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Efficacy and safety of oral premedication on pain following non-surgical root canal treatment – A

systematic review and network meta-analysis of randomized controlled trials.

Supplementary files

Appendix 1: Search strategies

Appendix 1.1- Search strategy for Medline database

Appendix 1.2- Search strategy for Ebscohost database

Appendix 2: Search process

Records identified through database searching

(medline n = 999; Ebscohost n=144) )

Scr

een

ing

Inc

lud

ed

Eli

gib

ilit

y

Ide

ntif

icat

ion

Additional records identified through other sources

(n = 0 )

Records after duplicates removed (n =1020)

Records screened (n = 1020)

Records excluded (n = 1002)

Full-text articles assessed for eligibility

(n = 19 )

Full-text articles excluded, with reasons

(n = 3 )

Studies included in qualitative synthesis

(n = 16)

Studies included in quantitative synthesis

(meta-analysis) (n = 11)

Five articles excluded due to no standard deviation (n= 3)

and no mean pain scores (n=2).

Appendix 3- Risk of bias assessment for included studies

Author Bias arising from the randomization process

Bias due to deviations from

intended interventions

Bias due to missing outcome

data

Bias in measurement

of the outcome

Bias in selection of

the reported result

Overall bias

Menke et al. (45) + + + + + +

Gopikrishna and Parameswaran (14)

? + + + + ?

Attar et al. (13) + + + + + +

Saatchi et al. (42) + + + + + +

Jalalzadeh et al. (12) + + + + + +

Arslan et al. (20) + + + + + +

Mirzaie et al. (44) + + + + + +

YaghootiKhorasani et al. (43) + + + + + +

Ashraf et al. (19) + + + + + +

Ramazani et al. (15) + + - + + -

Sethi et al. (18) + + + + + +

Isik et al. (17) + + + + + +

Author Bias arising from the randomization process

Bias due to deviations from

intended interventions

Bias due to missing outcome

data

Bias in measurement

of the outcome

Bias in selection of

the reported result

Overall bias

Mokhtari et al. (9) + + ? + + ?

Joshi et al. (16) + + + + + +

Praveen et al. (10) + + + + + +

Elkhadem et al. (11) + + + + + +

+symbol/green colour means ‘low risk of bias’; ?symbol/yellow colour means ‘some concerns’; - symbol/red colour means ‘high risk of bias’

Appendix 4: Results of meta-analyses of direct comparisons of treatment options based on based on pharmacological group.Appendix 4.1. Pairwise meta-analysis (Direct comparison) mean difference (and 95% CI) for post-operative pain (intervention groups were categorized based on pharmacological group).

Comparisons

No.

of

stud

ies

(Ref

)

No.

of

patie

nt

Pairwise meta-analysis mean difference (95% CI)

Heterogeneity I2

Fixed effect Random effect

at 6 hours

NSAIDs vs. Corticosteroid

1 (10) 59 -6.10(-13.32,1.12)

-6.10(-13.32,1.12)

N/A

Placebo vs. Corticosteroid

3 (10-12) 495 20.45(16.02,24.88)

20.18(3.82,36.54)

91.30%

Opioids vs. NSAIDs 1 (18) 56 -3.60(-10.84,3.64)

-3.60(-10.84,3.64)

N/A

Placebo vs. NSAIDs 4 (10,13,42,4

3)

233 0.16(-3.09,3.41)

5.75(-6.51,18.01)

91.60%

at 12 hours

Placebo vs. COX-2 1 (19) 28 18.06(-7.86,43.97)

18.06(-7.86,43.97)

N/A


1 (10) 59 12.96(7.18,18.74)

12.96(7.18,18.74)

N/A


3 (10-12) 495 19.03(14.94,23.13)

20.43(12.64,28.22)

65.60%

NSAIDs vs. Gabapentin 1 (17) 60 6.30(2.09,10.51)

6.30(2.09,10.51)

N/A

Placebo vs. Gabapentin 1 (17) 60 16.70(12.77,20.63)

16.70(12.77,20.63)

N/A


-3.30(-10.91,4.31)

N/A


, 17,43)

313 0.78(-0.50,2.06)

7.20(-3.66,18.06)

97.60%

at 24 hours

Placebo vs. COX-2 1 (19) 28 10.06(-9.54,29.66)

10.06(-9.54,29.66)

N/A


1 (10) 59 12.50(7.22,17.78)

12.50(7.22,17.78)

N/A


3 (10- 12) 495 14.58(10.84,18.31)

21.23(6.04,36.42)

92.60%

NSAIDs vs. Gabapentin 1 (17) 60 10.00(6.25,13.75)

10.00(6.25,13.75)

N/A

Placebo vs. Gabapentin 1 (17) 60 10.00(4.07,15.93)

10.00(4.07,15.93)

N/A


-6.60(-14.09,0.89)

N/A


, 17,43)

313 -2.40(-3.65,-1.14)

3.55(-4.82,11.91)

95.30%

Appendix 4.2. Forest plot of pairwise meta-analysis with a random-effects model of mean difference (and 95% CI) for post-operative pain at 6 hours (intervention groups were categorized based on pharmacological group)

.

.

.

.

NSAIDs - CorticosteroidPraveen et al (2017)Subtotal (I-squared = .%, p = .)

Placebo - CorticosteroidPraveen et al (2017)Jalalzadeh et al (2010)Elkhadem et al (2017)Subtotal (I-squared = 91.3%, p = 0.000)

Opioids - NSAIDsSethi et al (2014)Subtotal (I-squared = .%, p = .)

Placebo - NSAIDsSaatchi et al (2009)Attar et al (2008)YaghootiKhorasani et al (2012)Praveen et al (2017)Subtotal (I-squared = 91.6%, p = 0.000)

IDStudy

-6.10 (-13.32, 1.12)-6.10 (-13.32, 1.12)

3.56 (-4.73, 11.85)31.50 (19.57, 43.43)26.16 (20.33, 31.99)20.18 (3.82, 36.54)

-3.60 (-10.84, 3.64)-3.60 (-10.84, 3.64)

10.70 (2.99, 18.41)-8.93 (-13.35, -4.51)13.13 (2.91, 23.34)9.66 (2.04, 17.28)5.75 (-6.50, 18.01)

Difference (95% CI)Mean

-6.10 (-13.32, 1.12)-6.10 (-13.32, 1.12)

3.56 (-4.73, 11.85)31.50 (19.57, 43.43)26.16 (20.33, 31.99)20.18 (3.82, 36.54)

-3.60 (-10.84, 3.64)-3.60 (-10.84, 3.64)

10.70 (2.99, 18.41)-8.93 (-13.35, -4.51)13.13 (2.91, 23.34)9.66 (2.04, 17.28)5.75 (-6.50, 18.01)


0-43.4 0 43.4


.

.

.

.

.

.

.

Placebo - COX2Ashraf et al (2013)Subtotal (I-squared = .%, p = .)


Placebo - CorticosteroidElkhadem et al (2017)Jalalzadeh et al (2010)Praveen et al (2017)Subtotal (I-squared = 65.6%, p = 0.055)

NSAIDs - GabapentinIsik et al (2014)Subtotal (I-squared = .%, p = .)

Placebo - GabapentinIsik et al (2014)Subtotal (I-squared = .%, p = .)


