MMC 1

Supplementary Information
The efficacy of perioperative

pharmacological and regional pain
interventions in adult spine surgery: a
network meta-analysis and systematic
review of randomized controlled trials
Sandy Bae1, Abdulrahman Alboog1,2, Katherine Saied Esquivel1, Alina Abbasi1, James Zhou3, Jason Chui1
1 Department of Anaesthesia & Perioperative Medicine, Schulich School of Medicine and Dentistry, Western
University, London, Ontario, Canada
2 Department of Anaesthesia, University of Jeddah, Jeddah, Saudi Arabia
3 Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada

Contents
1. Search Strategy ........................................................................................................................................ 1
2 Definition of Covariates and Data Extraction ........................................................................................... 2
2.1 Sponsorship ....................................................................................................................................... 2
2.2 Total opioid consumption in 24 hours ............................................................................................... 2
2.3 24h Pain score ................................................................................................................................... 2
2.4 Data extraction and conversion ......................................................................................................... 2
Figures ................................................................................................................................................. 2
Median and interquartile range (IQR) ................................................................................................. 2
Median and range................................................................................................................................ 3
Combining mean and standard deviation............................................................................................ 3
2.5 Pre-operative, Intra-operative, and post-operative .......................................................................... 3
3. Transitivity ............................................................................................................................................... 4
3.1 Covariate: Surgical Time .................................................................................................................... 4
Pharmacological intervention: 24h opioid consumption..................................................................... 4
Pharmacological intervention: 24h pain score .................................................................................... 5
Regional Intervention: 24h opioid consumption ................................................................................. 6
Regional Intervention: 24h pain score ................................................................................................. 7
3.2 Covariate: Surgical complexity........................................................................................................... 8
Pharmacological Intervention: 24h opioid consumption .................................................................... 8
Pharmacological Intervention: 24h pain score .................................................................................... 9
Regional Intervention: 24h opioid consumption ............................................................................... 10
Regional Intervention: 24h pain score ............................................................................................... 11
3.3 Covariate: Uses of postoperative analgesic intervention ................................................................ 12
Pharmacological Intervention: 24h opioid consumption .................................................................. 12
Pharmacological Intervention: 24h pain score .................................................................................. 13
4 Risk of bias table of included studies ...................................................................................................... 14
4.1 Risk of bias assessment for included studies ................................................................................... 14
4.2 Summary of Risk of Bias................................................................................................................... 16
4.3 Risk of Bias by Analysis .................................................................................................................... 17
Pharmacological intervention: 24h opioid consumption................................................................... 17
Pharmacological Intervention: 24h pain score .................................................................................. 17
Regional Intervention: 24h opioid consumption ............................................................................... 18
Regional Intervention: 24h pain score ............................................................................................... 18
5 Meta-regression ..................................................................................................................................... 19
5.1 Model............................................................................................................................................... 19
5.2 Covariate: Covariate: Uses of postoperative analgesic intervention ............................................... 20
5.2.1: 24-hour total opioid consumption........................................................................................... 20
5.2.2 24-hour pain score .................................................................................................................... 20
5.3 Covariate: Surgical Time .................................................................................................................. 21
5.3.1 24-hour total opioid consumption ............................................................................................ 21
5.3.2 24-hour pain score .................................................................................................................... 22
5.3.3 24-hour total opioid consumption ............................................................................................ 23
5.3.4 24-hour pain score .................................................................................................................... 24
6 GRADE ..................................................................................................................................................... 25
7 Reference list of included studies ........................................................................................................... 27
8 Characteristics of included studies ......................................................................................................... 37
9 Definitions .............................................................................................................................................. 48
9.1 Outcome Definitions ........................................................................................................................ 48
9.2 Intervention Description .................................................................................................................. 55
9.2.1 Pharmacological Interventions ................................................................................................. 55
9.2.2 Regional Interventions .............................................................................................................. 61
10 Funnel plot ............................................................................................................................................ 66
10.1 Pharmacological Intervention........................................................................................................ 66
10.1.1 24h opioid consumption ......................................................................................................... 66
10.1.2 24h pain score ........................................................................................................................ 67
10.2 Regional Intervention .................................................................................................................... 68
10.2.1 24h opioid consumption ......................................................................................................... 68
10.2.2 24h pain score ........................................................................................................................ 69
11 League Table ......................................................................................................................................... 70
11.1 Head-to-head comparison for reduction in pain score (orange) and total intravenous morphine
equivalent consumption (mg) (green) at postoperative 24 hours of pharmacological agent
combinations. ........................................................................................................................................ 70
11.2 Head-to-head comparison for reduction in pain score (orange) and total intravenous morphine
equivalent consumption (mg) (green) at postoperative 24 hours of regional interventions. ............... 72
12. Analysis of all trials .............................................................................................................................. 73
12.1 Pharmacological Interventions ...................................................................................................... 73
12.1.1 24-hour total opioid consumption.......................................................................................... 73
12.1.2 24-hour pain score .................................................................................................................. 76
12.2 Regional Intervention .................................................................................................................... 79
12.2.1 24-hour total opioid consumption.......................................................................................... 79
12.2.2 24-hour pain score .................................................................................................................. 81
13 Pair-wise Comparison ........................................................................................................................... 83
13.1 Pharmacological Intervention: 24 hr opioid consumption ........................................................... 83
13.2 Pharmacological Intervention: 24h pains score ............................................................................ 92
13.3 Regional Intervention: Opioid Consumption ................................................................................. 98
13.4 Regional Intervention: 24h pain score ........................................................................................ 100
14 Testing Fixed vs Random Model ......................................................................................................... 104
14.1 Pharmacological Intervention...................................................................................................... 104
14.1.1 24h total opioid consumption .............................................................................................. 104
14.1.2 24h pain score ...................................................................................................................... 104
14.2 Regional Intervention .................................................................................................................. 105
14.2.1 24h total opioid consumption .............................................................................................. 105
14.2.2 24h pain score ...................................................................................................................... 105
15 Consistency ......................................................................................................................................... 106
15.1.1 24hour total opioid consumption ......................................................................................... 106
15.1.2 24hour pain score ................................................................................................................. 108
15.2 Regional Intervention .................................................................................................................. 111
15.2.1 24-hour total opioid consumption........................................................................................ 111
15.2.1 24-hour pain score ................................................................................................................ 113
16 Network Characteristics ..................................................................................................................... 115
16.1.2 24-hour pain score ................................................................................................................ 116
16.2 Regional Interventions ................................................................................................................. 118
16.2.2 24hour pain score ................................................................................................................. 119
1. Search Strategy
Search Strategy for Medline is showed below:
Database(s): Ovid MEDLINE(R) ALL Inception to January 25, 2021
# Searches
1 (an?esth* or analges* or neurosurg*).mp.
2 exp "ANESTHESIA AND ANALGESIA"/
3 Neurosurgery/
4 Orthopedics/
5 or/1-4
6 Spinal Diseases/su
7 Spine/su
8 (laminectomy or spinal fusion).sh.
9 exp Diskectomy/
10 ((spin* and surg*) or laminectom* or diskectom* or spinal fusion).mp.
11 or/6-10
12 Pain Management/
13 exp Pain/
14 exp Anti-Inflammatory Agents, Non-Steroidal/
15 (Ketamine or Anesthetics, Local).sh.
16 exp Methadone/
17 exp Steroids/
((pain or discomfort or sore* or suffer*) and (control* or manag* or relief or reduc* or treat* or medicat* or duration or
18
therap* or recover*)).mp.
(nonsteroidal anti-inflammatory drug* or gabapentinoid* or pregabalin or gabapentin or ketamine or methadone or
19
local anesthetic* or steroid*).mp.
20 (regional an?esths* or epidural analgesia or intrathecal or neuraxial).mp.
21 exp Anesthesia, Conduction/
22 exp Injections, Spinal/
23 Analgesia, Epidural/
24 or/12-23
(after surg* or following surg* or post?surg* or peri?operat* or peri?proced* or intra?operat* or intra?proced* or
25
post?opt*).mp.
26 exp Perioperative Period/
27 or/25-26
28 5 and 11 and 24 and 27
29 (systematic review or randomized controlled trial).pt.
30 28 and 29
31 limit 30 to humans
1
2 Definition of Covariates and Data Extraction
2.1 Sponsorship
Study was marked as being “sponsored” if it was indicated in the text that the study was funded/sponsored
by a pharmaceutical company, or if one or more of the authors were affiliated with any pharmaceutical
company. We rated the sponsorship as “unclear” if there were no declaration of conflicts of interest in the
text.
2.2 Total opioid consumption in 24 hours

All reported numbers were converted to IV morphine equivalent doses using the conversion provided at
http://www.cpsa.ca/wp-content/uploads/2017/06/OME-and-DDD-Conversion-Factors.pdf.
2.3 24h Pain score

To make the pain score comparable across all studies, we defined our pain at 24 hours as “back pain at rest at
24-hours after surgery”. If pain at 24 hours was not specified, then we used the pain scored reported for
post-operative day 1, preferentially the morning score if stated as such. If single pain score was reported
regardless of relation to movement or anatomical location, that pain score was used for analysis.
Two different scales were used by the identified studies – NRS (numeric rating sale) and VAS (visual analogue
scale). Depending on the studies, either scale of 0 – 100 or – 10 were used. All pain scores reported in 0 – 100
scale was converted to 0 – 10 scale.
2.4 Data extraction and conversion

Figures
For data reported in figure, we used WebPlotdigitizer (https://automeris.io/WebPlotDigitizer/). Most figures
were reported with mean +/- standard error, and standard error were converted to standard deviation for
analysis.
Median and interquartile range (IQR)

If the data was reported in median and IQR format, it was converted to mean and standard deviation via the
following formula from Wan et al. paper (Wan, X., Wang, W., Liu, J. et al. Estimating the sample mean and
standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res
Methodol 14, 135 (2014). https://doi.org/10.1186/1471-2288-14-135):
Calculation for mean:
Calculation for standard deviation:
2
Median and range
If the data was reported in median and range format, it was converted to mean and standard deviation from
via the following formula from the same paper.
Calculation for mean:
Calculation for standard deviation
Combining mean and standard deviation

For total 24-hour opioid consumption, some papers reported the opioid consumption in multiple time
periods i.e., 0 – 6 hrs, 6 – 12 hrs, 12 – 24 hrs. For these data, the total opioid consumption in 24 hours were
calculated via the sum of all means. The standard deviation was calculated by assuming total variance would
be sum of all variances:
If the opioid consumptions were reported for above time periods as median and IQR/range, due to the
increased risk of bias introduced by both the conversion of median to mean, and sum of the mean, we did
not include those data to our analysis.
2.5 Pre-operative, Intra-operative, and post-operative

For any intervention that was provided prior to induction of anesthesia, they were marked as pre-operative
interventions.
For any interventions that was provided from the induction of the anesthesia to the arrival to post-anesthetic
care unit or equivalent, they were marked as intra-operative interventions.
For any intervention that was provided in post-anesthetic care unit or equivalent until 24-hours/one-day
after surgery, they were marked as post-operative interventions.
3
3. Transitivity
3.1 Covariate: Surgical Time
Pharmacological intervention: 24h opioid consumption
- 21 studies missing surgical time
4
Pharmacological intervention: 24h pain score
5
Regional Intervention: 24h opioid consumption
6
Regional Intervention: 24h pain score
14 studies missing surgical time
7
3.2 Covariate: Surgical complexity
Simple spine surgery was defined as single-level spine surgery. Trials only included patients undergoing simple spine surgery were labelled as ‘1’
below.
Pharmacological Intervention: 24h opioid consumption
8
Pharmacological Intervention: 24h pain score
9
10
11
3.3 Covariate: Uses of postoperative analgesic intervention
The uses of postoperative analgesic intervention, if the study drug/combination either were given in the postoperative period or continued from
the pre-/intra-operative to the postoperative period. Trials which had given study drug/combination in the postoperative period were labelled as
‘yes’.
Pharmacological Intervention: 24h opioid consumption
12
13
4 Risk of bias table of included studies
4.1 Risk of bias assessment for included studies
Information bias indicates the measurement bias that may have arisen during data collection from the
studies. Risk of bias based on the mode of data presentation. In general, data presented in mean with
standard deviation had the lowest risk, followed by data presented in mean with either interquartile range or
range. The highest information bias came from data presented solely as figures where the numerical values
were extracted using WebPlotdigitizer (https://automeris.io/WebPlotDigitizer/). For studies with two
different outcomes, the final risk of bias was based on the average risk of bias presented between the two
outcomes.
The overall risk of bias does not include information bias.
Random Adequate Incomplete

Sequence allocation Participant Assessor outcome Reporting Information
Study Name Generation concealment blinding blinding data bias Overall bias
Some
Attia2017 Low Low Low Low Low Low Low concerns
No No No Some Some
Aubrun2000 information information information Low Low Low concerns concerns
No Some
Aveline2006 Low Low Low information Low Low concerns High
No No Some
Bedin2017 information information Low Low Low Low concerns Low
Boenigk2019 Low Low Low Low Low Low Low High
Cakan2008 Low Low Low Low Low Low Low High
Chang2013 Low Low Low Low Low Low Low High

No No Some
Chen2019 information information Low Low Low Low concerns High
Some
Choi2013 Low Low Low Low Low Low Low concerns
Cohen1997 Low Low Low Low Low Low Low Low

Some
Dehkordy2020 Low Low Low Low Low Low Low concerns
Some
Dhaliwal2019 Low Low Low Low Low Low Low concerns
Eiamcharoenwit2020 Low Low Low Low Low Low Low High

No Some Some
Emir2010 Low Low Low information Low Low concerns concerns
No Some
Esmail2008 Low Low Low information Low Low concerns Low
No Some
Etezadi2020 Low Low Low information Low Low concerns Low
Ezhevskaya2019 Low Low High High Low Low High Low
Farag2013 Low Low Low Low Low Low Low High
Farmery2009 Low Low Low Low Low Low Low High

Some
Firouzian2018 Low Low Low Low Low Low Low concerns
Fujita2016 Low Low Low Low Low Low Low High

Some
Garg2016 Low Low Low Low Low Low Low concerns
Some
Gianesello2012 Low Low Low Low Low Low Low concerns
Govil2020 Low Low Low Low Low Low Low Low
14
Guilfoyle2012 Low Low Low Low Low Low Low Low
Hadi2009 Low Low Low Low Low Low Low Low
Hans1993 Low Low Low Low Low Low Low Low
Hernandez-Palazon2001 Low Low Low Low Low Low Low High
Hurlbert1999 Low Low Low Low Low Low Low High
Ibrahim2018 Low Low Low Low Low Low Low Low
Javaherforooshzadeh2018 Low Low Low Low Low Low Low Low

