supplementary online content - jama...controlled trial.pt or controlled clinical trial.pt or...

Supplementary Online Content

Abdel Shaheed C, Maher CG, Williams KA, Day R, McLachlan AJ. Efficacy, tolerability, and dose-dependent effects of opioid analgesics for low back pain: a systematic review and meta-analysis [published online May 23, 2016]. JAMA Internal Medicine. doi:10.1001/jamainternmed.2016.1251

Table 1. Search Strategy ONE (OVID resources: MEDLINE, CENTRAL, PsycINFO, Cochrane database of Systematic Reviews)

eTable 2. Pedro ratings for eligible trials.

eTable 3. Data extraction Table

eTable 4. Main effect sizes and grading of evidence

eTable 5. Morphine equivalent dose conversion for opioid analgesic medicines evaluated in this review. eTable 6. Proportion of

participants who dropped out in run-in and trial phase

eTable 7. Adverse event rates for opioid analgesic vs placebo trials

eTable 8. Adverse event rates. Number (%) of participants with adverse events in placebo controlled studies of opioid analgesics

eFigure 1. Funnel plot of standard error by treatment effect; chronic low back pain. Egger’s test (two-tailed p-value 0·007) for the primary time point and outcome: short term pain relief. Circles represent one opioid analgesic vs placebo comparison

eFigure 2. Funnel plot of standard error by treatment effect; opioid analgesic studies; chronic low back pain: intermediate pain relief. Egger’s p=0·42

eFigure 3. Intermediate and short term effects on pain from head-to-head opioid analgesic trials; chronic low back pain. Note each comparison is individually presented. BTDS = buprenorphine transdermal system; NTX = naltrexone; bd = twice daily dosing; qid = four times daily dosing; µg/h = microgram per hour

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Online Appendix

Tables: 8

eTable 1. Search Strategy ONE (OVID resources: MEDLINE, CENTRAL, PsycINFO, Cochrane database of Systematic Reviews). eTable 2. Pedro ratings for eligible trials. eTable 3. Data extraction Table. eTable 4. Main effect sizes and grading of evidence. eTable 5. Morphine equivalent dose conversion for opioid analgesic medicines evaluated in this review. eTable 6. Proportion of participants who dropped out in run-in and trial phase. eTable 7. Adverse event rates for opioid analgesic vs placebo trials. eTable 8. Adverse event rates. Number (%) of participants with adverse events in placebo controlled studies of opioid analgesics. Figures: 3 eFigure 1. Funnel plot of standard error by treatment effect; chronic low back pain. Egger’s test (two-tailed p-value 0·007) for the primary time point and outcome: short term pain relief. Circles represent one opioid analgesic vs placebo comparison. eFigure 2. Funnel plot of standard error by treatment effect; opioid analgesic studies; chronic low back pain: intermediate pain relief. Egger’s p=0·42. eFigure 3. Intermediate and short term effects on pain from head-to-head opioid analgesic trials; chronic low back pain. Note each comparison is individually presented. BTDS = buprenorphine transdermal system; NTX = naltrexone; bd = twice daily dosing; qid = four times daily dosing; µg/h = microgram per hour.



eTable 1. Search Strategy ONE (OVID resources: MEDLINE, CENTRAL, PsycINFO, Cochrane database of Systematic Reviews).

Terms Searches MEDLINE

Study types 1. REVIEW, ACADEMIC.pt. OR REVIEW, TUTORIAL.pt. OR META–ANALYSIS.pt. OR META–ANALYSIS.sh. OR systematic$ adj25 review$ OR systematic$ adj25 overview$ OR meta-analy$ or metaanaly$.tw or (meta adj25 analy$).tw OR Randomized controlled trial.pt OR controlled clinical trial.pt or randomized controlled trials.mp OR controlled clinical trials.mp OR random allocation.sh OR double-blind method.sh OR single-blind method.sh OR clinical trial.pt OR exp clinical trial/ OR clin$ adj25 trial$.tw OR (singl$ or doubl$) adj25 (blind$ or mas$).tw OR placebos.sh OR placebo$.tw OR random$.tw OR research design.sh OR comparative study.sh OR exp evaluation studies/ OR follow-up studies.sh OR prospective studies.sh OR cross-over studies.sh OR (control$ or prospective$ or volunteer$).tw OR parallel-stud$.tw OR (parallel adj25 stud$).tw or (parallel.sh adj25 trial$).tw

2.

