*Article* **The Lack of Analgesic Efficacy of Nefopam after Video-Assisted Thoracoscopic Surgery for Lung Cancer: A Randomized, Single-Blinded, Controlled Trial**

**Hyean Yeo 1, Ji Won Choi 2,\*, Seungwon Lee 2, Woo Seog Sim 2, Soo Jung Park 2, Heejoon Jeong 2, Mikyung Yang 2, Hyun Joo Ahn 2, Jie Ae Kim <sup>2</sup> and Eun Ji Lee <sup>3</sup>**


**Abstract:** Nefopam is a centrally acting non-opioid analgesic, and its efficacy in multimodal analgesia has been reported. This study aimed to assess the analgesic efficacy of intraoperative nefopam on postoperative pain after video-assisted thoracoscopic surgery (VATS) for lung cancer. Participants were randomly assigned to either the nefopam or the control group. The nefopam group received 20 mg of nefopam after induction and 15 min before the end of surgery. The control group received saline. The primary outcome was cumulative opioid consumption during the 6 h postoperatively. Pain intensities, the time to first request for rescue analgesia, adverse events during the 72 h postoperatively, and the incidence of chronic pain 3 months after surgery were evaluated. Ninety-nine patients were included in the analysis. Total opioid consumption during the 6 h postoperatively was comparable between the groups (nefopam group [*n* = 50] vs. control group [*n* = 49], 19.8 [13.5–25.3] mg vs. 20.3 [13.9–27.0] mg; median difference: −1.55, 95% CI: −6.64 to 3.69; *p* = 0.356). Pain intensity during the 72 h postoperatively and the incidence of chronic pain 3 months after surgery did not differ between the groups. Intraoperative nefopam did not decrease acute postoperative opioid consumption or pain intensity, nor did it reduce the incidence of chronic pain after VATS.

**Keywords:** nefopam; video-assisted thoracoscopic surgery; acute postoperative pain; opioid consumption; chronic post-surgical pain; lung cancer

#### **1. Introduction**

Severe postoperative pain after thoracic surgery interferes with deep breathing and coughing and reduces pulmonary function, which increases the incidence of postoperative pulmonary complications [1,2]. Furthermore, severe pain in acute postoperative periods seems to be strongly associated with the development of chronic post thoracotomy pain syndrome (CPTPS) [3–5]. The CPTPS, defined as pain which persists or recurs longer than 3 months after thoracotomy [6], has been reported in its incidence up to 80% of patients at 3 months and 61% 1 year after surgery [1]. The patients with CPTPS suffer from neuropathic or sympathetically mediated pain as well as nociceptive pain, and it can interfere with patients' daily activities and further reduce their quality of life [3,4,6]. Therefore, several efforts have been made to manage or prevent acute and chronic postthoracotomy pain. Thoracic epidural analgesia was widely used as the gold standard for pain control. However, it has relatively common complications, such as hypotension and urinary retention, and has low cost effectiveness [7,8]. Opioids are also an important component of pain management; however, the indiscriminate use of opioids can result in

**Citation:** Yeo, H.; Choi, J.W.; Lee, S.; Sim, W.S.; Park, S.J.; Jeong, H.; Yang, M.; Ahn, H.J.; Kim, J.A.; Lee, E.J. The Lack of Analgesic Efficacy of Nefopam after Video-Assisted Thoracoscopic Surgery for Lung Cancer: A Randomized, Single-Blinded, Controlled Trial. *J. Clin. Med.* **2022**, *11*, 4849. https:// doi.org/10.3390/jcm11164849

Academic Editor: Marco Cascella

Received: 14 July 2022 Accepted: 17 August 2022 Published: 18 August 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

adverse events, such as decreased consciousness, delayed mobilization and constipation. Currently, multimodal analgesia is recommended to optimize analgesia and minimize opioid-related side effects [1,9,10].

Nefopam is a centrally acting, non-opioid, non-steroidal analgesic drug, and its efficacy in multimodal analgesia has been reported in some previous studies [11,12]. The mechanism of nefopam is not fully understood; however, the inhibition of serotonin, norepinephrine, and dopamine re-uptake is known to play a main role in its analgesic effect. It also reduces the activity of post-synaptic glutamate receptors, such as N-methyl-D-aspartate (NMDA) receptors, by modulating calcium and sodium channels [12–14]. Therefore, we expected that nefopam could decrease postoperative opioids consumption and, based on its mechanisms, contribute to reducing the incidence of CPTPS.

Although the analgesic efficacy of nefopam was reported in several surgeries, including abdominal and orthopedic surgeries [15–18], it has not been assessed in patients undergoing video-assisted thoracoscopic surgery (VATS). Therefore, this prospective study aimed to evaluate the analgesic efficacy of intraoperative nefopam on acute and chronic postoperative pain after VATS in lung cancer patients. The primary outcome was total opioid consumption during the first 6 h postoperatively. The secondary outcomes were pain intensities, the time to first request for rescue analgesia, adverse events during the 72 h postoperatively, and the incidence of chronic pain evaluated 3 months after surgery. We hypothesized that intraoperative nefopam would reduce postoperative opioid consumption after VATS for lung cancer.

