Introduction
Interpectoral and pectoserratus plane (PECs) blocks have been shown to provide excellent perioperative analgesia in mastectomy patients, leading to reduced opioid consumption and postoperative nausea and vomiting (PONV) [1]. It is consequently expected to enhance the speed and quality of recovery (QoR) after surgery, which is one of the most sought-after postoperative outcomes. However, previous studies on the impact of PECs blocks on the QoR score are controversial, with some reports showing that the block improved it and others suggesting the lack of benefit [2–4].
Favorable postoperative recovery is known to be negatively associated with preoperative psychological problems, such as depression, anxiety, or pain catastrophizing [5]. We also recently observed association of poor QoR-15 score with preoperative anxiety and neurotic personality [6]. It can be also assumed that pain sensitivity or pre-existing pain is related to recovery, given its strong association with the postoperative pain [7]. Using this information, we might be able to stratify the risks and warn the patients or provide additional treatments based on experiences. Given that most therapeutic modalities can hardly benefit all patients, identifying the factors that may influence the effects of specific interventions is crucial, especially in this era of precision medicine.
A previous study that reported differences in the analgesic effect of regional analgesia according to the level of catastrophic pain thinking [8] raised questions about whether the benefit of the nerve block on the QoR is modified by factors of psychological traits or pain perception. Because truncal nerve block is time and effort consuming, with the inevitable possibility of complications, the balance between risk and benefit needs to be assessed at the individual level, for which supporting evidence with appropriate statistical verification is currently insufficient.
Therefore, we aimed to investigate the factors that can modify the effect of the interpectoral and PECs blocks, the most widely used regional anesthesia for mastectomy, on the QoR-15 score on the day after surgery.
Materials and Methods
This study was approved by the Institutional Review Board (Protocol No. 3-2021-0468, Date of approval: January 5, 2022) and registered at ClinicalTrials.gov (NCT05266378). Patients aged between 20 and 80 years who underwent partial mastectomy and provided written informed consent were enrolled from March 7, 2022, to January 17, 2023. All processes were conducted in accordance with the tenets of the Declaration of Helsinki, 2013. The exclusion criteria included previous breast surgery, adverse reactions to local anesthetics, drug addiction, cancers other than breast cancer, chronic pain requiring analgesics, hospitalization for psychiatric disorders, moderate or severe hepatic impairment, body mass index > 35 kg/m2, blood clotting disorders, pregnant or lactating, breast surgery without axillary surgery, infection on the block procedure area, inability to read consent form, and/or did not accept to participate. In all patients, axillary staging was performed using sentinel lymph node biopsy (SLNB). If pathologically confirmed positive nodes were detected through intraoperative pathological examination after SLNB, the surgeon subsequently performed additional axillary lymph node dissection, guided by clinical risk factors such as axillary nodal status or prior receipt of neoadjuvant chemotherapy.
The patients were randomly assigned to one of the two groups using a randomization table by permuted block randomization; attending anesthesiologists, surgeons, and a trained clinical psychologist who handed out all perioperative questionnaires and assessed the postoperative outcomes were blinded to the assigned group.
Preoperative assessment of psychological traits, pain perception, and pain sensitivity
A preoperative psychological assessment was conducted the day before surgery. Psychosocial factors were assessed using the Hospital Anxiety and Depression Scale (HADS) and the Pain Catastrophizing Scale (PCS). The HADS is a valid questionnaire for hospitalized populations related to anxiety and depression (total scores range from 0 to 21 for anxiety and depression each). The PCS was used to assess thinking related to pain (scores ranging from 0 to 52). The PCS consists of three subscales: helplessness, rumination, and magnification [9]. Baseline pain perception and sensitivity were assessed using the Breast Cancer Pain Questionnaire (BCPQ), temporal pain summation (TPS), pressure pain threshold, and pressure pain tolerance. The BCPQ assessed pain severity (ranging from 0 to 10) and frequency (ranging from 0 to 5) in four surgically related areas [10]. The TPS was measured as previously described [11]. A single stimulation of the pinprick was given, using a 256-mN filament, to the dorsal aspect of the index finger of the dominant hand, and the pain intensity was assessed using the numeric rating scale (NRS), with the total score ranging from 0 to 100. Ten stimuli were given at a rate of 1 stimulation per second for 10 s, and the patients were asked to rate the mean pain score. The same evaluation was repeated four times with the index and middle fingers of both hands. The mean pain rating for the ten stimuli divided by the pain rating for the first single stimulus was calculated as the wind-up ratio (TPS). Pressure pain threshold and tolerance were assessed using a digital pressure algometer (Wagner Force TenTM FDX, Wagner instruments), as previously described [12]. The intensity of the pressure algometer was increased at a constant rate of 50 kPa/s. The intensity at which pain was first recognized was recorded as the pressure pain threshold, and the intensity that evoked unbearable pain was recorded as the pressure pain tolerance. The dorsal aspect of the proximal forearm and thenar area were tested bilaterally.
