Multimodal analgesia with ropivacaine wound infiltration and intravenous flurbiprofen axetil provides enhanced analgesic effects after radical thyroidectomy: a randomized controlled trial

Thyroidectomy is a common procedure that causes mild trauma. Nevertheless, postoperative pain remains a major challenge in patient care. Optimizing postoperative pain management is an important goal in the perioperative period. Tramadol is a synthetic opioid frequently used to treat moderate pain. In contrast to pure opioid agonists, tramadol has a low risk of respiratory depression and sedative effects [1‐4]. At our institution, tramadol is commonly prescribed to provide postoperative analgesia in patients undergoing thyroid surgery because it is effective in relieving mild to moderate pain, causes less respiratory depression and sedation than other opioids, and has a relatively low cost. However, tramadol has major adverse effects, including dizziness, nausea, and vomiting, which affect its clinical application and patient satisfaction [5]. Clinical research shows that postoperative nausea and vomiting (PONV) is primarily caused by the use of inhalational anesthesia and opioid analgesics [6]. Studies have shown that the incidence of PONV is reduced by the use of antiemetic drugs such as 5-HT3 receptor antagonists (e.g., dolasetron) and/or total intravenous anesthesia [7‐9]. However, despite impressive advances in the field of anesthesia, PONV remains an unpleasant postoperative experience that must be considered.

Postoperative analgesia can be improved by combination therapies targeting different sites of the pain pathway. Moreover, multimodal analgesia can decrease opioid consumption and adverse effects. Therefore, multimodal analgesia using a combination of analgesics and analgesic techniques has become increasingly popular for the control of postoperative pain. Investigations on multimodal analgesia have been carried out in upper extremity surgery, hip and knee arthroplasty, cardiac surgery, and other major operations [10‐14]. However, studies on multimodal analgesia in neck surgery remain limited.

Some inflammatory mediators released by damaged cells at the surgical site act directly on the nociceptor terminal to produce pain, while others lead to sensitization of the nociceptor terminal. Therefore, it has been proposed a multimodal analgesic regimen that includes anti-inflammatory drugs be used to control postoperative pain. Flurbiprofen axetil is a non-steroidal anti-inflammatory drug (NSAID) with a high affinity for inflamed tissues and a promising analgesic effect [15]. Local anesthetic wound infiltration has also been shown to reduce postoperative pain and opioid requirement in patients undergoing thyroid surgery [16, 17]. Ropivacaine is a popular long-acting local anesthetic that is widely used for local anesthesia due to its reduced toxic potential in comparison with other local anesthetic agents [18].

This prospective, randomized controlled trial aimed to evaluate the analgesic efficacy of multimodal analgesia with pre-incision ropivacaine wound infiltration and intravenous flurbiprofen axetil in patients undergoing radical thyroidectomy. The hypothesis was that multimodal analgesia benefits patients undergoing radical thyroidectomy by providing good analgesic effects with a low incidence of adverse effects. This is the first trial to compare a multimodal regimen consisting of pre-incision ropivacaine wound infiltration and intravenous flurbiprofen axetil versus a single dose of tramadol in patients undergoing thyroid surgery.

Forty-four patients were randomized from January to April 2019 (Fig. 1). Four patients were excluded due to missing data. Therefore, 40 patients were analyzed with 20 patients in each group. There were no significant differences between the groups in demographic characteristics or intraoperative data (Table 1). Compared with Group C, Group M had a lower mean blood pressure (MBP; P = 0.019) (Table 2). However, no significant differences were found between groups in HR (P = 0.119) or the use of vasoactive drugs (P = 0.507). In addition, the two groups did not differ in infusion volume (P = 0.634) or blood loss (P = 0.515).

Postoperative NRS scores are presented in Fig. 2 and Table 3. There was no significant difference between groups in the number of patients requiring additional analgesia postoperatively (P = 1.000).

No serious adverse events related to the agents used in the present study were observed. The incidence of adverse effects within the 48 h postoperative period was not significantly different between the groups (Table 4).

Flurbiprofen axetil is an injectable non-selective cyclooxygenase inhibitor. It is a prodrug prepared by enveloping flurbiprofen ester in a drug carrier of lipid microspheres, which congregate selectively in inflammatory tissues with a high affinity and provide sustained drug release. A meta-analysis of randomized controlled trials showed that patients treated with preoperative flurbiprofen axetil had significantly lower postoperative pain scores than those who did not receive flurbiprofen axetil [15]. Regional techniques such as local anesthetic wound infiltration also reduce postoperative pain and opioid requirements [16, 17]. In thyroid surgery, local anesthetic wound infiltration is safe and easy to perform and has shown good analgesic effects in some studies [16, 19‐22]; however, the results are controversial [23, 24]. In addition, the analgesic benefit of local wound infiltration seems to be maintained for only a short period of time after thyroid surgery [20, 25], and breast cancer surgery [26]; administration of local anesthetics significantly decreased pain only at 2 h postoperatively. Postoperative pain after total thyroidectomy reportedly reaches a maximum at 1 h postoperatively, and starts to decrease 3 h later [20]. Therefore, the first few hours following thyroidectomy are the most crucial for pain management.

