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 study author 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 envelopes...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"

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 for evaluation (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...".

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 (postsurgical breast infiltration): GA (sufentanil 0.3 µg/kg), at wound closure 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 (if VAS > 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 (if VAS > 30/100) nalbuphine 0.2 mg/kg

Adjuvants: none reported

Immediate post‐op pain control: analgesic rescue medication and VAS 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 initially 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

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 lidocaine (0.5%, 100 mL with epinephrine 5 µg/mL), post‐op as needed ketobemidone (oral, 5 mg) and paracetamol (1000 mg 3 x 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 x 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 lidocaine group than in the placebo group for the entire registration period of 10 h after wound closure"

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."

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/neurologic 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, post‐op 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 anaesthesiologist 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 randomization 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"

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 µg (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 µg fentanyl, 100 µg 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 maintained, 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, only per‐protocol. Flow diagram 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".

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 GA with 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 x 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: "iIntrathecal 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."

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, Hartford, 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.

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 T10) 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

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 x 48 h

Group 2 (thoracotomy wound infusion): 10 mL 0.15% bupivacaine infused at end of operation then continuous infusion 2 mL/h x 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 patient...were all blinded to the nature of the infusion".

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"

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."

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 mL 0.9% 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 12 h. 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 pre‐emptively through epidural catheter before the anaesthesia induction to provide the analgesia at two dermatome levels below and above the surgical incision dermatome (T4 to T10). 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: "the cases, who were not informed about which study group they were included 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."

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

Methods

Double‐blinded (participant, outcome assessor), clinical RCT

Sequence generation not described

Follow‐up for 6 months

Participants

Participants: 81 adults in 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)

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 the postoperative period, participants who needed postoperative revision for haemostasis, who had haemodynamic instability 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 µg/kg in addition to rocuronium 0.9 mg/kg for tracheal intubation. For maintenance of anaesthesia, desflurane 1 MAC, remifentanyl infusion (0.25 µg/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 µg + 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."

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 x 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 concealment, 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 anaesthesiologists, 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"

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 x 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: 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

The study author stated, "twenty five opaque envelopes were prepared for each group, each containing a note with [a] code...The night before surgery the anaesthesiologist pulled out one envelop from the bag containing the 100 envelops and according to the code inside administered to the patient the capsule from 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"

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, etc were 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"

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 consumption 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. Diclophenac (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."

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 route catheterization was performed, and participants were monitored according to ASA standards and bispectral index (BIS) anaesthetic depth. PVB was performed with single‐injection, 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 lock‐out 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: parecoxib, 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 with mobilization 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"

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, stopped 60 min after skin closure. Neither group received preanaesthetic medication. Both groups had the same GA protocol, including propofol 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"

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 mL NaCl 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, randomization, 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 anaesthesiologists"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Study author states "Dr L.K (anaesthesiologist) 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"

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/mL morphine (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 1 mg‐2 mg midazolam as needed during catheter placement. Standardized placement of epidural at T10 to 12 interspace, tested using 3 mL mepivacaine 2% with adrenaline then bolus dose of 3 mL to 4 mL mepivacaine 2% with adrenaline. Sensory blockade at T8 level. Standardized GA with propofol (participants 1‐55) or thiopentone (participants 56‐60), fentanyl, rocuronium, nitrous oxide in O₂, sevoflurane. Intraoperative analgesia with 2% mepivacaine with 2 mL/h‐5 mL/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' judgement

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 questionnaire themselves

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 significantly lower in group E compared with group P at 4–24 h after the operation"

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, 25 mL to 30 mL, doses maximum 150 mg; 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. 02 mcg/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 patient was 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

High risk

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"

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 T6/7/8, 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 T6/7/8, 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 (lung or oesophagus), and blinded randomized 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." Randomization method not detailed, but otherwise well documented.

Allocation concealment (selection bias)

Low risk

Participants unaware of allocation, concealment of allocation for providers described: "After obtaining ... written informed consent 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 infusion catheters were inserted at upper back (T7‐8 level) in Group C." This is acceptable, bias is unlikely.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessor "who was blinded to the postoperative pain management, interviewed patients by telephone, using a standard 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‐specified outcomes within manuscript were all reported on.

Null bias

High risk

Quote: "no statistically significant differences were found between the two groups with respect to NRS pain scores at rest or on motion within three days following surgery"

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 x daily ) rescue analgesia: 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 x daily) rescue analgesia: paracetamol (500 mg with codeine 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 12 months

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 postoperative 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 anaesthesiologists 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 anaesthesiologist 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 anaesthesiologists 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 bupivacaine 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"

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 clinicaltrials.gov/ct2/show/NCT00443404.

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"

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 x 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