Analgesic efficacy and safety of methylene blue combined with cocktail for periarticular infiltration following total knee arthroplasty: a prospective, randomized, controlled study

Abstract

Objective

This study aims to explore the analgesic effects and safety of periarticular injections of methylene blue (MB) combined with a cocktail formulation following total knee arthroplasty (TKA).

Methods

A total of 70 patients undergoing total knee arthroplasty were selected and divided into two groups based on the cocktail formula used for periarticular infiltration, including the methylene blue group (M group, n = 35) and the control group (C group, n = 35). Both groups underwent spinal anesthesia. At the end of the surgery, the M group received a 0.05% methylene blue combined cocktail for periarticular infiltration block, while the C group received a conventional cocktail infiltration block. Postoperatively, both groups used intravenous patient-controlled analgesia. Then, the rest and movement Numeric Rating Scale (NRS) scores, postoperative sufentanil consumption, postoperative inflammatory markers, and the occurrence of adverse reactions such as wound infection and poor wound healing were compared after postoperative 24 h, 48 h, 72 h, and 7-day, 14-day, 28-day between the two groups.

Results

The rest and during movement, NRS scores at postoperative 24 h, 48 h, 72 h, 7-day, 14-day, and 28-day were significantly lower in the C group compared with the M group (P < 0.05). The total sufentanil consumption at postoperative 72 h was less in the M group (98.9 ± 11.3 µg) compared to the C group (129.1 ± 12.3 µg) (P < 0.01). It also showed a lower IL-6 in the M group at postoperative 24 h and 72 h (P < 0.05). However, there were no significant differences in CRP levels between the two groups at 24 h and 72 h post-surgery (P > 0.05), and neither group experienced complications such as wound infection or poor wound healing.

Conclusion

Methylene blue combined with a cocktail can be safely used for local infiltration after knee arthroplasty, which reduces postoperative opioid consumption and suppresses the release of inflammatory factors. Moreover, it synergistically enhanced the local anesthetic analgesia and provided sustained pain relief for at least 4 weeks.

Introduction

Generally, total knee arthroplasty (TKA) is associated with significant trauma and severe postoperative pain. Hence, multimodal perioperative analgesia is advocated currently (Khaw et al. 2021), with periarticular cocktail injection as an important component of multimodal analgesia after TKA (Hannon et al. 2022a). Conventional cocktail analgesic regimens provide pain relief only within the first 24 h postoperatively (Hannon et al. 2022b), whereas patients undergoing knee replacement may experience pain for a duration of 1–3 months, and in some cases, the pain persists beyond 1 year (Kluger et al. 2022; Jørgensen et al. 2018). Poor early pain control may lead to central sensitization (Volcheck et al. 2023), causing acute postoperative pain to evolve into chronic pain (Kim et al. 2018).

It has shown that methylene blue (MB) possesses effective analgesic and anti-inflammatory properties in clinical treatment, with a prolonged duration of analgesia that may exist for 6 months (Wang et al. 2021). The primary mechanisms of its analgesic action include anti-inflammatory effects, blockade of sodium channels, antioxidant stress mitigation, and a direct dissolution of the myelin sheath (Lee and Han 2021; Lee et al. 2021; Li et al. 2022). Methylene blue, when combined with local anesthetics, has been used for intercostal nerve blocks, local infiltration at incision sites following lumbar fusion surgery, and paravertebral blocks. This combination has been shown to provide prolonged analgesia without any reported adverse reactions.(Yu et al. 2022). This study employs methylene blue combined with a cocktail for periarticular infiltration after TKA to explore the analgesic effects and safety of methylene blue post-knee replacement. It is the first to propose the combination of methylene blue and a cocktail for the postoperative analgesic treatment of TKA and concluded that the combination of the two has a long-term and safe analgesic effect. It may provide an effective strategy for the guidance of postoperative analgesia treatment of TKA.

