What is the role of locoregional anesthesia in breast surgery? A systematic literature review focused on pain intensity, opioid consumption, adverse events, and patient satisfaction

Background Breast surgery in the United States is common. Pain affects up to 50% of women undergoing breast surgery and can interfere with postoperative outcomes. General anesthesia is the conventional, most frequently used anaesthetic technique. Various locoregional anesthetic techniques are also used for breast surgeries. A systematic review of the use of locoregional anesthesia for postoperative pain in breast surgery is needed to clarify its role in pain management. Objectives To systematically review literature to establish the efficacy and the safety of locoregional anesthesia used in the treatment of pain after breast surgery. Methods Embase, MEDLINE, Google Scholar and Cochrane Central Trials Register were systematically searched in Mars 2020 for studies examining locoregional anesthesia for management of pain in adults after breast surgery. The methodological quality of the studies and their results were appraised using the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) checklist and specific measurement properties criteria, respectively. Results Nineteen studies evaluating locoregional anesthesia were included: 1058 patients underwent lumpectomy/mastectomy, 142 breast augmentation and 79 breast reduction. Locoregional anesthesia provides effective anesthesia and analgesia in the perioperative setting, however no statistically significant difference emerged if compared to other techniques. For mastectomy only, the use of locoregional techniques reduces pain in the first hour after the end of the surgery if compared to other procedures (p = 0.02). Other potentially beneficial effects of locoregional anesthesia include decreased need for opioids, decreased postoperative nausea and vomiting, fewer complications and increased patient satisfaction. All this improves postoperative recovery and shortens hospitalization stay. In none of these cases, locoregional anesthesia was statistically superior to other techniques. Conclusion The results of our review showed no differences between locoregional anesthesia and other techniques in the management of breast surgery. Locoregional techniques are superior in reducing pain in the first hour after mastectomy.


Rationale
Breast surgery in the United States is common. In 2020, an estimated 276,480 new cases of invasive breast cancer will be diagnosed among women and approximately 80% of patients will have surgery to remove their primary tumour [1]. In addition, an increasing number of women are turning to plastic surgeons for interventions of cosmetic: among these breast augmentation is the first procedure performed in the United States [2].
Pain affects up to 50% of women undergoing breast surgery and can interfere with postoperative outcomes. Breast pain is one of the factors determining patient distress, long hospital stay, and an increase in post-surgical admissions to the hospital [3].
Nociceptive/inflammatory pain is caused by tissue damage, whereas neuropathic pain is the consequence of a central and peripheral nerve damage [4], especially the intercostal nerves from T2 to T6. Neuropathic pain typically begins immediately after breast surgery and can be persistent, sometimes even for months [3].
The pain control is the main objective of anesthesia in breast surgery. The correct management of acute postoperative pain is essential to improve patient outcome and satisfaction.
Various anesthetic agents, devices, and strategies are currently available. For a long time, intravenous analgesia has been the main technique for postoperative pain relief. Over the years, the growing number of surgical procedures for breast cancer and cosmetic treatment has however stimulated the development of new anesthetic techniques with improved pain reduction and safety, and fewer complications.
The international guidelines recommended the use of a multimodal analgesia [5,6]. Regional anesthesia techniques are effective as a component of multimodal analgesia for management of postoperative pain associated with a number of surgical procedures. These techniques can be administered as a single shot or a continuous catheter, both prior to surgical incision or after surgery [5,6]. Local anesthetics infiltration also shows benefit for the surgical procedure. Wound infiltration can be performed either as a single injection of local anesthetic typically at the conclusion of surgery or as a continuous infusion of local anesthetic through a catheter at the incision site prior to skin closure [5,6]. Finally, the international guidelines suggest the use of intravenous (IV) lidocaine, especially in patients underwent open or laparoscopic abdominal surgical procedures [5,6]. Perioperative lidocaine infusion may be considered for patients undergoing mastectomy [7].

Objectives
We undertook this systematic review to identify the potential clinical role of locoregional anesthesia for breast surgery. We aimed to establish the efficacy and the safety of locoregional anesthesia in the pain management after breast surgery. Postoperative pain severity and opioid consumption during the first 48 h were designated as coprimary outcomes. For secondary objectives, we aimed to examine the effects on the immediate quality of recovery, in relation to adverse effects and patient satisfaction.

