Local anaesthetics and regional anaesthesia versus conventional analgesia for preventing persistent postoperative pain in adults and children

Erica J Weinstein; Jacob L Levene; Marc S Cohen; Doerthe A Andreae; Jerry Y Chao; Matthew Johnson; Charles B Hall; Michael H Andreae

doi:10.1002/14651858.CD007105.pub4

. 2018 Jun 21;2018(6):CD007105. doi: 10.1002/14651858.CD007105.pub4

Local anaesthetics and regional anaesthesia versus conventional analgesia for preventing persistent postoperative pain in adults and children

Erica J Weinstein ¹, Jacob L Levene ¹, Marc S Cohen ², Doerthe A Andreae ³, Jerry Y Chao ², Matthew Johnson ⁴, Charles B Hall ⁵, Michael H Andreae ^6,^✉

Editor: Cochrane Anaesthesia Group

PMCID: PMC6377212 NIHMSID: NIHMS1000227 PMID: 29926477

Abstract

Background

Regional anaesthesia may reduce the rate of persistent postoperative pain (PPP), a frequent and debilitating condition. This review was originally published in 2012 and updated in 2017.

Objectives

To compare local anaesthetics and regional anaesthesia versus conventional analgesia for the prevention of PPP beyond three months in adults and children undergoing elective surgery.

Search methods

We searched CENTRAL, MEDLINE, and Embase to December 2016 without any language restriction. We used a combination of free text search and controlled vocabulary search. We limited results to randomized controlled trials (RCTs). We updated this search in December 2017, but these results have not yet been incorporated in the review. We conducted a handsearch in reference lists of included studies, review articles and conference abstracts. We searched the PROSPERO systematic review registry for related systematic reviews.

Selection criteria

We included RCTs comparing local or regional anaesthesia versus conventional analgesia with a pain outcome beyond three months after elective, non‐orthopaedic surgery.

Data collection and analysis

At least two review authors independently assessed trial quality and extracted data and adverse events. We contacted study authors for additional information. We presented outcomes as pooled odds ratios (OR) with 95% confidence intervals (95% CI), based on random‐effects models (inverse variance method). We analysed studies separately by surgical intervention, but pooled outcomes reported at different follow‐up intervals. We compared our results to Bayesian and classical (frequentist) models. We investigated heterogeneity. We assessed the quality of evidence with GRADE.

Main results

In this updated review, we identified 40 new RCTs and seven ongoing studies. In total, we included 63 RCTs in the review, but we were only able to synthesize data on regional anaesthesia for the prevention of PPP beyond three months after surgery from 39 studies, enrolling a total of 3027 participants in our inclusive analysis.

Evidence synthesis of seven RCTs favoured epidural anaesthesia for thoracotomy, suggesting the odds of having PPP three to 18 months following an epidural for thoracotomy were 0.52 compared to not having an epidural (OR 0.52 (95% CI 0.32 to 0.84, 499 participants, moderate‐quality evidence). Simlarly, evidence synthesis of 18 RCTs favoured regional anaesthesia for the prevention of persistent pain three to 12 months after breast cancer surgery with an OR of 0.43 (95% CI 0.28 to 0.68, 1297 participants, low‐quality evidence). Pooling data at three to 8 months after surgery from four RCTs favoured regional anaesthesia after caesarean section with an OR of 0.46, (95% CI 0.28 to 0.78; 551 participants, moderate‐quality evidence). Evidence synthesis of three RCTs investigating continuous infusion with local anaesthetic for the prevention of PPP three to 55 months after iliac crest bone graft harvesting (ICBG) was inconclusive (OR 0.20, 95% CI 0.04 to 1.09; 123 participants, low‐quality evidence). However, evidence synthesis of two RCTs also favoured the infusion of intravenous local anaesthetics for the prevention of PPP three to six months after breast cancer surgery with an OR of 0.24 (95% CI 0.08 to 0.69, 97 participants, moderate‐quality evidence).

We did not synthesize evidence for the surgical subgroups of limb amputation, hernia repair, cardiac surgery and laparotomy. We could not pool evidence for adverse effects because the included studies did not examine them systematically, and reported them sparsely. Clinical heterogeneity, attrition and sparse outcome data hampered evidence synthesis. High risk of bias from missing data and lack of blinding across a number of included studies reduced our confidence in the findings. Thus results must be interpreted with caution.

Authors' conclusions

We conclude that there is moderate‐quality evidence that regional anaesthesia may reduce the risk of developing PPP after three to 18 months after thoracotomy and three to 12 months after caesarean section. There is low‐quality evidence that regional anaesthesia may reduce the risk of developing PPP three to 12 months after breast cancer surgery. There is moderate evidence that intravenous infusion of local anaesthetics may reduce the risk of developing PPP three to six months after breast cancer surgery.

Our conclusions are considerably weakened by the small size and number of studies, by performance bias, null bias, attrition and missing data. Larger, high‐quality studies, including children, are needed. We caution that except for breast surgery, our evidence synthesis is based on only a few small studies. On a cautionary note, we cannot extend our conclusions to other surgical interventions or regional anaesthesia techniques, for example we cannot conclude that paravertebral block reduces the risk of PPP after thoracotomy. There are seven ongoing studies and 12 studies awaiting classification that may change the conclusions of the current review once they are published and incorporated.

Plain language summary

Local and regional anaesthesia at the time of surgery to prevent longer‐term persistent pain after surgery

Review question

We set out to determine if the use of local anaesthetics (numbing medicine) at the time of surgery reduces the risk of having pain that persists for three months and more after surgery. The comparison was with pain killers alone, such as opioids and non‐steroidal anti‐inflammatory drugs.

Background

Pain that persists long after surgery is called persistent postoperative pain (PPP), and is not uncommon. Tissue damage and nerve injury can change pain pathways and sensibility to pain so that pain persists for months. A person may also feel pain more intensely or with a stimulus that normally is not perceived as pain. These changes can be permanent. Applying local anaesthetics close to nerves, bundles of nerves, or nerve roots in the central nervous system, as with an epidural, can interrupt the conduction of pain impulses from the surgical site to the central nervous system. Effective treatment of acute pain may prevent PPP. Wound infiltration uses a specially designed tube with multiple holes that is placed inside the wound to deliver the local anaesthetic.

Study characteristics

The evidence is current to December 2016. We found 63 randomized controlled trials (RCTs) with participants undergoing open chest, heart, breast, abdominal, vascular, gynaecological and other surgery, but not orthopaedic surgery. RCTs are studies where people are allocated by chance to one or the other of different treatments being studied. The studies included only adults, and were mostly conducted in Europe and North America, with some from China, Egypt and Brazil. The types of surgery included surgery with a high event rate of persistent pain after surgery, such as breast surgery, limb amputation and opening the chest, and surgery with a lower risk but high numbers of procedures, such as caesarean section.

We were able to pool results from 39 RCTs enrolling a total of 3027 participants for our inclusive analysis. Follow‐up was for 1293 participants at three months, 1365 participants at six months, 326 participants at 12 months, and 43 participants at 20 or more months after surgery. The RCTs did not report surgical and anaesthetic complications consistently and little information was available on these. The studies were mostly funded by the institutions conducting the studies.

Key results

Regional anaesthesia reduced the number of people who experienced persistent pain after undergoing non‐orthopaedic surgery. For open chest surgery, giving an epidural halved the odds of a person having persistent postoperative pain at three to 18 months after surgery (7 RCTs, 499 participants, moderate‐quality evidence). Seven people needed to be treated in this way for one to benefit.

