PROSPECT guideline for oncological breast surgery: a systematic review and procedurespecific postoperative pain management recommendations

Analgesic protocols used to treat pain after breast surgery vary significantly. The aim of this systematic review was to evaluate the available literature on this topic and develop recommendations for optimal pain management after oncological breast surgery. A systematic review using preferred reporting items for systematic reviews and meta-analysis guidance with procedure-specific postoperative pain management (PROSPECT) methodology was undertaken. Randomised controlled trials assessing postoperative pain using analgesic, anaesthetic or surgical interventions were identified. Seven hundred and forty-nine studies were found, of which 53 randomised controlled trials and nine meta-analyses met the inclusion criteria and were included in this review. Quantitative analysis suggests that dexamethasone and gabapentin reduced postoperative pain. The use of paravertebral blocks also reduced postoperative pain scores, analgesia consumption and the incidence of postoperative nausea and vomiting. Intra-operative opioid requirements were documented to be lower when a pectoral nerves block was performed, which also reduced postoperative pain scores and opioid consumption. We recommend basic analgesics (i.e. paracetamol and non-steroidal antiinflammatory drugs) administered pre-operatively or intra-operatively and continued postoperatively. In addition, pre-operative gabapentin and dexamethasone are also recommended. In major breast surgery, a regional anaesthetic technique such as paravertebral block or pectoral nerves block and/or local anaesthetic wound infiltration may be considered for additional pain relief. Paravertebral block may be continued postoperatively using catheter techniques. Opioids should be reserved as rescue analgesics in the postoperative period. Research is needed to evaluate the role of novel regional analgesic techniques such as erector spinae plane or retrolaminar plane blocks combined with basic analgesics in an enhanced recovery setting.

## Recommendations
1 Systemic analgesia should include paracetamol and non-steroidal anti-inflammatory drugs (NSAID) administered pre-operatively or intra-operatively and continued postoperatively.
2 Pre-operative gabapentin is recommended.
3 A single dose of intravenous (i.v.) dexamethasone is recommended for its ability to increase the analgesic duration of peripheral nerve blocks, decrease analgesia use and anti-emetic effects.
4 Opioids should be reserved as rescue analgesia in the postoperative period.
5 Paravertebral blockade is recommended as the firstchoice regional analgesic technique. Pectoral nerves block may be used as an alternative to paravertebral block. Local anaesthetic wound infiltration may be added to regional analgesia techniques.

## Why was this guideline developed?
Oncological breast surgery is associated with significant acute and chronic postoperative pain. The aim of this guideline is to provide clinicians with an evidence-based approach to pain management after oncological breast surgery, which may improve postoperative pain relief.
What other guidelines are available on this topic?
A systematic review was performed by the PROSPECT collaboration in 2006; however, several new analgesic regimens, particularly regional analgesia techniques have been introduced since the previous systematic review.
How does this guideline differ from other guidelines?
The procedure-specific postoperative pain management (PROSPECT) approach to developing guidelines is unique such that the available evidence is critically assessed for current clinical relevance. This approach reports true clinical effectiveness by balancing the invasiveness of the analgesic interventions and the degree of pain after surgery, as well as balancing efficacy and adverse effects.

# Introduction
Oncological breast surgery, hereafter simply referred to as breast surgery, is associated with significant acute and chronic postoperative pain [bib_ref] Pain after mastectomy and breast reconstruction, Vadivelu [/bib_ref]. A systematic review of analgesic strategies was performed in 2006, however, several new analgesic regimens, particularly regional analgesic techniques (e.g. pectoral nerves and erector spinae plane blocks) have been introduced since [bib_ref] Interfascial plane blocks: back to basics, Elsharkawy [/bib_ref]. An updated systematic review on analgesic interventions dedicated to breast surgery was consequently required.
The PROSPECT Working Group is a collaboration of surgeons and anaesthetists working to formulate procedurespecific recommendations for pain management after common but potentially painful operations [bib_ref] Procedure-specific pain management and outcome strategies, Joshi [/bib_ref] [bib_ref] Procedure-specific pain management (PROSPECT) -an update. Best Practice and Research, Lee [/bib_ref].The recommendations are based on a procedure-specific systematic review of randomised controlled trials (RCT). The methodology considers clinical practice, efficacy and adverse effects of analgesic techniques [bib_ref] Guidelines for perioperative pain management: need for re-evaluation, Joshi [/bib_ref].

