Introduction

Total knee arthroplasty (TKA) is commonly performed in patients with end-stage osteoarthritis or rheumatic arthritis of the knee to relieve joint pain, increase mobility, and improve quality of life. However, TKA is followed by moderate to severe postoperative pain and remains a significant clinical challenge [1]. Establishing optimal pain management requires a continuous re-evaluation of available data. After general or spinal anesthesia, the analgesic regimen often consists of epidural, intrathecal, and patient-controlled analgesia. Oral and intravenous opioids also continue to play a primary role in postoperative pain relief due to their effectiveness in relieving moderate to severe pain. However, because of their unfavorable side-effect profile [2], combinations of newer alternative therapies, mainly peripheral nerve blocks such as the IPACK and Adductor Canal Block, and periarticular injections have been used to replace frequent opioid use [3]. The purpose of this review was to summarize the data on the efficacy of commonly used modalities for the management of immediate postoperative pain following TKA.
Materials and methods

The literature was reviewed through four electronic databases: PubMed, Cochrane Library, and Embase. The search was performed in July 2022 by two authors (M.D. and T.R.). We evaluated studies published between 2017 and 2022 using the following search terms: “pain management” (title), “total knee arthroplasty” (title), and “pain control” (title). The titles, abstracts, and full texts of published studies were screened. As a result, only randomized controlled trials were included in this review. This entire process is depicted in Figure 1.
Results

The initial search yielded 415 articles. Eighty-seven relevant articles were ultimately selected based on relevance, recentness, quality of search and citations.

Discussion

Multimodal analgesia
With the exploration of the mechanisms underlying postoperative pain in total knee arthroplasty (TKA), it has been verified that both peripheral and central mechanisms are involved. Therefore, monotherapy alone is not enough to provide satisfactory postoperative pain relief after TKA. At present, multimodal analgesia is considered the optimal method for perioperative pain management of TKA through targeting numerous pain pathways. Multimodal analgesia includes preoperative, intraoperative, and postoperative analgesic regimens, aiming to maximize analgesic efficacy through the combination of several analgesic regimens while minimizing undesired adverse effects [4]. Adequate preemptive analgesia could prevent pain nociceptors from entering a state of hyperalgesia, and make acute postoperative pain easier to control, ultimately reducing opioid consumption. A preoperative IPACK block performed by an anesthetist and intraoperative local infiltration analgesia (LIA) that is performed by a surgeon near the conclusion of a procedure, directly prevent the generation and conduction of pain signals from the incision [5]. Several medicines are available for LIA during the surgery, which will be discussed in detail later. Postoperatively, multimodal analgesia includes pharmacologic agents, neuraxial anesthesia, and PNB, each of which will be described below. Compared with monotherapy, multimodal analgesia provides superior postoperative pain relief to promote the recovery of the knee and reduce opioid consumption and related side effects. Consequently, multimodal analgesia is the gold standard for perioperative pain control in patients undergoing TKA [6].

Preoperative analgesic regimens
Pre-emptive analgesia
Pre-emptive analgesia is defined as an antinociceptive intervention that starts before a surgical procedure. It is intended to prevent peripheral and central hypersensitivity, decrease the incidence of hyperalgesia, and reduce the intensity of postoperative pain. It also increases the pain threshold, contributing to the lower postoperative application of analgesic medication [7].

Corticosteroids
Corticosteroids are widely used in total knee arthroplasty (TKA) to relieve postoperative pain and prevent postoperative nausea [10,11]. Gasbjerg et al., [8] randomized 485 adult participants to receive 16 mg dexamethasone, given preoperatively and after 24 h, reduced morphine consumption (p < 0.017) at 48 h postoperatively. Chi Wing Chan et al., [9] evaluated that 16mg of dexamethasone given before TKA led to a reduction in postoperative pain (p = 0.005), and less opioid consumption (-6,4 mg; p = 0.025), with stronger quadricep muscle power, compared to 8 mg Dexamethasone. However, he did not observe long-term improvement in reduction in the pain and function of the knee.

NSAIDs
NSAIDs include a range of different analgesics, like commonly used ones: ibuprofen, diclofenac, ketorolac, and parecoxib. NSAIDs are widely used as one of the basic drugs in multimodal analgesia due to its proven reduction of opioid consumption [12-14]. Laoruengthana et al., [15] compared the analgesic effect between ketorolac and parecoxib. Both NSAIDs provide comparable analgesic effects, but the use of parecoxib is associated with significantly less blood loss (Hb g/dl -1.76 vs -1.35, p = 0.01).