#### **2. Materials and Methods**

#### *2.1. Study Design and Ethical Statements*

This prospective, single-blinded, randomized controlled trial was approved by the Institutional Review Board (IRB No: SMC 2020-12-167, approval date: 22 February 2021) and registered with the Korean Clinical Research Information Service (registration No: KCT0006246; principal investigator: Ji Won Choi; date of registration: 11 June 2021; http:// cris.nih.go.kr). Screening and enrollment for the study were conducted between March 2021 and September 2021 at a tertiary academic hospital in Seoul, South Korea. Written informed consent was obtained from all participants. This study was performed in accordance with the ethical principles of the 1964 Declaration of Helsinki and its later amendments. The trial was conducted following an original protocol and CONSORT guideline [19].

#### *2.2. Participants*

Patients between 20 and 70 years of age with ASA physical statuses I to III who were scheduled for elective VATS lung lobectomy were included. The exclusion criteria were as follows: patient refusal to participate, allergy to nefopam, renal dysfunction (serum creatinine > 1.5 mg/dL), hepatic dysfunction, history of seizure or epilepsy, recent myocardial infarction, current use of monoamine oxidase inhibitor, urinary tract disease causing urinary retention, and closed angle glaucoma.

#### *2.3. Randomization and Blinding Method*

Randomization was performed using a computer-generated random permuted block design, with a block size of 4 and 1:1 ratio. Allocation was sequentially numbered and sealed in opaque envelopes by the primary investigator. A study group member (HY) opened the envelope before induction of anesthesia and prepared the study drug according to the group allocation. The patients, outcome investigators, and surgeons were blinded to group assignment.

#### *2.4. Intervention, Anesthesia Protocol, and Perioperative Pain Management*

After standard monitoring (non-invasive blood pressure, electrocardiogram, pulse oximetry) and bispectral index monitoring (BIS; Medtronic, Minneapolis, NM, USA), 1.5–2 mg/kg of propofol, 0.8 mg/kg of rocuronium, and 0.05–0.20 μg/kg/min of remifentanil were administered for anesthesia induction. After intubation, anesthesia was maintained using sevoflurane within a BIS level of 40–60. Remifentanil was infused to maintain blood pressure and heart rate within 20% of baseline.

In the nefopam group, 20 mg of nefopam mixed with 100 mL of normal saline was administered intravenously during 15 min immediately after the induction of anesthesia and 15 min before the end of surgery. In the control group, 100 mL of normal saline was administered in the same manner. For postoperative pain control, 0.01 mg/kg of hydromorphone and 1 g of acetaminophen were administered intravenously 20 min before the end of surgery, and intravenous patient-controlled analgesia (IV-PCA; fentanyl 1000 μg diluted with 0.9% saline to make 100 mL of total volume, bolus dose of 1 mL, lockout time of 15 min, and basal infusion rate of 1 mL/h) was also applied for both groups. The tracheal tube was removed after the patient had fully recovered from neuromuscular block and was able to properly obey a command. After extubation, the patient was transferred to the post-anesthesia care unit (PACU) and monitored for approximately 1 h. Pain intensity was measured using a numeric rating scale (NRS; 0 = no pain, 10 = worst pain imaginable), and rescue analgesics (IV hydromorphone 0.01 mg/kg) were allowed with an NRS score ≥ 5. If a patient complained of pain with an NRS ≥ 5 more than 15 min after receiving rescue medication, more hydromorphone (0.3 mg) was administered intravenously.

Postoperative care was performed in the intensive care unit (ICU) during the first night after surgery, and most patients were then transferred to the general ward on the next day. The patients were routinely given 8 mg of hydromorphone orally beginning on the first postoperative day (POD 1). Intravenous hydromorphone (1 mg) or morphine (5 mg) was administered when the NRS score was ≥5. When patients required rescue analgesics more than 3 times per day, ibuprofen, acetaminophen, or tramadol was added orally as routine analgesics. Postoperative nausea and vomiting were treated with 0.3 mg of intravenous ramosetron hydrochloride (Naseron Inj., Boryung Co., Ltd., Seoul, Korea).

#### *2.5. Outcome Measurements*

The primary outcome was total morphine equivalent consumption during the first 6 h postoperatively. We also evaluated total opioid consumption (the IV-PCA and all rescue opioids) during the PACU stay and for the first 12, 24, and 72 h postoperatively. The dose of IV-PCA opioid was recorded by the intravenous pump device (Accumate 1200, Woo Young Medical, Jincheon-gun, Chungcheongbuk-do, South Korea). All opioid consumption was converted to the intravenous morphine milligram equivalent dose for comparison. The time to first request for rescue analgesics in the ICU or general ward after surgery was also recorded.

Acute postoperative pain was assessed with the NRS score during the PACU stay (the highest value of pain scores reported) and at 6, 12, 24, and 72 h postoperatively. Chronic postoperative pain was evaluated with the Brief Pain Intensity-short form (BPI-SF) questionnaire and the Neuropathic Pain Questionnaire-short form (NPQ-SF) via a phone call visit 3 months after surgery [20,21].

Adverse events, such as nausea and vomiting, dizziness, respiratory depression, and sedation (Richmond agitation sedation scale score of ≤−2 during the daytime), were also evaluated during the first 72 h postoperatively. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were monitored until POD 3.

#### *2.6. Statistical Analysis*

Based on a previous study, we hypothesized that cumulative opioid consumption during the first 6 h postoperatively would be decreased by 20% in the nefopam group [15]. With a two-tailed significance level of 0.05 and a power of 80%, the number of study subjects needed in each group to find statistical differences between the groups was 42. Considering a dropout rate of 15%, 50 patients were included in each group. All patients who were randomized and treated were included in the analysis based on the intention-totreat principle.