For the prevention of persistent pain three to 12 months after breast cancer surgery, seven people needed regional anaesthesia for one to benefit (18 RCTs, 1297 participants, low‐quality evidence). Infusion of local anaesthetic into a vein was shown to reduce the risk of persistent pain three to six months after breast surgery (2 RCTs, 97 participants, moderate‐quality evidence), with three people needing to be treated for one to benefit. Regional anaesthesia reduced the odds by more than half of a woman experiencing persistent pain after caesarean section (4 RCTs, 551 participants, moderate‐quality evidence). The number of women treated for one to benefit was 19.

Continuous local anaesthetic infusion of the site where bone tissue was obtained from the hip bone did not clearly reduce the number of people with persistent pain at three to 55 months (3 RCTs, 123 participants, low‐quality evidence).

We could not synthesize evidence for limb amputation, hernia repair, cardiac or abdominal surgery because of differences in how treatment was given or how results were reported.

Quality of the evidence

We found consistent evidence supporting the use of regional anaesthesia in adults to prevent persistent pain after a number of types of surgery. However, we observed variations in the effect sizes, and at different times after surgery. Some studies could not be blinded to the treatment received and our results are affected by the small number of studies and participants, and the loss to follow‐up of participants over time. The evidence was therefore of low or moderate quality.

Summary of findings

Background

Description of the condition

Pain arising from a surgical intervention and persisting beyond three months is termed persistent postoperative pain (PPP) (Kehlet 2006). PPP continues to be frequent and is sometimes severe, but often neglected (Bayman 2014; Gewandter 2015; Kehlet 2006; Perkins 2000). The risk of developing PPP varies from 5% after minor surgery to 50% for phantom limb pain or postmastectomy pain syndrome (Jung 2003; Perkins 2000). Young age, the surgical procedure and perioperative pain predict PPP, while genetic risk factors remain unknown (Lewis 2015; Montes 2015). PPP may be only mild or it may be severely disabling (Kehlet 2006). Even the relatively low risk (about 10%) of developing PPP after caesarean section is a major concern due to the frequency of caesarean sections (Sng 2009). Most clinical studies focus on acute postoperative pain, and few address the preventive effects of regional anaesthesia on PPP (MacRae 2001; MacRae 2008). Recent reviews deplored the poor quality of available studies and documented the high event rate after a variety of surgical interventions, from hernia repair to breast surgery (MacRae 2001; MacRae 2008). Our current review focuses on the ability of local anaesthetics or regional anaesthesia to reduce the risk of PPP.

Pain pathways, and hence pain perception, can be modulated, sensitized and permanently altered (Woolf 2000). Persistent pain, postoperative hyperalgesia and allodynia (Kehlet 2006), after surgery are the consequence of neuronal plasticity, that is permanent synaptic neuronal changes in the peripheral and central nervous system in response to tissue trauma and nerve injury; where hyperalgesia refers to pain felt more intensely and allodynia describes a painful sensation after a stimulus that normally is not perceived as pain (Wilder‐Smith 2006).

Description of the intervention

Before or after surgery, local anaesthetics may be applied locally to interrupt the conduction of pain impulses from the site of injury to the central nervous system. If local anaesthetics are applied locally at the site of surgery this is called local anaesthesia. If local aesthetics are applied close to nerves, but at a distance from the surgical site, this is called regional anaesthesia. Sometimes, local aesthetics are also applied intravenously. All three modes of administration of local aesthetics may prevent the central sensitization described in the Description of the condition. Epidural and spinal anaesthesia act at the nerve roots while nerve blocks, plexus anaesthesia and wound infiltration inhibit peripheral nerves. By blocking sympathetic nerves, local anaesthetics may also have desirable effects on bowel motility or unwanted effects on blood pressure. Systemically (for example intravenously) administered local anaesthetics might also exert beneficial effects including preventing PPP, hyperalgesia and allodynia (Duarte 2005; Herroeder 2007; Lavand'homme 2005; Strichartz 2008; Vigneault 2011). As in our previous review, in this update we also focused on the pre‐emptive (Kissin 1996), use of local anaesthetics with or without opioids or other adjuvants intravenously or in regional anaesthesia.

The local and regional anaesthesia techniques described above can be used as an alternative or in addition to conventional pain control. Opioids like morphine, non‐steroidal anti‐inflammatory drugs (NSAIDs) such as ibuprofen, and other analgesics like paracetamol (acetaminophen in the USA) are the most frequently used conventional pain killers. They are administered systemically and, therefore, often cause systemic side effects that limit their use, like the nausea and constipation caused by opioids or kidney damage as a result of use of NSAIDs. We have provided an explanation of regional anaesthesia and conventional analgesia in Appendix 1.

How the intervention might work

We hypothesize that preventing pain transmission using local or regional anaesthesia during or soon after surgery, or both, reduces the risk of PPP (Atchabahian 2015b; Woolf 1993). Local anaesthetics applied close to the nerves will block pain perception and prevent the central sensitization in the spinal cord that leads to hyperalgesia and PPP (Kehlet 2006) (see: Description of the condition). However, systemic toxicity of local anaesthetics is well described (Brown 1995), either as a side effect after absorption or when given intravenously (Herroeder 2007; Strichartz 2008). Anti‐hyperalgesic effects of systemic lidocaine persist days beyond drug delivery and cannot be explained by sodium channel blockage. The actual mechanism remains elusive (Strichartz 2008).

Our review focused on preventive analgesia. We defined preventive analgesia as antinociception with local anaesthetics or regional anaesthesia to reduce the risk of PPP regardless of the timing of the intervention in relation to surgery (Kissin 2000). We did not study if local anaesthetics or regional anaesthesia were more effective if applied before, during or after surgery (Bong 2005; Lavand'homme 2011).

Why it is important to do this review

PPP is frequent and difficult to treat (Kehlet 2006). Hence prevention of PPP is paramount (Gewandter 2015). We are interested in investigating whether local anaesthetics or regional anaesthesia prevent PPP several months after surgery. Clinical trials report conflicting results. For example, epidural anaesthesia may reduce the risk of PPP after thoracotomy (Ju 2008; Lu 2008; Senturk 2002), but these effects have not been consistently reproduced (Ochroch 2006). Our previous review and evidence synthesis (Andreae 2012), favoured regional anaesthesia for PPP after breast cancer surgery and thoracotomy; but these inferences were based on a few small studies and plagued by unit‐of‐analysis issues. Also we found that pertinent studies reported repeated outcomes at different and disparate follow‐up intervals (Andreae 2012). We did not find enough studies to allow us to make inferences for other surgical subgroups. No other meta‐analysis is presently available on the effect of local or regional anaesthesia on PPP six to 12 months after surgery. A systematic review by Ong focused mostly on immediate postoperative pain control and the timing of regional anaesthesia (Ong 2005); some have questioned his results and methods (Møiniche 2002). Existing narrative reviews of regional anaesthesia for PPP have not attempted evidence synthesis (MacRae 2001; MacRae 2008). Terkawi 2015a sought to synthesize the evidence on paravertebral block for the prevention of PPP, but found the outcome reporting of available randomized controlled trials (RCTs) disparate and hence evidence synthesis difficult.