Placebo - NSAIDsJoshi et al (2016)Praveen et al (2017)Attar et al (2008)Isik et al (2014)YaghootiKhorasani et al (2012)Mokhtari et al (2016)Subtotal (I-squared = 97.6%, p = 0.000)

IDStudy

18.06 (-7.85, 43.97)18.06 (-7.85, 43.97)

12.96 (7.18, 18.74)12.96 (7.18, 18.74)

19.52 (14.03, 25.01)33.00 (19.57, 46.43)14.53 (7.60, 21.46)20.43 (12.64, 28.22)

6.30 (2.09, 10.51)6.30 (2.09, 10.51)

16.70 (12.77, 20.63)16.70 (12.77, 20.63)

-3.30 (-10.91, 4.31)-3.30 (-10.91, 4.31)

30.00 (25.17, 34.83)1.57 (-5.93, 9.07)-7.12 (-11.70, -2.55)10.40 (6.59, 14.21)12.19 (0.86, 23.52)-3.09 (-4.62, -1.55)7.20 (-3.66, 18.06)


18.06 (-7.85, 43.97)18.06 (-7.85, 43.97)

12.96 (7.18, 18.74)12.96 (7.18, 18.74)

19.52 (14.03, 25.01)33.00 (19.57, 46.43)14.53 (7.60, 21.46)20.43 (12.64, 28.22)

6.30 (2.09, 10.51)6.30 (2.09, 10.51)

16.70 (12.77, 20.63)16.70 (12.77, 20.63)

-3.30 (-10.91, 4.31)-3.30 (-10.91, 4.31)

30.00 (25.17, 34.83)1.57 (-5.93, 9.07)-7.12 (-11.70, -2.55)10.40 (6.59, 14.21)12.19 (0.86, 23.52)-3.09 (-4.62, -1.55)7.20 (-3.66, 18.06)


0-46.4 0 46.4


.

.

.

.

.

.

.

Placebo - COX2Ashraf et al (2013)Subtotal (I-squared = .%, p = .)


Placebo - CorticosteroidJalalzadeh et al (2010)Elkhadem et al (2017)Praveen et al (2017)Subtotal (I-squared = 92.6%, p = 0.000)

NSAIDs - GabapentinIsik et al (2014)Subtotal (I-squared = .%, p = .)



Placebo - NSAIDsPraveen et al (2017)YaghootiKhorasani et al (2012)Mokhtari et al (2016)Joshi et al (2016)Attar et al (2008)Isik et al (2014)Subtotal (I-squared = 95.3%, p = 0.000)

IDStudy

10.06 (-9.54, 29.66)10.06 (-9.54, 29.66)

12.50 (7.22, 17.78)12.50 (7.22, 17.78)

44.00 (32.29, 55.71)10.84 (5.90, 15.78)11.96 (5.44, 18.48)21.23 (6.04, 36.42)

10.00 (6.25, 13.75)10.00 (6.25, 13.75)

10.00 (4.07, 15.93)10.00 (4.07, 15.93)

-6.60 (-14.09, 0.89)-6.60 (-14.09, 0.89)

-0.54 (-7.16, 6.08)9.06 (0.09, 18.03)-3.03 (-4.48, -1.58)29.10 (22.15, 36.05)-10.73 (-14.45, -7.01)0.00 (-5.93, 5.93)3.55 (-4.81, 11.91)


10.06 (-9.54, 29.66)10.06 (-9.54, 29.66)

12.50 (7.22, 17.78)12.50 (7.22, 17.78)

44.00 (32.29, 55.71)10.84 (5.90, 15.78)11.96 (5.44, 18.48)21.23 (6.04, 36.42)

10.00 (6.25, 13.75)10.00 (6.25, 13.75)

10.00 (4.07, 15.93)10.00 (4.07, 15.93)

-6.60 (-14.09, 0.89)-6.60 (-14.09, 0.89)

-0.54 (-7.16, 6.08)9.06 (0.09, 18.03)-3.03 (-4.48, -1.58)29.10 (22.15, 36.05)-10.73 (-14.45, -7.01)0.00 (-5.93, 5.93)3.55 (-4.81, 11.91)


0-55.7 0 55.7

Appendix 5: Results of meta-analyses of direct comparisons of treatment options based on based on chemical name.Appendix 5.1. Pairwise meta-analysis (Direct comparison) mean difference (and 95% CI) for post-operative pain (intervention groups were categorized based on chemical name).

Comparisons

No.

st

udie

s

No.

of

patie

nt


Heterogeneity I2


at 6 hours

Ibuprofen vs. Diclofenac 1 (42)

60 -5.00(-11.66,1.66)

-5.00(-11.66,1.66)

N/A

Placebo vs. Diclofenac 1 (42)

60 8.20(-0.58,16.98)

8.20(-0.58,16.98)

N/A

Ketorolac vs. Etodolac 1 (18)

38 -20.00(-28.84,-11.16)

-20.00(-28.84,-11.16)

N/A

Tapentadol vs. Etodolac 1 (18)

37 -13.60(-22.18,-5.02)

-13.60(-22.18,-5.02)

N/A

Placebo vs. Ibuprofen 3 (13,42,43)

131 -1.91(-5.57,1.75)

5.56(-11.57,22.69)

93.50%

Sulindac vs. Ibuprofen 1 (43)

32 1.25(-10.74,13.24)

1.25(-10.74,13.24)

N/A

Placebo vs. Ketorolac 1 (10)

56 9.66(2.04,17.28)

9.66(2.04,17.28)

N/A

Prednisolone vs. Ketorolac 1 (10)

59 6.10(-1.12,13.32)

6.10(-1.12,13.32)

N/A

Tapentadol vs. Ketorolac 1 (18)

37 6.40(-0.72,13.53)

6.40(-0.72,13.53)

N/A

Prednisolone vs. Placebo 3 (10-12)

495 -20.45(-24.88,-16.02)

-20.18(-36.54,-3.82)

91.30%

Sulindac vs. Placebo 1 (43)

32 -12.50(-24.92,-0.08)

-12.50(-24.92,-0.08)

N/A

at 12 hours

Placebo vs. Celecoxib 1 (19)

28 18.06(-7.85,43.97)

18.06(-7.85,43.97)

N/A


38 -21.60(-30.65,-12.55)

-21.60(-30.65,-12.55)

N/A


37 -14.10(-23.89,-4.31)

-14.10(-23.89,-4.31)

N/A

Lornoxicam vs. Gabapentin 1 (17)

60 6.30(2.09,10.51)

6.30(2.09,10.51)

N/A

Placebo vs. Gabapentin 1 (17)

60 16.70(12.77,20.63)

16.70(12.77,20.63)

N/A

Indomethacin vs. Ibuprofen 1 (9) 44 1.33(-0.88,3.54)

1.33(-0.88,3.54)

N/A

Placebo vs. Ibuprofen 3 (9,13,43

115 -2.83(-4.50,-1.16)

-2.48(-7.98,3.02)

73.50%

Comparisons

No.

st

udie

s

No.

of

patie

nt


Heterogeneity I2


)


32 -4.38(-13.99,5.23)

-4.38(-13.99,5.23)

N/A

Placebo vs. Indomethacin 1 (9) 44 -3.75(-5.71,-1.79)

-3.75(-5.71,-1.79)

N/A


56 1.57(-5.93,9.07)

1.57(-5.93,9.07)

N/A

Prednisolone vs. Ketorolac 1 (10)

59 -12.96(-18.74,-7.18)

-12.96(-18.74,-7.18)

N/A


37 7.50(1.35,13.65)

7.50(1.35,13.65)

N/A

Placebo vs. Lornoxicam 1 (17)

60 10.40(6.59,14.21)

10.40(6.59,14.21)

N/A

Placebo vs. Piroxicam 1 (16)

44 30.00(25.17,34.83)

30.00(25.17,34.83)

N/A


495 -19.03(-23.13,-14.94)

-20.43(-28.22,-12.64)

65.60%


32 -14.38(-26.36,-2.40)

-14.38(-26.36,-2.40)

N/A

at 24 hours

Placebo vs. Celecoxib 1 (19)

28 10.06(-9.54,29.66)

10.06(-9.54,29.66)

N/A


38 -22.60(-33.35,-11.85)

-22.60(-33.35,-11.85)

N/A


37 -17.90(-28.89,-6.91)

-17.90(-28.89,-6.91)

N/A

Lornoxicam vs. Gabapentin 1 (17)

60 10.00(6.25,13.75)

10.00(6.25,13.75)

