Novel multimodal analgesic regimen for perioperative pain management after hepatic artery infusion chemotherapy in patients with advanced hepatocellular carcinoma

Abstract

BACKGROUND

Hepatic artery infusion chemotherapy (HAIC) is a widely used local therapeutic approach for intermediate to advanced-stage hepatocellular carcinoma (HCC), exhibiting considerable efficacy. However, the prevalence of postoperative pain highlights the importance of pain management. Owing to the limitations inherent in existing pain management strategies, this study investigates and assesses the analgesic effectiveness of a multimodal treatment protocol in mitigating pain after HAIC procedures.

AIM

To provide patients with a more comprehensive and effective pain management strategy.

METHODS

A total of 100 patients with primary HCC who underwent HAIC were randomly assigned to a control group (n = 50) and a multimodal group (n = 50). Baseline characteristics and perioperative data were collected. Upon enrollment, patients in the multimodal group received parecoxib (40 mg) 30 minutes before HAIC, followed by 48 hours of patient-controlled analgesia with sufentanil. In contrast, the control group underwent standard preoperative preparation (psychological support) and received dezocine (5 mg) intraoperatively, with intravenous flurbiprofen (100 mg) administered every 12 hours for 48 hours postoperatively.

RESULTS

Compared to the control group, the multimodal analgesia group exhibited significantly lower resting and movement visual analog scale pain scores at postoperative 0, 2, 4, 6, and 12 hours (P < 0.05). Furthermore, the multimodal group experienced a reduced incidence of postoperative nausea and vomiting, as well as a lower overall frequency of adverse events, compared to the control group (P < 0.05). Patient satisfaction was also significantly higher in the multimodal group than in the control group (P < 0.05).

CONCLUSION

Our study demonstrates that multimodal analgesia is effective in reducing postoperative pain, minimizing adverse reactions, and improving patient satisfaction in HCC patients undergoing HAIC. This approach provides valuable clinical strategies for optimizing pain management in this patient population.

Key Words: Advanced hepatocellular carcinoma; Hepatic artery infusion chemotherapy; Multimodal analgesia regimen; Postoperative pain; Pain improvement

Core Tip: Multimodal analgesia is an approach that combines different analgesic medications and techniques to target multiple pain pathways, enhancing pain relief while minimizing adverse effects. This study investigates the effectiveness of a multimodal regimen in managing pain after hepatic artery infusion chemotherapy procedures.

INTRODUCTION

Hepatocellular carcinoma (HCC) is a prevalent malignant neoplasm worldwide, characterized by high incidence and mortality rates. It ranks third in cancer-related mortality globally[1]. HCC often presents insidiously, leading to most patients being diagnosed at the middle or advanced stage, missing the optimal window for surgical intervention[2]. Diagnosis of middle- and late-stage HCC primarily involves clinical symptoms, imaging examinations, and histopathological analysis[3]. Clinical symptoms, including severe abdominal pain, right flank pain, jaundice, and weight loss, are crucial indicators for initial evaluation[4,5]. Imaging methods, including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), can assess tumor size, lesion extent, and the presence of lymph nodes or distant metastasis, thereby aiding in determining the disease stage[6,7].

In advanced HCC, surgical resection is typically not the preferred initial treatment modality. This is attributed to the high prevalence of tumor spread or extrahepatic metastases, which make surgery technically demanding and hazardous[8]. Therefore, non-surgical therapies, such as chemotherapy, radiation therapy, targeted therapy, and immunotherapy, have become the primary treatment approaches[9].

Hepatic artery infusion chemotherapy (HAIC) is a localized chemotherapy approach for liver malignancies, particularly primary HCC, where high concentrations of chemotherapeutic drugs are directly infused into the hepatic artery, leveraging the fact that liver tumors are predominantly supplied by the hepatic artery. Following decades of ongoing research and development, HAIC technology has achieved considerable progress in clinical applications[10]. Moreover, the combination of HAIC with other therapeutic modalities (e.g., targeted therapies and immunotherapies) has amplified its efficacy, leading to enhanced patient outcomes and improved quality of life[11]. While HAIC offers advantages in the treatment of HCC, such as increased local drug concentration and reduced systemic toxicity and side effects, it has potential complications. These include hemorrhage, arterial rupture, nausea and vomiting, and bone marrow suppression. Among these, pain is a particularly considerable concern. During HAIC therapy, a substantial proportion of patients (approximately 64.6%) experience varying degrees of pain, which can considerably impair their quality of life and potentially contribute to reduced survival duration[12].