Objectives

To compare local anaesthetics and regional anaesthesia versus conventional analgesia for the prevention of PPP beyond three months in adults and children undergoing elective surgery.

Methods

Criteria for considering studies for this review

Types of studies

We included studies with a randomized, controlled design. We also included single‐blinded studies because regional anaesthesia causes numbness of the affected body part and, therefore, neither participant nor anaesthesia provider can be reliably blinded to the intervention. However, blinding of the outcome observer was a prerequisite for inclusion in this review.

Types of participants

We included studies in adults and children undergoing elective surgical procedures, encompassing general, thoracic, abdominal, vascular, gynaecological and other surgery. This included the main groups of surgery with a high event rate of persistent pain after surgery, such as breast surgery, limb amputation and thoracotomy, but also groups with a lower baseline risk but high surgical volume, such as caesarean section.

We excluded studies in participants undergoing orthopaedic procedures as they are covered by another Cochrane Review (Atchabahian 2015a).

Types of interventions

We included studies comparing local anaesthetics or regional anaesthesia versus conventional pain control (Appendix 1).

Interventions

We included studies comparing local anaesthetics and regional anaesthesia versus conventional pain control.

We defined local anaesthetics as any pharmacological agents acting on the sodium channel to block nerve conduction (Movassaghian 2013; Rodriguez‐Navarro 2011).

The inclusion criteria for the intervention groups were as follows.

Studies administering local anaesthetics or regional anaesthesia, including:

studies that employed local anaesthetics or regional anaesthesia for any length of time during the perioperative period;
studies that employed local anaesthetics by any route (Appendix 1);
studies that may also have employed adjuvants or opioids, either locally or systemically, in any one group.

The exclusion criteria for the intervention groups were:

studies that only compared different regional anaesthesia techniques or varying dose regimens of local anaesthetics during the same perioperative time span;
studies using local anaesthetics for other than anaesthetic or analgesic purposes (for example as anti‐arrhythmics).

The inclusion criteria for the comparator groups were:

studies that used conventional postoperative pain control (Appendix 1).

Types of outcome measures

We studied primary and secondary outcomes as follows.

Primary outcomes

Our primary outcome was persistent postoperative pain (PPP) at three or more months after surgery.

We defined PPP as new pain, (which did not exist before the operation), but lasting beyond three months after surgery. We defined our primary outcome of interest as a dichotomous contrast, namely the presence versus absence of pain elicited at that clinical encounter. We accepted the dichotomous pain outcomes as reported in the studies, mostly contrasting pain versus no pain, even though definitions varied at times. Use of pain medication is by some assessed as a dichotomous outcome (no pain medication versus pain medication) or as an ordinal outcome (no pain medication versus non‐opioid pain medication versus opioid pain medication) (Lavand'homme 2005). Some primary study authors define the presence or absence of pain in their study as pain exceeding a given threshold on a continuous pain scale, analogous to responder analysis. We accepted the thresholds used by the study authors, though they sometimes employed different scales or instruments. This responder analysis (Andreae 2015c; Dworkin 2009a), also employed during our previous version of this review (Andreae 2015), counts the number of people with an outcome above a defined threshold. Responder analysis informed our approach to missing data imputation (Andreae 2013b), as detailed below (Dealing with missing data). We discussed responder analysis and the heterogeneity of outcome reporting in greater detail in (Overall completeness and applicability of evidence). Studies elicited the presence of pain at different follow‐up intervals beyond our cut‐off of three months and we discuss the two approaches we took (inclusive versus classical analyses) to address this heterogeneity in Data synthesis.

We also assessed differences in scores based on validated pain scales, such as the visual analogue scale (VAS); the verbal rating score; or the McGill pain questionnaire (Dworkin 2009b).

Secondary outcomes

Our secondary outcomes were as follows.

Allodynia and hyperalgesia
Use of pain medication
Adverse effects of techniques and agents used

Acceptable continuous measures for allodynia or hyperalgesia may, for example, be the area of punctuate allodynia or hyperalgesia measured with von Frey hair (Lavand'homme 2005).

For adverse events we accepted any definition by the authors of the primary studies, who in the previous version of this review (Andreae 2012), sparsely reported on adverse events and most anecdotally or in narrative form. We discuss in Overall completeness and applicability of evidence, that registries are better suited to assess adverse events after regional anaesthesia given their rare occurrences.

Search methods for identification of studies

We performed an electronic search of common databases and handsearched reference lists of relevant studies and conference abstracts.

Electronic searches

In December 2016 we searched for studies on local anaesthetics or regional analgesia for the prevention of PPP in the Evidence‐Based Medicine Reviews (EBMR) via OVID‐Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 12), Ovid MEDLINE (1946 to December 2016), and Ovid Embase (1980 to December 2016).

We performed an additional search in December 2017 and added the results to Studies awaiting classification to be incorporated into the next update of this review.

We limited the results in MEDLINE using the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐maximizing version (2008 revision), as described in the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011). As there is, as yet, no Cochrane Highly Sensitivity Search Strategy for Embase, we limited the results in Embase using a filter we found at the University of Alberta library, based on a trial done in MEDLINE (Glanville 2006; University of Alberta Library Guide 2014).

We combined a free text search with a controlled vocabulary search, covering from the inception of the database to the present.

We searched for studies using local or regional anaesthesia for painful postsurgical conditions with an outcome follow‐up of weeks or months. Our MEDLINE, Embase and CENTRAL search terms are reproduced in the appendices (see:Appendix 2; Appendix 3; Appendix 4).

We did not impose a language restriction.

Searching other resources

We conducted a handsearch of the reference lists of included studies, review articles and other identified relevant studies for additional citations, and in the conference abstracts of the International Anesthesia Research Society (IARS) and the European Society of Regional Anaesthesia (ESRA) for 2005 through to 2007.

Because the yield of the handsearch was very low, we did not update this search in 2015.

We followed links for related articles in Pubmed Central. We searched the PROSPERO systematic review registry (Booth 2012), for related systematic reviews, which might list relevant studies.

Data collection and analysis

We present a diagram illustrating the process of the searches and selection and we followed the recommendations of the QUORUM and PRISMA statements (Moher 1999; Moher 2010; Figure 1).

The study flow diagram documents the search and selection process. We included 63 studies. We were able to pool data from 39 of the 63 included studies in our inclusive analysis; data from 24 studies were not available or otherwise could not be pooled (Appendix 11).

Selection of studies

We completed screening and data extraction using DistillerSR, a web‐based systematic review software.

The review authors (EJW, MSC, JLL, JYC, DAA and MHA) screened the citations and abstracts of all publications obtained by the search strategies. To avoid location bias, all articles detected by our search, (but not available via online subscription of our institutions) were requested through interlibrary loans. For studies that appeared to be eligible RCTs, we obtained and inspected the full articles to assess their relevance based on the preplanned criteria for inclusion. We noted the reasons for study exclusion and inserted them into the Characteristics of excluded studies table.

Data extraction and management

We developed a standard data collection form within DistillerSR based on a template provided by Cochrane Anaesthesia, Critical and Emergency Care (ACE) for the first version of this review (Andreae 2012). We recorded details of study design, participant characteristics, interventions and outcome measures. We performed a pilot run and revised our data sheet accordingly, published as an appendix in our previous review (Andreae 2012). For this review update, at least two review authors independently collected and extracted data (EJW, JLL, MSC, JYC, MHA and DAA), using the DistillerSR software, based on the previously used data extraction form (Andreae 2012). EJW, JLL, MSC, MHA and DAA checked and entered the data into Review Manager 5 (RevMan 5) (RevMan 2014), computer software.

