Clinical applications of periarticular cocktail drug injection for unicompartmental knee arthroplasty: A narrative review

Local anesthetics

Local anesthetics serve as the primary components of cocktail drugs, with commonly used agents including ropivacaine and bupivacaine. Chen et al. ¹⁴ demonstrated that incorporating bupivacaine into cocktail drugs for injection facilitates postoperative pain control, enables early mobilization, and reduces hospital stay in joint replacement patients. A study by Nakasone et al. ¹⁵ revealed that using bupivacaine as the local anesthetic component in cocktail drugs provides effective analgesia and supports the achievement of enhanced recovery goals. To prolong the duration of action, liposomal bupivacaine has also been incorporated into cocktail drugs, theoretically extending postoperative analgesia to 72 h. ¹⁶ Liposomal bupivacaine has been reported to exhibit a prolonged duration of action and reduced peak plasma concentration compared to conventional bupivacaine. ¹⁷

However, Bowen et al. ¹⁸ found that while liposomal bupivacaine achieves comparable analgesic effects, its high cost suggests that surgeons and hospitals should consider it a potential area for cost savings. A comparative cohort study by Danoff et al. ¹⁹ demonstrated that although bupivacaine in cocktail drugs provides certain pain control benefits, ropivacaine is preferred due to its lower cost and fewer adverse effects. Weston-Simons et al. ²⁰ reported that adding ropivacaine to cocktail drugs in knee arthroplasty results in effective postoperative pain management, facilitating early rehabilitation. Ropivacaine exhibits lower central nervous system toxicity and, at low doses, selectively blocks sensory nerves without impairing motor function. This property makes it suitable for patients requiring early postoperative functional exercise. ²¹ A review by King et al. ²² indicated that ropivacaine’s motor nerve blockade effect is dose-dependent. Studies evaluating concentrations between 0.25% and 0.75% suggest that higher concentrations provide superior pain relief but may increase the risk of nausea and vomiting. Currently, ropivacaine is typically diluted with normal saline to approximately 0.1–0.25% for clinical use, though specific ratios and dosage vary based on individualized needs.

Corticosteroids

Corticosteroids effectively suppress the release of inflammatory factors, reducing edema and exudation caused by inflammatory responses. They can decrease the sensitivity of peripheral nociceptors and neural excitability, thereby alleviating postoperative pain in knee arthroplasty patients. ²³ When using corticosteroids clinically, caution is required because of concerns regarding potential infection risk, particularly with systemic administration. However, in cocktail drug therapy, corticosteroids are applied locally, which results in lower systemic exposure compared with systemic administration. Zhong et al. ²⁴ found that adding corticosteroids to cocktail drugs significantly enhanced analgesic effects and promoted early rehabilitation without increasing postoperative infection rates.

Common corticosteroids used in cocktail drugs include dexamethasone, betamethasone, triamcinolone acetonide, and methylprednisolone. Wang ²⁵ observed that adding dexamethasone to cocktail drugs in joint arthroplasty reduced opioid consumption and decreased postoperative nausea and vomiting. Liu et al. ²⁶ evaluated the efficacy and safety of betamethasone in cocktail drugs for UKA, demonstrating its effectiveness in providing early acute analgesia and improving knee function recovery without elevating complication rates. In a controlled study using UKA conducted by Ng et al., ²⁷ the addition of triamcinolone acetonide to LIA reduced postoperative pain and inflammatory response, facilitated early recovery of knee function, and was associated with no major complications. Kulkarni et al. ²⁸ incorporated methylprednisolone into cocktail drugs and found it effectively relieved early postoperative pain while accelerating knee flexion recovery.

The study confirmed that the use of corticosteroid in the cocktail drugs for UKA does not increase inflammatory complications by monitoring inflammatory markers (CRP and ESR).^26–28 Although current clinical evidence does not strongly associate local corticosteroid use with significant changes in wound drainage, periprosthetic joint infection rates, or wound healing speed, local administration is considered relatively safe. However, injection sites should be carefully selected to avoid direct needle contact with cartilage tissue.