Pain management is an essential component of the perioperative period of HAIC for HCC[13]. Traditional single-mode analgesia, such as the exclusive use of opioids, can provide pain relief but often leads to adverse effects such as respiratory depression, nausea, vomiting, constipation, and addiction[14,15]. In recent years, with the evolution of pain management concepts and advancements in analgesic techniques, there has been growing attention to multimodal analgesia schemes[16]. Multimodal analgesia, also known as balanced analgesia, combines different analgesic drugs with different mechanisms of action and uses multiple analgesic methods to target various pain conduction pathways. This approach achieves a synergistic analgesic effect while minimizing adverse reactions and enhancing pain relief[17]. A coalition of 14 professional societies recently recommended multimodal analgesia, advocating for the combined use of various analgesics and techniques alongside nonpharmacologic interventions[18]. Pain is a complex, multifactorial phenomenon that requires multimodal analgesic regimens, using combinations of analgesics with diverse mechanisms of action and/or different administration routes. Such strategies have demonstrated improved postoperative pain relief and reduced opioid consumption, thereby minimizing opioid-related adverse events[19,20]. Consequently, the implementation of multimodal analgesia in the perioperative period of HAIC can not only effectively alleviate treatment-related pain but also reduce the dosage of individual analgesic medications and lower the incidence of adverse reactions. This ultimately enhances patients’ treatment experience and compliance. More specifically, the multimodal analgesia regimen may incorporate the prophylactic administration of nonsteroidal anti-inflammatory drugs (NSAIDs) or selective cyclooxygenase-2 (COX-2) inhibitors preoperatively, the use of local anesthesia or regional nerve blocks intraoperatively, and the postoperative combined application of opioids and analgesic pumps[21].

Despite the known benefits of multimodal analgesia, it is deemed unsuitable for routine clinical practice[22]. An analysis of 315 hospital administrative databases involving approximately 800000 patients undergoing four common major surgical procedures (open lobectomy, open colectomy, total knee replacement, and below-knee amputation) revealed considerable variations in the utilization of multimodal analgesia[23]. Analgesic combinations are frequently irrational, and multimodal protocols often fail to address different types of pain responses (e.g., nociceptive and inflammatory pain)[24,25]. Currently, there are few or insufficient studies on perioperative pain relief in HAIC. Consequently, there is a lack of strong evidence supporting the implementation of multimodal analgesic programs. This knowledge gap hinders our comprehensive understanding and widespread application of multimodal analgesia in patients with HCC undergoing HAIC. Therefore, this study aims to address the pain management challenges faced by HCC patients receiving HAIC by introducing multimodal analgesia. Our aim is to investigate more effective and safer pain management approaches and contribute novel insights to the development of comprehensive treatment strategies for HCC patients.

MATERIALS AND METHODS

Patients

A total of 100 patients undergoing HAIC surgery for primary HCC at Xijing Hospital, The Fourth Military Medical University from January to December 2023 were included based on standard criteria. All patients were diagnosed with primary HCC through pathology, imaging, clinical symptoms, and laboratory examinations.

To maintain the objectivity and neutrality of the research findings, a randomized approach was used to assign patients to groups using a random number table. The procedure involved assigning a distinct identification number to each of the 100 cases of postoperative patients with primary liver cancer undergoing HAIC. Subsequently, a computer-generated random number table was used to randomly allocate the patients into two groups: The control group (n = 50) and the multimodal group (n = 50). The objective of randomization was to mitigate or eliminate possible selection biases and to guarantee that the baseline characteristics of the two patient groups were closely aligned, thereby facilitating an accurate evaluation of the impact of multimodal treatment on pain management after HAIC.

Measures to ensure the reliability of double-blind assessment

(1) In this study, the double-blind principle indicates that both the researchers performing the assessments (including data analysts) and the patients receiving treatment were unaware of group assignments. To maintain this confidentiality, all treatment-related information, such as group labels and treatment regimens, was concealed or encrypted during the data collection and analysis phases. Data were independently collected by investigators who were not involved in determining treatment assignments to reduce the potential for bias. Statistical analysis was performed in a blinded manner, with data analysts processing the data and analyzing results without knowledge of group assignments; and (2) A dedicated quality control team was established during the study to oversee the entire process, including randomization, data collection, and evaluation, ensuring that all procedures adhered to the study protocol and upheld the double-blind principle.

