Characteristics of included studies [ordered by study ID]

Albi-Feldzer 2013
Methods	Triple-blinded (participant, provider, outcome assessor) clinical RCT Assignments were computer-generated Follow-up: 1 year
Participants	Participants: 260 women aged 18–85 from 4 cancer hospitals in France Operation: breast cancer surgery (both breast-conserving and mastectomy with or without axillary or sentinel node dissection) 2 groups, size: 117/119 Age(±SD):56 (±12), 57 (±13) Men/women: 0/117, 0/119 Patient co-morbidities: breast-conserving surgery with axillary lymph node dissection, group 1, 2 (± SD) 53 (± 45.3), 62 (± 52.1), mastectomy with axillary lymph node dissection or sentinel lymph node dissection, group 1, 2 (± SD): 53 (± 45.3), 48 (± 40.3), mastectomy without axillary lymph node dissection or sentinel lymph node dissection, group 1, 2 (± SD): 11 (± 9.4), 9 (± 7.6)
Interventions	Group 1 (ropivacaine): at end of surgery before suturing, 3 mL-4 mL infiltration of 0. 375% ropivacaine along each site of SC and deep layers of breast and axillary incisions, 2nd and 3rd intercostal space, humeral insertion of major pectoralis (received 3 mg/kg of 0.375% ropivacaine) Group 2 (saline): at end of surgery before suturing, 3 mL-4 mL infiltration of saline along each site of SC and deep layers of breast and axillary incisions, 2nd and 3rd intercostal space, humeral insertion of major pectoralis (receive 0.8 mL/kg saline Both groups: premedicated with oral hydroxyzine (2 mg/kg) 1 h before surgery. GA induction with propofol, sufentanil, maintenance with nitrous oxide in O2, sevoflurane or desflurane, sufentanil bolus as required. Post-op pain control with oral paracetamol and ketoprofen and rescue with morphine PCA for 24 h (bolus dose 1 mg on demand, lockout 5 min). Ondanestron 4 mg for nausea/vomiting +/- droperidol 1.25 mg every 8 h Adjuvants: none Immdiate post-op pain control: significantly improved
Outcomes	Dichotomous: pain/no pain at 3 months only Continuous: BPI score at 3, 6, 12 months Other reported: neuropathic pain score, hospital anxiety and depression score at 3, 6, 12 months
Notes	For dichotomous pain, BPI score of > 3 was used as cut off Funding sources: support was from institutional/departmental sources. The studyauthor responded to our request that “Astra Zeneca only paid the insurance for the study and Astra Zeneca had no role in conceiving the study, designing the protocol, executing the trial and or analysing and interpreting the results” Conflicts of interest: there were no other conflicts of interest to report
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “a balanced block stratified randomization scheme was used for patient allocation. Stratification was performed on the basis of hospital and type of surgery (conservative or not). Patients were randomized in randomly permuted blocks of four or six patients in each striatum. Assignments were computer generated”
Allocation concealment (selection bias)	Low risk	Quote: [Assignments were] “maintained in sequentially numbered, opaque, sealed en- velopes...the envelope was opened in an isolated room on the day of surgery, and patients were assigned to either the placebo group or the ropivacaine group”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “before induction of anaesthesia, an operating room nurse read the results of randomization to prepare the solution of normal saline or ropivacaine in identical syringes... The solution was prepared in an isolated room and the nurse did not have any further contact with the patient. No other physician or nursing staff member was aware of the contents”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “pain was evaluated by a nurse who was blinded to the treatment group”. Patients filled out questionnaires at inclusion and 3 months, 6 months and 1 year after surgery to evaluate chronic pain
Incomplete outcome data (attrition bias) All outcomes	Low risk	24 participants were excluded after randomization because of withdrawal of consent or failure to meet inclusion criteria. The groups to which these belonged was not reported, but there were fairly equal numbers in those that were included and received treatment (117 vs 119). At 3 months, there were 6 participants who were lost to follow-up or had missing outcome data in the ropivacaine group, and 11 participants lost to follow-up or with missing BPI data in the placebo group. these are low numbers when compared to the total studied population, and fairly balanced and reasons are listed for each group. No report on the exact number of participants with missing data at 6 or 12 months’ follow-up, only states ”The maximum percentage of missing data for each point (0, 3, 6, and 12 months) in both arms was less than 5% (range: 0%-5%). ITT was performed
Selective reporting (reporting bias)	Low risk	The primary and secondary outcomes listed in the protocol were all reported
Null bias	Low risk	Quote: “measurement of pain on the VAS showed lower scores at rest and during mobilization in the first 90 min after the end of surgery in the ropivacaine group than in the control group (P < 0.001)... Ropivacaine wound infiltration decreased immediate postoperative pain in the PACU and increased the percentage of pain-free patients (VAS = 0) for the first 48h”
Barkhuysen 2010
Methods	Double-blinded, clinical RCT Randomization scheme not described Follow-up: 1 year
Participants	Participants: 200 adults in a hospital setting in Nijmegen, Netherlands Operation: ICBG for cranio-maxillofacial surgery 2 groups, size: 100/100 Age (range): 56 (21–74), 57 (21–80) Men/women: 25/31, 14/28
Interventions	Group 1 (bupivacaine): intraop: after wound closure, participants received a single dose of bupivacaine (10 cc of 2.5 mg/mL bupivacaine with 1:80.000 epinephrine) Group 2 (control): no intervention given Adjuvants: epinephrine Immediate post-op pain control: no difference between VAS and post-op NSAID use between groups
Outcomes	Dichotomous: pain/no pain questionnaire at 1 year Continuous: none Other reported: use of paracetamol (Acetaminophen) and ibuprofen after surgery, duration of surgery, blood loss, and length of incision Adverse events: perforation of the lateral cortex of the iliac crest, haematoma
Notes	Financial support statement: “none.” Conflict of interest statement: “none declared”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomization scheme was not described
Allocation concealment (selection bias)	Low risk	Quote: “for each patient an envelope was drawn”
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding of participants and personnel were not described.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of the outcome assessors was not described.
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: “79 questionnaires were sent out. After exclusion of the incorrectly filled and nonreturned questionnaires, 58 remained forevaluation (59%).”
Selective reporting (reporting bias)	Low risk	No protocol available but all specified outcomes were reported on
Null bias	High risk	Quote: “No statistically significant differences in outcome were detected between these groups...”
Baudry 2008
Methods	Quadruple-blinded (participant, provider, surgeon, outcome assessor), randomized, placebo-controlled clinical trial Sequence generation by random number tables Follow-up: 1 year (effectively, in treatment group: 17 months, control group 15 months)
Participants	Participants: 96 women included (78 analysed), from 1 university hospital, Besancon, France Operation: breast cancer surgery (mastectomy and lumpectomy with sentinel node biopsy) 2 groups, size: 40/38 Age (groups 1, 2): 52.4 years (SD ± 11.2), 57.7 (SD ± 12.6) Only women
Interventions	Group 1 (postsurgicalbreastinfiltration): GA(sufentanil 0.3μg/kg), atwoundclosure single-shot local infiltration with ropivacaine (0.475%, 40 mL), post-op: paracetamol (1 g, intravenously, every 6 h), ketoprofen (100 mg, intravenously, every 12 h) rescue analgesic (ifVAS > 30/100) nalbuphine 0.2 mg/kg Group 2 (placebo postsurgical breast infiltration): GA (sufentanil 0.3 μg/kg), at wound closure single-shot placebo infiltration with normal saline (40 mL), post-op: paracetamol (1 g, intravenously, every 6 h), ketoprofen (100 mg, intravenously, every 12 h) rescue analgesic (ifVAS > 30/100) nalbuphine 0.2 mg/kg Adjuvants: none reported Immediate post-op pain control: analgesic rescue medication andVAS were not different between groups
Outcomes	Dichotomous: pain/no pain at 1 year (effectively at 17 months in the experimental and at 15 months in the control group) Continuous: McGill Questionnaire described, but results not reported Effective regional anaesthesia not reported, and treatment did not reduce the severity of immediate postoperative pain or the consumption of rescue pain medication
Notes	Article in French, extracted by authors Funding sources: none reported Conflicts of interest: no conflict of interest statement was provided
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomized with the use of a “randomization table”
Allocation concealment (selection bias)	Unclear risk	Participants were randomized “after inclusion”. Unclear how the allocation was concealed
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “the anaesthetist in charge, the surgeon, the investigator were blinded”. “The anaesthetic was administered with the patients anaesthetized”. “The solution was prepared by personnel not taking care of the patient”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “the investigator was blinded”. “The solution was prepared by personnel not taking care of the patient”
Incomplete outcome data (attrition bias) All outcomes	High risk	Significant attrition due to post hoc exclusion/lost participants and lost data that were reported but not analysed with ITT. Unclear how many participants were ini-tially randomized to which group, hence attrition cannot even be assessed. Participants initially excluded for missing data were later included for the 1-year analysis
Selective reporting (reporting bias)	Unclear risk	Primary outcomes fully reported on
Null bias	High risk	Quote: “au cours des 24 premières heures postopératoire, l’EVA a varié significativement au cours du temps...sans différence significative entre les deux groupes... Le nombre de patientes ayant eu recours au traitement antalgiue de secours et la dose de nalbuphine consummée n’était pas statistiquement différente entre les deux groupes”. Analogical visual scale pain score, antalgic consumption were similar between groups
Bell 2001
Methods	Double-blinded (participants, outcome assessors), placebo-controlled, clinical RCT Sequence generation randomized but not described Follow-up: 6 months
Participants	Participants: 8 adults in a university setting in Bergen, Norway Operation: bilateral reduction mammoplasty 2 groups, size: 8/8 Age: 28.5 years (range 18–34) Men/women: 0/8 Remarks: body sides, not participants randomized
Interventions	Breast group 1 (preop infiltration): GA (fentanyl), preincision: infiltration with li- docaine (0.5%, 100 mL with epinephrine 5 μg/mL), post-op as needed ketobemidone (oral, 5 mg) and paracetamol (1000 mg 3 × daily) Breast group 2 (placebo): GA (fentanyl), preincision: infiltration with normal saline (100 mL with epinephrine 5 μg/mL), post-op as needed ketobemidone (orally, 5 mg) and paracetamol (1000 mg 3 × daily) Adjuvants: none Immediate post-op pain control: significantly improved in treated breasts
Outcomes	Dichotomous: pain at 6 months Continuous: none reported Secondary: thermal thresholds were reported as tables, touch allodynia, or hyperalgesia
Notes	Some details, reported as graphs, are difficult to compare and extract. We acknowledge the study author’s response regarding sources of funding and conflict of interest statement Funding sources: the author informed us that this was an investigator-initiated study,supported by an unrestricted grant from Astra Zeneca initially to study the effects of ropivacaine. When the study authors could not obtain approval to study this drug, the company maintained their support. The study author wrote that “the results were analysed with the help of a statistician at Astra Zeneca... we were allowed to keep the equipment... and that Astra financed my travel to a conference...” Conflicts of interest: the author had “no conflict of interest... and did not receive any [other] salary or economic compensation from Astra Zeneca.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “patients’ breasts were randomized to test and control groups”, but the method was not described in detail
Allocation concealment (selection bias)	Unclear risk	Efforts to conceal allocation were not described. Bias is rather unlikely, because body sides, not participants were randomized
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “the procedure was performed double blind”, however blinding of participants and personnel not explicitly described
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: “the procedure was performed double blind”, however outcome assessor blinding not explicitly described
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawals and attrition reported as none, except one participant excluded for drug spillage. With only one withdrawal, body parts randomized not participants, even though no ITT analysis was performed, bias seems unlikely
Selective reporting (reporting bias)	Unclear risk	Quote: “some details, reported as graphs, are difficult to compare and extract”
Null bias	Low risk	Quote: “the sum of VAS scores for pain intensity was significantly lower in the lido- caine group than in the placebo group for the entire registration period of 10 h after wound closure”
Besic 2014
Methods	Double-blinded (patient/outcome assessor), RCT Sequence generation by a computer-based, random numbers generator Follow-up: 3 months
Participants	Participants: 120 women in a hospital setting in Ljubljana, Slovenia Operation: axillary lymphadenectomy and breast reconstruction Groups, size: 60/60 Age (lymphadenectomy, reconstruction): 60, 48 All female participants Comorbidities: none
Interventions	Group 1 (levobupivacaine): intraop: before wound closure, a fenestrated wound catheter was placed under the pectoralis major muscle and upon the entire length over the upper side of the wound. The wound catheter was fenestrated along 15 cm in the distal part. A bolus of 15 mL of 0.25% levobupivacaine was injected into the wound through the catheter immediately after wound closure. Surgical drains and the fenestrated catheter were clamped for 5 min to enable bolus absorption. Elastomeric pump was connected containing 100 mL of 0.25% levobupivacaine. Infusion at 2 mL/h was continuous for 50 h Group 2 (piritramide): intraop: continuous intravenous infusion with piritramide (30 mg), metoclopramide (20 mg) and metamizole (2.5 g) in 100 mL of 0.9% sodium chloride (3 mL/h-6 mL/h) until 24 h postoperatively Adjuvants: none Immediate post-op pain control: significantly improved, significantly reduced analgesic consumption
Outcomes	Continuous: none Dichotomus: overall pain/no pain at 3 months No adverse events reported
Notes	Study characteristics and data combined with Strazisar 2014. Axillary lymphadenectomy and breast reconstruction performed on 60 participants per procedure. Results from both procedures were combined to best represent pain outcomes Funding sources: financial support was not described. Conflicts of interest: no conflict of interest statement was provided
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “the research nurse performed randomization using random numbers generated by a computer...”
Allocation concealment (selection bias)	Low risk	Quote: “randomization and numbers were placed in sealed opaque envelopes to ensure concealment of allocation at enrollment”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “participants were randomly grouped”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “clinicians who recorded data about chronic pain were blinded about randomisation group of patients.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants completed the follow-up evaluation.
Selective reporting (reporting bias)	Low risk	No subgroup analysis or selective reporting was noted.
Null bias	Low risk	Quote: “a smaller portion of patients treated with local anesthetics had chronic pain in comparison to the control group.” “Chronic pain three months after operation is less frequent in the test group.”
Blumenthal 2005
Methods	Triple-blinded (participant, provider, outcome assessor) randomized placebo-controlled clinical trial Sequence generation via randomized list Follow-up: 3 months
Participants	Participants: 36 adult participants at a university clinic in Zurich, Switzerland Operation: Bakart repair for shoulder instability using autogenous bone graft, harvested from iliac crest 2 groups, size: 18/18 Age (± SD), group 1, 2: 25 (± 5), 26 (± 4) Men/women, group 1, 2: 14/4, 13/5 Comorbidities: none reported Remarks: autogenous bone harvested through lateral oblique incision just cephalic to anterior iliac crest using classical surgical technique
Interventions	Group 1 (ropivacaine): at end of surgery, bolus of 30 mL ropivacaine 0.5% via iliac crest catheter and in PACU, continuous infusion 0.2% ropivacaine at 5 mL/h started, continued for total of 48 h Group 2 (placebo): at end of surgery, bolus of 30 mL saline via iliac crest catheter, in PACU, continuous infusion saline 5 mL/h started, continued for total of 48 h Both groups: premedicated with midazolam 1 h before arrival to induction room, and interscalene brachial plexus block performed. GA with propofol, rocuronium and fentanyl. Autogenous bone harvested through lateral oblique incision cephalad to anterior iliac crest using classical surgical technique. Catheter placed in direct contact with self- resorbing foam pad dressing touching bone, tunnelled and secured to skin using sutures and adhesive dressing. In PACU, all participants also received continuous interscalene analgesia with 0.2% ropivacaine at 10 mL/h 6 h after initial block. Both groups got IV PCA containing 1 mg/mL morphine, 2 mg dose lockout interval 15, no baseline, or 4 h limit, with 2 mg IV morphine top up by nurse for VAS > 30. After discharge, 25 mg oral rofecoxib/d and 2 mg oral paracetamol as needed during 3 weeks post-op Adjuvants: none Immediate post-op pain control: pain significantly lower at the iliac crest donor site at rest (except at t40 h) and during motion (except at t48 h) in the ropivacaine group with significantly decreased morphine consumption at 24 h and 48 h
Outcomes	Dichotomous: none Continuous: VAS at rest and on motion at iliac crest at 3 months Other reported: post-op pain at shoulder and presence of numbness/paraesthesias/neu- rologic damage at 3 months Adverse events: post-op nausea/vomiting, pruritis, inflammation at catheter site
Notes	Interscalene block performed in both groups. Comparison of interest is ropivacaine vs placebo continuous infusion at iliac crest donor site Funding sources: “support was provided solely from institutional and/or departmental sources.” Conflicts of interest: no conflict of interest statement was provided
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “patients were given a number between 1 and 36...according to a randomization list”
Allocation concealment (selection bias)	Low risk	Quote: “patients were given a number between 1 and 36 by choosing a sealed envelope containing a number.. Each patient’s number was passed on to a pharmacist, who prepared the anaesthetic set (bolus and maintenance package) of either ropivacaine or placebo, according to a randomization list”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “double-blind study”. Participants, block performers/anaesthesiologists, postop providers all blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “all the patients were observed independently by a surgeon and an anaesthe- siologist 3 months after surgery to assess the pain (anaesthesiologist) at rest and during motion at the operated IC and operated shoulder”. Only pharmacy was aware of contents of anaesthetic set based on ran-domization list
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: “all patients completed the study. All interscalene catheters were successfully placed, and no disconnection or other technical problems were encountered during the course of the study”
Selective reporting (reporting bias)	Low risk	Primary outcomes fully reported on
Null bias	Low risk	Quote: “pain was significantly lower at the donor site at rest (except at t40hrs) and during motion (except at t48hrs) in the ropivacaine group”
Bollag 2012
Methods	Triple-blinded (participant, provider, outcome assessor) RCT Sequence generation with computer-generated list of random numbers Follow-up: 12 months
Participants	Participants: 90 healthy non-labouring pregnant women from Maternity Hospital in Sao Paulo, Brazil Operation: caesarean delivery, scheduled (under SA with Pfannenstiel incision) Three groups, size: 30/25/26 Age (± SD), group 1, 2, 3: 30.5 (± 6.7), 31.8 (± 4.5), 29.5 (± 6.7) Only female participants Comorbidities: previous caesarean delivery (%), group 1, 2, 3: 46/48/35. Gestational age in weeks, mean (± SD), group 1, 2, 3: 38 (± 1), 38 (± 1), 38 (± 1.5)
Interventions	Group 1 (placebo/control): TAP block with 20.5 mL 0.9% NaCL per side. Group 2 (bupivacaine TAP): TAP block with 20 mL bupivacaine 0.375% + 0.5 mL NaCl 0.9% per side Group 3 (bupivacaine + clonidine group): TAP block with 20 mL bupivacaine 0. 375% + 75 pg (0.5 mL) clonidine per side All TAP blocks were performed in PACU within 1 h post-op All groups: spinal anaesthetic with 12 mg hyperbaric bupivacaine, 25 pg fentanyl, 100 pg morphine. IV ketoralac at skin closure. Post-op analgesia: in PACU, IV morphine as needed; in postpartum unit paracetamol (1 g every 6 h standing) and diclofenac (75 mg every 8 h standing), with tramadol 50 mg as needed Adjuvants: clonidine (group 3 only) Immediate post-op pain control: significantly reduced morphine use in TAP groups compared to placebo in PACU but no change in resting pain scores Effective regional anaesthesia: reported. “Block success and dermatomal extent of the sensory analgesia were assessed bilaterally by pinprick after recovery from the spinal anaesthetic”
Outcomes	Dichotomous: pain/no pain at 3, 6, 12 months Continuous: short-form McGill Pain questionnaire at 3, 6 and 12 months
Notes	We contacted the study author who provided dichotomous pain data for 3, 6, and 12 months' follow-up Funding sources: no financial support was received for the study Conflicts of interest: “the authors declare no conflict of interest.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “a computer-generated list of random numbers was used (www.randomizer.org) for group allocation of the participants”
Allocation concealment (selection bias)	Low risk	Quote: “each woman was assigned a study number upon enrolment and received a TAP block with the corresponding numbered syringe. The allocation sequence was concealed from investigators and patients”. While it does not state method with which allocation was concealed, it states it was concealed thus little risk of bias
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “an investigator with no clinical involvement in the trial prepared the solutions following exact preparation guidelines. All syringes were labelled with the amount and concentrations of all possible contents, as well as a study number. Both operator [who performed TAP block] and patient were blinded to the study group.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “hyperalgesia was evaluated by the same research investigator (who was not involved in placement or evaluation of the TAP blocks in the PACU)”. “At 3, 6, and 12 months, telephone interviews were performed to assess development of chronic postoperative pain using the Short- Form McGill Pain Questionnaire 2 (SF- MPQ-2)”. While it does not explicitly state chronic pain assessment was performed by a blinded investigator, based on the other descriptions of how participants were assigned to groups and blinding was main-tained, it seems very unlikely the telephone interviewers knew which group they were assigned to
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: “five women from [group 2] and 4 women from [group 3] were excluded from the study because of block failure (absence of sensory block on the abdomen assessed by pinprick after recovery from the spinal anesthetic)”. No ITT analysis was performed, onlyper-protocol. Flowdi- agram depicts loss of follow-up for each group at 3-, 6-, 12-month periods, with 2 participants in the control, 6 participants in [group 2] and 5 participants in [group 3] lost at 12 months, and fewer in each group at 3 and 6 months. SF-36 survey reports “return rate” at each time point in terms of percent but does not provide raw numbers. Discordance between flow diagram and numbers included in analysis in neuropathic pain descriptors (table 4)
Selective reporting (reporting bias)	Low risk	Protocol reviewed and primary outcomes fully reported on
Null bias	High risk	Quote: “the incidence of wound hyperalgesia and the WHI were similar among groups at 24 hours (Fig. 2). At 48 hours, the incidence of wound hyperalgesia was not different among groups”
Brown 2004
Methods	Triple-blinded (participant, provider, outcome assessor) clinical RCT Sequence via computer-generated list Follow-up: 3 months
Participants	Participants: 100 men at university hospital in Minnesota, USA Operation: elective radical retropubic prostatectomy 2 groups, size: 50/49 (completed) Age ± SD (group 1, 2): 61.0 (± 7.5), 61.6 (± 7.0) All male participants Exclusion criteria: age < 35 or > 85
Interventions	Group 1 (control): after sedation, lumbar region injected with 1% lidocaine SC in one of lumbar interspaces between 2nd-5th vertebral bodies. SC injection of sterile saline instead of intrathecal injection into subarachnoid space. Received IV fentanyl citrate bolus (4 μg/kg) immediately after induction, followed by continuous infusion (2 μg/kg/ h) until fascial closure. Group 2 (active intrathecal block): after sedation, lumbar region injected with 1% lidocaine SC in one of lumbar interspaces between 2nd-5th vertebral bodies. Mixture of bupivacaine (15 mg isobaric, 0.75%), clonidine (75 μg), morphine (0.2 mg) injected into subarachnoid space. No intraoperative fentanyl in this group, rather equal volume of saline as a bolus and infusion. Both groups had sedation with IV fentanyl and midazolam. Standardized GAwith sodium thiopental, succinylcholine, cisatracurium, isoflurane and nitrous oxide in O2. When study drug infusion discontinued, IV ketoralac 30 mg to both groups. Phenylephrine and ephedrine were used as needed to maintain an adequate blood pressure. In PACU, both groups treated with morphine (1 mg to 2 mg IV every 10 min as needed), droperidol for nausea, then naloxone if persisted diphenhydramine for pruritus initially then naloxone infusion if persisted. Once on the floor, postoperative pain management with scheduled Ketoralac (15 mg IV every 6 h × 6 doses), PCA morphine (1 mg bolus, 10-min lockout, no basal infusion) for 24 h then oral paracetamol/codeine (650/30 mg) every 6 h as needed Adjuvants: clonidine Immediate post-op pain control: significantly improved, significantly reduced analgesic consumption
Outcomes	Dichotomous: pain/no pain at 3 months Continuous: numerical pain scale, SF-36 at 3 months Other reported: none
Notes	Funding sources: not reported Conflicts of interest: no conflict of interest statement was provided
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly assigned by a “computer-generated list that made assignments based on enrolment number”
Allocation concealment (selection bias)	Low risk	Quote: “assigned to a treatment group using a sealed envelope”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “patients and providers were masked to treatment assignments...To maximize masking of the study, a consulting anaesthesiologist familiar with the study but not responsible for the intraoperative care of the patient performed the regional procedure. During this time, the anaesthesiologist for the clinical conduct of anaesthesia left the operating room...the anaesthesia team was blinded to the identity of the bolus and infusion”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “patients and providers were masked to treatment groups”
Incomplete outcome data (attrition bias) All outcomes	Low risk	One participant assigned to active block group had severe bradycardia after induction and surgery was cancelled. 3 participants in control group, 2 in active block group could not be reached at 12 weeks. Balanced numbers, low attrition rate, low risk of bias
Selective reporting (reporting bias)	Low risk	Primary outcomes fully reported on
Null bias	Low risk	Quote: “ilntrathecal analgesia improved current, least, and worst pain scores on the day of surgery and current and worst pain scores at 06:00 h the next day.”