Sympathetic nervous system modulators

Sympathetic nervous system modulators play a regulatory role in cocktail drug formulations by modulating sympathetic nerve activity, improving blood circulation, and prolonging the intensity and duration of analgesic effects. ²⁹ Commonly used agents include epinephrine and dexmedetomidine.

Edinoff et al. ³⁰ demonstrated that when used as an adjunct in LIA, epinephrine constricts small blood vessels around the knee joint, slowing the absorption of cocktail drugs by surrounding tissues. Essving et al. ¹² confirmed its efficacy through a cohort study of epinephrine administered as part of a cocktail therapy regimen for UKA. Chareancholvanich et al. ¹³ also confirmed that this prolongs drug retention in the surgical area, enhancing and extending the analgesic effect of nerve blockade. Nikhar et al. ³¹ reported that adding dexmedetomidine to nerve blocks significantly increased the duration of motor blockade, sensory blockade, and analgesia, thereby improving the efficacy and longevity of cocktail drugs. Emerging evidence suggests that magnesium ions may also indirectly reduce excessive sympathetic nervous system activation. ³² In a study by Wang et al., ⁹ the addition of magnesium sulfate (MgSO₄) to traditional cocktail drugs markedly extended analgesia duration and reduced opioid consumption.

Wyns et al. ³³ highlighted that chronic pain patients often exhibit sympathetic nervous system dysregulation. Prolonged stress not only exacerbates pain but also contributes to sleep disturbances and mood disorders. Appropriate modulation of sympathetic activity may improve sleep, mood, and overall quality of life.

Analgesic agents

Analgesic agents are primarily used to alleviate pain of varying intensities. Depending on the type and severity of pain, commonly used options include opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and selective COX-2 inhibitors. Burda et al. ³⁴ demonstrated that the rational use of analgesic agents significantly improves patient comfort and plays a crucial role in postoperative recovery. However, the trend in selecting analgesic agents for cocktail drugs has evolved over time, with a growing emphasis today on multimodal and opioid-sparing analgesic strategies.

Frequently employed NSAIDs include flurbiprofen axetil and ketorolac. In a cohort study of joint arthroplasty, Wang et al. ³⁵ incorporated flurbiprofen axetil into cocktail drugs, revealing that it markedly enhanced analgesic efficacy and improved patients’ sleep quality. Laoruengthana et al. ³⁶ observed that adding ketorolac to cocktail drugs resulted in superior postoperative knee flexion and straight-leg raising compared to controls, achieving effective analgesia without adverse effects. Another study comparing the selective COX-2 inhibitor parecoxib with ketorolac found comparable analgesic outcomes. ³⁷ However, caution is warranted: research indicates that NSAIDs (e.g., ketorolac) in cocktail drugs for patients with chronic kidney disease (CKD) undergoing knee arthroplasty may increase the risk of acute kidney injury. ³⁸

Common opioids such as morphine and fentanyl have also been utilized. Luo et al. ³⁹ reported that cocktail drugs containing morphine provided superior and longer-lasting analgesia compared to ropivacaine alone, while also improving sleep quality and accelerating rehabilitation. Campos et al. ⁴⁰ found that fentanyl as an adjunct in cocktail drugs enhanced postoperative pain control, reduced the need for sustained opioid use, and did not increase postoperative bleeding. Current perioperative analgesia strategies increasingly emphasize opioid-sparing approaches in order to minimize opioid-related adverse effects such as nausea, sedation, and respiratory depression. Consequently, the routine inclusion of opioids in cocktail drugs is not universally recommended. Their use should be considered selectively and balanced against the broader goal of minimizing perioperative opioid exposure.