ANIMAL/ not HUMAN/

3.

1 NOT 2

Low back pain 4.

Low back pain.sh OR low back ach$.tw OR lumbago.mp OR (low$ adj25 back pain).tw OR (low$ adj25 back ach$).tw OR low back strain.tw OR low$ back pain$.tw OR (simpl$ adj25 low$ back pain).mp. OR (mechanic$ adj25 low$ back pain).mp OR (non-specific adj25 low$ back pain).mp. backache.mp OR back pain.sh OR back pain.mp OR exp "sprains and strains"/ and exp SPINE/ OR exp Intervertebral Disk Displacement/ OR Intervertebral Disk Displacement.mp OR back pain.tw OR simple back pain.tw OR low back syndrome.tw OR low back dysfunction.tw OR non-specific back pain.tw OR lumbar pain.tw



5.

3 and 4

Opioids 6.

NO2A$.tw OR (opioid$ adj25 analges$).tw OR opioid$.tw OR (opioid$ adj25 med$).tw OR (opioid$ adj25 drug$).tw OR narcotic$.tw OR (narcotic$ adj25 drug$).tw OR (narcotic$ adj25 analges$).tw OR morphine.tw OR (morphine adj25 sul$).tw OR ordine.tw OR hydromorphone.tw OR dilaudid.tw OR oxy$.tw OR oxycodone.tw OR endone.tw OR targin.tw OR oxymorphone.tw OR OPANA$.tw OR codeine.tw OR dihydrocodeine.tw OR (opi$ adj25 alkaloid$).tw OR ketobemidone.tw OR (phenylpiperidine adj25 deriv$).tw OR pethidine.tw OR Fentanyl.tw OR durogesic.tw OR diphenylpropylamine.tw OR dextromoramide.tw OR piritramide.tw OR dextropropoxyphene.tw OR di-gesic.tw OR capodex.tw OR bezitramide.tw OR methadone.tw OR physeptone.tw OR (benzomorphan adj25 deriv$).tw OR pentazocine.tw OR phenazocine.tw OR (oripavine adj25 deriv$).tw OR buprenorphine.tw OR norspan.tw OR suboxone.tw OR subutex.tw OR etorphine.tw OR (morphinan adj25 deriv$).tw OR tilidine.tw OR trama$.tw or tramadol.tw OR dezocine.tw OR tapendatol.tw OR meptazinol.tw

7.

5 and 6



eTable 2. Risk of bias (PEDro) ratings for eligible trials.

Study 1 2 3 4 5 6 7 8 9 10 11 Total Score

Allan, 20051 0 1 0 0 0 0 0 0 1 1 1 4 Buynak, 20102 0 1 1 1 1 1 1 0 0 1 1 8 Chu 20123 1 1 1 1 1 1 1 0 0 1 1 8 Cloutier, 20134 1 1 1 1 1 1 1 0 0 1 1 8 Gordon, 20105 0 1 1 0 1 1 1 0 0 1 1 7 Hale, 20106 0 1 1 1 1 1 1 0 0 1 1 8 Hale, 20057 0 0* 1 0 1 1 1 0 0 1 1 6 Hale, 20078 0 1 1 1 1 1 1 0 0 1 1 8 Katz 20079 1 1 1 1 1 1 1 0 0 1 1 8 Peloso, 200410 1 1 1 1 1 1 1 1 1 1 1 10 Perrot, 200611 0 1 1 1 1 1 1 1 0 1 1 9 Rauck 201412 0 1 1 0 1 1 1 0 0 1 1 7 Ruoff, 200313 0 1 1 1 1 1 1 0 0 1 1 8 Schiphrost 201314 1 1 1 0 0 0 0 1 1 1 1 6 Schnitzer, 200015 0 1 0 0 1 1 1 0 0 1 1 6 Steiner, 201116 0 1 1 1 1 1 1 0 0 1 1 8 Steiner, 201117 1 1 1 1 1 1 1 1 1 1 1 10 Uberall, 201218 1 1 1 1 1 1 1 1 1 1 1 10 Vorsanger, 200819 0 1 1 1 1 1 1 0 0 1 1 8 Webster, 200620 0 1 1 1 1 1 1 0 0 1 1 8

*randomisation took place in the oxycodone vs oxymorphone phase, but not opioid vs placebo phase.