We extracted the following primary outcome data on pain: any patient‐reported chronic pain outcome (dichotomous, continuous or multidimensional instrument) at three months or beyond after surgery.

Where dichotomous data on persistent postoperative pain were not reported, we attempted to obtain these from the study authors. If unavailable, we used continuous pain assessment and outcome measures (for example the VAS or the Numerical Rating Scale (NRS)) or complex instruments to evaluate chronic pain (for example the Brief Pain Inventory (BPI)).

We extracted the following secondary outcomes, where provided: allodynia and hyperalgesia, use of pain medication.

We also extracted the following data: exclusion criteria; comorbidity; regional anaesthesia technique and local anaesthetic used; quality assurance of the intervention; quality of pain control; assessment of hyperalgesia and allodynia; use of adjuvants; and surgery performed. We extracted data on adverse effects and attrition.

Assessment of risk of bias in included studies

For each report, at least two of the review authors (EJW, MSC, JLL, JYC, MHA and DAA) independently evaluated each report meeting the inclusion criteria. We contacted study authors for missing information regarding their methods. We graded study quality in a 'Risk of bias' table on the basis of a checklist of design components. This comprised randomization, concealed allocation, observer blinding, and intention‐to‐treat analysis. We extracted information on conflicts of interest and funding (see: Characteristics of included studies). We achieved consensus by informal discussion. We judged risk of bias to be unclear, high or low (Higgins 2011a).

In regional anaesthesia interventions, blinding of participants and anaesthesia providers can be difficult and hence this criterion received less weight in the evaluation of performance bias, but not with regard to detection bias. We listed excluded studies with detailed reasons (see: Characteristics of excluded studies).

If the randomization and allocation process was open to substantial bias, for example pseudo‐randomization, we did not include the study data in the data analysis.

Null bias

In response to the first version of this review (Andreae 2013b), clinicians expressed concern about null bias. Null bias might cause studies to underestimate the benefit of regional anaesthesia for the prevention of persistent pain after surgery, if the regional anaesthesia interventions were not effectively delivered (Higgins 2011a; Woods 1995). Indeed, a number of included studies reported no improved pain control in the immediate postoperative period in the experimental (regional anaesthesia) group, as evidenced by inconsequential differences in pain scores between groups perioperatively, or similar requirements of rescue analgesic medications between groups in the immediate postoperative period (Barkhuysen 2010; Baudry 2008; Bollag 2012; Can 2013; Choi 2016; Fassoulaki 2000; Ibarra 2011; Ju 2008; Karmakar 2014; Katz 1996; Lam 2015; Lee 2013; Liu 2015; Loane 2012; McKeen 2014; Micha 2012; Purwar 2015; Singh 2013; Smaldone 2010; Terkawi 2015b; Vrooman 2015; Xu 2017; Zhou 2016). Two review authors therefore extracted information on null bias for each included study and documented their judgement with supporting evidence (see: Characteristics of included studies).

Exploring the influence of attrition and follow‐up interval on effect size.

We explored the possible influence of attrition and follow‐up duration on effect size. We plotted attrition (in percent of participants lost at follow‐up from participants randomized) versus effect size (log odds ratio) for the major groups of studies investigating regional anaesthesia for the prevention of persistent postoperative pain, where we had most studies with repeated measurements. We connected repeated sequential effect measures at consecutive follow‐up visits within one study. We wanted to test the hypothesis that increasing attrition and outcome reporting at later follow‐ups leads to bias in the effect size estimation. If we found evidence to refute our null hypothesis of no association, then pooling studies reporting outcomes at different follow‐up intervals or with differential attrition might lead to biased pooled estimates and we would avoid this mode of analysis.

Measures of treatment effect

As the summary statistic for our dichotomous primary outcome, we chose the odds ratio (OR) (Bland 2000). We reported the OR with 95% confidence intervals (CI). We calculated the number needed to treat for an additional beneficial outcome (NNTB) for the surgical subgroups, for example, for thoracotomy and breast cancer surgery, but not for the overall effect across all types of surgery (Cook 1995). We used the open source statistical software package R (R 2015), to compute the NNTB and its 95% CI according to the Cochrane Handbook for Systematic Reviews of Interventions chapter 12.5.4.3 Computing absolute risk reduction or NNTB from an OR (Schünemann 2011a), as documented in Appendix 5.

Risk ratios (RR) and ORs are equally accepted measures of treatment effect (Deeks 2011). The planned integration of dichotomous outcomes with continuous outcomes implied the use of ORs (see: Data synthesis). After this integration turned out to be of marginal importance for our analysis, we decided to stick to our protocol to eliminate any reasonable doubt about a postanalysis decision that might inappropriately influence our results (Andreae 2008).

For the continuous pain scales we calculated the mean difference between groups when all studies in a given subgroup used the same scale, and standardized mean differences (SMD) between groups when studies being compared used different scales.

Unit of analysis issues

Some studies have the surgical site (e.g. left or right hernia) as unit of analysis as opposed to the study participant (Bell 2001; Kurmann 2015), which could, in theory, confound results as absorbed lidocaine from the treated site could exert effects on the non‐treated site if they were randomized to discordant interventions (Strichartz 2008).

For our inclusive evidence synthesis (Analysis 1.1; Analysis 1.3; Analysis 1.4; Analysis 1.5; Analysis 1.6; Analysis 1.7; Analysis 1.8; Analysis 1.9; Analysis 1.10; Analysis 1.11), we pooled studies reporting outcomes at variable follow‐up intervals. When one study reported the results at several subsequent follow‐up intervals, we used only the latest outcome reported, because the most sustained effect would be most interesting clinically.