Other adjunctive agents

In cocktail drug formulations, additional agents such as tranexamic acid (TXA) and sodium bicarbonate (NaHCO₃) play significant roles. Tranexamic acid reduces postoperative bleeding by inhibiting fibrinolysis, thereby improving surgical outcomes. ⁴¹ A systematic review and meta-analysis by Weng et al., ⁴² incorporating nine clinical studies involving 744 patients, demonstrated that adding TXA to cocktail drugs during UKA significantly reduced perioperative transfusion rates, primary blood loss, postoperative drainage volume, hidden blood loss, and total blood loss compared to control groups. Wiktor et al. ⁴³ found that local injection of TXA in UKA decreased perioperative blood loss without increasing wound complication risks, while also shortening hospital stays. However, Moorthy et al. ⁴⁴ reported that although TXA effectively reduced bleeding in UKA patients, it did not significantly improve postoperative knee function. Zhu et al. ⁴⁵ incorporated NaHCO₃ as an adjunct in UKA cocktail drugs, showing that this modified formulation prolonged postoperative analgesia, reduced analgesic consumption, and enhanced functional recovery. These findings were corroborated by similar research from Wang et al. ⁹

Intraoperative local infiltration

In UKA procedures, the predominant method for administering cocktail drugs is periarticular local infiltration. Studies on injection sites reveal that knee joint tissues contain abundant nociceptors. ²⁹ Particularly pain-sensitive structures include the patellar tendon, infrapatellar fat pad, lateral collateral ligament insertion, iliotibial band insertion, suprapatellar bursa, and posterior capsule (Figure 3). Current evidence supports injections into the lateral capsule, collateral ligaments, tendon sheaths, quadriceps tendon, fat pad, and subcutaneous tissues. ⁴⁶ Tran et al. ⁴⁷ provided anatomical confirmation of neural distribution within the posterior capsule, theoretically supporting posterior capsular injections for neural blockade.OPEN IN VIEWER

Among the currently available published literature, the posterior capsular injection (PCI) has been predominantly studied in the context of TKA. There is a notable paucity of randomized controlled trials and prospective cohort studies specifically evaluating the role of PCI preservation in UKA. The study by Fang et al. ⁴⁸ suggests that PCI during TKA can help alleviate postoperative knee pain, but it should avoid the central area of the posterior capsule to prevent proximity to the popliteal vascular and nerve bundles. Schwartz’s ⁴⁹ review also indicates that the LIA area covering the posterior capsule is gradually being adopted by more people. However, the randomized controlled trial conducted by Pinsornsak et al. ⁵⁰ shows that PCI in TKA does not significantly improve postoperative pain or the use of opioids, and there is no significant difference compared to using only standard peri-articular infiltration. These different research results remind us to be cautious when choosing PCI, and to combine the surgeon’s familiarity with the anatomical structure to avoid damaging blood vessels and nerves, and avoid injecting excessive amounts of medication.

Currently, in the current surgical practice, there is no unified standard for injection volume and specific sites. ⁵¹ Most available data are derived from TKA populations, and direct UKA-specific comparative studies are scarce. The potential role of PCI in UKA is primarily based on anatomical considerations and extrapolations from TKA experience. However, its clinical efficacy and safety in UKA cohorts require further studies. Based on the current understanding of knee joint pain receptors distribution, the following injection scheme may be considered: after the osteotomy step and before the implantation of the artificial prosthesis, ensure safety and consider injecting into the posterior capsule (Figure 4). Then, sequentially inject into the anterior capsule, the quadriceps tendon, the infrapatellar fat pad, and the attachment points of the ligaments.OPEN IN VIEWER

Combine other analgesia methods

Guided by the ERAS guidelines, various different analgesic methods have been developed. Among these, adductor canal block (ACB) has been investigated in both TKA and UKA populations. Clinical studies in UKA have shown that ACB can reduce postoperative pain, decrease opioid usage, without significant reduction in quadriceps muscle strength was observed.^52,53

Another technique that has gained attention in knee arthroplasty is the infiltration between the popliteal artery and capsule of the posterior knee (iPACK) block. Poonam et al. ⁵⁴ suggested that iPACK block has the potential to alleviate postoperative pain in TKA. Zhang et al. ⁵⁵ and Bohumilik et al. ⁵⁶ both indicated that iPACK block can enhance the analgesic effect in the posterior part of the knee joint after TKA and accelerate pain relief. However, in the currently available literature, iPACK block is almost exclusively studied in the context of TKA, and there are few reports specifically evaluating the effect of iPACK block in UKA as an operation type. The application of iPACK block in UKA should be considered largely extrapolated from TKA literature. While its anatomical rationale suggests potential benefit for posterior knee pain control, its effectiveness and safety in UKA remain to be validated by future clinical studies.