N/A

Placebo vs. Gabapentin 1 (17)

60 10.00(4.07,15.93)

10.00(4.07,15.93)

N/A

Indomethacin vs. Ibuprofen 1 (9) 44 4.30(3.08,5.52)

4.30(3.08,5.52)

N/A

Placebo vs. Ibuprofen 3 (9,13,43

)

115 -1.85(-3.10,-0.60)

-2.20(-10.51,6.11)

92.80%


32 -1.88(-8.80,5.04)

-1.88(-8.80,5.04)

N/A

Placebo vs. Indomethacin 1 (9) 44 -5.18(-6.71,-3.65)

-5.18(-6.71,-3.65)

N/A


56 -0.54(-7.16,6.08)

-0.54(-7.16,6.08)

N/A

Prednisolone vs. Ketorolac 1 59 -12.50 -12.50 N/A

Comparisons

No.

st

udie

s

No.

of

patie

nt


Heterogeneity I2


(10) (-17.78,-7.22) (-17.78,-7.22)


37 4.70(-0.23,9.63)

4.70(-0.23,9.63)

N/A

Placebo vs. Lornoxicam 1 (17)

60 0.00(-5.93,5.93)

0.00(-5.93,5.93)

N/A

Placebo vs. Piroxicam 1 (16)

44 29.10(22.15,36.05)

29.10(22.15,36.05)

N/A


495 -14.58(-18.31,-10.84)

-21.23(-36.42,-6.04)

92.60%


32 -10.00(-19.30,-0.70)

-10.00(-19.30,-0.70)

N/A

Appendix 5.2: Forest plot of pairwise meta-analysis with a random-effects model of mean difference (and 95% CI) for post-operative pain at 6 hours (intervention groups were categorized based on chemical name)

.

.

.

.

.

.

.

.

.

.

.

Ibuprofen - DiclofenacSaatchi et al (2009)Subtotal (I-squared = .%, p = .)

Placebo - DiclofenacSaatchi et al (2009)Subtotal (I-squared = .%, p = .)

Ketorolac - EtodolacSethi et al (2014)Subtotal (I-squared = .%, p = .)

Tapentadol - EtodolacSethi et al (2014)Subtotal (I-squared = .%, p = .)

Placebo - IbuprofenAttar et al (2008)YaghootiKhorasani et al (2012)Saatchi et al (2009)Subtotal (I-squared = 93.5%, p = 0.000)

Sulindac - IbuprofenYaghootiKhorasani et al (2012)Subtotal (I-squared = .%, p = .)

Placebo - KetorolacPraveen et al (2017)Subtotal (I-squared = .%, p = .)

Prednisolone - KetorolacPraveen et al (2017)Subtotal (I-squared = .%, p = .)

Tapentadol - KetorolacSethi et al (2014)Subtotal (I-squared = .%, p = .)

Prednisolone - PlaceboElkhadem et al (2017)Jalalzadeh et al (2010)Praveen et al (2017)Subtotal (I-squared = 91.3%, p = 0.000)

Sulindac - PlaceboYaghootiKhorasani et al (2012)Subtotal (I-squared = .%, p = .)

IDStudy

-5.00 (-11.66, 1.66)-5.00 (-11.66, 1.66)

8.20 (-0.58, 16.98)8.20 (-0.58, 16.98)

-20.00 (-28.84, -11.16)-20.00 (-28.84, -11.16)

-13.60 (-22.18, -5.02)-13.60 (-22.18, -5.02)

-8.93 (-13.35, -4.51)13.75 (2.41, 25.09)13.20 (5.22, 21.18)5.56 (-11.57, 22.69)

1.25 (-10.74, 13.24)1.25 (-10.74, 13.24)

9.66 (2.04, 17.28)9.66 (2.04, 17.28)

6.10 (-1.12, 13.32)6.10 (-1.12, 13.32)

6.40 (-0.72, 13.52)6.40 (-0.72, 13.52)

-26.16 (-31.99, -20.33)-31.50 (-43.43, -19.57)-3.56 (-11.85, 4.73)-20.18 (-36.54, -3.82)

-12.50 (-24.92, -0.08)-12.50 (-24.92, -0.08)


-5.00 (-11.66, 1.66)-5.00 (-11.66, 1.66)

8.20 (-0.58, 16.98)8.20 (-0.58, 16.98)

-20.00 (-28.84, -11.16)-20.00 (-28.84, -11.16)

-13.60 (-22.18, -5.02)-13.60 (-22.18, -5.02)

-8.93 (-13.35, -4.51)13.75 (2.41, 25.09)13.20 (5.22, 21.18)5.56 (-11.57, 22.69)

1.25 (-10.74, 13.24)1.25 (-10.74, 13.24)

9.66 (2.04, 17.28)9.66 (2.04, 17.28)

6.10 (-1.12, 13.32)6.10 (-1.12, 13.32)

6.40 (-0.72, 13.52)6.40 (-0.72, 13.52)

-26.16 (-31.99, -20.33)-31.50 (-43.43, -19.57)-3.56 (-11.85, 4.73)-20.18 (-36.54, -3.82)

-12.50 (-24.92, -0.08)-12.50 (-24.92, -0.08)


0-43.4 0 43.4


.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

Placebo - CelecoxibAshraf et al (2013)Subtotal (I-squared = .%, p = .)



Lornoxicam - GabapentinIsik et al (2014)Subtotal (I-squared = .%, p = .)


Indomethacin - IbuprofenMokhtari et al (2016)Subtotal (I-squared = .%, p = .)

Placebo - IbuprofenYaghootiKhorasani et al (2012)Attar et al (2008)Mokhtari et al (2016)Subtotal (I-squared = 73.5%, p = 0.023)


Placebo - IndomethacinMokhtari et al (2016)Subtotal (I-squared = .%, p = .)




Placebo - LornoxicamIsik et al (2014)Subtotal (I-squared = .%, p = .)

Placebo - PiroxicamJoshi et al (2016)Subtotal (I-squared = .%, p = .)

Prednisolone - PlaceboElkhadem et al (2017)Praveen et al (2017)Jalalzadeh et al (2010)Subtotal (I-squared = 65.6%, p = 0.055)


IDStudy

18.06 (-7.85, 43.97)18.06 (-7.85, 43.97)

-21.60 (-30.65, -12.55)-21.60 (-30.65, -12.55)

-14.10 (-23.89, -4.31)-14.10 (-23.89, -4.31)

6.30 (2.09, 10.51)6.30 (2.09, 10.51)

16.70 (12.77, 20.63)16.70 (12.77, 20.63)

1.33 (-0.88, 3.54)1.33 (-0.88, 3.54)

10.00 (-2.64, 22.64)-7.12 (-11.70, -2.55)-2.42 (-4.23, -0.61)-2.48 (-7.98, 3.02)

-4.38 (-13.99, 5.23)-4.38 (-13.99, 5.23)

-3.75 (-5.71, -1.79)-3.75 (-5.71, -1.79)

1.57 (-5.93, 9.07)1.57 (-5.93, 9.07)

-12.96 (-18.74, -7.18)-12.96 (-18.74, -7.18)

7.50 (1.35, 13.65)7.50 (1.35, 13.65)

10.40 (6.59, 14.21)10.40 (6.59, 14.21)

30.00 (25.17, 34.83)30.00 (25.17, 34.83)

-19.52 (-25.01, -14.03)-14.53 (-21.46, -7.60)-33.00 (-46.43, -19.57)-20.43 (-28.22, -12.64)

-14.38 (-26.36, -2.40)-14.38 (-26.36, -2.40)


18.06 (-7.85, 43.97)18.06 (-7.85, 43.97)

-21.60 (-30.65, -12.55)-21.60 (-30.65, -12.55)

-14.10 (-23.89, -4.31)-14.10 (-23.89, -4.31)

6.30 (2.09, 10.51)6.30 (2.09, 10.51)