No No Some
Javery1996 information information Low Low Low Low concerns Low
Some
Jirarattanaphochai2007 Low Low Low Low Low Low Low concerns
Jirarattanaphochai2008 Low Low Low Low Low Low Low Low
Kang2013 Low Low Low Low Low Low Low High

Some
Kesimci2011 Low Low Low Low Low Low Low concerns
Khajavi2013 Low Low Low Low Low Low Low High
Khajavikhan2016 Low Low Low Low Low Low Low Low
Khan2011 Low Low Low Low Low Low Low Low
Kien2019 Low Low Low Low Low Low Low Low

No No Some
Kim2014 information information Low Low Low Low concerns High
Some
Kim2016a Low Low Low Low Low Low Low concerns
Kim2016b Low Low High High Low Low High Low
Kraiwattanapong2020 Low Low Low Low Low Low Low High

No No
Li2016 information information High High Low Low High Low
Some
Li2019 Low Low Low Low Low Low Low concerns
Lotfinia2007 Low Low Low Low Low Low Low Low
Mariappan2015 Low Low Low Low Low Low Low Low

No Some
McGlew1991 Low Low Low information Low Low concerns Low
No No Some
Milligan1993 information information Low Low Low Low concerns Low
Some
Naik2016 Low Low Low Low Low Low Low concerns
Some
Nielsen 2015 Low Low Low Low Low Low Low concerns
Nikooseresht2016 Low Low High High Low Low High Low
Ozgencil2011 Low Low Low Low Low Low Low Low
Pandey2004 Low Low Low Low Low Low Low Low
Pandey2005 Low Low Low Low Low Low Low Low
Park2016 Low Low High High Low Low High High
Pobereskin2000a Low Low Low Low Low Low Low Low
Pobereskin2000b Low Low Low Low Low High High Low
Polat2015 Low Low Low Low Low Low Low Low

No No Some
Pookarnjanamorakot2002 information information Low Low Low Low concerns Low
No No Some
Reuben1997 information information Low Low Low Low concerns Low
Some
Samoladas2019 Low Low Low Low concerns High High High
15
Schenk2006 Low Low Low Low Low Low Low Low
Some
Sekar2004 Low Low Low Low Low Low Low concerns
ServiclKuchler2014 Low Low Low Low Low Low Low High

No No Some
Shimia2014 information information Low Low Low Low concerns Low
Some
Singh2019 Low Low High High Low Low High concerns
Some
Singhatanadgige2020 Low Low Low Low Low Low Low concerns
Song2013 Low Low Low Low Low Low Low Low
Spreng2011 Low Low Low Low Low Low Low High

No No
Tang2017 information information High High Low Low High Low
Some Some
Tsaousi2020 Low Low Low Low Low concerns concerns High
Some
Turan2004 Low Low Low Low Low Low Low concerns
Ueshima2019 Low Low Low Low Low Low Low High
Vasigh2016 Low Low Low Low Low Low Low Low
Vasigh2016b Low Low Low Low Low Low Low Low

Some Some Some
Wang2020 Low Low concerns Low Low Low concerns concerns
Some
Wittayapairoj2017 Low Low Low Low Low Low Low concerns
Xu2017 Low Low High High Low Low High High
Yamauchi2008 Low Low Low Low Low Low Low High

No No Some
Yeom2012 information information Low Low Low Low concerns Low
Some
Yorukoglu2005 Low Low Low Low Low Low Low concerns
No No
Yukawa2005 information information High High Low Low High Low
Zarei2016 Low Low Low Low Low Low Low Low

Some Some
Zhang2021 Low Low concerns Low Low Low concerns High
4.2 Summary of Risk of Bias
16
4.3 Risk of Bias by Analysis
Pharmacological intervention: 24h opioid consumption
Alpha-2 Agonist 100

Control 79 21
Dexamethasone 100
Duloxetine 100
Gabapentinoid (High dose) 100
Gabapentinoid (Low dose) 100
Ketamine Infusion (Intraop) 50 50
Ketamine Infusion (Postop) 75 25
Lidocaine Infusion 100
NSAID 10 60 30
NSAID and Gabapentinoid 100
NSAID with Adjunct 100
Naloxone 100
Nefopam 100
Paracetamol 7 71 21
Paracetamol NSAID and Gaba 100
Paracetamol NSAID with Adjunct 80 20
Paracetamol and NSAID 71 29
Paracetamol with Adjunct 100
0 20 40 60 80 100
percent of sum of freq
High Low
Some concerns
Alpha-2 Agonist 100

Buprenorphine Patch 100
Control 3 68 29
Dexamethasone 100
Duloxetine 100
Gabapentinoid (High dose) 100
Gabapentinoid (Low dose) 100
Ketamine Inf (Intraop) w Adj 100
Ketamine Infusion (Intraop) 100
Ketamine Infusion (Postop) 60 40
Lidocaine Infusion 50 50
NSAID 18 55 27
NSAID and Gabapentinoid 100
Naloxone 100
Nefopam 100
Paracetamol 10 60 30
Paracetamol NSAID and Gaba 50 50
Paracetamol NSAID with Adjunct 80 20
Paracetamol and NSAID 71 29
Paracetamol with Adjunct 100
0 20 40 60 80 100
percent of sum of freq
High Low
Some concerns
17
Control 14 71 14
Epidural LA (SS) 100
Epidural LA with Adjunct (SS) 100
Epidural Steroid (SS) 100
Fascial Plane Block (SS) 25 50 25
LA Infiltration (SS) 17 50 33
LA Infiltration with Adjunct (SS) 100
Neuraxial Opioid (SS) 67 33
0 20 40 60 80 100
Percentage (%)
High Low
Some concerns
Control 32 52 16
Epidural LA (C) 50 50
Epidural LA (SS) 100
Epidural LA with Adjunct (C) 60 40
Epidural LA with Adjunct (SS) 33 67
Epidural Steroid (SS) 100
Fascial Plane Block (SS) 25 25 50
LA Infiltration (C) 100
LA Infiltration (SS) 17 33 50
LA Infiltration with Adjunct (SS) 100
Neuraxial Opioid (SS) 75 25
0 20 40 60 80 100
Percentage (%)
High Low
Some concerns
18
5 Meta-regression
5.1 Model
The network meta-regression was implemented linear model !!" = $! + &!" + '($!",$!#) ()!" − )̅ )
Where,
$! is the fixed effect on the treatment from arm 1 in study i (control treatment)
&!" is the random effect of the treatment from the arm k of study I relative to the treatment in arm 1 and
&!' = 0 for . = 1, … , 2
)!" is the covariate available in arms 3 = 1, … , 4! of studies . = 1, … , 2
)̅ = average of the )!" ’s across studies
'($!",$!#) = '(',$!#) − '(',$!") are regression coefficients for the effect of the covariate on the relative effect of
treatments 5!' and 5!" , with '(',') = ⋯ = '((,() = 0.
Prior specified on the meta-regression coefficient was ..8 5(0, 9) , 1).
The treatment effects for the forest plot are produced by specifying a value for covariate.
The R package BUGSnet calculate the treatment comparisons by computing the posterior quantities of
interest at a specified covariate value ) * as 8($!",$!#) + '($!",$!#) () * − )̅ ) and using the transitivity relations
8($!",$!#) = 8(',$!# ) − 8(',$!") and '($!",$!#) = '(',$!#) − '(',$!") .
19
5.2 Covariate: Covariate: Uses of postoperative analgesic intervention
The uses of postoperative analgesic intervention, if the study drug/combination either were given in the
postoperative period or continued from the pre-/intra-operative to the postoperative period. Trials which
had given study drug/combination in the postoperative period were labelled as ‘yes’.
5.2.1: 24-hour total opioid consumption
5.2.2 24-hour pain score
20
5.3 Covariate: Surgical Time
5.3.1 24-hour total opioid consumption
Covariate: surgical time > 120 minutes = 1; mean difference against control
Covariate: surgical time ≤ 120 minutes= 0; mean difference against control
21
Covariate: surgical time ≤ 120 minutes = 0; mean difference against control
22
23
24
6 GRADE
The goal of using GRADE approach is to provide a rating for the quality of the estimates of effect for a specific
comparison and a specific outcome. Due to high amount of indirectness in our network, we only incorporated
GRADE assessment on the comparison between the intervention and the placebo (control group). The
methodology listed below follows the recommendation from GRADE working group approach for rating the
quality of treatment effect estimates from network meta-analysis (Milo A Puhan et al: A GRADE Working
Group approach for rating the quality of treatment effect estimates from network meta-analysis 2014:1–10
doi:10.1136/bmj.g5630). The results of ratings could be one of the followings:
• High quality (⊕⊕⊕⊕)—We are very confident that the true effect lies close to that of the estimate
of the effect
• Moderate quality (⊕⊕⊕O)—We are moderately confident in the effect estimate: the true effect is
likely to be close to the estimate of the effect, but there is a possibility that it is substantially
different.
• Low quality (⊕⊕OO)—Our confidence in the effect estimate is limited: the true effect may be
substantially different from the estimate of the effect
• Very low quality (⊕OOO)—We have very little confidence in the effect estimate: the true effect is
likely to be substantially different from the estimate of effect
All randomised trials that form the evidence base were considered as high quality at the start. The quality
rating may be rated down by −1 (serious concern) or −2 (very serious concern) for the following reasons:
Table of reasons for downgrading
1) Risk of bias (RoB): We downgraded by one level when the contributions from low RoB studies were
less than 30%, contribution from moderate RoB studies were 70% or greater, and studies from high
RoB comparisons were 50% or greater.
2) Imprecision: We downgrade by two levels if the range of CrI was more than 40 mg, and by one level
if the range was more than 20 mg for opioid consumption. We downgraded by two levels if the
range of CrI was more than 3, and by one level if it was more than 2 for pain score.
3) Inconsistency: For evaluation of inconsistency, we looked at two entities – heterogeneity and
incoherence. We downgraded interventions with heterogeneity of more than 75% (Turner, Rebecca
M., et al. "Predicting the extent of heterogeneity in meta-analysis, using empirical data from the
Cochrane Database of Systematic Reviews." International journal of epidemiology 41.3 (2012): 818-
827.) in pair-wise comparison. We did not downgrade the evidence when it was already downgraded
for imprecision. For incoherence, we looked at the result of node splitting, and downgraded the
comparison with important inconsistency (p < 0.10), where it was not downgraded for imprecision
(Cipriani, Andrea, et al. "Comparative efficacy and acceptability of 21 antidepressant drugs for the
acute treatment of adults with major depressive disorder: a systematic review and network meta-
analysis." Lancet 16.4 (2018): 420-429.). If the intervention was both heterogeneous and incoherent,
it was downgraded by one level, if it was not already downgraded by two levels due to imprecision.
4) Indirectness and Intransitivity: We downgraded the evidence by one level if more than 50% of the
studies were conducted for patients undergoing single-level minimally invasive surgery. We
25
downgraded singly-connected nodes for indirectness if it was not already downgraded for
imprecision because evaluation of transitivity for such nodes is unclear.
5) Publication Bias: The presence of publication bias is assessed using funnel plot.
26
7 Reference list of included studies
1. Attia2017
• Attia JZ, Mansour HS. Perioperative Duloxetine and Etoricoxibto improve postoperative pain
after lumbar Laminectomy: A randomized, double-blind, controlled study. BMC Anesthesiol.
2017;17(1):1-8. doi:10.1186/s12871-017-0450-z
2. Aubrun2000
• Aubrun F, Langeron O, Heitz D, Coriat P, Riou B. Randomised, placebo-controlled study of the
postoperative analgesic effects of ketoprofen after spinal fusion surgery. Acta Anaesthesiol
Scand. 2000;44(8):934-939. doi:10.1034/j.1399-6576.2000.440807.x
3. Aveline2006
• Aveline C, Hetet H Le, Vautier P, Gautier JF, Bonnet F. Peroperative ketamine and morphine for
postoperative pain control after lumbar disk surgery. Eur J Pain. 2006;10(7):653.
doi:10.1016/j.ejpain.2005.10.005
4. Bedin2017
• Bedin A, Caldart Bedin RA, Vieira JE, Ashmawi HA. Duloxetine as an Analgesic Reduces Opioid
Consumption after Spine Surgery. Clin J Pain. 2017;33(10):865-869.
doi:10.1097/AJP.0000000000000471
5. Boenigk2019
• Boenigk K, Echevarria GC, Nisimov E, et al. Low-dose ketamine infusion reduces postoperative
hydromorphone requirements in opioid-tolerant patients following spinal fusion: A randomised
controlled trial. Eur J Anaesthesiol. 2019;36(1):8-15. doi:10.1097/EJA.0000000000000877
6. Cakan2008
• Cakan T, Inan N, Culhaoglu S, Bakkal K, Başar H. Intravenous paracetamol improves the quality of
postoperative analgesia but does not decrease narcotic requirements. J Neurosurg Anesthesiol.
2008;20(3):169-173. doi:10.1097/ANA.0b013e3181705cfb
7. Chang2013
• Chang WK, Wu HL, Yang CS, et al. Effect on Pain Relief and Inflammatory Response Following
Addition of Tenoxicam to Intravenous Patient-Controlled Morphine Analgesia: A Double-Blind,
Randomized, Controlled Study in Patients Undergoing Spine Fusion Surgery. Pain Med (United
States). 2013;14(5):736-748. doi:10.1111/pme.12067
8. Chen2019
• Chen K, Wang L, Ning M, Dou L, Li W, Li Y. Evaluation of ultrasound-guided lateral thoracolumbar
interfascial plane block for postoperative analgesia in lumbar spine fusion surgery: A
prospective, randomized, and controlled clinical trial. PeerJ. 2019;2019(10).
doi:10.7717/peerj.7967
9. Choi2013
• Choi YS, Shim JK, Song JW, Kim JC, Yoo YC, Kwak YL. Combination of pregabalin and
dexamethasone for postoperative pain and functional outcome in patients undergoing lumbar
spinal surgery: A randomized placebo-controlled trial. Clin J Pain. 2013;29(1):9-14.
doi:10.1097/AJP.0b013e318246d1a9
10. Cohen1997
27
• Cohen BE, Hartman MB, Wade JT, et al. Postoperative pain control after lumbar spine fusion:
Patient- controlled analgesia versus continuous epidural analgesia. Spine (Phila Pa 1976).
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11. Dehkordy2020
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8 Characteristics of included studies
Continued/
No. No. arms
No of Sponsor sample Mean Weight Surgery %
Study Name Year arms in included Country Surgery Started in Intervention
Sites ship Post-op size age (SD) (SD) (kg) duration Female
study in NMA
Period
YES Paracetamol 30 47 (9) 81 (13) 101 (11) 50
Paracetamol
YES 30 45.(8) 82 (3) 116 (10) 43
single level and NSAID
Attia2017 2017 4 4 Egypt 1 No lumbar Paracetamol
YES 30 48 (10) 81 (13) 113 (14) 40
laminectomy with Adjunct
Paracetamol
YES NSAID with 30 48 (10) 79 (17) 118 (10) 47
Adjunct
YES Paracetamol 25 51 (13) 69 (12) 172 (75) 60
spinal fusion
Aubrun2000 2000 2 2 France 1 Yes
surgery Paracetamol
YES 25 46 (15) 72 (10) 178 (50) 44
and NSAID
elective surgical
lumbar NO Control 23 44 (11) 68 (13) 37 (15) 57
discectomy with
Aveline2006 2006 3 2 France 1 No
partial
laminectomy and
nucleotomy Ketamine
NO Infusion 22 45 (8) 76 (9) 41 (18) 50
(Intraop)
lumbar spinal
YES NSAID 29 418 (14) 81 (15) 166 (65) 55
fusion of 1
Bedin2017 2017 2 2 Brazil 1 No
segment under
open surgery NSAID with
YES 28 48 (12) 83 (18) 161 (55) 54
Adjunct
NO Paracetamol 34 NA NA NA 56
lumbar fusion
Boenigk2019 2019 2 2 USA 1 Yes surgery at two or Ketamine
more levels YES Infusion 24 NA NA NA 54
(Postop)
elective lumbar
NO Control 20 44 (10) NA 137 (29) 55
multiple level
Cakan2008 2008 2 2 USA 1 No
laminectomy and
discectomy
YES Paracetamol 20 41 (10) NA 127 (40) 60
37
elective posterior
spinal NO Control 32 64 (9) NA 205 (53) 69
Chang2013 2013 3 2 Taiwan 1 No decompression,
fusion, and
instrumentation
YES NSAID 28 60 (12) NA 212 (51) 46
NO Control 30 54 (12) 63 (11) 160 (25) 50