# Results
The preferred reporting items for systematic review and meta-analysis (PRISMA) flow chart demonstrating the search data is presented in . The methodological quality assessments of the 53 RCTs and nine meta-analyses included for the final qualitative analysis are summarised in . The characteristics of the included studies are shown in.

## Pre-operative interventions
Two meta-analyses of parallel group, placebo-controlled RCTs have evaluated the efficacy of the pre-operative use of gabapentin for the treatment of acute and chronic postoperative pain following breast cancer surgery [bib_ref] The efficacy of gabapentin in reducing pain intensity and morphine consumption after..., Jiang [/bib_ref] [bib_ref] Preoperative pregabalin or gabapentin for acute and chronic postoperative pain among patients..., Rai [/bib_ref].
The meta-analysis by Rai et al. [bib_ref] Preoperative pregabalin or gabapentin for acute and chronic postoperative pain among patients..., Rai [/bib_ref] included all the studies of the meta-analysis by Jiang et al. [bib_ref] The efficacy of gabapentin in reducing pain intensity and morphine consumption after..., Jiang [/bib_ref] but also included one that pre-operative pregabalin reduced pain scores and morphine consumption in the PACU [bib_ref] Preoperative pregabalin or gabapentin for acute and chronic postoperative pain among patients..., Rai [/bib_ref]. However, no significant difference was observed in pain scores at 24 h with the addition of pregabalin [bib_ref] Preoperative pregabalin or gabapentin for acute and chronic postoperative pain among patients..., Rai [/bib_ref]. No significant differences in gabapentin-related side-effects were observed. The incidence of sedation was increased with pregabalin but not that of blurred vision or dizziness [bib_ref] The efficacy of gabapentin in reducing pain intensity and morphine consumption after..., Jiang [/bib_ref] [bib_ref] Preoperative pregabalin or gabapentin for acute and chronic postoperative pain among patients..., Rai [/bib_ref].

## Intra-operative interventions
Two placebo-controlled studies have investigated the effect of systemic dexamethasone on postoperative pain, nausea and vomiting after conservative oncologic breast surgery and mastectomy [bib_ref] Preoperative dexamethasone reduces postoperative pain, nausea and vomiting following mastectomy for breast..., G Omez-Hern Andez [/bib_ref] [bib_ref] Effects of preoperative dexamethasone on postoperative pain, nausea, vomiting and respiratory function..., Cort Es-Flores [/bib_ref]. Both studies reported similar results. In particular, patients receiving i.v.