Burney 2004
Methods	Single-blinded (outcome assessor), clinical RCT Sequence generation by random number tables Follow-up: 6 months
Participants	Participants: 34 adults in a university setting in Ann Arbor, Michigan, USA Operation: unilateral inguinal hernia repair 2 groups, size: 15/18 Age: not reported Men/women: not reported Remarks: recurrent hernias or bilateral hernias were excluded
Interventions	Group 1 (spinal): spinal with lidocaine (5% with 7.5% dextrose, volume not reported), postincision: illio-inguinal block with bupivacaine (0.5%, 8 mL to 10 mL), post-op regimen not reported Group 2 (control): GA (fentanyl), postincision: illio-inguinal block with bupivacaine (0.5%, 8–10 mL), post-op regimen not reported Adjuvants: none Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: none reported Continuous: health status measured by SF-36 at 6 months, but without randomization list
Notes	We contacted the study author for missing information on SF-36 outcome. He provided original data and comments, but regretted that the randomization list was no longer available. Therefore the data could not be included Funding sources: this study was supported by a grant from the Aetna Foundation, Hart-ford, Conn, USA Conflicts of interest: no conflict of interest statement was provided
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “randomization was carried out using a blocked and balanced random number table.”
Allocation concealment (selection bias)	Low risk	Quote: “a sealed opaque envelope with the randomization assignment was opened only after the patient had given informed consent for the study.” The well-described method makes bias unlikely
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants and caregivers were not blinded, but this is acceptable
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessor blinding was not reported, but participants filled out the questionnaire alone. Study author responded: “research assistants collecting the data were blinded as to experimental groups during initial data collection. All data collection was by questionnaire. Research assistants were present for early data collection, but at 6 months I think it was only by mail.”
Incomplete outcome data (attrition bias) All outcomes	High risk	Loss to follow-up reported, but not assigned to groups or outcomes. Initially 34 participants were recruited, but only 23 questionnaires were collected at 6 months. Participants erroneously assigned to the wrong group were analysed with ITT. Bias is likely due to the unclear group allocation of participants lost to follow-up
Selective reporting (reporting bias)	Low risk	Primary outcomes fully reported on
Null bias	Unclear risk	Quote: “twelve (80%) of 15 patients in group 1 and 17 (94%) of 18 in group 2 received pain medication in the PACU (P = .3). In group 1, 10 (67%) of 15 patients received narcotic medication, and 6 (40%) of 15 patients received non- narcotic medication. In the group 2,17 (94%) of 18 received narcotic medication, and 7 (39%) of 18 received nonnarcotic medication (P = .07 for narcotic medication; P > 0.99 for nonnarcotic medication).” No significantly decreased analgesic consumption in the PACU, however pain scores not reported
Can 2013
Methods	Double-blind, clinical RCT Randomization using “the envelope method” but no report on sequence generation technique Follow-up: 6 months
Participants	Participants: 60 adult participants from university-affiliated hospital in Turkey Operation: thoracotomy, elective 3 groups, size: 20/20/20 Age (± SD), group 1, 2, 3: 52.20 (± 17.05), 45.00 (± 17.46), 50.9 (± 16.12) Men/women, group 1, 2, 3: 15/5, 15/5, 15/5 Comorbidities: no concomitant disease
Interventions	Group 1 (control): preoperative and intraoperative analgesia with 0.25 μg/kg/h to 0. 60 μg/kg/h remifentanil infusion. No epidural analgesic medication before or during operation through epidural catheter Group 2 (incision-sensitized): preoperative analgesia with 0.25 μg/kg/h to 0.60 μg/ kg/h remifentanil infusion. 10 min after surgical incision, epidural admin 10 mL to 15 mL 0.1% levobupivacaine and remifentanil infusion then remifentanil continued for 20 more min for a total of 30 min then 10 mL 0.1% levobupivacaine epidural every 45 min Group 3 (pre-emptive analgesia group): preop analgesia: 0.1% levobupivacaine 10 mL to 15 mL at 2nd dermatome superior and inferior to incision dermatome (between T4 to T14) through epidural catheter prior to induction. Intraop analgesia: 10 mL 0.1% levobupivacaine epidural injection every 45 min In all groups epidural catheters were placed preoperatively at 6th-7th or 7th-8th thoracic intervals. All received the same GA regimen. Postoperatively all received morphine (3 mg) + fentanyl (50 μg) in 15 mL isotonic solution via epidural route at skin closure and every 12 h for 48 h Adjuvants: none Immediate post-op pain control: not significantly improved
Outcomes	Dichotomous: pain/no pain at 3 and 6 months Continuous: VAS score 3 and 6 months Other reported: participant satisfaction levels at discharge and at month 6
Notes	Presence of chronic pain defined as VAS score > 3. Epidural catheters were placed in all participants, and after placement a 3 mL test dose of 2% lidocaine with 1/200,000 adrenalin was injected. Thus, all participants did receive small amount of lidocaine via epidural catheter. We acknowledge the study author’s response on allocation concealment, blinding, source of funding and whether there was any conflict of interest Funding sources: response from study author, “the authors declare... [their] university... funded this study” Conflicts of interest: “the authors declare... that they have no conflict of interest to the publication of this article...”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomized envelopes drawn “when patient come to operation room a staff get an envelope and open it”, from study author
Allocation concealment (selection bias)	Low risk	On questioning, study author responded “Envelopes are opaque and include equal groups symbols. When patient come to operation room a staff get an envelope and open it.”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “double blind” study. When questioned, study author responded “The personal collecting the pain data was not involved in the previous study phases”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “the outcome assessor collecting pain levels postoperatively and at 1, 3, 6 months was blinded” says the study author
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: “2 patients from control group and 1 patient from preemptive analgesia group died and 1 patient from preemptive analgesia and other one patient from incision sensitized group wound infection were excluded” stated author. “New participants that were compliant with the inclusion criteria were enrolled.”
Selective reporting (reporting bias)	Low risk	No protocol available but all specified outcomes were reported on
Null bias	High risk	Table 3 demonstrates no significant difference in VAS scores between the 3 groups at hours 1, 4, 24 or 48 after surgery
Chiu 2008
Methods	Triple-blind (participant, provider, outcome assessor) placebo-controlled, clinical RCT Sequence generation method not described Follow-up: 3 months
Participants	Participants: 40 adults at a teaching hospital in New Taipei City, Taiwan Operation: minimally invasive cardiac surgery (coronary artery bypass performed through left thoracotomy via 4th or 5th intercostal space without cardiopulmonary bypass, valvular surgery through a right lateral thoracotomy via 4th intercostal space with cardiopulmonary bypass) 2 groups, size: 19/19 (actually completed) Age (± SD), group 1, 2: 57.4 (± 15.2), 59.7 (± 13.8) Men/women (group 1,2): 12/7, 13/6 Remarks: 40 participants were randomized, but 2 were excluded, 1 per group, because of protocol violation Surgery type: coronary artery bypass/valve surgery (group 1,2): 5/14, 6/13
Interventions	Group 1 (placebo): 10 mL saline infused via catheter at end of operation, continuous infusion saline 2 mL/h × 48 h Group 2 (thoracotomy wound infusion): 10 mL 0.15% bupivacaine infused at end of operation then continuous infusion 2 mL/h × 48 h Both groups had same GA regimen with etomidate, fentanyl, rocuronium and sevoflurane and multi-orifice catheter placed at a SC layer during wound closure. Post-op breakthrough analgesia for both groups with IV PCA (morphine 0.5 mg/mL, fentanyl 5 μg/ mL, tenoxicam 0.8 mg/mL) basal infusion rate 0.1 mL/h, bolus 1 mL, lockout 15 min. After 72 h, oral or parenteral NSAIDs or opioids were used Adjuvants: none Immediate post-op pain control: significantly improved, significantly reduced analgesic consumption
Outcomes	Dichotomous: none Continuous: VAS Other reported: IV PCA consumption in first 72 h post-op
Notes	Funding sources: source of funding not reported. Conflicts of interest: no conflict of interest statement given
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “patients were randomly assigned” but no description of method of randomization or at what time point it was done
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “the nurse connecting the infusion bag to the catheter, the surgeons, the pa-tient...were all blinded to the nature of the infusion”
Chiu 2008
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The nurse evaluating the pain score was blinded to the nature of the infusion. Does not explicitly say, but likely the individual evaluating pain score at 90 days after was also blinded
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	1 participant in each group was excluded as a result of “protocol violation (limited consciousness)”. No ITT analysis was done. Did not report on the number of individuals assessed at 3-month follow-up time point (or if any lost to follow-up)
Selective reporting (reporting bias)	Low risk	No protocol available but primary outcomes specified in paper were fully reported on
Null bias	Low risk	Quote: “not only did the bupivacaine wound infusion reduce pain during the first 48-hour infusion period, but it also provided reduced pain at 24 hours after cessation of the infusion”
Choi 2016
Methods	Placebo-controlled, RCT Sequence generation not described Follow-up for 3 months
Participants	Participants: 84 adults in a university setting in Korea Operation: robot-assisted thyroidectomy 2 groups, size: 41/43 Age (± SD), group 1, 2: not described Men/women, group 1,2: not described Exclusion criteria: not described
Interventions	Group 1 (lidocaine): after induction of anaesthesia, participants received a bolus of 2 mg/kg of lidocaine intravenously followed by continuous infusion at a rate of 3 mg/kg/ h during surgery. Further details of anaesthetic regimen were not provided Group 2 (control): same as above except 0.9% saline was substituted for lidocaine Adjuvants: none Immediate post-op pain control: no improvement
Outcomes	Dichotomous: pain vs no pain Continuous: none Other reported: quality of recovery and pain scores during 24 h and 48 h postoperatively
Notes	Study published only as an abstract. We were unable to obtain additional information about methods, randomization or blinding methods from the study author Funding sources: funding of study not described Conflicts of interest: conflicts of interest statement not provided
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Patients were “randomly allocated” but no further description of sequence generation was included
Allocation concealment (selection bias)	Unclear risk	Concealment of allocation not described
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding of participants and personnel not described
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome assessors not described
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Degree of attrition not described
Selective reporting (reporting bias)	Unclear risk	Use of subgroup analysis not described
Null bias	High risk	Quote: “pain scores for 2 days after surgery were not different between the two groups.
Comez 2015
Methods	Double-blinded (participant, outcome assessor), RCT Sequence generation not described Follow-up for 3 and 6 months
Participants	Participants: 60 adults in a university setting in Turkey Operation: thoracotomy 3 groups, size: 20/20/20 Age (± SD), group 1, 2, 3: 45.95 (18.248), 51.05 (19.324), 44.35 (19.712) Men/women, group 1, 2, 3: 10/10, 15/5, 11/9 Exclusion criteria: no concomitant systemic disease with functional limitations, ASA III- IV
Interventions	Group 1 (control): an epidural catheter was inserted using an 18 Ga. Tuohy needle with the help of the negative pressure hanging drop method from the levels of thoracic 6-7 or thoracic 7–8 in the preoperative period. Following the determination of epidural catheter, 2 mL 2% lidocaine was applied to cases as a test dose No IV dexketoprofen and pre-emptive epidural analgesic medication was applied to cases. Intraoperative analgesia was provided with 50–100 mcg/h fentanyl citrate and O2/ N2O 40% to 60% Pre-oxygenation was provided for all cases with 6 L/min-8 L/min 100% O2 (3–5 min) Following 2 mg/kg propofol induction and the sufficient muscle relaxation that was provided with 0.6 mg/kg-1 mg/kg rocuronium bromide, the cases were intubated using a double-lumen endobronchial tube. The area of the endobronchial tube was confirmed with fibreoptic bronchoscopy. The maintenance of the anaesthesia was provided with 6%-8% desflurane within 45% O2, between MAC 1 to1.5. During one-lung ventilation (OLV), the amount of oxygen was increased according to the saturation of the case. 50 mcg/h fentanyl and O2 + 50%-60% N2O were given for the analgesia in the intraoperative period. Dosage of the fentanyl was increased to 100 mcg/h during the OLV At the end of the operation, 1.5 mg neostigmine and 0.5 mg atropine were applied for the antagonism of the muscle relaxant. Postoperative analgesia was provided with 3 mg morphine + 50 mcg fentanyl within 15 mL0.9% NaCl through epidural catheter shortly before the operation while stitching the skin sutures. Analgesia of the cases was followed for 48 h and postoperative epidural analgesic fluid was applied at intervals of 12h. When the VAS score became > 3, an additional dose of postoperative epidural analgesic fluid was applied Group 2 (pre-emptive epidural): same GA technique used as above. 10 mL to 15 mL 0.125% levobupivacaine was given to cases in 5 mL with intervals of 5 min preemptively through epidural catheter before the anaesthesia induction to provide the analgesia at two dermatome levels below and above the surgical incision dermatome (T4 to T14). Sufficiency of the analgesia was determined by performing hot-cold test and the anaesthesia induction was then started. Intraoperative analgesia was provided with 10 mL 0.125% levobupivacaine injection, which was repeated every 60 min through epidural catheter Group 3 (pre-emptive epidural and dexketoprofen): same GA technique as described for previous 2 groups. Levobupivacaine applied as described in group 2. In addition, 50 mg dexketoprofen trometamol was given within 100 mL 0.9% NaCl with IV infusion in 15 min, and it was finished 15 min before the surgical incision Adjuvants: dexketoprofen, morphine, and fentanyl Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: pain vs no pain Continuous: VAS Secondary: participant satisfaction scores at 1, 3, 6 months, surgery duration, and VAS scores and frequency of pain at 1 h, 4 h, 24 h, 48 h, discharge, and 1 month
Notes	We were unable to obtain additional information about randomization and blinding methods from the study author Funding sources: funding of study not described Conflicts of interest: study authors had no conflicts of interest
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Sequence generation for randomization not described
Allocation concealment (selection bias)	Low risk	Quote: “ about which study group they were in-cluded in, were divided into 3 groups … with the random envelope method”
Blinding of participants and personnel (performance bias) All outcomes	High risk	Sham block was used, however the control group did not receive LA or sham saline loading
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Assesors were masked
Incomplete outcome data (attrition bias) All outcomes	Low risk	There was no attrition
Selective reporting (reporting bias)	High risk	Epidurals that were not effective were excluded from the analysis
Null bias	Low risk	Quote: “A statistically significant decrease was determined in the VAS score in Group PED … compared to the other groups
Di-Gennaro 2013
Methods	Data not available
Participants	Participants: 80 women, ASA II, aged 30–55, in Italy Operation: central quadrantectomy and reconstruction with Grisotti’s inferior dermo- glandular flap for retroareolar breast cancer 2 groups, size: 40/40
Interventions	Group 1 (tramadol): participants of group 1 were administered tramadol 100 mg/20 mL Group 2 (levobupivacaine): participants of group 2 were administered levobupivacaine 2.5% 20 mL Both groups: perioperative pain management was treated with paracetamol 1000 mg/ 100 mL postoperatively (3 times/d for 48 h) Adjuvants: none Immediate post-op pain control: data not available
Outcomes	NRS data not available
Notes	Multiple attempts to contact study author were not successful and thus we were unable to obtain results from study Funding sources: funding source not described Conflicts of interest: conflict of interest statement not given
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Sequence generation was not described
Allocation concealment (selection bias)	Unclear risk	Concelament of allocation was not described
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding of participants and personnel was not described
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome assessors was not described
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Data collection and outcomes not described
Selective reporting (reporting bias)	Unclear risk	Selective reporting not described
Null bias	Unclear risk	No results reported
Dogan 2016
Methods	Double-blinded (participant, outcome assessor), clinical RCT Sequence generation not described Follow-up for 6 months
Participants	Participants: 81 adultsin a university setting in Turkey Operation: coronary artery bypass graft 2 groups, size: 40/41 Age (± SD), group 1,2: 64.18 (10.46), 60.22 (13.27) 2 Men/women, group 1,2: 31/9, 32/9 Exclusion criteria: allergy to any of the study medications, severe renal, pulmonary, liver,or endocrine systemic disease, a history of alcohol or drug abuse, a history of chronic pain,psychiatric problems, or difficulty in communication. During thepostoperative period,participants who needed postoperative revision for haemostasis, who had haemodynamicinstability or infections, or severe bleeding, or who died were also excluded
Interventions	Group 1 (parasternal block): anaesthesia was induced by etomidate 0.2–0.5 mg/kg and fentanyl 3 pg/kg in addition to rocuronium 0.9 mg/kg for tracheal intubation. For maintenance of anaesthesia, desflurane 1 MAC, remifentanyl infusion (0.25 pg/ kg/min) and rocuronium (0.1 mg/kg/h) following induction was used in both groups. The participants were ventilated with a tidal volume of 6–8 mL/kg, fraction of inspired oxygen (FiO2 ) of 50% in air, the respiratory rate was modulated to keep the end-tidal carbon dioxide at normal values of 35–45 mm Hg and adjusted to arterial PCO2 values, and a positive end-expiratory pressure of 5 cm H2O was applied. Coronary artery bypass graft surgery was initiated with a sternotomy incision. The participants were anticoagulated with 300 U/kg of heparin to provide an activated clotting time (ACT) > 400 s. Cardiopulmonary bypass (CPB) was started following the cannulation of the aorta and the right atrium. Membrane oxygenators (Terumo Corporation, Tokyo, Japan) were primed with 1000–1500 mL of Ringer’s lactate to maintain a hematocrit level of 26% ± 2%. A nonpulsatile pump flow was set at 2.2 to 2.4 L/min/m2 to maintain mean arterial pressure between 50 and 70 mmHg. CPB was performed at mild hypothermia with a core temperature of 33°C. Intermittent antegrade cardioplegia was used for myocardial protection. The participants were rewarmed to a temperature of 37°C. When the heart was paced in the atrioventricular sequential mode at a rate of 90 beats/min, the participants were weaned from CPB. Protamine sulfate was used to antagonize the heparin. Before sternal wire placement, sternotomy and mediastinal tube sites were infiltrated with 50 mL of study solution (levobupivacaine 25 mL (chirocaine, 50 mg/10 mL, Abbott Lab) + fentanyl 100 pg + 23 mL saline) by the surgeon. This mixture was infiltrated as follows: bilateral 5 costa levels (underside of them) and every level 2 mL on both sides of the sternum, over sternal periosteum 20 mL and the entrance of chest tubes deep infiltration 10 mL. At the end of the surgery, 1 g paracetamol and 1 mg/kg tramadol were given to all participants. At the end of the surgery, all anaesthetics were discontinued and participants were transferred to the intensive care unit (ICU) where they were mechanically ventilated. The participants were extubated if they met the following criteria: participant awake and responsive to commands, fully warmed with core temperature > 36°C, haemodynamically stable without significant dysrhythmias, well- perfused with adequate urine output ( > 1.0 mL/kg/h), no active bleeding, respiratory rate 10–30/min, SpO2 > 95 when 50% oxygen + air. Patients were to receive tramadol infusion with an intravenous PCA device for postoperative analgesia when they came to the ICU. The PCA device was set to deliver a 10 mg/h continuous dose and a 20 mg/h demand dose with a lock-out interval of 30 min and with a maximum 4-h limit of 200 mg for every participant. All participants were given additional IV NSAID Group 2 (control): same anaesthetic regimen as described above except no LA was applied before sternal wire placement Adjuvants: fentanyl Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: pain vs no pain Continuous: VAS Other reported: presence of allodynia, thermal pain, or dysesthesia, tramadol consumption, cross clamp time, duration of operation, left internal mammary artery harvested or not, duration of mechanical ventilation, haemodynamic parameters, VAS at 1, 2, 3, 4, 8, 24, and 48 h postoperatively
Notes	We were unable to obtain additional information regarding continuous pain outcomes or about randomization and blinding methods from the study author Pain on a dichotomous scale was defined as Leeds Assessment of Neuropathic Symptoms and Signs >12 Funding sources: “no financial support was received for this study.” Conflicts of interest: “the author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Sequence generation not described
Allocation concealment (selection bias)	Low risk	Quote: “patients were randomly allocated by opening an envelope... before the entry in the operating room.”
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding of personnel not specified
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “six months after surgery, an investigator who was blinded to acute pain treatment examined the patients’ chronic pain.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No participants were lost to follow-up and ITT analysis was performed
Selective reporting (reporting bias)	Low risk	No subgroup analysis was performed
Null bias	Low risk	Quote: “parasternal block had a beneficial effect on the management of postoperative acute pain.”