lumbar spinal
Chen2019 2019 2 2 China 1 No
fusion Fascial Plane
NO 30 59 (9) 62 (7) 173 (39) 47
Block (SS)
lumbar NO Control 36 NA NA 123 (72) 56

Choi2013 2013 3 2 Korea 1 No laminectomy or
spinal fusion Gabapentinoid
YES 36 NA NA 134 (59) 42
(High dose)
NO Control 21 45 (3) NA NA NA
posterior lumbar
Cohen1997 1997 2 2 USA 1 No
fusion Epidural LA
YES 21 45 (3) NA NA NA
with Adjunct (C)
Lumbar spinal
NO Paracetamol 40 46 (13) 80 (12) 225 (69) 65
fusion surgery,
Dehkordy2020 2020 2 2 Iran 1 No
not more than
three-level Paracetamol
NO 40 50 (12) 77 (13) 218 (86) 58
with Adjunct
Elective, NO Control 76 60 (13) 237 (81) 61
Dhaliwal2019 2019 2 2 Canada 1 No instrumented
Neuraxial
lumbar fusion NO 74 64 (11) 221 (65) 54
Opioid (SS)
NO Control 21 NA NA NA 62
Eiamcharoenwit202 Lumbosacral spine
2020 4 2 Thailand 1 No
0 surgery
NO Nefopam 21 NA NA NA 57
NO Control 30 48 (9) 78 (6) 174 (40) 63

spinal vertebral
Emir2010 2010 2 2 Turkey 1 Unclear
surgery
YES Paracetamol 30 45 (12) 76 (7) 163 (38) 73
lumbar NO Control 52 43 (14) NA 104 (31) 67

Esmail2008 2008 2 2 Iran 1 No laminectomy/disc
LA Infiltration
ectomy NO 86 41 (11) NA 115 (3) 43
(SS)
NO Control 70 51 (9) 80 (8) 204 (12) 43
2020 Elective lumbar
Etezadi2020 2 2 Iran 1 Unclear
1 spine surgery Ketamine Inf
NO 70 49 (7) 78 (6) 187(11) 46
(Intraop) w Adj
38
anterior,
posterior, or
combined anterior
and posterior NO Control 60 46 (5) 65 (9) 160 (15) 23
Ezhevskaya2019 2019 2 2 Russia 1 No spinal fusion of 2
or more levels
within the
thoracolumbar
spine
Epidural LA
YES 27 44 (6) 68 (9) 168 (11) 67
with Adjunct (C)
elective multilevel
NO Control 58 54 (11) NA NA 40
spine surgery with
Farag2013 2013 2 2 USA 1 No
or without
instrumentation Lidocaine
YES 58 58 (11) NA NA 40
Infusion
Paracetamol
YES 34 54 (15) NA 69 (16) 59
lumbar and NSAID
Farmery2009 2009 2 2 England 1 No decompression or Paracetamol
discectomy YES NSAID with 31 57 (19) NA 73 (15) 55
Adjunct
elective, single NO Control 40 39 (9) NA NA 53

Firouzian2018 2018 2 2 Iran 1 No level open
discectomy YES Naloxone 40 36 (8) NA NA 60
NO Control 29 65 (2) 58 (10) 127 (42) 66

posterior lumbar
Fujita2016 2016 3 2 Japan 1 No
interbody fusion Gabapentinoid
NO 30 60 (14) 59 (10) 125 (41) 67
(Low dose)
NO Control 22 36 (14) 65 (16) NA 27
Ketamine
elective spine
Garg2016 2016 3 3 India 1 No YES Infusion 22 36 (14) 62 (15) NA 41
surgery
(Postop)
YES Alpha-2 Agonist 22 37 (15) 66 (14) NA 36
elective
63.5
decompressive NO Control 30 85 (17) 110 (95) 53
(9.9)
Gianesello2012 2012 2 2 Italy 1 No lumbar
laminectomy with
spinal fusion Gabapentinoid 66.2
YES 30 80 (28) 133.7 (85) 70
(High dose) (10.8)
decompression or 43
NO Control 46 NA 108 (241) 52
instrumentation (15.1)
Govil2020 2020 2 2 India 1 No
for lumbar
radiculopathy YES Duloxetine 46 41 (15) NA 113 (20) 50
Guilfoyle2012 2012 2 2 England 1 No NO Control 31 66 (12) NA 113 (38) 55
39
lumbar
Neuraxial
decompression or NO 29 70 (10) NA 113 (36) 45
Opioid (SS)
discectomy
scoliosis surgery NO Control 20 NA NA 240 (3) 60

with a spine
Hadi2009 2009 2 2 Jordan 1 No
curvature greater
than 40 degrees Ketamine
NO Infusion 20 NA NA 239 (4) 65
(Intraop)
NO Control 20 38 (11) 70 (12) 67 (27) 45
elective lumbar
Hans1993 1993 2 2 Belgium 1 No
disc surgery
YES Paracetamol 20 38 (9) 73 (12) 77 (25) 20
elective
decompressive NO Control 21 38 (8) 69 (11) 209 (52) 43
Hernandez-
2001 2 2 Spain 1 No lumbar
Palazon2001
laminectomy with
spinal fusion YES Paracetamol 21 41 (9) 73 (7) 193 (33) 48
lumbar surgery NO Control 30 50 (3) 79 (4) NA NA

Hurlbert1999 1999 2 2 Canada 1 Yes for discectomy or
spinal stenosis Epidural Steroid
NO 30 53 (3) 86 (5) NA NA
(SS)
Paracetamol
YES 20 43 (5) 82 (7) 111 (24) 35
and NSAID
spinal fusion
Ibrahim2018 2018 2 2 Egypt 1 No Paracetamol
surgery
YES NSAID with 20 41 (8) 77 (9) 108 (26) 45
Adjunct
spinal surgery at
NO Control 30 48 (6) 82 (6) 75 (5) 50
Javaherforooshzade two or three
2018 3 2 Iran 1 No
h2018 levels Gabapentinoid
laminectomy NO 30 45 (6) 79 (6) 80 (5) 53
(Low dose)
NO Control 20 40 (7) 84 (11) NA 15

elective lumbar
Javery1996 1996 2 2 USA 1 No Ketamine
microdiscectomy
YES Infusion 22 37 (10) 84 (11) NA 23
(Postop)
elective posterior
lumbar
discectomy,
NO Control 52 51 (13) 62 (7) 117 (27) 48
Jirarattanaphochai2 decompressive
007 laminectomy with
or without
instrumented
spinal fusion LA Infiltration
NO 51 53 (10) 60 (7) 115 (28) 59
(SS)
40
posterior lumbar
discectomy, NO Control 60 52 (11) 61 (10) 91 (40) 62
Jirarattanaphochai2
2008 2 2 Thailand 1 No decompressive
008
laminectomy, or
spinal fusion
YES NSAID 60 51 (13) 60 (8) 88 (42) 5.3
one-level
posterior lumbar
interbody
arthrodesis with
decompression
NO Control 34 NA NA NA NA
South for the treatment
Kang2013 2013 2 2 1 No
Korea of severe stenosis
and/or
spondylolisthesis
accompanied by
segmental
instability
NO Epidural LA (SS) 32 NA NA NA MA
NO Control 25 41 (13) 80 (16) 85 (29) 48

elective single
Kesimci2011 2011 3 3 Turkey 1 Unclear level lumbar disc NO NSAID 25 45 (9) 75 (13) 84 (30) 40
surgery
NO Paracetamol 25 42 (12) 76 (12) 83 (26) 44
elective lumbar
NO Control 40 45 (5) 80 (8) 119 (5) 20
one- or two-level
Khajavi2013 2013 2 2 Iran 1 No laminectomy/disc
ectomy for the
first time Epidural LA
NO with Adjunct 40 51 (3) 78 (7) 121 (7) 25
(SS)
NO Control 38 50 (7) NA 127 (14) 26
elective lumbar
Khajavikhan2016 2016 2 2 Iran 1 No
laminectomy
YES NSAID 38 50 (4) NA 149 (15) 24
NO Control 25 41 (11) 79 (6) 155 (18) 40

elective single-
Gabapentinoid
Khan2011 2011 7 3 Iran 1 No level lumbar NO 25 44 (11) 77 (5) 163 (31) 36
(Low dose)
laminectomy
Gabapentinoid
NO 25 40 (10) 78 (5) 162 (24) 36
(High dose)
NO Control 30 48 (2) 55 (7) 128 (22) 60
elective spine
Kien2019 2019 2 2 Vietnam 1 No
fusion surgery NSAID and
NO 30 45 (10) 57 (6) 128 (21) 40
Gabapentinoid
41
elective one-level
NO Control 26 NA 65 (7) NA 46
South lumbar
Kim2014 2014 2 2 1 No
Korea laminectomy or Lidocaine
discectomy NO 25 NA 64 (10) NA 72
Infusion
1 to 2 level
posterior lumbar NO Control 53 NA 61 (9) 148 (64) NA
South
Kim2016a 2016 2 2 1 No spinal fusion or
Korea
laminectomy
surgery YES Paracetamol 53 NA 60 (10) 138 (68) NA
primary posterior
lumbar interbody
fusion (PLIF)
South
Kim2016b 2016 2 2 1 No surgery for
Korea
symptomatic
lumbar 4–5
stenosis Paracetamol
YES NSAID and 40 68 (8) NA NA NA
Gaba
One or two levels NO Control 26 67 (6) 61 (12) 140 (37) 69

Kraiwattanapong20 of lumbar spinous
20 process splitting
LA Infiltration
laminectomy 137
NO with Adjunct 23 68 (6) 64 (9) 70
(31)
(SS)
elective posterior
lumbar interbody
fusion (PLIF) NO Control 55 65 (10) 599 (9) 173 (27) 73
Li2016 2016 2 2 China 1 No surgery for
symptomatic
single-level (L4-L5
or L5-S1) stenosis
Epidural LA
YES 65 63 (10) 58 (13) 166 (38) 75
with Adjunct (C)
NO Control 28 52 (11) NA 126 (11) 43
spinal fusion
Li2019 2019 2 2 China 1 No
surgeries
NO Alpha-2 Agonist 29 49 (13) NA 133 (10) 38
NO Control 50 39 (0) 76 (0) 73 (0) 52

standard hemi-
/partial Epidural Steroid
Lotfinia2007 2007 3 3 Iran 1 Unclear NO 50 37 (0) 74 (0) 74 (0) 54
laminectomy and (SS)
discectomy
NO Epidural LA (SS) 50 38 (0) 75 (0) 70 (0) 60
single- or two-
Mariappan2015 2015 2 2 Canada 1 No level anterior NO Control 23 52 (12) NA 232 (12) 30
cervical
42
decompression Fascial Plane
NO 23 48 (9) NA 254 (16) 44
and fusion Block (SS)
Lumbar
laminotomy or
lumbar
laminectomy;
Anterior cervical
fusion; Cervical
laminectomy or
NO Control 45 48 (11) 73 (14) NA 42
Australi cervical
McGlew1991 1991 2 2 1 No
a discectomy;
Posterior
lumbar/cervical
fusion and plating;
Lumbar
laminectomy
multilevel
decompression
YES NSAID 43 46 (10) 75 (13) NA 37
elective lumbar NO Control 30 43 (12) 74 (12) 53 (20) 37

Milligan1993 1993 2 2 Ireland 1 No disc
decompression LA Infiltration
NO 30 41 (12) 70 (11) 60 (18) 40
(SS)
multilevel (>3
levels) thoracic
and/or lumbar
spine surgery
requiring either YES Paracetamol 68 NA NA NA NA
Naik2016 2016 2 2 USA 1 No somatosensory
evoked potential,
motor evoked
potential, and/or
electromyography
monitoring
Paracetamol
YES 63 NA NA NA NA
with Adjunct
1-level or 2-level Paracetamol