Should thoracic epidural anaesthesia or conventional pain control be used to prevent persistent pain after open thoracotomy
Patient or population: people undergoing open thoracotomy  Settings: university and teaching hospitals in China, Turkey and Canada  Intervention: thoracic epidural anaesthesia  Comparison: conventional pain control
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Conventional pain control	Thoracic epidural anaesthesia
Persistent pain 3 to 18 months after thoracotomy (We defined persistent postsurgical pain as new pain that did not exist before the operation, measured using differences in scores based on validated pain scales; patient interview between 3 to 18 months after surgery.)	Study population		OR 0.52 (0.32 to 0.84)	499  (7 studies)	⊕⊕⊕⊝  moderate^1,2,3	All studies investigated persistent pain after open thoracotomy. The results cannot be extended to video‐assisted thoracotomy or other (minimally invasive) surgeries of the chest. The five of the seven included studies using thoracic epidural anaesthesia showed the strongest effect. The results cannot be extended to other interventions like paravertebral blocks. Conventional pain control with opioids and NSAID was the comparator. Event rates of persistent pain after thoracotomy were reported between 25% to 65% Regional anaesthesia may prevent persistent (chronic) pain after open thoracotomy in one out of seven people treated, thoracic epidural anaesthesia in one out of five people treated.
	525 per 1000	332 per 1000  (230 to 453)
	Low
	250 per 1000	130 per 1000  (83 to 200)
	Moderate
	500 per 1000	310 per 1000  (213 to 429)
Adverse effects of epidural anaesthesia ‐ not reported	See comment	See comment	Not estimable	‐	See comment	Adverse effects of epidural anaesthesia were not systematically reported and due to their low frequency are better investigated in patient registries.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; NSAID: nonsteroidal anti‐inflammatory drugs; OR: odds ratio
GRADE Working Group grades of evidence  High quality: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.  Low quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.  Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Should regional anaesthesia or conventional pain control be used to prevent persistent pain following breast cancer surgery
Patient or population: women with breast cancer undergoing elective surgery  Settings: cancer, community and university hospitals in Europe, China and North America  Intervention: various regional anaesthesia techniques including paravertebral block, nerve blocks or local infiltration  Comparison: conventional pain control
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Conventional pain control	Paravertebral block
Persistent pain 3 to 12 months after breast cancer surgery (We defined persistent postsurgical pain as new pain that did not exist before the operation, measured using differences in scores based on validated pain scales; patient interview between 3 to 12 months after surgery.)	Study population		OR 0.43 (0.28 to 0.68)	1297  (18 studies)	⊕⊕⊝⊝  low^1,2	Conventional pain control with opioids and NSAID was the comparator. Event rates of persistent pain after breast cancer were reported around 30%. Pooling all studies, regional anaesthesia may prevent persistent pain after breast surgery in one out of every seven women. Limiting the analysis to paravertebral block, the number of women needed to treat for one person to benefit was 11.
	427 per 1000	239 per 1000  (162 to 340)
	Low
	200 per 1000	95 per 1000  (61 to 147)
	High
	600 per 1000	387 per 1000  (281 to 509)
Adverse effects of paravertebral block for breast cancer surgery	See comment	See comment	Not estimable	‐	See comment	Adverse effects of regional anaesthesia after breast surgery were not systematically reported and due to their low frequency are better investigated in registries.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; NSAID: nonsteroidal anti‐inflammatory drugs; OR: odds ratio
GRADE Working Group grades of evidence  High quality: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.  Low quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.  Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Should local or regional anaesthesia be used for the prevention of chronic pain after caesarean section
Patient or population: women after caesarean section  Settings: maternity and university hospitals in South and North America, Egypt and Europe  Intervention: local or regional anaesthesia Comparison: conventional pain control
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Local or regional anaesthesia
Persistent pain 3 to 8 months after caesarean section (We defined persistent postsurgical pain as new pain that did not exist before the operation, measured using differences in scores based on validated pain scales; patient interview between 3 to 8 months after surgery.)	Study population		OR 0.46   (0.28 to 0.78)	551 participants  (4 studies¹)	⊕⊕⊕⊝  moderate^2,3	Event rates of persistent pain after caesarean section are reported around 10%. The number of women needed to be treated for one woman to benefit from regional anaesthesia after caesarean section was 19.
	179 per 1000	91 per 1000  (58 to 145)
	Low
	50 per 1000	24 per 1000  (15 to 39)
	Moderate
	100 per 1000	49 per 1000  (30 to 80)
Adverse effects of local or regional anaesthesia ‐ not reported	See comment	See comment	Not estimable	‐	See comment	Adverse effects of local or regional anaesthesia after caesarean section were not systematically reported and due to their low frequency are better investigated in registries.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; OR: odds ratio
GRADE Working Group grades of evidence  High quality: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.  Low quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.  Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Should continuous donor site local anaesthetic infusion or conventional pain control be used for the prevention of persistent postoperative pain after iliac crest bone graft harvesting
Patient or population: people after iliac crest bone graft harvesting  Settings: university hospitals in Europe and North America  Intervention: continuous donor site local anaesthetic infusion Comparison: conventional pain control
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Continous donor site local anaesthetic infusion
Persistent pain 3 to 55 months after iliac crest bone graft harvesting (We defined persistent postsurgical pain as new pain that did not exist before the operation, measured using differences in scores based on validated pain scales; patient interview between 3 to 55 months after surgery)	Low		OR 0.20   (0.04 to 1.09)	123  (3 studies¹)	⊕⊕⊝⊝  low¹	We accepted study author classification of the presence of persistent postoperative pain. Some assessed only pain vs no pain, others pain and dysaesthesia vs none. Event rates of persistent pain after iliac crest bone graft harvesting were reported between 20% to 40% and was assumed to be around 30%.
	200 per 1000	48 per 1000  (10 to 214)
	Moderate
	400 per 1000	118 per 1000  (26 to 421)
	High
	600 per 1000	231 per 1000  (57 to 620)
Adverse effects of continuous local anaesthetic infusion ‐ not reported	See comment	See comment	Not estimable	‐	See comment	Adverse effects of regional anaesthesia after iliac crest bone graft harvesting were not systematically reported and due to their low frequency are better investigated in registries.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; OR: odds ratio
GRADE Working Group grades of evidence  High quality: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.  Low quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.  Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Should continuous intravenous local anaesthetic infusion or conventional pain control be used for the prevention of persistent pain after breast cancer surgery
Patient or population: women with breast cancer undergoing elective surgery  Settings: university hospitals in Ireland and the USA  Intervention: continuous intravenous local anaesthetic infusion Comparison: conventional pain control
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Continous intravenous local anaesthetic infusion
Persistent pain 3 to 6 months after breast cancer surgery (We defined persistent postsurgical pain as new pain that did not exist before the operation, measured using differences in scores based on validated pain scales; patient interview between 3 to 6 months after surgery.)	Study population		OR 0.24   (0.08 to 0.69)	97  (2 studies)¹	⊕⊕⊕⊝  moderate¹	Event rates of persistent pain after breast cancer surgery ranged in this population between 20% to 40%. One in three women benefited on average from continuous intravenous infusion of local anaesthetics after breast cancer surgery.
	370 per 1000	123 per 1000  (45 to 288)
	Low
	200 per 1000	57 per 1000  (20 to 147)
	High
	600 per 1000	265 per 1000  (107 to 509)
Adverse effects of continuous local anaesthetic infusion ‐ not reported	See comment	See comment	Not estimable	‐	See comment	Adverse effects of intravenous infusion of local anaesthetics after breast cancer surgery were not systematically reported and due to their low frequency are better investigated in registries.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; OR: odds ratio
GRADE Working Group grades of evidence  High quality: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.  Low quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.  Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Date	Event	Description
4 October 2018	Amended	Acknowledgement section amended to include Co‐ordinating Editor
13 June 2018	New citation required but conclusions have not changed	We corrected the number of pooled studies and participants in the following sections: abstract (main results); results of the search (descriptive characteristics of participants); PRISMA figure; and Appendix 8 (removal of cardiac studies).
13 June 2018	Amended	We corrected the number of participants, and studies which were pooled in the inclusive analysis throughout the text and captions. Previously the text referred to 41 pooled studies (3143 participants). We corrected the text to read 39 studies, enrolling a total of 3027 participants. We removed the cardiac studies from Appendix 8 'Table of included participants', where previously the cardiac studies had erroneously been listed; even though due to heterogeneity, no data synthesis was performed for this surgical subgroup. Figure 1 and Appendix 8, and the text now consistently refer to the studies we included and pooled in our inclusive analysis.
8 December 2016	New search has been performed	We updated the review. We ran the search to December 2016. We identified 40 new RCTs and seven ongoing studies that met our inclusion criteria. We reran the search in December 2017 and added 11 studies to Studies awaiting classification.
8 December 2016	New citation required and conclusions have changed	Several authors have joined the team (Weinstein EJ, Levene JL, Cohen MS, Chao JY, Johnson M, Hall CB). The conclusions are changed by the inclusion of new studies, leading to stronger inferences in some subgroups and new inferences in others. We have updated the methods by including any outcomes after three months, with the inclusion of Bayesian hierarchical modelling and the inclusive analysis of studies by subgroup. In particular, we added additional analysis to estimate study level effects from outcomes observed at subsequent follow‐up visits in a study for a more coherent and stable effect estimate for the surgical groups.
2 July 2013	Amended	Journal version of review (Andreae 2013a) cited in ‘Other published versions of this review’