16.70 (12.77, 20.63)16.70 (12.77, 20.63)

1.33 (-0.88, 3.54)1.33 (-0.88, 3.54)

10.00 (-2.64, 22.64)-7.12 (-11.70, -2.55)-2.42 (-4.23, -0.61)-2.48 (-7.98, 3.02)

-4.38 (-13.99, 5.23)-4.38 (-13.99, 5.23)

-3.75 (-5.71, -1.79)-3.75 (-5.71, -1.79)

1.57 (-5.93, 9.07)1.57 (-5.93, 9.07)

-12.96 (-18.74, -7.18)-12.96 (-18.74, -7.18)

7.50 (1.35, 13.65)7.50 (1.35, 13.65)

10.40 (6.59, 14.21)10.40 (6.59, 14.21)

30.00 (25.17, 34.83)30.00 (25.17, 34.83)

-19.52 (-25.01, -14.03)-14.53 (-21.46, -7.60)-33.00 (-46.43, -19.57)-20.43 (-28.22, -12.64)

-14.38 (-26.36, -2.40)-14.38 (-26.36, -2.40)


0-46.4 0 46.4


.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

Placebo - CelecoxibAshraf et al (2013)Subtotal (I-squared = .%, p = .)



Lornoxicam - GabapentinIsik et al (2014)Subtotal (I-squared = .%, p = .)


Indomethacin - IbuprofenMokhtari et al (2016)Subtotal (I-squared = .%, p = .)

Placebo - IbuprofenMokhtari et al (2016)YaghootiKhorasani et al (2012)Attar et al (2008)Subtotal (I-squared = 92.8%, p = 0.000)


Placebo - IndomethacinMokhtari et al (2016)Subtotal (I-squared = .%, p = .)




Placebo - LornoxicamIsik et al (2014)Subtotal (I-squared = .%, p = .)

Placebo - PiroxicamJoshi et al (2016)Subtotal (I-squared = .%, p = .)

Prednisolone - PlaceboJalalzadeh et al (2010)Elkhadem et al (2017)Praveen et al (2017)Subtotal (I-squared = 92.6%, p = 0.000)


IDStudy

10.06 (-9.54, 29.66)10.06 (-9.54, 29.66)

-22.60 (-33.35, -11.85)-22.60 (-33.35, -11.85)

-17.90 (-28.89, -6.91)-17.90 (-28.89, -6.91)

10.00 (6.25, 13.75)10.00 (6.25, 13.75)

10.00 (4.07, 15.93)10.00 (4.07, 15.93)

4.30 (3.08, 5.52)4.30 (3.08, 5.52)

-0.88 (-2.22, 0.46)8.12 (-1.83, 18.07)-10.73 (-14.45, -7.01)-2.20 (-10.51, 6.11)

-1.88 (-8.80, 5.04)-1.88 (-8.80, 5.04)

-5.18 (-6.71, -3.65)-5.18 (-6.71, -3.65)

-0.54 (-7.16, 6.08)-0.54 (-7.16, 6.08)

-12.50 (-17.78, -7.22)-12.50 (-17.78, -7.22)

4.70 (-0.23, 9.63)4.70 (-0.23, 9.63)

0.00 (-5.93, 5.93)0.00 (-5.93, 5.93)

29.10 (22.15, 36.05)29.10 (22.15, 36.05)

-44.00 (-55.71, -32.29)-10.84 (-15.78, -5.90)-11.96 (-18.48, -5.44)-21.23 (-36.42, -6.04)

-10.00 (-19.30, -0.70)-10.00 (-19.30, -0.70)


10.06 (-9.54, 29.66)10.06 (-9.54, 29.66)

-22.60 (-33.35, -11.85)-22.60 (-33.35, -11.85)

-17.90 (-28.89, -6.91)-17.90 (-28.89, -6.91)

10.00 (6.25, 13.75)10.00 (6.25, 13.75)

10.00 (4.07, 15.93)10.00 (4.07, 15.93)

4.30 (3.08, 5.52)4.30 (3.08, 5.52)

-0.88 (-2.22, 0.46)8.12 (-1.83, 18.07)-10.73 (-14.45, -7.01)-2.20 (-10.51, 6.11)

-1.88 (-8.80, 5.04)-1.88 (-8.80, 5.04)

-5.18 (-6.71, -3.65)-5.18 (-6.71, -3.65)

-0.54 (-7.16, 6.08)-0.54 (-7.16, 6.08)

-12.50 (-17.78, -7.22)-12.50 (-17.78, -7.22)

4.70 (-0.23, 9.63)4.70 (-0.23, 9.63)

0.00 (-5.93, 5.93)0.00 (-5.93, 5.93)

29.10 (22.15, 36.05)29.10 (22.15, 36.05)

-44.00 (-55.71, -32.29)-10.84 (-15.78, -5.90)-11.96 (-18.48, -5.44)-21.23 (-36.42, -6.04)

-10.00 (-19.30, -0.70)-10.00 (-19.30, -0.70)


0-55.7 0 55.7

Appendix 6: Results of network meta-analysis

Estimates are presented as mean difference (MD) and 95% confidence intervals. Treatments are ordered by rankings for each outcome. Comparisons between treatments should be read from column to row for each outcome (row treatment is reference). For efficacy outcomes, mean difference less than 0 favour the column-defining treatment. To obtain mean difference for comparisons in the opposite direction, reciprocals should be taken.

Figure 6.1. Network estimated mean difference (95% confidence intervals) of treatment options (categorized based on pharmacological group) for post-operative pain at 6 hours.

Corticosteroid

-6.15(-37.66,25.36)

Opioids

-9.75(-27.44,7.94)

-3.60(-

29.68,22.48)NSAIDs

-18.14(-32.90,-3.37)

-11.99(-

41.03,17.05)

-8.39(-

21.17,4.39)Placebo

* Treatments are ordered by SUCRA rank. Comparisons between treatments should be read from column to row for each outcome (row treatment is reference).


Corticosteroid

-4.11(-41.75,33.52)

COX-2

-6.82(-31.77,18.13)

-2.71(-43.65,38.23)

Gabapentin

-11.18(-40.45,18.09)

-7.07(-51.01,36.88)

-4.36(-36.96,28.24)

Opioids

-14.48(-30.15,1.20)

-10.36(-46.70,25.97)

-7.66(-28.91,13.60)

-3.30(-28.01,21.42)

NSAIDs

-22.17(-36.03,-8.32)

-18.06(-53.05,16.94)

-15.35(-36.60,5.89)

-10.99(-37.57,15.58)

-7.70(-17.46,2.07)

Placebo



Corticosteroid

-9.17(-39.29,20.96)

Gabapentin

-10.35(-45.36,24.66)

-1.18(-

40.42,38.05)Opioids

-11.44(-49.85,26.96)

-2.28(-

45.53,40.98)

-1.10(-

48.19,46.00)COX-2

-16.95(-35.66,1.76)

-7.78(-

33.54,17.98)

-6.60(-

36.19,23.00)

-5.50(-

42.14,31.14)NSAIDs

-21.50(-37.95,-5.06)

-12.33(-

38.16,13.49)

-11.15(-

43.00,20.69)

-10.06(-

44.76,24.64)

-4.56(-

16.31,7.20)Placebo


Figure 6.4. Network estimated mean difference (95% confidence intervals) of treatment options (categorized based on chemical name) for post-operative pain at 6 hours.