Intervention
The PECs block was performed under ultrasound guidance after induction of anesthesia; 10 ml of 0.375% ropivacaine (Carbiropivacaine® injection, Fresenius Kavi Korea Co., Ltd.) was injected into the fascia between the pectoralis major and minor muscles (interpectoral plane block) and 20 ml was injected between the pectoralis minor and serratus anterior muscles (pectoserratus plane block). In the Control group, a sham block was not performed to avoid unwanted complications.
Anesthetic protocol
Anesthesia was induced with propofol (1 mg/kg), sevoflurane, and remifentanil at a target effective site concentration of 3.5–5.0 ng/ml. Rocuronium at 0.6 mg/kg was used to facilitate orotracheal intubation. Anesthesia was maintained using sevoflurane and adjusted to maintain the patient state index (PSI, SEDLineTM, Masimo Corporation) at 25–50. Remifentanil infusion was titrated during surgery by 0.5 ng/ml within the range of 1.0–5.0 ng/ml. All subjects were intravenously administered 1 g of acetaminophen (Acetphen® premix at 1 g/100 ml; CJ Healthcare Korea) and 0.3 mg of ramosetron (Nasea® injectable; Daiichi Sankyo Korea) 30 min before the end of the surgery. For patients complaining of pain with a visual analogue scale (VAS) score > 4 in the PACU, 50 μg of fentanyl was intravenously administered with the maximal dose of 2 μg/kg to avoid considerable side effects.
Study endpoints
The primary endpoint was the global QoR-15 score on postoperative day (POD) 1. The QoR-15 evaluates five dimensions of recovery: physical comfort, physical independence, emotional state, psychological support, and pain. The global score ranged from 0 to 150 [13]. The secondary endpoints included postoperative pain assessed using a verbal numeric rating scale (VNRS, 0–10). Opioid consumption calculated as morphine milligram equivalents, PONV assessed using the VNRS, and adverse events were also evaluated.
Statistical analysis
As there are no previous studies on the QoR-15 scores of partial mastectomy patients to our knowledge, we calculated the sample size according to our preliminary data on 50 patients who underwent partial mastectomy and did not receive the nerve block in which the global QoR-15 score on the day after surgery was 130.3 ± 13.4. To detect a minimal clinically important difference of 6.0 [14], 142 patients were required to achieve 80% power at a significance level of 0.05. Considering a dropout rate of 10%, we enrolled 156 patients. All statistical analyses were performed using SPSS ver. 23 (SPSS Inc.) and SAS version 9.4 (SAS Institute). Continuous data were presented as mean ± SD or median (Q1, Q3), with comparisons between the groups made using Student’s t-test or Mann–Whitney U test according to the results of the Kolmogorov–Smirnov test. Categorical variables were presented using frequency distributions, with comparisons between the groups made using the χ2 test or Fisher’s exact test, as appropriate. In order to evaluate the moderating role of patient psychophysical factors on the efficacy of the PECs block, the patients were divided into two groups for each variable, defined as the subgroup belonging to the upper 20% of each item scale (high risk group) and the subgroup belonging to the lower 80% (low risk group) (Supplementary Table 1). Exceptionally, the lower 20% and upper 80% were used for pressure pain threshold and tolerance. The interaction test was conducted by aligned rank transform one-way analysis of variance in which the main effects (PECs vs. Control) and interaction effects of risk (20% vs. 80%) for each variable were analyzed. Comparisons between the PECs and the Control groups in each subgroup were performed by Mann–Whitney U test, and the differences (PECs group values minus Control group values) and 95% CIs of the main effects were estimated by the Hodges–Lehmann estimation method. P values of < 0.05 and < 0.15 (for the interaction tests) [15,16] were considered statistically significant.