Protocol and registration
We performed a systematic review based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [8]. Randomized controlled trials that compared the effects of locoregional anesthesia to systemic analgesia alone in patients undergoing breast surgery were sought. Studies were evaluated using a pre-designed protocol. The protocol was not published, and the review was not registered with the International prospective register of systematic reviews (PROSPERO).

Eligibility criteria
The population, intervention, comparison, and outcome (PICO) criteria were applied to the research question (see Table 1). Patients older than 18 years undergoing breast surgery were considered as the population (P); the intervention (I) was postoperative analgesia with locoregional anesthesia techniques; the comparison (C) concept was standard pain treatment provided in each study; pain intensity, opioid consumption, adverse events (AEs), and patient satisfaction were considered the outcomes (O) for this systematic review. We included randomized controlled trials (RCTs) published from 2010 to the present. No language restrictions were placed on study inclusion.

Literature search
We identified the articles by searching electronic databases (Embase, MEDLINE, Google Scholar and Cochrane Central Trials Register). We included other relevant studies from the reference lists of systematic reviews and meta-analyses. These databases were initially searched from Mars 2020.
The search strategy was developed using medical subject headings and keywords relating to the central research question of this paper. Namely, the search terms included in the search strategy covered the following key domains: "breast augmentation", "breast reduction", "mastectomy", "mastopexy", "local anesthetic agent", "postoperative pain" and "randomized clinical trial".
We applied no language restrictions in searches.
The studies included in this review evaluated adult patients undergoing breast surgery and receiving any type of locoregional anesthesia to treat postoperative pain.

Primary outcomes
Pain scores and opioid consumption in the first 48 h postoperatively were the primary outcomes of interest. Pain intensity was assessed via a Numeric Rating Scale (NRS) at 1, 6, 12, 24 and 48 h after surgery. Pain intensity data assessed by means other than a zero to 10 NRS were converted to this scale. The other primary outcome was the average per patient opioid consumption in the Post-Anesthesia Care Unit (PACU) and in the 48 h after surgery. Opioid consumption was converted to morphine sulfate equivalents [9].

Secondary outcomes
We extracted data on the following secondary outcomes: 1. Adverse Events (AEs) were recorded. Evaluated safety outcomes included postoperative opioid related side-effects (postoperative nausea and vomiting, sedation/respiratory depression, pruritus, hypotension, urinary retention, or constipation), and complications related to the nerve block (pneumothorax, block failure, or local anesthetic systemic toxicity). Complications during wound healing were also analysed. 2. Patient Satisfaction. All measures of patient satisfaction were reported as "satisfied" and "not satisfied".

Selection of studies
Two independent reviewers (P.S. and L.G.G.) initially assessed the results from the literature search based on title and abstract. The full-text citations of potentially eligible articles were subsequently retrieved and reviewed again by the same two independent reviewers. In case of disagreement between the two reviewers on eligibility, a discussion was initiated. If consensus could not be reached after discussion, a third reviewer (M.C.P.) evaluated the study and made the final decision. The methodological quality of the included studies was evaluated and rated using the COSMIN checklist, based on a 4-point rating scale.

Data extraction and management
A standardized data extraction form was used. Data collected included information relating to: Age, weight, height and body mass index (BMI) of participants; Number of participants enrolled and completing the study; Type of operation; Regional anesthesia technique (local anesthetic and dose); Pain intensity for all-time points at which it was measured; Opioid consumption; Patient satisfaction; Severity or incidence of adverse events.

Statistical analyses
For continuous outcomes, we extracted the mean and standard deviation (SD). In situations where these are not reported, the median and interquartile range were used to approximate these values. Similarly, in situations where the mean and 95% CI are reported, statistical conversions were used to estimate the mean and SD.
For dichotomous outcomes (side effects, complications), data were converted to overall incidence numbers.
We designated a p value < 0.05 as a threshold of statistical significance for the primary and secondary outcomes. All tests were two-tailed. Patients of at least 18 years undergoing breast surgery.
Comparator Standard pain treatment.

Outcomes
Pain Intensity, Opioid Consumption, Adverse Events, Patient Satisfaction.

Study TYPE
Randomized Controlled Trial.

Time
From 2010 to present.