YES 76 45 (14) 79 (15) NA 34
primary lumbar and NSAID
Denmar
Nielsen 2015 2015 2 2 1 No discectomy during
k
general Paracetamol
anesthesia YES NSAID with 77 45 (14) 80 (17) NA 58
Adjunct
Nikooseresht2016 2016 2 2 Iran 1 No laminectomy YES Paracetamol 51 43 (10) 68 (10) 71 (22) NA
43
YES NSAID 51 44 (10) 70 (9) 71 (21) NA
decompressive
NO Control 30 496 (7) 74 (9) 134 (20) 57
lumbar
Ozgencil2011 2011 3 2 Turkey 1 No
laminectomy and
discectomy Gabapentinoid
YES 30 51 (9) 71 (10) 139 (27) 50
(High dose)
single-level NO Control 28 39 (12) 59 (11) 216 (24) 26

Pandey2004 2004 2 2 India 1 No lumbar
discoidectomy Gabapentinoid
NO 28 39 (7) 61 (10) 204 (24) 29
(Low dose)
NO Control 20 40 (12) 62 (11) 160 (30) 40
single-level
Gabapentinoid
Pandey2005 2005 5 3 India 1 No lumbar NO 20 40 (11) 60 (13) 150 (38) 20
(Low dose)
diskectomy
Gabapentinoid
NO 20 42(13) 67 (7) 167 (40) 35
(High dose)
one- or two-level
posterior NO Control 41 67 (8) NA 158(36) 46
South
Park2016 2016 2 2 1 No decompression
Korea
and lumbar
interbody fusion YES Epidural LA (C) 45 66 (9) NA 173 (42) 56
elective lumbar NO Control 31 NA 74 (15) 68 (29) 42

Pobereskin2000a 2000 3 2 UK 1 No spine surgery via a
posterior incision Epidural Steroid
NO 31 NA 78 (13) 62 (25) 61
(SS)
cervical spine
NO Control 25 NA NA NA NA
surgery using a
Pobereskin2000b 2000 2 2 UK 1 No
posterior LA Infiltration
approach NO 25 NA NA NA NA
(SS)
elective single NO Control 20 43 (11) NA 74 (9) 40
level unilateral
Polat2015 2015 3 3 Turkey 1 No microsurgical NO NSAID 20 45 (10) NA 78 (8) 45
lumbar
discectomy NO Paracetamol 20 45 (10) NA 82 (11) 50
discectomy or
NO Control 20 50 (12) 58. (10) 119 (39) 70
Pookarnjanamorako single-level
t2002 lumbar
laminectomy YES NSAID 27 50 (13) 63 (11) 119 (27) 67
elective
NO Control 20 41 (9) 76 (16) 277 (44) NA
decompressive
Reuben1997 1997 4 2 USA 1 No
lumbar
laminectomy YES NSAID 20 45 (10) 74 (15) 266 (45) NA
one or two levels
Samoladas2019 2019 2 2 Greece 1 No lumbar Epidural LA
discectomy NO with Adjunct 30 NA NA NA 43
(SS)
44
combined
German anterior-posterior
Schenk2006 2006 2 2 1 No
y spine fusion
surgery Epidural LA
YES 28 NA NA NA 46
with Adjunct (C)
discectomy in the
lumbosacral spine NO Control 40 NA NA NA 40
by the posterior
Sekar2004 2004 2 2 India 1 No
approach, with or
without
instrumentation Epidural LA
NO with Adjunct 42 NA NA NA 38
(SS)
spondylolisthesis
with spinal fusion NO Control 35 63 (15) NA 139 (42) 77
Servicl-Kuchler2014 2014 2 2 Slovenia 1 Unclear at one or two
levels with
instrumentation
YES Epidural LA (C) 33 60 (13) NA 144 (40) 79
elective lumbar
Shimia2014 2014 2 2 Iran 1 No
discectomy
NO Paracetamol 24 47 (14) NA NA NA
NO Control 20 35 (10) NA 145 (8) 10

elective lumbar
Singh2019 2019 2 2 India 1 No
spinal surgery Fascial Plane
NO 20 35 (8) NA 149 (6) 15
Block (SS)
LA Infiltration
NO 40 66 (9) 66 (14) 176 (32) 68
(SS)
Singhatanadgige202 One-level lumbar
2020 2 2 Thailand 1 No LA Infiltration
0 interbody fusion
NO with Adjunct 40 66 (8) 66 (12) 173 (33) 80
(SS)
1 - 2 level NO Control 25 NA 60 (10) 191 (58) NA

South posterior lumbar
Song2013 2013 2 2 1 No Ketamine
Korea spinal fusion
surgery YES Infusion 24 NA 59 (7) 208 (67) NA
(Postop)
Paracetamol
YES 24 43 (8) 77 (147) 62 (31) 46
elective lumbar and NSAID
Spreng2011 2011 2 2 Norway 1 No single level
microdiscectomy Paracetamol
YES NSAID and 22 44 (11) 77 (15) 64 (27) 50
Gaba
YES NSAID 32 52 (18) 68 (10) 39 (9) 44
lumbar single
Tang2017 2017 3 2 China 1 No
level discectomy Buprenorphine
YES 32 48 (14) 68 (12) 39 (9) 44
Patch
45
Elective or semi- Paracetamol
YES 36 49 (15) NA 118 (43) 58
elective single- and NSAID
Tsaousi2020 2020 2 2 Greece 1 No space lumbar
spine Paracetamol
laminectomy YES NSAID with 35 60 (11) NA 115 (39) 63
Adjunct
Elective lumbar
NO Control 25 45 (8) 75 (13) 160 (45)
discectomy or
Turan2004 2004 2 2 Turkey 1 No
spinal fusion
surgery
Gabapentinoid
NO 25 48 (9) 73 (15) 156 (34) 42
(High dose)
primary lumbar
laminoplasty of
Ueshima2019 2019 2 2 Japan 1 No
less than three
levels Fascial Plane
NO 35 NA NA NA 34
Block (SS)
NO Control 38 50 (7) NA 127 (14) 26
elective Gabapentinoid
Vasigh2016a 2016 3 3 Iran 1 No YES 38 50 (6) NA 136 (17) 18
laminectomy (High dose)
YES NSAID 38 50 (4) NA 130 (21) 24
NO Control 38 50 (7) NA 127 (14) 26

elective Gabapentinoid
Vasigh2016b 2016 3 3 Iran 1 No YES 38 50 (6) NA 136 (17) 18
laminectomy (High dose)
NSAID and
YES 38 49 (6) NA 130. (21) 34
Gabapentinoid
LA Infiltration
Elective multilevel NO 43 66 (8) NA 157 (47) 49
(SS)
Wang2020 2020 2 2 China 1 No lumbar
laminectomy Neuraxial
NO 44 66 (5) NA 163 (51) 52
Opioid (SS)
lumbar NO Control 40 57 (8) 68 (14) 87 (40) 65

Wittayapairoj2017 2017 2 2 Thailand 1 No decompressive
laminectomy Dexamethason
NO 40 59 (6) 63 (9) 82 (45) 60
e
elective posterior NO Control 35 49 (11) NA 246 (5) 49

Xu2017 2017 2 2 China 1 No thoracolumbar
spinal surgery LA Infiltration
YES 35 52 (11) NA 252 (83) 46
(C)
NO NSAID 67 57 (14) 70 (7) 124 (48) 8

posterior cervical
Yamauchi2008 2008 3 2 Japan 1 Unclear or lumbar spinal Ketamine
surgery YES Infusion 69 65 (17) 67 (13) 116 (36) 9
(Postop)
46
NO Control 20 65 (12) 65 (11) 180 (42) 65
1-2 level posterior
South
Yeom2012 2012 2 2 1 Unclear lumbar spinal Ketamine
Korea
fusion YES Infusion 20 61 (10) 59 (14) 168 (30) 75
(Postop)
NO Control 20 45 (11) 75 (10) 91 (31) 60
elective
uncomplicated Neuraxial
Yorukoglu2005 2005 4 3 Turkey 1 Unclear NO 20 46 (11) 74 (10) 87 (32) 40
lumbar Opioid (SS)
discectomy LA Infiltration
NO 20 44 (10) 73 (10) 90 (28) 45
(SS)
LA Infiltration
YES 22 59 (15) 60 (10) 161 (27) 32
posterior lumbar (C)
interbody fusion Epidural LA
Yukawa2005 2005 3 3 Japan 1 No YES 23 59 (15) 59 (10) 158 (30) 57
with with Adjunct (C)
instrumentation
YES Control 27 62 (15) 59 (8) 163 (35) 56
lumbar disc NO Control 35 44 (9) NA 65 (19) 40

Zarei2016 2016 3 2 Iran 1 No surgery with one
operable disc level Gabapentinoid
YES 35 40 (10) NA 67 (20) 51
(High dose)
Open posterior NO Control 30 60 (12) NA 141 (33) 70

Zhang2021 2021 2 2 China 1 No lumbar spinal
fusion surgery Fascial Plane
NO 30 60 (10) NA 153 (39) 80
Block (SS)
47
9 Definitions
9.1 Outcome Definitions
VAS = Visual Analogue Scale
NRS = Numeric Rating Scale
Name of Study Pain Outcome Reported Opioid Consumption Outcome Reported Opioid in
format format (opioid PCA/rescue
(pain) consumption)
Attia2017 pain score (NRS) at median and total morphine requirement at 24h mean and SD morphine IV
rest at 24h IQR
Aubrun2000 pain intensity at 24h figure total morphine requirement at 24h mean and SD morphine IV
(VAS 0 - 100)
Aveline2006 pain at rest 24h (VAS median and total morphine consumption at 24h median and IQR morphine IV
0 - 100) IQR in figure
Bedin2017 pain score at 24h total consumption fentanyl at 24h mean and SD fentanyl IV
(VAS 0 - 10)
Boenigk2019 pain at 24h (NPS 0 - figure cumulative hydromorphone figure (mg/kg) Hydromorphone
10) consumption during first 24h after IV
surgery
Cakan2008 24h pain score during figure cumulative morphine consumption figure Morphine IV
rest (VAS 0 - 10) at 24h
Chang2013 pain at 24h at rest figure cumulative morphine consumption figure morphine IV
at 24h
Chen2019 pain at 24h at rest figure sufentanil IV
(VAS 0 - 10)
Choi2013 pain at 24h at rest median and fentanyl IV
(VAS 0 - 100) IQR
Cohen1997 POD1 pain score (VAS mean and none
0 - 10) SD
48
Dehkordy2020 Pain at 24h (VAS 0 – Mean and 24h postoperative cumulative Mean and SD Morphine IV
100) SD morphine consumption
Dhaliwal2019 pain at 24h at rest figure cumulative 24h postoperative mean and SD morphine IV
(VAS 0 - 100) analgesia
Eiamcharoenwit2020 Pain at 24h (NRS 0 – Median and 24h cumulative morphine dose Median and IQR Morphine IV
10) IQR received by PCA
Emir2010 pain at 24h (VAS 0 - figure total tramadol dose mean and SD pethidine IM
100)
Esmail2008 pain at 24h in supine mean and morphine IM
position (VAS 0 - 100) SD
Etezadi2020 Pain at 24h (NRS 0 – Mean and Morphine IV
10) SD
Ezhevskaya2019 pain at 24h at rest mean and morphine IV
(NRS 0 - 10) SD
Farag2013 POD1 pain score (VRS figure morphine IV
0 - 10)
Farmery2009 pain score at 24h figure average morphing consumption figure (mg/hr) morphine IV
(VPS 0 - 10) rate at mg/hour at 24h
Firouzian2018 24h pain at rest (VAS mean and 24h total morphine consumption median and IQR morphine IV
0 - 10) SD
Fujita2016 24h pain at rest (VAS figure morphine IV
0 - 100)
Garg2016 24h pain score (NRS 0 median and rescue morphine requirement in mean and SD morphine iv
- 10) IQR first 24h
Gianesello2012 24h pain score at rest figure morphine consumption in 24h mean and SD morphine iv
(VAS 0 - 10)
Govil2020 24h pain score (NRS 0 mean and total morphine (rescue analgesia) mean and SD morphine IV
- 10) SD consumed in 24h
Guilfoyle2012 Day 1 pain score (VAS mean and likely IV PCA
0 - 10) SD
49
Hadi2009 total 24h morphine consumption mean and SD morphine IV
Hans1993 cumulative piritramide mean and SD piritramide IM

consumption at 24h
Hernandez-Palazon2001 24h cumulative dose of morphine figure morphine IV
Hurlbert1999 cumulative morphine consumption figure morphine IV

in first 24h post-op
Ibrahim2018 24h pain score (VAS 0 mean and 24h total morphine consumption low risk morphine IV
- 10) SD
Javaherforooshzadeh2018 24h pain score (VAS 0 mean and
- 10) SD
Javery1996 24h pain score (VAS 0 mean and 24h total morphine consumption mean and SD morphine IV
- 10) SD
Jirarattanaphochai2007 24h pain at rest (NRS median and 24h total morphine consumption median and morphine IV
0 - 10) range range
Jirarattanaphochai2008 24h pain at rest (0 - mean and 24h total morphine consumption mean and SD morphine IV
10) SD
Kang2013 24h pain score (NRS 0 figure 24h total morphine consumption figure (mg/hr) fentanyl IV
- 10)
Kesimci2011 24h pain score (VAS 0 figure morphine consumption by PCA at mean and SD morphine IV
- 10) the end of 24 hours
Khajavi2013 pain at 24h (VAS 0 - figure total analgesic requirement for the figure morphine IV
10) first 24 hours (morphine)
Khajavikhan2016 severity of pain at mean and morphine consumption mean and SD morphine
24h (VAS 0 - 10) SD
Khan2011 total morphine sulfate mean and SD morphine IV
consumption during the first 24h
50
Kien2019 24h pain at rest (VAS mean and morphine consumption by PCA at mean and SD morphine IV
0 - 10) SD 24h with fentanyl IV
as rescue
Kim2014 pain at 24h (VAS 0 - figure fentanyl consumption at 24h after figure (mcg/hr) fentanyl IV
100) surgery
Kim2016a IV-PCA analgesics converted into median and fentanyl IV
equianalgesic doses of morphine range
from 0-24h
Kim2016b pain at POD1 (VAS 0 - mean and morphine IV
10) SD
Kraiwattanapong2020 24h pain at rest (VAS Figure 24h opioid consumption Mean and SD Morphine IV
0 – 10) (need to be
combined)
Li2016 24h pain at rest (VAS mean and IV-PCA morphine consumption in sufentanil IV vs
0 - 10) SD first 24h post-op epidural
Li2019 pain at 24h (VAS 0 - figure mean and SD morphine IV