PEDro Items: 1. Eligibility criteria; 2. Randomisation; 3. Concealed allocation; 4. Baseline comparability; 5. Patient blinding; 6. Clinician blinding; 7. Assessor blinding; 8. Adequate follow-up >85%, 9. Intention to treat analysis; 10. Between group statistical comprisons; 11. Point measures and measures of variability



eTable 3. Data extraction Table.

Study Outcome measure

Mean (SD) Treatment

Number Mean (SD) Control

Number Mean difference

Clinically significant

Vorsanger, 200819 Tramadol ER 300mg vs placebo Note: SD from randomisation used for placebo and treatment groups

VAS (0-100) Week 1 Week 8 Week 12

38.0 (23.7) 34.0 (23.7) 33.0 (23.7)

127 127 127

45.0 (25.9) 40.0 (25.9) 39.0 (25.9)

126 126 126

-7.0 (-13.1 to -0·9) -6.0 (-12.1 to 0.1) -6.0 (-12.1 to 0.1)

NO NO NO

Vorsanger, 200819 Tramadol ER 200mg vs placebo

VAS (0-100) Week 1 Week 8 Week 12

SD from randomisation 39.0 (26.0) 35.0 (26.0) 38.0 (26.0)

129 129 129

45.0 (25.9) 40.0 (25.9) 39.0 (25.9)

126 126 126

-6.0 (-12.4 to 0.4) -5.0 (-11.4 to 1.4) -1.0 (-7.4 to 5.4)

NO NO NO

Schnitzer, 200015 Tramadol vs placebo

VAS Day 49

35.0 (27.9)

127

51.0 (29.8)

127

-16.0 (-23.1 to -8.9)

YES

Schnitzer, 200015 Tramadol vs placebo

RMDQ Day 49

36.7 (25.8)

127

42.5 (25.8)

127

-5.8 (-12.1 to 0.5)

NO

Uberall, 201218 Tramadol vs placebo

mean change NRS Week 4

-21.0 (20.0)

107

-20.0 (18.0)

110

-1.0 (-6.1 to 4.1)

NO

Peloso, 200410 Tramadol/paracetamol vs placebo Note: SD for placebo and treatment groups taken from baseline data

VAS Day 91

47.4 (15.0)

167

62.9 (15.5)

169

-15.5 (-18.8 to -12.2)

YES

Ruoff, 200313 Tramadol/Paracetamol combination Note: SD for placebo and treatment groups taken from baseline data

VAS Day 91

44.4 (14.5)

91

52.3 (14.9)

74

-7.9 (-12.4 to -3.4)

NO

Ruoff, 200313 Tramadol/Paracetamol combination vs placebo

RMDQ Day 91

44.6 (26.3)

91

48.3 (26.3)

74

-3.7 (-11.8 to 4.4)

NO

Perrot, 200611 Tramadol+paracetamol vs tramadol monotherapy Note: SD for placebo and treatment group

VAS Day 10

27.9 (13.0)

51

24.8 (14.6)

48

3.1 (-1.9 to 8.1)

NO



taken from baseline data Study Outcome

measure Mean (SD) Treatment




Hale, 20106 Hydromorphone Note: values estimated from graph in Figure 4 of study – clinic visits. SD from screening used for placebo and treatment groups

NRS (0-10) Week 1 Week 8 Week 12

34.0 (19.4) 31.0 (19.4) 32.0 (19.4)

133 133 133

41.0 (18.8) 41.0 (18.8) 41.0 (18.8)