Fassoulaki 2000
Methods	Triple-blinded (participants, providers, outcome assessors) randomized placebo-controlled clinical trial Sequence generation was randomized but not described Follow-up: 3 months
Participants	Participants: 46 female participants at a university hospital in Athens, Greece Operation: modified radical mastectomy or lumpectomy and axillary lymph node dissection 2 groups, size: 23/22 (completed) Age ± SD (group 1, 2): 49 ± 6, 49 ± 8 All female participants Exclusion criteria: age > 60 years Remarks: participants undergoing modified radical mastectomy with axillary node dissection/lumpectomy (group 1, 2): 10/13, 7/15. Participants undergoing chemotherapy post-op (group 1/2): 16/16. Participants undergoing radiotherapy post-op (group 1/2): 13/8
Interventions	Group 1 (EMLA): 5 g EMLA to sternal area 5 min before induction. Immediately after extubation 5 g EMLA on supraclavicular area, 10 g around axilla (away from site of incision), then covered with Tegaderm. Same total dose of cream (20 g) applied daily on the 4 days after surgery Group 2 (control/placebo): exactly the same as above, only placebo cream was used. Both groups received premedication with droperidol and metoclopramide and the same GA technique with thiopental and propofol, sevoflurane and nitrous oxide in O2 with rocuronium. No analgesics were given to either group during surgery. Post-op analgesia in all participants: 75 mg propoxyphene and 600 mg paracetamol IM as needed × 24 h, then paracetamol oral or paracetamol/codeine oral ± hydroxyzine Adjuvants: propoxyphene Immediate post-op pain control: no significant improvement in post-op pain or analgesic consumption. Time to first analgesic requirement was significantly longer in EMLA group
Outcomes	Dichotomus: pain/no pain at 3 months (also broken down by site, including chest wall, arm, axilla) Continous: verbal intensity scale of 0 = no pain to 3 = severe pain at 3 months Other reported: absent/decreased sensation, home analgesic use at 3 months
Notes	We acknowledge the response by the study author providing details on allocation con cealment, blinding, and sources of support and conflict of interest statement Funding sources: study author replied, “the study was funded from Departmental sources only.” Conflicts of interest: study author replied, “none of the authors has conflict of interest relevant to the study,”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “patients were randomized before induction of anesthesia using sealed opaque envelopes containing code A or B”
Allocation concealment (selection bias)	Low risk	Quote: study author responded “sealed opaque envelopes containing code A or B” were used
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “the EMLA or the placebo cream was applied by an anaesthesiologist who was not involved in patients’ anaesthesia or data collection. All other anaesthesiolo- gists, anaesthetic or ward nurses, as well as the patient, were not aware of the group of assignment”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “an independent observer who was not involved in patient randomization or anaesthesia administration was assessing and recording pain scores”
Incomplete outcome data (attrition bias) All outcomes	Low risk	One participant in the EMLA group with cutaneous allergy was excluded and not replaced. Otherwise no other participants lost. No ITT analysis was done, only per-protocol
Selective reporting (reporting bias)	Low risk	No protocol available for review but pre specified outcomes within manuscript were reported on
Null bias	High risk	Quote: “The VAS scores at rest and after movement recorded 0, 3, 6, 9, and 24 h, as well as 2, 3, 4, 5, and 6 days postoperatively did not differ significantly between the 2 groups”
Fassoulaki 2001
Methods	Double-blinded, placebo-controlled randomized clinical trial Sequence generation via “coded envelopes”, but not explicitly described Follow-up: 3 months
Participants	Participants: 100 adult women at a university hospital in Athens, Greece Operation: breast cancer surgery (modified radical mastectomy or lumpectomy + axillary node dissection) 4 groups, size: 23/24/25/24 (completed) Age, group 1, 2, 3,4 (SD not reported): 46, 46, 44, 44 All female participants Exclusion criteria: women over 59 years of age or those who received radiotherapy or chemotherapy preoperatively Number of participants who underwent modified radical mastectomy (group 1, 2, 3, 4): 8, 10, 11, 7 Number of participants who underwent radiotherapy post-op (group 1, 2, 3, 4): 9, 9, 4, 12 Number of participants who underwent chemotherapy post-op (group 1, 2, 3, 4): 18,15, 23, 18
Interventions	Group 1 (ropivacaine and mexiletine): mexiletine 200 mg by mouth evening before surgery and 200 mg twice daily for first 6 post-op days, brachial plexus infiltrated 12 mL ropivacaine 10 mg/mL and 6 mL 3rd-5th intercostal spaces after axillary dissection Group 2 (ropivacaine and placebo): placebo tablet oral evening before surgery and twice daily for first 6 post-op days, brachial plexus infiltrated 12 mL ropivacaine 10 mg/mL and 6 mL 3rd-5th intercostal spaces after axillary dissection Group 3 (placebo and mexiletine): mexiletine 200 mg by mouth evening before surgery and 200 mg twice daily for first 6 post-op days, brachial plexus infiltrated 12 mL saline and 6 mL 3rd-5th intercostal spaces after axillary dissection Group 4 (placebo and placebo): placebo tablet oral evening before surgery and twice daily for first 6 post-op days, brachial plexus infiltrated 12 mL saline and 6 mL 3rd-5th intercostal spaces after axillary dissection All groups received IV metoclopramide and droperidol 5 min before induction. Standardized GA regimen with thiopental, propofol, recouronium, sevoflurane, nitrous oxide in O2. All groups received same post-op analgesia regimen of 75 mg propoxyphene + 600 mg paracetamol IM every 5 h as needed × first 24 h then post-op day 2, oral tablet of 10 mg codeine + 400 mg paracetamol every 5 h as needed Adjuvants: mexiletine (2/4 groups), propoxyphene (4/4 groups) Immediate post-op pain control: significantly improved, significantly reduced analgesic consumption in group 2 compared with all other groups
Outcomes	Dichotomous: pain/no pain at 3 months (also reported by site, including chest, axilla) Continuous: VAS at 3 months Other: absent/decreased sensation, analgesic use at 3 months
Notes	We acknowledge the response by the study author providing details on randomization, allocation concealment, blinding of participants, personnel and outcome assessors as well as sources of support and conflicts of interest Funding sources: study author responded, “The study was funded from Departmental sources only.” Conflicts of interest: studyauthor responded, “None of the authors has conflict of interest relevant to the study,”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The study author stated, “twenty five opaque envelopes were prepared for each group, each containinganotewith [a] code. ..The night before surgery the anaesthesiol-ogist pulled out one envelop fromthe bag containing the 100 envelops and according to the code inside administered to the patient the capsulefrom the jar with the same code”
Allocation concealment (selection bias)	Low risk	The study author stated: “twenty five opaque envelopes”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The study author stated: “patients surgeons and anaesthesiologists ALL were blinded except for an anaesthesiologist not participating in the study”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study author responded that the outcome assessors were blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: “four patients failed to complete the protocol and were not replaced. Data are unavailable for chronic follow up of two others”. Does not state which group specifically the participants belonged to, but can see the numbers of attrition in each group. Overall low numbers and fairly balanced
Selective reporting (reporting bias)	Low risk	No available protocol but primary outcome specified in manuscript completely reported on
Null bias	Low risk	Quote: “regional block reduced the number of intramuscular (IM) injections required the first 24 hours (P = 05), the R +PL group requiring less injections versus the PL + M group (P = .037). Three hours postoperatively, the R +PL group had less pain at rest when compared with all other groups”
Fassoulaki 2005
Methods	Double-blind (participant, outcome assessor), placebo-controlled, randomized clinical trial Sequence generation by computer-generated random number tables Follow-up: 6 months
Participants	Participants: 50 adults in a university setting in Athens, Greece Operation: breast surgery (modified radical mastectomy and lumpectomy plus axillary dissection) for breast cancer 2 groups, size: 25/25 Age (group 1, 2): 49 years (SD ± 8.4), 48 (SD ± 8.1) Men/women: 0/50
Interventions	Group 1 (multimodal): GA, brachial plexus irrigation with ropivacaine (0.75%, 10 mL), intercostal ropivacaine (0.75%, 3 mL) at intercostal spaces 3–5, post-op for 3 d topical (wound, sternum, axilla) EMLA cream (20 g, 2.5% lidocaine/prilocaine), codeine, paracetamol Group 2 (control): GA, brachial plexus irrigation with normal saline, sham intercostal block at intercostal spaces 3–5, post-op for 3 d topical (wound and axilla) placebo cream, codeine, paracetamol Adjuvants: Group 1: gabapentin (400 mg, orally every 6 h starting the night before surgery) for 8 d, Group 2: placebo as above Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: pain, analgesic consumption at 6 months Continuous: none reported Adverse effects, withdrawal and attrition were reported with group allocation
Notes	We contacted the study author and we acknowledge the response, providing details on source of funding and conflict of interest Funding sources: study author responded “the study was funded from Departmental sources only.” Conflicts of interest: the study author responded “none of the authors has conflict of interest relevant to the study.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “fifty envelopes, 25 containing odd and 25 containing even numbers, obtained from a computer-generated table, were prepared and sealed...,” this is an adequate description of an acceptable randomization technique. Bias is unlikely
Allocation concealment (selection bias)	Low risk	Quote: “an independent anesthesiologist, who did not participate in the study or data collection, read the number contained in the envelope and made group assignments. ” Bias is unlikely
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “except for the independent anesthesiologist, [not involved in the study] no other physician or nursing staff member was aware of the interventions administered to each patient.” “Regarding EMLA cream and possible interference with blinding, EMLA or placebo was applied in the morning after pain assessment”... “pain was assessed by an anesthesiologist blinded to group assignment.” “Placebo capsules were identical in appearance with the gabapentin capsules. The same number of capsules was packaged in group-specific bottles and coded as bottle A and bottle B for the control and treatment groups, respectively. A white odourless cream was the control treatment corresponding to the EMLA cream. Similarly, cream for each group was kept in boxes labelled as A and B for the control and treatment groups, respectively.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “except for the independent anesthesiologist, (not involved in the study) no other physician or nursing staff member was aware of the interventions administered to each patient.” “Pain was assessed by an anesthesiologist blinded to group assignment.”
Incomplete outcome data (attrition bias) All outcomes	High risk	Study authors provide a good account of attrition, including group allocation, but considered no ITT analysis: dropouts, participants lost to follow-up, failures, etcwere all excluded
Selective reporting (reporting bias)	Low risk	Primary outcomes fully reported on
Null bias	Low risk	Quote: “the treatment group consumed less paracetamol in the PACU... and fewer Lonalgal® tablets... than the controls, exhibited lower visual analog scale scores at rest in the PACU... and on postoperative Days 1, 3, and 5”
Fassoulaki 2016
Methods	Triple-blind (participant, provider, and outcome assessor), placebo controlled, randomized clinical trial Sequence generation by computer-generated random number tables Follow-up: 3 months
Participants	Participants 110 adults in a university setting in Greece Operation: laparoscopic cholecystectomy 2 groups, size: 55/55 Age (± SD), group 1, 2: 51 years (11.2), 48 (SD ± 12.5) Men/women, group 1, 2: 17/38, 14/41 Exclusion criteria: central nervous system, kidney, or liver disease, chronic pain, or con-sumption of analgesics and/or calcium channel blockers during the last month
Interventions	Group 1 (ropivacaine): premedication was omitted in all cases. In the operating room an 18-G catheter was inserted in a peripheral vein on the dorsum of the left hand and metoclopramide 10 mg, ranitidine 50 mg, and droperidol 0.75 mg were injected IV before induction of anaesthesia. Pulse oximetry, electrocardiogram, noninvasive blood pressure, inspired and end tidal oxygen concentration, capnography, inspired and end tidal sevoflurane concentration, and neuromuscular block were monitored (Datex Ohmeda S/5TM, Anesthesia Monitor, Helsinki, Finland) (Multistim VARIO, Pajunk, Geisingen, Germany). Participants were preoxygenated for 3 min. Thiopental (5–6 mg/kg) and fentanyl (2 mg/kg) were administered to induce anaesthesia, followed by rocuronium (0. 6 mg/kg) to facilitate tracheal intubation. Anaesthesia was maintained with sevoflurane 2%-3% inspired concentration in an oxygen nitrous oxide mixture of 1:1 L/min. Di- clophenac (75 mg IV) was infused slowly within 30 min before pneumoperitoneum. After induction of anaesthesia and before beginning the operation the surgeon inserted SC a “PAINfusor” multihole catheter 75 mm long (PLAN 1 Health, Baxter, Amaro-UD, Italy) below and parallel to the subcostal area under aseptic conditions. The catheter was connected to a 130 mL elastomeric pump (Baxter Health-Care Corporation, Deerfield, IL) delivering fluid at 2 mL/h. The pump was filled with 48 mL of 0.75% ropivacaine under sterile conditions by an anaesthetic nurse not participating in the study and having access to the randomization sets. The infusion was maintained for the first 24 h. Laparoscopic cholecystectomy using the 4-port technique was performed by the same surgeon in all participants. During the pneumoperitoneum the intra-abdominal pressure ranged between 12 and 14 mmHg. The total amount of CO2 used was recorded. At the end of the procedure each of the 4 holes was infiltrated with 2 mL of ropivacaine 0.75%. After skin closure residual neuromuscular block was reversed with sugammadex (2 mg/ kg), and the participant was extubated and transferred to the PACU. In the PACU, the participants were asked to score their pain using the VAS and received paracetamol IV 1 g if VAS was > 40 mm or if the participant asked for analgesia. If paracetamol was not effective then tramadol (100 mg IV) was administered. Participants who experienced vomiting were given ondansetron 4 mg IV. During the first 48 h postoperatively participants were given paracetamol (400 mg) and codeine (10 mg) (Lonarid tablets) on demand or when the VAS scores exceeded the 40 mm in the VAS 100 mm scale. If the participant experienced nausea/vomiting, then ondansetron (4 mg IV) was given Group 2 (control): the same intervention as above was used except 0.9% saline was substituted for ropivacaine Adjuvants: none Immediate post-op pain control: no difference
Outcomes	Dichotomous: pain vs no pain Continuous: VAS scores Other reported: pain at rest and pain during cough recorded 2, 4, 8, 24, and 48 h postoperatively, paracetamol and tramadol consumption in the PACU and cumulative Lonarid tablets consumption during the first postoperative 48 h, incidence of shoulder pain
Notes	Funding sources: source of funding not stated Conflicts of interest: “the authors declare no conflicts of interest.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was carried out by means of a computer-generated table with 1 set of 55 numbers for the range 1–110. In a second set the remaining 55 numbers were included corresponding to the control group
Allocation concealment (selection bias)	Low risk	Each number for the ropivacaine and the control group remained unique
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “The pump was filled with 48 mL of 0.75% ropivacaine or equal volume of saline 0.9% under sterile conditions by an anesthetic nurse not participating in the study and having access to the randomization sets.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Sham block was used to maintain blinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Attrition rates were low and ITT analysis was performed.
Selective reporting (reporting bias)	Unclear risk	Not discussed
Null bias	Low risk	Quote: “Subcutaneous ropivacaine...was associated with less pain in the PACU and 4 hours after surgery.”
Gacio 2016
Methods	Triple-blind (participant, provider, outcome assessor), clinical RCT Sequence generation was randomized but not described Follow-up: 6 months
Participants	Participants: 80 participants at a university hospital in Portugal Operation: lumpectomy with axillary dissection, modified radical mastectomy (MRM), and mastectomy with or without axillary dissection 2 groups, size: 40/40 Age (± SD), group 1, 2: 55.10 (9.8), 52.68 (8.9) All women Exclusion criteria: allergy to NSAIDs, LAs, propofol, opioids, paracetamol, or antiemetics, participants on chronic treatment with antibiotics, obesity (BMI > 30), bilateral or multiple surgical procedures, contraindication to PVB (including coagulation disorders/anatomical changes), severe respiratory disease, pregnancy, inability to understand the VAS
Interventions	Group 1 (ropivacaine PVB): before the induction of anaesthesia, peripheral routecatheterization was performed, and participants were monitored according to ASA standards and bispectral index (BIS) anaesthetic depth. PVB was performed with singleinjection, according to the classic technique at the T4 level with Tuohy needle 18 G, with 0.5% ropivacaine + adrenaline 3 g/mL, with a volume of 0.3 mL/kg (maximum total volume of 30 mL). Subsequently, anaesthesia was induced with propofol (1.5 mg kg–1 h—1) and fentanyl (2 g kg–1) and LMA was inserted. Anaesthesia was induced with propofol (1.5 mg kg—1 h—1) and fentanyl (2g kg—1) and LMA was inserted. The maintenance of anaesthesia was performed in both groups with desflurane to maintain BIS values at 45–60 with a mixture of O2/air. Both groups received parecoxib 40 mg IV before the start of surgery. During maintenance, fentanyl (1.5 g kg—1) was administered if there was an increase of 20%from baseline values of mean arterial pressure (MAP) and heart rate (HR). For maintenance of haemodynamic stability, ephedrine or atropine was administered, at the anaesthesiologist’s discretion, if verified a decreased in MAP > 20%or HR < 50 beats/min of baseline values. The institutional protocol for the prevention of nausea and vomiting was administered, according to the predictive model by Apfel and colleagues, with three antiemetic intervention lines. At the end of surgery, PCA with morphine was initiated, programmed with bolus of 2 mg on demand and 5 min lockout and a maximum dose of 6 mg h—1 during the first 24 h postoperatively Group 2 (general anaesthesia): same anaesthetic technique as above but no PVB was administered Adjuvants: parecoxi, fentanyl, morphine, and adrenaline Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: pain vs no pain Continuous: none Other reported: anxiety was assessed using the Hospital Anxiety and Depression scale (HADS), pain at rest according to the VAS score (0–10), as well as pain withmobilization of the ipsilateral arm interpreted as 90° arm abduction 0 h, 1 h, 6 h, and 24 h after surgery, postoperative nausea and vomiting at 24 hours after surgery
Notes	Pain defined as DN4 score > 4 We acknowledge the study author’s response regarding blinding and randomization technique Funding sources: funding for the study was not described. Conflicts of interest: “the authors declare no conflicts of interest.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The study author responded, quote: “a stratified randomization was performed using Excel software for that purpose.”
Allocation concealment (selection bias)	Low risk	The study author responded, quote: “ in this study the anesthesiologist who proceeded to the technique became aware of the randomization sequence (in groups of 4 patients) the same day of the procedure.”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The study author responded, quote: “ the surgical team did not know the group to which the patient belongs.” However, “In the first part of the study (assessment of acute pain in the peri-operative and up to the first 24 hours) the anesthesiologist who proceeded to the technique knew in which group the patient was.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The study author responded, quote: “the investigator who interviewed the patients and carried out the records in the peri-operative period. did not know the group to which the patient belongs.”
Incomplete outcome data (attrition bias) All outcomes	High risk	14 participants were not included in the final analysis
Selective reporting (reporting bias)	Low risk	No subgroup analysis was performed
Null bias	Low risk	“The Visual Analog Scale (VAS) values of paravertebral group at rest were lower throughout the 24 h of study”
Grigoras 2012
Methods	Triple-blind (participants, providers, outcome assessors) randomized controlled study Sequence generation by computer-generated codes Follow-up: 3 months
Participants	36 participants at Cork University Hospital in Cork, Ireland Operation: mastectomy or wide local excision + axillary node dissection, including sentinel node 2 groups, size: 17/19, all women Age (± SD): 55.9 (± 10.4), 56.8 (± 14.4)
Interventions	Group 1 (lidocaine group): immediately after intubation, IV bolus lidocaine (1.5 mg/kg in 10 min) followed by continuous IV infusion (1.5 mg/kg/h), stopped 60 min after skin closure Group 2 (control group): immediately after intubation, IV bolus saline followed by continuous IV infusion of saline, topped 60 min after skin closure. Neither group received preanaesthetic medication. Both groups had the same GAprotocol, including propo-fol and fentanyl for induction, sevoflurane and nitrous oxide in O2 for maintenance. The remaining analgesic regimen was identical between groups, including intraoperative paracetamol 1 g and diclofenac 75 mg IV with morphine as needed and postoperative morphine PCA (1 mg max every 5 min), diclofenac (50 mg oral/rectal every 12 h as needed), paracetamol (1 g oral/rectal every 6 h as needed), tramadol (100 mg IM/oral as needed as rescue) Adjuvants: none Immediate post-op pain control: improved
Outcomes	Dichotomous: pain/no pain at 3 months Continuous: short form McGill Pain Questionnaire (SF-MPQ) at 3 months Other reported outcomes: measurement of area of peri-incisional hyperalgesia, pain catastrophizing scale at 3 months post-op (broken down by question), Hosptial Anxiety and Depression scale at 3 months post-op
Notes	Funding Sources: source of funding not stated Conflicts of interest: “the authors declare no conflict of interest.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “patients were randomly allocated to 1 of 2 groups based on computer generated codes”
Allocation concealment (selection bias)	Low risk	Codes were, quote: “maintained in sequentially numbered opaque envelopes”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “on the morning of surgery an anaesthetist who was not involved in the patient’s evaluation opened the envelope and prepared either 1%lidocaine or normal saline in coded 50mL syringes. None of the investigators involved in patient management or data collection were aware of the group assignment…The anaesthetist, surgeon, and nursing staff were all blinded to the group allocations”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote:“a dedicated investigator, unaware of the patients’ group assignment” performed the outcome assessments. “None of the investigators involved in patient management or data collection were aware of the group assignment”
Incomplete outcome data (attrition bias) All outcomes	Low risk	There were no dropouts; all participants randomized were included in the final analysis at 3 months
Selective reporting (reporting bias)	Low risk	A post-hoc analysis of preoperative factors comparing participants who did and those who did not develop persistent postsurgical pain was done, but this was specified. The rest of listed outcomes were all reported
Null bias	Low risk	Quote: “VAS pain scores at rest, 4 hours postoperatively were less in lidocaine group compared with control group”
Gundes 2000
Methods	Triple-blind (participant, provider, outcome assessor) clinical RCT Sequence generation was randomized but not described Follow-up: 3 months
Participants	Participants: 45 participants (no age requirement) at a university hospital in Kocaeli, Turkey Operation: iliac crest bone harvesting (surgical procedures included vertebral fusion, fracture grafting and grafting for tumour resection) 3 groups, size: 15/15/15 Age (range), group 1, 2, 3: 46 (16-70), 48 (18-71), 51 (19-73) Men/women, group 1, 2, 3: 5/10, 6/9, 6/9 Comorbidities: vertebral fusion (n), group 1, 2, 3: 6, 5, 6. Fracture grafting (n), group 1, 2, 3: 6, 7, 7. Tumour grafting (n), group 1, 2, 3: 3, 3, 2
Interventions	Group 1 (control): 20 mL of 0.9% sodium chloride solution via iliac crest catheter within 10 min after surgery Group 2 (bupivacaine only): 20 mL of 0.9% NaCl with 50 mg bupivacaine via iliac crest catheter within 10 min after surgery Group 3 (morphine-bupivacaine group): 20 mL of 0.9% NaCl solution with 5 mg morphine and 50 mg bupivacaine via iliac crest catheter within 10 min after surgery. All groups: standardized general anaesthesia with thiopental, vecuronium, N2 in O2 and isoflurane. Regional infusions via fine bore epidural catheter at iliac crest donor site, tip between muscle and bone at lateral surface of ilium, started 10 min after surgery Post-op pain control: participants requested reinjection of LA at iliac crest when donor site became painful (5 mL 0.9% NaCl with 12.5 mg bupivacaine), morphine PCA 1 mg bolus, 5 min lockout, 4-h limit 20 mg Adjuvants: none Immediate post-op pain control: significantly improved, significantly reduced analgesic consumption
Outcomes	Dichotomous: pain and dysaesthesia vs none at 3 months post-op Continuous: none Other reported: none
Notes	Postoperatively, all participants in all groups received reinjection of LA (5 mLNaCl and 12.5 mg bupivacaine) into iliac crest when donor site became painful. Thus, control group did receive some bupivacaine in post-op period. Average number of injections received reported by group We acknowledge the response provided by the study author regarding blinding, random-ization, allocation concealment and source of funding and conflict of interest statement Funding sources: the study author reports the study was “not funded by any kind of resource.” Conflicts of interest: “the authors have no conflict of interests of any kind (financial, commercial or otherwise).”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Study author responded that he “did a simple randomization; as every second patient was included in group two; every third patient was included in group three, then reversing it as every fourth patient in group three, every fifth patient in group two, every sixth patient in group one; and so on”. He did not mention this to his collaborators and he did not perform or attend any surgeries in the study. He did not mention his randomization technique to the other collaborators
Allocation concealment (selection bias)	Low risk	Study author responded, quote: “all the medications had been prepared by senior anesthesiology resident, according to me or my chief residents’ instructions. All were prepared in 50 cc identical syringes without any label”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study author responded they, quote: “blinded both the patients and anaesthesi- ologists”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study author states “Dr L.K (anaesthesiol- ogist) did the postoperative (24 hour) evaluation of the patient including VAS score without knowing the group of the patient. He also evaluated patients 12 weeks after the surgery, also without knowing the group of the patient
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Low risk	Published report includes all expected outcomes
Null bias	Low risk	Quote: “the VAS score, analgesic consumption and request for reinjection of local anaesthetic into the donor site in the early postoperative period (24th hour) were significantly higher in the control group than in the other two study groups”
Gupta 2006
Methods	Triple-blinded (participants, providers, outcome assessors) randomized placebo-controlled trial Sequene generation by computer-generated randomized numbers Follow-up: 3 months
Participants	Participants: 60 men from a university hospital in Orebro, Sweden Operation: radical retropubic prostatectomy (for prostatic cancer) 2 groups, size: 28/28 (completed) Age ± SD), group 1, 2: 64.5 ±4.9), 61.1 (± 4.3) All male participants Exclusion criteria: age >70 Remarks: Gleason score, median (range), group 1, 2: 6 (5–9), 6 (5–9)
Interventions	Group 1 (epidural group): on arrival to PACU, ropivacaine-fentanyl-adrenaline epidurally at 10 mL/h, IV PCA with 0.9% saline (bolus dose 1 mL, lockout 6 min, used NRS >3) Group 2 (placebo group): on arrival to PACU, 0.9% saline via epidural at 10 mL/h, IV PCA with 1 mg/mLmorphine (bolus dose 1 mg, lockout 6 min, used NRS > 3). In both groups, preoperative anxiolysis with 10 mg diazepam oral 1 h before scheduled surgery and 1mg-2mgmidazolamas needed during catheter placement. Standardized placement of epidural at T14 to 12 interspace, tested using 3 mL mepivacaine 2% with adrenaline then bolus dose of 3mL to 4mLmepivacaine 2%with adrenaline. Sensory blockade atT12 level. StandardizedGAwith propofol (participants 1-55) or thiopentone (participants 56-60), fentanyl, rocuronium, nitrous oxide in O2, sevoflurane. Intraoperative analgesiawith 2%mepivacaine with 2mL/h-5mL/h adrenaline by epidural infusion in all participants. Immediately before transfer to PACU epidural infusion was turned off. In PACU, nurse allowed to administer 1 mg-2mg morphine bolus as needed if NRS > 5. 1 g paracetamol oral before surgery and every 6 h post-op during hospitalization Adjuvants: adrenaline Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: none Continuous: SF-36 at 3 months Adverse effects: postoperative nausea, vomiting, sedation and bleeding were reported
Notes	We contacted study author for clarification on attrition, source of funding and conflict of interest but received no response Funding sources: source of funding not reported. Conflicts of interest: conflict of interest statement not provided
Risk of bias
bias	Authors’ judgemen	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “computer-generated randomized numbers”, randomized “after successful insertion of the epidural catheter”
Allocation concealment (selection bias)	Low risk	Quote: “every precaution was taken to achieve double blinding…hospital pharmacy sent two double-blinded bags”
Blinding of participants and personnel(performance bias) All outcomes	Low risk	Quote: “the patients and surgeons, anaesthesiologists and nurses involved in patient treatment were unaware of method of analgesia and every precaution was taken to achieve double blinding”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “the SF-36 was given before and 1 and 3 months after the operation to each patient”. Participants, as well as providers, were blinded and the participants filled out the questionnairethemselves
Incomplete outcome data (attrition bias) All outcomes	Low risk	60 participants were randomized, 4 participants were excluded after randomization with reasons and group assignments listed and balanced between groups
Selective reporting (reporting bias)	Low risk	Primary outcomes fully reported
Null bias	Low risk	Quote: “median pain at rest at the incision site was low (< 4) and significantlylower in group E compared with group P at 4-24 h after the operation”
Ibarra 2011
Methods	Blinded (PACU nurses, outcome assessor), controlled, randomized clinical trial Computer-generated randomization in blocks of 2 using sealed, opaque envelopes Follow-up: 5 months
Participants	Participants: 40 adults in a university hospital setting in Albacete, Spain Operation: radical mastectomy and conservative breast surgery for breast cancer 2 groups, size: 20/20 Age: not reported Men/women: 0/40
Interventions	Group 1 (preoperative PVB): single shot PVB at T4 with ropivacaine (0.5% without epinephrine, 25mL to 30mL, dosesmaximum150mg; using nerve stimulations according to Naja but only one single injection), GA (LMA using sevoflurane and remifentanil 0.05 to 0.1 mcg/kg/min only in the first 20-30 min), post-op: intravenous morphine (0.1 mg/kg), dexketoprofen 50 mg IV plus 25 mg every 8 h as needed for pain and paracetamol (1 g every 6 h) Group 2 (no block): no block, GA (LMA using sevoflurane and remifentanil 0.05 mcg/kg/min to 0. 02mcg/kg/min), post-op: IV morphine (0.1 mg/kg), dexketoprofen 50 mg IV plus 25 mg every 8 h as needed for pain and paracetamol (1 g every 6 h) Adjuvants: none Immediate post-op pain control: not significantly improved
Outcomes	Dichotomous: number of participants with pain (including detailed number per group on myofascial pain, breast phantom pain or neuropathic pain) at 3 and 5 months per group Continuous: not reported Effective regional anaesthesia: one participant had an unsuccessful block but was NOT excluded, yet PVBs did not reduced the severity of postoperative pain
Notes	We acknowledge the study author’s response regarding randomization, allocation concealment and blinding, dosing and attrition Funding sources: source of funding not stated Conflicts of interest: conflict of interest not reported
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “computer generated list”, “randomization in blocks of two”. Low risk of bias
Allocation concealment (selection bias)	Low risk	Quote: “patients were assigned as they arrived in the preoperative clinic”, “The anaesthesiologist [enrolling the participant] did not know in which group the patientwas going to be enrolled”. “The anaesthesiologist [in the OR] did not know the group allocation, until the patient reached the operating room.” “The randomization number was included in the chart in a sealed opaque envelope.” Low risk of bias
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: “the recovery room nurses did not know the anaesthetic technique used in each case.” “The surgeon knew” if a block was performed. Participants were not blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “the outcome observer conducting the interview did not know the group allocation.”