10)
Lotfinia2007 back pain at 24h (VAS mean and meperidine IM
0 - 10) SD
Mariappan2015 24h opioid consumption in mean and SD fentanyl IV
morphine equivalents
McGlew1991 Day 1 p.m. pain (VAS mean and Day 1 pethidine usage mean and SD pethidine IM
0 - 100) SD
Milligan1993 24h pain score (VAS 0 mean and total morphine consumption in mean and SD morphine IV
- 100) SD POD0
Naik2016 pain at POD1 (VAS 0 - median and POD1 opioid consumption in median and IQR hydromorphone
10) IQR morphine equivalents iv
Nielsen 2015 24h pain at rest (VAS figure 24h total morphine consumption mean and SD morphine IV
0 - 100)
Nikooseresht2016 pain at 24h (VAS 0 - mean and consumed fentanyl after 24h mean and SD fentanyl IV
10) SD
51
Ozgencil2011 pain at 24h (VAS 0 - mean and 24h total morphine consumption, mean and SD morphine IV
10) SD mg/kg X mean weight
Pandey2004 total fentanyl consumed in the first mean and SD fentanyl IV

24 h
Pandey2005 24h pain (VAS 0 - 10) mean and 24h total fentanyl consumption mean and SD fentanyl IV
SD
Park2016 24h pain (VAS 0 - 10) figure oxycontin PO
and demerol IV
Pobereskin2000a 24h spinal pain at mean and 24h total morphine consumption mean and SD morphine IV
rest (VAS 0 - 100) SD
Pobereskin2000b 24h spinal pain at mean and 24h total morphine consumption mean and SD morphine IV
rest (VAS 0 - 100) SD
Polat2015 0 total tramadol consumption over mean and SD tramadol IV
24h
Pookarnjanamorakot2002 24h pain score (VAS 0 mean and morphine IV
- 10) SD
Reuben1997 24h pain (VAS 0 - 10) mean and total morphine consumption mean and SD morphine IV
SD
Samoladas2019 pain at 24h (VAS 0 - median and none
10) IQR in
figure
Schenk2006 pain at 24h at rest mean and none
(VAS 0 - 10) SD
Sekar2004 pain at 24h (VAS 0 - median and none
100) IQR
ServiclKuchler2014 Day 1 pain score (VAS figure piritramide IV
0 - 10)
Shimia2014 pain severity 24h mean and dosages of morphine administered mean and SD morphine IV
after surgery (VAS 0 - SD post-op within 24h after surgery
10)
52
Singh2019 pain at 24h (NRS 0 - median and cumulative morphine consumption mean and SD morphine IV
10) IQR during the first 24 hours postop
Singhatanadgige2020 Pain at 24h (VAS 0 – Mean and Intravenous morphine Mean and SD Morphine IV
10) SD consumption in the first 24h (need to be
combined)
Song2013 Cumulative dose of fentanyl mean and SD fentanyl IV
consumed
Spreng2011 24 pain at rest (VAS 0 figure 24h morphine consumption figure morphine IV
- 100)
Tang2017 pain at POD1 (VAS 0 - mean and tramadol IM
10) SD
Tsaousi2020 Pain at 24h after Figure Cumulative intravenous analgesic Mean and SD
surgery (VAS 0 – 10) consumption in morphine
equivalents within 24h after
emergence from anesthesia
Turan2004 24h pain score (VAS 0 median and 24h total morphine consumption mean and SD morphine IV
- 10) IQR
Ueshima2019 24h pain at rest (VAS median and cumulative dose of fentanyl figure fentanyl IV
0 - 100) IQR consumed
Vasigh2016a pain at 24h (VAS 0 - mean and morphine consumption mean and SD morphine IV
10) SD
Vasigh2016b pain at 24h (VAS 0 - mean and morphine consumption at 24h mean and SD morphine IV
10) SD
Wang2020 Pain at 24h post-op Figure 24h sufentanil Mean and SD sufentanil IV
(VAS 0 – 10)
Wittayapairoj2017 24h pain at rest (NRS mean and 24h morphine consumption mean and SD morphine IV
0 - 10) SD (in time
intervals)
Xu2017 24h pain at rest (VAS figure none
0 - 10)
53
Yamauchi2008 24h pain at rest (VAS figure fentanyl IV
0 - 100)
Yeom2012 POD1 pain at rest mean and fentanyl IV
(NRS 0 - 10) SD
Yorukoglu2005 pain at 24h (VAS 0 - figure total consumption of meperidine at mean and SD meperidine IM
10) 24h
Yukawa2005 pain at 24h (VAS 0 - mean and pentazocine IM
100) SD
Zarei2016 24h back pain (NRS 0 mean and morphine IV
- 10) SD
Zhang2021 24h pain at rest (NRS Figure 24h cumulative sufentanil Median and IQR sufentanil IV
0 – 10)
54
9.2 Intervention Description
- Intervention description only shows drugs given in pre-operative, intra-operative and 24 hours post-
operative period
9.2.1 Pharmacological Interventions

Control
Study Intervention Description
1 Aveline2006 intra-op: morphine 0.1mg/kg IV x1
2 Cakan2008 intra-op and post-op normal saline
3 Chang2013 opioid-only PCA
4 Choi2013 pre-op and post-op placebo pill
5 Eiamcharoewit2020 transparent, colorless solution containing placebo
6 Emir2010 opioid-only PCA
7 Etezadi2020 Normal saline bolus
8 Farag2013 pre-op, intra-op, and post-op normal saline
9 Firouzian2018 post-op normal saline
10 Fujita2016 pre-op: diazepam 5 mg
11 Garg2016 post-op normal saline
12 Gianesello2012 pre-op and post-op placebo pill
13 Govil2020 post-op placebo pill
14 Hadi2009 intra-op remifentanil 0.2 mcg/kg/min
15 Hans1993 post-op normal saline
16 Hernandez-Palazon2001 intra-op and post-op normal saline
17 Javaherforooshzadeh2018 pre-op placebo pill
18 Javery1996 opioid-only PCA
19 Jirarattanaphochai2008 pre-op and post-op active placebo
20 Kesimci2011 pre-op placebo pill
21 Khajavikhan2016 pre-op and post-op placebo pill
22 Khan2011 pre-op placebo pill
23 Kien2019 pre-op placebo pill
24 Kim2014 intra-op normal saline
25 Kim2016a post-op normal saline
26 Kim2016b pre-op and post-op placebo pill
27 Li2019 intra-op ropivacaine 0.5% 20 mL x1, SC
28 McGlew1991 pre-op and post-op placebo suppository
29 Ozgencil2011 pre-op and post-op placebo pill
30 Pandey2004 pre-op placebo pill
31 Pandey2005 pre-op placebo pill
55
32 Polat2015 pre-op placebo pill
33 Pookarnjanamorakot2002 pre-op and post-op placebo pill
34 Reuben1997 post-op normal saline
35 Shimia2014 intra-op normal saline
36 Song2013 intra-op and post-op normal saline
37 Turan2004 pre-op placebo
38 Vasigh2016a pre-op and post-op placebo pill
39 Vasigh2016b pre-op and post-op placebo pill
40 Wittayapairoj2017 intra-op normal saline
41 Yeom2012 intra-op and post-op normal saline
42 Zarei2016 pre-op and post-op placebo pill
Alpha-2 Agonist
1 Garg2016 post-op: dexmedetomidine 0.5 mcg/kg bolus then infusion
0.3 mcg/kg/hr IV x 24h
2 Li2019 intra-op: 20 mL 0.5% ropivacaine and 1 mcg/kg of
dexmedetomidine SC x1
Buprenorphine Patch
TD: transdermal

1 Tang2017 post-op buprenorphine 5 mg TD patch
Dexamethasone
1 Wittayapairoj2017 intra-op: dexamethasone 0.2 mg kg-1 IV x 1
Duloxetine
1 Govil2020 pre-op: duloxetine 30 mg once a day x 2 days
post-op: duloxetine 60 mg once a day
Gabapentinoid (Low dose)

Pregabalin < 300 mg/day or gabapentin < 900 mg/day
56
1 Fujita2016 pre-op: pregabalin 75 mg
2 Javaherforooshzadeh2018 pre-op: gabapentin 600 mg
3 Khan2011 pre-op: gabapentin 600 mg
4 Pandey2004 pre-op: gabapentin 300 mg
Gabapentinoid (High dose)

Pregabalin ≥ 300 mg/day or gabapentin ≥ 900 mg/day

1 Choi2013 pre-op: pregabalin 150 mg
post-op: pregabalin 150 mg BID
2 Gianesello2012 pre-op: pregabalin 300 mg
post-op: pregabalin 150 mg BID
3 Khan2011 pre-op: gabapentin 600 mg
4 Ozgencil2011 pre-op: gabapentin 600 mg
post-op: gabapentin 1200 mg
6 Turan2004 pre-op: gabapentin 1200 mg
7 Vasigh2016a pre-op: gabapentin 600 mg
post-op: gabapentin 300 mg
8 Vasigh2016b pre-op: gabapentin 600 mg 5 hours before surgery
post-op: gabapentin 300 mg 6 hours after surgery
9 Zarei2016 pre-op: pregabalin 300 mg 8 hours before surgery
post-op: pregabalin 150 mg 12 and 24 hours after surgery
Ketamine Infusion (Intra-op)

1 Aveline2006 intra-op: ketamine 0.15mg kg-1 IV x1
2 Hadi2009 intra-op: ketamine 1 mcg kg-1 min-1 IV infusion
Ketamine Infusion (Intra-op) with Adjuncts

1 Etezadi2020 Intra-op: ketamine 0.5 mg kg-1 IV x1 then 0.25mg kg-1 hr-1
infusion and magnesium 1g x1 then 0.5g hr-1 infusion during
surgery
Ketamine Infusion (Post-op)

57
1 Boenigk2019 intra-op: paracetamol 1g IV x1
post-op: ketamine 0.2 mg kg-1 IV x1 then 0.12 mg kg-1 hr-1
IV x 24 hours
2 Garg2016 post-op: ketamine 0.25mg kg-1 IV x1 then 0.25 mg kg-1 hr-1
IV x 24 hours
3 Javery1996 post-op: ketamine mixed with IV PCA: infusion: none; bolus:
1 mg; lockout: 6 minutes
4 Song2013 intra-op: ketamine 0.3 mg kg-1 x1
post-op: ketamine mixed with IV PCA: infusion: 0.03 mg kg-1
hr; bolus 0.03 mg kg-1 ; lockout 15 minutes
5 Yamauchi2008 intra-op: diclofenac 50 mg suppository
post-op: ketamine 1 mg kg-1 IV x1 then 0.083 mg kg-1 hr-1 IV
infusion
6 Yeom2012 intra-op: ketamine 0.2mg/kg IV x1
post-op: ketamine mixed with PCA: infusion: 0.03mg kg-1 hr-
1
; bolus: 0.03mg kg-1 ; lockout: 15 minutes
Lidocaine Infusion
1 Farag2013 pre-op: lidocaine 2mg kg-1 hr-1 IV infusion
intra-op: lidocaine 2 mg kg-1 hr-1 IV infusion
post-op: lidocaine 2 mg kg-1 hr-1 IV infusion
2 Kim2014 intra-op: lidocaine 1.5 mg kg-1 IV x1 then 2 mg kg-1 hr-1 IV
infusion
NSAID
1 Bedin2017 post-op: ketorolac 0.4 mg kg-1 IV q6h
2 Chang2013 intra-op: tenoxicam 20 mg IV bolus
post-op: tenoxicam 0.03 mg kg-1 IV x1 then mixed into PCA:
infusion: 0.003mg kg-1 hr-1; bolus: 0.012mg kg-1; lockout 10
minutes
3 Jirarattanaphochai2008 pre-op: parecoxib 40 mg IV
post-op: parecoxib 40 mg IV BID
4 Kesimci2011 pre-op: dexketoprofen 25 mg PO
5 Khajavikhan2016 pre-op: celecoxib 400 mg PO 2 hours before surgery
post-op: celecoxib 200 mg PO 6 hours after surgery
6 McGlew1991 pre-op: indomethacin 100 mg suppository
post-op: indomethacin 100 mg suppository BID
7 Nikooseresht2016 intra-op: diclofenac 100 mg suppository
post-op: diclofenac 100 mg suppository 12 hours after
surgery
58
8 Polat2015 pre-op naproxen 550 mg and codeine 30 mg PO
9 Pookarnjanamorakot2002 pre-op: piroxicam 40 mg PO
post-op: piroxicam 40 mg PO daily
10 Reuben1997 post-op: ketorolac 30 mg IV q6h
11 Tang2017 pre-op: parecoxib 40 mg IV
post-op: parecoxib 40 mg IV BID
12 Vasigh2016a pre-op: celecoxib 400 mg PO 2 hours before surgery
post-op: celecoxib 200 mg PO 6 hours after surgery
13 Yamauchi2008 intra-op: diclofenac 50 mg rectal
NSAID with Adjunct

1 Bedin2017 pre-op: duloxetine 60 mg PO
post-op: ketorolac 0.4 mg kg-1 IV q6h
NSAID and Gabapentinoid
1 Kien2019 pre-op: pregabalin 150 mg PO and celecoxib 200 mg PO
pre-op: celecoxib 200 mg PO and gabapentin 300 mg PO 2
hours before surgery
2 Vasigh2016b
post-op: celecoxib 200 mg PO and gabapentin 300 mg PO 6
hours after surgery
Naloxone
1 Firouzian2018 post-op: naloxone 0.25 mcg kg-1 hr-1 IV infusion
Nefopam
1 Eiamcharoenwit2020 intra-op: nefopam 30 mg IV 30 minutes before surgical
incision and nefopam 30 mg IV 30 minutes before the end of
surgery
Paracetamol
1 Attia2017 intra-op: paracetamol 1g IV
post-op: paracetamol 1g IV q6h
2 Aubrun2000 post-op: paracetamol 2g IV q6h
3 Boenigk2019 intra-op: paracetamol 1g IV
4 Dehkordy2020 Intra-op: paracetamol 1g IV
5 Cakan2008 intra-op: paracetamol 1 g IV at the end of surgery
59
post-op: paracetamol 1 g IV q6h
6 Emir2010 post-op: paracetamol 1g IV q6h
7 Hans1993 post-op: paracetamol 2g IV q6h
8 Hernandez-Palazon2001 intra-op: paracetamol 2g IV
9 Kesimci2011 pre-op: paracetamol 400 mg PO
10 Kim2016a post-op: paracetamol mixed in PCA: infusion: 4 mg hr-1;
bolus: 1 mg: lockout 15 minutes
11 Naik2016 post-op: acetaminophen unknown dose and frequency
12 Nikooseresht2016 intra-op: paracetamol 1g IV
post-op: paracetamol 1g IV BID
13 Polat2015 pre-op: paracetamol 300 mg PO and codeine 300 mg PO
14 Shimia2014 intra-op: paracetamol 1 g IV
Paracetamol and NSAID