Results
Our search strategy identified 40 citations. Searching additional sources yielded an additional 9 potentially eligible citations. Of these, 30 were excluded based on title and abstract screening, because of duplicated papers (n = 5), missing outcomes (n = 7), or the lack of a standardized pain treatment in the control group (n = 18). Thus a total of 19 randomized controlled trials were included in this systematic review. The flow diagram (see Fig. 1) shows the results from the literature search and the study selection process.
The characteristics of included studies and outcomes assessed in this review are presented in Table 2a, b and c.
The 19 randomized controlled trials involved a total of 1307 patients, of which 749 received nerve blocks, 330 received local infiltration, 115 received IV lidocaine, 73 received infusion of local anesthetic via pump, and 40 received tumescent anesthesia.
According to the COSMIN checklist, all studies included in this review showed an excellent-to-good quality. The majority of clinical trials had a low risk of bias.

Lumpectomy/mastectomy
In the included studies 1086 patients underwent lumpectomy/mastectomy. There were no demographic differences between the two groups as shown in Table 3.
Local infiltration was reported in 3 studies. In Campbell et al 2014 [10], patients received 20 mL of bupivacaine 0.25% with or without adrenaline to be infiltrated into the breast wound and a further 20 mL of bupivacianee 0.25% with adrenaline to be infiltrated into the axilla wound when applicable. In Mohamed et al 2013, 5 ml of bupivacaine 0.5% with or without clonidine were diluted with saline 0.9% to 15 mL volume and irrigated into the surgical field before skin closure. An infusion pump of levobupivacaine 0.50% for approximately 48 h was evaluated in Ferreira Laso et al 2014.
Couceiro et al [11] and Terkawi et al 2014 investigated i.v. lidocaine infusion. In the first paper, a bolus dose of lidocaine was not administered and, after incision, a lidocaine infusion at 3 mg/kg was started. In the other study, lidocaine was administered as a bolus to all patients before anesthetic induction, at a dose of up to 1.5 mg/kg, followed by a lidocaine infusion at 2 mg/kg/h until 2 h after arrival in PACU.
Almost all studies were conducted under general anesthesia, except for Ilfeld et al 2014 conducted under sedation. General anesthesia was induced and then maintained with opioids, such as alfentanil (Ferreira

Pain intensity
Different investigators recorded this outcome on different scales and at different intervals. We normalized all NRS to a zero to 10 range (see Table 4). The majority of authors reported pain intensity at 1, 6, 12, 24 and 48 h after surgery. As shown in Fig. 2 One study, Couceiro et al [11], did not report NRS at any interval: only 2 (9.09%) vs 3 (13.6%) patients in the lidocaine and placebo groups, respectively, experienced severe to very severe pain 24 h after surgery.

Opioid consumption
The most frequently used opioids were codeine (Camp- At discharge from PACU, the overall mean amounts of morphine consumed in the intervention and placebo groups were 3.0 ± 3.63 mg and 4.87 ± 5.76 mg, respectively, with the difference being not statistically significant (p = 0.51).
After 48 h, the overall mean amounts of morphine consumed in the intervention and placebo groups were,   Table 5 shows the mean amounts of morphine consumed in the intervention and placebo groups.
In Couceiro et al [11], opioid consumption in the first 24 h after surgery was similar in the lidocaine and placebo groups.

Adverse events (AEs)
An adverse event is defined as any undesirable experience associated with the use of a medical product in a patient. A total of 379 AEs were recorded. Three studies (Couceiro et al., [11]; Ilfeld et al., 2014; Versyck et al., 2017) did not report the number of AEs. The most frequently reported AEs were nausea, vomiting and postoperative nausea and vomiting (PONV), pruritus, dizziness, haematoma/bleeding, seroma and bruising (see Table 6 and Fig. 3). Some studies did not specify the timing of adverse events.

Patient satisfaction
Patient satisfaction results were presented as different degrees of subjective satisfaction levels. We normalized all of them to "satisfied / not satisfied".
Among the intervention group, there were 164 satisfied patients vs 14 not satisfied patients; in the placebo group 149 patients were satisfied and 40 not satisfied. No statistically significant difference was observed between the two groups (satisfied, p = 0.28; not satisfied, p = 0.14).
In Versyck et al 2017, both patient-groups were very satisfied with their management; while in Yao et al 2019, patient satisfaction scores were higher in the SPB group.