Incomplete outcome data (attrition bias) All outcomes		The numbers excluded in each group for radiotherapy and lost to follow-up, respectively are unclear. Significant attrition with unclear group allocation may have caused bias, but no ITT analysis considered
Selective reporting (reporting bias)	Low risk	Expected primary outcomes fully reported on
Null bias	High risk	Quote: “no significant differences in acute pain were observed”
Ju 2008
Methods	Double-blind (participants and outcome assessor), sham epidural-controlled, clinical RCT Sequence generation was randomized, but not described Follow-up: 12 months
Participants	Participants: 114 adults in a university setting in Beijing, China Operation: posterolateral thoracotomy for lung and oesophageal disease 2 groups, size: 57/57 Age (group 1, 2): 61.80 years (SD ± 13.78), 61.41 (SD ± 11.78) Men/women (group 1, 2): 41/13, 38/15 (completed the protocol) Remarks: pulmonary/oesophageal operation (group 1, 2): 28/26, 25/28 7 participants with dislodged catheters were excluded
Interventions	Group 1 (preincision epidural): epidural at T10/7/8, preincision epidural ropivacaine (0. 5%, bolus 5 mL to 10 mL), GA (fentanyl), post-op for 72 h PCEA (0.125% bupivacaine + 0.05 mg/mL morphine + 0.02 mg/mL droperidol, basal 3 mL/h, demand 3 mL, lock out 15 min) Group 2 (control/cryotherapy): sham epidural at T10/7/8, GA (fentanyl), cryoalgesia, post-op for 72 h PCA through sham epidural (SC, 1 mg/mL morphine, demand 2 mL, lock-out in 30 min, no basal) Adjuvants: none Immediate post-op pain control: not significant
Outcomes	Dichotomous: pain at 6 and 12 months Continuous: not reported Secondary: allodynia at 6 and 12 months
Notes	Funding sources: study supported by grants from Research and Development Foundation of Peking University People’s Hospital Conflicts of interest: no conflict of interest statement given
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “Patients were stratified by disease sites (lungoroesophagus), andblinded ran- domized to receive either epidural analgesia (Epidural Group, Group E) or intercostal nerve cryoanalgesia (Cryo Group, Group C), in order to ensure that both groups had comparable operation methods.” Random- ization method not detailed, but otherwise well documented
Allocation concealment (selection bias)	Low risk	Participants unaware of allocation, conceal- ment of allocation for providers described: “After obtaining … written informed con- sent from the prospective patient cases, 114 physical status I or II patients scheduled for posterolateral thoracotomy for lung or oesophagus diseases were enrolled in the study.”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Intraoperative anaesthesia providers were not blinded. An effort was made to blind study participants Quote: “in order to make the patients blinded to the analgesic method, SC infu- sion catheters were inserted at upper back (T11–8 level) in Group C.” This is accept- able, bias is unlikely
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessor “who was blinded to the postoperative pain management, inter- viewed patients by telephone, using a stan- dard questionnaire.”
Incomplete outcome data (attrition bias) All outcomes	High risk	Attrition was reported, but no ITT analysis was considered.
Selective reporting (reporting bias)	Unclear risk	No protocol was available, but pre-speci- fied outcomes within manuscript were all reported on
Null bias	High risk	Quote: “no statistically significant differ- ences were found between the two groups with respect to NRS pain scores at rest or on motion within three days following surgery”
Kairaluoma 2006
Methods	Triple-blinded (participant, providers, outcome assessor), sham- and placebo-controlled,randomized clinical trial Sequence generation was not described Follow-up: 12 months
Participants	Participants: 60 adults in a university setting in Helsinki, Finland Operation: conservative breast surgery with sentinel lymph node biopsy for cancer 2 groups, size: 30/30 Age: not reported Men/women: 0/60
Interventions	Group 1 (preincision PVB): single shot PVB at T3 with bupivacaine (0.5%, 1.5 mL/kg), GA, post-op: oral ibuprofen (10 mg/kg) and paracetamol (1 g, 3 × daily ) rescueanalgesia: paracetamol (500 mg with codeine 30 mg) or tramadol (50–100 mg) Group 2 (sham PVB): sham PVB at T3 with normal saline, GA, post-op: oral ibuprofen(10 mg/kg) and paracetamol (1 g, 3 × daily) rescue analgesia: paracetamol (500 mg withcodeine 30 mg) or tramadol (50–100 mg) Adjuvants: none Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: NRS larger 3 at 6 and at 12 months, use of pain medication at 6 and 12months Continuous: pain at rest and in motion reported as NRS, number of pain descriptors,all at 6 and 12 months Effective regional anaesthesia not reported, but treatment reduced the severity of post operative pain and oxycodone consumption, postoperatively
Notes	We acknowledge the study author’s response regarding randomization and allocation concealment Funding sources: source of funding not reported Conflicts of interest: conflict of interest statement not provided
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants “were randomly assigned.” Sequence generation was “randomized”, “performed in a randomized fashion”, but the exact method of randomization was not explained. The study author responded “The randomization was done using the opaque sealed envelope method.”
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not described in the original report
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “the patients and the study anaes- thesiologists who performed the analysis remained blinded to the use of PVB with bupivacaine or a sham block throughout the entire study period.” “Procedure behind a drape curtain” The study author responded, also that “the patient, the anaes- thesiologist providing anaesthesia and the staff taking care of the patient were blinded to the study group. The curtains and drapes were hung so that the block was performed behind the curtains on the back side of the patient while the patient’s head and front side and her nurse were on the other side of the curtains. The anaesthesiologist and nursing staff giving general anaesthesia were blinded to the study group...”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “the patients and the study anaes- thesiologists who performed the analysis remained blinded to the use of PVB with bupivacaine or a sham block throughout the entire study period.”, “telephone interviews by a blinded interviewer.” “A group- blinded study assistant conducted all telephone interviews.” The study author responded also that “A non-medical study assistant blinded to the study group performed the follow-up telephone interviews at predestined time points up to 12 months postoperatively”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Attrition explained in detail, ITT analysis performed
Selective reporting (reporting bias)	Unclear risk	Primary outcomes fully reported
Null bias	Low risk	Quote: “the patients given PVB with bupi- vacaine had less postoperative pain, as indicated by longer times to first analgesic dose, lower VAS scores, and 40% smaller oxycodone consumption in the PACU... On the first postoperative day, the number of patients who experienced continuous aching pain and pain at rest was significantly smaller in the PVB group”
Karanikolas 2006
Methods	Double-blind (participants, outcome assessor) placebo-controlled, randomized clinical trial Sequence generation was randomized Follow-up: 6 months
Participants	Participants: 65 adults in a university setting in Patras, Greece Operation: lower limb amputation with pain score > 60/100 VAS 48 h prior to amputation 5 groups, group size: 13 Age: group means ranging 69.2 to 74.3 with largest SD 13 Men/women: 35/53
Interventions	Group 1 (Epi/Epi/Epi): preop: lumbar epidural analgesia bupivacaine (0.2%, fentanyl 2 μg/mL at 4 mL/h to 8 mL/h) for 48 h, GA preincision: epidural bupivacaine (0.5% 10 mL to 15 mL, fentanyl 100 μg), post-op epidural bupivacaine (0.2% fentanyl 2 μg/ mL at 4 mL/h to 8 mL/h) Group 2 (PCA/Epi/Epi): preop: PCA fentanyl (IV, demand 25 μg, lockout 20 min), preincision: epidural bupivacaine (0.5% 10 mL to 15 mL, fentanyl 100 μg), post-op epidural bupivacaine (0.2%, fentanyl 2 μg/mL at 4 mL/h to 8 mL/h) Group 3 (PCA/Epi/PCA): preop: PCA fentanyl (IV, demand 25 μg, lockout 20 min), preincision: epidural bupivacaine (0.5% 10 mL to 15 mL, fentanyl 100 μg), post-op PCA fentanyl (IV, demand 25 μg, lockout 20 min) Group 4 (PCA/GA/PCA): preop: PCA fentanyl (IV, demand 25 μg, lockout 20 min), general anaesthesia with LMA, sevoflurane and remifentanil infusion, post-op PCA fentanyl (IV, demand 25 μg, lockout 20 min) Group 5 (control/GA/control): preop: meperidine (50 mg 4–6 x/d IM) paracetamol/ codeine 30/500 mg orally plus as-needed IV paracetamol 650 mg 3 x/d and parecoxib 40 mg 2 x/d, GA with LMA, sevoflurane and remifentanil infusion, post-op: meperidine (IM) paracetamol/codeine 30/500 mg orally plus as-needed IV paracetamol 650 mg 3 x/d and parecoxib 40 mg 2 x/d Immediate pain control: significantly improved preop and post-op
Outcomes	Dichotomous: phantom limb pain at 6 months Continuous: VAS and McGill pain questionnaire and phantom limb pain frequency scores for phantom and stump pain at 6 months Effective regional anaesthesia not reported, but interventions reduced the severity of pain pre- and postoperatively
Notes	There are minor discrepancies regarding the dosing described between the preliminary report of the ongoing registered trial (Karanikolas 2006) and the final report. We reported the treatment according to the latest publication. We contacted the study author for confirmation and additional information, but received no response. Hence, we could only use the data extracted from the publications and the information provided on cl inicaltrial s. gov/ ct2/show/N CT00443404 Funding sources: “support was provided solely from institutional and/or departmental sources.” Conflicts of interest: no conflict of interest statement was provided
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Described as “prospective, randomized, clinical trial”, with “computer generated blocks with five treatment groups and 13 patients per group.”
Allocation concealment (selection bias)	Low risk	Quote: “sequentially numbered sealed envelope... concealed until after consent was obtain.” Recruitment, outcome assessment and protocol management clearly separated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The trial is described as “double-blind” in the title. Detailed description of blinding procedures. Quote: “control group patients had an epidural catheter placed subcutaneously.” D.A. i.e. the person “responsible for adjusting the epidural...” may not have been blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Detailed description of blinding procedures. Quote: “a second blinded investigator interviewed all participants.” “A third blinded investigator conducted all interviews during the analgesic protocol.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Only minor attrition is reported, and attributed to groups. Seemingly, attrition affected mainly the control groups. ITT analysis is reported. Per protocol or ITT analysis did not change results
Selective reporting (reporting bias)	Low risk	Protocol review and primary outcomes fully reported on
Null bias	Low risk	Quote: “all patients had severe ischemic pain before analgesia started, but pain scores improved markedly and were significantly lower in all intervention groups compared with control at all times while the protocol was in effect”
Karmakar 2014
Methods	Blinded (outcome assessor), RCT Sequence generation by computer-generated allocation number Follow-up: 6 months
Participants	Participants: 180 adult women in University Hospital in Hong Kong, China Operation: modified radical mastectomy (including axillary lymph node clearance) 3 groups, size: 60, 57, 60 Age (± SD), group 1, 2, 3: 51 (± 9), 54 (± 9), 53 (± 8) All female participants
Interventions	Group 1 (GA group): standardized GA as described below Group 2 (GA + single shot PVB + placebo infusion): pre-op thoracic paravertebral catheter placed opposite third thoracic spine, ipsilateral to side of surgery, ropivacaine (2 mg/kg) + epinephrine (5 μg/mL) in total volume of 20 mL with normal saline injected slowly then epidural catheter inserted into thoracic paravertebral space. Intraoperatively, continuous infusion of 0.9% saline started at 0.10 mL/kg/h via catheter and maintained constant until 72 h post-op Group 3(GA+ PVB): pre-op thoracic paravertebral catheter placed opposite third thoracic spine, ipsilateral to side of surgery, ropivacaine (2 mg/kg) + epinephrine (5 μg/ mL) in total volume of 20 mL with normal saline injected slowly then epidural catheter inserted into thoracic paravertebral space. Intraoperatively, continuous infusion of ropivacaine 0.25% started at 0.10 mL/kg/h via catheter, maintained constant until 72 h post-op All participants had standardized GA, which included IV fentanyl, propofol and rocuronium. Intraoperative morphine (0.1 mg/kg) IV to every participant, then morphine (1 mg IV) as needed, ondansetron 4 mg IV 30 min before end of surgery. In the PACU, all participants had nurse-administered IV morphine for rescue analgesia as needed. On post-op ward, analgesia was with diclofenac (75 mg) oral 2 × 72 h, IM morphine (0.1 mg/kg, as needed every 3 h) or Dologesic (paracetamol 325 mg and dextropropoxyphene 32.5 mg, 2 tablets as needed every 6 h) as rescue Adjuvants: none Immediate pain control: not significantly improved
Outcomes	Dichotomous: incidence of chronic pain at all sites (operated site, axilla, arm) and over operated site at 3 and 6 months Continuous: chronic pain scores at rest and on movement at all sites (operated site, axilla, arm) and over operated site at 3 and 6 months Other reported outcomes: HRQOL (Chinese-HK version of SF-36) at 3 and 6 months, Chronic pain symptom and sign score at 3 and 6 months, physical health summary score, mental health summary score (of SF-36) at 3 and 6 months
Notes	Funding sources: this research workwas fullyfunded by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China (RGC reference no. CUHK4406/05, project code 2140452) Conflicts of interest: the study authors declare no conflict of interest
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “patients were randomized tolof 3 study groups... with a computer-generated allocation number”
Allocation concealment (selection bias)	Low risk	Quote: “sequentially numbered, coded, sealed opaque envelopes...The sealed envelopes were prepared by a third party (research assistant) who took no further part in the study”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “patients in groupl, who had received standardized GA with no paravertebral intervention, could not be blinded for obvious reasons..For the other 2 study groups that had a thoracic paravertebral catheter placed, we adopted a double-blind methodology... The principal investigator performed all the thoracic paravertebral catheter placements, collected procedural data, injected the ropivacaine bolus for the TPVB [thoracic paravertebral block], conducted the GA, and took no further part in data collection.. Theparavertebral infusion (ropivacaine 0.25% or 0.9% saline) was prepared.. by a postanaesthetic care unit (PACU) nurse not involved in the study... A single surgeon, who was also blinded to the group allocation, performed or supervised all the surgical procedures”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “a research nurse blinded to the group allocation recorded data preopera- tively, in the PACU, and at regular intervals in the postoperative ward...The telephone interview at 3 and 6 months after surgery was also conducted by the same research nurse (blind to group allocation)”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: “the primary analyses were performed on a modified intention-to- treat basis (i.e., patients were analysed according to their randomized allocated groups but were excluded from the analysis if they did not adhere to the protocol after randomization)”. 1 participant lost to follow-up in group 2 and reason given (returned overseas after surgery). 2 excluded from the analysis in group 2 because of protocol violation/diagnosed contralateral breast cancer. Very small numbers of attrition, with reasons reported for each exclusion and modified ITT protocol used
Selective reporting (reporting bias)	Low risk	All primary outcomes in protocol were fully reported on
Null bias	High risk	Quote: “there was no significant difference in acute pain scores at rest (Fig. 2) or on movement (Fig. 3) between the study groups (both P = 0.22) during the 72 hours after surgery”
Katsuly-Liapis 1996
Methods	clinical RCT Sequence generation randomized, but not described Follow-up: one year
Participants	Participants: 45 adults in a university setting in Athens, Greece Operation: lower limb amputation 3 groups, size: 15/12/18 Age: not reported Men/women: not reported
Interventions	Group 1 (preoperative epidural): for 72 h preop: bupivacaine (0.25% and morphine) via epidural catheter (level not specified), (intraop anaesthesia not specified), post-op for 72 h epidural bupivacaine infusion (not specified) Group 2 (post-op epidural): for72h preop: opioids andNSAIDs (not specified), (intraop anaesthesia not specified), post-op for 72 h epidural bupivacaine infusion (not specified) Group 3 (control): for 72 h preop: opioids and NSAID (not specified), (intraop anaesthesia not specified), post-op opioids and NSAIDs (not specified) Adjuvants: none Immediate post-op pain control: not reported, phantom pain risk not significantly reduced for the first three days
Outcomes	Dichotomous: phantom limb pain at 6 and 12 months Continuous: none reported
Notes	We were unable to find the contact information for any of the authors using Google and PubMed or the institution and therefore no additional information beyond the abstract could be obtained or extracted Funding sources: no source of funding reported. Conflicts of interest: no conflict of interest statement given
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Patients were “randomly allocated”, but the exact method was not explained
Allocation concealment (selection bias)	Unclear risk	Concealment of allocation was not reported.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding was not reported in the abstract.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding was not reported in the abstract.
Incomplete outcome data (attrition bias) All outcomes	High risk	Attrition is not reported. ITT analysis is not mentioned.
Selective reporting (reporting bias)	Unclear risk	No protocol available for review and only abstract available
Null bias	Unclear risk	Immediate post-op pain control not reported, however phantom pain risk not significantly reduced for the first three days
Katz 1996
Methods	Triple-blind (participants, providers, outcome assessors), sham/placebo-controlled, randomized clinical trial Sequence generation was by random number tables Follow-up: 18 months
Participants	Participants: 30 adults in a university setting in Toronto, Ontario, Canada Operation: lateral thoracotomy for pulmonary or oesophageal disease 2 groups, size: 15/15 Age (group 1, 2): 54.6 years (range 19–75), 58.9 (range 46–72) Men/women (group 1, 2): 5/10, 8/7
Interventions	Group 1 (preincision intercostal block): placebo rectal suppository, intramuscular midazolam (0.05 per kg), GA (fentanyl 1 μg/kg), preincision intercostal nerve block with bupivacaine (0.5% with epinephrine (1:200.000), 3 mL/interspace) 2 spaces above and below planned incision, post-op for 72 h PCA morphine (demand 1.5 mg-2 mg, lockout 6 min, max dose 30 mg/4 h) Group 2 (sham/placebo block): IM morphine (0.15 mg/kg) and perphenazine (0.03 mg/kg), indomethacin (100 mg, rectal suppository), GA (fentanyl 1 μg/kg), preincision sham intercostal nerve block with normal saline (3 mL/level) 2 spaces above and below planned incision, post-op for 72 h PCA morphine (demand 1.5 mg-2 mg, lockout 6 min, max dose 30 mg/4 h) Adjuvants: none Immediate post-op pain control: initial analgesic consumption reduced
Outcomes	Dichotomous: pain and analgesic consumption at 18 months Continuous: verbal rating scale at 18 months Secondary: allodynia at 6 and 12 months
Notes	We contacted the study author for missing information. He provided a data table with unpublished data from the follow-up study to Kavanagh 1994, the second manuscript reporting on (Katz 1996). Funding sources: “this study was supported by a research scholarship from the Medical Research Council of Canada (MRC) and by MRC grant MT-12052 to Dr Katz.” Conflicts of interest: a conflict of interest statement was not given
Risk of bias
Bias	Authors’judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “a table of random numbers was used to allocate patients.”
Allocation concealment (selection bias)	Low risk	Quote: “..investigator (who had no further involvement with that patient) who administered the medications in accordance with the instructions in the envelope...”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “the patients and all other personnel involved in subsequent patient management and assessment were completely blinded as to group allocation,...thus maintain the blind and (patients) also received a placebo rectal suppository.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “other personnel involved in subsequent patient management and assessment were completely blinded as to group allocation,...thus maintain the blind and (patients) also received a placebo rectal suppository.”
Incomplete outcome data (attrition bias) All outcomes	High risk	Attrition was described with regards to group allocation. Per-participant analysis was performed, with no ITT analysis considered. Bias is unlikely, as an ITT analysis would not alter the lack of the statistical significance
Selective reporting (reporting bias)	Unclear risk	Primary outcomes fully reported on
Null bias	High risk	Quote: “in the original study, use of preemptive multimodal analgesia during surgery was not found to be more effective than the placebo in reducing the intensity of acute postoperative pain”
Katz 2004
Methods	Double-blinded, placebo/sham-controlled, randomized clinical trial Sequence generation by computer-generated random numbers Follow-up: 6 months
Participants	Participants: 152 adults in a university setting in Toronto, Canada Operation: laparotomy for major gynaecological surgery 3 groups, size: 49/56/47 Age: 44 years (SD ± 8.9), 47 (SD ± 10.6), 44 (SD ± 9.6) Men/women: women only
Interventions	Group 1 (preincisional epidural): epidural catheter at L2/3/4 tested, GA, preincision: lidocaine (2% with epinephrine (1:200,000), 12 mL plus 0.8 mL for each 2.5cm (1 inch) of height above 152cm (60 inch), plus 4 μg/kg fentanyl), 40 min after incision epidural normal saline (12 mL), post-op morphine PCA (loading dose 4 mg, then bolus 1.0–1.5 mg, lockout time 5 min, max 40 mg in 4 h, no basal rate) Group 2 (postincision epidural): epidural catheter at L2/3/4 tested, GA, preincision: epidural normal saline (12 mL), 40 min after incision: lidocaine (2% with epinephrine (1:200,000), 12 mL plus 0.8 mL for each inch of height above 60 inch, plus 4 μg/kg fentanyl), post-op morphine PCA (loading dose 4 mg, then bolus 1.0–1.5 mg, lockout time 5 min, max 40 mg in 4 h, no basal rate) Group 3 (sham epidural): sham epidural catheter at L2/3/4 tested, GA (fentanyl 1 μg/ kg), preincision: epidural normal saline (12 mL), 40 min after incision epidural normal saline (12 mL), post-op morphine PCA (loading dose 4 mg, then bolus 1.0–1.5 mg, lockout time 5 min, max 40 mg in 4 h, no basal rate) Adjuvants: none Immediate post-op pain control: not significant
Outcomes	Dichotomous: pain at 6 months, analgesic consumption at 6 months Continuous: Pain Disability Index, Mental Health Inventory-18 and McGill Pain Questionnaire at 6 months Secondary: allodynia/hyperalgesia
Notes	Funding sources: supported by grants from the National Institutes of Health and the Canadian Institutes of Health Conflicts of interest: conflicts of interest were not reported
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “a randomization schedule was computer generated by a biostatistician.”