1 Attia2017 pre-op: etoricoxib 90 mg PO
intra-op: paracetamol 1g IV
2 Aubrun2000 post-op: paracetamol 2g IV q6h, ketoprofen 100 mg IV q8h
3 Farmery2009 pre-op: paracetamol 1g PO, ibuprofen 600 mg PO
post-op: paracetamol 1 g PO q6h
4 Ibrahim2018 intra-op: paracetamol 1g IV, ketorolac 30 mg IV
post-op: paracetamol 1g IV q8h, ketorolac 30 mg IV q8h
5 Nielsen2015 pre-op: paracetamol 1g PO, ibuprofen 400 mg PO
post-op: paracetamol 1g PO q6h, ibuprofen 400 mg PO q6h
6 Spreng2011 pre-op: paracetamol 1 – 1.5g diclofenac 50 mg PO
post-op: paracetamol 1 – 1.5g q6h, diclofenac 50 mg PO q8h
7 Tsaousi2020 Post-op: paracetamol 1g q6h and lornoxicam 8 mg BID
Paracetamol NSAID and Gaba (gabapentinoid)

1 Kim2016b pre-op: celecoxib 200 mg PO, pregabalin 75 mg PO,
acetaminophen 500 mg PO, oxycodone 10 mg PO
post-op: celecoxib 200 mg PO daily, pregabalin 75 mg PO
BID, acetaminophen 500 mg PO BID, oxycodone 10 mg PO
BID
2 Spreng2011 pre-op: paracetamol 1000 - 1500 mg, diclofenac 50 mg PO,
pregabalin 150 mg PO
post-op: paracetamol 1000 - 1500 mg q6h, diclofenac 50 mg
PO q8h
60
Paracetamol NSAID with Adjunct
1 Attia2017 pre-op: duloxetine 60 mg PO, etoricoxib 90 mg PO
intra-op: paracetamol 1g IV
2 Farmery2009 pre-op: paracetamol 1g PO, ibuprofen 600 mg PO
intra-op: clonidine 1.5 mcg kg-1 epidural
post-op: paracetamol 1 g PO q6h, clonidine 25 mcg hr-1
epidural infusion
3 Ibrahim2018 intra-op: paracetamol 1g IV, ketorolac 30 mg IV, lidocaine
2mg kg-1 x1 then 3mg kg-1 hr-1 infusion
post-op: paracetamol 1g IV q8h, ketorolac 30 mg IV q8h
4 Nielsen2015 pre-op: paracetamol 1g PO, ibuprofen 400 mg PO
intra-op: dexamethasone 16 mg IV x1
post-op: paracetamol 1g PO q6h, ibuprofen 400 mg PO q6h
5 Tsaousi2020 Pre-op: magnesium sulfate 20mg kg-1 in isotonic saline 100
mL IV 15 minutes before anesthesia induction
Intra-op: magnesium sulfate infusion 20 mg kg-1 hr-1 from
the end of the bolus dosing until surgery completion
Post-op: paracetamol 1g q6h and lornoxicam 8 mg BID
Paracetamol with Adjunct

1 Attia2017 pre-op: duloxetine 60 mg PO
intra-op: paracetamol 1 g IV
2 Dehkordy2020 Pre-op: magnesium sulfate 50 mg kg-1 in 100 mL saline IV 15
minutes before induction
Intra-op: magnesium sulfate infusion 15 mg kg-1 hr-1 IV
during the operation and paracetamol 1g IV 30 minutes
before the end of surgery
3 Naik2016 intra-op: dexmedetomidine 1 mcg kg-1 (IBW) x1 then
dexmedetomidine 0.5 mcg kg-1 hr-1 (IBW) IV infusion
post-op: acetaminophen unknown dose
9.2.2 Regional Interventions

No Regional Intervention
1 Chen2019 intra-op: flurbiprofen 50 mg Iv x1
2 Cohen1997 post-op: opioid only IV PCA
3 Dhaliwal2019 intra-op: intrathecal saline
61
4 Esmail2008 intra-op: saline with epinephrine SC
5 Ezhevskaya2019 opioid only IV PCA
6 Guilfoyle2012 intra-op: normal saline in epidural space
7 Hurlbert1999 intra-op: placebo paste in epidural space
8 Jirarattanaphochai2007 intra-op: normal saline injection to affected nerve roots and
paravertebral space
9 Kang2013 intra-op: normal saline in epidural space
10 Khajavi2013 none
11 Kraiwattanapong2020 none
12 Li2016 post-op: opioid only IV PCA
13 Lotfinia2007 intra-op: normal saline in epidural space
14 Mariappan2015 post-op: acetaminophen 300 mg or 325 mg x 1
15 Milligan1993 no injection
16 Park2016 post-op: opioid only IV PCA and Tylenol at variable doses
17 Pobereskin2000a none
18 Pobereskin2000b intra-op: normal saline IM
19 Samoladas2019 intra-op: normal saline in epidural space
20 Sekar2004 post-op: opioid only IV PCA
21 Sekar2004 intra-op: diclofenac 75 mg IV and caudal normal saline
injection
22 ServiclKuchler2014 intra-op: normal saline in epidural space
post-op: normal saline in epidural space
23 Singh2019 post-op: diclofenac 1.5mg kg-1 IV q8h
24 Ueshima2019 post-op: paracetamol 1g IV q8h, celecoxib 200 mg PO BID
25 Xu2017 post-op: flurbiprofen 3mg/hg, pentazocine 48 mg hr-1
infusion
26 Yorukoglu2005 intra-op: normal saline paraspinally
post-op: naproxen 75 mg PO PRN for VAS > 4
27 Yukawa2005 Post-op: diclofenac sodium of unspecified dose
28 Zhang2021 Pre-op: subcutaneous infiltration of 1 mL of 1% lidocaine on
each side
Post-op: flurbiprofen 1.5 mg kg-1 at the end of surgery then
continuous infusion of 6 mg hr-1 for total of 300 mg
Epidural LA (C)
1 Park2016 intra-op: ropivacaine 0.2% with epinephrine (1: 200 000) x 3
mL in epidural space
post-op: ropivacaine 0.2% continuous epidural infusion
2 ServiclKuchler2014 intra-op: 0.125% levobupivacaine bolus calculated according
to Bromage scheme
62
post-op: 0.125% levobupivacaine at 0.1 mL kg-1 hr-1
Epidural LA (SS)
1 Kang2013 intra-op: ropivacaine 0.1% x 10 mL in epidural space
2 Lotfinia2007 intra-op: bupivacaine 0.5% x 2mL and normal saline x 2mL in
epidural space
Epidural LA with Adjunct (C)

1 Cohen1997 postop: bupivacaine 0.0625% and morphine sulfate 0.004%
in epidural space, continuous infusion
2 Ezhevskaya2019 intra-op: 0.5% ropivacaine x 5 mL and fentanyl 100 mcg x1
then continuous infusion of 0.1% ropivacaine and 1mcg mL-1
fentanyl at 2 - 8 mL hr-1
post-op: 0.1% ropivacaine and 1mcg/mL of fentanyl at 2 - 8
mL/hr
3 Li2016 post-op: PCEA: 75 mcg sufentanil, 150 mg ropivacaine, and
2.5 mg droperidol mixed in 100 mL normal saline; loading 30
mL, infusion: 2 mL hr-1 , bolus: 2 mL; lockout 15 minutes
4 Schenk2006 post-op: PCEA: loading: 0.2% ropivacaine x 14mL and 10 mcg
sufentanil; infusion: ropivacaine 0.125% with sufentanil 1
mcg mL-1 x 14 mL hr-1 ; bolus: 5mL; lockout 15 minutes
5 Yukawa2005 post-op: lidocaine 1.2%, morphine 0.4 mg mL-1 in epidural
space, continuous infusion
Epidural LA with Adjunct (SS)

1 Khajavi2013 intra-op: 0.25% bupivacaine x 18 mL and 100 mcg fentanyl in
epidural space
2 Samoladas2019 intra-op: 2% ropivacaine x 9 mL and 3 mg betamethasone in
epidural space
post-op: paracetamol 1g q8h IV
3 Sekar2004 intra-op: 0.5% bupivacaine x 15 mL and 50 mg tramadol in
caudal space, NSAID unspecified
Epidural Steroid (SS)

1 Hurlbert1999 intra-op: epidural paste of microfibrillar collagen,
methylprednisolone, morphine, and aminocaproic acid of
unspecified dose
2 Lotfinia2007 intra-op: methylprednisolone 40 mg in epidural space
63
3 Pobereskin2000a Intra-op: triamcinolone 40 mg in extra-dural space
Fascial Plane Block (SS)

1 Chen2019 pre-op: TLIP block (0.375% ropivacaine x 30 mL)
intra-op: flurbiprofen 50 mg IV
2 Mariappan2015 intra-op: superficial cervical plexus block (0.25% bupivacaine
x 10 mL)
post-op: acetaminophen 300 mg or 325 mg x 1
3 Singh2019 pre-op: erector spinae block (0.5% bupivacaine x 20 mL)
post-op: diclofenac 1.5 mg kg-1 IV q8h
4 Ueshima2019 intra-op: bilateral TLIP block (0.375% levobupivacaine x
20mL on each side)
post-op: paracetamol 1g IV q8h, celecoxib 200 mg PO BID
5 Zhang2021 Pre-op: ultrasound guided bilateral erector spinae block
(0.4% ropivacaine x 20 mL each side)
Post-op: flurbiprofen 1.5 mg kg-1 at the end of surgery then
continuous infusion of 6 mg hr-1 for total of 300 mg
LA Infiltration (C)
1 Xu2017 intra-op: 1% ropivacaine x 6mL into paraspinal muscles
bilaterally
post-op: 0.33% ropivacaine at 5mL hr-1 into the wound
2 Yukawa2005 intra-op: morphine 1.2mg mL-1, 1.1% lidocaine at 0.5 mL hr-1
subcutaneously
post-op: morphine 1.2mg mL-1, 1.1% lidocaine at 0.5 mL hr-1
subcutaneously
LA Infiltration (SS)
1 Esmail2008 intra-op: lidocaine 2% with epi (1:200 000) x 20 mL
subcutaneously
2 Jirarattanaphochai2007 intra-op: 0.375% bupivacaine x 30 mL and
methylprednisolone 80 mg paravertebrally
3 Milligan1993 intra-op: 0.5% bupivacaine x 10mL into the wound, x 5mL
into the erector spinae muscle, an x5mL subcutaneously
4 Pobereskin2000b intra-op: 0.25% bupivacaine x 40 mL into the wound
5 Singhatanadgige2020 Intra-op: 0.5% bupivacaine x 20 mL and epinephrine 0.5 mg
in 0.5 mL prepared, 10mL given into cephalad and caudal
facet joints at the same level of procedure under
fluoroscopy before incision then 10.5 mL injected into skin
64
and subcutaneous and thoracolumbar fascia intraoperatively
before wound closure
6 Wang2020 Pre-op: skin infiltration with 2 mL of 0.9% saline
Intra-op: 0.25% ropivacaine x 40 mL in subcutaneous tissue
surrounding the skin incision
Post-op: diclofenac sodium suppository 50 mg and/or
parecoxib 50 mg IV
7 Yorukoglu2005 Intra-op: 0.25% bupivacaine x 30 mL paraspinally
Post-op: naproxen 75 mg PO PRN for VAS > 4
LA Infiltration w Adj (SS)

1 Kraiwattanapong2020 Intra-op: multimodal drug solution containing
levobupivacaine 100 mg, morphine 5 mg, ketorolac
tromethamine 30 mg, and epinephrine (1:1000) 0.25 mg
mixed with normal saline to total volume of 50 mL infiltrated
subcutaneously around the wound (30 mL) and for
paraspinal muscles bilaterally (20 mL)
2 Singhatanadigige2020 Intra-op: multimodal drug solution containing bupivacaine
92.5 mg, ketorolac 30 mg, morphine 5 mg, and epinephrine
0.5 mg in 20.5 mL solution, 10mL given into cephalad and
caudal facet joints at the same level of procedure under
fluoroscopy before incision then 10.5 mL injected into skin
and subcutaneous and thoracolumbar fascia intraoperatively
before wound closure
Neuraxial Opioid (SS)