133 133 133

-7.0 (-11.6 to -2.4) -10.0 (-14.6 to -5.4) -9.0 (-13.6 to -4.4)

NO YES NO

Gordon, 20105 Transdermal buprenorphine vs placebo

Pain intensity VAS Week 4

40.9 (20.2)

37

48.0 (22.5)

42

-7.1 (-16.5 to 2.3)

NO

Steiner, 201116 Buprenorphine transdermal vs placebo SE converted to SD

Average pain over past 24 hours NRS Week 12

38.1 (19.4)

257

43.9 (21.2)

283

-5.8 (-9.2 to -2.4)

NO

Steiner, 201117 Buprenorphine (transdermal) 5 µg/h vs Buprenorphine (transdermal) 20 µg/h SE converted to SD

Week 8 Week 12

38.3 (19.0) 40.2 (20.2)

138 127

33.5 (17.9) 33.5 (16.6)

164 142

4.8 (0.6 to 9.0) 6.7 (2.3 to 11.1)

NO NO

Steiner, 201117 Buprenorphine (transderamal) 5 µg/h vs oxycodone 40 mg

Week 8 Week 12

38.3 (19.0) 40.2 (20.2)

138 127

32.4 (19.1) 32.6 (18.9)

173 154

5.0 (1.6 to 1.0) 7.6 (3.0 to 12.2)

NO NO

Steiner, 201117 Buprenorphine 20 µg/h vs oxycodone 40 mg

Week 8 Week 12

33.5 (17.9) 33.5 (16.6)

164 142

32.4 (19.1) 32.6 (18.9)

173 154

1.1 (-2.8 to 5.0) 9.0 (-3.1 to 4.9)

NO NO

Hale, 20057 Oxymorphone vs placebo Note: used SD from Table 1 of study

Mean change from baseline in pain intensity (VAS) Week 1 Day 18

+8.0 (23.9) +8.5 (23.9)

71 71

+26.0 (23.8) +27.5 (23.8)

67 67

-18.0 (-26.0 to -10.0) -19.0 (-27.0 to -11.0)

YES YES

Hale, 20078 Oxymorphone (OPANA er) vs placebo Note: SD from screening used

VAS Day 10 < 3 months

28.0 (16.8) 31.0 (16.8)

70 49

51.0 (15.4) 55.0 (15.4)

72 18

-23.0 (-28.3 to -17.7) -24.0 (-32.5 to -15.5)

YES YES



Study Outcome





Katz, 20079 Oxymorphone ER vs placebo Used SD from Table 2 of study

Week 1 Week 8 Day 90

32.0 (24.5) 33.0 (24.5) 31.0 (24.5)

105 105 105

45.0 (27.9) 45.0 (27.9) 47.0 (27.9)

100 100 100

-13.0 (-20.2 to -5.8) -12.0 (-19.2 to -4.8) -16.0 (-23.2 to -8.8)

YES YES YES

Hale, 20057 Oxycodone vs placebo SD from Table 1 of study

Mean change from baseline in pain intensity (VAS) Week 1 Day 18

+9.0 (23.8) +6.5 (23.8)

75 75

+26.0 (23.8) +27.5 (23.8)

67 67

-17.0 (-24.8 to -9.2) -21.0 (-28.8 to -13.2)

YES YES

Webster, 200620 Oxycodone four times daily vs placebo

Pain 0-10 converted to 0-100 Week 1 Week 12

39.0 (25.3) 40.0 (25.3)

206 206

54.0 (28.7) 52.0 (30.5)

101 101

-15.0 (-21.6 to -8.4) -12.0 (-18·9 to -5·1)

YES YES

Buynak, 20102 Oxycodone vs placebo

Pain 0-10 converted to 0-100 Week 1 Week 8 Week 12

60.8 (18.7) 46.2 (17.5) 46.2 (16.4)

322 171 145

67.6 (17.0) 53.8 (19.0) 55.1 (18.3)

313 177 166

-6.8 (-9.6 to -4.0) -7.6 (-11.4 to -3.8) -8.9 (-12.8 to -5.0)