This study was approved by the Medical Ethics Committee of the hospital (document number: KY20232191-F-1), and all patients signed informed consent.

Diagnostic criteria: The diagnostic criteria for patients with primary HCC are based on the Diagnostic Guidelines for Primary HCC[26]. A clinical diagnosis of HCC can be established when the following conditions are simultaneously met: Either condition (1) + (2)a or condition (1) + (2)b + (3). The criteria are as follows: (1) Evidence of cirrhosis along with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, indicated by positive HBV and/or HCV antigen status; (2) Typical HCC imaging characteristics observed on contemporaneous multi-detector CT scans and/or dynamic contrast-enhanced MRI, showing rapid and heterogeneous vascular enhancement of the liver mass during the arterial phase (arterial hypervascularity), followed by rapid washout in the venous or delayed phase (venous or delayed phase washout). If the liver mass diameter is ≥ 2 cm, the presence of the abovementioned HCC characteristics in either CT or MRI is sufficient for diagnosing HCC; if the liver mass diameter is 1-2 cm, both CT and MRI must display the abovementioned HCC characteristics for a definitive diagnosis, enhancing diagnostic specificity; and (3) Serum alpha fetoprotein (AFP) levels ≥ 400 µg/L sustained for one month or ≥ 200 µg/L sustained for two months, with other causes of AFP elevation excluded, including pregnancy, germ cell tumors of the reproductive system, active liver diseases, and secondary liver cancers.

Inclusion criteria[27]: (1) Chinese Liver Cancer Staging Scheme (CNLC) stages IIb, IIIa, IIIb; (2) Adjuvant HAIC post-HCC resection to prevent recurrence; (3) Locally advanced liver cancer with good liver function (Child-Pugh grade A or B) suitable for conversion therapy; (4) Combined radiotherapy for HCC with portal vein thrombus to achieve a higher conversion rate; (5) Locally advanced intrahepatic and hilar cholangiocarcinoma; and (6) Inoperable liver metastases originating from colorectal and gastric cancer.

Exclusion criteria[27]: (1) Severe liver dysfunction (Child-Pugh grade C), along with obvious jaundice, hepatic encephalopathy, refractory abdominal fluid, or hepatorenal syndrome; (2) Severely decreased coagulation function that cannot be corrected; (3) Presence of active hepatitis or severe infection that cannot be treated simultaneously; (4) Extensive distant metastasis of the tumor with an estimated survival time of less than 3 months; (5) Cachexia or multiple organ failure; (6) Substantially reduced peripheral blood white blood cell (WBC) count and platelet (PLT) count, specifically WBC < 3.0 × 10⁹/L (note: This is a non-absolute contraindication because WBC reduction in hypersplenism differs from chemotherapy) and PLT < 60 × 10⁹/L; and (7) Renal dysfunction indicated by creatinine levels > 176.8 μmol/L (2 mg/dL) or creatinine clearance < 30 mL/min.

Analgesic regimen

To ensure the continuity and effectiveness of the analgesic regimen, the same team of anesthesiologists, who were familiar with the patient’s condition and specific analgesic plan, administered anesthesia.

Control group: The control group received standard preoperative preparation, which included psychological support, and was given 5 mg of dezocine during HAIC. After the treatment, flurbiprofen 100 mg was intravenously infused every 12 hours over a 48-hour period. If the patient’s resting visual analog scale (VAS) pain score exceeded 3, tramadol 100 mg or an equivalent opioid was administered intravenously.

Multimodal group: In the multimodal group, patients received an intravenous injection of 40 mg parecoxib sodium 30 minutes prior to the start of HAIC, while the patient-controlled analgesia (PCA) pump was activated simultaneously with the initiation of HAIC. This consisted of sufentanil (100 μg) and dexmedetomidine (200 μg), diluted with a 0.9% saline solution to a total volume of 100 mL. The initial dose was set at 2 mL, with an on-demand push also at 2 mL and a lockout interval of 5 minutes. The infusion rate was 2 mL/h, decreasing to 0 mL/h after surgery. If the patient’s resting VAS pain score averaged over two assessments was greater than 3, the background infusion rate was increased to 1 mL/h. PCA was available for use in 48 minutes after surgery (Figure 1).

Figure 1 Flowchart exhibiting course of the study. HAIC: Hepatic artery infusion chemotherapy; PCA: Patient-controlled analgesia; VAS: Visual analog scale.