Allocation concealment (selection bias)	Low risk	Quote: “an opaque envelope containing the patient number and group assignment was prepared, sealed, and numbered for each patient by the hospital pharmacist, not involved in the study otherwise...All patients and personnel involved in patient management and data collection were unaware of the group to which the patient had been allocated. The anesthesiologist in charge of the case was aware of group allocation for control group patients and was not involved in postoperative management or data collection.”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “all patients and personnel involved in patient management and data collection were unaware of the group to which the patient had been allocated. The anaesthe- siologist in charge of the case was aware of group allocation for control group patients and was not involved in postoperative management or data collection.” but the anaes- thesiologist in charge of the case was aware of group allocation for control group participants
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “neither the person conducting the interview nor the patient was aware of the group to which the patient had been assigned,” “personnel involved in... data collection were unaware of the group to which the patient had been allocated.”
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: “both an intention to treat analysis and a protocol-compliant analysis were performed.” “There was no appreciable difference in the results of the intention-to-treat analyses and the protocol compliant analyses. Data and results of significance tests reported below are therefore based on the intention to treat analyses.” But ITT was only done for early outcomes, not for questionnaire data at 6 months, when significant attrition occurred
Selective reporting (reporting bias)	Unclear risk	Primary outcomes fully reported on
Null bias	Low risk	Quote: “preincisional administration of epidural lidocaine and fentanyl was associated with a significantly lower rate of morphine use, lower cumulative morphine consumption, and reduced hyperalgesia compared with a sham epidural condition”
Kurmann 2015
Methods	Triple-blinded (participants, providers and outcome assessors) placebo-controlled, group sequential clinical trial Sequence generation with computer-generated block sequences Follow-up: 12 months
Participants	Participants: 357 adult participants underwent 403 hernia operations at a teaching hospital in Lucerne, Switzerland Operation: single- or double-sided primary or recurrent inguinal hernia repair 2 groups, participant population size: 162/174 Age (± SD), group 1, 2: 50 (± 16), 51 (± 15) Men/women, group 1, 2: 145/8, 161/8 Comorbidities: unilateral/bilateral hernia (n), group 1, 2: 148/14, 162/12 Primary/ recurrent hernia (n), group 1, 2: 167/14, 186/12 Remarks: the unit of analysis published was the hernia not the participant
Interventions	Group 1 (placebo): “operative procedures were performed under general or SA at the request of the patient”. After closure of the incision, infiltration of 20 mL saline 0.9% in specified region Group 2 (intervention): “operative procedures were performed under general or SA at the request of the patient”. After closure of the incision, infiltration of 20 mLbupivacaine 0.25% in specified region Both groups: infiltration started with the laterocranial puncture 1 finger below and 1 finger medial to the anterior superior iliac spine at the lateral end of the incision; 10 mL of study drug was injected in a fan-shaped manner lateral to and 4 mL medial to the laterocranial puncture. The mediocaudal puncture was located directly above the pubic tubercle; 4 mL of study drug were injected in a fan-shaped manner lateral to and 2 mL medial to the mediocaudal puncture Adjuvants: none Immediate post-op pain control: not reported
Outcomes	Dichotomous: pain/no pain at 3 (and at 12 months, but not published) Continuous: VAS at rest, with various types of movements at 3 and 12 months Other: quality of life at 1 year, neuralgia at 3 and 12 months
Notes	Unit of analysis was the hernia in the original publication. The study authors provided additional information on methodological quality. Absorbed lidocaine from 1 hernia may have mitigated the chronic pain for the other hernia in those with discordant randomization, i.e. participants undergoing bilateral hernia repair in whom one side was treated while the other was not Funding sources: funding provided by NIH grant NCT00484731 Conflicts of interest: Drs Anita Kurmann, Henning Fischer, Salome Dell-Kuster, Rachel Rosenthal, Laurent Audige, Guido Schupfer, Jurg Metzger, and Philipp Honigmann have no conflicts of interest or financial ties to disclose
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “the randomization, based on computer-generated block randomization sequences, was performed in a 1:1 ratio between investigational and control arms”
Allocation concealment (selection bias)	Low risk	Quote: “the hospital pharmacy provided similar-looking syringes containing either bupivacaine 0.25% or saline 0.9% solution according to the randomization sequence”. In the protocol states the syringes are numbered according to “randomization sequence that is kept confidential”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “the patient, surgeon, and the physician performing the examinations during follow-up visits were blinded to the treatment”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “the patient, surgeon, and the physician performing the examinations during follow-up visits were blinded to the treatment. Unblinding was performed after completion of the analysis as described in the study protocol”. Sham techniques would make it difficult for the practitioner to know which group he or she was work-ing with
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow-up was 16% in intervention group and 11.2% in the placebo group at 3 months post-op for primary endpoint. One participant was excluded from placebo group because syringe became unsterile. Participants were excluded retrospectively because did not meet inclusion criteria. Numbers lost to follow-up at each stage clearly delineated. ITT analysis was done, with exception of 1 participant excluded from placebo group described above
Selective reporting (reporting bias)	Low risk	Protocol available and reviewed. Primary outcome of pain at 3 months measured by VAS was fully reported on
Null bias	Unclear risk	No data on immediate postoperative pain control.
Lam 2015
Methods	Placebo-controlled, randomized clinical trial Sequence generation by computer-generated random numbers Follow-up for 6 months
Participants	Participants: 36 adults in a university setting in Alberta, Canada Operation: unilateral total breast mastectomy +/- axillary lymph node dissection 2 groups, size: 18/18 Age (± SD), group 1, 2, 4: 63.9 years (16.7), 60.2 (13.1) All women Exclusion criteria: not specified
Interventions	Group 1 (PVB): participants received an ultrasound-guided PVB (regional anaesthetic not specified) or combined with a multimodal regimen consisting of propofol-based total intravenous anaesthesia with ketorolac, gabapentin, ranitidine, paracetamol, and ondansetron Group 2 (control): same intervention as above except sham block was substituted for local anaesthesia Adjuvants: none Immediate post-op pain control: no improvement
Outcomes	Dichotomous: pain vs no pain Continuous: none Other reported: propofol and fentanyl consumption, postoperative morphine equivalent consumption, frequency of postoperative nausea and vomiting
Notes	We were unable to obtain additional information about randomization and blinding methods from the study author Funding sources: funding for the study not reported Conflicts of interest: there was no statement on conflict of interest
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “following patient allocation with a computer-generated sequence...”
Allocation concealment (selection bias)	Low risk	Quote: “consenting patients were random- ized to either the treatment group or the control group via sealed envelopes”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Sham block was used and participants were well blinded. No comment on personnel blinding
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome assessors not described
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Degree of attrition not described
Selective reporting (reporting bias)	Low risk	No subgroup analysis noted
Null bias	High risk	Quote: “pain scores were similar at all time points within the first 24 hours”
Lavand’homme 2005
Methods	Double-blinded (participant, outcome assessor), placebo/sham-controlled, randomized clinical trial Sequence generation by computer-generated random numbers Follow-up for 12 months
Participants	Participants: 85 adults in a university setting in Brussels, Belgium Operation: colonic resection (xiphopubic incision) of rectal adenocarcinoma 4 groups, size: 20/20/20/20 Age (group 1, 2, 3, 4): 53 years (SD ± 8), 54 (SD ± 8), 55 (SD ± 8), 53 (SD ± 10) Men/women (total: group 1, 2, 3, 4): 49/31: 12/8, 13/7, 12/8, 12/8 Remarks: intraoperative discovery of an extended tumour resulted in participants’ exclu- sion from the study
Interventions	Group 1 (IV/IV): epidural catheter at T12, GA (sufentanil 2.5 μg) IV (lidocaine 2 mg/ kg + 0.5 mg/kg/h, clonidine 4 μg/kg + 1 μg/kg/h, sufentanil 0.1 μg/kg + 0.07 μg/kg/ h) post-op IV PCA (lidocaine bolus per request 7.5 mg, clonidine bolus per request 15 μg, morphine bolus per request 1.3 mg) (0.75 mL solution per demand, lockout time 7 min, max 15 mL per 4 h) Group 2 (IV/epidural): epidural catheter at T12, GA (sufentanil 2.5 μg); IV (lidocaine 2 mg/kg + 0.5 mg/kg/h, clonidine 4 μg/kg + 1 μg/kg/h, sufentanil 0.1 μg/kg + 0.07 μg/kg/h), before recovery (epidural bolus 7 mL bupivacaine 0.5%, clonidine 1 μg/kg, sufentanil 0.03 μg/kg) post-op epidural PCEA (bupivacaine 5 mL 0.0675% + 5 mL/h 0.0675%, clonidine 3.5 μg + 3.5 μg/kg/h, sufentanil 0.05 μg + 0.05 μg/h) (continuous infusion of 5 mL and bolus of 5 mL on request, 40 min lockout time) Group 3(epidural/epidural): epidural catheter at T12, GA (sufentanil 2.5 μg), preincision epidural (bupivacaine 7 mL 0.5% + 5 mL/h 0.125%, clonidine 1 μg/kg + 0.5 μg/kg/h, sufentanil 0.03 μg/kg + sufentanil 0.015 g/kg/h) post-op epidural PCEA (bupivacaine 5 mL 0.0675% + 5 mL/h 0.0675%, clonidine 3.5 μg + 3.5 μg/kg/h, sufentanil 0.05 μg + 0.05 μg/h) (continuous infusion of 5 mL and bolus of 5 mL on request, 40 min lockout time) Group 4 (epidural/IV): epidural catheter at T12, GA (sufentanil 2.5 μg), preincision epidural (bupivacaine 7 mL 0.5% + 5 mL/h 0.125%, clonidine 1 μg/kg + 0.5 μg/kg/h, sufentanil 0.03 μg/kg + sufentanil 0.015 g/kg/h), post-op IV PCA (lidocaine bolus per request 7.5 mg, clonidine bolus per request 15 μg, morphine bolus per request 1.3 mg) (0.75 mL solution per demand, lockout time 7 min, max 15 mL per 4 h) Adjuvants: ketamine from skin incision to the end of surgery (0.5 mg/kg bolus followed by continuous infusion at 0.25 mg/kg/h), clonidine as detailed above Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: pain at 6 and 12 months Continuous: Pain Disability Index at 6 months, Mental Health Inventory-18 at 6 months Secondary: punctuate wound hyperalgesia was reported for the first 72 h
Notes	We contacted the study authors for missing data and they responded, but with some data inconsistencies that could not be verified or corrected. The study authors reported an unusually high success rate of epidural analgesia with only 2 failures in 60 participants Funding sources: “support was provided solely from institutional and/or departmental sources.” Conflicts of interest: no conflict of interest statement provided
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias	Low risk	Quote: ”according to a computer-gener- ated table of random number assignments, each patient was assignedto one of four double-blinded groups.“ Bias is unlikely
Allocation concealment (selection bias)	Unclear risk	The timing of allocation and concealment not detailed. Risk of bias is unclear
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: ”all of the analgesic solutions were prepared by an anesthesiologist who was not involved in the patients’ care.“ Testing the epidural in the PACU “prevented a true double blinding in the postoperative period.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	However, (quote:) ”postoperative param- eters were recorded by an anesthesiolo- gist who was not aware of the intraop- erative treatment administered to the pa- tient“, ”mobilization assessed by a blinded observer“, telephone interviews were ”per- formed by the research nurse.“ The study author responded: ” the research nurse (outcome assessor) was blinded to the group allocation …“ as there was no ran- dom code on questionnaire. Bias is unlikely
Incomplete outcome data (attrition bias) All outcomes	High risk	Adverse effects and attrition were reported with group allocation. “Absence of ther- moanalgesia level as well as intraoperative discovery of an extended tumor resulted in the patient’s exclusion from the study. ” ”One was excluded during surgery after discovery of widespread neoplastic disease, and two other patients were excluded for postoperative early dislocation of epidu- ral catheter (before 72-h follow-up).” “… one who died of a cardiac arrest at home 2 months” before completion. Results re- ported on a per-participant basis, with no ITT analysis considered
Selective reporting (reporting bias)	Low risk	Primary outcomes fully reported on
Null bias	Low risk	Quote: “patients in group 1 (intra- venous-intravenous) experienced signifi- cantly more severe pain than patients in the three other groups. Cumulative number of satisfied analgesic requirements was signif- icantly higher in group 1 (intravenous-in- travenous) than in the other groups ”
Lavand’homme 2007
Methods	Triple-blinded (participants, provider, outcome assessor), placebo/sham-controlled, ran- domized clinical trial Sequence generation by computer-generated random numbers Follow-up: 6 months
Participants	Participants: 92 adults in a university setting in Brussels, Belgium Operation: elective caesarean section (Pfannenstiel incision) 3 groups, size: 30/30/30 Age (group 1, 2, 3): 33 years (SD ± 5), 31 (SD ± 5), 31 (SD ± 6) Men/women: 0/92 Remarks: no previous caesarean delivery
Interventions	Group 1 (ropivacaine): spinal bupivacaine (1.8-2 mL hyperbaric 0.5%, sufentanil 1 μg/ kg), post-op for 48 h continuous wound irrigation (ropivacaine (0.2%, 5 mL/h), every 12 h diclofenac (75 mg in 50 mL/20 min)), PCA (morphine, no basal rate, demand 1 mg, lockout 5 min, max 25 mg/4 h), as needed paracetamol (1 g/6 h) Group 2 (diclofenac): spinal bupivacaine (1.8 mL–2 mL hyperbaric 0.5%, sufentanil 1 μg/kg), post-op for 48 h continuous wound irrigation (diclofenac (300 mg in 240 mL, 5 mL/h) IV saline 50 mL/20 min every 12 h), PCA (morphine, no basal rate, demand 1 mg, lockout 5 min, max 25 mg/4 h), as needed paracetamol (1 g/6 h) Group 3 (saline): spinal bupivacaine (1.8mL to 2 mL hyperbaric 0.5%, sufentanil 1 μg/ kg), post-op for 48 h continuous wound irrigation (saline (5mL/h), every 12 h diclofenac (75 mg in 50 mL/20 min)), PCA (morphine, no basal rate, demand 1 mg, lockout 5 min, max 25 mg/4 h), as needed paracetamol (1 g/6 h) Adjuvants: none Immediate post-op pain control: pain and analgesic consumption significantly improved
Outcomes	Dichotomous: ”chronic postsurgical pain“ and scar/wound pain at 6 months Continuous: none reported Secondary: punctuate wound hyperalgesia for the first 48 h. Analgesic consumption at 6 months. Wound healing and complications such as hypotension, nausea or vomiting
Notes	The study author responded to our request for clarification, but with information differing from the published data Funding sources: “support was provided solely from institutional and/or departmental sources.” Conflicts of interest: no conflict of interest statement was given
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “...according to a randomized, prospective, blinded protocol...The parturients were randomly assigned using computer-generated random numbers...”
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not explicitly described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: ”the patient, the person in charge of perioperative management,... were not aware of the patient group assignment.“
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: ”the staff involved in data collection were not aware of the patient group assignment.“ The study author responded to our inquiry that ”the research nurse was blinded to the group allocation- there was no code on the questionnaire, she used.“
Incomplete outcome data (attrition bias) All outcomes	Low risk	A per-participant analysis was performed, with no attrition reported. But the study author responded: “patients were excluded from the data analysis (intraoperative failure of intrathecal anaesthesia and intrawound catheter out, which did not allow a 48h postoperative follow up). We continued the inclusion of patients following the randomisation and at the end of the random list, we add 1 patient in ropivacaine group and 1 patient in diclofenac group (in the same order than those patients were excluded from the study).” Even though no formal ITT analysis was performed, only 2/90 participants were excluded, reducing the likelihood of bias
Selective reporting (reporting bias)	Low risk	Study protocol not available but published report includes all the expected outcomes
Null bias	Low risk	Quote: “for the first 12 h after surgery, patients receiving a subcutaneous infusion of ropivacaine reported lower VAS pain scores at rest and during movement than those receiving local saline infusion... Wound infiltration with ropivacaine was also more effective than saline to relieve visceral pain at 12 h after surgery.”
Lee 2013
Methods	Single-blinded (outcome assessor) clinical RCT Sequence generation using random numbers table Follow-up: 3 months
Participants	Participants: 51 adults in a university setting in Cork, Ireland Operation: breast surgery (mastectomy or breast tumour resection) with axillary node clearance 2 groups, size: 26/25 Age, years (± SD), group 1, 2 : 57.8 (± 14.5), 54.3 (± 11.5) Men/women: all women Comorbidities: wide local excision/mastectomy/mastectomy and reconstruction, n (group 1, 2): 16/9/1, 13/11/1. Chemotherapy, n (group 1, 2): 13, 18. Further surgery, n: None/wide local excision/mastectomy/wide local excision and mastectomy (group 1, 2): 18/4/1/3, 18/3/2/2 Remarks: exclusion criteria included pre-existing pain conditions other than those due to breast lump biopsy
Interventions	Group 1 (Group C, control): as needed morphine IV intro. Post-op morphine 2 mg IV as needed in PACU until morphine PCA × 48 h post-op (2 mg bolus, 5 min lockout, no background, max dose 30 mg 4 h), diclofenac 50 mg oral/PR every 8 h as needed, paracetamol 1 g oral/PR/IV every 6 h as needed Group 2 (Group P, paracetamol and paravertebral): paravertebral catheter inserted prior to induction, 10 mL bupivacaine 0.25% injected with repeat aspiration tests then catheter inserted. 10 mL bupivacaine 0.25% 4 h post-op then every 12 h × 48 h Both groups: GA induction with propofol 2–2.5 mg/kg, maintenance with sevoflurane in O2/N2O mixture, vecuronium with 75 mg IV diclofenac sodium and 1 g IV paracetamol intraoperatively. All participants received 100 mg tramadol oral as rescue if required Adjuvants: pregabalin Immediate post-op pain control: not significantly improved, but with significantly decreased analgesic consumption
Outcomes	Dichotomous: pain/no pain at 3 months Continuous: Short-form McGill Pain questionnaire at 3 months Secondary: Hospital Anxiety and Depression score, Spielberger Tate-Trait Anxiety Inventory at 3 months, allodynia/hyperalgesia
Notes	Funding sources: “PL received a research grant from the South of Ireland Association of Anaesthetists.” Conflicts of interest: “nothing to declare”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “using a random numbers table, patients were randomly allocated to one of two groups”
Allocation concealment (selection bias)	Low risk	Upon contacting study author: quote: “these pieces of paper were then placed in opaque sealed numbered envelopes”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Upon contacting study author: quote: “the envelopes were not opened until all study information was gathered and data analysis had begun”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “patients were interviewed three months postoperatively...by an investigator blinded to their group assignment”
Incomplete outcome data (attrition bias) All outcomes	Low risk	No participants were lost to follow-up. ITT analysis performed
Selective reporting (reporting bias)	Low risk	All expected outcomes were reported on.
Null bias	High risk	Quote: “patients in the two groups were similar in terms of reported pain intensity in the early postoperative period,”
Liu 2015
Methods	Assessor-blinded, randomized clinical trial Sequence generation not described Follow-up for 3 months
Participants	Participants: 120 adults in a university setting in China Operation: open thoracotomy 2 groups, size: 60/60 Age (± SD), group 1, 2: 61 (10), 58 (10) Men/women, group 1, 2: 33/27, 36/24 Exclusion criteria: paralysis, known allergy to LAs, active bacterial infection, clinically severe liver or kidney diseases, neurologic dysfunction, chronic use of systemic lidocaine, NSAIDs or opioids, insulin-dependent diabetes mellitus and para-aminobenzoic acid
Interventions	Group 1 (ropivacaine wound infusion): the moment participants entered the operating room, standard monitoringwas performed by 5-lead electrocardiography, pulse oximetry, and non-invasive arterial pressure measurement. GA was induced with midazolam at 0.05 mg/kg, propofol at 1.5 mg/kg to 2.5 mg/kg and fentanyl at μ3 g/kg. When loss of consciousness was confirmed, a bolus of 0.8 mg/kg rocuronium was intravenously injected for tracheal intubation. Anaesthesia was maintained with continuous infusion of propofol and a bolus of fentanyl at 1 μg/kg/h to 2 μg/kg/h in order to keep the bispectral index monitor (BIS, Aspect 1000, Aspect Medical System Inc., Natick, MA, USA) between 40 and 60. Neuromuscular blockade was conducted by continuous infusion of cis-atracurium at 0.06–0.07 mg/kg/h. Participants in both groups were accessible to rescue analgesia via pethidine, if needed, during the postoperative period. The catheter was positioned in the SC tissues above the fascia along the inferior edge of the rib along the incision. The catheter consisted of a multi-orifice tube that was connected to an elastomeric infusion pump (Beijing tech-bio-med medical equipment Corporation, China) for postoperative continuous SC infusion with an anaesthetic at the end of surgery. After skin closure, the infusion pump containing 0.5% ropivacaine (Naropin®- produced by AstraZeneca) was connected, and the wound was infused at 2 mL/h Group 2 (control): same intervention induction procedure as above. No catheter was inserted. Sufentanil was injected intravenously via an analgesia pump after surgery, followed by intravenous PCA with sufentanil at 2 mL/h Adjuvants: fentanyl Immediate post-op pain control: no difference
Outcomes	Dichotomous: pain vs no pain Continuous: none Secondary: the level of sedation, severity of pain at rest and movement, the amount of opioid analgesics administered, and participants’ satisfaction with their postoperative pain management
Notes	We were unable to obtain additional information about randomization and blinding methods from the study author Funding sources: “this work was supported by Natural Science Foundation of Jinling Hospital.” Conflicts of interest: the study authors have no conflicts of interest to disclose
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomization technique not described
Allocation concealment (selection bias)	Unclear risk	Allocation of concealment not described
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding of participants and personnel not described
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “postoperative evaluations were performed by an observer blind to this study.”
Incomplete outcome data (attrition bias) All outcomes	High risk	There was a substantial degree of attrition.