Breast augmentation
One hundred forty-two patients underwent breast augmentation. As shown in Table 8, the groups were similar in age, weight, height and body mass index.
All patients underwent subpectoral bilateral cosmetic breast augmentation.
Regional anesthetic techniques were performed in two studies: PVB in Gardiner et al [24]; association of Pecs type II and PSB in Schuitemaker et al [26]. In the other study, Picard et al [25], a local infiltration was performed.
Patients received general anesthesia in Schuitemaker et al [26], and sedation in Gardiner et al [24]. In both studies patients received fentanyl. Picard et al [25] did not report the anesthesia protocol.

Pain intensity
Different investigators recorded this outcome on different scales and at different intervals. We normalized all NRS to a zero to 10 range (see Table 9). The majority of authors reported pain intensity at 1, 6, 24 and 72 h after surgery. As shown in Fig. 5, the average NRS scores were 3.4 ± 0.5 at 1 h, 3.0 at 6 h, 3.65 ± 1.15 at 24 h and 3.05 ± 0.25 at 72 h in the intervention group; in the placebo group NRS scores were recorded of 5.25 ± 0.05 at 1 h, 3.0 at 6 h, 3.65 ± 1.15 at 24 h and 4.2 ± 0.5 at 72 h.

Opioid consumption
In Gardiner et al [24], 6 patients in the placebo group required supplementary opioid use. No patient received opioids in the intervention group.
After 24 h in Schuitemaker et al [26], the overall mean amounts of morphine consumed in the intervention and placebo groups were 0.2 ± 0.8 mg and 0.6 ± 1.2 mg, respectively, with the difference being not statistically significant (p = 0. 29).
No data on opioid consumption was available in Picard et al [25].

Adverse events (AEs)
A total of 19 (9 vs 10) AEs were recorded. Gardiner et al [24] reported 12 episodes of nausea and vomiting (5 vs 7, p = 0.36). In this study, hypotension occurred 3 times among patients in the intervention group and once in the placebo group. A single case of bradycardia occurred in both groups.
No differences were observed between groups concerning the appearance of AEs in Schuitemaker et al [26].
No adverse effects were reported in Picard et al 2017.

Patient satisfaction
Only Schuitemaker et al [26] reported data about patient satisfaction: after 24 h, 80% vs 53% of patients in intervention and placebo groups were satisfied.

Breast reduction
Seventy-nine patients underwent breast reduction. The mean age was 38.28 ± 2.71 years vs 38.78 ± 3.21 years (see Table 10). All patients underwent breast reduction surgery. Tumescent anesthesia was performed in Christie et al 2017; in Valente et al 2014 [28], patients received local infiltration. All patients in these studies underwent general anesthesia.

Pain intensity
Different investigators recorded this outcome on different scales and at different intervals. We normalized all NRS to a zero to 10 range (see Table 11). The authors reported pain intensity at 24 h after surgery.
The average NRS score was 2.55 ± 1.72 in the intervention group; in the placebo group a NRS score was recorded of 2.85 ± 1.14 (p = 0.89).

Opioid consumption
After 24 h in Christie et al 2017, the overall mean amounts of morphine consumed in the intervention and placebo groups were 0.58 mg and 0.64 mg, respectively, with the difference being not statistically significant (p = 0.71).
No data on opioid consumption is available in Valente et al 2014 [28].

Adverse events (AEs)
There was no significant difference in occurrence of nausea or vomiting in the first 24 h between the two groups in Christie et al 2017. No adverse effects were reported in Valente et al 2014 [28].

Patient satisfaction
The level of satisfaction was not reported in these studies.

Discussion
Our systematic review is the first to demonstrate the analgesic benefits of locoregional anesthesia following breast surgery, and to demonstrate the clinical utility of these techniques. For perioperative and postoperative analgesia, locoregional anaesthesia can be used as a standalone anaesthetic technique, or in association with sedation or general anaesthesia. In almost all the studies of this review, locoregional anesthesia was performed to reduce pain as an "adjuvant technique".

Lumpectomy/mastectomy Pain intensity
Pain intensity on a numeric rating scale (NRS) was lower in the intervention group than in the placebo group at 1, 6, 12, 24 and 48 h after surgery. The difference of NRS at 1 h between the groups was statistically significant (p = 0.02); no statically significant difference was reported at other intervals.
In We considered NRS lower than 4 as an optimal cut-off point between mild and moderate pain. This cut-off was identified as the tolerable pain threshold [29].