HAIC surgery

HAIC was performed by the same team of doctors using the Seldinger technique for arterial catheterization[28]. During the procedure, angiography of the celiac trunk and superior mesenteric artery was performed to identify the blood supply arteries of the tumor. Additional angiography of other arteries was performed as needed for a comprehensive evaluation. The catheter was then advanced in a selective manner to reach the main feeding artery of the tumor, after which the non-primary feeding arteries were addressed. Chemotherapy drugs were administered through the catheter, with a heparin solution used during the procedure to prevent catheter occlusion. The exposed portion of the catheter was secured and protected. During chemotherapy, the patient remained in bed, avoiding bending or exerting force on the catheterized limb. Upon completion of chemotherapy, the catheter was removed, and the puncture site was compressed and dressed. The patient was allowed to ambulate once the bleeding had stopped.

Data collection

Patient demographics, including age, gender, Child-Pugh classification, history of HAIC, lifestyle-related challenges, prior liver conditions, and complications, were documented. Additionally, perioperative information, such as the duration of HAIC treatment and length of the post-HAIC hospital stay, was recorded.

The evaluation of patients’ VAS scores at rest and during exercise[29] was performed at the following time points: Preoperative, intraoperative, and postoperative at 1 hour (T0), 2 hours (T2), 4 hours (T4), 6 hours, 12 hours (T12), 24 hours (T24), and 48 hours (T48).

Patient satisfaction[30] was recorded 48 hours after surgery, using a five-point scale: 1 is "very bad," 2 is "bad," 3 is "moderate," 4 is "good," and 5 is "very good."

The sedation score[31] was assessed 48 hours after surgery. The scoring system was as follows: 0 is "awake," 1 is "mildly sedate," 2 is "inclined to sleep," and 3 is "deep sleep, unable to wake up."

Additionally, postoperative adverse drug reactions were recorded in a 48-hour period, including symptoms such as nausea, vomiting, constipation, difficulty urinating, fatigue, bradycardia (slow heart rate), hypotension (low blood pressure), and respiratory depression.

Statistical analysis

Statistical analyses were performed using SPSS version 27.0 (SPSS Inc., Chicago, IL, United States). Patient characteristics and perioperative data were compared between the two groups using t-tests, Fischer’s exact test, and χ² tests for categorical variables. Time-course changes in pain scores were compared using t-tests. Bar graphs comparing the VAS pain scores of the two groups were generated using GraphPad Prism 9.5 software. The distribution of percentages, patient satisfaction levels, and adverse drug reactions were analyzed using Fisher’s exact test or χ² tests. All results are presented as mean ± SD and patient counts (%), with statistical significance set at P < 0.05.

RESULTS

Comparison of general and perioperative data between the two groups

After applying the patient grouping and selection criteria for this study, no patients were excluded from the analysis (Figure 1). There were no statistically significant differences in age, sex, Child-Pugh grade, history of HAIC, adverse life history, liver disease history, or comorbidities between the two groups. Consequently, no significant differences in baseline characteristics were observed between the control group (n = 50) and the multimodal group (n = 50) (P > 0.05). During the perioperative period, no significant differences were found in the duration of HAIC (t = 0.425, P = 0.809) or the length of hospital stay after HAIC (t = 0.839, P = 0.403) between the two groups. Detailed information is provided in Table 1.

Table 1 Comparison of general and perioperative data between the two groups, n (%).

Classification	Control group	Multimodal group	t/χ2	P value
Cases	50	50
Age	55.10 ± 8.61	52.00 ± 9.74	1.686	0.095
Gender			0.378	0.539
Male	29 (58)	32 (64)
Female	21 (42)	18 (36)
Child-Pugh class			0.367	0.545
A	27 (54)	30 (60)
B	23 (46)	20 (40)
History of HAIC			0.161	0.688
First time	26 (52)	28 (56)
Twice or more	24 (48)	22 (44)
Adverse life history			0.174	0.677
No	19 (38)	17 (34)
Yes	31 (62)	33 (66)
History of liver disease			0.178	0.673
No	16 (32)	18 (36)
Yes	34 (68)	32 (64)
Complication			0.198	0.656
No	13 (26)	15 (30)
Yes	37 (74)	35 (70)
Duration of HAIC (min)			0.425	0.809
< 30 minutes	32 (64)	35 (70)
30-60 minutes	17 (34)	14 (28)
> 60 minutes	1 (2)	1 (2)
Duration of hospital stay after (day)	3.78 ± 1.87	3.48 ± 1.71	0.839	0.403

HAIC: Hepatic artery infusion chemotherapy.