Categorical variables are presented as frequency (percentage), and continuous variables are presented as mean ± standard deviation or median [interquartile range] according to their normality, which we evaluated with the Shapiro–Wilk test. The *t*-test or the Wilcoxon rank sum test was used to compare continuous variables between two groups, and the chi-square test or Fisher's exact test was used to compare categorical variables. For median differences, 95% confidence intervals (CI) were computed by the 2.5th and 97.5th percentiles of the bootstrap distribution with 1000 bootstrap replications. Bonferroni correction was used for multiple testing. A two-sided, *p*-value < 0.05 was considered statistically significant, and all statistical analysis were performed using Statistical Analysis System (SAS) version 9.4 (SAS Institute, Cary, NC, USA).

#### **3. Results**

A flow diagram of the study is shown in Figure 1. Between March 2021 and September 2021, 118 patients scheduled for elective VATS for lung cancer were assessed for eligibility. Among those 118 patients, 14 patients who refused to participate in the study and four patients diagnosed with benign disease were excluded. Thus, 100 patients were randomly allocated to the control (*n* = 50) or nefopam (*n* = 50) group. One patient allocated to the nefopam group dropped out because of withdrawal of consent. The operations of 4 patients were converted to thoracotomy, and 11 patients underwent a wedge resection or segmentectomy due to intraoperative changes in the surgical plan. Those 15 patients are included in the analysis based on the intention-to-treat principle. Therefore, 99 patients completed the 72 h follow-up. Of them, 75 patients (37 from the control group, 38 from the nefopam group) completed the 3-month follow-up measures.

**Figure 1.** CONSORT flow diagram.

The baseline demographics and intraoperative data were comparable between the groups, except that the infusion dose of intraoperative remifentanil was higher in the nefopam group (0.450 [0.300–0.550] mg vs. 0.300 [0.250–0.450] mg; *p* = 0.013; Table 1).


**Table 1.** The baseline characteristics and perioperative clinical data.

Values are *<sup>n</sup>* (%), mean ± standard deviation or median [interquartile range].<sup>1</sup> *<sup>p</sup>*-value < 0.05; ASA: American Society of Anesthesiologists, VATS: video-assisted thoracoscopic surgery.

Total opioid consumption during the first 6 h postoperatively did not differ between the nefopam and control groups (19.8 [13.5–25.3] mg vs. 20.3 [13.9–27.0] mg; median difference: −1.55 mg, 95% CI: −6.64 to 3.69; *p* = 0.356). Opioid consumption during the PACU stay and at 12, 24, and 72 h postoperatively was also comparable between the two groups. These data are shown in detail in Table 2. The time between the end of surgery and the first request for rescue analgesia in the ICU or general ward was likewise comparable between the nefopam and control groups (212.5 [104.0–371.0] min vs. 259.5 [142.0–432.0] min; median difference: −47.0 min, 95% CI: −169.00 to 73.95; *p* = 0.302; Table 2). The NRS pain scores at rest during the first 72 h postoperatively did not differ significantly between the groups at any time (Table 3). Likewise, the incidence of adverse events did not differ significantly between the groups. Changes in AST and ALT between the preoperative value and POD 1 or POD 3 did not differ significantly between the groups. The duration of ICU stay and hospitalization did not differ between the groups either (Table 3).

**Table 2.** Postoperative analgesic outcomes between the groups.


Values are presented as morphine milligram equivalent doses and median [interquartile range]. For median difference, 95% CI are computed by the 2.5th and 97.5th percentiles of the bootstrap distribution by 1000 bootstrap replications.; <sup>1</sup> Primary outcome: amount of morphine equivalent consumption includes both IV-PCA and all rescue opioids.; <sup>2</sup> Bonferroni's method was used for multiple comparisons at four time points; during PACU stay, 12, 24 and 72 h postoperatively.; <sup>3</sup> For the postoperative 12 h readings, *n* = 98 due to 1 follow up loss of PCA data; *n* = 49 for both groups; CI, confidence interval; PACU, post-anesthesia care unit.


**Table 3.** NRS pain scores at each time point and postoperative clinical outcomes between the groups.

Values are *n* (%) or median [interquartile range]. For median difference, 95% CI are computed by the 2.5th and 97.5th percentiles of the bootstrap distribution by 1000 bootstrap replications.; <sup>1</sup> Highest NRS score during PACU stay; <sup>2</sup> Bonferroni's method was used for multiple comparisons.; <sup>3</sup> Changes in AST and ALT were calculated by subtracting the preoperative value from POD1 or POD3 value. CI, confidence interval; NRS, numeric rating scale; PACU, post-anesthesia care unit; PONV, postoperative nausea and vomiting; AST, aspartate aminotransferase; ALT, alanine aminotransferase.; ICU, intensive care unit.

Thirty-seven patients from the control group and thirty-eight patients from the nefopam group responded to a phone call visit 3 months postoperatively. The incidence of chronic pain at 3 postoperative months was 55 and 65% in the nefopam and control groups, respectively (*p* = 0.540). Among the 45 patients who answered that they had persistent pain, the pain scores differed insignificantly between the groups (Table 4). The interference of pain with daily function also differed insignificantly between the groups (online Supporting Information, Table S1).