Sulindac

-2.84(-

17.41,11.72)Ketorolac

-3.75(-

17.46,9.96)

-1.46(-

13.08,10.16)Diclofenac

-8.94(-

23.87,5.98)

-6.10(-

13.32,1.12)

-4.64(-

16.71,7.43)Prednisolone

-9.24(-

25.45,6.97)

-6.40(-

13.52,0.72)

-4.94(-

18.57,8.68)

-0.30(-10.44,9.84)

Tapentadol

-12.50(-24.92,-

0.08)

-9.66(-17.28,-

2.04)

-8.20(-

16.98,0.58)

-3.56(-11.85,4.73)

-3.26(-

13.69,7.17)Placebo

1.25(-

10.74,13.24)

3.54(-

7.49,14.57)

5.00(-

1.66,11.66)

9.64(-1.87,21.14)

9.94(-

3.19,23.07)

13.20(5.22,21.18)

Ibuprofen

-22.83(-39.86,-

5.79)

-19.99(-28.83,-11.16)

-18.53(-33.12,-

3.93)

-13.89(-25.30,-

2.48)

-13.60(-22.17,-

5.02)

-10.33(-

21.99,1.34)

-23.53(-37.66,-

9.40)Etodolac



Piroxicam

-9.35(-25.09,6.39)

Prednisolone

-13.30(-31.56,4.96)

-3.95(-19.44,11.54)

Gabapentin

-11.94(-43.40,19.51)

-2.59(-32.53,27.34)

1.36(-29.97,32.69)

Celecoxib

-19.60(-37.83,-1.37)

-10.25(-25.71,5.21)

-6.30(-19.15,6.55)

-7.66(-38.97,23.66)

Lornoxicam

-22.41(-42.03,-2.78)

-13.05(-29.80,3.69)

-9.11(-28.53,10.32)

-10.46(-42.61,21.68)

-2.81(-22.21,16.60)

Sulindac

-25.01(-43.34,-6.68)

-15.66(-28.29,-3.03)

-11.71(-29.83,6.41)

-13.07(-44.44,18.30)

-5.41(-23.50,12.68)

-2.60(-22.03,16.82)

Ketorolac

-30.00(-43.06,-16.94)

-20.65(-29.44,-11.86)

-16.70(-29.46,-3.94)

-18.06(-46.67,10.56)

-10.40(-23.12,2.32)

-7.59(-22.25,7.06)

-4.99(-17.85,7.87)

Placebo

-32.51(-55.34,-9.68)

-23.16(-41.72,-4.60)

-19.21(-41.86,3.45)

-20.57(-54.76,13.63)

-12.91(-35.54,9.72)

-10.10(-33.82,13.61)

-7.50(-21.10,6.10)

-2.51(-21.23,16.21)

Tapentadol

-31.63(-47.12,-16.14)

-22.28(-33.93,-10.64)

-18.33(-33.57,-3.10)

-19.69(-49.49,10.11)

-12.03(-27.23,3.17)

-9.23(-23.27,4.82)

-6.62(-21.86,8.61)

-1.63(-9.96,6.70)

0.88(-19.55,21.30)

Ibuprofen

-33.36(-50.73,-15.99)

-24.01(-38.25,-9.76)

-20.06(-37.20,-2.92)

-21.42(-52.24,9.40)

-13.76(-30.87,3.36)

-10.95(-28.35,6.44)

-8.35(-25.53,8.83)

-3.36(-14.81,8.09)

-0.85(-22.76,21.07)

-1.73(-13.20,9.74)

Indomethacin

-46.61(-70.38,-22.84)

-37.26(-56.97,-17.55)

-33.31(-56.92,-9.70)

-34.67(-69.50,0.17)

-27.01(-50.60,-3.42)

-24.20(-48.83,0.42)

-21.60(-36.74,-6.46)

-16.61(-36.47,3.26)

-14.10(-29.69,1.49)

-14.98(-36.45,6.50)

-13.25(-36.15,9.65)

Etodolac



Piroxicam

-7.75(-39.81,24.31)

Prednisolone

-19.10(-58.06,19.86)

-11.35(-43.20,20.51)

Gabapentin

-19.04(-62.25,24.17)

-11.29(-48.22,25.64)

0.06(-43.00,43.12)

Celecoxib

-24.13(-61.75,13.48)

-16.38(-46.55,13.78)

-5.03(-42.47,32.40)

-5.09(-46.93,36.75)

Sulindac

-24.84(-62.21,12.52)

-17.09(-42.10,7.92)

-5.74(-42.93,31.45)

-5.80(-47.42,35.82)

-0.71(-36.47,35.06)

Ketorolac

-29.54(-75.77,16.69)

-21.79(-58.75,15.18)

-10.44(-56.52,35.64)

-10.50(-60.23,39.23)

-5.41(-50.35,39.54)

-4.70(-31.93,22.53)

Tapentadol

-29.10(-68.06,9.86)

-21.35(-53.20,10.51)

-10.00(-37.04,17.04)

-10.06(-53.12,33.00)

-4.97(-42.40,32.47)

-4.26(-41.45,32.93)

0.44(-45.64,46.52)

Lornoxicam

-29.10(-56.77,-1.43)

-21.35(-37.54,-5.15)

-10.00(-37.43,17.43)

-10.06(-43.25,23.13)

-4.97(-30.44,20.51)

-4.26(-29.37,20.86)

0.44(-36.59,37.47)

-0.00(-27.43,27.43)

Placebo

-30.59(-62.48,1.29)

-22.84(-45.48,-0.20)

-11.49(-43.18,20.19)

-11.55(-48.33,25.23)

-6.46(-31.70,18.78)

-5.75(-35.44,23.94)

-1.05(-41.33,39.22)

-1.49(-33.18,30.19)

-1.49(-17.35,14.36)

Ibuprofen

-34.59(-71.57,2.40)

-26.83(-56.23,2.56)

-15.49(-52.30,21.32)

-15.55(-56.83,25.73)

-10.45(-43.91,23.01)

-9.74(-44.86,25.37)

-5.05(-49.47,39.38)

-5.49(-42.30,31.32)

-5.49(-30.03,19.06)

-3.99(-28.53,20.54)

Indomethacin

-47.44(-94.64,-0.24)

-39.69(-77.87,-1.50)

-28.34(-75.41,18.72)

-28.40(-79.04,22.24)

-23.31(-69.25,22.64)

-22.60(-51.45,6.26)

-17.90(-46.85,11.05)

-18.34(-65.41,28.72)

-18.34(-56.59,19.90)

-16.85(-58.24,24.55)

-12.85(-58.29,32.59)

Etodolac


Appendix 7: Treatment ranking and surface under the cumulative ranking curves (SUCRA) for post-operative pain

Appendix 7.1. SUCRA ranking curve for post-operative pain at 6 hours (intervention groups were categorized based on pharmacological group).

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

1 2 3 4 1 2 3 4

1 2 3 4 1 2 3 4

01_Corticosteroid 02_Opioids

03_NSAIDs 04_Placebo

Prob

abili

ties

RankGraphs by Treatment


0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6

1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6

01_Corticosteroid 02_COX2 03_Gabapentin

04_Opioids 05_NSAIDs 06_Placebo

Prob

abili

ties


10.1%38.1%47.9%

61.2%62.4%80.3%

10.6%47.5%

58.4%83.5%


0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6

1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6

01_Corticosteroid 02_Gabapentin 03_Opioids

04_COX2 05_NSAIDs 06_Placebo

Prob

abili

ties


Appendix 7.4. SUCRA ranking curve for post-operative pain at 6 hours (intervention groups were categorized based on chemical name).

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8

1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8

1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8

01_Sulindac 02_Ketorolac 03_Diclofenac

04_Prednisolone 05_Tapentadol 06_Placebo

07_Ibuprofen 08_Etodolac

Prob

abili

ties


6.7%8.7%

35.6%51.4%52.8%

73.7%83.8%87.2%

18.9%36.0%50.8%

54.0%57.5%82.6%


0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112

1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112

1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112

01_Piroxicam 02_Prednisolone 03_Gabapentin 04_Celecoxib

05_Lornoxicam 06_Sulindac 07_Ketorolac 08_Placebo

09_Tapentadol 10_Ibuprofen 11_Indomethacin 12_Etodolac

Prob

abili

ties



0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112

1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112

1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 101112

01_Piroxicam 02_Prednisolone 03_Gabapentin 04_Celecoxib

05_Sulindac 06_Ketorolac 07_Tapentadol 08_Lornoxicam

09_Placebo 10_Ibuprofen 11_Indomethacin 12_Etodolac

Prob

abili

ties


3.5%22.1%26.1%27.4%

31.8%47.8%53.6%59.8%

72.9%75.6%83.7%95.7%

14.1%30.1%36.4%39.5%

40.4%42.5%50.6%51.4%

59.7%61.5%84.3%89.4%

Appendix 8: Assessment of inconsistency for each outcome networkEvaluation of the global inconsistency in networks using the ‘design-by-treatment’ interaction model for post-operative pain.