VAS pain score

As shown in Table 2 and Figure 2, the baseline VAS pain scores measured 1 hour before (t = 0.358, P = 0.721) and during HAIC (t = 0.775, P = 0.440) showed no statistically significant differences between the two groups (Figure 2, Table 2). However, significant differences in VAS pain scores at rest and during movement were observed at various time points after HAIC: 0 hour (rest: T = 8.667, P = 0.001; movement: T = 8.733, P = 0.001), 2 hours (rest: T = 5.040, P = 0.006; movement: T = 3.133, P = 0.002), 4 hours (rest: T = 6.928, P = 0.001; movement: T = 6.928, P = 0.001), 6 hours (rest: T = 0.640, P = 0.001; movement: T = 6.640, P = 0.001), and 12 hours (rest: T = 8.883, P = 0.001; movement: T = 7.310, P = 0.001). In contrast, no statistically significant differences were observed in VAS pain scores between resting and movement at 24 hours (rest: T = 1.939, P = 0.055; movement: T = 0.165, P = 0.869) and 48 hours after HAIC (rest: T = 1.497, P = 0.458; movement: T = 0.503, P = 0.616).

Figure 2 Visual analog scale scores of the control group and the multimodal group at different time points. A: Score at rest; B: Score at movement. ^aP < 0.05 vs control group. VAS: Visual analog scale.

Table 2 Compared two groups of visual analog scale pain score.

	Time point	Control group (n = 50)	Multimodal group (n = 50)	t	P value
Rest	1 hour before HAIC	0.58 ± 0.57	0.54 ± 0.54	0.358	0.721
	During the HAIC	0.38 ± 0.49	0.46 ± 0.54	0.775	0.440
	T0	1.5 ± 0.58	0.56 ± 0.50	8.667	0.001
	T2	1.8 ± 0.73	1.14 ± 0.57	5.040	0.006
	T4	1.88 ± 0.77	0.96 ± 0.53	6.928	0.001
	T6	1.78 ± 0.51	0.98 ± 0.68	6.640	0.001
	T12	1.62 ± 0.49	0.7 ± 0.54	8.883	0.001
	T24	0.56 ± 0.58	0.34 ± 0.56	1.939	0.055
	T48	0.52 ± 0.58	0.36 ± 0.48	1.497	0.138
Movement	1 hour before HAIC	0.7 ± 0.54	0.62 ± 0.53	0.745	0.458
	During the HAIC	0.5 ± 0.51	0.62 ± 0.60	-1.079	0.283
	T0	1.68 ± 0.51	0.8 ± 0.49	8.733	0.001
	T2	1.9 ± 0.89	1.44 ± 0.54	3.133	0.002
	T4	1.94 ± 0.77	1.58 ± 0.50	6.928	0.001
	T6	1.96 ± 0.45	0.96 ± 0.53	6.640	0.001
	T12	1.64 ± 0.69	0.74 ± 0.53	7.310	0.001
	T24	0.84 ± 0.47	0.82 ± 0.72	0.165	0.869
	T48	0.52 ± 0.58	0.46 ± 0.61	0.503	0.616

HAIC: Hepatic artery infusion chemotherapy.

Comparison of patient satisfaction between the two groups 48 hours after surgery

The findings revealed that patient satisfaction levels, assessed 48 hours post-surgery, were significantly higher in the multimodal group compared to the control group (χ² = 11.753, P = 0.008). Specifically, in the control group, 20% of patients reported "excellent" satisfaction, 44% reported "good," 30% reported "moderate," and 6% reported "poor." In contrast, in the multimodal group, 50% of patients reported "excellent" satisfaction, 30% reported "good," and 20% reported "moderate." Refer to Table 3 for detailed information.

Table 3 Comparison of patient satisfaction between the two groups 48 hours after surgery, n (%).