The surgical trauma of UKA is less than that of TKA, and the selection of analgesic methods can be determined based on the actual situation. If the pain threshold is normal, there is no significant previous chronic knee pain, the surgical period, and the postoperative pain score remains within an acceptable range, a cocktail drug LIA can be used alone during the surgery. For patients with anticipated low pain tolerance or intolerance to specific analgesics, the adjunctive use of an ACB or iPACK block may be considered to improve surgical satisfaction. To clarify the differences in evidence sources for these techniques (Table 1), summarizes the currently available UKA-specific and TKA-derived evidence for PCI, ACB, and iPACK block.

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Table 1.

Comparison of UKA-specific and TKA-derived evidence for PCI, ACB, and iPACK block.

Technique	UKA-specific evidence	Evidence derived from TKA	Interpretation for UKA
PCI	Limited direct UKA studies identified	Several TKA studies suggest PCI may improve posterior knee analgesia as part of periarticular infiltration protocols48–50	Potential adjunct technique based on anatomical rationale and TKA experience; clinical value in UKA remains uncertain
ACB	Clinical studies in UKA demonstrate reduced pain scores and opioid use while preserving quadriceps strength52,53	Widely studied in TKA as part of multimodal analgesia protocols	Relatively stronger evidence base among regional techniques discussed for UKA
iPACK block combined with LIA	Direct UKA-specific evidence currently very limited	Multiple TKA studies report improved posterior knee analgesia when combined with LIA or other blocks54–56	Application in UKA mainly extrapolated from TKA literature; requires further validation

Differences in drug formulations

Compared to UKA, TKA involves greater surgical trauma, more extensive tissue exposure, and larger osteotomy areas, resulting in more severe pain. Thus, TKA cocktail drugs emphasize multimodal analgesia and synergistic effects. ⁶² These regimens commonly incorporate long-acting local anesthetics, corticosteroids, and adjunctive agents (such as epinephrine or morphine) to synergistically alleviate both inflammatory responses and acute postoperative pain.

In contrast, UKA’s smaller trauma profile warrants a focus on targeted local analgesia and minimizing systemic side effects. Since the contralateral compartment retains native cartilage, reducing or avoiding corticosteroids may be preferable. NSAIDs may be considered for inclusion in the formulation to control local inflammatory responses while potentially reducing opioid consumption.

Differences in drug dosages

Wiktor et al. ⁴³ retrospectively analyzed UKA cocktail drugs volumes, noting they are typically half those used in TKA, as excessive fluid may increase wound drainage risks. TKA’s greater postoperative pain often necessitates higher total drug doses. According to the systematic review by King et al., ²² it may be suggested that for TKA procedures where ropivacaine is selected as the local anesthetic, concentrations of (0.25%∼0.5% & 2.5∼5 mg/ml),total doses of approximately (150–200 mg) could be considered. The appropriate use of low-dose corticosteroids may also be recommended. At present, there is no research that directly compares the systematic differences in the local anesthetic concentration design between UKA and TKA. However, by combining the relevant research on TKA, it can be inferred that for UKA, lower ropivacaine concentrations (0.1%∼0.25% & 1∼2.5 mg/ml) or reduced total doses (100–150 mg), minimal corticosteroids, and lower NSAID doses align with the “minimum effective dose” principle. This approach mitigates postoperative nausea or cardiovascular risks while supporting rapid recovery. Dosage adjustments should account for individual pain tolerance and clinical context.