Network outcome Chi-square P value for test of global inconsistency

Based on pharmacological group

at 6 hours 5.05 0.0802

at 12 hours 0.39 0.9422

at 24 hours 0.48 0.9232

Based on chemical name

at 6 hours 53.10 <0.0001

at 12 hours 2.58 0.4602

at 24 hours 0.61 0.8947

Appendix 9: Subgroup analysesTable 9.1. Subgroup analyses for the mean difference of post-operative pain at 6 hours with treatment options (based on pharmacological group) in differing populations.The following table shows the effect sizes (mean difference) and the rank order (SUCRA ranks) compared to placebo before (standard analysis) and after sensitivity analyses.

Treatment Standard analysis SUCRA rank Trial with single visit SUCRA rank Trial with multiple visit

SUCRA rank

Corticosteroid -18.14 (-32.90, -3.37) 1 -3.56 (-11.85, 4.73) 1 N/A

Opioids -11.99 (-41.03, 17.05) 2 N/A -14.30 (-24.88, -3.72) 1

NSAIDs -8.39 (-21.17, 4.39) 3 -9.66 (-17.28, -2.04) 2 -10.70 (-18.41, -2.99) 2

Placebo 0 4 0 3 0 3

Global inconsistency chi2 (P value) 5.05 (P=0.0802) 23.16 (P<0.0001) 7.39 (P=0.0065)

Table 9.2. Subgroup analyses for the mean difference of post-operative pain at 12 hours with treatment options (based on pharmacological group) in differing populations.The following table shows the effect sizes (mean difference) and the rank order (SUCRA ranks) compared to placebo before (standard analysis) and after sensitivity analyses.


SUCRA rank

Corticosteroid -22.17 (-36.03, -8.32) 1 -22.85 (-37.15, -8.56) 1 N/A

COX-2 -18.06 (-53.05, 16.94) 2 -18.06 (-53.51, 17.40) 2 N/A

Gabapentin -15.35 (-36.60, 5.89) 3 N/A -16.70 (-20.63, -12.77) 1

Opioids -10.99 (-37.57, 15.58) 4 N/A -13.70 (-22.21, -5.19) 2

NSAIDs -7.70 (-17.46, 2.07) 5 -10.72 (-23.01, 1.57) 3 -10.40 (-14.21, -6.59) 3

Placebo 0 6 0 4 0 4

Global inconsistency chi2 (P value) 0.39 (P=0.9422) 0.57 (P=0.7515) 0.72 (P=0.3952)

Table 9.3. Subgroup analyses for the mean difference of post-operative pain at 24 hours with treatment options (based on pharmacological group) in differing populations.The following table shows the effect sizes (mean difference) and the rank order (SUCRA ranks) compared to placebo before (standard analysis) and after sensitivity analyses.


SUCRA rank

Corticosteroid -21.50 (-37.95, -5.06) 1 -22.58 (-39.84, -5.32) 1 N/A

Gabapentin -12.33 (-38.16, 13.49) 2 N/A -10.00 (-15.93, -4.07) 1

Opioids -11.15 (-43.00, 20.69) 3 N/A -6.60 (-16.15, 2.95) 2

COX-2 -10.06 (-44.76, 24.64) 4 -10.06 (-45.89, 25.77) 2 N/A

NSAIDs -4.56 (-16.31, 7.20) 5 -9.44 (-24.41, 5.54) 3 0.00 (-5.93, 5.93) 3

Placebo 0 6 0 4 0 4

Global inconsistency chi2 (P value) 0.48 (P=0.9232) 0.53 (P=0.7673) 2.98 (P=0.0841)

Table 9.4. Subgroup analyses for the mean difference of post-operative pain at 6 hours with treatment options (based on chemical name) in differing populations.The following table shows the effect sizes (mean difference) and the rank order (SUCRA ranks) compared to placebo before (standard analysis) and after sensitivity analyses.

Treatment Standard analysis SUCRA rank Trial with single visit SUCRA rank Trial with multiple visit*

SUCRA rank

Sulindac -12.50 (-24.92, -0.08) 1 -12.50 (-24.92, -0.08) 3 N/A

Ketorolac -9.66 (-17.28, -2.04) 2 -9.66 (-17.28, -2.04) 4 N/A

Diclofenac -8.20 (-16.98, 0.58) 3 N/A N/A

Prednisolone -3.56 (-11.85, 4.73) 4 -3.56 (-11.85, 4.73) 1 N/A

Tapentadol -3.26 (-13.69, 7.17) 5 N/A N/A

Placebo 0 6 0 5 N/A


SUCRA rank

Ibuprofen -13.20 (-21.18, -5.22) 7 -13.75 (-25.09, -2.41) 2 N/A

Etodolac 10.33 (-1.34, 21.99) 8 N/A N/A

Global inconsistency chi2 (P value) 53.10 (P<0.0001) 22.32 (P<0.0001)

*Analysis could not be performed due to disconnected network.



SUCRA rank

Piroxicam -30.00 (-43.06, -16.94) 1 -30.00 (-44.46, -15.54) 1 N/A

Prednisolone -20.65 (-29.44, -11.86) 2 -20.85 (-30.37, -11.33) 2 N/A

Gabapentin -16.70 (-29.46, -3.94) 3 N/A N/A

Celecoxib -18.06 (-46.67, 10.56) 4 -18.06 (-47.34, 11.22) 3 N/A

Lornoxicam -10.40 (-23.12, 2.32) 5 N/A N/A

Sulindac -7.59 (-22.25, 7.06) 6 -9.77 (-25.99, 6.44) 4 N/A

Ketorolac -4.99 (-17.85, 7.87) 7 -5.04 (-19.11, 9.03) 5 N/A

Placebo 0 8 0 7 N/A

Tapentadol 2.51 (-16.21, 21.23) 9 N/A N/A

Ibuprofen 1.63 (-6.70, 9.96) 10 -1.97 (-13.49, 9.55) 6 N/A

Indomethacin 3.36 (-8.09, 14.81) 11 1.57 (-11.70, 14.83) 8 N/A

Etodolac 16.61 (-3.26, 36.47) 12 N/A

Global inconsistency chi2 (P value) 2.58 (P=0.4602) 1.77 (P=0.4135)




SUCRA rank

Piroxicam -29.10 (-56.77, -1.43) 1 -29.10 (-58.59, 0.39) 1 N/A

Prednisolone -21.35 (-37.54, -5.15) 2 -21.45 (-38.69, -4.21) 2 N/A

Gabapentin -10.00 (-37.43, 17.43) 3 N/A N/A

Celecoxib -10.06 (-43.25, 23.13) 4 -10.06 (-44.78, 24.66) 3 N/A

Sulindac -4.97 (-30.44, 20.51) 5 -7.52 (-35.38, 20.33) 4 N/A

Ketorolac -4.26 (-29.37, 20.86) 6 -4.29 (-31.09, 22.50) 5 N/A

Tapentadol 0.44 (-36.59, 37.47) 7 N/A N/A

Lornoxicam -0.00 (-27.43, 27.43) 8 N/A N/A

Placebo 0 9 0 7 N/A

Ibuprofen 1.49 (-14.36, 17.35) 10 -3.37 (-24.22, 17.48) 6 N/A

Indomethacin 5.49 (-19.06, 30.03) 11 3.05 (-23.90, 30.00) 8 N/A

Etodolac 18.34 (-19.90, 56.59) 12 N/A N/A



Appendix 10 Sensitivity analysesAppendix 10.1. Sensitivity analyses for the mean difference of post-operative pain at 6 hours with treatment options (based on pharmacological group) in differing populations.The following table shows the effect sizes (mean difference) and the rank order (SUCRA ranks) compared to placebo before (standard analysis) and after sensitivity analyses.