Selective reporting (reporting bias)	Low risk	ITT principle was used and no subgroup analysis was performed
Null bias	High risk	Quote “There were no statistical differences in the VAS scores... between the two groups”
Loane 2012
Methods	Double-blind (participant, outcome assessor) randomized clinical trial Sequence generation by computer-generated table Follow-up: 3 months
Participants	Participants: 69 adult women at university hospital in Vancouver, British Columbia, Canada Operation: elective caesarean delivery with low transverse incision (under SA) 2 groups, size: 33/33 (completed) Age (± SD), group 1, 2: 35 (± 3), 34 (± 5) All female participants Comorbidities: number of multiparous women (group 1,2): 25/21
Interventions	Group 1 (intrathecal morphine): 100 μg intrathecal morphine at time of spinal insertion. At end of surgery, sham TAP block with capped needle pushing against skin Group 2 (TAP block): no intrathecal morphine was given. At the end of surgery, TAP block 5 mL increments of ropivacaine into transversus abdominis plane on each side (0. 5% ropivacaine, 1.5 mg/kg on each side to max of 100 mg (20 mL)) Both groups received standardized SA with 0.75% hyperbaric bupivacaine 11.25 mg + fentanyl 10 μg and at the end of surgery, rectal naproxen 500 mg + paracetamol 975 mg. Both had same post-op analgesia regimen with 500 mg naproxen every 12 h standing, oral hydromorphone 2 mg–4 mg every 4 h as needed with IV PCA (bolus 1.5 mg, lockout 7 min, max 10 mg/h) if needed Adjuvants: none Immediate post-op pain control: pain scores were higher in participants receiving a TAP block at all time points but this was only significant at 10 h; statistically significant increase in morphine consumption 24 h post-op in TAP group, but not at earlier time point
Outcomes	Dichotomous: pain/no pain “in the operative area” at 3 months Continuous: none Adverse events: incidence of wound infection, nausea/vomiting, pruritus, sedation
Notes	We contacted the study author for clarification on participant flow details, but received no response Funding sources: “the authors received no external funding for this project.” Conflicts of interest: “Dr Joanne Douglas is an Editor of the International Journal of Obstetric Anesthesia. She had no involvement with the editorial process or decision to accept this article.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomly assigned using “computer-generated table” after consent and enrolment
Allocation concealment (selection bias)	Low risk	Quote: “group allocation was concealed in an opaque envelope until the woman was consented and enrolled”
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: “women, postoperative care providers..were blinded to treatment group...The anaesthesiologist caring for the woman, as well as the anaesthesiologist performing the TAP block, were not blinded”. Bias during operation by nonblinded providers possible, e.g. by administering additional morphine, but not very likely
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “women, postoperative care providers and research staff collecting postoperative data were blinded to treatment group”
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	69 women were randomized, but 1 in intrathecal morphine group and 2 in TAP group were excluded because of protocol violation. 3-month follow-up was obtained from 31 (of 33) in group 1 and 28 (of 33) in group 2. Numbers of attrition provided per group, fairly balanced. However, numbers presented in text do not match the numbers presented in the flow chart (reversed groups)
Selective reporting (reporting bias)	Low risk	Primary outcome in protocol fully reported on. Investigator left the study and this led to premature termination of the study before the intended time
Null bias	High risk	Quote: “pain scores on rest and movement were higher in the TAP block group at all times although this only reached statistical significance at 10 h (P = 0.001)”
Lu 2008
Methods	Placebo-controlled, randomized clinical trial Sequence generation was randomized Follow-up: 6 months
Participants	Participants: 105 adults in a university setting in Guangdong, China Operation: thoracotomy for tumour resection 3 groups, size randomized (completed): 36 (32)/36 (30)/33 (28) Age (median group 1, 2, 3): 57, 55, 59 years Men/women (group 1, 2, 3): 24/8, 18/12, 20/8 Remarks: 2 participants excluded intraop, 13 participants excluded post-op with group allocation not specified
Interventions	Group 1 (preincision epidural): epidural at T11/8, 3 mL 1% lidocaine (test dose), preincision 10 mL ropivacaine (0.25%, with morphine 0.2 mg/mL) epidurally, GA, post-op 2 mL/h (0.15% ropivacaine and 1.5 μg/kg/mL morphine) epidurally for 48 h, additional analgesics and rescue medication not described Group 2 (post-op epidural): epidural at T11/8, 3 mL 1% lidocaine (test dose), GA, post-op 2 mL/h (0.15% ropivacaine and 1.5 μg/kg/mL morphine) epidurally for 48 h, additional analgesics and rescue medication not described Group 3 (control): GA (0.1 mg fentanyl), post-op IV fentanyl (0.25 μg/kg/mL at basal 2 mL/h + 0.05 mg/mL demand) for 48 h, additional analgesics and rescue medication not described Adjuvants: none Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: pain at 3 and 6 months Continuous: not reported
Notes	Article published in Mandarin. Data extracted from the abstract and tables, methodological information extracted with the help of a Mandarin-speaking statistician Funding sources: source of funding not reported Conflicts of interest: conflict of interest statement not given
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The allocation was by “random numbers generation”. Bias is unlikely
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not described. Bias is possible, but unclear
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: “the attending physician called the patient”. No detail provided neither in the English abstract nor the Mandarin methods section
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: “the attending physician called the patient”. No detail provided neither in the English abstract nor the Mandarin methods section
Incomplete outcome data (attrition bias) All outcomes	High risk	Attrition was described with reasons, but it is unclear what the reasons for the attrition were in each group. Attrition was larger in control group. No ITT analysis described. Bias is likely
Selective reporting (reporting bias)	Low risk	No protocol available, primary outcomes specified in text fully reported on
Null bias	Low risk	Quote: “VAS scores in the first 48h after operation were significantly lower in group PE and group E than in the group IV (P < 0.05)”
McKeen 2014
Methods	Double-blinded (participant, outcome assessor) randomized placebo-controlled clinical trial Sequence generation by computer-generated random numbers Follow-up: 6 months
Participants	Participants: 74 pregnant women from university hospital in Halifax, Canada Operation: scheduled caesarean delivery (planned SA) 2 groups, size: 35/39 (completed) Age (± SD), group 1, 2: 32.1 (± 5.3), 31.4 (± 5.8) All female participants Comorbidities: gravidity (n) 1/2/3/4/5, group 1, 2: 1/1/11/16/5, 2/1/12/15/9; parity (n) 0/1/2/3, group 1, 2: 7/21/7/0, 10/18/10/1
Interventions	Group 1 (ropivacaine): at conclusion of surgery, 20 mL0.25% ropivacaine injected deep to tissue fascial plane between interior oblique and transversus abdominis Group 2 (placebo): at conclusion of surgery, 20 mL 0.9% saline injected deep to tissue fascial plane between interior oblique and transversus abdominis. All participants received antacid prophylaxis. Standardized spinal anaesthetic technique hyperbaric bupivacaine, fentanyl, morphine. At conclusion of procedure, ketorolac, ondansetron, paracetamol and bilateral TAP blocks under ultrasound. Post-op pain control with naproxen 250 mg every 8 h, paracetamol 1 g every 6 h, and oxycodone 2.5 mg–5mg every 6 h as needed Adjuvants: none Immediate post-op pain control: no significant decrease in pain or morphine consumption
Outcomes	Dichotomous: none Continuous: SF-36 Other: adverse effects reported on include nausea, vomiting, pruritus, urine retention
Notes	We acknowledge the study author’s response that no dichotomous pain data were collected at 6 months, only SF-36 Funding sources: “Dr McKeen acknowledges the support of the Canadian Anesthesiologists’ Society (CAS) GE Healthcare Canada Research Award in Perioperative Imaging Operating Grant. Dr George held an IWK Recruitment & Establishment Grant and acknowledges the support of a CAS Career Scientist Award. Dr Allen held a Canadian Institutes of Health Research New Investigator Award and a Dalhousie University Clinical Research Scholar Award. Dr Pink acknowledges Dalhousie University Medical Research Foundation Summer Research Studentship Funding.” Conflicts of interest: “none declared”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “computer-generated block randomized table. Blocks were permuted at ten patients per block with equal allocation of patients between the two groups”
Allocation concealment (selection bias)	Low risk	Quote: “sealed opaque envelopes” labelled with a study number based on order of recruitment with randomization to 1 of two groups (A or B) inside envelope. The pharmacy supplied sterile blinded study drug syringes labelled TAP Block Study Drug “A” or “B”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The pharmacy supplied sterile blinded study drug syringes labelled TAP Block Study Drug “A” or “B” Quote: “prior to each patient’s discharge from the PACU (once spinal motor block had regressed), one of the investigators (D. M. or R.G.) assessed the adequacy of the TAP.” This was only known after the participant had left the PACU and was receiving the same ward orders no matter what group
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “research personnel unaware of the patients’ randomization or adequacy of block assessment collected data until the patients left the PACU (minimum two hours), then 24 h and 48 h postoperatively via a ward visit... research personnel contacted patients via telephone at 30 days and six months to complete a five minute Short Form-36 Health Survey (SF-36)”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Balanced, low rates of attrition between groups. Reasons for exclusion/missing data are listed for each group
Selective reporting (reporting bias)	Low risk	Quote: “trial registration was not congruent with the final study protocol and did not include cumulative opioid consumption at 24 h postoperatively as a primary outcome”. However, this value was not statistically significant and did not add effect to their results, thus low risk of reporting bias
Null bias	High risk	Quote: “pain scores at 24 hr were slightly higher in the TAP 0.25% ropivacaine group. These differences were not statistically significant”
Micha 2012
Methods	Double-blinded (participant/outcome assessor), placebo-controlled, randomized clinical trial Sequence generation by computer-generated random numbers Follow-up: 6 months
Participants	Participants: 35 adults in a hospital setting, Athens, Greece Operation: modified radical mastectomy with axillary dissection Groups, size: 17/18 Age: not specified All female participants, 13/7 Comorbidities: none included
Interventions	Group 1 (ropivacaine): at conclusion of surgery, 20mL 0.25%ropivacaine injected deep to tissue fascial plane between interior oblique and transversus abdominis Group 2 (placebo): at conclusion of surgery, 20 mL 0.9% saline injected deep to tissue fascial plane between interior oblique and transversus abdominis. All participants received antacid prophylaxis. Standardized spinal anaesthetic technique hyperbaric bupivacaine, fentanyl, morphine. At conclusion of procedure, ketorolac, ondansetron, paracetamol and bilateral TAP blocks under ultrasound. Post-op pain control with naproxen 250 mg every 8 h, paracetamol 1 g every 6 h, and oxycodone 2.5 mg-5mg every 6 h as needed Adjuvants: none Immediate post-op pain control: no significant decrease in pain or morphine consumption
Outcomes	Dichotomus: none Continuous: SF-36 Other: adverse effects reported on include nausea, vomiting, pruritus, urine retention
Notes	We acknowledge the study author’s response that no dichotomous pain data were collected at 6 months, only SF-36 Funding sources: “Dr McKeen acknowledges the support of the Canadian Anesthesiologists’ Society (CAS) GE Healthcare Canada Research Award in Perioperative Imaging Operating Grant. Dr George held an IWK Recruitment & Establishment Grant and acknowledges the support of aCAS Career Scientist Award. Dr Allen held aCanadian Institutes of Health Research New Inv stigator Award and a Dalhousie University Clinical Research Scholar Award. Dr Pink acknowledges Dalhousie University Medical Research Foundation Summer Research Studentship Funding.” Conflicts of interest: “none declared”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “computer-generated block randomized table. Blockswere permuted at ten patients per block with equal allocation of patients between the two groups”
Allocation concealment (selection bias)	Low risk	Quote: “ sealed opaque envelopes” labelled with a study number based on order of recruitment with randomization to 1 of two groups (A or B) inside envelope. The pharmacy supplied sterile blinded study drug syringes labelled TAP Block Study Drug“A” or “B”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The pharmacy supplied sterile blinded study drug syringes labelled TAP Block Study DrugA” or “B” Quote: “prior to each patient’s discharge from the PACU (once spinal motor block had regressed), one of the investigators (D. M. or R.G.) assessed the adequacy of the TAP.” This was only known after the participant had left the PACU and was receiving the same ward orders no matter what group
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “research personnel unaware of the patients’ randomization or adequacy of block assessment collected data until the patients left the PACU (minimum two hours), then 24 h and 48 h postoperatively via a ward visit... research personnel contacted patients via telephone at 30 days and sixmonths to complete a fiveminute Short Form-36 Health Survey (SF-36)”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Balanced, low rates of attrition between groups. Reasons for exclusion/missing data are listed for eachgroup
Selective reporting (reporting bias)	Low risk	Quote: “trial registration was not congruent with the final study protocol and did not include cumulative opioid consumption at 24 h postoperatively as a primary outcome”. However, this value was not statistically significant and did not add effect to their results, thus low risk of reporting bias
Null bias	High risk	Quote: “pain scores at 24 hr were slightly higher in the TAP 0.25% ropivacaine group. These differences were not statistically significant”
Mounir 2010
Methods	Double-blinded (participant/outcome assessor), placebo-controlled, randomized clinical trial Sequence generation unclear Follow-up: 6 months
Participants	Participants: men in a military teaching hospital in Rabat, Morocco Operation: inguinal hernia repair groups, size: 20/22 Age: years (range ): 46 ± 5; 40 ± 4 Men/women (group 1, 2): 20/0; 22/0 Comorbidities (group 1, 2, 3): none reported Remarks: only ASA I and II
Interventions	Group 1 (bupivacaine wound infiltration): spinal (12.5 mg hyperbaric bupivacaine + 25 μg fentanyl, intrathecally), postincision SC infiltration of the skin with bupivacaine (0.5%, 20 mL), post-op 1 g paracetamol, ketoprofen (100 mg), morphine 3 mg as needed for breakthrough pain Group 2 (saline/placebo wound infiltration): spinal (12.5 mg hyperbaric bupivacaine + 25 μg fentanyl, intrathecally), postincision SC infiltration of the skin with saline (0.9%, 20 mL), post-op 1 g paracetamol, ketoprofen (100 mg), morphine 3 mg as needed for breakthrough pain Adjuvants: none Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: pain/no pain at 3 and 6 months, (pain differentiated in mild, moderate and severe) Continuous: none Secondary:
Notes	The report leaves it unclear if postoperative analgesics were given intravenously or orally. We contacted the study author for clarification of randomisation, allocation and blinding methods, but did not get a response Funding sources: no funding sources specified Conflicts of interest: no conflict of interest declared
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “etude prospective randomisee”, (prospective randomized trial) “La randomisation etait realise au cours de la visite preanesethesique par envelopes cachetees et numerotees...” (the randomization was realized during the preoperative visit with numbered and sealed envelopes) Even so the study is reportedly “randomized”, the randomization method is not explained, hence bias is possible
Allocation concealment (selection bias)	Unclear risk	Quote: “la randomisation etait realise au cours de la visite preanesethesique par envelopes cachetees et numerotees...” It is unclear if and how and how long the allocation was concealed to the person enrolling the participants or to the anaesthesia provider. Bias is therefore possible
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “l’anesthesiste remettait au chirurgien une seringue”, “le chirurgien, qui ignorait la solution de in-filtration”, (The anesthesiologist passed a syringe to the surgeon,... the surgeon did not know the solutions to be infiltrated. ) Possibly no blinding of the anaesthesia providers, but participant and surgeonwere blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote:” a six mois“ ”evaluee grace a un questionnaire rempli par tous les patients lors de leur consultation de chirurgie de controle?”. (at six months... evaluated by a questionnaire filled out by all participants during their surgical follow-up visit) The outcome observer (surgeon) was blinded and the outcomewas reportedwith the use of a questionnaire
Incomplete outcome data (attrition bias) All outcomes	Low risk	The uneven numbers of 22 and 20 in both groups leaves open the possibility of an error in the allocation process, cross over, attrition or incorrect randomisation and this is not addressed in the report. Bias seems still unlikely, due to the low attrition
Selective reporting (reporting bias)	Low risk	Primary outcomes fully reported on
Null bias	Low risk	Quote: “there was a significant reduction of postoperative pain in the bupivacaine group at rest as well as with coughing”
O’Neill 2012
Methods	Single-blind (outcome assessor), RCT Sequence generation by computer-generated random numbers Follow-up: 3 months
Participants	Participants: 67 women aged 18-50 years, gestational age 37-42 at hospital setting in Lisbon, Portugal Operation: elective caesarean section delivery (with Pfannenstiel incision) Groups, size: 29/29 Age (years ± SD; group 1, group 2): 33 ± 5, 33 ± 5 Men/women (group 1, 2): 0/29, 0/29 Primary caesarean delivery (n, group 1/2): 25/24
Interventions	Group 1 (continuous wound infusion group): anaesthesia was performed through SAB with hyperbaric bupivacaine and sufentanil with single-shot SA. Intra-op: catheter placed in wound below fascia after peritoneum closed, 10 mL ropivacaine 10 mg/mL injected during wound closure, then continuous infusion ropivacaine 2 mg/mL at 5 mL/h for 48 h Group 2 (epiduralmorphine): anaesthesia initiated with combined spinal-epidural technique to site epidural catheter, single-shot SA. Intra-op: upon partial recovery from motor blockade (Bromage score 2), initiated 2 mg/10 mL bolus epidural morphine every 12 h (x 4 times). Neither group received any preanaesthetic medication. Both received standardized post-op analgesia with paracetamol 1 g every 6 h × 48 h, breakthrough pain (VAS > 3) with IM diclofenac 75 mg every 6 h as needed, ondansetron 4 mg IV for nausea or vomiting as needed Adjuvants: none Immediate post-op pain control: significantly improved
Outcomes	Continuous: presence or absence of “residual pain related to the scar or pain that the patient related to caesarean delivery” at 3 months Dichotomus: none Other reported: neurologic sequelae (paraesthesia, tactile hyperaesthesia), surgical wound healing impairment, surgical wound infection, impact on care provided to newborn/relationship, satisfaction score all at 3 months Adverse events: nausea, vomiting and anti-emetic therapy requirements, incidence of pruritus, urinary retention, sedation, incidence of neurologic alterations (paraesthesia, tactile hyperaesthesia, headache)
Notes	Because no events were detected in either arm, we could not include the study in the meta-analysis Funding sources: “Dr Patricia O’Neill received speaker fees from Baxter Healthscore in 2010. B. Brain and Baxter were contacted simultaneously by authors to provide devices to perform the study. B Braun declined and Baxter showed interest and provided the devices for the study. Dr O’Neill helped design the study, conduct the study, analyse the data and write the manuscript and was paid by the company providing the devices for the study, to speak, after the study was finished being conducted but the results were not yet published. All four other authors reported no conflict of interest.” Conflicts of interest: “we do not see a conflict of interest for the authors and no risk of bias of undue sponsor influence.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “computer-generated random number list”
Allocation concealment (selection bias)	Low risk	Quote: “ list concealed in an opaque envelope”. Randomization was done after consent and prior to initiation of anaesthesia
Blinding of participants and personnel (performance bias) All outcomes	High risk	The intraoperative and postoperative anaesthesiamanagerswere not blinded, nor were the surgeons, This is acceptable for inclusion
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “Three months after discharge, patients were interviewed by telephone by an investigator blinded to group assignment”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Per protocol analysis done, no ITTanalysis. Number of participants in each group who were excluded is given, as well as the reasons for exclusion (e.g. accidental removal of catheter, did not receive allocated intervention, etc). Low overall attrition, fairly balanced numbers between groups
Selective reporting (reporting bias)	Low risk	Primary outcomes listed in manuscript completely reported on. No protocol available for review
Null bias	Low risk	Pain scores (quote:) “at rest at 2, 6, and 48 hours were lower in the continuous wound infusion group than in the epidural morphine group... (pain scores) evaluated at mobilization were higher in the epidural morphine group at 2 and 6 hours”
O’Neill 2014
Methods	Double-blinded (participant/outcome assessor), placebo-controlled, randomized clinical trial Sequence generation unclear Follow-up: 4-6 months
Participants	Participants: 40 adults in a university setting, Nashville, TN, USA Operation: ICBG for spinal fusion Groups, size: 20/20 Age (± SD), group 1, 2: 66 (± 12), 62 (± 8) Men/women (group 1, 2): 13/7, 13/7 Comorbidities: tobacco use, group 1, 2 (18, 16); alcohol use, group 1, 2 (7, 6)
Interventions	Group 1 (bupivacaine): intra-op: rectangular window of approximately 4 × 1 cm was created in the cortex of the posterior superior iliac spine using osteotomes and was then hinged open to allow access to cancellous bone. After graft harvest, a gel foam soaked in 10 mL 0.25% bupivacaine was packed into the wound. The cortical bone window was replaced and the wound closed Group 2 (saline): intra-op: same method of gel-foam packing into cortex of posterior superior iliac spine. Gel was soaked in 10 mL 0.9% saline Adjuvants: none Immediate post-op pain control: not reported
Outcomes	Continuous: VAS at 4-6 months Dichotomus: none Other reported: surgical data included the type of surgery, surgical indication, number of levels fused, the use of instrumentation, and the operative time. Health outcomes were back and neck pain, satisfaction with surgical results, and mental/physical states as determined by the Short Form-12 Adverse events: 1 participant in the saline group had infection
Notes	The reported continuous data were insufficient for inclusion in the additional Bayesian inclusive analysis Funding sources: “the authors have no relevant financial relationships to disclose.” Conflicts of interest: conflicts of interest statement not provided
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “a block randomization schemewas used,” but the method of randomization was not described
Allocation concealment (selection bias)	Low risk	Quote: “a sealed envelope containing the group assignment was opened and the appropriate intervention was performed”
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Participants and surgeons were blinded, but knowledge of anaesthesia team not described
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “all forms were administered and collected by a research nurse without knowledge of the assigned group”
Incomplete outcome data (attrition bias) All outcomes	Low risk	19/20 in the treatment group and 17/20 in the control group completed the final evaluation Quote: “thismet the goal of 17 patients per group as determined from the sample size calculation.”
Selective reporting (reporting bias)	Unclear risk	The protocol defined the VAS at 3 months as the primary outcome, but it remained unclear fromthemanuscript if the pain was recorded at rest or at movement and if the current or the average pain was the initial primary outcome
Null bias	Low risk	Experimental treatment was effective in improving immediate postoperative pain control for some outcome measures at least
Okur 2016
Methods	Randomized clinical trial Sequence generation by ”simple random sampling“ Follow-up for 6 months
Participants	Participants: 90 adults in a university setting in Turkey Operation: inguinal herniorrhaphy 3 groups, size: 30/30/30 Age (± SD), group 1, 2, 3: not described Men/women, group 1, 2, 3: not described Exclusion criteria: not described
Interventions	Group 1 (spinal): SAB was administered. Further detail about anaesthetic regimen and timing of intervention was not provided Group 2 (TAP): in addition to SAB, TAP block was performed. No additional detail about anaesthetic regimen or timing of intervention provided Group 3 (IINB): in addition to SAB, ilioinguinal/iliohypogastric nerve block was performed. No additional detail about anaesthetic regimen or timing of intervention provided Adjuvants: none Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: none Continuous: NRS score Other reported: NRS score and amount of analgesia given in perioperative period
Notes	Published only as abstract. We were unable to obtain data on pain outcomes or additional information about randomization and blinding methods from the study author Funding sources: funding of study not described Conflicts of interest: the study authors have no conflicts of interest to disclose
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Sequence generation by, quote: ”simple random sampling“
Allocation concealment (selection bias)	Unclear risk	Concealment of allocation not described
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding of participants and personnel not described
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome assessors not described
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Rate of attrition not described
Selective reporting (reporting bias)	Unclear risk	Unclear if subgroup analysis performed
Null bias	Low risk	Quote: ”NRS scores... in TAP block were significantly smaller in all measurements...“.”
Paxton 1995
Methods	Double-blind, placebo-controlled, randomized clinical trial Sequence generation “at random”, but not described Follow-up: 12 months
Participants	Participants: 70 adults from a university setting in Belfast, Northern Ireland Operation: vasectomy for contraception 2 groups, size: 70 total, (group size not given) Age: years (range ): 35 years (range 26-45), 34 years (28-45) Men/women: 70/0 Remarks: in the intervention group, body sides were randomized to receive treatment or placebo
Interventions	Group 1a (intervention, body side treated): GA, intraop: bupivacaine (0.5% 1 mL) injected into the lumen of the vas deferens, post-op NSAID Group 1b (intervention, placebo body side): GA, intraop: normal saline injected into the lumen of the vas deferens, post-op NSAID Group 2 (control, both sides): GA, intraop: no injection, post-op NSAID Adjuvants: none Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: testicular discomfort at 12 months Continuous: duration of testicular discomfort Secondary: none
Notes	No available contact info to email study author to inquire about study sponsorship Funding sources: source of funding not reported Conflicts of interest: no conflict of interest statement given
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “randomly....at random..,” but exact method of sequence generation not reported. Still, with excellent description of allocation concealment and blinding, we judge that bias is unlikely
Allocation concealment (selection bias)	Low risk	Allocation was done after education and enrolment, (it remains unclear when the vas deferens side was randomized, but this is unlikely to cause bias.) Bias is unlikely
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Bias during operation by non-blinded providers possible, e.g. by administering additional fentanyl, but not very likely
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “all the replies were analysed by one of the authors who was unaware of the treatment”
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: “the questionnaire was valid for 61 (91%) patients only.” Six participants did not respond and “...threewere excluded because of development of wound infection and scrotal haematoma.” A per-participant analysis was performed, withdrawals and attrition were reported, but allocation to groups or subgroup was not reported. Bias is likely, but unlikely to change the result of the study
Selective reporting (reporting bias)	Low risk	No protocol available but all specified outcomes were reported on
Null bias	Low risk	Quote: “the VAS scores for pain on days 1..were significantly lower on the side of the bupivacaine infiltration in the treatment group compared with the saline side of this group and the control group”
Pinzur 1996
Methods	Double-, possibly triple-blind (participant, provider and possibly outcome assessor), placebo/sham-controlled randomized clinical trial Sequence generation ”with use of a table of random numbers“ Follow-up: 6 months
Participants	Participants: 21 adults, at a university setting, Chicago, Illinois, USA Operation: lower limb amputation because of ischaemic necrosis secondary to peripheral vascular disease 2 groups, size: 11/10 Age: 68.3 years (SD ± 12.96) Men/women: 10/11 Comorbidities: diabetes mellitus in 9 participants
Interventions	Group 1 (treatment): GA or spinal, post-op nerve sheath irrigation (bupivacaine 0.5%, 1 mL/h) and PCA (morphine, no basal rate, demand 2 mg, lockout 15 min, max 30 mg/4 h) for 72 h Group 2 (placebo): GA or spinal, post-op nerve sheath irrigation (normal saline, 1 mL/h) and PCA (morphine, no basal rate, demand 2 mg, lockout 15 min, max 30 mg/4 h) for 72 h Adjuvants: none Immediate post-op pain control: significantly improved analgesic consumption
Outcomes	Dichotomous: pain at 6 months Continuous: McGill Pain Questionnaire at 6 months Secondary: none
Notes	Reported data not allocated to groups. No graphics that reported data. We contacted the study author for missing information and outcome data. He responded that the data were not accessible. Hence, outcome data could not be included Funding sources: ”no benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.“ Conflicts of interest: no conflicts of interest statement given
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were ’divided into two groups with use of a table of random numbers.”