## Postoperative interventions
In 39 out of the 62 included studies and meta-analyses, paracetamol, NSAIDs or cyclo-oxygenase-2 (COX-2)
inhibitors were given postoperatively. We retrieved one study comparing paracetamol, metamizole and placebo.
The authors reported analgesic superiority of paracetamol (4 g daily) as 42% of patients did not require rescue analgesia compared with 4% in the placebo group and 4%
in the metamizole group [bib_ref] Paracetamol versus metamizol in the treatment of postoperative pain after breast surgery:..., Ohnesorge [/bib_ref]. Another study documented that paracetamol 1 g administered at the end of surgery improved pain control during recovery [bib_ref] Single dose systemic acetaminophen to improve patient reported quality of recovery after..., Oliveira [/bib_ref]. In yet another study, paracetamol was documented to be equivalent to metamizole but the number of patients included (n = 40) was insufficient to draw definite conclusions [bib_ref] Clinical equivalence of IV paracetamol compared to IV dipyrone for postoperative analgesia..., Kampe [/bib_ref]. The combination of postoperative paracetamol with codeine was found to be as effective as the combination of paracetamol and ibuprofen [bib_ref] A randomized, controlled trial comparing acetaminophen plus ibuprofen versus acetaminophen plus codeine..., Mitchell [/bib_ref]. One study compared the combination of paracetamol and ibuprofen with the combination of paracetamol, codeine and caffeine in ambulatory patients. Both analgesic protocols had comparable effect on pain intensity but the incidence of nausea and constipation was reduced in the group receiving paracetamol and ibuprofen [bib_ref] A randomized, controlled trial comparing acetaminophen plus ibuprofen versus acetaminophen plus codeine..., Mitchell [/bib_ref].
Only one study in the search period specifically examined postoperative pain control with NSAIDs after oncologic breast surgery. The addition of systemic COX-2 inhibitors (parecoxib and celecoxib) to paravertebral block has been demonstrated to decrease the intensity of pain on movement on day five [bib_ref] Hyperalgesia and persistent pain after breast cancer surgery: a prospective randomized controlled..., Van Helmond [/bib_ref] but has no effect on the occurrence of postoperative hyperalgesia. Studies included RCTs (n = 53) and meta-analyses (n = 9) Identification Screening Eligibility Included Flow diagram of studies included in this systematic review. no significant difference in the incidence of postoperative nausea and vomiting was reported [bib_ref] Ultrasound-guided single-vs double-level thoracic paravertebral block for postoperative analgesia in total mastectomy..., Kasimahanti [/bib_ref]. The time required to perform a single-injection paravertebral block was shorter compared with the multiple-injection group (5 min vs. 10 min; median difference 4 min; 95%CI -6 to -3 min; p < 0.001) [bib_ref] Single-injection versus multiple-injection technique of ultrasound-guided paravertebral blocks: a randomized controlled study..., Uppal [/bib_ref]. Ultrasound guidance was used to perform paravertebral injections or catheter positioning in eight studies [bib_ref] Ultrasound-guided multilevel paravertebral blocks and total intravenous anesthesia improve the quality of..., Abdallah [/bib_ref] [bib_ref] Analgesic efficacy of ultrasound-guided paravertebral block versus serratus plane block for modified..., Gupta [/bib_ref] [bib_ref] Ultrasound-guided single-vs double-level thoracic paravertebral block for postoperative analgesia in total mastectomy..., Kasimahanti [/bib_ref] [bib_ref] Paravertebral catheter for three-level injection in radical mastectomy: a randomised controlled study, Sundarathiti [/bib_ref] [bib_ref] Single-injection versus multiple-injection technique of ultrasound-guided paravertebral blocks: a randomized controlled study..., Uppal [/bib_ref] [bib_ref] A combination of levobupivacaine and lidocaine for paravertebral block in breast cancer..., Zup Ci C M [/bib_ref] [bib_ref] Treatment of postmastectomy pain with ambulatory continuous paravertebral nerve blocks: a randomized,..., Ilfeld [/bib_ref] [bib_ref] Comparison of the post-operative analgesic effect of paravertebral block, pectoral nerve block..., Syal [/bib_ref] , whereas 16 other studies did not use ultrasound [bib_ref] Thoracic paravertebral block versus pectoral nerve block for analgesia after breast surgery, Wahba [/bib_ref] [bib_ref] Comparison of the post-operative analgesic effect of paravertebral block, pectoral nerve block..., Syal [/bib_ref] [bib_ref] Efficacy of pectoral nerve block versus thoracic paravertebral block for postoperative analgesia..., Kulhari [/bib_ref]. There was no significant difference in pain scores between the paravertebral block and the PECS block groups between 2 and 18 postoperative hours [bib_ref] Comparison of the post-operative analgesic effect of paravertebral block, pectoral nerve block..., Syal [/bib_ref]. However, after 18 h the paravertebral block group had lower pain scores [bib_ref] Thoracic paravertebral block versus pectoral nerve block for analgesia after breast surgery, Wahba [/bib_ref]. One study evaluated the effect of adding a PECS-1 block to multimodal analgesia, including local anaesthetic infiltration [bib_ref] Pectoral I block does not improve postoperative analgesia after breast cancer surgery:..., Cros [/bib_ref]. No reduction in pain scores was documented postoperatively in patients having a PECS-1 block but the sub-group of patients scheduled for major breast surgery had lower pain scores after a PECS block.
One study compared PECS block with erector spinae plane block [bib_ref] Comparison of the effects of modified pectoral nerve block and erector spinae..., Altiparmak [/bib_ref]. Initial pain scores were similar with both blocks, but became quickly inferior in the PECS block group and postoperative opioid consumption was also inferior in the PECS block group.
In one study, the combination of a transversus thoracic muscle plane block with PECS-2 blocks provided lower pain scores and less rescue analgesia consumption than PECS block alone [bib_ref] Addition of transversus thoracic muscle plane block to pectoral nerves block provides..., Ueshima [/bib_ref].
Compared with placebo, serratus plane block provided lower pain scores at rest, but there was no significant difference in reducing postoperative opioid consumption [bib_ref] Ultrasound-guided serratus plane block enhances pain relief and quality of recovery after..., Yao [/bib_ref]. In two studies [bib_ref] Analgesic efficacy of ultrasound-guided paravertebral block versus serratus plane block for modified..., Gupta [/bib_ref] [bib_ref] Pectoralis-serratus interfascial plane block vs thoracic paravertebral block for unilateral radical mastectomy..., Hetta [/bib_ref] , serratus plane block was compared with paravertebral block and was documented to be less effective. In both studies, pain intensity was not different, but total rescue morphine consumption was significantly higher in the serratus plane block group. In another study, different volumes of the same local anaesthetic solution (40 ml vs. 20 ml ropivacaine 0.375%) used for serratus plane block provided no difference in pain relief [bib_ref] Injection volume and anesthetic effect in serratus plane block, Kunigo [/bib_ref].
Three studies compared erector spinae plane block with general anaesthesia alone [bib_ref] Ultrasound guided erector spinae plane block reduces postoperative opioid consumption following breast..., Gurkan [/bib_ref] [bib_ref] Ultrasound-guided erector spinae plane block for postoperative analgesia in modified radical mastectomy:..., Singh [/bib_ref] or with PECS block [bib_ref] Comparison of the effects of modified pectoral nerve block and erector spinae..., Altiparmak [/bib_ref]. The patients receiving erector spinae plane block reported no difference in pain scores, but had decreased morphine consumption compared with general anaesthesia alone [bib_ref] Ultrasound guided erector spinae plane block reduces postoperative opioid consumption following breast..., Gurkan [/bib_ref] [bib_ref] Ultrasound-guided erector spinae plane block for postoperative analgesia in modified radical mastectomy:..., Singh [/bib_ref]. Compared with PECS block, erector spinae plane block initially provided no difference in pain scores [bib_ref] Comparison of the effects of modified pectoral nerve block and erector spinae..., Altiparmak [/bib_ref]. But after the first postoperative hour, pain scores and opioid consumption were both lower in the PECS block group [bib_ref] Comparison of the effects of modified pectoral nerve block and erector spinae..., Altiparmak [/bib_ref]. In three studies comparing local anaesthetic wound infiltration with paravertebral block, analgesia was improved in the group who had a paravertebral block, with lower pain scores, and in one study, a reduction in rescue analgesic requirement [bib_ref] Comparison of the post-operative analgesic effect of paravertebral block, pectoral nerve block..., Syal [/bib_ref] [bib_ref] A comparative randomized study of paravertebral block versus wound infiltration of bupivacaine..., Bansal [/bib_ref] [bib_ref] A prospective comparison of continuous wound infiltration with ropivacaine versus single-injection paravertebral..., Sidiropoulou [/bib_ref]. In one of those studies [bib_ref] A prospective comparison of continuous wound infiltration with ropivacaine versus single-injection paravertebral..., Sidiropoulou [/bib_ref] , pain scores appeared to be lower in the paravertebral block group up to 4 h postoperatively, but at 16 h and 24 h, wound infiltration was associated with lower pain scores.