Study ID	Regional technique	Timing of intervention	Adjuvants	Outcomes	Continuous	Follow‐up(month)
Breast cancer surgery
Albi‐Feldzer 2013	Wound instillation and intervertebral block	Postincision, single shot vs placebo	None	Pain/no pain	Brief Pain Index	3, 6 and 12 months
Baudry 2008	Local Infiltration	Single shot, postincision vs control	None	Pain/no pain	McGill results not reported	18 months
Besic 2014	Local Infiltration	Postincision, continuous post‐op vs control	None	Pain/no pain	None	3 months
Fassoulaki 2000	Topical application	Preincision, continuous post‐op vs placebo	Propoxyphene	Pain/no pain	Verbal Intensity Scale	3 months
Fassoulaki 2001	Brachial plexus block	Postincision, single shot vs placebo	Mexiletine, propoxyphene	Pain/no pain	VAS	3 months
Fassoulaki 2005	Topical application	Postincision, continuous postop vs control	Gabapentin	Pain/no pain	Analgesic consumption	6 months
Gacio 2016	Paravertebral block	Single shot, preincision vs control	Parecoxib, fentanyl, morphine, and adrenaline	Pain/no pain	None	6 months
Grigoras 2012	IV lidocaine	Preincision, continuous intra‐op vs placebo	None	Pain/no pain	Short‐form McGill Pain Questionnaire	3 months
Ibarra 2011	Single shot, paravertebral block	Single shot, preincision vs control	None	Myofascial, phantom or neuropathic pain	None	3 and 5 months
Kairaluoma 2006	Single shot, paravertebral block	Single shot, preincision vs control	None	NRS > 3	Analgesic consumption	12 months
Karmakar 2014	Thoracic paravertebral block	Single shot, preincision vs pre incision, continuous vs control	Epinephrine	Pain/no pain	VRS	3 and 6 months
Lam 2015	Paravertebral block	Not specified	None	Pain/no pain	None	6 months
Lee 2013	Paravertebral block	Preincision, continuous intra‐op and post‐op vs control	Pregabalin	Pain/no pain	Short‐form McGill Pain Questionnaire	3 months
Micha 2012	Local infiltration with brachial plexus and interscalene block	Postincision, single shot vs placebo	None	DN4	None	6 months
Strazisar 2012	Local infiltration	Postincision, continuous post‐op vs control	None	Pain/no pain	None	3 months
Strazisar 2014	Local infiltration	Postincision, continuous post‐op vs control	None	Pain/no pain	None	3 months
Tecirli 2014	Intercostal nerve block	Postincision, single shot vs control	None	DN4	VAS	3 months
Terkawi 2015b	IV lidocaine	Preincision, continuous intra‐op and post‐op vs placebo	None	Pain/no pain	VAS	6 months
Caesarean section
Bollag 2012	Transversus abdominis plane block	Single shot, post‐op vs placebo	Clonidine	None	Short form McGill Pain Questionnaire	3, 6 and 12 months
Lavand'homme 2007	Wound irrigation	Preincision, continuous post‐op vs control	None	Pain/no pain	Analgesic consumption	6 months
Loane 2012	Transversus abdominis plane block	Postincision, single shot vs placebo	None	Pain/no pain	None	3 months
McKeen 2014	Transversus abdominis plane block	Postincision, single shot vs placebo	None	None	SF‐36	6 months
Shahin 2010	Peritoneal instillation	Postincision, single shot vs placebo	None	Pain/no pain	NRS	8 months
Singh 2013	Transversus abdominis plane block	Postincision, single shot vs placebo	None	None	NRS	3 months
Iliac crest bone graft
Barkhuysen 2010	Local infiltration	Postincision, single shot vs control	Epinephrine	Pain/no pain	None	1 Year
Gundes 2000	Wound instillation	Postincision, single shot vs placebo	None	Pain and dysaesthesia vs none	None	3 months
Singh 2007	Wound irrigation	Postincision, continuous post‐op vs control	None	Pain/no pain	VAS, pain frequency, functional activity score, overall satisfaction	4.7 years
Prostatectomy
Brown 2004	Spinal	Preincision, continuous intra‐op vs placebo	Clonidine	Pain/no pain	Numerical Pain Scale, SF‐36	3 months
Gupta 2006	Epidural	Continuos, post‐op vs placebo	Adrenaline	None	SF‐36	3 months
Thoracatomy
Can 2013	Epidural	Single shot, preincision vs preincision, continuous vs control	None	Pain/no pain	VAS, patient satisfaction	6 months
Comez 2015	Epidural	Preincision, continuous intra‐op vs control	Dexketoprofen, morphine, and fentanyl	Pain/no pain	VAS	3 and 6 months
Ju 2008	Epidural	Preincision and post‐op vs control	None	Pain/no pain	Allodynia	12 months
Katz 1996	Intercostal nerve block	Single shot, postincision vs control	None	Pain/no pain	VRS, analgesic consumption	18 months
Liu 2015	Wound irrigation	Postincision, continuous post‐op vs control	Fentanyl	Pain/no pain	None	3 months
Lu 2008	Epidural	Preincision vs post‐op vs control	None	Pain/no pain	None	6 months
Senturk 2002	Epidural	Preincision vs post‐op vs control	None	Pain/no pain	NRS, pain affecting daily living	6 months
Vaginal hysterectomy
Purwar 2015	Spinal	Single shot, preincision vs control	Fentanyl	None	VAS, SF‐36	3 months
Sprung 2006	Spinal	Single shot, preincision vs control	Clonidine	None	NRS, SF‐36	3 months
Abdominal hysterectomy
Wodlin 2011	Spinal	Single shot, preincision vs control	None	None	SF‐36	6 months
DN4: Douleur Neuropathique 4, a pain questionnaire; NRS: numerical rating scale; SF‐36: Short Form Health Survey; VAS: visual analogue scale; VRS: verbal rating scale

Participants included	Inclusive analysis	3 months	6 months	12 months	20 months	48 months
Thoracotomy	499 (7 studies)	120	279	77	23	0
Breast cancer surgery	1297 (18 studies)	745	439	113	0	0
Caesarean section (dichotomous)	551 (4 studies)	59	414	78	0	0
Caesarean section (continuous)	110 (2 studies)	39	71
Iliac crest bone graft	123 (3 studies)	45	0	58	0	20
Prostatectomy	150 (2 studies)	150	0	0	0	0
Hysterectomy	297 (3 studies)	135	162	0	0	0
Sum	3027 (39 studies)	1293	1365	326	23	20
The table of included participants provides a detailed census of the 3027 participants in 39 studies pooled in our inclusive analysis (Data synthesis/inclusive analysis). We provide a breakdown of the number of participants that contributed data at different follow‐up intervals. The first column lists the total number of participants pooled for each surgical subgroup; subsequent columns break the participants down by follow‐up interval. The last row sums participants at different follow‐ups. Most of the study data were observed at three and six months after surgery. If a study reported outcomes at more than one follow‐up, we counted the study data only once, at the last follow‐up reported for that study (Unit of analysis issues).