Results
Among the patients who underwent screening, two individuals declined to participate and 14 who received breast-conserving surgery alone without axillary surgery were subsequently excluded from the study before randomization. After randomization, one subject declined to complete the study protocol; therefore, a per-protocol analysis was performed on the data of 70 and 69 subjects in the Control and PECs groups, respectively (Fig. 1). The baseline characteristics are presented in Table 1. The cut-off points for psychological problems were consistent with the known values used to define pathological cases in the general population [17,18]. The cut-off point of the BCPQ score was 1, indicating that our study participants were divided by any pre-existing pain versus no pre-existing pain (Supplementary Table 1).
The QoR-15 score at 1 day after surgery was not significantly different between the groups (Control: 136.50 [124.00, 144.00] vs. PECs: 141.00 [127.00, 148.00], P = 0.061). The pain VNRS score 1 day after surgery was also not different between the groups (Control: 2.00 [2.00, 3.00] vs. PECs: 2.00 [2.00, 3.00], P = 0.125). The maximal pain VNRS score during hospitalization differed significantly between the groups (6.00 [5.00, 7.00] in the Control group vs. 4.00 [4.00, 6.00] in the PECs group, P < 0.001). The morphine-equivalent opioid dose administered up to POD 2 or discharge was significantly higher in the Control group than in the PECs group (0.00 [0.00, 5.00] vs. 0.00 [0.00, 0.00], respectively; P < 0.001). There was a trend towards a higher incidence of PONV during hospitalization in the Control group (38.6% vs. 23.2%, respectively, P = 0.050); (Table 2).
Factors moderating the effects of PECs on the QoR-15 score
Interaction tests revealed that the effect of the PECs block on QoR-15 1 day after surgery was moderated by the HADS depression, PCS rumination, and BCPQ scores (Fig. 2). In detail, the global QoR-15 was significantly higher in the PECs group than in the Control group in patients with high HADS depression (Control: 125.00 [111.00, 130.00] vs. PECs: 141.00 [119.50, 148.00], P = 0.044), low PCS rumination (Control: 134.50 [124.00, 144.00] vs. PECs: 144.00 [135.00, 148.00], P = 0.007), and low BCPQ scores (Control: 137.00 [125.00, 144.00] vs. PECs: 144.00 [134.00, 148.00], P = 0.0162) as opposed to in the patients with low HADS depression, high PCS rumination, and high BCPQ correspondingly, in whom the block did not improve the QoR-15.
Factors moderating the effects of PECs on pain score
The interaction test revealed that the effect of the PECs block on the pain VNRS score 1 day after surgery was moderated by TPS (Fig. 3). The VNRS was significantly lower in the PECs group than in the Control group for patients with a high TPS (Control: 3.00 [2.00, 3.00] vs. PECs: 2.00 [1.00, 3.00], P = 0.0072), as opposed to those with a low TPS.
Discussion
In this prospective, single-blind randomized controlled trial, the PECs block did not significantly improve QoR on the day after surgery. However, we hypothesized that the block’s efficacy might vary depending on specific patient characteristics, such as psychological traits or pain sensitivity. To explore this, we employed an interaction test to identify whether certain subgroups of patients responded differently to the PECs block. Our findings confirmed that several patient factors moderated the block’s effectiveness: the QoR was enhanced in patients with depressive symptoms before surgery, but not in those without these symptoms. Similarly, the block improved QoR in patients who did not ruminate excessively about pain or did not have preoperative pain in the surgical area, while it showed no benefit for those with these characteristics. Although the PECs block did not reduce pain scores overall, it was effective in patients who were highly sensitive to pain.
Fascial blocks are known to exhibit a high degree of clinical variability due to multiple factors, including anatomical differences, technique variability, the volume and concentration of the local anesthetic used, and patient-specific characteristics such as tissue composition [19]. Our results further highlight the role of psychological factors and pain perception in influencing the benefits of the PECs block for mastectomy patients. These findings may help explain the inconsistent results of clinical trials assessing the efficacy of the PECs block [2,20], underscoring the need for an individualized approach to perioperative pain management. In this context, the interaction test serves as a method to determine whether a new treatment may be more effective for specific groups of people based on their unique characteristics. For instance, while a medication might not demonstrate an overall benefit in the general population, it could still prove highly effective in a particular subgroup, such as individuals with certain health conditions or lifestyle factors. Similarly, our study found that although the PECs block did not improve the QoR-15 score for everyone, it was significantly more effective in patients with specific emotional traits or pain sensitivities.