**Table 4.** The short form of brief pain inventory on 3 months after surgery.


Values are *n* (%) or median [interquartile range]. For median difference, 95% CI are computed by the 2.5th and 97.5th percentiles of the bootstrap distribution by 1000 bootstrap replications.; Each item (except for presence of pain) is rated on a numeric rating scale from 0 (no pain) to 10 (worst) or from 0 (no interference) to 10 (interferes completely). <sup>1</sup> Pain intensity scores and interference items were analyzed only among the patients that they have current pain (control group, *n* = 24; nefopam group, *n* = 21). <sup>2</sup> The median (IQR) value of all interference items was the same as above, and details are attached as supplementary data.; CI, confidence interval; NS: not significant.

In their answers to the NPQ-SF questionnaire, 43 patients (57%) indicated that they had at least one neuropathic pain component, and the incidence of neuropathic pain did not differ significantly between the groups (18/38 [47%] vs. 25/37 [68%], *p* = 0.103). The severity of pain and numbness was also comparable between the groups (online Supporting Information, Table S2).

#### **4. Discussion**

In this study, intraoperative nefopam administration did not decrease total opioid consumption or postoperative pain intensity during the first 72 h after VATS for lung cancer. It also did not reduce the incidence of chronic post-surgical pain 3 months after surgery.

Several studies have shown promising results for the multimodal opioid-sparing analgesia of nefopam on acute postoperative pain [15–18,22,23]. In those studies, the nefopam groups required fewer opioids via IV-PCA or rescue analgesics or showed reductions in pain scores compared with the control groups during the postoperative period. As potential causes of its analgesic effects, those authors suggested triple neurotransmitter inhibition, NMDA receptor antagonism, and the modulation of presynaptic glutaminergic transmission [11–14].

However, conflicting results have also been reported, especially in surgeries anticipated to cause moderate to severe pain [24–27]. Cuvillon et al. reported that continuous intravenous infusion of nefopam (120 mg) during the first 48 h after open colectomy did not reduce perioperative opioid consumption and produced no differences in patient satisfaction or adverse events compared with the control group [24]. Eiamcharoenwit et al. administered 30 mg of nefopam before incision, at the end of spine surgery, or at both times and compared the outcomes with placebo. They also found no significant difference in postoperative morphine consumption among the four groups [26]. Other studies have also shown that nefopam had no or limited efficacy on postoperative pain management when it was used as a part of multimodal analgesia [28,29].

Our results are consistent with those studies reporting that the opioid-sparing effect of nefopam is unclear. Many of the studies that demonstrated the analgesic efficacy of nefopam involved surgeries with mild to moderate postoperative pain, such as laparoscopic cholecystectomy, mastectomy, thyroidectomy, and middle ear surgery [22,30–32]. 20 mg of intravenous nefopam is comparable to 6–12 mg of intravenous morphine [33], and the median effective dose (ED50) of nefopam for moderate surgical pain was 21.7–28 mg [34–36]. We administered 20 mg of nefopam twice during surgery. Although that dose was higher than the ED50 found in previous studies, it might still have been insufficient because the ED50 value was not determined based on thoracic surgery. Although post-surgical pain after VATS is less than that after thoracotomy, it is still severe during the acute postoperative period, and the incidence of CPTPS does not differ from that following thoracotomy [3].

Furthermore, no adequate dose, infusion rate, or duration of nefopam administration has yet been established for postoperative pain control. In previous studies, nefopam was administered in three major ways [11,12]. The first is administration before surgical incision and at the end of surgery, as in our study. The second is continuous infusion for 24–48 h beginning at the end of surgery, and the third is continuous infusion during surgery after an initial administration. The dose of nefopam used in previous studies varied from 20 to 120 mg per day, depending on the type of surgery, operation time, and administration method. However, in those studies, the analgesic effects were different, not uniform.

To prevent the development of CPTPS involving a neuropathic pain component, perioperative pain control is very important [1,3–5]. The action of nefopam on the glutaminergic pathway was proven in in vitro studies, and its antiallodynic and antinociceptive effect on neuropathic pain was also demonstrated in in vivo animal studies [37]. Ok et al. reported that additive nefopam in IV-PCA reduced neuropathic pain after percutaneous endoscopic lumbar discectomy [18]. In this study, however, nefopam did not reduce the incidence of acute, chronic or neuropathic pain after VATS for lung cancer. This result could reflect an inadequate dose of nefopam. One study in laparoscopic colectomy also reported that 20 mg of nefopam did not reduce acute or chronic postoperative pain [38]. Those authors suggested that a low dose of nefopam caused negative preemptive analgesic results, which might not be enough to prevent nociceptive transmission and central sensitization for moderate to severe pain [38]. On the other hand, a study in breast surgery reported that 20 mg of nefopam administered before surgical incision reduced the use of rescue analgesics and lowered the incidence of chronic postoperative pain [30].

In this study, five patients who complained of moderate to severe pain (NRS score ≥ 5) 3 months after surgery were all in the control group. Although there was no statistically significant difference between the groups, that result could suggest that nefopam has a potential role in attenuating severe pain in CPTPS. Further studies will be needed to clarify the effect of nefopam on chronic postoperative pain.

A characteristic finding of this study is that the dose of remifentanil infused during surgery was significantly higher in the nefopam group. We attribute that finding to the tachycardia effect of nefopam [11]. However, a study reported that nefopam had analgesic efficacy after laparoscopic gastrectomy and that intraoperative remifentanil consumption was lower in the nefopam group than in the control group [15]. The mean infusion rate of the control group in that study was 0.13 ± 0.06 μg/kg/min. As an explanation for their finding, those authors suggested that nefopam might be an NMDA receptor antagonist and thereby prevent remifentanil-induced hyperalgesia. In our study, on the other hand, the mean infusion rate in the nefopam and control groups was 0.07 ± 0.03 μg/kg/min and 0.05 ± 0.02 μg/kg/min, respectively. Only one patient in the nefopam group was given a dose of remifentanil greater than 0.1 μg/kg/min, which could induce remifentanil-induced hyperalgesia [39]. Therefore, it is unlikely that the difference in remifentanil infusion between the groups affected postoperative opioid consumption.