1 Dhaliwal2019 Intra-op: morphine 0.2mg intrathecal
2 Guilfoyle2012 Intra-op: fentanyl 100 mcg epidural space
3 Wang2020 Pre-op: skin infiltrated with 2 – 3 mL of 1% lidocaine, 0.2 mg
of morphine administered intrathecally
Intra-op: 0.25% ropivacaine x 40 mL in subcutaneous tissue
surrounding the skin incision
Post-op: diclofenac sodium suppository 50 mg and/or
parecoxib 50 mg IV
4 Yorukoglu2005 Intra-op: morphine 2 mg epidural space
Post-op: naproxen 75 mg PO PRN for VAS >4
65
10 Funnel plot
10.1 Pharmacological Intervention
10.1.1 24h opioid consumption
When listed from most effective intervention to least effective intervention
P = 0.6571 (Egger)
66
10.1.2 24h pain score
p = 0.9267 (Egger)
67
10.2 Regional Intervention
10.2.1 24h opioid consumption
p = 0.3545 (Egger)
68
p = 0.0903 (Egger)
69
11 League Table
11.1 Head-to-head comparison for reduction in pain score (orange) and total intravenous morphine equivalent
consumption (mg) (green) at postoperative 24 hours of pharmacological agent combinations.
-2.12 -7.43 -7.36 -6.71 -7.90 -8.35 -9.19 -8.88 -9.52 -14.34 -14.58 -15.51 -16.27 -16.83 -18.08 -28.36 -25.74 -29.27
Control (-19.27 (-13.24 (-16.88 (-24.21 (-25.02 (-26.56 (-21.43 (-27.65 (-21.29 (-20.39 (-25.95 (-25.35 (-28.15 (-29.15 (-24.50 (-52.74 (-39.03 (-47.45
to 14.99) to -1.61) to 2.17) to 10.83) to 9.31) to 9.80) to 3.12) to 9.88) to 2.18) to -8.49) to -3.18) to -5.80) to -4.23) to -4.43) to -11.76) to -3.95) to -12.43) to -11.17)
-0.00 -5.31 -5.25 -4.59 -5.78 -6.24 -7.07 -6.77 -7.41 -12.22 -12.46 -13.40 -14.15 -14.72 -15.97 -26.25 -23.63 -27.15
(-1.12 Dulox (-23.40 (-24.85 (-29.07 (-30.05 (-31.27 (-28.17 (-32.14 (-28.09 (-30.48 (-33.01 (-33.21 (-34.93 (-35.80 (-34.26 (-56.02 (-45.28 (-52.16
to 1.12) to 12.79) to 14.38) to 19.89) to 18.46) to 18.78) to 14.08) to 18.69) to 13.38) to 5.83) to 8.16) to 6.21) to 6.83) to 6.38) to 2.31) to 3.66) to -1.96) to -2.35)
1.08 1.08 0.06 0.72 -0.47 -0.93 -1.76 -1.46 -2.10 -6.91 -7.15 -8.09 -8.84 -9.41 -10.66 -20.94 -18.32 -21.84
(0.64 (-0.13 Para (-11.06 (-17.67 (-18.50 (-20.03 (-15.32 (-21.08 (-15.08 (-14.23 (-19.87 (-19.06 (-19.22 (-20.25 (-19.25 (-44.64 (-30.30 (-40.47
to 1.51) to 2.28) to 11.22) to 19.19) to 17.70) to 18.14) to 11.90) to 18.19) to 10.87) to 0.23) to 5.65) to 2.73) to 1.67) to 1.52) to -2.16) to 2.83) to -6.34) to -3.32)
0.22 0.23 -0.85 0.66 -0.53 -0.99 -1.82 -1.52 -2.16 -6.97 -7.22 -8.15 -8.90 -9.47 -10.72 -21.00 -18.38 -21.91
Gaba
(-0.41 (-1.07 (-1.62 (-19.18 (-20.22 (-21.53 (-17.34 (-22.54 (-17.29 (-18.20 (-21.81 (-21.83 (-24.15 (-25.07 (-20.83 (-47.20 (-34.78 (-42.43
(Low)
to 0.85) to 1.50) to -0.09) to 20.70) to 19.18) to 19.51) to 13.76) to 19.56) to 12.89) to 4.06) to 7.38) to 5.40) to 6.43) to 6.14) to -0.70) to 5.23) to -1.99) to -1.56)
0.50 0.50 -0.58 0.27 -1.19 -1.65 -2.48 -2.18 -2.81 -7.63 -7.87 -8.81 -9.56 -10.13 -11.38 -21.66 -19.03 -22.56
(-0.80 (-1.21 (-1.94 (-1.16 Dexa (-25.71 (-26.89 (-23.88 (-27.86 (-23.85 (-26.20 (-28.73 (-28.91 (-30.67 (-31.49 (-30.05 (-51.64 (-41.08 (-47.76
to 1.79) to 2.21) to 0.79) to 1.72) to 23.27) to 23.47) to 18.91) to 23.51) to 18.20) to 10.76) to 13.04) to 11.18) to 11.64) to 11.33) to 7.18) to 8.37) to 2.95) to 2.47)
0.15 0.15 -0.93 -0.07 -0.35 -0.46 -1.29 -0.99 -1.62 -6.44 -6.68 -7.61 -8.37 -8.93 -10.18 -20.46 -17.84 -21.37
(-0.90 (-1.38 (-2.06 (-1.29 (-2.01 Naloxone (-25.47 (-22.42 (-26.51 (-22.51 (-24.73 (-27.24 (-27.48 (-29.24 (-30.05 (-28.60 (-50.25 (-39.58 (-46.45
-0.17 -0.16 -1.24 -0.39 -0.66 -0.32 -0.83 -0.53 -1.17 -5.98 -6.22 -7.16 -7.91 -8.48 -9.73 -20.01 -17.39 -20.91
(-1.44 (-1.86 (-2.59 (-1.81 (-2.48 (-1.97 Nefopam (-22.75 (-26.68 (-22.83 (-25.23 (-27.68 (-27.86 (-29.62 (-30.43 (-29.01 (-50.38 (-39.93 (-46.70
-0.12 -0.12 -1.20 -0.34 -0.62 -0.27 0.05 0.30 -0.33 -5.15 -5.39 -6.33 -7.08 -7.65 -8.90 -19.18 -16.55 -20.08
Ketamine
(-3.16 (-3.36 (-4.25 (-3.45 (-3.93 (-3.48 (-3.26 (-22.13 (-17.37 (-18.95 (-22.17 (-22.17 (-24.17 (-25.03 (-22.80 (-46.52 (-34.66 (-42.06
(Intraop)
0.95 0.95 -0.12 0.73 0.45 0.80 1.12 1.07 -0.64 -5.45 -5.69 -6.63 -7.38 -7.95 -9.20 -19.48 -16.86 -20.38
(0.01 (-0.51 (-1.16 (-0.40 (-1.14 (-0.61 (-0.47 (-2.12 Lido (-22.82 (-25.24 (-27.59 (-27.87 (-29.71 (-30.39 (-29.05 (-50.18 (-39.90 (-46.67
0.55 0.55 -0.53 0.33 0.05 0.40 0.72 0.67 -0.40 -4.82 -5.06 -5.99 -6.74 -7.31 -8.56 -18.84 -16.22 -19.75
(-0.24 (-0.83 (-1.42 (-0.68 (-1.46 (-0.91 (-0.79 (-2.49 (-1.63 A2A (-17.99 (-21.35 (-19.34 (-23.32 (-24.21 (-21.94 (-45.74 (-33.89 (-41.38
1.12 1.12 0.05 0.90 0.62 0.97 1.29 1.24 0.17 0.57 -0.24 -1.17 -1.93 -2.50 -3.75 -14.03 -11.40 -14.93
(0.77 (-0.05 (-0.44 (0.19 (-0.71 (-0.13 (-0.03 (-1.84 (-0.83 (-0.28 NSAID (-12.87 (-12.45 (-14.51 (-15.43 (-12.04 (-38.74 (-25.31 (-32.04
0.84 0.84 -0.24 0.61 0.34 0.69 1.00 0.96 -0.11 0.29 -0.28 -0.93 -1.69 -2.25 -3.50 -13.78 -11.16 -14.69
NSAID-
(0.18 (-0.46 (-1.02 (-0.28 (-1.11 (-0.55 (-0.43 (-2.17 (-1.26 (-0.74 (-1.03 (-16.04 (-18.14 (-18.97 (-15.71 (-40.60 (-28.67 (-36.16
Gaba
1.79 1.79 0.71 1.56 1.29 1.63 1.95 1.90 0.83 1.23 0.66 0.95 Ketamine -0.75 -1.32 -2.57 -12.85 -10.23 -13.76
(1.21 (0.52 (0.07 (0.71 (-0.13 (0.44 (0.55 (-1.20 (-0.27 (0.31 (0.04 (0.07 (Pos (-15.68 (-16.61 (-14.19 (-38.67 (-26.33 (-34.27
to 2.36) to 3.04) to 1.36) to 2.42) to 2.70) to 2.83) to 3.35) to 4.99) to 1.95) to 2.16) to 1.27) to 1.82) top) to 14.54) to 14.20) to 9.09) to 13.32) to 6.01) to 6.80)
1.58 1.58 0.50 1.35 1.08 1.42 1.74 1.69 0.62 1.02 0.45 0.74 -0.21 -0.57 -1.82 -12.10 -9.47 -13.00
(0.80 (0.22 (-0.15 (0.36 (-0.43 (0.12 (0.25 (-1.45 (-0.59 (-0.07 (-0.36 (-0.28 (-1.12 Para-Adj (-13.10 (-15.41 (-36.53 (-22.67 (-34.44
1.41 1.41 0.33 1.18 0.91 1.25 1.57 1.52 0.45 0.85 0.28 0.57 -0.38 -0.17 -1.25 -11.53 -8.91 -12.44
(0.59 (0.02 (-0.41 (0.15 (-0.62 (-0.08 (0.06 (-1.64 (-0.79 (-0.27 (-0.58 (-0.49 (-1.34 (-0.97 Para-NSAID (-15.23 (-32.64 (-17.09 (-34.02
to 2.22) to 2.79) to 1.08) to 2.22) to 2.45) to 2.58) to 3.09) to 4.65) to 1.70) to 1.99) to 1.14) to 1.61) to 0.58) to 0.62) to 12.48) to 9.56) to -0.81) to 8.98)
0.83 0.83 -0.25 0.60 0.33 0.68 0.99 0.94 -0.13 0.28 -0.30 -0.01 -0.96 -0.75 -0.58 -10.28 -7.66 -11.19
Gaba
(0.46 (-0.36 (-0.81 (-0.08 (-1.01 (-0.43 (-0.34 (-2.14 (-1.13 (-0.59 (-0.79 (-0.71 (-1.63 (-1.61 (-1.47 (-35.45 (-22.29 (-30.28
(High)
to 1.20) to 2.01) to 0.32) to 1.30) to 1.68) to 1.79) to 2.32) to 4.01) to 0.89) to 1.15) to 0.19) to 0.69) to -0.28) to 0.11) to 0.32) to 15.04) to 7.11) to 7.83)
1.43 1.43 0.35 1.20 0.93 1.27 1.59 1.54 0.47 0.87 0.30 0.59 -0.36 -0.15 0.02 0.60 Para- 2.62 -0.91
(0.55 (0.00 (-0.56 (0.13 (-0.63 (-0.08 (0.05 (-1.63 (-0.80 (-0.30 (-0.63 (-0.51 (-1.39 (-1.21 (-0.93 (-0.35 NSAID- (-20.04 (-31.09
to 2.31) to 2.85) to 1.27) to 2.29) to 2.49) to 2.64) to 3.14) to 4.70) to 1.77) to 2.06) to 1.24) to 1.68) to 0.68) to 0.91) to 0.99) to 1.55) Gaba to 25.21) to 29.10)
2.28 2.28 1.20 2.05 1.78 2.13 2.44 2.40 1.32 1.73 1.16 1.44 0.49 0.70 0.87 1.45 0.85 -3.53
Para-
(1.42 (0.87 (0.43 (0.99 (0.23 (0.77 (0.91 (-0.78 (0.06 (0.57 (0.26 (0.36 (-0.49 (-0.12 (0.38 (0.52 (-0.18 (-25.61
NSAID-Adj
1.06 1.06 -0.02 0.84 0.56 0.91 1.23 1.18 0.11 0.51 -0.06 0.22 -0.72 -0.52 -0.34 0.23 -0.36 -1.22 NSAID-Adj
(-0.03 (-0.50 (-1.16 (-0.42 (-1.13 (-0.60 (-0.45 (-2.06 (-1.33 (-0.83 (-1.10 (-1.05 (-1.93 (-1.83 (-1.69 (-0.91 (-1.76 (-2.58
to 2.16) to 2.63) to 1.14) to 2.11) to 2.26) to 2.43) to 2.91) to 4.41) to 1.56) to 1.86) to 0.98) to 1.50) to 0.48) to 0.81) to 1.01) to 1.38) to 1.03) to 0.16) BPN
0.86 0.86 -0.22 0.64 0.36 0.71 1.03 0.98 -0.09 0.31 -0.26 0.02 -0.92 -0.71 -0.54 0.03 -0.56 -1.42 0.20 Ket
(-0.19 (-0.67 (-1.35 (-0.59 (-1.31 (-0.78 (-0.63 (-2.25 (-1.51 (-1.01 (-1.38 (-1.22 (-2.13 (-2.03 (-1.88 (-1.09 (-1.94 (-2.77 (-1.32 (Intraop) -
to 1.91) to 2.40) to 0.93) to 1.87) to 2.03) to 2.19) to 2.68) to 4.19) to 1.32) to 1.63) to 0.84) to 1.26) to 0.27) to 0.59) to 0.79) to 1.15) to 0.80) to -0.06) to 1.72) Adj
70
Morphine equivalent Pain Score Comparison
Legend: Drugs are reported in the order of worst to best (i.e., right to left) for reduction in morphine equivalent dose reduction. Data is shown as mean differences and 95% credible intervals in the
column-defining treatment compared with row-defining treatment.
For morphine equivalent consumption (green), negative values (i.e., values < 0) favour the column defining treatment combination. For pain score (orange), positive valves (i.e., values > 0) favour the
row-defining treatment combination. Significant results are in bold, underscored and in deeper color.
Abbreviation: Dulox = duloxetine; Para = paracetamol; Gaba (Low) = gabapentinoid (low dose); Nal = naloxone; A2A = alpha-2 agonist; Lido = lidocaine infusion; Para – Adj = paracetamol with adjunct;
NSAID = non-steroidal anti-inflammatory drug; Ketamine (intraop) = intraoperative ketamine infusion; Para – NSAID = paracetamol and NSAID; Ketamine (Postop) = postoperative ketamine infusion;
NSAID – Adj = NSAID with adjunct; Gaba (High) = high dose gabapentinoid; Para – NSAID – Adj = paracetamol, NSAID, and Adjunct.
71
11.2 Head-to-head comparison for reduction in pain score (orange) and total intravenous morphine equivalent
consumption (mg) (green) at postoperative 24 hours of regional interventions.
No Regional -4.29 (-10.72 to -2.01 (-15.23 to -9.99 (-22.62 to -10.28 (-18.68 to - -11.68 (-24.37 to -8.06 (-17.60 to -5.00 (-11.56 to
Intervention 2.04) 11.24) 2.61) 1.86) 0.94) 1.41) 1.66)
0.13 (-0.82 to 2.28 (-12.34 to -5.71 (-19.79 to -5.99 (-13.90 to -7.39 (-21.55 to -3.78 (-13.22 to -0.71 (-9.78 to
LA Infiltration (SS)
1.08) 17.01) 8.42) 2.06) 6.77) 5.75) 8.56)
0.09 (-1.37 to -0.04 (-1.78 to
LA Infiltration (C)
1.55) 1.70)
0.30 (-1.06 to 0.17 (-1.48 to 0.21 (-1.79 to -7.99 (-26.27 to -8.27 (-23.95 to -9.67 (-28.03 to -6.06 (-22.38 to -2.99 (-17.79 to
Epidural LA (SS)
1.67) 1.84) 2.21) 10.29) 7.38) 8.53) 10.24) 11.84)
0.47 (-0.84 to 0.34 (-1.27 to 0.38 (-1.59 to 0.17 (-1.73 to Epidural LA with -0.29 (-15.40 to -1.68 (-19.50 to 1.93 (-13.91 to 5.00 (-9.18 to
1.80) 1.96) 2.35) 2.06) Adjunct (SS) 14.87) 16.02) 17.73) 19.24)
0.62 (-0.33 to 0.49 (-0.86 to 0.53 (-1.11 to 0.32 (-1.36 to 0.15 (-1.48 to Epidural LA with
1.56) 1.83) 2.15) 1.97) 1.76) Adjunct (C)
0.88 (-0.24 to 0.75 (-0.43 to 0.79 (-1.06 to 0.58 (-1.21 to 0.41 (-1.33 to 0.26 (-1.20 to Neuraxial Opioid -1.40 (-16.66 to 2.22 (-9.56 to 5.28 (-5.35 to
1.98) 1.92) 2.61) 2.32) 2.12) 1.71) (SS) 13.74) 13.85) 15.97)
0.92 (-0.48 to 0.79 (-0.90 to 0.83 (-1.19 to 0.63 (-1.00 to 0.45 (-1.46 to 0.30 (-1.39 to 0.04 (-1.74 to Epidural Steroid 3.61 (-12.14 to 6.68 (-7.52 to
2.39) 2.54) 2.90) 2.29) 2.43) 2.06) 1.90) (SS) 19.48) 21.03)
1.33 (-0.19 to 1.20 (-0.31 to 1.23 (-0.87 to 1.03 (-1.02 to 0.86 (-1.16 to 0.70 (-1.07 to 0.44 (-1.32 to 0.40 (-1.71 to LA Infiltration with 3.07 (-8.45 to
2.86) 2.72) 3.35) 3.07) 2.88) 2.51) 2.25) 2.47) Adjunct (SS) 14.70)
1.51 (-0.28 to 1.30 (-0.43 to 1.13 (-0.55 to 0.98 (-0.41 to 0.72 (-0.78 to 0.68 (-1.11 to 0.27 (-1.57 to Fascial Plane Block
1.60 (0.57 to 2.62) 1.47 (0.06 to 2.86)
3.29) 2.99) 2.79) 2.38) 2.23) 2.40) 2.10) (SS)
1.78 (-0.25 to 1.38 (-0.69 to 1.10 (-0.62 to
2.70 (1.31 to 4.10) 2.57 (0.89 to 4.26) 2.61 (0.59 to 4.63) 2.40 (0.45 to 4.35) 2.23 (0.30 to 4.15) 2.08 (0.40 to 3.78) 1.82 (0.05 to 3.62) Epidural LA (C)
3.75) 3.44) 2.85)
Morphine equivalent Pain Score Comparison
Legend: Drugs are reported in the order of worst to best (i.e. right to left) for reduction in morphine equivalent dose reduction. Data is shown as mean differences and 95% credible intervals in the
column-defining treatment compared with row-defining treatment.
For morphine equivalent consumption (green), negative values (i.e. values < 0) favour the column defining treatment combination. For pain score (orange), positive valves (i.e. values > 0) favour the
row-defining treatment combination. Significant results are in bold, underscored and in deeper color.
NB: None of the studies identified in this review compared total morphine consumption in 24 hours for continuous epidural anesthesia against other regional intervention or no intervention.
Abbreviation: SS = Single shot; C= Continuous infusion
72
12. Analysis of all trials
12.1 Pharmacological Interventions
Probability table
73
SUCRA
Intervention SUCRA
1 NSAID with Adjunct 90.36
2 Paracetamol NSAID with 88.6
Adjunct
Paracetamol NSAID and Gaba 85.73
4 Gabapentinoid High dose 72.33
5 Paracetamol and NSAID 64.61
6 Paracetamol with Adjunct 63.38
7 Ketamine Infusion (Postop) 61.78
8 NSAID and Gabapentinoid 57.83
9 NSAID 57.56
10 Alpha 2 Agonist 39.07
11 Lidocaine Infusion 38.83
12 Ketamine Infusion (Intraop) 38.22
13 Nefopam 37.08
14 Naloxone 35.41
15 Dexamethasone 31.91
16 Gabapentinoid Low dose 30.9
17 Paracetamol 29.35
18 Duloxetine 19.43
19 Control 7.61
74
Probability curve
75
Probability Table
76
SUCRA
RANK Intervention SUCRA
1 Paracetamol NSAID with 97.69
Adjunct
2 Ketamine Infusion (Postop) 89.03
3 Paracetamol with Adjunct 81.73
4 Paracetamol NSAID and Gaba 75.2
5 Paracetamol and NSAID 74.58
6 NSAID 64.09
7 Paracetamol 60.75
8 Buprenorphine Patch 59.24
9 Lidocaine Infusion 54.89
10 Ketamine Inf (Intraop) w Adj 50.8
11 NSAID and Gabapentinoid 49.3
12 Gabapentinoid (High dose 47.85
13 Dexamethasone 36.51
14 Alpha 2 Agonist 36.46
15 Ketamine Infusion (Intraop) 28.43
16 Gabapentinoid (Low dose 23.08
17 Naloxone 22.63
18 Duloxetine 18.42
19 Nefopam 15.26
20 Control 14.08
77
Probability curve
78
Probability Table
SUCRA
Rank Intervention SUCRA
1 Epidural Steroid (SS) 76.52
2 Neuraxial Opioid (SS) 75.3
3 Epidural LA with Adjunct (SS) 70.13
4 LA Infiltration with Adjunct (SS) 61.88
5 Fascial Plane Block (SS) 42.68
6 LA Infiltration (SS) 36.47
7 Epidural LA (SS) 27.9
8 No Regional Intervention 9.14
79
Probability curve
80
Probability Table
SUCRA
Rank Intervention SUCRA
1 Epidural LA (C) 97.07
2 Fascial Plane Block (SS) 80.39
3 LA Infiltration with Adjunct (SS) 70.45
4 Epidural Steroid (SS) 57.37
5 Neuraxial Opioid (SS) 57.2
6 Epidural LA with Adjunct (C) 46.87
7 Epidural LA with Adjunct (SS) 40.03
9 LA Infiltration (C) 26.18
11 No Regional Intervention 16.87
81
Probability curve
82
13 Pair-wise Comparison
R read the data as “Experimental” vs. “Control”
Intervention with single direct comparison not shown
13.1 Pharmacological Intervention: 24 hr opioid consumption