Materials and methods

General information

Initially, patients with osteoarthritis of the knee scheduled for TKA were recruited at the Affiliated Hospital of Panzhihua University between March 2023 and September 2023 as subjects for this study. The screening criteria are as follows: inclusion criteria: ① patients aged 50 years or older, classified as ASA I-III by the American Society of Anesthesiologists, regardless of gender; ② Preoperative diagnosis of knee osteoarthritis; ③ scheduled for primary total knee arthroplasty; ④ able to independently complete the NRS pain scale and provide informed consent; ⑤ no history of psychiatric illness and demonstrating good compliance. Exclusion criteria: ① known allergy to any component of the cocktail formula; ② Severe cardiovascular or respiratory disease, preoperative opioid use, or use of anticoagulant or antiplatelet medications; ③ active peptic ulcer, recent gastrointestinal bleeding, severe varus or valgus knee deformity, or any central or peripheral neurological disorder; ④ severe renal impairment (serum creatinine > 200 µmol/L) or morbid obesity (BMI > 35 kg/m²); ⑤ presence of hematologic disorders, such as anemia, thrombocytopenia, or coagulation abnormalities; ⑥ contraindications to spinal anesthesia. Then a total of 70 patients were selected. They were divided into two groups randomly, including the methylene blue group (n = 35) and the control group (n = 35), which received an infiltration of either 0.05% methylene blue combined cocktail or conventional cocktail, respectively. The allocation results were kept confidential until the day of surgery when they were disclosed to the anesthesiologist and surgeon, who would not participate in subsequent research. This research was registered with the Chinese Clinical Trial Registry (Registration No.: ChiCTR2300068973) and approved by the Ethics Committee of the Affiliated Hospital of Panzhihua University (Ethics Approval No.: 2022–12–045). All eligible patients signed written informed consent prior to surgery.

Anesthesia and knee periarticular injection infiltration technique

Anesthesia technique

Upon entering the operating room, all patients were monitored for respiration, electrocardiogram (ECG), non-invasive blood pressure, and oxygen saturation. All patients received spinal anesthesia, with the puncture site between the 3rd and 4th lumbar vertebrae. After the successful puncture, 2 mL of 0.5% isobaric bupivacaine was administered with cephalad. The sensory block level was maintained above T10, and the patients were positioned supine. In this study, a total of 70 patients received subarachnoid (spinal) anesthesia 5 h.

Knee periarticular cocktail injection infiltration

All surgeries were performed by the same surgical team. The cocktail injection sites included the knee joint capsule, the origin and insertion points of the medial and lateral collateral ligaments, the deep band of the iliotibial tract, the quadriceps and patellar tendons, the peripatellar synovium, the infrapatellar fat pad, the subperiosteum, and the periarticular region of the knee. After the injections, the cocktail was allowed to infiltrate locally at the injection sites for a period of time, specifically after testing the prosthesis placement but before closing the surgical incision. The control group received a conventional cocktail injection, while the experimental group had 0.05% methylene blue added to the standard cocktail formula. The control group’s cocktail formula consisted of 100 mg of ropivacaine, 1 mL of compound betamethasone (7 mg), 0.2 mg of epinephrine, and saline, making up a total volume of 40 mL. Additionally, 20 mL of 0.2% ropivacaine was separately prepared for subcutaneous infiltration around the surgical incision.

Postoperatively, ketorolac 30 mg was administered TID for 3 days. A uniform intravenous analgesia pump was set up postoperatively for 72 h, delivering sufentanil 150 µg + granisetron 9 mg + saline = 150 mL; background dose: 1 mL/h, Patient-controlled analgesia (PCA): 5 mL, lockout interval: 30 min.

Outcomes

Primary outcomes

Postoperative pain was assessed using the Numeric Rating Scale (NRS) at rest and during movement at 24, 48, and 72 h, as well as on postoperative days 7, 14, and 28. Total sufentanil consumption within the first 72 h postoperatively was recorded as part of rescue analgesia. If a patient’s NRS score at rest reached 5 or higher, 5 µg of sufentanil was administered via IV PCA. Prior to study inclusion, patients were thoroughly instructed on the NRS scoring system and trained on the use of the PCA pump, ensuring they understood how to self-administer analgesia when needed.