Acetaminophen
The efficacy of intravenous acetaminophen in multimodal pain management in patients undergoing TKA is controversial. Murata-Ooiwa et al., [16] proved that even in the setting of multimodal pain management including the periarticular multidrug injection, intravenous acetaminophen provided better pain relief. However, O’Neal et al. [17] randomized 174 patients to receive that intravenous and oral acetaminophen did not provide additional analgesia in the immediate postoperative period when administered as an adjunct to multimodal analgesia. Despite all Lubis et al., [18] use of perioperative combination of paracetamol and ibuprofen proved that it reduced total morphine requirement (7.5 vs 15.0 vs 9.0; p = 0.391) and provided adequate pain control compared with the administration of a paracetamol or an ibuprofen injection alone.

Buprenorphine
Recently, transdermal buprenorphine patches have been used successfully for postoperative pain control after many kinds of surgery. Xu et al., [19] evaluated that the use of the transdermal buprenorphine TDB patch provides effective pain relief (VAS:7.6 vs 8.1 (p = 0.001)) and reduces the requirement for rescue morphine (4.6 vs 6.3 mg; (p < 0.05) without increasing the side effects in comparison with oral celecoxib during the early post-operative stage following TKA. Also, Londhe et al., [20] randomized 200 patients aged 60-75 years to receive the TDB patch is more efficacious in reducing postoperative pain (VAS: mean of 3 on day 1 to 1 on day 7; p = 0.0083) and can be safely used with fewer systemic side effects when compared to conventional analgesics.
Intraoperative analgesic regimens
Local infiltration analgesia (LIA)
LIA is performed by a surgeon intraoperatively without specialist equipment, commonly near the conclusion of the procedure [21]. Local anesthetic combined with opioids, antibiotics, NSAID, or epinephrine are injected into periarticular regions, including the posterior capsule, collateral ligaments, capsular incision, the quadriceps tendon, and subcutaneous tissues, which directly prevents the generation and conduction of pain signals from the incision. Common LIA cocktails are listed in Table 1.
As shown in the table there is still no consensus on the optimal composition of LIA. Multimodal cocktail injections comprising corticosteroids are the most suggested adjuvant (Tab. 1). Nevertheless, Peng et al., [46] demonstrated that the addition of betamethasone to an LIA has no additional effectiveness.
Also, using liposomal bupivacaine did not bring significant clinical benefit over the standard of care in TKA [47–50]. However, Dysart et al., [51] randomized 139 patients to receive that LIA with 266 mg liposomal bupivacaine plus bupivacaine hydrochloric was associated with a 91% reduction in opioid consumption (p = 0.009) and pain intensity (p = 0.142) after TKA compared with bupivacaine hydrochloric alone.
Over recent years, different researchers have added different adjuvants to LIA cocktails.
Not all are equally effective in relieving postoperative pain. Adding morphine [29,31,39,40] or epinephrine [41,42] into an analgesic cocktail of LIA does not improve early pain relief or accelerate functional recovery or provide clinical benefits for TKA patients.
Recent studies have shown that LIA combined with ACB [24,25] or FNB [1] has addictive effects on pain relief and opioid consumption after TKA. On the other hand, Mayr et al., [43] evaluated that there is no significant difference in pain relief comparing LIA to continuous peripheral nerve blocks in perioperative pain management. However, Wang et al., [44] suggested that a visualized nerve block, performed by a surgeon, through a minimally invasive far medial-subvastus approach distal to the adductor canal, combined with LIA, is more effective than simple per-articular infiltration analgesia in providing pain relief (p < 0.05) after TKA.
There is no consensus on the optimal timeframe of periarticular LIA in TKA. Laoruengthana et al., [45] revealed that postoperative pain reduction and the functional recovery of TKA with early (just after the knee arthrotomy) and late (before prosthetic implantation) LIA administration were not significantly different.
As an essential component of multimodal analgesia approaches after TKA, LIA can be classified into peri-articular injections and intra-articular injections according to administration techniques. Cheng et al., [30] randomized 60 patients to receive that the peri-articular injection had a superior performance of pain relief (NRS:0.68 vs 2.63; p <. 0.001) and improvement of range of motion to the intra-articular injection.
However, among the patients undergoing TKA, those who received intraoperative LIA, improved pain scores and comparable satisfaction levels, with reduced total narcotic consumption in the early postoperative period [32-38].