This study has several limitations. First, the patients in this study were not completely blinded. Although they did not know which group they were in during the acute postoperative period, they could have known their group if they read their medical records later. Second, we only evaluated postoperative pain intensities at rest. Assessing pain scores during coughing or movement would have been more appropriate. Third, we could not evaluate the incidence of tachycardia and sweating during the perioperative period, and they are known to be frequent adverse effects of nefopam. However, it was difficult to evaluate the occurrence of tachycardia during surgery because many factors can induce tachycardia during VATS. Fourth, the chronic pain evaluation was conducted by telephone, rather than in face-to-face interviews. Finally, the sample size of this study was not determined by the incidence of CPTPS. Furthermore, only 37 patients in the control group and 38 patients in the nefopam group were evaluated chronic pain at postoperative 3 months due to the follow-up loss. This sample size was rather small to demonstrate the incidence of chronic pain or compare it between the two groups.

#### **5. Conclusions**

In conclusion, intraoperative nefopam administration did not decrease total opioid consumption or postoperative pain intensity during the first 72 h after VATS for lung cancer. It also did not reduce the incidence of chronic post-surgical pain 3 months after surgery, compared with the control group. Further studies are required to elucidate the potential role of nefopam in multimodal analgesia for patients undergoing VATS.

**Supplementary Materials:** The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jcm11164849/s1, Table S1: The details of Brief pain inventoryshort form on 3 months after surgery; Table S2: The short form of neuropathic pain questionnaire on 3 months after surgery.

**Author Contributions:** Conceptualization, E.J.L. and J.W.C.; methodology, J.W.C., H.J. and E.J.L.; software, H.Y. and S.J.P.; validation, W.S.S., M.Y. and J.A.K.; formal analysis, S.L. and H.J.A.; investigation, H.Y. and S.L.; resources, M.Y. and J.A.K.; data curation, H.Y. and S.J.P.; writing—original draft preparation, H.Y., H.J. and J.W.C.; writing—review and editing, H.J. and J.W.C.; visualization, E.J.L. and H.Y.; supervision, J.W.C., W.S.S. and H.J.A.; project administration, H.Y., E.J.L. and J.W.C. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** This study was approved by the Institutional Review Board of Samsung Medical Center (IRB No: SMC 2020-12-167, approval date: 22 February 2021) and was performed in accordance with the ethical principles of the 1964 Declaration of Helsinki and its later amendments. The trial was conducted following an original protocol and CONSORT guideline. This study is registered at the Clinical Trial Registry of Korea (http://cris.nih.go.kr; accessed on 11 June 2021; identifier: KCT0006246).

**Informed Consent Statement:** Written informed consent was obtained from all individual participants included in the study.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


### *Article* **Is the Erector Spinae Plane Block Effective for More than Perioperative Pain? A Retrospective Analysis**

**Uri Hochberg 1,2,\*, Silviu Brill 1,2, Dror Ofir 2,3, Khalil Salame 2,3, Zvi Lidar 2,3, Gilad Regev 2,3 and Morsi Khashan 2,3**


**Abstract: Introduction:** The thoracic Erector Spinae Plane Block (ESPB) is an ultrasound-guided block that has gained popularity and is widely used in acute pain setups. However, data regarding its role in chronic and cancer-related pain are anecdotal. **Material and Methods:** The study is a retrospective analysis of patients who underwent ESPB. The cohort was divided into subgroups based on three determinants: etiology, pain type, and chronicity. **Results:** One hundred and ten patients were included, and genders were affected equally. The average age was 61.2 ± 16.1 years. The whole group had a statistically significant reduction in a numerical rating scale (NRS) (7.4 ± 1.4 vs. 5.0 ± 2.6, *p*-value > 0.001). NRS reduction for 45 patients (41%) exceeded 50% of the pre-procedural NRS. The mean follow-up was 7.9 ± 4.6 weeks. Baseline and post-procedure NRS were comparable between all subgroups. The post-procedural NRS was significantly lower than the pre-procedural score within each group. The proportion of patients with over 50% improvement in NRS was lower for those with symptom duration above 12 months (*p*-value = 0.02). **Conclusions:** Thoracic ESPB is a simple and safe technique. The results support the possible role of ESPB for chronic as well as cancer-related pain.

**Keywords:** chronic pain; cancer-related pain; ESP block; pain management; ultrasound-guided

#### **1. Introduction**

Chronic pain is a common, complex, and distressing condition that impacts many aspects of patients' health and quality of life. Therefore, it can place a significant burden on patients and on the broader healthcare system. The Global Burden of Disease Study of 2016 reaffirmed that the high prominence of pain and pain-related diseases is the leading cause of disability and disease burden globally [1,2].

The Erector Spinae Plane Block (ESPB) belongs to a growing number of ultrasoundguided blocks that aim to deliver an analgesic solution to the soft tissue, or the interfascial plane, as opposed to the classic method of a direct nerve block. Shortly after its first description, the ESPB was adopted in clinical practice for multiple types of thoracic, abdominal, and extremity surgeries [3]. It is regarded as an effective, safe, and simple method for acute pain management [4]; however, despite its popularity, both the mechanism of the block and the extent of injectate spread are unclear [5].