Depressive symptoms strongly moderated the effect of the PECs block on the QoR in the current study that was expected given that depression is a major risk factor for impaired QoR [21]. Since depressed patients would feel much more distress during the recovery process, enhanced analgesia-induced emotional and physical well-being could be of greater benefit to them than to patients with no underlying depression. Indeed, among the five subdimensions of the QoR-15, physical comfort (P = 0.035) and emotional state (P = 0.031) were enhanced by the PECs block in the depressed subgroup. On the other hand, depressive symptoms did not moderate the effect of the PECs block on the pain VNRS the day after surgery that appears to be incoherent in light of the strong association between pain and QoR. This might be attributable to the fact that PONV or high opioid consumption that must have decreased due to the block could have dominated how the depressed patients felt during the recovery process more than the pain itself.
Regarding pain catastrophizing, only the rumination subcategory significantly interacted with the efficacy of the PECs block on the QoR. The block was not effective in patients who ruminated aberrantly during pain, but it improved the QoR in patients who did not ruminate. This makes sense considering that the rumination score defining the high-risk subgroup was 8 of 16 that is quite high in the population of non-psychiatric patients [18]. People who keep thinking of pain would not feel that their recovery process is going smoothly, even if better analgesia is provided. Previous studies have reported that breast cancer patients with high levels of rumination tend to suffer more from depressive or traumatic symptoms after mastectomy [22], and this could explain why highly ruminating patients did not benefit from the PECs block in our study. The total PCS score did not show interactions with the effects of the PECs block on the QoR and pain VNRS scores in our study, in contrast to the result of a previous study that highlighted the moderating role of total PCS score on the benefit from the regional analgesia for the first time [8]. The authors stated that truncal nerve blocks in breast surgery provided greater analgesia in patients with high PCS scores (top 20%) that they attributed to the high pain susceptibility and consequently increased benefit from the nerve block and anxiolysis. Since the top 20% of the total PCS scores of our study participants were ≥ 16, much higher than those in a previous study (≥ 10) [8], our high-risk subgroup might have been catastrophizing the pain to such a large extent that they did not gain any benefit from the nerve block. In addition, differences in study design (observational vs. RCT), type of surgery, type of block, and statistical verification (lack vs. presence of an interaction test) could have led to discrepancies between the studies.
Our results on the moderating role of the preoperative BCPQ score (≥ 1 = any vs. 0 = none) indicate that any pre-existing pain around the surgery-related area hinder the efficacy of the PECs block in enhancing QoR, possibly because those areas continue to be impacted by pain postoperatively. Even if pain perception is induced by psychological causes and not by actual painful stimuli, it would not disappear by nerve block or surgery. Relatively low level of pain with a narrow range on the day after surgery could have resulted in a lack of interaction between the BCPQ score and the effect of the block on the pain VNRS. In contrast, baseline pain sensitivity, represented by the TPS score, modified the effects of the PECs block on the pain VNRS score. Pain sensitivity measured by the TPS, pressure pain threshold, or tolerance was reported to be a dominating factor for postoperative pain [12,23,24]. Thus, it could have affected the efficacy of the intervention on the pain score, unlike psychological problems and pre-existing pain, despite the low and narrow distribution of pain intensities. Moreover, pain sensitivity, represented by pressure pain tolerance, showed a tendency to interact with the effects of the PECs block on the QoR.
This study had a few limitations. First, since this study explored various factors, the sample size was calculated according to the overall effect of the PECs block, and it is unclear whether this would be a valid power to prove the effects in each subgroup analysis. To overcome this weakness, we used the interaction test that is a specialized method for revealing the effect of modification by a third factor. Second, our approach of splitting the study subjects at a 20:80 ratio might not perfectly represent the actual risk stratification. However, the cut-off values used for psychological factors were approximations of those reported as aberrant or abnormal in the general population, thus indicating the validity of our results [18].
Our analysis indicated that the PECs block did not significantly enhance the global QoR-15 score or pain intensity 1 day after partial mastectomy overall. However, the block was found to improve the QoR in specific subgroups of patients: those with depressive symptoms, without pre-existing pain in the surgical area, and those who do not ruminate pain pathologically. Additionally, patients with high pain sensitivity benefited from its analgesic effects. These findings underscore the importance of identifying psychophysical factors to optimize patient selection for the PECs blocks.
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