Post-TKA discomfort is a major clinical issue. Pain slows recovery, prolongs stay and increases costs [1]. An optimal analgesic regimen demands constant data analysis. Epidural, intrathecal and patient-controlled analgesia are used after general or spinal anesthesia. Oral and injectable opioids continue to treat moderate to severe postoperative pain. However, due to their poor side-effect profile [2], combinations of newer alternative therapies and variable oral analgesics such cyclooxygenase 2 (COX-2) inhibitors, Nonsteroidal Anti-Inflammatory Medications (NSAIDs) and gabapentinoids have been employed to augment and replace frequent opioid use. Periarticular and peripheral nerve blocks are also used. 5 Liposomal bupivacaine is a periarticular injection that releases slowly over ~96 hours [3].

This review summarized the efficacy of common TKA postoperative pain management techniques. We looked at recent TKA studies that talked about oral analgesics, periarticular injections, peripheral nerve blocks, multimodal pain regimens and new ways to treat pain.

Oral Analgesics

Oral analgesics are routinely used postoperatively. Opioids are effective, but they often cause side effects like vomiting, constipation, confusion and respiratory depression [4], which has led to a shift toward alternative and multimodal analgesia regimens like acetaminophen, NSAIDs and neuroleptic agents like gaba-pentin and pregabalin for pre-emptive or post-operative pain management.

Multimodal pain relief frequently starts with acetaminophen. Politi compared oral to intravenous acetaminophen (1 g preoperatively and then postoperatively every 6 hours for 24 hours in both cohorts) in 120 total joint arthroplasty patients and found no changes in 24-hour postoperative VAS scores or hydromorphone equivalent dosages [5]. COXs inhibit prostaglandin and inflammation with NSAIDs.

They produce stomach erosions and ulcers due to their nonspecific prostaglandin action. Pre-emptive oral analgesia hindered bone ingrowth on implant surfaces and depressed postexercise protein synthesis in skeletal muscle. Nonspecific NSAIDs may impede bone healing and fracture repair after TKAs. Alternatively, selective COX-2 inhibitors have been utilized, which block prostaglandins with only limited effects on the gastric mucosa, thus decreasing the negative effects asso- ciated with standard NSAIDs. NSAIDs have been used preemptively and postoperatively to treat TKA discomfort. Additional consideration for their utilization is addressed in the following sections.

Preemptive Oral Analgesia

Pre-emptive analgesia decreases pain better than thereafter. Pre- and post-incisional analgesia prevents acute and long-term pain from retraction, tissue manipulation and postoperative inflammation. Epidural, local, N-methyl-D-aspartate antagonists, NSAIDs, opioids and combinations have been tested. Pre-emptive analgesia in TKA patients lowers surgery-related inflammatory chemicals to change peripheral and central pain pathways. Pre-emptive oral analgesia improves post-TKA recovery regimens [6]. Oral acetaminophen, opioids, COX-2 inhibitors, pregabalin, gabapentin.

Pre-operative analgesia relieves pain. Mun-teanu et al. [7], randomly assigned 165 patients to pre- (120 mg etoricoxib 1 hour before surgery, placebo after surgery and 120 mg 24 hours after surgery) or post- (placebo before surgery, 120 mg after surgery and 24 hours after surgery) treatment. Preoperative etoricoxib reduced 48-hour opioid intake (44 vs. 52 mg; p-value <0.002) without severe side effects. Mallory et al. [8], evaluated epidural analgesia with and without pre-emptive COX-2 inhibitors in 251 patients. Pre-emptive analgesia reduced breakthrough pain, nausea and confusion better than epidural (p-value <0.009). Pre-emptive oral analgesia prevents sensitization and hyperexcitability, improving TKA analgesia. Several medication classes are promising.

Postoperative Oral Analgesia

Nonsteroidal Anti-Inflammatory Drugs:            In a randomized, double-blind study of 150 TKA patients, Gong et al. [9], compared celecoxib (300 mg twice daily) to placebo on opioid use. Postoperatively, celecoxib patients (with and without muscle relaxants) used significantly less opioids than placebo patients (198 vs. 225 vs. 255 mg; p-value <0.0001). VAS ratings were lower 7 days postoperatively (2.0 vs. 2.7 vs. 3.4 points; p-value <0.0005) Gabapentin, pregabalin and selective SNRIs can alleviate postsurgical and neuropathic pain [10].

Neuroleptics

In a prospective, randomized research, Jain et al. [11], compared pregabalin (75 mg twice daily) to placebo in 40 TKA patients (twice daily). Compared to the placebo group, the pregabalin group had lower opioid intake (3.6 vs. 7.2 mg; p-value <0.05) and decreased postoperative pain (measured with 11-point verbal rating score) (3 vs. 4.3 points; p-value = 0.001). The placebo cohort used more patient-controlled epidural anesthesia in the first 24 hours than the pregabalin cohort (17 vs. 40 mg; p-value <0.001).