	Cases (n)	1 = very bad	2 = bad	3 = moderate	4 = good	5 = very good	χ2	P value
Control group	50	0 (0)	3 (6)	15 (30)	22 (44)	10 (20)	11.753	0.008
Multimodal group	50	0 (0)	0 (0%)	10 (20)	15 (30)	25 (50)

Comparison of adverse reactions between the two groups

Compared to the control group, the multimodal group exhibited significantly lower incidences of postoperative nausea and vomiting (PONV) (χ² = 4.882, P = 0.027) and total adverse reactions (χ² = 10.306, P = 0.001). At 48 h post-surgery, the control group experienced adverse reactions including PONV (n = 15), constipation (n = 7), dysuria (n = 6), and hypersomnia (n = 10), while the multimodal group reported reduced incidences with PONV (n = 6), constipation (n = 4), dysuria (n = 4), and hypersomnia (n = 5). Refer to Table 4 for detailed information.

Table 4 Comparison of adverse reactions between the two groups, n (%).

Adverse reactions	Control group (n = 50)	Multimodal group (n = 50)	χ2	P value
PONV	15 (30)	6 (12)	4.882	0.027
Constipation	7 (14)	4 (8)	0.919	0.338
Dysuria	6 (12)	4 (8)	0.444	0.505
Hypersomnia	10 (20)	5 (10)	1.961	0.161
Total	33 (66)	19 (38)	10.306	0.001

PONV: Postoperative nausea and vomiting.

DISCUSSION

This study has emphasized the substantial advantages of using a multimodal analgesia regimen in managing postoperative pain after HAIC for advanced-stage HCC. Our findings demonstrated that, in comparison to conventional analgesia, the multimodal analgesia regimen was more effective in alleviating pain, minimizing side effects, and enhancing patient satisfaction.

Pain continues to pose a considerable global health challenge. For many years, μ-opioid receptor agonists and NSAIDs have been the primary modalities relied upon by clinicians for pain management[32]. While μ-opioid receptor agonists are effective in pain relief, their associated adverse effects are substantial, often leading physicians to adjust treatment regimens or even discontinue medication, making it difficult to adequately control pain[33]. Currently, the serious issue of opioid abuse has further exacerbated the need for safer and more effective analgesic solutions.

The findings of this study demonstrated that the multimodal group exhibited superior analgesic efficacy compared to the control group. It is hypothesized that the combination of an NSAID (parecoxib sodium) and an opioid (sufentanil) in the multimodal group produces a synergistic effect, enhancing analgesia and potentially reducing the dosage of each drug, thereby minimizing adverse effects. Additionally, the adjunctive use of an α2-adrenergic receptor agonist (dexmedetomidine) further enhances analgesia while providing improved sedation and comfort. Parecoxib sodium, a prodrug of an NSAID, exerts its effects after conversion to valdecoxib in the body. By inhibiting the activity of COX-2, parecoxib sodium reduces prostaglandin synthesis and is commonly used in perioperative pain management[34]. The combined use of parecoxib sodium and opioids in the multimodal analgesia approach has been shown to be a more effective pain management strategy than relying solely on opioids[35]. This combined therapy not only considerably reduces the intensity of postoperative pain but also effectively decreases opioid dependence and overall consumption[36]. Studies have demonstrated that a multimodal analgesia regimen incorporating parecoxib and sufentanil improves postoperative pain management in HCC patients undergoing transarterial chemoembolization (TACE)[37]. Therefore, the positive effects demonstrated by the multimodal analgesia regimen in this study align with previous findings that have used the same analgesic strategy in various surgical settings. This observation further confirms the broad effectiveness and superiority of this analgesic strategy for all surgical procedures. Despite variations in surgical types among the participants, the analgesic regimen’s core components-the synergistic activity of a NSAID (parecoxib sodium) with an opioid (sufentanil) and the adjunct effect of an α2-adrenergic receptor agonist (dexmedetomidine)-remained unchanged[38]. Both additives considerably enhanced the analgesic effect, potentially enabling lower drug doses and reducing adverse reactions. This points to an improved postoperative pain management strategy and a better patient experience. This finding solidifies the role of multimodal analgesia in clinical practice while also providing robust support for future pain management strategies.