Thoracic origin chronic pain represents a particular challenge as the interventional aspect requires its own special consideration. As with all neuraxial techniques, thoracic neuraxial procedures have contraindications and limitations (for example, coagulopathies, thoracic spine deformations, patient refusal) and other possible complications with considerable potential morbidity, including pneumothorax and neurovascular damage.

**Citation:** Hochberg, U.; Brill, S.; Ofir, D.; Salame, K.; Lidar, Z.; Regev, G.; Khashan, M. Is the Erector Spinae Plane Block Effective for More than Perioperative Pain? A Retrospective Analysis. *J. Clin. Med.* **2022**, *11*, 4902. https://doi.org/10.3390/jcm11164902

Academic Editor: Marco Cascella

Received: 19 July 2022 Accepted: 19 August 2022 Published: 21 August 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Although the first description of the block was for chronic neuropathic pain, most publications are concerned with acute pain management. The current literature addressing its use for chronic and cancer-related pain is scarce and mostly anecdotal in nature [6–10].

In this paper, we described the outcomes of the ESPB applied to patients at our pain institute, a regional referral center within a tertiary, university-affiliated medical center. We compared outcomes between different groups of patients based on the origin of the pain, type of pain, and symptom duration.

#### **2. Materials and Methods**

#### *2.1. Study Design*

A retrospective analysis.

#### *2.2. Setting and Study Population*

The study was conducted at the Pain Institute Center of the Tel Aviv Souraski Medical Center and was approved by the hospital's ethics committee (No. 0003-20-TLV). A retrospective review was carried out on the medical records of all patients who underwent thoracic ESPB between October 2018 and August 2021.

All participants provided written informed consent prior to undergoing the procedure, similar to other invasive procedures in our center. Inclusion criteria included: age of 18 years or above, diagnosis of thoracic back pain, a numerical rating scale (NRS) for pain ≥ 6, no significant motor weakness, no signs or symptoms of myelopathy, failure of other conservative treatment (i.e., physical therapy and oral analgesics), and at least a one-month post-procedure follow up.

Exclusion criteria: Allergy or hypersensitivity to steroid or amide local anesthetics, pregnancy, and breastfeeding.

#### *2.3. Thoracic ESP Block Technique*

The procedure was carried out under ultrasound guidance. The patient was placed in a prone position, and the ultrasound probe was set 2.5–3 cm laterally to the spinous process at the desired thoracic vertebral level on a parasagittal plane. Normally, a high-frequency linear probe was used. In the case of obese patients, a curvilinear (2–5 MHz) probe was used. Under ultrasound guidance, a 22 G needle measuring 50 or 100 mm was then inserted in a craniocaudal direction using the in-plane technique. The injection takes place at the fascial plane, deeper into the erector spinae muscle group. The solution injected was 10 mL of 1% lidocaine with dexamethasone 10 mg for a unilateral injection and 15–20 mL of 1% lidocaine with dexamethasone 10 mg for a bilateral injection.

#### *2.4. Data Collection*

Pre-procedural baseline demographic, clinical, and imaging data were collected. Demographic and procedural variables included: age, gender, pre-procedural NRS, and duration of symptoms at the first visit. Procedural variables included the side and level of the injection. Post-procedural variables included post-procedural NRS scores and the total number of ESPBs performed. Adverse effects were also monitored and documented. The data were collected and recorded by the pain physician in charge of the patient at the pain institute.

Thoracic pain was defined as pain experienced in the thoracic area, between the T1 and T12 boundaries, and across the posterior aspect of the trunk [11].

The main outcome measured was the change in pain intensity which was assessed using an 11-point numerical rating scale (NRS), with a range from 0 (no pain) to 10 (worst possible pain). In order to evaluate clinical significance, we used a minimal clinically important change (MCID) of 2.5 [12] for NRS, and we looked at a patient with more than 50% reduction in baseline NRS.

We divided the patients into different groups based on etiology, dominant pain type, and pain chronicity. For etiology, we divided the patients into two groups: one with

patients suffering from cancer-related pain and the other with patients suffering from non-cancer-related pain. Cancer-related pain was defined as pain originating directly from a thoracic neoplastic lesion.

Regarding the dominant pain type, we divided the patients again into three groups according to the pain type: nociceptive, neuropathic, and mixed pain. The neuropathic pain type was defined using strict criteria, following the current International Association for the Study of Pain (IASP) definition of "definite neuropathic pain" [13]. In cases where a discrete pathophysiological classification of pain was not either purely neuropathic or purely nociceptive, a "mixed type" diagnosis was given [14].

In order to analyze the effect of chronicity, the cohort was divided into three groups according to the duration of symptoms: up to four months, four to twelve months, and more than twelve months.

The patient clinical assessments were conducted before the procedure and at the postprocedure follow-up appointments. The pre- and post-procedural NRS were compared in the entire group and within each of the sub-groups.

At the post-procedure follow-up, patients with motor neurological deficits were referred for further surgical evaluation. Patients with significant pain (NRS > 6) were offered a second thoracic ESPB. A maximum of three procedures were allowed for each patient. Patients with no significant pain (NRS < 4) at the follow-up visit, were either discharged or offered an additional second follow-up.