Control vs Alpha-2 Agonist
Ketamine Infusion (postop) vs. Alpha-2 Agonist
Control vs. Dexamethasone
83
Control vs. Duloxetine
Control vs. Gabapentinoid (High dose)
Control vs. Gabapentinoid (Low dose)
84
Control vs. Ketamine Infusion (Intraop)
Control vs. Ketamine Infusion (Postop)
Control vs. Lidocaine Infusion
85
Control vs. Naloxone
Control vs. Nefopam
Control vs. NSAID
86
Control vs. NSAID and Gabapentinoid
Control vs. Paracetamol
Gabapentinoid (Low dose) vs Gabapentionid (High dose)
87
Gabapentinoid (High dose) vs. NSAID
Gabapentinoid (High dose) vs. NSAID and Gabapentinoid
Paracetamol vs Ketamine Infusion (Postop)
NSAID vs. NSAID with Adjunct
88
NSAID vs. Paracetamol
Paracetamol and NSAID vs. Paracetamol, NSAID, and Gabapentinoid
Paracetamol and NSAID vs. Paracetamol NSAID with Adjunct
89
Paracetamol and NSAID vs Paracetamol with Adjunct
Paracetamol with Adjunct vs Paracetamol NSAID with Adjunct
Paracetamol vs Paracetamol and NSAID
90
Paracetamol vs Paracetamol NSAID with adjunct
Paracetamol vs Paracetamol with Adjunct
91
13.2 Pharmacological Intervention: 24h pains score
Control vs. Alpha-2 Agonist
Ketamine Infusion (Postop) vs. Alpha-2 Agonist
NSAID vs. Buprenorphine Patch
Control vs. Dexamethasone
92
Control vs. Duloxetine
Control vs. Gabapentinoid (High dose)
Control vs. Gabapentinoid (Low dose)
Control vs. Ketamine Infusion (Intraop) w Adj
Control vs. Ketamine Infusion (Intraop)
93
Control vs. Ketamine Infusion (Postop)
Control vs. Lidocaine Infusion
Control vs. Naloxone
Control vs. Nefopam
Control vs. NSAID
94
Control vs. NSAID and Gabapentinoid
Control vs. Paracetamol
Control vs. Paracetamol NSAID and Gaba
Gabapentinoid (Low dose) vs. Gabapentinoid (High dose)
Gabapentinoid (High dose) vs. NSAID
95
Gabapentinoid (High dose) vs. NSAID and Gabapentinoid
NSAID vs. Ketamine Infusion (Postop)
Paracetamol vs. Ketamine Infusion (Postop)
NSAID vs Paracetamol
Paracetamol and NSAID vs. Paracetamol NSAID and GABA
96
Paracetamol and NSAID vs Paracetamol, NSAID with Adjunct
Paracetamol and NSIAD vs Paracetamol with Adjunct
Paracetamol vs Paracetamol and NSAID
Paracetamol vs. Paracetamol NSAID with Adjunct
Paracetamol vs. Paracetamol with Adjunct
97
13.3 Regional Intervention: Opioid Consumption
No Regional Intervention vs. Epidural LA (SS)
No Regional Intervention vs. Epidural LA with Adjunct (SS)
No Regional Intervention vs. Epidural Steroid (SS)
No Regional Intervention vs. Fascial Plane Block (SS)
LA Infiltration (SS) vs. LA Infiltration with Adjunct (SS)
98
LA Infiltration (SS) vs. Neuraxial Opioid (SS)
No Regional Intervention vs. LA Infiltration (SS)
LA Infiltration with Adjunct (SS) vs No Regional Intervention
Neuraxial Opioid (SS) vs No Regional Intervention
99
13.4 Regional Intervention: 24h pain score
No Regional Intervention vs. Epidural LA (C)
Epidural Steroid (SS) vs. Epidural LA (SS)
No Regional Intervention vs. Epidural LA (SS)
LA Infiltration (C) vs. Epidural LA with Adjunct (C)
No Regional Intervention vs. Epidural LA with Adjunct (C)
100
No Regional Intervention vs. Epidural LA with Adjunct (SS)
No Regional Intervention vs. Epidural Steroid (SS)
No Regional Intervention vs. Fascial Plan Block (SS)
101
LA Infiltration (C) vs. No regional Intervention
LA Infiltration with Adjunct (SS) vs LA Infiltration (SS)
LA Infiltration (SS) vs. Neuraxial Opioid (SS)
No Regional Intervention vs. LA Infiltration (SS)
LA Infiltration with Adjunct (SS) vs. No Regional Intervention
102
No Regional Intervention vs. Neuraxial Opioid (SS)
103
14 Testing Fixed vs Random Model
14.1.1 24h total opioid consumption
104
14.2.1 24h total opioid consumption
105
15 Consistency
15.1.1 24hour total opioid consumption
106
Node splitting
107
15.1.2 24hour pain score
108
Node splitting
109
110
111
Node splitting
112
113
Node splitting
114
16 Network Characteristics
115
116
117
16.2 Regional Interventions
118
16.2.2 24hour pain score
119

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Supplementary Information

The efficacy of perioperative

2 Department of Anaesthesia, University of Jeddah, Jeddah, Saudi Arabia

3 Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada

2.2 Total opioid consumption in 24 hours

2.3 24h Pain score

2.4 Data extraction and conversion

Median and interquartile range (IQR)

Calculation for mean:

Calculation for standard deviation:

Calculation for mean:

Calculation for standard deviation

Combining mean and standard deviation

2.5 Pre-operative, Intra-operative, and post-operative

The overall risk of bias does not include information bias.

Random Adequate Incomplete

Boenigk2019 Low Low Low Low Low Low Low High

Cakan2008 Low Low Low Low Low Low Low High

Chang2013 Low Low Low Low Low Low Low High

Cohen1997 Low Low Low Low Low Low Low Low

Eiamcharoenwit2020 Low Low Low Low Low Low Low High

Ezhevskaya2019 Low Low High High Low Low High Low

Farag2013 Low Low Low Low Low Low Low High

Farmery2009 Low Low Low Low Low Low Low High

Fujita2016 Low Low Low Low Low Low Low High

Govil2020 Low Low Low Low Low Low Low Low

Hadi2009 Low Low Low Low Low Low Low Low

Hans1993 Low Low Low Low Low Low Low Low

Hernandez-Palazon2001 Low Low Low Low Low Low Low High

Hurlbert1999 Low Low Low Low Low Low Low High

Ibrahim2018 Low Low Low Low Low Low Low Low

Javaherforooshzadeh2018 Low Low Low Low Low Low Low Low

Jirarattanaphochai2008 Low Low Low Low Low Low Low Low

Kang2013 Low Low Low Low Low Low Low High

Khajavi2013 Low Low Low Low Low Low Low High

Khajavikhan2016 Low Low Low Low Low Low Low Low

Khan2011 Low Low Low Low Low Low Low Low

Kien2019 Low Low Low Low Low Low Low Low

Kim2016b Low Low High High Low Low High Low

Kraiwattanapong2020 Low Low Low Low Low Low Low High

Lotfinia2007 Low Low Low Low Low Low Low Low

Mariappan2015 Low Low Low Low Low Low Low Low

Nikooseresht2016 Low Low High High Low Low High Low

Ozgencil2011 Low Low Low Low Low Low Low Low

Pandey2004 Low Low Low Low Low Low Low Low

Pandey2005 Low Low Low Low Low Low Low Low

Park2016 Low Low High High Low Low High High

Pobereskin2000a Low Low Low Low Low Low Low Low

Pobereskin2000b Low Low Low Low Low High High Low

Polat2015 Low Low Low Low Low Low Low Low

ServiclKuchler2014 Low Low Low Low Low Low Low High

Song2013 Low Low Low Low Low Low Low Low

Spreng2011 Low Low Low Low Low Low Low High

Ueshima2019 Low Low Low Low Low Low Low High

Vasigh2016 Low Low Low Low Low Low Low Low

Vasigh2016b Low Low Low Low Low Low Low Low

Xu2017 Low Low High High Low Low High High

Yamauchi2008 Low Low Low Low Low Low Low High

Zarei2016 Low Low Low Low Low Low Low Low

4.2 Summary of Risk of Bias

Alpha-2 Agonist 100

Pharmacological Intervention: 24h pain score