IPACK block
The IPACK – Ultrasound-guided infiltration of local anesthetic between the interspace between the popliteal artery and capsule of the knee provides effective motor-sparing knee analgesia for total knee arthroplasty [52,53]. Recent studies have shown that IPACK combines with ACB has additive effects on pain relief and opioid consumption after TKA [23,54-56]. Kim et al., [23] randomized 86 patients to receive that the addition of IPACK and ACB to PAI significantly improves analgesia (NRS -3.5 vs -1.0; p < 0.001) and reduces opioid consumption (p = 0.005), compared with PAI alone. On the other hand, Kampitak et al., [57] evaluated that IPACK did not provide any superior postoperative analgesia or improvement in immediate functional performance. However, it resulted in lower opioid consumption (0.0 vs 0.2; p = 0.008) postoperatively when compared with intraoperative PAI. Vichainarong et al., (58) added IPACK to LIA and continuous ACB and found that it did not reduce postoperative opioid consumption or improve analgesia.
These studies suggest that the IPACK block performed by an anesthesiologist is similar to LIA performed by a surgeon and might be used interchangeably.

Postoperative analgesic regimens
Peripheral Nerve Block
Peripheral nerve blocks are widely used for surgical anesthesia as well as for both postoperative and nonsurgical analgesia. But motor weakness is the most sensitive objective indicator of functional recovery after TKA. The sciatic nerve block [22,59] is an effective adjunctive technique for early postoperative pain control, without an increase in motor weakness. Adductor canal blocks are an alternative to femoral nerve blocks [60,61] because they do not impact quadricep strength. On the other hand, Lim et al., [62] did not find statistically significant differences in analgesic effects, quadricep strength, or functional recovery postoperatively between ACB and FNB.
ACB theoretically does not have enough analgesic effects on posterior sensory nerves. LIA increased its analgesic effect on the posterolateral knee. LIA combined with ACB reduced opioid requirements [63-65]. On the other hand, Meftah et al., [66] compared ACB to LIA and showed there was no difference (p = 0.91) regarding the accumulative daily converted morphine equivalent consumption or total consumption. Kampitak et al., [67] revealed that an obturator nerve block or a tibial nerve block combined with continuous ACB, and LIA was superior to ACB and LIA alone in improving analgesia (p = 0.006), opioid consumption (3.4 vs 6.0; p < 0.001) and functional outcomes in the immediate postoperative period after TKA. Choi et al., [68] concluded that the addition of magnesium to local anesthetic in ACB decreases pain scores (VAS:5.1 vs 3.5; p = 0.000) and opioid consumption (33.2 vs 21.3; p = 0.003), without increasing nausea when compared with ACB with local anesthetic alone. Biswas et al., [69] suggested an improved analgesic profile in the first 48 hours postoperatively when both an adductor canal block and low-dose intrathecal 100 mcg morphine are added to local infiltration analgesia.
Wang et al., [70] explored the efficacy of two unique combinations of nerve blocks on postoperative pain and functional outcome after TKA. He concluded that adding a sham obturator nerve block, a sham lateral femoral cutaneous nerve block, and a sham lateral femoral cutaneous block to ACB and the IPACK block reduced morphine consumption (11.2 vs 17.2; p = 0.001) compared to ACB and IPACK alone. However, the absolute change in morphine consumption, VAS scores, and QoR-15 scores did not exceed minimal clinically important differences. Similarly, Li et al., [71] randomized 200 patients and received that combining ACB with both an iPACK and a lateral femoral cutaneous nerve block is an effective method for decreasing early postoperative pain (p < 0.05) in TKA without increasing complications or affecting early rehabilitation.