#### *2.5. Statistical Analysis*

The statistical analysis was performed using SPSS version 19 (IBM Corp., Armonk, NY, USA). Significant differences between the groups were determined using one sample *t*-test, the X2 test, and the Fisher exact test to evaluate categorical variables' independence. ANOVA and independent *t*-test were used to compare NRS values between the symptom duration groups. Pre-procedure to post-Procedure NRS changes within each group were analyzed with paired *t*-tests. A *p*-value < 0.05 was considered statistically significant.

#### **3. Results**

#### *3.1. Participant Characteristics*

One hundred and ten patients underwent the procedure, and both genders were affected equally. The average age was 61.2 ± 16.1. Sixty-one (55%) patients underwent unilateral injections, and 49 (45%) underwent bilateral injections (Table 1). Seventy-two patients (65%) were discharged from the pain clinic after one injection, and 35 (32%) patients were discharged after two injections. The most common level of injection was T3 (26 patients) (Table 2).


**Table 1.** Demographic and preprocedural variables.


**Table 2.** Level of injection.


#### *3.2. Demographic and Preprocedural Variables*

When observing the etiology groups, no significant difference was found between patients with cancer-related pain and patients with non-cancer pain (Table 1). As for the pain type groups, we found significant differences in the side of injection (Table 1). In the mixed pain group, no patients received bilateral injections (*p*-value = 0.003). Analysis of pain duration groups showed a significant difference in the distribution of the injection site (*p*-value < 0.001) (Table 1).

#### *3.3. Average Pain Intensity*

A statistically significant reduction in NRS was found when the mean pre- and postprocedural NRS were compared across the entire cohort (*p*-value > 0.001). In fifty-eight (53%) patients, the NRS improvement exceeded the MCID, and in 45 (41%), it exceeded 50% of the pre-procedural NRS (Table 3).


**Table 3.** Average pain intensity.

The etiology group comparison showed comparable pre-procedural NRS. The postprocedural NRS was significantly lower than the pre-procedural score within each etiological group. The proportion of patients who achieved improvement higher than MCID as well as above 50% of the baseline NRS was higher in the non-cancer related group, yet, without statistical significance (*p*-value = 0.51) (Table 3).

Comparing the pain type groups showed comparable pre- and post-NRS scores. However, in the mixed pain group, the improvement in NRS did not reach statistical significance (*p*-value = 0.334) (Table 3).

In the pain chronicity groups, the pre- and post-NRS were comparable between the groups, and the improvement in these scores was found to be statistically significant within each group. The proportion of patients with more than 50% improvement in NRS was significantly lower in patients with symptoms duration of more than 12 months (*p*-value = 0.02) (Table 3).

There were no major adverse effects reported. The main adverse effect was injection site soreness. Other adverse effects reported were systemic response attributed to steroid exposure, none requiring hospitalization.

#### **4. Discussion**

Thoracic spine pain is prevalent, affecting about 20% of people in their lifetime. However, research related to thoracic pain is sparse compared to lumbar and cervical spine pain [11].

Thoracic ESPB has gained popularity since its introduction and is being widely used in acute pain setups; however, data regarding its role in chronic pain are mostly anecdotal.

In this work, our purpose was to evaluate the role of ESPB in the management of chronic and cancer-related thoracic pain. We compared the outcomes based on three fundamental determinants: etiology, the dominant pain quality, and the chronicity of pain.

Our results are consistent with those of previously published reports describing the possible benefits of ESPB [6–10]. The mean reduction in NRS in our study was 2.4 points (*p*-value > 0.001), with 53% reporting NRS improved by more than 2.5 points, and 41% with NRS score improved by more than 50% compared to pre-procedure score. In our study, a successful, clinically meaningful procedure was defined as either a reduction in the NRS score by 2.5 or more points [15] or as a reduction of 50% compared to baseline NRS. This strict threshold, which was also selected by other trials [16,17], was chosen over the more common 30% improvement in NRS score to exclude the potential placebo effect.

Cancer patients frequently suffer from a wide range of other symptoms, and the multi-factorial causes result in a "total pain experience" [18]. As such, an etiology-based sub-group analysis was carried out, comparing patients with cancer-related pain to patients suffering from pain caused by other conditions. The first sub-group included all patients with an active neoplastic disease that causes intractable pain that is refractory to a medical regimen treatment. The proportion of patients who achieved improvement exceeding the 50% of the baseline NRS was higher in the non-oncological patients, showing a strong tendency toward statistical significance (*p*-value = 0.51).

Of the 66 cases of non-cancer-related pain, 33 were nociceptive (50%), 28 were neuropathic (42.4%), and 5 (7.6%) were mixed pain types. The nociceptive group included pain resulting from vertebral or rib fractures, deformations including kyphosis and scoliosis, soft tissue myofascial pain [19], degenerative changes in the disc and the facet joints, and bones lesions including hemangiomas. Within the 33 cases of the nociceptive group, 11 cases were due to degenerative spinal changes, 7 were myofascial pain, 6 cases were due to pain secondary to osteoporotic thoracic vertebrae fracture, 4 cases were due to consistent pain after the fracturing of ribs, 3 cases were due to pain secondary to traumatic thoracic vertebra fracture, and 2 cases were due to post-operative pain for correction of scoliosis.

These results suggest that although the ESPB analgesic effect may differ slightly, overall, this effect is comparable between patients with pain originating from oncological and non-oncological sources and that ESPB can have a potential role in treating pain with these conditions.

A second subgroup analysis, based on the dominant pain type, did not reveal significant differences in either the pre- or post-pain NRS score nor in the portion of patients who reported more than 50% improvement.