To overcome the problems of the short duration of analgesia obtained with incisional infiltration and the insufficient analgesia provided by NSAIDs, we administered a combined analgesia protocol of ropivacaine wound infiltration plus intravenous flurbiprofen axetil. Ropivacaine was chosen for its longer block duration, lower toxicity, and greater safety compared with other local anesthetics; plasma levels and risks are associated with the total dose used and the extent of absorption [27]. According to previous studies, ropivacaine concentrations of 0.25, 0.5 and 0.75% provide adequate analgesia via wound infiltration [27‐29]. Based on the literatures and our experiences, we chose to use 0.5% ropivacaine because it provides good analgesia with few adverse effects. To prolong local anesthetic action and reduce vascular absorption, epinephrine was added to the ropivacaine. However, epinephrine should be applied with caution in patients with severe hypertension, or cardiovascular and cerebrovascular diseases, as it may cause tachycardia and hypertension if absorbed intravascularly. In our study, postoperative pain reached its maximum at 2 h postoperatively in Group C, similarly to previous findings [20], and remained at a relatively high level until 8 h postoperatively. The pain scores of Group C at maximum (2 h postoperatively) were 1.6 at rest and 2.6 during coughing/swallowing. The average NRS pain scores of Group C were 1.4 at rest and 2.0 during coughing/swallowing during the 2–8 h postoperative period, whereas the average NRS pain scores of Group M were 0.6 at rest and 1.2 during coughing/swallowing. The postoperative pain score reached its maximum at 24 h postoperatively at rest and 8 h postoperatively during coughing/swallowing in Group M (0.6 at rest and 1.4 during coughing/swallowing). However, the maximum postoperative pain scores in Group M were still relatively low compared to that in Group C at the same observation timepoint. Thus, multimodal analgesia delayed the occurrence of maximum postoperative pain (the maximum pain score was still relatively low), and successfully achieved pain relief during the early postoperative period (2–8 h postoperatively). This is meaningful, as several studies have indicated that the first few hours following thyroidectomy are the most crucial for pain management because patients experienced maximum pain during this period. Our results also demonstrate that the analgesic effects in Group M were significantly better than those in Group C on the first postoperative day both at rest and during coughing/swallowing; the average NRS pain score in Group M was also significantly lower than that in Group C within the first 2 postoperative days. These results showed that multimodal analgesia enhanced postoperative pain relief not only during the early postoperative stage, but throughout the 48 h postoperative period. This is a meaningful improvement compared with several studies that reported insufficient maintenance of pain control after administration of local anesthesia [20, 25]. One of the adverse effects of tramadol is nausea, which may result in higher frequency of swallowing and could explain the higher NRS scores during coughing/swallowing in Group C versus Group M. However, the incidence of nausea did not significantly differ between the two groups, which means that the two groups had a similar frequency of swallowing. Therefore, we believe that the comparison between the two groups of pain scores during coughing/swallowing was not affected by nausea caused by tramadol.

Consistent with previous studies [30‐33], 80.0% of patients had NRS scores lower than 4 (only one patient had a NRS score of greater than 6), indicating that thyroidectomy causes mild to moderate postoperative pain. Additional rescue analgesics were not usually required, and the need for additional rescue analgesics did not significantly differ between the groups. However, the intensity of postoperative pain may vary with surgical approach, anesthetic management, and pain-control protocols. In our study, the application of a small incision (approximately 4–7 cm) in thyroidectomy may have resulted in minimal pain in both groups. Our study showed that pain control after thyroid surgery can generally be accomplished with either a multimodal analgesia regimen of pre-incision wound infiltration and flurbiprofen axetil or with a single dose of tramadol, mostly without additional analgesics. Several previous studies suggested that local anesthetic wound infiltration decreases opioid consumption [16, 17, 34]. However, the present study found that intraoperative remifentanil use did not differ between the groups, consistent with a previous study [25].

Multimodal approaches to pain management have been shown to reduce adverse effects such as dizziness and PONV in patients undergoing surgical procedures [14, 35]. However, our results showed no significant differences in drug-associated adverse effects between the groups. In our study, the incidence of PONV was relatively low compared with data reported in a previous study [36]. PONV was only experienced by four (20.0%) patients in Group M and three (15.0%) in Group C. We assume that PONV was prevented by the combined use of dolasetron and propofol infusion (which allowed a lower concentration of sevoflurane during surgery). Furthermore, the relatively low incidence of PONV in Group C may be related to the slow injection of tramadol over a 5-min period. NSAIDs are associated with many adverse effects, including platelet aggregation inhibition, gastrointestinal mucosal injury, and renal failure. However, no adverse events were observed in our study. There were no significant differences between the two groups in intraoperative blood loss, and none of the patients experienced postoperative hemorrhage, probably because only a single dose of flurbiprofen axetil injection was administered. Similar data have been reported in other studies [37, 38]. Overall, our results demonstrated a low incidence of adverse effects due to multimodal analgesia with ropivacaine wound infiltration and intravenous flurbiprofen axetil (both administered within their recommended doses and volume) in patients undergoing thyroidectomy.

A previous study showed that patients treated with preoperative local infiltration exhibited lower MBP than other patients [25]. Similar changes were observed in our study, with a lower MBP in Group M than in Group C. In the previous study, the MBP reduction was explained as the result of preoperative local infiltration [25]. However, in our study, there were no significant differences between groups in vasoconstrictor requirement during surgery, indicating that the two groups had similar proportions of patients with hemodynamic changes within 30% of base line. Therefore, the differences in MBP may not be considered clinically significant.

The present study had some limitations. A sex ratio disparity existed among the participants, as 30 of the 40 patients analyzed were female. This distribution may be inevitable, as thyroid cancer is more common in women [39]. Nevertheless, these results need to be confirmed in a larger trial.

Multimodal analgesia with ropivacaine wound infiltration and intravenous flurbiprofen axetil improves the quality of postoperative analgesia in patients undergoing radical thyroidectomy, and has few adverse effects. This approach has advantages over tramadol for patients undergoing radical thyroidectomy. We recommend that this multimodal regimen be used in the clinical setting as described.