NO NO NO

Webster, 200620 Oxycodone plus low dose naltrexone four times daily vs placebo

Pain 0-10 converted 0-100 Week 1 Week 12

41.0 (25.1) 42.0 (25.6)

206 206

54.0 (28.7) 52.0 (30.5)

101 101

-13.0 (-19.6 to -6.4) -10.0 (-16.9 to -3.1)

YES YES

Webster, 200620 Oxycodone plus low dose naltrexone twice daily vs placebo

Pain 0-10 Converted to 0-100 Week 1 Week 12

42.0 (25.5) 43.0 (25.5)

206 206

5.4 (28.7) 52.0 (30.5)

101 101

-12.0 (-18.6 to -5.4) -9.0 (-15.9 to -2.1)

YES YES

Webster, 200620 Oxycodone four times daily vs oxycodone/naltrexone four times daily

Week 1 Week 12

39.0 (25.3) 40.0 (25.3)

206 206

41.0 (25.1) 42.0 (25.6)

206 206

-2.0 (-6.9 to 2.9) -2.0 (-6.9 to 2.9)

NO NO



VAS: Visual Analogue Scale; NRS: Numeric rating scale; RMDQ: Roland Morris Disability Questionnaire. Note: We used methods endorsed in the Cochrane Handbook for missing data. We adopted median scores for missing means and used standard deviation (SD) values from baseline (or the most similar eligible study) as a substitute for missing SDs.

Study Outcome





Webster, 200620 Oxycodone four times daily vs oxycodone/naltrexone twice daily

Week 1 Week 12

39.0 (25.3) 40.0 (25.3)

206 206

42.0 (25.5) 43.0 (25.5)

206 206

-3.0 (-7.9 to 1.9) -3.0 (-7.9 to 1.9)

NO NO

Webster, 200620 Oxycodone/naltrexone four times daily vs oxycodone/naltrexone twice daily

Week 1 Week 12

41.0 (25.1) 42.0 (25.6)

206 206

42.0 (25.5) 43.0 (25.5)

206 206

-1.0 (-5.9 to 3.9) -1.0 (-5.9 to 3.9)

NO NO

Cloutier, 20134 Oxycodone/naloxone vs placebo

VAS Week 8

48.6 (23.1)

32

55.9 (25.4)

31

-7.3 (-19.3 to 4·7)

NO

Allan, 20051 Transdermal fentanyl vs morphine

VAS (at rest) Week 1

58.5 (23.9)

338

59.9 (25.9)

342

-1.4 (-5.1 to 2.3)

NO

Allan, 20051 Transdermal fentanyl vs morphine

VAS (at rest) Month 13

56.0 (27.6)

338

55.8 (27.7)

342

0.2 (-4.0 to 4.4)

NO

Buynak, 20102 Tapendatol vs placebo

Pain 0-10 converted to 0-100 scale Week 1 Week 8 Week 12

65.6 (17.0) 47.4 (20.6) 46.4 (19.9)

313 201 183

67.6 (17.0) 53.8 (19.0) 55.1 (18.3)

313 177 166

-2.0 (-4.8 to 0.6) -6.4 (-10.4 to 2.4) -8.7 (-12.7 to -4.7)

NO NO NO

Chu, 20123 Morphine vs placebo

VAS mean change from baseline Month 1

-21.1 (15.9)

48

-12.5 (19.2)

55

-8.6 (-15.4 to -1.8)

NO

Chu, 20123 Morphine vs placebo

Mean change RMDQ Month 1

-8.4 (12.8)

48

-2.1 (17.3)

55

-6.3 (0.5 to 12.1)

NO

Rauck, 201412 Hydrocodone vs placebo

Mean change in pain intensity score (0-10)

Day 85

+4.8 (15.6)

151

+9.6 (15.5)

151

-4.8 [-8.3 to –1.3]

NO

Schiphorst, 201314 Mean Change in VAS (mm) Week 2 RMDQ (converted to 0-100 scale)

-10.0 (14.5) -6.2 (26.3)