Secondary outcomes

High-sensitivity hsCRP and IL-6 were measured by the immunoturbidimetry and immunochemiluminescence assay at 24 and 72 h postoperatively. Routine postoperative lower extremity vascular ultrasound examinations were performed, and postoperative adverse events and complications were recorded.

Statistical analysis

Data were analyzed using SPSS 21.0. Categorical data were expressed as counts and percentages and analyzed using the chi-square test. If more than 20% of the expected cell frequencies were less than 5, Fisher’s exact test was applied as an alternative. Continuous data were assessed for normality using the Shapiro–Wilk test. For normally distributed data, comparisons between groups were performed using the Student’s t-test. For non-normally distributed data, the Mann–Whitney U test was used to compare differences between groups. All statistical tests were two-tailed, and a P-value of < 0.05 was considered statistically significant.

Results

The comparison of general data

Initially, a total of 92 patients were recruited for this study. However, three patients were excluded due to severe obesity, two due to thrombocytopenia, five because they refused spinal anesthesia, and twelve declined to participate, leaving 70 patients in the final cohort, with no loss to follow-up (Fig. 1). There were no statistically significant differences in baseline characteristics between the two groups (P > 0.05), as shown in Table 1.

Fig. 1

Flow diagram of patient selection

Table 1 Patient baseline characteristics

Postoperative NRS scores at different time points

We also analyzed the postoperative NRS scores at different time points. It was shown that the postoperative NRS scores were significantly reduced at rest and during movement at 24 h, 48 h, 72 h, and 7 days, 14 days, 28 days (Fig. 2).

Fig. 2

Postoperative NRS at rest and during motion in both groups. The M group had markedly lower NRS than the C group. The values are shown as x̅ ± SD.*P < 0.05

Sufentanil consumption at 72 h postoperatively and postoperative inflammatory markers

It was shown that the M group showed a significant reduction in total sufentanil consumption at 72 h postoperative (Table 2). And the IL-6 levels at 24 h and 72 h were lower in the M group compared to the C group (P < 0.05). However, there was no significant difference in CRP between the two groups at 24 h and 72 h postoperative (Table 2).

Table 2 Postoperative 72 h Sufentanil consumption and inflammatory markers

Postoperative complications

Postoperatively, 5 patients in the M group and 7 in the C group experienced nausea and vomiting. In the C group, there was one case of intermuscular venous thrombosis on the surgical side. Neither group experienced complications such as wound infection, poor wound healing, hematoma, skin itching, or somnolence(Table 3).

Table 3 Comparison of postoperative complications

Discussion

It has been reported that the knee joint capsule, the origins and insertions of the medial and lateral collateral ligaments, the deep band of the iliotibial tract, tendons of the quadriceps and patellar tendons, peripatellar synovium, infrapatellar fat pad, and subperiosteum are densely populated with nociceptors (Ross et al. 2017). Therefore, total knee arthroplasty (TKA) patients experience considerable surgical trauma, with acute postoperative pain primarily resulting from damage to tissues such as skin, muscles, ligaments, and synovium during surgery. Between 24 and 48 h postoperatively, neocollagenesis occurs at the trauma site, peaking around 5–7 days postoperatively. To improve postoperative knee mobility, functional exercise is essential in the early postoperative period. Thus, effective and sustained analgesia is required.

Currently, perioperative analgesic regimens for TKA have limitations. Conventional cocktail infiltration provides analgesic effects that last less than 24 h postoperatively, and femoral nerve block may reduce the strength of the quadriceps femoris, increasing the risk of falls (Lützner et al. 2020). Furthermore, adductor canal block does not affect quadriceps strength but is compromised by catheter dislodgement when continuous pain relief is achieved via catheter placement (Fujino et al. 2023). Therefore, there is a clinical need for a perioperative analgesic regimen that not only alleviates acute postoperative pain but also provides sustained analgesia after TKA. Herein, we attempt to explore the effect of methylene blue combined with the conventional cocktail in periarticular infiltration blocks following TKA.