Allocation concealment (selection bias)	Unclear risk	Concealment of allocation not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “the patients and the staff were blinded to the contents of the bag, which were known only to the research pharmacist.”
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Outcome assessor blinding was not described, but (quote:) “the patients and the staff were blinded to the contents of the bag,which were known only to the research pharmacist.”
Incomplete outcome data (attrition bias) All outcomes	High risk	The study authors report on attrition, (2 participants died, 5 did not participate in the questionnaire), but patients lost to follow up were neither allocated to groups nor considered for an ITT analysis. The authors found no statistically meaningful difference in phantom pain, but it remains unclear which participant numbers were taken as the basis for their analysis. An ITT analysis would likely only have confirmed the lack of significance, however
Selective reporting (reporting bias)	Low risk	Primary outcomes appropriately reported on
Null bias	Low risk	Quote: “the patients in Group A used significantly less morphine during the first and second days after the operation than did those in Group B”
Purwar 2015
Methods	Randomized clinical trial Sequence generation by computer-generated random numbers Follow-up: 3 months
Participants	Participants: 60 adults in a university setting in the UK Operation: vaginal surgery for pelvic floor disorders (tape, repair, or hysterectomy) 2 groups, size: 29/31 Age (± SD), group 1, 2: 65.1 (12.5), 60.6 (11.5) All women Exclusion criteria: American Society of Anesthesiologists (ASA) grade 3, contraindication to Spinal Anesthesia (SA), a lack of capacity to provide consent, and an inability to read and write in English
Interventions	Group 1 (GA): anaesthesia was induced with propofol (3 mg/kg) and maintained with isoflurane in oxygen-enriched air to achieve an inspired oxygen fraction (FiO2) of 33%. Ondansetron 4 mg IV was given as prophylaxis against postoperative nausea and vomiting. The operating surgeon was a urogynaecology consultant (JC) or specialist trainee signed off as competent for independent practice for the type of surgery performed. Anaesthesia was provided by 1 of two anaesthetic specialists (NT or AF). Anaesthesia was augmented by surgical infiltration with LA solution comprising 30 mL of 0.5% levobupivacaine, 27mL of normal saline and 3mL of adrenaline 1:10,000. Hypotension (systolic blood pressure < 85 mmHg) was treated with metaraminol in aliquots of 0.5 mg and bradycardia (heart rate < 60 beats per min) was treated with glycopyrrolate in aliquots of 200 μg. Women were prescribed ibuprofen 400 mg every 4 h orally with food when required and either co-codamol (30/500) two tablets every 4 h or paracetamol 1 g IV or orally every 4 h. If pain was not controlled with the above regimen, morphine was prescribed. Postoperative nausea and vomiting were initially treated with prochlorperazine 12.5 mg IM every 6 h with ondansetron 4 mg to8 mg IV if required Group 2 (SA): a 25-G Whitacre needle was inserted at the L3-L4 interspace following skin infiltration with 1%lidocaine, under aseptic conditions, the participant in the sitting position. Initially, the SA regimen consisted of 1 mL of 0.5% hyperbaric bupivacaine with 10 μg of fentanyl diluted to a volume of 3.0 mL using normal saline. Participants remained in the sitting position for 5 min following the introduction of SA. However, owing to suboptimal pain control in the first few participants, the protocol was revised and the spinal anaestheticmixture was amended to 2.0mL 0.5%heavy bupivacaine with 10 μg fentanyl, diluted to 3 mL, with the participant’s position immediately changed to semi-recumbent following spinal injection. Participants’ complaints of pain were treated with IV fentanyl in aliquots of 50 μg. Additional intraoperative sedation was achieved by IV midazolam as required. Levobupivacaine was used to augment anaesthesia as described above. Hypotension was treated as described above Adjuvants: fentanyl Immediate post-op pain control: no improvement
Outcomes	Dichotomous: none Continuous: VAS score, SF-36 Other reported: VAS in the perioperative period 2 h, 24 h, 2 weeks, Incontinence ModularQuestionnaire on Vaginal Symptoms (ICIQ-VS), data regarding the time taken from the induction of anaesthesia to commencing surgery, operating time, duration of stay in the postoperative recovery room in min, use of analgesia postoperatively, and length of hospital stay
Notes	We acknowledge the response provided by the study author regarding blinding, randomization, allocation concealment and source of funding and conflict of interest statement Funding sources: “this study was funded by a Research Award from the North Staffordshire Medical Institute, UK.” Conflicts of interest: the study authors have no conflicts of interest
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “an internet-based sequence allocation randomisation was carried out by the Nottingham (UK) Clinical Trials Support Unit with random permuted blocks of randomly varying size.”
Allocation concealment (selection bias)	High risk	Quote: “The anaesthetist was informed of the random allocation allocated by the computer.”
Blinding of participants and personnel (performance bias) All outcomes	High risk	The study author responded, quote: “Owing to the nature of the interventions, itwas not possible to blind either patients or the assessing team to the intervention given.”
Blinding of outcome assessment (detection bias) All outcomes	High risk	Outcome assessors not blinded
Incomplete outcome data (attrition bias) All outcomes	High risk	Significant attrition
Selective reporting (reporting bias)	Low risk	No subgroup analysis was performed
Null bias	High risk	Quote: “no statistically significant differences were noted between the groups with regard to pain...”
Senturk 2002
Methods	Single-blind (outcome assessor), clinical RCT Sequence generation was random, but not described Follow-up: 6 months
Participants	Participants: 112 adults at a university setting in Istanbul, Turkey Operation: open thoracotomy for a mix of lung resections 3 groups, size: 28/29/28 Age (group 1, 2, 3): 49 (SD 9), 52 (SD 11), 50 (SD 11) years Men/women: 56/13 (reported at end of study) Comorbidities: not reported
Interventions	Group 1 (preincision): epidural at T11-8, preincision bupivacaine bolus 10 mL, 7 mL/h infusion (0.1% + 0.1 mg/mL morphine), GA, post-op 48 h PCEA (0.1% bupivacaine + 0.05 mg/mL morphine, basal rate 5 mL/h, demand 3 mL, lockout 30 min) Group 2 (postsurgery): epidural at T11-8, GA (fentanyl), postsurgical bupivacaine bolus 10 mL (0.1% + 0.1 mg/mL morphine), post-op 48 h PCEA (0.1% bupivacaine + 0.05 mg/mL morphine, basal rate 5 mL/h, demand 3 mL, lock time 30 min) Group 3 (control): GA (fentanyl), PCA (morphine, bolus 5 mg, no basal rate, demand 2 mg, lockout 15 min) Adjuvants: none Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: pain at 6 months, pain affecting daily life at 6 months Continuous: NRS at 6 months Secondary: none
Notes	Regional anaesthesia catheter placement was verified under fluoroscopy. The study author responded and provided additional information regarding randomization allocation concealment, sources of funding and conflicts of interest Funding sources: “the study was not funded” Conflicts of interest: the authors “have no conflict of interest”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were “randomly divided into three groups”, “using sealed envelopes technique.”
Allocation concealment (selection bias)	Low risk	Quote: “randomization was performed at the first presentation of the patient to our department, i.e. 5-7 days before the operation (just before the anaesthetic evaluation). The result of the randomization was “hidden” by the secretary of the department until the operation date.”
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: “patientswere not blinded to group, anaesthesia providers aware of allocation at least during treatment.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors “were blinded to the analgesic method.” Blinding of only outcome assessors is acceptable
Incomplete outcome data (attrition bias) All outcomes	High risk	Allocation of excluded participants is not reported, no ITT analysis was considered. Considerable attrition prior to, during and after intervention make bias likely. Adverse effectswere not, but attrition was described albeit without group allocation 27 participants were excluded preoperatively, 6 intra-operatively, and 10 postoperatively, without specification of their group allocation. Comorbiditieswere the preoperative, inoperability the intraoperative and recurrence of pain due to metastasis & reoperation were the postoperative exclusion criteria
Selective reporting (reporting bias)	Low risk	All expected outcomes included
Null bias	Low risk	Quote: “during movement and cough, Group Pre-TEA had significantly less pain compared with the other two groups during the entire period. At rest, patients in Group Pre-TEA reported having significantly lower pain scores during the first 12 h compared with those in Group Post-TEA and during the first 48 h compared with those in Group IV-PCA. There were statistically significant differences between Group Post-TEA and Group IV-PCA during rest from8 h after surgery until the end of 48 h, but no difference during cough or movement was recorded”
Shahin 2010
Methods	Double-blinded (participant/outcome assessor), placebo/sham-controlled, randomized clinical trial Sequence generation by computer-generated random numbers Follow-up: 8 months
Participants	Participants: parturients in a university setting in Assiut, Egypt Operation: caesarean section for delivery groups, size: 185/185 Age: 25 years (SD ± 1.5 ) Men/women (group 1, 2): 0/185, 0/185 Comorbidities (group 1/2/3): none reported Remarks:
Interventions	Group 1 (intraperitoneal lidocaine instillation): spinal (details not reported), postincision, preperitoneal closure single-shot instillation of peritoneal lidocaine (2%, 10 mL) into the pelvis, post-op paracetamol 1 g intravenously every 6 h for 36 h, rectal suppository of 10 mg followed by oral 400 mg ibuprofen for 72 h, plus intravenous morphine 2 mg for breakthrough pain Group 2 (intraperitoneal placebo/saline instillation): spinal (details not reported), postincision, preperitoneal closure single-shot instillation of peritoneal saline (0.9%, 10 mL) into the pelvis, post-op paracetamol 1 g intravenously every 6 h for 36 h, rectal suppository of 10 mg followed by oral 400 mg ibuprofen for 72 h, plus intravenous morphine 2 mg for breakthrough pain Adjuvants: none Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: overall pain/no pain at 8 months, differentiated also in wound, global abdominal and epigastric pain Continuous: at 8 months: NRS
Notes	Funding sources: “No... funding acknowledgementwas declared by either of the authors.” Conflicts of interest: the study authors have no conflict of interest
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer-based random allocation
Allocation concealment (selection bias)	Low risk	Placed in sealed, opaque, consecutively numbered envelopes... just after providing consent the women were given the next number on the random list..., (allocation) was concealed from the residents and care-givers
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “the surgeon involved complied with the instruction but was not further involved” data “collection sheets with corresponding codes,.. a number of syringes equal in size;” “preparation and administration of the medication was carried out by a nurse not involved in themanagement of the patient”, “access to randomization code was only available to the secretary of the statistics department”, “randomization code was not broken until the completion of the study”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “access to randomization code was only available to the secretary of the statistics department”, “randomization code was not broken until the completion of the study”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Analysis was per protocol, not ITT, but the low number of participants lost to follow-up with almost equal attrition in both groups and the similar demographics in both groups make bias unlikely
Selective reporting (reporting bias)	Low risk	No protocol available but all outcomes specified in the article were reported on
Null bias	Low risk	Quote: “control group patients received significantly more morphine injections in the first 24 hours than lidocaine patients”. Significantly more participants in the control group reported pain in all sites in the first 24 h than in the lidocaine group
Singh 2007
Methods	Triple-blind (participant/provider/outcome assessor), placebo-controlled, clinical RCT Sequence generation by a computer-based, random numbers generator Follow-up: mean of 4.7 years (range 4.5-5.4 years)
Participants	Participants : 26 adults in a university setting, Houston, Texas, USA Operation: ICBG for spinal arthrodesis 2 groups, size: 11/14 Age (all, 1, 2): 64 (range 34-84), 66, 63 years Sex: not reported Comorbidities: not reported Remarks: 11 anterior ICBG included in the initial stage were later excluded
Interventions	Group 1 (treatment): GA, at closure continuous wound irrigation (bupivacaine hydrochloride and epinephrine (Marcaine) 0.5% 2 mL/h) for 48 h post-op + PCA (hydromorphone hydrochloride (Dilaudid)) (basal, bolus and lock-out time not specified) Group 2 (control): GA, at closure continuous wound irrigation (normal saline, 2 mL/h) for 48 h post-op + PCA (Dilaudid) (basal, bolus and lock-out time not specified) Adjuvants: none Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: graft site pain at around 55 months Continuous: VAS at around 55 months Secondary: pain frequency in days, functional activity score, overall satisfaction with the surgical procedure at around 55 months
Notes	Funding sources: “no funds were received in support of this work” Conflicts of interest: “no benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “the method used to generate the randomization consisted of a computerbased number generator. Moreover, to account for the size of the sample groups, randomization attempted to balance baseline characteristics by stratification, such as age.”
Allocation concealment (selection bias)	Low risk	Quote: “the participants were randomized and allocated by a different individual than the one who enrolled the patient.” “Randomization and allocation to group type was concealed and not made public to the individual enrolling the patients, the treating physician, or to the nursing staff.” “Patients were assigned to receive either one or the other (treatment) solutions at the time of surgery based on a coded sequence enclosed within an envelope.”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “blinded and identical in appearance, solutions of saline andMarcaine were prepared.” “Physicians, patients, nursing staff, and research personnel conducting the statistical analyses were blinded to the infusion solution until the end of the study to minimize potential for performance and detection bias.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “the physician conducting the telephone interview as well as recording the data were blinded to the treatment group.” “Research personnel conducting the statistical analyses were blinded to the infusion solution until the end of the study to minimize potential for performance and detection bias.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Study authors report details of attrition with reference to the groups participants were randomized to. “An intent-to-treat analysis was considered to preserve randomization and to offer the best representation of the clinical population.” “Even if we assume that any treatment patient that was lost to follow-up (n = 6 patients) was considered to be a failure (chronic dysesthesias, an ICBGVAS score of 8, 15 days of narcotic usage/mo, functional activity score of 4, and an overall dissatisfaction with the procedure), a statistical difference was still noted in the 2 groups (p = 0.05).”
Selective reporting (reporting bias)	Low risk	Primary outcomes fully reported on
Null bias	Low risk	Quote: “narcotic dosage, demand frequency, and mean VAS pain score were significantly less in the treatment (Marcaine) group at 24 and 48 hours”
Singh 2013
Methods	Double-blinded (participant/outcome assessor), randomized clinical trial Sequence generation by a computer-based, random numbers generator Follow-up: 3 months
Participants	Participants: 60 women at a university hospital in Ontario, Canada Operation: caesarean section Groups, size: 20/20/20 Age (± SD), group 1, 2, 3: 33 (± 3), 32 (± 7), 33 (± 4) All female participants Comorbidities: previous caesarean delivery, groups 1, 2, 3 (16, 14, 15) Remarks: ASA I, II, and III
Interventions	All participants received SA with 0.75% bupivacaine 10 mg-12 mg, fentanyl 10 μg and morphine 150 μg Group 1 (high-ropivacaine): post-op: a 22-G, 50 mm or 80mm Pajunk Uniplex nanoline needle was introduced into the fascia between the internal oblique and transversus abdominis muscles. After confirmation of needle placement, the study solution was injected in 5 mL increments after negative aspiration. Study solution for high-ropivacaine group consisted of 0.5% ropivacaine 3 mg/kg (up to a maximum of 300 mg) plus saline to total 60 mL of fluid. TAP blocks were performed bilaterally Group 2 (low-ropivacaine): post-op: same method as group 1, but study solution consisted of 0.25% ropivacaine 1.5 mg/kg (up to amaximum of 150 mg) plus saline to total 60 mL. TAP blocks were performed bilaterally Group 3 (placebo): post-op: TAP blocks consisting of 60mL of salinewere administered bilaterally using same method as groups 1 and 2 Adjuvants: none Immediate post-op pain control: no difference
Outcomes	Dichotomus: none Continuous: NRS at 3 months Other reported: the time to first request for additional analgesia, the total consumption of opioids, antiemetics and anti-pruritics 72 h postoperatively Adverse events: none reported
Notes	Funding sources: “this study was supported in part by a grant from the Lawson Health Research Institute.” Conflicts of interest: “the authors have no conflicts of interest to declare.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “patients were randomly assigned using a computer generated table of random numbers to one of three groups.”
Allocation concealment (selection bias)	Low risk	Quote: “group allocations were concealed in sealed opaque envelopes that were opened only after patient consent was obtained..”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “the patients, anesthesiologists, and nursing staff involved in direct patient care were unaware of the study group allocations.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “patients were interviewed at regular intervals by an investigator unaware of group allocation...”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Of the 60 participants enrolled, 59 completed the study.
Selective reporting (reporting bias)	Low risk	No subgroup analysis or selective reporting was noted.
Null bias	High risk	Quote: “neither high- or low-dose TAP blocks as part of a multimodal analgesia regimen including intrathecal morphine improved pain scores.”
Smaldone 2010
Methods	Double-blinded (participant/outcome assessor), randomized clinical trial Sequence generation not specified Follow-up: 3, 6 months
Participants	Participants: 60 men in a hospital setting in Philadelphia, PA Operation: open radical retropubic prostatectomy Groups, size: 29/31 Age: not specified All male participants
Interventions	Group 1 (multimodal analgesia): pre-op: PVB with 5 mL of 0.5% ropivacaine per level (T14-T16) and oral celecoxib (400 mg preoperatively and 200 mg twice daily for 7 days postoperatively). Intra-op: IV ketamine (10 mg) following induction. Post-op: all participants had access to morphine (PCA) Group 2 (PCA): pre-op: participants received placebo equivalents as treatment group - sham tablets and sham saline injections. Post-op: all participants had access to morphine (PCA) Adjuvants: none Immediate post-op pain control: significantly improved, significantly reduced analgesic consumption
Outcomes	Continuous: SF-36 at 3, 6 months Dichotomus: none Other reported: VAS at 24 hours, morphine consumption postoperatively Adverse events: none reported
Notes	We were unable to obtain additional information regarding pain outcomes or about randomization and blinding methods from the study author Funding sources: none received Conflicts of interest: conflict of interest not discussed
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Sequence generation not specified
Allocation concealment (selection bias)	Unclear risk	Concealment of allocation not specified
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “all patients, staff and physicians were blinded to treatment group assignment.”
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome assessors not discussed
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Amount of follow-up and attrition not specified
Selective reporting (reporting bias)	Low risk	No subgroup analysis or selective reporting was noted
Null bias	High risk	Quote: “there were no significant differences detected in SF-36 scores at 2, 12, and 24 weeks.”
Sprung 2006
Methods	Single-blinded (outcome assessor), randomized clinical trial Sequence generation via computer-generated list Follow-up: 3 months
Participants	Participants: 89 women from a university hospital in Minnesota, USA Operation: elective vaginal hysterectomy (with or without repair of cystocoele and rectocoele) 2 groups, size: 45/44 Age (± SD), group 1, 2: 52.2 (± 11.9), 51.8 (± 12.8) All female participants Comorbidities: postmenopausal, group 1, 2: 21/17. Procedure, group 1, 2: hysterectomy only 27/27, hysterectomy + cystocoele 1/1, hysterectomy + rectocoele 4/4, hysterectomy + cystocoele + rectocoele 13/7
Interventions	Group 1 (regional): sedation with IV midazolam and propofol. SAB performed in lumbar region between 3rd and 5th vertebral bodies. After cerebrospinal fluid free flow, 0.75% hyperbaric bupivacaine (15 mg), preservative-free clonidine (1 μg/kg), morphine (2 μg/kg, max 200 μg) injected to subarachnoid space. Intraoperative sedation with IV midazolam and propofol as needed. No intraoperative IV opioids. 30 mg ketorolac IV at end of surgery. On floor IV PCA 1.0 mg every 10 min with 4-h lock out max of 15 mg in regional group (lower than general group, to decrease likelihood of delayed respiratory depression). Additional IV morphine per attending physician as needed Group 2 (general): 2 μg/kg fentanyl after pre-oxygenation GA with sodium thiopental, succinylcholine, vecuronium bromide, isoflurane and 50% inspired nitrous oxide. A morphine sulphate 0.1 mg/kg IV in divided doses, no additional morphine was allowed. All participants received 30 mg IV ketoralac at end of surgery. On floor IV PCA 1.0 mg every 10 min, 4-h lockout max of 30 mg Both groups: in PACU 2 mg IV morphine every 5-10 min as needed for NRS > 3. On floor, morphine PCA, with differences in maximum noted above. Scheduled ketorolac 30mg IMevery 8 h until oralD3. After 24 h, IV PCA stopped and oral paracetamol and codeine (650 mg/30 mg) every 6 h as needed. In both groups, pruritis managed with diphenhydramine then naloxone if needed. Nausea/vomiting managed with droperidol, if later stages ondansetron, then naloxone if persisted Adjuvants: clonidine (into subarachnoid space) Immediate post-op pain control: significantly improved, significantly reduced analgesic consumption
Outcomes	Dichotomous: none Continuous: NRS at 3 months, SF-36 pain subcomponent at 3 months Secondary: none Effective regional anaesthesia: reported. ”Confirmation of an adequate dermatomal level of blockade“ Adverse events reported on included use of intraoperative pressors, nausea/vomiting, pruritis
Notes	We acknowledge the study author’s clarification on blinding methods Funding sources: ”intramural grant from the Mayo Foundation.“ Conflicts of interest: ”none declared.“
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: ”computer-generated list“ Allocation concealment (selection bias) Low risk Quote: ”patients were randomized...using a sealed envelope“
Blinding of participants and personnel (performance bias) All outcomes	High risk	The anaesthesiologist, participants and providers were not blinded. This is acceptable for our purposes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	SF-36 was filled out by participant and mailed in at 12 weeks. Study author contacted, stated the research co-ordinator performing telephone follow-up ”was blinded regarding the study group“
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote. ”in three patients in the SAB group, the block failed and the patient received general anesthesia. For all analyses presented in this report these patients are included in the SAB group (intention-totreat)“. Fairly balanced, low rate of participants lost to follow-up at 12-week follow-up
Selective reporting (reporting bias)	Low risk	All primary outcomes fully reported on.
Null bias	Low risk	Quote: ”the patients in the general anesthesia group received more morphine in the PACU... compared to patients receiving SAB“ and this continued into the 12 hours after PACU discharge. Numerical pain score values tended to be lower in participants receiving SAB compared to the general anesthesia group through 14:00 hr on postoperative day two (the day after surgery), with significant differences noted at the time of floor arrival and at 14:00 hr on postoperative day two”
Strazisar 2012
Methods	Double-blinded (participant/outcome assessor), randomized clinical trial Sequence generation by a computer-based, random numbers generator Follow-up: 3 months
Participants	Participants: 60 women in a hospital setting in Ljubljana, Slovenia Operation: breast cancer surgery with axillary lymphadenectomy Groups, size: 30/30 Age (all, 1, 2): 60 (30-84), 57.4, 62.9 All female participants Comorbidities: diabetes, groups 1, 2 (4, 8); depression, groups 1, 2 (1, 4) Remarks: ASA I, II, and III
Interventions	Group 1 (levobupivacaine): intra-op: beforewound closure, a fenestrated wound catheter was placed near the axillary vein and upon the whole length over the upper side of the wound. The wound catheter was fenestrated along 15 cm in the distal part. A bolus of 15 mL of 0.25% levobupivacaine was injected into the wound through the catheter immediately after wound closure. Surgical drains and the fenestrated catheter were clamped for 5 min to enable bolus absorption. Elastomeric pump was connected containing 100 mL of 0.25% levobupivacaine. Infusion at 2 mL/h was continuous for 50 h Group 2 (piritramide): intra-op: continuous IV infusion with piritramide (30 mg), metoclopramide (20 mg) and metamizole (2.5 g) in 100 mL of 0.9% sodium chloride (3 mL/h to 6 mL/h) until 24 h postoperatively Adjuvants: none Immediate post-op pain control: significantly improved, significantly reduced analgesic consumption
Outcomes	Continuous: none Dichotomus: overall pain/no pain at 3 months Other reported: nausea, opioid consumption, and length of hospital stay and were measured Adverse events: 3 participants (2, 1) underwent additional surgical procedures due to haematoma and 9 participants (5, 4) experienced inflammation postoperatively
Notes	Funding sources: no funding source given Conflicts of interest: “no potential conflicts of interest were disclosed.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was performed using random numbers generated by a computer
Allocation concealment (selection bias)	Low risk	Quote: “randomization and numbers were placed in sealed opaque envelopes to ensure concealment of allocation at enrollment.”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “participants were randomly grouped.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “clinicianswho recorded data about chronic pain were blinded about randomisation group of patients.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants completed the follow-up evaluation.
