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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
NSAIDs vs. Corticosteroid
1 (10) 59 12.96(7.18,18.74)
12.96(7.18,18.74)
N/A
Placebo vs. Corticosteroid
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
Opioids vs. NSAIDs 1 (18) 56 -3.30(-10.91,4.31)
-3.30(-10.91,4.31)
N/A
Placebo vs. NSAIDs 6 (9,10,13,16
, 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
NSAIDs vs. Corticosteroid
1 (10) 59 12.50(7.22,17.78)
12.50(7.22,17.78)
N/A
Placebo vs. Corticosteroid
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
Opioids vs. NSAIDs 1 (18) 56 -6.60(-14.09,0.89)
-6.60(-14.09,0.89)
N/A
Placebo vs. NSAIDs 6 (9,10,13,16
, 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)
Difference (95% CI)Mean
0-43.4 0 43.4
Appendix 4.3. Forest plot of pairwise meta-analysis with a random-effects model of mean difference (and 95% CI) for post-operative pain at 12 hours (intervention groups were categorized based on pharmacological group)
.
.
.
.
.
.
.
Placebo - COX2Ashraf et al (2013)Subtotal (I-squared = .%, p = .)
NSAIDs - CorticosteroidPraveen et al (2017)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 = .)
Opioids - NSAIDsSethi 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)
Difference (95% CI)Mean
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)
Difference (95% CI)Mean
0-46.4 0 46.4
Appendix 4.4. Forest plot of pairwise meta-analysis with a random-effects model of mean difference (and 95% CI) for post-operative pain at 24 hours (intervention groups were categorized based on pharmacological group)
.
.
.
.
.
.
.
Placebo - COX2Ashraf et al (2013)Subtotal (I-squared = .%, p = .)
NSAIDs - CorticosteroidPraveen et al (2017)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 - GabapentinIsik et al (2014)Subtotal (I-squared = .%, p = .)
Opioids - NSAIDsSethi 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)
Difference (95% CI)Mean
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)
Difference (95% CI)Mean
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
Pairwise meta-analysis mean difference (95% CI)
Heterogeneity I2
Fixed effect Random effect
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
Ketorolac vs. Etodolac 1 (18)
38 -21.60(-30.65,-12.55)
-21.60(-30.65,-12.55)
N/A
Tapentadol vs. Etodolac 1 (18)
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
Pairwise meta-analysis mean difference (95% CI)
Heterogeneity I2
Fixed effect Random effect
)
Sulindac vs. Ibuprofen 1 (43)
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
Placebo vs. Ketorolac 1 (10)
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
Tapentadol vs. Ketorolac 1 (18)
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
Prednisolone vs. Placebo 3 (10-12)
495 -19.03(-23.13,-14.94)
-20.43(-28.22,-12.64)
65.60%
Sulindac vs. Placebo 1 (43)
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
Ketorolac vs. Etodolac 1 (18)
38 -22.60(-33.35,-11.85)
-22.60(-33.35,-11.85)
N/A
Tapentadol vs. Etodolac 1 (18)
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%
Sulindac vs. Ibuprofen 1 (43)
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
Placebo vs. Ketorolac 1 (10)
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
Pairwise meta-analysis mean difference (95% CI)
Heterogeneity I2
Fixed effect Random effect
(10) (-17.78,-7.22) (-17.78,-7.22)
Tapentadol vs. Ketorolac 1 (18)
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
Prednisolone vs. Placebo 3 (10-12)
495 -14.58(-18.31,-10.84)
-21.23(-36.42,-6.04)
92.60%
Sulindac vs. Placebo 1 (43)
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)
Difference (95% CI)Mean
-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)
Difference (95% CI)Mean
0-43.4 0 43.4
Appendix 5.3: Forest plot of pairwise meta-analysis with a random-effects model of mean difference (and 95% CI) for post-operative pain at 12 hours (intervention groups were categorized based on chemical name)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Placebo - CelecoxibAshraf et al (2013)Subtotal (I-squared = .%, p = .)
Ketorolac - EtodolacSethi et al (2014)Subtotal (I-squared = .%, p = .)
Tapentadol - EtodolacSethi et al (2014)Subtotal (I-squared = .%, p = .)
Lornoxicam - GabapentinIsik et al (2014)Subtotal (I-squared = .%, p = .)
Placebo - 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)
Sulindac - IbuprofenYaghootiKhorasani et al (2012)Subtotal (I-squared = .%, p = .)
Placebo - IndomethacinMokhtari et al (2016)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 = .)
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)
Sulindac - PlaceboYaghootiKhorasani et al (2012)Subtotal (I-squared = .%, p = .)
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)
Difference (95% CI)Mean
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)
Difference (95% CI)Mean
0-46.4 0 46.4
Appendix 5.4: Forest plot of pairwise meta-analysis with a random-effects model of mean difference (and 95% CI) for post-operative pain at 24 hours (intervention groups were categorized based on chemical name)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Placebo - CelecoxibAshraf et al (2013)Subtotal (I-squared = .%, p = .)
Ketorolac - EtodolacSethi et al (2014)Subtotal (I-squared = .%, p = .)
Tapentadol - EtodolacSethi et al (2014)Subtotal (I-squared = .%, p = .)
Lornoxicam - GabapentinIsik et al (2014)Subtotal (I-squared = .%, p = .)
Placebo - 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)
Sulindac - IbuprofenYaghootiKhorasani et al (2012)Subtotal (I-squared = .%, p = .)
Placebo - IndomethacinMokhtari et al (2016)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 = .)