Surgery	Study ID	Reason for non‐inclusion
Cardiac surgery	Dogan 2016	Data N/A
	Chiu 2008	Too heterogeneous
	Vrooman 2015	Too heterogeneous
Breast cancer surgery	Di‐Gennaro 2013	Data N/A
Plastic surgery of the breast	Bell 2001	Different type of intervention
Iliac crest bone graft	Blumenthal 2005	Data N/A
Iliac crest bone graft	O'Neill 2014	Data N/A
Laparotomy	Katz 2004	Too heterogeneous
Laparotomy	Lavand'homme 2005	Too heterogeneous
Caesarean section	O'Neill 2012	No events
Hernia repair	Burney 2004	Data N/A
	Kurmann 2015	Too heterogeneous
	Mounir 2010	Too heterogeneous
	Okur 2016	Data N/A
Prostatectomy	Smaldone 2010	Data N/A
Vasectomy	Paxton 1995	Single study
Limb amputation	Kairaluoma 2006	Inconsistent regional application
	Katsuly‐Liapis1996	Inconsistent regional application
	Pinzur 1996	Data N/A
Pectus excavatum	Weber 2007	Single study
Cholecystectomy	Fassoulaki 2016	Single study
Spinal surgery	Xu 2017	Single study
Thyroidectomy	Choi 2016	Single study
Craniotomy	Zhou 2016	Single study

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 PPP three to 18 months after thoracotomy	7	499	Odds Ratio (M‐H, Random, 95% CI)	0.52 [0.32, 0.84]
2 PPP three to six months after cardiac surgery	2	116	Mean Difference (IV, Random, 95% CI)	‐0.76 [‐1.73, 0.21]
3 PPP three to twelve months after breast cancer surgery	18	1297	Odds Ratio (M‐H, Random, 95% CI)	0.43 [0.28, 0.68]
3.1 Paravertebral block	6	419	Odds Ratio (M‐H, Random, 95% CI)	0.61 [0.39, 0.97]
3.2 Intravenous lidocaine	2	97	Odds Ratio (M‐H, Random, 95% CI)	0.24 [0.08, 0.69]
3.3 Multimodal block	4	402	Odds Ratio (M‐H, Random, 95% CI)	0.76 [0.32, 1.77]
3.4 Local infiltration	6	379	Odds Ratio (M‐H, Random, 95% CI)	0.29 [0.12, 0.73]
4 PPP three to eight months after caesarean section	4	551	Odds Ratio (M‐H, Random, 95% CI)	0.46 [0.28, 0.78]
5 Pain score three to six months after caesarean section	2	110	Std. Mean Difference (IV, Random, 95% CI)	0.14 [‐0.34, 0.61]
6 PPP three to 55 months after Iliac crest bone graft	3	123	Odds Ratio (M‐H, Random, 95% CI)	0.20 [0.04, 1.09]
7 PPP six to 12 months after amputation	2	108	Odds Ratio (M‐H, Random, 95% CI)	0.53 [0.21, 1.33]
8 PPP six to 12 months after laparotomy	2		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9 PPP three to 12 months after hernia repair	2		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10 Pain score three months after prostatectomy	2	150	Std. Mean Difference (IV, Random, 95% CI)	0.06 [‐0.26, 0.38]
11 SF‐36 bodily pain score at three to six months after hysterectomy	3	297	Mean Difference (IV, Random, 95% CI)	1.70 [‐1.06, 4.46]

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 (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."

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 PPP after thoracotomy	6		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1 Three months follow‐up	5	428	Odds Ratio (M‐H, Random, 95% CI)	0.70 [0.40, 1.20]
1.2 Six months follow‐up	5	370	Odds Ratio (M‐H, Random, 95% CI)	0.39 [0.24, 0.63]
2 PPP after cardiac surgery	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.1 Three months follow‐up	2	116	Mean Difference (IV, Random, 95% CI)	‐0.77 [‐1.74, 0.20]
3 PPP after breast cancer surgery	19		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 Three months follow‐up	11	966	Odds Ratio (M‐H, Random, 95% CI)	0.34 [0.19, 0.61]
3.2 Six months follow‐up	9	515	Odds Ratio (M‐H, Random, 95% CI)	0.56 [0.37, 0.84]
3.3 12 months follow‐up	2	113	Odds Ratio (M‐H, Random, 95% CI)	0.63 [0.04, 10.47]
4 PPP after caesarean section	4		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
4.1 Three months follow‐up	2	137	Odds Ratio (M‐H, Random, 95% CI)	1.09 [0.39, 3.07]
4.2 Six months follow‐up	3	492	Odds Ratio (M‐H, Random, 95% CI)	0.44 [0.26, 0.74]
5 PPP after amputation	2		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
6 PPP after laparotomy	2		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
7 PPP after hernia repair	2		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
8 PPP after hysterectomy	2	135	Mean Difference (IV, Random, 95% CI)	1.90 [‐1.23, 5.02]
8.1 Three months follow‐up	2	135	Mean Difference (IV, Random, 95% CI)	1.90 [‐1.23, 5.02]

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	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	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"

PERMALINK

Local anaesthetics and regional anaesthesia versus conventional analgesia for preventing persistent postoperative pain in adults and children

Erica J Weinstein

Jacob L Levene

Marc S Cohen

Doerthe A Andreae

Jerry Y Chao

Matthew Johnson

Charles B Hall

Michael H Andreae

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

1.

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Null bias

Exploring the influence of attrition and follow‐up interval on effect size.

Measures of treatment effect

Unit of analysis issues

1.1. Analysis.

1.3. Analysis.

1.4. Analysis.

1.5. Analysis.

1.6. Analysis.

1.7. Analysis.

1.8. Analysis.

1.9. Analysis.

1.10. Analysis.

1.11. Analysis.

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Inclusive model

Pooling across different follow‐up intervals

Stratified analysis

Bayesian model

Model estimation, implementation and convergence testing

Pooling groups with different timing of regional anaesthesia interventions or varying use of adjuvants in regards to the surgical intervention

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' table and GRADE

Summary of findings for the main comparison. Thoracic epidural anaesthesia versus conventional pain control to prevent persistent pain after open thoracotomy.

Summary of findings 2. Regional anaesthesia compared to conventional pain control for breast cancer surgery.

Summary of findings 3. Local or regional anaesthesia for the prevention of chronic pain after caesarean section.

Summary of findings 4. Continous donor site local anaesthetic infusion for the prevention of persistent postoperative pain after iliac crest bone graft harvesting.

Summary of findings 5. Continous intravenous local anaesthetic infusion for the prevention of persistent pain after breast cancer surgery.