Selective reporting (reporting bias)	Low risk	No subgroup analysis or selective reporting was noted.
Null bias	Low risk	Quote: “pain (at 3 months) was reported by 17%and 50%of patients.” Continuous infusion of local anesthetic reduced pain compared to control
Strazisar 2014
Methods	Doubl-blinded (participant/outcome assessor), randomized clinical trial Sequence generation by a computer-based, random numbers generator Follow-up: 3 months
Participants	Participants: 60 women in a hospital setting in Ljubljana, Slovenia Operation: radical mastectomy and breast reconstruction Groups, size: 30/30 Age (range, 1, 2): 25-64, 47.6, 48.0 All female participants Comorbidities: smoking, groups 1, 2 (9, 10); depression, groups 1, 2 (3, 1) Remarks: ASA I, II, and III
Interventions	Group 1 (levobupivacaine): intra-op: before wound closure, a fenestrated wound catheter was placed under the pectoralis major muscle and upon the entire length over the upper side of the wound. The wound catheter was fenestrated along 15 cm in the distal part. A bolus of 15 mL of 0.25% levobupivacaine was injected into the wound through the catheter immediately after wound closure. Surgical drains and the fenestrated catheter were clamped for 5 min to enable bolus absorption. Elastomeric pump was connected containing 100 mL of 0.25% levobupivacaine. Infusion at 2 mL/h was continuous for 50 h Group 2 (piritramide): intra-op: continuous IV infusion with piritramide (30 mg), metoclopramide (20 mg) and metamizole (2.5 g) in 100 mL of 0.9% sodium chloride (3 mL/h to 6 mL/h) until 24 h postoperatively Adjuvants: none Immediate post-op pain control: significantly improved, significantly reduced analgesic consumption
Outcomes	Continuous: none Dichotomus: overall pain/no pain at 3 months Other reported: nausea, opioid consumption, and length of hospital stay were measured Adverse events: 2 participants (1, 1) underwent additional surgical procedures due to haematoma, 4 participants (1, 3) experienced inflammation postoperatively, and unilateral lymphoedema of the arm was present in 2 participants (1, 1)
Notes	Funding sources: “study was entirely financed by the Institute of Oncology as a part of public service.” Conflicts of interest: “the authors declare that they have no competing interests.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “randomization was made by using random numbers generated by a computer. ”
Allocation concealment (selection bias)	Low risk	Quote: “randomization and numbers were placed in sealed opaque envelopes to ensure concealment of allocation at enrollment.”
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Participants were blinded, but no description of medical staff ’s knowledge other than, quote: “after randomization... the principal investigator was informed about the treatment allocation of the patient.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “data about pain were collected by nursing staff, that is, by an independent observer.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants completed the follow-up evaluation.
Selective reporting (reporting bias)	Low risk	No subgroup analysis or selective reporting was noted.
Null bias	Low risk	Quote: “in the test and the control groups of patients, pain was reported in 16.7%(5/30) and 50% (15/30), respectively.” “We observed that patients treated with a LA experienced a lower frequency of chronic pain compared to patients treated with standard analgesic.”
Tecirli 2014
Methods	Double-blinded (participant/outcome assessor), randomized clinical trial Sequence generation not described Follow-up: 3 months
Participants	Participants: 60 women in university hospital in Ankara, Turkey Operation: radical mastectomy (with axillary lymph node dissection) Groups, size: 30/30 Age: not listed All female participants Comorbidities: not listed
Interventions	Group 1 (bupivacaine): intra-op: intercostobrachial nerve was blocked with 10 cc 0.5% bupivacaine before being sectioned Group 2 (control): intra-op: intercostobrachial nerve sectioned without blockage Adjuvants: none Immediate post-op pain control: no difference
Outcomes	Continuous: VAS at 3 months Dichotomus: pain questionnaire at 3 months Other reported: analgesic consumption Adverse events: reported as none
Notes	Pain score ≥ 4 was accepted as pain Funding sources: no explanation of financial support Conflicts of interest: no conflict of interest statement given
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Sequence generation not explained
Allocation concealment (selection bias)	Unclear risk	Concealment of allocation not explained
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding of medical personnel not explained
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Knowledge of outcome assessors not indicated
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants completed the follow-up evaluation
Selective reporting (reporting bias)	Low risk	No subgroup analysis or selective reporting was noted
Null bias	Low risk	Quote: “this study shows that intercostobrachial nerve block is an effective method to reduce the chronic neuropathic pain development after a breast cancer surgery.”
Terkawi 2015b
Methods	Triple-blind (participant/provider/outcome assessor), placebo-controlled, randomized clinical trial Sequence generation using website random number generator Follow-up: 6 months
Participants	Participants: 61 adult patients at a university hospital in Virginia, USA Operation: mastectomy (including simple and modified radical, with or without axillary dissection) for breast cancer surgery 2 groups, size: 27/34 Age (± SD), group 1, 2: 55.2 (± 10.9), 55.0 (± 13.7) All female participants Exclusion criteria: Age > 80 Comorbidities: simple mastectomy (n), group 1, 2: 19/20. Modified radical (n), group 1, 2: 8/14. Axillary direction (n), group 1, 2: 3/13. Breast implant (n), group 1, 2: 5/8. Chemotherapy, (n), group 1, 2: 11/18. Radiotherapy (n), group 1, 2: 9/14. Hormone therapy (n), group 1, 2: 10/7 Remarks: the demographic data above are for participants who were available for follow-up at 6 months and included in the analysis
Interventions	Group 1 (placebo): 0.9% NaCl IVinfusion beginning before induction, at equal volume to lidocaine group, until 2 h after arrive to PACU or at discharge fromPACU (whichever earlier) Group 2 (lidocaine): 2mg/kg/h IV lidocaine infusion beginning before induction (max 200 mg/h) until 2 h after arrive to PACU or at discharge from PACU (whichever earlier) Both groups: lidocaine bolus before induction, up to 1.5 mg/kg, max 150 mg. Premedication, induction drug, muscle relaxant for GA chosen by anaesthesiologist. Maintenance sevoflurane. Post-op analgesia fentanyl 50 μg every 10 min as needed or morphine 4 mg every 20 min as needed, with morphine PCA if needed. Nausea treated with ondansetron 4 mg IV as needed then promethazine 6.25 mg IV every 20 min as needed Adjuvants: none Immediate post-op pain control: no significant improvement
Outcomes	Dichotomous: pain/no pain at 6 months Continuous: VAS collected but not reported Other: logistic regression model (Best model) to assess efficacy of lidocaine Adverse events: incidence of lymphoedema, evidence of lidocaine toxicity, post-surgery infection or complications
Notes	Funding sources: “the studywas funded by theDepartment of Anesthesiology, University of Virginia, Charlottesville, VA.” Conflicts of interest: “the authors declare no conflict of interest.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “a website random number generator was used (www.randomization.com)...and the patient was asked to select one envelope on the morning of surgery.”
Allocation concealment (selection bias)	Low risk	Quote: “numberswere concealed in opaque sealed envelopes”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “both the patients and research team remained blinded until after all data were analysed.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “a research associate, who was blinded to treatment group and management, conducted a telephone interview with the patients 6 months after surgery.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: “seven patients in the placebo group and 3 in the lidocaine group could not be reached for follow-up, despite multiple phone call attempts (14% dropout). Therefore, we analysed 61 patients, 27 in the placebo group and 34 in the lidocaine group”. Slightly higher loss in the placebo group but overall low numbers of attrition
Selective reporting (reporting bias)	Low risk	The study maintained a defined protocol, which they did not deviate from
Null bias	High risk	Quote: “themean postoperative pain scores at rest (Fig. 2A) were 3.88 ± 2.92 at 2 hours, 2.66 ± 2.66 at 24 hours, and 3.09 ± 2.80 at 48 hours in the placebo group, whereas they were 2.94 ± 2.74 at 2 hours, 2.91 ± 2.21 at 24 hours, and 2.72 ± 2.25 at 48 hours in the lidocaine group. Overall pain scores in both groups were similar with no statistical difference by repeated-measures ANOVA”. No significant difference in pain scores on movement or perioperative morphine consumption either
Vrooman 2015
Methods	Triple-blinded (participant, provider, outcome assessor), placebo-controlled, randomized clinical trial Sequence generation by computer-generated random numbers Follow-up for 3 and 6 months
Participants	Participants: 78 adults in a university setting in USA Operation: robotic cardiac surgery 2 groups, size: 39/39 Age (± SD), group 1, 2: 56 (11), 58 (10) Men/women, group 1, 2: 31/8, 29/10 Exclusion criteria: history of severe psychiatric issues (e.g. depression, somatoform conversion disorder, and borderline personality disorder); addiction to alcohol, opioids, or illegal substances; known history of sensitivity to amide LAs; severe hepatic disease; or pregnant
Interventions	Group 1 (lidocaine): anaesthetic technique not described. The 5% lidocaine transdermal patches contained 700 mg of lidocaine. Each self-adhesive patch was 10 cm × 14 cm. Up to 3 patches were applied to maximize analgesia while reducing the risk of systemic toxicity. Patches were applied for 12 h, removed for the subsequent 12 h, and then new patches were applied. This process was continued for 6 months or until participants no longer required analgesia. Additional postoperative analgesia was provided by participant-controlled fentanyl (20 mg bolus, 6-min lockout, no hourly limit). Morphine or hydromorphone was substituted in participants reporting sensitivity to fentanyl. PCA was continued for up to 3 days, with the exception of a single participant who was treated for 5 days, until participants could tolerate oral opioid medications such as oxycodone 5 mg to 10 mg every 4-6 hours as needed. Participants who required more than 40 mg of oxycodone, or equivalent, per day were supplemented with fentanyl 25 mg/h transdermal patches Group 2 (control): same intervention as above except sham patches were used Adjuvants: none Immediate post-op pain control: no improvement
Outcomes	Dichotomous: none Continuous: VAS/VRS Secondary: VAS at POD 3; VRS at 1 week and 1 month, the Depression Anxiety Stress Score recorded the day before surgery, GPE-a measure of participant satisfaction, recorded after 1 week, 1 month, 3 months, and 6 months. PDI at 3 and 6 months
Notes	Funding sources: funding for the study was provided by Endo Pharmaceuticals Conflicts of interest: “none of the authors has a personal financial interest in this research.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “randomization was performed by our Research Pharmacy and was based on computer-generated codes”
Allocation concealment (selection bias)	Unclear risk	Allocation of concealment was not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “all investigators and clinicians were fully blinded to treatment.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “incisional pain was evaluated over 6 months with data collected by an independent study coordinator who was blinded to treatment.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	There was no attrition and ITT analysis was performed
Selective reporting (reporting bias)	Low risk	No subgroup analysis was performed
Null bias	High risk	Quote: “lidocaine 5% patches did not influence any measure of acute or persistent incisional pain”
Weber 2007
Methods	Single-blinded (outcome observer) clinical RCT Sequence generation via computer-generated randomization list Follow-up: 6 months
Participants	Participants children and adolescents ≥ 10 years at a university hospital in Vienna, Austria Operation: pectus excavatum repair (minimally invasive using a thorascope for creation of retrosternal tunnel) 2 groups, size: 20/20 Age (± SD), group 1, 2: 16.7 (± 5.2), 14.8 (± 4.2) Men/women, group 1, 2: 17/3, 15/5 Comorbidities: except for 1 participant in TEA group, all procedures were primary operations. Vertebral index (vertebral diameter × 100/sagittal diameter + vertebral diameter), group 1, 2 (± SD) = 32.05 (± 36.2), 31.85 (± 4.15)
Interventions	Group 1 (PCA): post-op IV PCA 0.02 mg/kg morphine bolus, lockout 6 min, max 6 bolus/h, no continuous rate. Postoperatively, both groups 1 mg/kg diclofenac IV every 8 h scheduled until POD 4, rescue pain medication with IV paracetamol 15 mg/kg, followed by 1.5 mg piritramide IV bolus as needed Group 2 (TEA): catheter placed once in operating room by median approach at T10/7 or T11/8 corresponding with likely insertion site of steel bar. After induction, bolus of 0.2 mg/kg ropivacaine 0.2% with 2 μg/mL fentanyl, then continuous rate of 0.2 mL/h same mixture throughout surgery, continued until POD 4 (96 h). Post-op scheduled 1 mg/kg diclofenac IV every 8 h until POD4 rescue pain medication with IV paracetamol 15 mg/kg, followed by epidural bolus of 0.1 mL/kg ropivacaine 0.2% with 2 μg/mL fentanyl as needed Both groups received standardized GA with propofol, fentanyl, rocuronium. 15 min before end, IV paracetamol bolus Adjuvants: none Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: pain/no pain at 3 and 6 months Continuous: VAS pain score 3 and 6 months Secondary: satisfaction with type of anaesthesia at 3 and 6 months Adverse events reported: sedation, nausea, pruritis
Notes	Presence of pain defined by VAS ≥ 3. We acknowledge the study author for providing response regarding VAS cutoff for presence of pain, allocation concealment, blinding and source of funding Funding sources: “AstraZeneca, Bristol Myers-Squibb, and SmithsMedical Austria supported the study with an unrestricted grant”. We contacted the study author on their specific involvement, who responded, “Funding by the three companies included just paying for the insurance (approximately one third by each company). None of the companies were involved in conducting the study or writing the manuscript.” Conflicts of interest: no direct conflicts of interest statement given
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “computer generated randomization list”
Allocation concealment (selection bias)	Low risk	Study author specified “Group allocation was concealed in an opaque envelope”
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants, surgeons and providers were not blinded. The study author clarified that “the PCA pump and the TEA continuous infusion (depending on the study group) were hidden from the persons assessing the VAS scores”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The study author stated “For postoperative data collection, the PCA pump and the TEA continuous infusion (depending on the study group) were hidden from the persons assessing the VAS scores. The persons who made the follow up questioning [at 3 and 6months] were unaware to which group the patients were assigned”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Study author specified “All 40 patientswere available at three and 6 months for followup”
Selective reporting (reporting bias)	Low risk	Primary outcomes fully reported on
Null bias	Low risk	Quote: “Patients treated with a thoracic epidural catheter after pectus excavatum repair reported lower postoperative pain scores... than did patients treated with intravenous PCA containing morphine. Postoperative pain scores in the intravenous PCA group were higher despite higher intraoperative fentanyl use in the intravenous PCA group”
Wodlin 2011
Methods	Single-blinded (outcome assessor), clinical RCT Sequence generation using computer-generated block randomization table Follow-up: 6 months
Participants	Participants: 162 women aged 18-60 from five hospitals in Sweden Operation: abdominal subtotal or total hysterectomy (for benign gynaecological disorders) 2 groups, size: 80/82 Age (range), groups 1, 2: 45 (33-58), 46 (35-58) All female participants Exclusion criteria: former or concomitant bilateral oophorectomy, postmenopausal without hormone therapy, gynaecological malignancy (cervical dysplasia not included) Comorbidities: indication of hysterectomy, group 1, 2: bleeding disturbances: 46, 46, mechanical symptoms: 27, 29, cervical dysplasia or endometrial hyperplasia: 4, 5, endometriosis or dysmenorrhoea: 3, 2. Total abdominal hysterectomy, group 1, 2: 55/51. Subtotal abdominal hysterectomy, group 1, 2: 25, 31. Mode of skin incision, group 1, 2: midline: 6, 7, low transverse 74, 75
Interventions	Group 1 (GA): GA with propofol, fentanyl, rocuronium. 5 mg IV morphine administered 20 min before surgery complete Group 2 (SA): at L3/4 or L2/3 intervertebral space, 20mg hyperbaric bupivacaine (5mg/mL) and 0.2 mg morphine (0.4 mg/mL) administered. 15 min later, confirmed neural blockade with cold test. Sedation throughout operation with continuous IV propofol Both groups, 2 g oral paracetamol 1 h preoperatively. Surgeon injected 40 mL bupivacaine (2.5 mg/mL) SC and pre-fascially in abdominal wall before end of surgery. Post-operatively, oral paracetamol and diclofenac scheduled 3 × day during hospitalization. Oral or IV opioids given if necessary. Rescue antiemetic with droperidol, then 5-HT3 receptor antagonist if still necessary. Pruritus treated with clementine and if necessary, naloxone Adjuvants: none Immediate post-op pain control: significantly reduced analgesic consumption
Outcomes	Dichotomous: none Continuous: SF-36 at 6 months Other reported: list of major and minor complications
Notes	Funding sources: “the Medical Research Council of South East Sweden, Linköping University and the County Council of Östergötland supported the trial financially.” Conflicts of interest: “the authors have stated explicitly that there are no conflicts of interest in connection with this article.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “a computer generated the randomisation sequences into blocks of ten, with an equal number of the two modes of anaesthesia for each of the five participating centres”
Allocation concealment (selection bias)	Low risk	Quote: “the allocated mode of anaesthesia, written on a label, was sealed in opaque consecutively numbered envelopes. At each centre the envelopes were opened in consecutive number order of patient inclusion in the study”
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: “blinding and/or placebo control was not possible in this study. The temporary paralysis of the lower extremities after SA would, for obvious reasons, be observed immediately by the patient, aswell as by the staff. The lack of blindingmay pose a risk of bias. In order to reduce such potential bias the women were informed and monitored in a standardised fashion, and the mode of incision and type of abdominal hysterectomy were decided prior to randomisation”
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported on whether outcome assessor was blinded or not
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: “in the SF-36, a missing cell was substituted by the truncated mean value of the other items in the specific subscale for the individual. If all cells in a subscale were missing, the cells were substituted by the truncated mean value of each cell in the group. If a questionnaire was missing completely on one occasion, each cell was substituted by the truncated mean value of the cell for the group on that occasion. Missing cells for the SF-36 on all three occasions made up 0.44%, and a complete SF-36 was missing in 2.26% (11 of 486 cases). ”
Selective reporting (reporting bias)	Low risk	Primary outcomes fully reported
Null bias	Low risk	Quote: “spinal anaesthesia was associated with a significantly lower use of opioids” compared to general anaesthesia
Xu 2017
Methods	Clinical RCT Sequence generation by computer-generated random numbers Follow-up for 3 months
Participants	Subjects: 71 adults in a military hospital in China Operation: thoracolumbar spinal surgery 2 groups, size: 35/36 Age (± SD), group 1, 2: 51.91 (11.44), 49.06 (11.20) Men/women, group 1, 2: 19/16, 19/17 Exclusion criteria: a history of cardiopulmonary disease, coagulation and merging with multiple injuries
Interventions	Group 1 (ropivacaine): continuous wound infusion with ropivacaine was used as primary analgesia. This group received an initial wound infiltration with 6 mL 1% ropivacaine (100 mg; AstraZeneca AB, Sweden) and followed by continuous infusion with 0.33% ropivacaine via a double lumen catheter system at a rate of 5 mL/h (disposable postoperative local analgesia system, Beijing Heng Yuan Tongji Medical Technology Corporation, China) for 48 h. Participants in this group did not receive postoperative IV continuous constant-dose analgesia (ICCA) for pain control. Participants were premedicated with phenobarbital 100 mg and atropine 0.5 mg, 30 min before the induction of anesthesia. After baseline measurements of heart rate, noninvasive blood pressure, respiratory rate and oxygen saturation, each participant was preoxygenated for 3 min before induction. All participants received the target-controlled infusion with propofol 2–3 μg/mL using the Marsh pharmacokinetic model and remifentanil at 3 ng/mL to 4 ng/mL using the Minto pharmacokinetic model for induction. Following the induction of anaesthesia, cisatracurium 0.15 mg/kg was given as an IV injection. After tracheal intubation, mechanical ventilation was initiated with 100% oxygen and adjusted to maintain the end tidal carbon dioxide tension between 35 mmHg and 45 mmHg. Intermittent bolus injection of cisatracurium was used to maintain full muscle relaxation. At the end of surgery, residual neuromuscular block was reversed, if needed, with amixture of atropine and neostigmine. Participants were given pentazocine 60 mg when surgery was completed prior to extubation. All participants expanded on the use of the supplementary analgesic (flurbiprofen 50 mg IV injection) if necessary (VAS > 4) Group 2 (control): exactly the same as described above except there was no wound infiltration with ropivacaine. Additionally, this group relied on ICCA for postoperative pain control involving flurbiprofen axetil 150mg, pentazocine 240mg and palonosetron 0.5 mg in 100 mL normal saline, at a rate of 2 mL/h. All participants expanded on the use of the supplementary analgesic (flurbiprofen 50 mg IV injection) if necessary (VAS > 4) Adjuvants: none Immediate post-op pain control: no improvement
Outcomes	Dichotomous: pain vs no pain Continuous: none Other reported: demographic and operation data including disease, date of birth, gender, operating time, preoperative VAS, perioperative remifentanil and propofol doses, and length of surgical incision, pain score at rest during first 48 h postoperative using VAS, and Ramsay scores, times of rescue analgesia requests, incidence of postoperative nausea and vomiting, antiemetic therapy requirements and incidence of pruritus (participants were asked about the desire to scratch) at 2, 4, 6, 12, 24, 36 and 48 h postoperatively
Notes	We were unable to obtain additional information about randomization and blinding methods from the study author Funding sources: funding for the study was provided by Guangzhou General Hospital of Guangzhou Military Command Conflicts of interest: “all the authors declare they have no competing of interests.”
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“All participants were randomly assigned using a computer-generated random number table.”
Allocation concealment (selection bias)	Unclear risk	Concealment of allocation not described
Blinding of participants and personnel (performance bias) All outcomes	High risk	No sham was employed and blinding of participants/personnel not described
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome assessors not described
Incomplete outcome data (attrition bias) All outcomes	Low risk	“All enrolled patients successfully completed the study and were included in the main analysis.”
Selective reporting (reporting bias)	Low risk	No subgroup analysis was performed
Null bias	High risk	“There were no significant differences in the pain level between the two groups”
Zhou 2016
Methods	Double-blinded, placebo controlled, randomized clinical trial Sequence generation not described Follow-up for 3 months
Participants	Subjects: 106 adults in a university setting in China Operation: craniotomy 2 groups, size: 53/53 Age (± SD), group 1, 2: not described Men/women, group 1, 2: not described Exclusion criteria: not described
Interventions	Group 1 (ropivacaine): after the anesthesia induction, skin along the incision was infiltrated with 0.5%ropivacaine. Morphine was used as rescue analgesic postoperatively. Anaesthetic regimen not further described Group 2 (control): exactly the same as above except 0.9% saline was substituted for ropivacaine Adjuvants: none Immediate post-op pain control: significantly improved
Outcomes	Dichotomous: pain vs no pain Continuous: VAS Other reported: morphine consumption, heart rate and mean arterial pressure were recorded before anesthesia induction, after anesthesia induction, after scalp infiltration, during skull drilling, mater cutting, and skin closure
Notes	We were unable to obtain additional information about randomization and blinding methods from the study author Funding sources: funding of study not described Conflicts of interest: study authors declare no conflicts of interest
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomization methods not described
Allocation concealment (selection bias)	Unclear risk	Concealment of allocation not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Sham block was used. Blinding of personnel not described.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome assessors not described
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Rate of attrition not described
Selective reporting (reporting bias)	Unclear risk	Unclear if subgroup analysiswas performed
Null bias	High risk	Quote: “the incidence of pain... showed no difference between groups.”

5-HT3: 5-hydroxytryptamine; ANOVA: analysis of variance; ASA: American Society of Anesthesiology perioperative risk classification; BPI: brief pain inventory; EMLA: eutectic mixture of local anaesthetics; Epi: epinephrine; GA: general anaesthesia; h: hour; HRQOL: health-related quality of life; ICBG: iliac crest bone graft harvesting; IM: intramuscular; ITM: intrathecal morphine; ITT: intention-to-treat; IV: intravenous; Kg: kilogram; L2: lumbar segment number 2; LA: local anaesthetic; LMA: laryngeal mask airway; MAC: minimum alveolar concentration; mg: milligram; mL: millilitre; NIH: National Institute of Health; NSAID: nonsteroidal anti-inflammatory drugs; NRS: numerical rating scale; paracetamol: acetaminophen; PACU: postanaesthesia care unit; PCA: participant controlled analgesia; PCEA: patient controlled epidural analgesia; POD: postoperative day; PVB: paravertebral block; RCT: randomized controlled trial; SA: spinal anaesthesia; SAB: subarachnoid block; SC: subcutaneous; SD: standard deviation; SF-36: Short Form (36) Health Survey; SF-MPQ-2: Short Form MacGill Pain Questionaire; T4: thoracic segment 4; TAP: transabdominal plane block; TEA: thoracic epidural analgesia; μg: microgram; VAS: visual analogue scale