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)
Sulindac - PlaceboYaghootiKhorasani et al (2012)Subtotal (I-squared = .%, p = .)
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)
Difference (95% CI)Mean
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)
Difference (95% CI)Mean
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).
Figure 6.2. Network estimated mean difference (95% confidence intervals) of treatment options (categorized based on pharmacological group) for post-operative pain at 12 hours.
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
* Treatments are ordered by SUCRA rank. Comparisons between treatments should be read from column to row for each outcome (row treatment is reference).
Figure 6.3. Network estimated mean difference (95% confidence intervals) of treatment options (categorized based on pharmacological group) for post-operative pain at 24 hours.
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
* Treatments are ordered by SUCRA rank. Comparisons between treatments should be read from column to row for each outcome (row treatment is reference).
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
* Treatments are ordered by SUCRA rank. Comparisons between treatments should be read from column to row for each outcome (row treatment is reference).
Figure 6.5. Network estimated mean difference (95% confidence intervals) of treatment options (categorized based on chemical name) for post-operative pain at 12 hours.
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
* Treatments are ordered by SUCRA rank. Comparisons between treatments should be read from column to row for each outcome (row treatment is reference).
Figure 6.6. Network estimated mean difference (95% confidence intervals) of treatment options (categorized based on chemical name) for post-operative pain at 24 hours.
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
* Treatments are ordered by SUCRA rank. Comparisons between treatments should be read from column to row for each outcome (row treatment is reference).
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
Appendix 7.2. SUCRA ranking curve for post-operative pain at 12 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
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
RankGraphs by Treatment
10.1%38.1%47.9%
61.2%62.4%80.3%
10.6%47.5%
58.4%83.5%
Appendix 7.3. SUCRA ranking curve for post-operative pain at 24 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
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
RankGraphs by Treatment
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
RankGraphs by Treatment
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%
Appendix 7.5. SUCRA ranking curve for post-operative pain at 12 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
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
RankGraphs by Treatment
Appendix 7.6. SUCRA ranking curve for post-operative pain at 24 hours (intervention groups were categorized based on chemical name).
0.2
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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
RankGraphs by Treatment
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.
Treatment Standard analysis SUCRA rank Trial with single visit SUCRA rank Trial with multiple visit
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.
Treatment Standard analysis SUCRA rank Trial with single visit SUCRA rank Trial with multiple visit
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
Treatment Standard analysis SUCRA rank Trial with single visit SUCRA rank Trial with multiple visit*
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.
Table 9.5. Subgroup analyses for the mean difference of post-operative pain at 12 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
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)
*Analysis could not be performed due to disconnected network.
Table 9.6. Subgroup analyses for the mean difference of post-operative pain at 24 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
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
Global inconsistency chi2 (P value) 0.61 (P=0.8947) 0.35 (P=0.8388)
*Analysis could not be performed due to disconnected network.
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.
Treatment Standard analysis SUCRA rank Excluding sample size <25%
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
Global inconsistency chi2 (P value) 0.39 (P=0.9422) 0.33 (P=0.9538)
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.
Treatment Standard analysis SUCRA rank Excluding sample size <25%
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
Global inconsistency chi2 (P value) 0.48 (P=0.9232) 0.67 (P=0.8810)
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.
Treatment Standard analysis SUCRA rank Excluding sample size <25%
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)
Appendix 10.5. Sensitivity analyses for the mean difference of post-operative pain at 12 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 Excluding sample size <25%
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
Global inconsistency chi2 (P value) 2.58 (P=0.4602) 4.86 (P=0.0881)
Appendix 10.6. Sensitivity analyses for the mean difference of post-operative pain at 24 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 Excluding sample size <25%
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
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A vs B A vs D B vs C B vs D
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A vs B A vs D B vs C B vs D
Abbreviation: A=Corticosteroid, B=NSAIDs, C=Opioids, D=Placebo.
Appendix 11.2: Comparison-adjusted funnel plot for the network of post-operative pain at 12 hours in all comparisons based on pharmacological group. (Left: all studies, Right: after omitting small studies)
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A vs F B vs D B vs F C vs D C vs F D vs ED vs F
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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 11.3: Comparison-adjusted funnel plot for the network of post-operative pain at 24 hours in all comparisons based on pharmacological group. (Left: all studies, Right: after omitting small studies)
01
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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)
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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)
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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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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)
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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
12 hour-pain scorePlacebo vs. Corticosteroid 21.73
(6.19,37.27)⨁⨁⨁◯Moderate c
27.73(-
23.31,78.77)
Very low b 22.17(8.32,36.03)
Moderate
Placebo vs. NSAIDs 7.20(-3.29,17.68)
⨁◯◯◯Very Low a
23.43(-
34.86,81.71)
Very low b 7.70(-2.07,17.46)
Very low
Placebo vs. Opioids NA NA 10.99(-
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
24 hour-pain scorePlacebo vs. Corticosteroid 21.56
(2.96,40.16)⨁◯◯◯Very Low a
22.21(-
39.59,84.01)
Very low b 21.50(5.06,37.95)
Very low
Placebo vs. NSAIDs 3.79(-8.72,16.30)
⨁◯◯◯Very Low a
28.27(-
40.60,97.15)
Very low b 4.56(-7.20,16.31)
Very low
Placebo vs. Opioids NA NA 11.15(-
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
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
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.
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. Ketorolac 9.66
(-12.35,31.67)
⨁◯◯◯Very Low a
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)
⨁◯◯◯Very Low a
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
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
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;