24 24

-2.0 (14.9) -0.0 (26.3)

25 25

-8.0 [-16.2, 0.2] -6.2 [-20.9, 8.5]

NO NO



Steiner, 201117,18: SE from baseline used and converted to SD Allan, 20051: SD calculated from SE Note with Hale, 20057 mean change represented by a positive (+) score as this represents worsening pain in both groups (oxymorphone, oxycodone and placebo). Favourable mean change from baseline is represented by a negative (-) outcome value. Also Note: Most studies reported average pain (on the VAS or NRS) at present or within the past 24-hours. We extracted outcomes for average pain (not worst or least pain) and where specified, this was pain at rest (not with activity). Two studies which were included reported average pain over the preceding 2 weeks or average pain over the past week respectively. We used this same approach for data extraction for disability outcomes for consistency.



eTable 4. Main effect sizes and grading of evidence.

Outcome Condition Drug Class Time period MD [95% CI] GRADE Level of evidence

Number of trials

Comments

Pain Chronic LBP

Opioid analgesics Short term -10.1 [-12.8, -7.4] Moderate 13 Downgraded for publication bias

Pain Chronic LBP

Opioid analgesics Intermediate term

-8.1 [-10.2, -6.0] High 6 All domains fulfilled

Disability Chronic LBP

Combination opioid analgesic medicines containing a simple analgesic

Intermediate -3.7 [-11.8, 4.4] Very Low 1 Single study (Ruoff, 2003) of Tramadol/paracetamol downgraded for imprecision, inconsistency and publication bias



Short term -6.2, [-8.5, 20.9] Very Low 1 Single study (Schiphorst, 2013) of Tramadol/paracetamol downgraded for imprecision, inconsistency and publication bias

Pain Chronic LBP


Short term -8.0, [-16.2, 0.2] Very Low 1 Single study (Schiphorst, 2013) of Tramadol/paracetamol downgraded for imprecision, inconsistency and publication bias


Opioid analgesic Short -6.3 [0.5, 12.1] Very Low 1 Single study of morphine (Chu, 2012) downgraded for imprecision, inconsistency and publication bias

Pain Chronic LBP


Intermediate term

-11.9 [-19.3, -4.4] Moderate 2 Two studies (Ruoff, 2003 and Peloso, 2004) Downgraded for publication bias



eTable 5. Morphine equivalent dose conversion for opioid analgesic medicines evaluated in this review.

Study Drug (comparison group and reference in main text) Morphine equivalent dose mg/day*21

Vorsanger, 200819 tramadol 200.0 mg/d (a) tramadol 300.0 mg/d (b)

40.0 60.0

Ruoff, 200313 tramadol 157.5 mg/d 31.5 Hale, 20106 hydromorphone 12.0 – 64.0 mg/d 48.0 – 256.0 (median dose 152.0 mg)

Steiner, 201116 buprenorphine (transdermal administration) 10.0 or 20.0 ug/h over 7 days 36.0

Gordon, 20105 buprenorphine (transdermal administration) 29.8 ug/h (7 days) 60.0

Hale, 20057 oxycodone CR 155.0 mg/day (a) oxymorphone 79.4 mg/day (b)

232.5 238.2

Webster, 200620

oxycodone/naltrexone (oxycodone) four times daily dosing 34.5 mg/day (b) 51.8 Oxycodone/naltrexone (oxycodone) twice daily dosing 34.7 mg/day (a) 52.1 Oxycodone 39.0 mg/day (c) 58.5

Allan, 20051 SRM (sustained release morphine) 60.0 – 80.0 mg/day TDF (transdermal fentanyl) 25.0 – 50.0 ug/h

60.0 – 80.0 60.0 – 120.0

Perrot, 200611

Paracetamol + tramadol 172.5 mg/d tramadol 227.3 mg/d

9.32 11.94

Hale, 20078 oxymorphone 80.9 mg/d 242.7

Buynak, 20102 oxycodone 53.0 mg/d (a) tapentadol 313.2 mg/d (b)