Opioid consumption
Postoperative use of opioids was lower in the interventional group both upon discharge from the PACU and after 48 h, although there was no statistically significant difference. The difference in opioid use was statistically

Patient satisfaction
Patient satisfaction was high, with minimum 92% of satisfaction among patients treated with locoregional anesthesia. The satisfaction rate was also high in the placebo group (79%).

Breast augmentation
Pain intensity on a numeric rating scale (NRS) was lower in the intervention group than in the placebo group at 1, 6, 24 and 72 h after surgery. No statically significant difference was reported at these intervals.
Postoperative use of opioids was lower in the interventional group after 24 h, although there was no statistically significant difference.  Concerning safety, no difference was noticed between interventional and placebo groups.

Breast reduction
Pain intensity on a numeric rating scale (NRS) was lower in the intervention group than in the placebo group after 24 h. No statically significant difference was reported.
Postoperative use of opioids was lower in the interventional group after 24 h, although there was no statistically significant difference.
No difference was noticed between interventional and placebo groups about AEs incidence.
We considered continuous IV infusion of lidocaine for our review. Various are the reasons that led us to consider this technique. Local anesthetics exert their pharmacological action through the block of sodium channels in neural tissues, thereby interrupting neuronal transmission. This action is best demonstrated when the drug comes directly in contact of neural tissues. However, the systemic effects of lidocaine are also probably or at least partially, related to this mechanism [39]. The IV lidocaine shares many of the effects of local anesthetics when used in regional anesthesia techniques. It can lead to better postoperative analgesia, reduced opioid consumption and improved intestinal motility [40]. In addition to the analgesic action, local anesthetics have anti-inflammatory action, justifying also the use of intravenous lidocaine to modulate the inflammatory response resulting from postoperative pain [41].
Locoregional anesthesia provides effective anesthesia and analgesia in the perioperative setting. The beneficial analgesic effect of the regional block is well known, and also confirmed in our analysis. After mastectomy, the use of locoregional anesthesia techniques seems to reduce pain especially in the first hour after the end of the surgery.
Other potentially beneficial effects of locoregional anaesthesia and analgesia on other perioperative outcomes include decreased need for opioids for controlling postoperative pain, decreased postoperative nausea and vomiting, fewer complications and increased patient satisfaction. In our review, there was no statistically significant difference between the analysed anesthesia techniques.
The effective management and relief of postoperative pain plays a vital role in overall surgical outcome. Untreated pain has been linked to prolonged hospital stays, deep venous thrombosis, pulmonary embolism, pneumonia, bowel dysmotility, insomnia, and impaired wound healing [42]. Reduced occurrence of nausea and vomiting is related to better analgesia and opioids/inhalational anaesthetics sparing effect by regional blocks [43,44]. All this improves post-operative recovery and shortens hospitalization stay.

Limitations
Our review has several limitations. First, some outcomes were characterized by high levels of heterogeneity. Reasons for this may be attributable to subtle variations in surgical technique and differences in anesthetic and analgesic regimens. Second, for 3 studies included in this review (Campbell et al 2014 [10], Lanier et al 2018 and Picard et al [25]), it is not possible to assess whether only regional anesthesia for breast surgery was performed. The impact of locoregional anesthesia on nociception as a "pure" or "adjuvant" technique is different, notably because of the different dosage of local anesthetics. We decided not to exclude these studies and to accept the possible bias during the analysis. Third, many of the included studies had small sample sizes, which decreases their effect and limits external validity. Fourth, another major limitation of this review was the large and unexplained statistical heterogeneity between the studies. Finally, we included two studies (Couceiro et al [11]; Terkawi et al 2014) analysing the use of i.v. lidocaine. Systemic lidocaine is not "really" a locoregional anesthesia technique, nevertheless we decided to include it in our review accepting the possible bias arising from systemic effects of this local anesthetic.
All these limitations reduced the quality of the evidence for most of the outcomes.

Conclusion
In this systematic review we found evidence for an effect of locoregional anesthesia on the pain due to breast surgery as one the major predefined outcomes. The difference of NRS at 1 h between the groups was statistically significant among patients who underwent lumpectomy/mastectomy; no statically significant difference was reported at other intervals.
The postoperative opioids consumption, the incidence of PONV and other AEs, and the patient satisfaction were not different among patients who underwent locoregional anesthesia or conventional analgesia.