Continuous peripheral nerve block
More and more reports have appeared in recent years that single-shot PNB provides effective analgesia in the first 24 hours after TKA, but the duration of analgesia does not cover the entire period of moderate to severe pain. That is why recent studies emphasize continuous PNB, especially ACB [72] because continuous FNB impaired mobilization capability due to the weakness of the quadricep muscle. [73-75].
There is a growing body of evidence in favor of continuous ACB [76], especially combined with IPACK [77] or LIA for TKA, because it provides superior ambulation, lower pain scores, faster discharge, and greater patient satisfaction when compared to epidural anesthesia [78,79]. On the other hand, Elkassabany et al., [80] randomized 156 patients to receive that there were no benefits for a continuous adductor canal block for 48 hours in terms of reducing the number of patients with moderate pain and improving the quality of pain management.
A continuous adductor canal block provides postoperative analgesia while preserving quadricep strength. However, there have been inconsistencies regarding the optimal location for a continuous catheter block. Lee et al., [81] showed that a continuous femoral triangle, a proximal adductor canal, and distal adductor canal blocks in the setting of periarticular local anesthetic infiltration provide comparable postoperative analgesia after TKA. Also, Chuan et al., [82] showed that there were no differences in immediate postoperative functional mobility, analgesia, and opioid consumption provided by catheters inserted into the femoral triangle or adductor canal compartment.
Kim et al., [83] compared two methods of insertion of a catheter for a continuous nerve block. He randomized 70 patients to receive that the catheter-over-needle method was able to shorten the procedure time while reducing the incidence of leakage at the catheter insertion site to the catheter-through-needle method (p < 0.5), and showed similar effects in postoperative pain management.
Recently some researchers have added different adjuvants to local anesthetics used for peripheral nerve blocks. Turner et al., [84] in his randomized, controlled, equivalency trial compared a multimodal single-injection adductor canal block (20 mL of 0.25% bupivacaine, 1.67 mcg/mL of clonidine, 2 mg of dexamethasone, 150 mcg of buprenorphine, and 2.5 mcg/mL of epinephrine) with a continuous adductor canal block (20 mL 0.25% of bupivacaine injection with 2.5 mcg/mL of epinephrine followed by an 8 mL/h infusion of 0.125% bupivacaine continued through postoperative day 2) and came to the conclusion that a multimodal single-injection adductor canal block provides equivalent analgesia (NRS:5.5 vs 5.7) for up to 36 hours after block placement when compared to a continuous adductor canal block. On the other hand, Lee et al., [85] randomized 177 patients to receive that a single injection of ACB, with and without dexamethasone, is non-inferior to ACB catheters in 24-hour opioid consumption (24.2 vs 21), and may be an attractive option for early- discharge, fast-track TKA.
Perioperative regional anesthesia protects from persistent postsurgical pain (PPSP) and improves outcomes after TKA. Bugada et al., [86] randomized 563 patients to conclude that continuous regional anesthesia (an epidural or a peripheral nerve block) provided analgesic benefits for up to 1 month post surgery but did not influence PPSP at 6 months (21.6% of patients experienced PPSP). Better pain control at 1 month was associated with reduced PPSP compared with a single shot peripheral nerve block.

Alternative pain management techniques
The use of complementary and alternative medicine has become popular worldwide over recent years. Mishra et al., [87] evaluated that conventional genicular nerve radiofrequency ablation (GN-RFA) of the superior lateral, superior medial and inferior medial genicular nerves, when performed before TKA, did not provide any clinically significant pain relief or improvement in functional status at 2 or 6 weeks postoperatively. Thijs et al., [88] randomized sixty patients to receive that postoperative computer-assisted cryotherapy (CAC) can be of added value in patients following an outpatient surgery pathway for TKA, resulting in reduced experienced pain (NRS: 0.9 vs 0.7; p = 0.008) and opioid consumption (47 vs 83; p = 0.001) during the first postoperative days. Acupuncture-related remedies, such as nonpharmacological treatments, have been shown to relieve pain through mechanisms that increase β-endorphin and reduce the neurotransmission of substances. P. Huang et al., [89] randomized 82 patients to receive that low-level laser acupuncture gradually reduced postoperative pain intensity (p = 0.01) and morphine consumption (p < 0.05) within the first 72 h after TKA for osteoarthritis. Low-level laser acupuncture may have benefits as an adjuvant pain management technique for clinical care. However, Petersen et al., [90] did not support the addition of acupuncture to routine rehabilitation.

Summary

With the aging of the population, there will be an increasing number of elderly patients receiving TKA. Perioperative pain management in patients undergoing TKA is very important to improve rehabilitation, patient satisfaction, and overall outcomes. Furthermore, surgeons together with anesthesiologists must decide on perioperative pain management after TKA, taking into consideration each patient individually. At present, multimodal analgesia is the optimal analgesic regimen for TKA. Multimodal analgesia could improve perioperative pain control and patient satisfaction through the combination of several analgesic regimens while reducing opioid consumption and opioid-related adverse effects. However, the optimal protocol of multimodal analgesia requires further investigation in the future.

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