7 (1.45) 57 (42.9) 32 (24.1) 83 (62.4) * 0.2 (1.9) 124 (72.5) 97 (56.7) Placebo: 0.3 (2.1) 100 (57.8) 82 (47.4) 0.1 (1.69) 105 (53.6) 74 (37.8) 116 (64.4) Placebo: 1.3 (2.41) 81 (42.2) 53 (27.6) 68 (38.4) 0.7 (2.05) 32 (15.7) * Placebo: 0.3 (2.48) 25 (12.1) * 3.81 (0.16) 136 (53) 113 (44) 61 (23.7) WOMAC: 1.6 (18.0) WOMAC: 5.8 (16.8) 10.11 (8.61) 7.19 (10.85) Placebo: 4.39 (0.15) 130 (46) 102 (36) 42 (16.1) 6.12 (8.86) 3.34 (11.69) 0.48 (1.56) 102 (68) 72 (48) 74 (52) * Placebo: 0.96 (1.55) 47 (31) 35 (23) 50 (34) * 0.28 (2.0) 92 (55.4) 67 (40.4) 99 (66.0) Placebo: 1.3 (2.4) 69 (45.4) 44 (28.9) 63 (45.3) 3.7 (1.93) 192 (65) 142 (48) 173 (61.0) Placebo: 4.23 (2.04) 155 (53) 114 (39) 131 (49) 0.29 (2.08) 95 (49.2) 74 (38.3) 129 (66.8) BPI Pain interference: 3.0 (2.07) BPI Pain Interference: 2.6 (2.38) 0.1 (6.52) 0.20 (9.00) 2.3 (6.40) 0.8 (9.37) RMDQ: 0.4 (4.83) 7.52 (10.13) 2.55 (10.42)
Author Year Hale 2015a x Hale 2015b Rauck 2016 Drug / Placebo Change PI Score from BL to Week 12 30% 50% PGIC or PGASM* Placebo: 1.85 (3.08) 65 (33.2) 48 (24.5) 91 (46.4) 0.64 (1.61) 16 (11) 8 (6) Placebo: 0.03 (1.88) 35 (24) 22 (15) 0.11 (1.93) 19 (13) Placebo: 0.74 (2.01) 25 (19) 0.94 (1.85) 132 (63) 86 (41) Placebo: 1.59 (2.04) 99 (47) 70 (33) Change in Function RMDQ: 0.7 (5.32) Life PCS Life MCS 3.62 (9.43) 0.67 (11.17) RMDQ: 1.29 (4.98) RMDQ: 1.57 (4.82) RMDQ: 0.6 (5.37) RMDQ: 1.2 (5.75) *PGASM The SD was calculated based on the median of all other SDs that were reported in manuscripts that used the 0 100 scale. X The mean and/or (SD) of the primary outcomes are not stated in the papers and were obtained via personal communication with the authors.
Table S4. Primary and Secondary Analysis Summary Primary Analysis 30% Response Secondary Analysis 50% Response PGIC PGA PGASM PCS MCS RMDQ WOMAC Pain Author Year Intensity Hale 2007 Katz 2007 Vorsanger 2008 Hale 2010 Katz 2010 Schwartz Friedmann Steiner Rauck 2014 Vinik 2014 Wen 2015 Katz 2015 Hale 2015a Hale 2015b Rauck 2016