79.5 114.9

Chu, 20123 morphine 78.3 mg/d 78.3

Cloutier, 20134 oxycodone 36.5 mg/d 18.2 mg/d naloxone (opioid antagonist NA)

54.8 NA



Study Drug (comparison group and reference in main text) Morphine equivalent dose mg/day*21

Steiner, 201117

oxycodone 40.0 mg/day 60.0 *Buprenorhpine 5.0 ug/h *Buprenorhpine 20.0 ug/h

Peloso, 200410 tramadol 158.0 mg/day + paracetamol 1369.0 mg/day 31.6 Uberall, 201216 tramadol 200.0 mg/d 40.0 Katz, 20079 oxymorphone 39.2 mg/d 117.6 Schnitzer, 200015 Tramadol 200.0 mg/d 48.5 Rauck, 201412 Hydrocodone 119.0 mg/d 119.0 Schiphorst, 201314 Tramadol 201.6 mg/d + paracetamol paracetamol 1746.9 mg/d 40.3

Note: The dose equivalence of transdermal buprenorphine and oral morphine is unclear. Dose conversions for buprenorphine listed here are based on those suggested by the manufacturer i.e. dose range covered by the three patch strengths may be equivalent to oral morphine up to 90 mg/day. Other literature suggests higher strength patches i.e. Buprenorphine 20·0 ug/ h patch might be equivalent to oral morphine up to 36·0 mg/day or 53·0 mg/day.22-25



eTable 6. Proportion of participants who dropped out in run-in and trial phase.

Study

Run-in phase: dropped out due to adverse events or lack of efficacy

Run-in phase: dropped out due to loss to follow-up

Trial phase: dropped out due to adverse events or lack of efficacy

Trial phase: dropped out due to loss to follow-up

Contributes to efficacy estimate (n)

Contributes to efficacy estimate (%)

Buynak 2010a2 NA NA 114 87 133 39.8

Webster 2006b20 NA NA 67 52 87 42.2

Webster 2006a20 NA NA 82 26 98 47.6

Webster 2006c20 NA NA 64 41 101 49.0

Gordon 20105 NA NA 17 2 20 51.3

Peloso 200410 NA NA 77 4 86 51.5

Buynak 2010b2 NA NA 64 91 166 51.7

Ruoff 200313 NA NA 61 10 91 56.2

Chu 20123 NA NA 0 21 48 69.6

Uberall 201218 NA NA 15 18 85 72.0 Cloutier 20134 NA NA 6 3 30 75.0 Schiphorst 201314 NA NA 2 2 21 84.0 Hale 20106 116 75 25 43 66 20.3 Steiner 2011a16 382 101 66 24 170 23.0 Vorsanger 2008b19 169 64 26 16 86 23.8 Vorsanger 2008a19 169 64 24 18 87 24.0 Hale 20078 57 51 15 6 49 27.5 Katz 20079 63 58 21 13 71 31.4 Rauck, 201412 63 145 16 11 124 34.5 Schnitzer 200015 101 25 30 6 91 36.0 Hale 2005b7 32 21 18 4 58 43.6 Hale 2005a7 30 12 17 4 59 48.4

Note: Trials in shaded rows employed an enrichment study design whereby participants who tolerated and responded to the trial medicine were eligible to continue to the trial phase phase.



eTable 7. Adverse event rates for opioid analgesic vs placebo trials.

Study

Length of treatment

Treatment and dose*

Morphine equivalent dose (mg/d)

TER: Treatment Event Rate; PER: Placebo Event Rate Risk Ratio (p-value) Constipation Nausea Dizziness Headache Vomiting Pruritus Somnolence Dry mouth

Buynak, 20102

12 weeks Tapentadol 313.2 mg daily

114.9 TER: 0.1 (44/318) PER: 0.1 (16/319) 2.8 (


Study

Length of treatment

Treatment and dose*



Hale, 20106

12 weeks Hydromorphone 12.0 – 64.0 mg daily

152.0 (median dose)

TER: 0.1 (10/134) PER: 0.0 (5/134) 2.0 (0.20)

TER: 0.1 (12/134) PER: 0·1 (10/134) 1.2 (0.7)