When the pre- and post-NRS scores were compared within the mixed pain [14] group, the improvement did not reach statistical significance (*p*-value = 0.334). However, due to the small number of patients in this subgroup, this finding should be interpreted carefully, and conclusions should not be drawn.

An analysis of the chronicity of the pain experience duration was also carried out. More than 60% of the study population experienced pain for more than a year prior to the execution of the ESPB. Given that our clinic serves as a tertiary center, often with long waiting times, such a proportion is expected. Although all three subgroups reported statistically significant NRS reduction, the largest proportion of patients with pain reduction of more than 50% was found in the patients with symptom durations of less than four months. These results support previous findings regarding the importance of early treatment and support the recommendation of early referral to a pain specialist for early intervention [20,21].

#### *4.1. Procedure-Related Aspects*

As mentioned above, much is yet unknown about thoracic ESPB. Not only regarding its indications and efficacy but also various technical aspects. As the procedure is a single shot, not a continuous infusion, the dosage delivered should not exceed the recommended daily dosage. We use 10 mL of 1% lidocaine with dexamethasone 10 mg for a unilateral injection and 15–20 mL of 1% lidocaine with dexamethasone 10 mg for a bilateral procedure. Corticosteroid has an established role in the management of both neuropathic and cancer pain [22–24]. The choice of Dexamethasone is for two sets of reasons. As a corticosteroid, it

has high potency, a long duration of action, and minimal mineralocorticoid effect. Moreover, the solution is non-particulate; hence, it confers a lower risk of vascular damage in the thoracic area and is the recommended corticosteroid for thoracic injection [25].

#### *4.2. Safety Aspects*

Most chronic pain patients are treated at an ambulatory outpatient clinic. This should be considered when evaluating the approach and safety aspects of such a procedure.

In the immediate vicinity of the needle performing the block, there are no neurovascular structures at risk. To date, there have been minimal procedure-related complications reported with this block compared to the traditional thoracic neuraxial blocks [8,26,27]. Our data support this notion, as no major adverse effects were recorded. A total of 145 procedures were carried out, of which 45% were in a bilateral manner. The only adverse effects reported were a systemic response to steroids consisting of a mild and expected transient increased level of blood glucose level and increased blood pressure, none of which required further investigation or hospital admission.

The classification of the American Society of Regional Anesthesia (ASRA) for pain procedures considers musculoskeletal injections and thoracic facet medial branch block as procedures with a low risk for bleeding [28,29]. Recent reports also suggest a low risk of bleeding from the ESPB [30]. However, some patients are at higher risk due to various co-morbidities, and hence, we perform a personal stratification of risk for bleeding for each patient before recommending the procedure. Three patients underwent the procedure while treated with Enoxaparin at therapeutic dosage. Those patients were instructed to stay on bed rest for an hour following the procedure and were later discharged without adverse effects.

#### *4.3. Post-Procedure Aspects*

All patients undergoing lower thoracic ESPB are tested for motor function following the procedure to screen for any unintended motor weakness. However, we do not carry out sensory tests to evaluate the dermatomal coverage.

We do not perform additional procedures before evaluating the response of the first procedure. A follow-up is routinely scheduled 6–8 weeks after the procedure. A patient that reports a substantial improvement is discharged with a set of recommendations for future maintenance by their primary care physician.

#### *4.4. Limitations*

This study is a single-center trial and is limited by its retrospective nature. Part of the challenge associated with retrospective analyses is the possibility that pharmaceutical changes or other manual manipulations unbeknown to the team might affect the outcomes. However, in our pain institute, we avoid the use of pharmaceutical changes following ESP in order to allow for precise estimation of the analgesic effect of the procedure for future reference in cases of additional pain management advice. Even though a substantial percentage presented an NRS improvement exceeding 50%, our results should be interpreted carefully due to the sample size of the study. Another limitation that future studies should address is the long follow-up time, as the positive effect of the block may wane over time. Furthermore, a distinction of possible spinal anatomical structures and mechanisms (i.e., facet joint degeneration, discogenic changes, etc.) is missing and should be explored on a larger scale study.

In summary, thoracic pain is common and could lead to substantial disability and other negative impacts on the patient's life and society. It was argued that thoracic pain should be considered a discrete and important clinical entity, independent of pain experienced in other areas of the spine [31]. This study was conducted with the aim of better understanding and providing pain management for thoracic pain.

#### **5. Conclusions**

Thoracic ESPB is a simple and safe technique. The results support the possible role of ESPB for chronic as well as cancer-related pain.

Due to the simplicity of the ESPB, it could potentially be applied in multiple disciplines and setups, such as the emergency department and at an ambulatory practice.

In the future, prospective trials should be carried out to expand our knowledge and determine the proper and safe application of this type of block.

**Author Contributions:** U.H. and S.B. performed the procedures. All the above authors (U.H., S.B., D.O., K.S., Z.L., G.R. and M.K.) took an active role in creating the concept and design of the study. S.B. and G.R. oversaw the collection and recording of the data. U.H. and M.K. carried out the analysis and interpretation of data. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study received the approval of the Research Ethics Board of our institution, the Tel-Aviv Souraski Medical Centre. Research, Development, and innovation division, Helsinki committee, Trial registration number: (No. 0003-20-TLV). All the patients in this study gave their written informed consent for the procedure.

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author.

**Acknowledgments:** The authors would like to thank Vivian Serfaty and Basma Fahoum for proofreading this paper.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