Mechanism research and clinical application situation

Existing evidence indicates that LIA and regional anesthesia techniques can mitigate postoperative stress, reduce inflammatory responses, and suppress cytokine release. However, these findings are predominantly extrapolated from TKA and THA studies, with a notable paucity of independent research focusing specifically on UKA. Kuchálik et al. ⁶³ performed LIA with a cocktail of ketorolac and local anesthetics during THA surgery. They found that the interleukin-6 (IL-6) and CRP levels in the experimental group decreased compared to the control group, showing a better anti-inflammatory effect. Wang et al. ⁶⁴ conducted a randomized controlled trial on TKA in which glucocorticoids were incorporated into the cocktail drugs. The results demonstrated that, 24 h postoperatively, the experimental group exhibited significantly lower levels of IL-6 and CRP, reduced pain intensity, and improved knee range of motion compared to the control group. However, it should be noted that the efficacy of cocktail drugs stems from the combination of several pharmacological mechanisms. Glucocorticoids, NSAIDs, and local anesthetics each exert their effects through different inflammatory pathways. The analgesic effect itself can also reduce postoperative stress responses and the release of cytokines. Therefore, the specific pharmacological mechanism of the cocktail drugs should be determined based on different drug formulations. Evidence specific to UKA remains limited and requires further investigation.

In clinical studies, Meier et al. ⁶⁵ found that the use of cocktail drugs for LIA during UKA significantly reduced the pain scores of patients during postoperative activities. In the UKA controlled experiment conducted by Essving et al., ¹² the experimental group that used cocktail drugs for LIA experienced a significant reduction in pain, a shorter hospital stay, and improved early knee joint range of motion. The studies by Liu et al. ⁶⁶ and Lan et al. ⁵³ also consistently demonstrated that the use of cocktail drugs for LIA in UKA can reduce the frequency of analgesic drug use and improve the early range of knee joint movement, without affecting motor function. Luo et al. ³⁹ further reported that cocktail drugs formulations can extend analgesic efficacy up to 48 h postoperatively, enhance sleep quality, and accelerate rehabilitation without increasing adverse events. The research findings by Salwan et al. ⁶⁷ indicate that the cocktail drugs therapy can effectively reduce opioid requirements and shorten the average hospital stays. Furthermore, current evidence reveals no significant negative impact on postoperative infection rates or wound healing time. In summary, existing studies suggest that periarticular cocktail drugs injections may improve postoperative pain control in UKA.

Drug safety and precautions

Cocktail drugs are administered via local injection and generally exhibit favorable applicability and safety profiles. However, in clinical practice, it is not advisable to apply a uniform formulation across all patients; instead, treatment should be tailored by comprehensively considering individual patient conditions and the distinct pharmacological characteristics of the drugs involved.

As the primary component in cocktail drugs combinations, local anesthetics are administered at higher doses during LIA, necessitating vigilance against the risk of local anesthetic systemic toxicity (LAST). Current research supports limiting the total ropivacaine dose to approximately 3 mg/kg during LIA, with a maximum total volume not exceeding 200∼225 mg. ⁶⁸ The maximum tolerable dose is influenced by patient weight, concomitant epinephrine use, and factors such as multiple injections within a short timeframe or overlapping nerve blocks. During and following LIA, heightened monitoring of patient consciousness, hemodynamics, and cardiac rhythm is essential. Previous reports indicate that although the incidence of LAST associated with LIA is considered low, it is not negligible, particularly in elderly or frail patients and in situations where multiple regional anesthesia techniques are combined. In cases of suspected LAST, treatment should follow established lipid rescue protocols. Current guidelines from the American Society of Regional Anesthesia and Pain Medicine (ASRA) recommend an initial intravenous bolus of 20% lipid emulsion at approximately 1.5 mL/kg, followed by a continuous infusion of 0.25 mL/kg/min. If cardiovascular instability persists, the bolus may be repeated and the infusion rate increased, while respecting recommended maximum cumulative doses. Lipid emulsion should therefore be immediately available wherever large doses of local anesthetics are administered. ⁶⁹ This precaution is particularly important when periarticular infiltration is combined with additional regional blocks, which may increase the cumulative dose of local anesthetics.