Results

Description of studies

Results of the search

Electronic search

Handsearch

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 (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	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
Notes	Funding sources: this research work was fully funded by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China (RGC reference no. CUHK4406/05, project code 2140452). Conflicts of interest: the study authors declare no conflict of interest
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were randomized to 1 of 3 study groups... with a computer‐generated allocation number"
Allocation concealment (selection bias)	Low risk	Quote: "sequentially numbered, coded, sealed opaque envelopes...The sealed envelopes were prepared by a third party (research assistant) who took no further part in the study"
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "patients in group1, who had received standardized GA with no paravertebral intervention, could not be blinded for obvious reasons..For the other 2 study groups that had a thoracic paravertebral catheter placed, we adopted a double‐blind methodology... The principal investigator performed all the thoracic paravertebral catheter placements, collected procedural data, injected the ropivacaine bolus for the TPVB [thoracic paravertebral block], conducted the GA, and took no further part in data collection.. The paravertebral infusion (ropivacaine 0.25% or 0.9% saline) was prepared.. by a postanaesthetic care unit (PACU) nurse not involved in the study ... A single surgeon, who was also blinded to the group allocation, performed or supervised all the surgical procedures"
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "a research nurse blinded to the group allocation recorded data preoperatively, in the PACU, and at regular intervals in the postoperative ward...The telephone interview at 3 and 6 months after surgery was also conducted by the same research nurse (blind to group allocation)"
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "the primary analyses were performed on a modified intention‐to‐ treat basis (i.e., patients were analysed according to their randomized allocated groups but were excluded from the analysis if they did not adhere to the protocol after randomization)". 1 participant lost to follow‐up in group 2 and reason given (returned overseas after surgery). 2 excluded from the analysis in group 2 because of protocol violation/diagnosed contralateral breast cancer. Very small numbers of attrition, with reasons reported for each exclusion and modified ITT protocol used.
Selective reporting (reporting bias)	Low risk	All primary outcomes in protocol were fully reported on
Null bias	High risk	Quote: "there was no significant difference in acute pain scores at rest (Fig. 2) or on movement (Fig. 3) between the study groups (both P = 0.22) during the 72 hours after surgery".

Methods	clinical RCT Sequence generation randomized, but not described Follow‐up: one year
Participants	Participants: 45 adults in a university setting in Athens, Greece Operation: lower limb amputation 3 groups, size: 15/12/18 Age: not reported Men/women: not reported
Interventions	Group 1 (preoperative epidural): for 72 h preop: bupivacaine (0.25% and morphine) via epidural catheter (level not specified), (intraop anaesthesia not specified), post‐op for 72 h epidural bupivacaine infusion (not specified) Group 2 (post‐op epidural): for 72 h preop: opioids and NSAIDs (not specified), (intraop anaesthesia not specified), post‐op for 72 h epidural bupivacaine infusion (not specified) Group 3 (control): for 72 h preop: opioids and NSAID (not specified), (intraop anaesthesia not specified), post‐op opioids and NSAIDs (not specified) Adjuvants: none Immediate post‐op pain control: not reported, phantom pain risk not significantly reduced for the first three days
Outcomes	Dichotomous: phantom limb pain at 6 and 12 months Continuous: none reported
Notes	We were unable to find the contact information for any of the authors using Google and PubMed or the institution and therefore no additional information beyond the abstract could be obtained or extracted. Funding sources: no source of funding reported. Conflicts of interest: no conflict of interest statement given.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Patients were "randomly allocated", but the exact method was not explained.
Allocation concealment (selection bias)	Unclear risk	Concealment of allocation was not reported.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding was not reported in the abstract.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Blinding was not reported in the abstract.
Incomplete outcome data (attrition bias)   All outcomes	High risk	Attrition is not reported. ITT analysis is not mentioned.
Selective reporting (reporting bias)	Unclear risk	No protocol available for review and only abstract available
Null bias	Unclear risk	Immediate post‐op pain control not reported, however phantom pain risk not significantly reduced for the first three days.

Methods	Double‐blinded, placebo/sham‐controlled, randomized clinical trial Sequence generation by computer‐generated random numbers Follow‐up: 6 months
Participants	Participants: 152 adults in a university setting in Toronto, Canada Operation: laparotomy for major gynaecological surgery 3 groups, size: 49/56/47 Age: 44 years (SD ± 8.9), 47 (SD ± 10.6), 44 (SD ± 9.6) Men/women: women only
Interventions	Group 1 (preincisional epidural): epidural catheter at L2/3/4 tested, GA, preincision: lidocaine (2% with epinephrine (1:200,000), 12 mL plus 0.8 mL for each 2.5cm (1 inch) of height above 152cm (60 inch), plus 4 µg/kg fentanyl), 40 min after incision epidural normal saline (12 mL), post‐op morphine PCA (loading dose 4 mg, then bolus 1.0‐1.5 mg, lockout time 5 min, max 40 mg in 4 h, no basal rate) Group 2 (postincision epidural): epidural catheter at L2/3/4 tested, GA, preincision: epidural normal saline (12 mL), 40 min after incision: lidocaine (2% with epinephrine (1:200,000), 12 mL plus 0.8 mL for each inch of height above 60 inch, plus 4 µg/kg fentanyl), post‐op morphine PCA (loading dose 4 mg, then bolus 1.0‐1.5 mg, lockout time 5 min, max 40 mg in 4 h, no basal rate) Group 3 (sham epidural): sham epidural catheter at L2/3/4 tested, GA (fentanyl 1 µg/kg), preincision: epidural normal saline (12 mL), 40 min after incision epidural normal saline (12 mL), post‐op morphine PCA (loading dose 4 mg, then bolus 1.0‐1.5 mg, lockout time 5 min, max 40 mg in 4 h, no basal rate) Adjuvants: none Immediate post‐op pain control: not significant
Outcomes	Dichotomous: pain at 6 months, analgesic consumption at 6 months Continuous: Pain Disability Index, Mental Health Inventory‐18 and McGill Pain Questionnaire at 6 months Secondary: allodynia/hyperalgesia
Notes	Funding sources: supported by grants from the National Institutes of Health and the Canadian Institutes of Health. Conflicts of interest: conflicts of interest were not reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “a randomization schedule was computer generated by a biostatistician.”
Allocation concealment (selection bias)	Low risk	Quote: "an opaque envelope containing the patient number and group assignment was prepared, sealed, and numbered for each patient by the hospital pharmacist, not involved in the study otherwise...All patients and personnel involved in patient management and data collection were unaware of the group to which the patient had been allocated. The anesthesiologist in charge of the case was aware of group allocation for control group patients and was not involved in postoperative management or data collection."
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "all patients and personnel involved in patient management and data collection were unaware of the group to which the patient had been allocated. The anaesthesiologist in charge of the case was aware of group allocation for control group patients and was not involved in postoperative management or data collection." but the anaesthesiologist in charge of the case was aware of group allocation for control group participants.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "neither the person conducting the interview nor the patient was aware of the group to which the patient had been assigned," "personnel involved in ... data collection were unaware of the group to which the patient had been allocated."
Incomplete outcome data (attrition bias)   All outcomes	High risk	Quote: "both an intention to treat analysis and a protocol‐compliant analysis were performed." "There was no appreciable difference in the results of the intention‐to‐treat analyses and the protocol compliant analyses. Data and results of significance tests reported below are therefore based on the intention to treat analyses." But ITT was only done for early outcomes, not for questionnaire data at 6 months, when significant attrition occurred.
Selective reporting (reporting bias)	Unclear risk	Primary outcomes fully reported on
Null bias	Low risk	Quote: "preincisional administration of epidural lidocaine and fentanyl was associated with a significantly lower rate of morphine use, lower cumulative morphine consumption, and reduced hyperalgesia compared with a sham epidural condition"