Treatment Standard analysis SUCRA rank Excluding sample size <25%

SUCRA rank

Corticosteroid -18.14 (-32.90, -3.37) 1 -3.56 (-11.85, 4.73) 3

Opioids -11.99 (-41.03, 17.05) 2 -13.26 (-23.77, -2.75) 1

NSAIDs -8.39 (-21.17, 4.39) 3 -9.66 (-17.28, -2.04) 2

Placebo 0 4 0 4

Global inconsistency chi2 (P value) 5.05 (P=0.0802) 20.96 P<0.0001)

Appendix 10.2. Sensitivity analyses for the mean difference of post-operative pain at 12 hours with treatment options (based on pharmacological group) in differing populations.The following table shows the effect sizes (mean difference) and the rank order (SUCRA ranks) compared to placebo before (standard analysis) and after sensitivity analyses.


SUCRA rank

Corticosteroid -22.17 (-36.03, -8.32) 1 -19.19 (-34.52, -3.86) 1

COX-2 -18.06 (-53.05, 16.94) 2 N/A

Gabapentin -15.35 (-36.60, 5.89) 3 -16.59 (-36.82, 3.65) 2

Opioids -10.99 (-37.57, 15.58) 4 -13.47 (-39.08, 12.15) 3

NSAIDs -7.70 (-17.46, 2.07) 5 -10.17 (-20.37, 0.03) 4

Placebo 0 6 0 5


Appendix 10.3. Sensitivity analyses for the mean difference of post-operative pain at 24 hours with treatment options (based on pharmacological group) in differing populations.The following table shows the effect sizes (mean difference) and the rank order (SUCRA ranks) compared to placebo before (standard analysis) and after sensitivity analyses.


SUCRA rank

Corticosteroid -21.50 (-37.95, -5.06) 1 -13.50 (-28.92, 1.93) 1

Gabapentin -12.33 (-38.16, 13.49) 2 -13.32 (-33.89, 7.25) 2

Opioids -11.15 (-43.00, 20.69) 3 -12.99 (-38.82, 12.84) 3

COX-2 -10.06 (-44.76, 24.64) 4 N/A

NSAIDs -4.56 (-16.31, 7.20) 5 -6.39 (-16.69, 3.91) 4

Placebo 0 6 0 5


Appendix 10.4. Sensitivity analyses for the mean difference of post-operative pain at 6 hours with treatment options (based on chemical name) in differing populations.The following table shows the effect sizes (mean difference) and the rank order (SUCRA ranks) compared to placebo before (standard analysis) and after sensitivity analyses.


SUCRA rank

Sulindac -12.50 (-24.92, -0.08) 1 -12.50 (-24.92, -0.08) 2

Ketorolac -9.66 (-17.28, -2.04) 2 -9.66 (-17.28, -2.04) 3

Diclofenac -8.20 (-16.98, 0.58) 3 -8.20 (-16.98, 0.58) 4

Prednisolone -3.56 (-11.85, 4.73) 4 -3.56 (-11.85, 4.73) 5

Tapentadol -3.26 (-13.69, 7.17) 5 -3.26 (-13.69, 7.17) 6

Placebo 0 6 0 7

Ibuprofen -13.20 (-21.18, -5.22) 7 -13.20 (-21.18, -5.22) 1

Etodolac 10.33 (-1.34, 21.99) 8 10.34 (-1.33, 22.01) 8

Global inconsistency chi2 (P value) 53.10 (P=<0.0001) 19.12 (P=0.0001)



SUCRA rank

Piroxicam -30.00 (-43.06, -16.94) 1 -30.00 (-40.24, -19.76) 1

Prednisolone -20.65 (-29.44, -11.86) 2 -17.21 (-24.97, -9.45) 2

Gabapentin -16.70 (-29.46, -3.94) 3 -16.70 (-26.55, -6.85) 3

Celecoxib -18.06 (-46.67, 10.56) 4 N/A

Lornoxicam -10.40 (-23.12, 2.32) 5 -10.40 (-20.20, -0.60) 4

Sulindac -7.59 (-22.25, 7.06) 6 -8.81 (-22.23, 4.61) 5

Ketorolac -4.99 (-17.85, 7.87) 7 -3.15 (-13.85, 7.55) 6

Placebo 0 8 0 8

Tapentadol 2.51 (-16.21, 21.23) 9 4.35 (-10.94, 19.64) 10

Ibuprofen 1.63 (-6.70, 9.96) 10 -0.81 (-10.46, 8.83) 7

Indomethacin 3.36 (-8.09, 14.81) 11 2.15 (-7.22, 11.53) 9

Etodolac 16.61 (-3.26, 36.47) 12 18.45 (1.78, 35.12) 11




SUCRA rank

Piroxicam -29.10 (-56.77, -1.43) 1 -29.10 (-37.25, -20.95) 1

Prednisolone -21.35 (-37.54, -5.15) 2 -11.30 (-16.31, -6.29) 2

Gabapentin -10.00 (-37.43, 17.43) 3 -10.00 (-17.30, -2.70) 3

Celecoxib -10.06 (-43.25, 23.13) 4 N/A

Sulindac -4.97 (-30.44, 20.51) 5 -4.89 (-14.53, 4.74) 5

Ketorolac -4.26 (-29.37, 20.86) 6 0.95 (-5.97, 7.88) 6

Tapentadol 0.44 (-36.59, 37.47) 7 5.65 (-3.85, 15.16) 10

Lornoxicam -0.00 (-27.43, 27.43) 8 0.00 (-7.30, 7.30) 4

Placebo 0 9 0 8

Ibuprofen 1.49 (-14.36, 17.35) 10 -0.43 (-8.01, 7.15) 7

Indomethacin 5.49 (-19.06, 30.03) 11 4.50 (-0.93, 9.93) 9

Etodolac 18.34 (-19.90, 56.59) 12 23.55 (10.07, 37.04) 11

Global inconsistency chi2 (P value) 0.61 (P=.8947) 3.16 (P=0.2064)

Appendix 11: Comparison-adjusted funnel plot for post-operative pain outcome from the network meta-analyses

Appendix 11.1: Comparison-adjusted funnel plot for the network of post-operative pain at 6 hours in all comparisons based on pharmacological group. (Left: all studies, Right: after omitting small studies)

0.5

11.

52

2.5

33.

54

4.5

55.

56

Stan

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-20 -10 0 10 20Effect size centred at comparison-specific pooled effect (yiXY-XY)

A vs B A vs D B vs C B vs D

0.5

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2.5

33.

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4.5

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rror

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-15 -10 -5 0 5 10Effect size centred at comparison-specific pooled effect (yiXY-XY)

A vs B A vs D B vs C B vs D

Abbreviation: A=Corticosteroid, B=NSAIDs, C=Opioids, D=Placebo.


01

23

45

67

89

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1213

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A vs F B vs D B vs F C vs D C vs F D vs ED vs F

01

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-10 0 10 20 30Effect size centred at comparison-specific pooled effect (yiXY-XY)

A vs C A vs E B vs C B vs E C vs D C vs E

Abbreviation: A=COX-2, B=Corticosteroid, C=Gabapentin, D=NSAIDs, E=Opioids, F=Placebo.


01

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-20 -10 0 10 20 30Effect size centred at comparison-specific pooled effect (yiXY-XY)

A vs F B vs D B vs F C vs D C vs F D vs ED vs F

0.5

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2.5

33.