In UKA, a portion of the native articular cartilage is retained, which has raised theoretical concerns regarding potential chondrotoxicity associated with certain agents used in cocktail drugs, particularly local anesthetics and corticosteroids.^70,71 It should be emphasized that most experimental and clinical evidence describing chondrotoxic effects originates from studies involving intra-articular exposure, where drugs are directly in contact with cartilage tissue. In contrast, LIA is typically administered in peri-capsular and soft-tissue structures rather than directly within the joint cavity. Although these findings justify cautious drug selection in UKA, the clinical significance of chondrotoxicity associated with periarticular infiltration remains uncertain. At present, there is limited direct evidence linking periarticular cocktail injections in UKA to adverse outcomes such as cartilage deterioration or increased revision risk. Consequently, these concerns should be interpreted primarily as precautionary considerations rather than confirmed clinical risks. Epinephrine is commonly added at low concentrations to induce local vasoconstriction, thereby reducing bleeding and delaying systemic absorption of local anesthetics, which prolongs analgesic duration. However, studies have shown that certain high-volume regimens are associated with an increased incidence of early incision exudation, ⁷² suggesting that high-dose or high-concentration protocols should be avoided. NSAIDs may precipitate acute renal impairment by inhibiting renal prostaglandin synthesis, ³⁸ especially elderly patients, those with hypovolemia, or those with pre-existing chronic kidney disease. The use of cocktail drugs should be considered to carry potential nephrotoxicity, and thus they should be administered with caution or at reduced dosages. Existing evidence from broader arthroplasty populations suggests that TXA can be used safely in many patients when appropriate perioperative thromboprophylaxis protocols are followed. ⁷³ However, these findings should not be generalized to all patients with thrombotic risk factors. Careful individualized risk assessment remains essential. In particular, patients with recent thromboembolic events, active thrombosis, or severe renal dysfunction may require additional caution or avoidance of TXA according to existing clinical recommendations.

Theoretically, any drug carries potential safety risks; however, the extent of available evidence and degree of clinical attention vary considerably among different agents. Thus, rather than attempting to exhaustively list all possible adverse effects for every drug, this section focuses on briefly discussing several of the more commonly referenced drugs mentioned above, with the aim of reinforcing awareness regarding drug safety.

Evidence directly in UKA

Evidence directly derived from UKA remains limited but informative. Several UKA-specific trials and cohort studies have reported that periarticular LIA using cocktail drugs is associated with reduced postoperative pain, decreased opioid consumption, and facilitated early functional recovery [11, 12, 52, 53, 65, 66, etc.]. Survey-based data also indicate that periarticular injection is widely adopted in UKA practice, reflecting its perceived clinical utility among experienced surgeons. ¹¹ However, most UKA studies are single-center, involve relatively small sample sizes, and primarily focus on short-term outcomes. Therefore, its findings should be interpreted with caution.

Evidence extrapolated from TKA

Meanwhile, another portion of the pharmacological rationale and technical considerations for the use of cocktail drugs in UKA is extrapolated from studies conducted in TKA. Evidence from TKA consistently demonstrates that periarticular LIA can reduce postoperative pain, inflammatory response, and opioid requirements [9, 14, 19, 22, 39, 62, etc.]. Given the shared surgical field, innervation patterns, and periarticular anatomy, these findings provide a theoretical basis for application in UKA.

Expert inference

As the existing body of literature on UKA remains limited, leaving evidence gaps in certain areas, some of the proposed strategies inherently depend on expert inference. These include proposed modifications to injection sites, drug selection, and dosage adjustments to reflect the smaller surgical trauma and lower postoperative pain burden associated with UKA. Such inferences are supported by pharmacological principles, anatomical considerations, and accumulated clinical experience [30, 32, 47, 56, 68, 70, etc.], but they should not be interpreted as evidence-based recommendations. Further prospective UKA-focused studies are required to validate these assumptions.