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.