## Local anaesthetic wound infiltration
Compared with continuous paravertebral block, one study reported that continuous local anaesthetic wound infiltration was equally effective in terms of pain control [bib_ref] Continuous paravertebral block for postoperative pain compared to general anaesthesia and wound..., Bouman [/bib_ref]. . The use of NSAIDs is supported by studies performed before 2006 in breast surgery [bib_ref] Placebo-controlled trial of local anaesthesia for treatment of pain after breast reconstruction, Legeby [/bib_ref] [bib_ref] Analgesia for day surgery. Evaluation of the effect of diclofenac given before..., Chan [/bib_ref] [bib_ref] Efficacy of intravenous ketoprofen for pre-emptive analgesia, Priya [/bib_ref] , although there are no recent data. In addition, the analgesic benefits and opioid-sparing effects of paracetamol and NSAIDs are well described in a range of peri-operative settings [bib_ref] Non-opioid analgesics in adults after major surgery: systematic review with network meta-analysis..., Martinez [/bib_ref] [bib_ref] Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of..., Ong [/bib_ref]. A balance of the analgesic efficacy and potential risks of the analgesic intervention determine these recommendations.

# Discussion
Pre-operative gabapentin is recommended as it has been shown to reduce postoperative pain scores and opioid consumption. However, a wide range of doses were administered in different clinical trials without any documented dose-response effect. Surprisingly, the well-documented side-effects of gabapentinoids, such as dizziness, blurred vision or sedation, were not reported in the studies dedicated to postoperative analgesia after breast surgery, even in patients receiving high doses.
Overall, gabapentin is recommended but with caution, as high doses may induce side-effects that could be especially concerning in ambulatory patients [bib_ref] Do surgical patients benefit from perioperative gabapentin/pregabalin? a systematic review of efficacy..., Tiippana [/bib_ref]. Pregabalin is not recommended as the observed pain relief did not last up to 24 h. Intravenous dexamethasone administration is recommended as it provides additional pain relief as well as reducing postoperative nausea and vomiting [bib_ref] Consensus guidelines for the management of postoperative nausea and vomiting, Gan [/bib_ref]. Overall recommendations for pain management in patients undergoing oncological breast surgery.

## Recommendations
Minor breast surgery Major breast surgery These findings should be interpreted with caution as these studies did not use 'basic' simple non-opioid analgesics (i.e.
paracetamol, NSAIDs or COX-2 selective inhibitors) in a fully implemented multimodal analgesia programme. Not surprisingly, a cost effectiveness study reported higher costs of continuous paravertebral block [bib_ref] Preoperative paravertebral blocks for the management of acute pain following mastectomy: a..., Offodile [/bib_ref] ; however, these costs would be offset by the reduced duration of hospital stay [bib_ref] Improving analgesic efficacy and safety of thoracic paravertebral block for breast surgery:..., Terkawi [/bib_ref] [bib_ref] Ultrasound-guided multilevel paravertebral blocks and total intravenous anesthesia improve the quality of..., Abdallah [/bib_ref] [bib_ref] Multiple levels paravertebral block versus morphine patient-controlled analgesia for postoperative analgesia following..., Fallatah [/bib_ref] [bib_ref] Efficacy of dexmedetomidine as an adjuvant in paravertebral block in breast cancer..., Mohta [/bib_ref]. Interfascial plane blocks also improve postoperative analgesia with lower pain scores and opioid consumption than general anaesthesia alone. However, data concerning the use of these bocks are limited and the choice of the appropriate block (i.e. PECS 1, PECS 2 and serratus plane blocks) remains to be validated. It should also be noted that for anatomical reasons neither the PECS nor paravertebral blocks can reliably provide sufficient analgesia to the axilla (i.e. T1 nerve distribution) [bib_ref] Combined thoracic paravertebral and pectoral nerve blocks for breast surgery under sedation:..., Pawa [/bib_ref]. Thus, supplemental local anaesthetic wound infiltration may be beneficial for these cases.
Interfascial plane bocks such as the retrolaminar block or erector spinae plane block have been recently described and could potentially provide an alternative to paravertebral block. However, retrolaminar block has only been studied in one RCT in the context of breast surgery [bib_ref] Retrolaminar block: analgesic efficacy and safety evaluation, Murouchi [/bib_ref]. Three studies compared erector spinae plane block with general anaesthesia alone [bib_ref] Ultrasound guided erector spinae plane block reduces postoperative opioid consumption following breast..., Gurkan [/bib_ref] [bib_ref] Ultrasound-guided erector spinae plane block for postoperative analgesia in modified radical mastectomy:..., Singh [/bib_ref] In summary, this review has identified analgesic regimens for optimal pain management after breast surgery . In addition, we also identified analgesic interventions that are not recommended for pain management in patients undergoing breast surgery ( Interfascial plane blocks such as PECS blocks could be performed in major breast surgery as an alternative to paravertebral blocks. Importantly, opioids should be used only as a rescue medication if non-opioid analgesics and regional analgesic techniques are do not provide effective pain control. Future studies are necessary to assess the role of novel regional analgesic techniques such as erector spinae plane blocks when combined with basic analgesics in an enhanced recovery setting.

## Supporting information
Additional supporting information may be found online via the journal website. . Quality assessment and level of evidence assigned to the randomised trials included in this review for analgesia in oncological breast surgery.
[table] Table 2: Analgesic interventions that are not recommended for pain management in patients undergoing oncological breast surgery. [/table]
[table] Table S2: Summary of key results from studies evaluating systemic analgesics, systemic analgesic adjuncts, regional analgesia and surgical procedures in patients undergoing oncological breast surgery. This is not part of the table title, therefore it can be removed from here, and only kept as explaination in the supporting information section. [/table]
[table] Table S3: Summary of key results from studies evaluating regional anaesthetic techniques and adjuncts used to support interventions that are not recommended for analgesic benefit in patients undergoing oncological breast surgery. [/table]