Research has confirmed that methylene blue combined with local anesthetics—when used for intercostal nerve blockade, local infiltration of incisions post-lumbar fusion surgery, and paravertebral blockade—extends the duration of analgesia (Yu et al. 2022). Its analgesic mechanisms mainly include anti-inflammatory actions, blockade of sodium channels, antioxidant stress reduction, and reversible demyelination of nerves at low concentrations (Lee and Han 2021; Li et al. 2022). Different concentrations of methylene blue (0.025%, 0.05%, and 0.1%) have all been shown to decrease pain scores in oral mucositis induced by cancer (Roldan et al. 2022). Herein, we used 0.05% methylene blue for periarticular infiltration of the knee joint. At 24, 48, and 72 h postoperatively, patients in the M group had lower NRS scores both at rest and during movement compared to the C group, along with a significant reduction in total sufentanil consumption, without any drug-related complications. These findings demonstrate that methylene blue can be safely combined with a conventional cocktail for periarticular infiltration blocks following TKA surgery. Research has shown that methylene blue-induced nerve demyelination typically repairs within 4 weeks, and this reversible myelin sheath damage is likely the primary factor contributing to sustained postoperative analgesia (Ji et al. 2022). Our 4-week follow-up revealed that NRS scores, particularly during movement, were lower in the M group, promoting better joint exercises and accelerating functional recovery.

Surgical trauma can stimulate monocytes and macrophages to synthesize and release IL-6. A study on total knee arthroplasty and unicompartmental knee arthroplasty showed that plasma IL-6 levels are closely related to the intensity of perioperative stimulation and the extent of tissue metabolic damage (Su et al. 2018). The inflammatory response is one of the main causes of postoperative pain (Sommer et al. 2018); trauma and pain stimulate the production of inflammatory factors, and the increase in inflammatory factors amplifies the pain effect, creating a vicious cycle (Ji et al. 2018). Methylene blue is a classic antioxidant with strong neuroaffinity, capable of mitigating inflammatory responses and oxidative stress through antioxidant enzymes Nrf2 and PRDX1 (Li et al. 2022). TKA involves significant surgical trauma and a severe perioperative inflammatory response. We measured inflammatory markers CRP and IL-6 at 24 h and 72 h postoperatively and found that IL-6 levels were significantly lower in the M group, confirming that combining methylene blue with the cocktail can reduce the inflammatory response.

The combination of methylene blue with the conventional cocktail raises concerns regarding potential drug interactions, the formation of new substances, and the possibility of toxic side effects. Methylene blue is known for its antioxidant and anti-inflammatory properties and has been used in various local anesthetic formulations without significant adverse reactions when used in low concentrations (e.g., 0.05%) (Lee and Han 2021). In this study, we added methylene blue to the standard cocktail at a concentration of 0.05%, a concentration commonly used in clinical applications for its beneficial effects on local anesthetics.

Methylene blue, at low concentrations, has been shown to have minimal systemic toxicity, and no significant adverse effects have been reported in combination with other local anesthetics, corticosteroids, or adrenergic agents like epinephrine. The pharmacological mechanisms of methylene blue primarily involve the inhibition of oxidative stress and the reduction of neuroinflammation (Lee and Han 2021; Li et al. 2022). At the concentrations used in this study, methylene blue is expected to be well-tolerated and to work synergistically with the cocktail components, enhancing their analgesic and anti-inflammatory effects without causing toxicity.

However, as with any new combination of drugs, we acknowledge the importance of monitoring for potential interactions and side effects. In our study, we did not observe any adverse reactions or significant complications related to the methylene blue cocktail. Future research, including larger clinical trials, would be necessary to further evaluate the long-term safety and any potential drug interactions or toxicities associated with this combination.

Conclusion

In conclusion, methylene blue combined with a conventional cocktail can be safely used for local periarticular infiltration analgesia after TKA, reducing postoperative opioid consumption and inflammatory response, and synergistically enhancing the analgesic effect of the conventional cocktail therapy with sustained pain relief of at least 4 weeks. However, as a new method of post-TKA analgesia, methylene blue combined with a conventional cocktail is relatively understudied, so more research is needed to guide its clinical application in the future.