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4.5

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-10 0 10 20 30Effect size centred at comparison-specific pooled effect (yiXY-XY)

A vs C A vs E B vs C B vs E C vs D C vs E

Abbreviation: A=COX-2, B=Corticosteroid, C=Gabapentin, D=NSAIDs, E=Opioids, F=Placebo.

Appendix 11.4:Comparison-adjusted funnel plot for the network of post-operative pain at 6 hours in all comparisons based on chemical name. (Left: all studies, Right: after omitting small studies)

0.5

11.

52

2.5

33.

54

4.5

55.

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6.5

Stan

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-10 0 10 20Effect size centred at comparison-specific pooled effect (yiXY-XY)

A vs C A vs E B vs D B vs H C vs E C vs GD vs E D vs F D vs H E vs F E vs G

01

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-10 0 10 20Effect size centred at comparison-specific pooled effect (yiXY-XY)

A vs C A vs E B vs D B vs H C vs E C vs GD vs E D vs F D vs H E vs F E vs G

Abbreviation: A=Diclofenac, B=Etodolac, C=Ibuprofen, D=Ketorolac, E=Placebo, F=Prednisolone, G=Sulindac, H=Tapentadol.

Appendix 11.5: Comparison-adjusted funnel plot for the network of post-operative pain at 12 hours in all comparisons based on chemical name. (Left: all studies, Right: after omitting small studies)

01

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A vs I B vs L B vs F C vs G C vs I D vs KD vs E D vs I E vs I F vs J F vs L F vs IG vs I H vs I I vs J I vs K

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-10 0 10Effect size centred at comparison-specific pooled effect (yiXY-XY)

A vs K A vs E B vs F B vs H C vs J C vs DC vs H D vs H E vs K E vs H E vs I F vs HG vs H H vs J H vs I

Abbreviation: A=Celecoxib, B=Etodolac, C=Gabapentin, D=Ibuprofen, E=Indomethacin, F=Ketorolac, G=Lornoxicam, H=Piroxicam, I=Placebo, J=Prednisolone, K=Sulindac, L=Tapentadol.

Appendix 11.6: Comparison-adjusted funnel plot for the network of post-operative pain at 24 hours in all comparisons based on chemical name. (Left: all studies, Right: after omitting small studies)

01

23

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-30 -20 -10 0 10 20Effect size centred at comparison-specific pooled effect (yiXY-XY)

A vs I B vs L B vs F C vs G C vs I D vs KD vs E D vs I E vs I F vs J F vs L F vs IG vs I H vs I I vs J I vs K

01

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A vs K A vs E B vs F B vs H C vs J C vs DC vs H D vs H E vs K E vs H E vs I F vs HG vs H H vs J H vs I

Abbreviation: A=Celecoxib, B=Etodolac, C=Gabapentin, D=Ibuprofen, E=Indomethacin, F=Ketorolac, G=Lornoxicam, H=Piroxicam, I=Placebo, J=Prednisolone, K=Sulindac, L=Tapentadol.

Appendix 12 Evaluation of the quality of evidence using GRADE framework for primary outcomesAppendix 12.1. Estimates of effects and quality ratings for comparison of treatment options (based on pharmacological group) in post-operative pain.

Comparison Direct evidence Indirect evidence Network meta-analysis

MD (95% CI)

Quality of evidence

(Using GRADEpro

)

MD (95% CI)

Quality of evidence

MD (95% CI)

Quality of evidence

6 hour-pain scorePlacebo vs. Corticosteroid 20.15

(4.67,35.63)⨁◯◯◯Very Low a

-6.86(-

61.66,47.94)

Very low b 18.14(3.37,32.90)

Very low

Placebo vs. NSAIDs 5.48(-4.00,14.95)

⨁◯◯◯Very Low a

59.52(16.72,102.3

1)

Very low b 8.39(-4.39,21.17)

Very low

Placebo vs. Opioids NA NA 11.99(-

17.05,41.03)

Very low b 11.99(-

17.05,41.03)

Very low


(6.19,37.27)⨁⨁⨁◯Moderate c

27.73(-

23.31,78.77)

Very low b 22.17(8.32,36.03)

Moderate



23.43(-

34.86,81.71)

Very low b 7.70(-2.07,17.46)

Very low


15.58,37.57)

Very low b 10.99(-

15.58,37.57)

Very low

Placebo vs. COX-2 NA NA 18.06(-

16.94,53.05)

Very low b 18.06(-

16.94,53.05)

Very low

Placebo vs. Gabapentin 16.70(-9.04,42.44)

⨁◯◯◯Low d

10.27(-

39.95,60.49)

Very low b 15.35(-5.89,36.60)

Low


(2.96,40.16)⨁◯◯◯Very Low a

22.21(-

39.59,84.01)

Very low b 21.50(5.06,37.95)

Very low



28.27(-

40.60,97.15)

Very low b 4.56(-7.20,16.31)

Very low


20.69,43.00)

Very low b 11.15(-

20.69,43.00)

Very low

Placebo vs. COX-2 -0.38(-1.13,0.37)

⨁◯◯◯Low d

10.06(-

24.64,44.76)

Very low b 10.06(-

24.64,44.76)

Low

Placebo vs. Gabapentin 10.00(-

⨁◯◯◯Low d

20.96(-

Very low b 12.33(-

Low


MD (95% CI)

Quality of evidence

(Using GRADEpro

)

MD (95% CI)

Quality of evidence

MD (95% CI)

Quality of evidence

21.49,41.49) 39.84,81.75) 13.49,38.16)a Severe inconsistency (explained by heterogeneity) and imprecision; b Contributing direct evidence of very low or low and intransitivity; c inconsistency (moderate heterogeneity); dimprecision. Abbreviation: CI, confidence interval; MD, mean difference;

Appendix 12.2. Estimates of effects and quality ratings for comparison of treatment options (based on chemical name) in post-operative pain.


MD (95% CI)

Quality of evidence

(Using GRADEpro

)

MD (95% CI)

Quality of evidence

MD (95% CI)

Quality of evidence

6 hour-pain scorePlacebo vs. Ketorolac 9.66

(-12.35,31.67)


59.44(9.71,109.17)

Very low b 9.66(2.04,17.28)

Very low

Prednisolone vs. Placebo -20.17(-36.12,-

4.22)

⨁◯◯◯Very Low c

-1.80(-

1,574.17,1,570.57)

Very low b -3.56(-11.85,4.73)

Very low

Sulindac vs. Placebo -12.50(-

43.49,18.49)


11.31(-

55.80,78.42)

Very low d -12.50(-24.92,-

0.08)

Very low

Placebo vs Ibuprofen NA NA 13.20(5.22,21.18)

Very low b 13.20(5.22,21.18)

Very low

12 hour-pain scorePlacebo vs. Piroxicam NA NA 30.00

(16.94,43.06)Very low a 30.00

(16.94,43.06)Very low

Prednisolone vs. Placebo -20.65(-29.45,-11.85)

⨁⨁⨁◯Moderate e

-30.15(-

1,576.83,1,516.53)

Very low d -20.65(-29.44,-11.86)

Moderate

24 hour-pain scorePlacebo vs. Piroxicam NA NA 29.10

(1.43,56.77)Very Low a 29.10

(1.43,56.77)Very low

Prednisolone vs. Placebo -21.35(-37.56,-

⨁◯◯◯Very Low c

-31.20(-

Very low d -21.35(-37.54,-

Very low


MD (95% CI)

Quality of evidence

(Using GRADEpro

)

MD (95% CI)

Quality of evidence

MD (95% CI)

Quality of evidence

5.14) 1,617.51,1,555.11) 5.15)a severe imprecision; b Contributing direct evidence of low or very low, Intransitivity; c severe inconsistency (heterogeneity), Imprecision; d Contributing direct evidence of very low, Intransitivity, Incoherence; e inconsistency (moderate heterogeneity), not serious imprecision Abbreviation: CI, confidence interval; MD, mean difference;

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