NA TER: 0.1 (7/134) PER: 0.1 (10/134) 0.7 (0.5)

TER: 0.1 (8/134) PER: 0.0 (6/134) 1.3 (0.6)

NA TER: 0.0 (1/134) PER: 0.0 (0/134) 3.00 (0.50)

NA

Hale, 20057 18 days Oxymorphone 79.4 mg daily

238.2 TER: 0.4 (39/110) PER: 0.1 (12/108) 3.2 (


Study

Length of treatment

Treatment and dose*



Peloso, 200410

91 days Tramadol 158.0 mg daily (+paracetamol)

31.6 TER: 0.1 (17/167) PER: 0.0 (2/169) 8.6 (


Note: Morphine equivalent doses derived from Boudreau, 2009. IM – intramuscular administration.

.

Study

Length of treatment

Treatment and dose*



Vorsanger, 200819

12 weeks Tramadol 200.0 mg daily

20.0 TER: 0.1 (7/129) PER: 0.0 (1/129) 7 (0.0)

TER: 0.1 (10/129) PER: 0.1 (9/129) 1.1 (0.8)

TER: 0.1 (13/129) PER: 0.1 (12/129) 1.1 (0.8)

TER: 0.1 (15/129) PER: 0.1 (14/129) 1.1 (0.8)

NA NA NA NA

Vorsanger, 200819

12 weeks Tramadol 300.0 mg daily

30.0 TER: 0.2 (19/128) PER: 0.0 (1/129) 19.2 (


eTable 8. Adverse event rates. Number (%) of participants with adverse events in placebo controlled studies of opioid analgesics.

Study Run-in phase-active drug RCT phase-placebo (%) RCT Phase-active drug Buynak, 20102 - 190/319 (59.6%) Tapentadol: 240/318

(75.5%) Oxycodone: 278/328 (84.5%)

Hale, 20106 - 73/134 (54.5%) Hydromorphone: 64/134 (47·8%) Hale, 20078 “During the open-label titration period, 174

(70.0%) patients reported adverse events.” Unclear Unclear

Katz, 20079 224/325 (68.9%) patients experienced at least on adverse event

44/100 (44.0%) Oxymorphone: 61/105 (58.1%)

Ruoff, 200313 - 73/157 (46.5%) Tramadol/paracetamol: 111/161 (68.9%) Steiner, 201116 - 146/283 (51.6%) Buprenorphine: 140/256 (54.7%) Uberall, 201218 - 44/120 (36.7%) Tramadol: 98/116 (84.5%) Vorsanger, 200819 499/619 (80.6%) had adverse events during

the run in period Unclear Unclear



eFigure 1. Funnel plot of standard error by treatment effect; chronic low back pain. Egger’s test (two-tailed p-value 0·007) for the primary time point and outcome: short term pain relief. Circles represent one opioid analgesic vs placebo comparison.



eFigure 2. Funnel plot of standard error by treatment effect; opioid analgesic studies; chronic low back pain: intermediate pain relief. Egger’s p=0·42.



eFigure 3. Intermediate and short term effects on pain from head-to-head opioid analgesic trials; chronic low back pain. Note each comparison is individually presented. BTDS = buprenorphine transdermal system; NTX = naltrexone; bd = twice daily dosing; qid = four times daily dosing; µg/h = microgram per hour.



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http://www.ncbi.nlm.nih.gov/pubmed/?term=Pascual%20ML%5BAuthor%5D&cauthor=true&cauthor_uid=18557165http://www.ncbi.nlm.nih.gov/pubmed/?term=Fleming%20RR%5BAuthor%5D&cauthor=true&cauthor_uid=18557165http://www.nps.org.au/__data/assets/pdf_file/0008/14687/buprenorphine.pdf%20Accessed%20February%204http://www.nps.org.au/__data/assets/pdf_file/0008/14687/buprenorphine.pdf%20Accessed%20February%204http://www.wales.nhs.uk/sites3/Documents/814/OpiateConversionDoses%5BFinal%5DNov2010.pdf