This study demonstrated that the multimodal analgesia group experienced considerably lower VAS pain scores at various postoperative time points (0, 2, 4, 6, and 12 hours, both at rest and during movement) compared to the control group. These findings highlight the effectiveness of the multimodal analgesia protocol in providing substantial pain relief. Conventional analgesic medications frequently fall short of adequately managing pain related to HAIC, hindering effective pain control. While high-dose potent opioids can provide analgesia, they may be associated with serious complications, such as respiratory depression, restricting their clinical use[39]. Lidocaine, previously used as a local anesthetic and for treating cardiac arrhythmias, has recently attracted attention among researchers for its application during arterial chemoembolization procedures, demonstrating its substantial analgesic properties[12]. Studies have shown that using lidocaine during arterial chemoembolization can reduce the incidence and severity of pain after surgery[40]. Moreover, Wu et al[12] reported that lidocaine was effective in 96% (361/376) of patients undergoing HAIC, resulting in an 85.6% reduction in VAS scores. This is particularly crucial for HAIC patients because uncontrolled pain can hinder their recovery and overall well-being. By alleviating pain, the multimodal analgesia regimen can contribute to a better recovery experience and improved patient outcomes.

The findings of this study demonstrated that the overall incidence of PONV and the total rate of adverse reactions were considerably lower in the multimodal group compared to the control group, highlighting the safety of this analgesia regimen. PONV is a common and distressing postoperative complication, and it can lead to delayed patient discharge, prolonged recovery, and increased healthcare expenses[41]. During the perioperative period, patients may experience frequent vomiting, making it difficult for oral medications to be absorbed effectively or maintain adequate blood concentrations, which can impact analgesia efficacy[42]. Moreover, patients who rely on opioids for chronic pain management often experience a range of adverse effects, including mild and manageable symptoms such as nausea, vomiting, sedation, and urinary retention, as well as more severe and complex health issues such as increased drug dependence, refractory constipation, and the potential risk of drug addiction[43]. Despite efforts to address PONV, its high incidence persists[44]. Therefore, reducing PONV is essential for patient comfort and early mobilization.

Furthermore, the findings of this study demonstrated a substantially higher level of patient satisfaction in the multimodal analgesia group compared to the conventional group, highlighting the importance of multimodal pain management strategies in improving patient outcomes. By effectively alleviating pain and minimizing adverse reactions, the multimodal analgesia regimen provided a more positive experience for patients. Research has also shown that a multimodal analgesia regimen incorporating parecoxib and sufentanil resulted in higher patient satisfaction in HCC patients undergoing TACE compared to the control group[37], further validating its clinical superiority. Therefore, it is evident that multimodal analgesia, compared to single-mode pain management methods, not only effectively reduces patients’ pain but also substantially decreases the incidence of adverse reactions, ultimately leading to a more comfortable and positive treatment experience for patients.

This study offers valuable insights into optimal pain management strategies after HAIC. The multimodal analgesia regimen presented can serve as a model for developing evidence-based guidelines for pain management in this patient population. However, we acknowledge several limitations. While this study provided insights into multimodal analgesia for pain management after HAIC treatment of advanced HCC, the assessment of pain and satisfaction levels was inherently subjective, relying on self-reported descriptions from individuals. Additionally, the study was limited in duration and did not address the long-term recovery effects. Additionally, the sample size of the study was relatively small, which may limit the generalizability of the results. Larger studies are needed to validate the current findings. The multimodal analgesic regimen, which included preemptive multimodal analgesia in this study, may differ from those applied at other medical centers or in different regions. Variations in multimodal pain regimens could influence the results. Additionally, only cases undergoing HAIC were included. Thus, the findings cannot be generalized to cases treated with other surgical procedures.

CONCLUSION

In summary, this study underscored the therapeutic importance of a multimodal analgesia approach in effectively managing postoperative pain in patients undergoing HAIC for advanced-stage HCC. By providing effective pain relief, minimizing adverse reactions, and enhancing patient satisfaction, this regimen represents a considerable advancement in cancer-related pain management, leading to improved patient outcomes and quality of life. It offers the HCC treatment team a practical and feasible pain management regimen, facilitating more individualized and accurate pain control. By promoting the concept of multimodal analgesia, healthcare institutions can improve their existing pain management protocols, strengthen interdisciplinary collaboration, and provide patients with more comprehensive and effective pain management services. This not only enhances patients’ treatment experience and satisfaction but also expedites postoperative recovery, reduces the occurrence of complications, and ultimately improves patients’ prognosis and well-being. This study has important implications for guiding future pain management strategies in similar surgical procedures. It encourages clinicians to fully consider the complexity of pain management during surgical planning and postoperative care, actively incorporating multimodal analgesia regimens to achieve comprehensive pain control. As multimodal analgesia regimens are applied and validated across more surgical fields, they are likely to emerge as a pivotal trend in future pain management, contributing to an overall improvement in the quality of medical care.