Serotonin–Norepinephrine Reuptake Inhibitors

Few studies have used duloxetine in post-TKA patients. Ho et al. [12], randomly assigned 50 TKA patients to receive duloxetine (60 mg 2 hours before surgery and on the first postoperative day) or placebo. Compared to the placebo group, the duloxetine group needed less morphine at 24 and 48 hours (13 and 20 mg, respectively; p = 0.039). Both cohorts had similar pain scores. In conclusion, postoperative oral analgesics may reduce opioid use and relieve pain. Anti-inflammatory, neuroleptic and SNRI drugs. Celecoxib and pregabalin, like most oral analgesics, reduced postoperative opioid use.

Periarticular Injections of Local Anesthetic

TKA pain can be managed with periarticular injections. Due to their ease of administration and avoidance of neurologic complications, quadriceps muscle weakness and falls from nerve blocks and systemic effects from oral analgesics, they are recommended [13]. These injections contain one or more multi-modal medicines, as detailed below.

Periarticular Injections of Various Mixtures

Maheshwari et al. pioneered multimodal intra- or periarticular injections [14]. In combination with Parvataneni et al., they proposed a multimodal injection of 0.5% bupivacaine (200–400 mg), morphine sulphate (4–10 mg), epinephrine 1/1,000 (300 μg), methylprednisolone acetate (40 mg) and cefuroxime (750 mg). Compared to FNB and patient-controlled analgesia (PCA). On POD 1 (3.8 vs. 5.6 points; p-value <0.05), POD 2 (2.8 vs. 4.1 points) and POD 3, the injection group reported lower pain scores (2.6 vs. 4.5 points).

Motififard et al. [15], compared bupivacaine, morphine, epinephrine and ketorolac against epinephrine alone in 137 patients in a double-blind, randomized experiment. Injections were 15 minutes before incision. The combo group had higher VAS ratings at 24 hours (6.3 vs. 8.8 points; p-value <0.001), 48 hours (5 vs. 6 points) and 6 weeks (3.5 vs. 4.1 points; p 0.02). The study cohort had higher Knee Society Scores (KSS) at 6 weeks (113.6 vs. 99.8 points; p-value <0.001). The combination cohort had a greater range of motion than the control cohort at 24 hours (107 vs. 94 degrees; p-value <0.001), 48 hours (113 vs. 96 degrees) and 6 weeks postoperatively (127 vs 120 degrees).

Jiang et al. [16], meta-analyzed 21 randomized, controlled trials on Periarticular Multimodal Drug Injection (PMDI) in TKA patients. The study employed ropivacaine, bupivacaine, adrenaline, NSAIDs and corticosteroids. PMDI had lower 6- and 24-hour VAS scores than placebo (p-value <0.05). PMDI patients used less opioids 24 hours postoperatively (p-value <0.05). Cohorts had identical stay lengths. In a meta-analysis by Teng et al.47, PMDI lowered VAS ratings and narcotic use to POD 3. Periarticular "multimodal" injections improved postoperative pain, function, range of motion and narcotic use. Each study used a different drug combination, making recommendations difficult.

Liposomal Bupivacaine

Liposomal bupivacaine, a suspension of lipid-based vesicles, provides longer-lasting analgesia than injection [17]. Sporer and Rogers [18], studied 597 TKA patients who received bupivacaine FNB and low-dose liposomal or high-dose (266 mg) alone. High-dose liposomal bupivacaine alone reduced break-through pain medication (17 vs. 36%; p-value <0.001), VAS ratings at 12 hours postoperatively (3.2 vs. 3.6 points; p-value 0.003) and duration to ambulation (30 vs 32 hours; p-value = 0.05). In a randomized, double-blind experiment on 138 TKA patients, Bramlett et al. compared liposomal (133, 266, 399 and 532 mg) to periarticular bupivacaine for postoperative pain and opiate intake. Only the high-dose (522 mg) group improved cumulative pain scores (measured by area under the curve) on POD 5 (10 vs. 16 units; p-value <0.05) compared to the normal bupivacaine injection. Dasta et al. 52 showed that liposomal bupivacaine (266 mg) reduced opioid intake on POD 3 (12.2 vs. 19 mg; p-value <0.0001) compared to conventional periarticular (up to 200 mg). Barrington et al. found liposomal bupivacaine equal to intrathecal morphine in a multicenter randomized trial of 119 TKA patients and recommended it due to its decreased side-effect profile.

Liposomal bupivacaine may shorten hospital stays. Chughtai et al. [19], examined a large hospital database of 94,828 TKA patients who got liposomal bupivacaine or no periarticular injection. Liposomal bupivacaine patients had shorter hospitalizations (2.6 vs. 3 days; p-value <0.05) and higher home release rates (73 vs 67%). Kirkness et al. [20], retrospectively evaluated ACB and liposomal bupivacaine to FNB in 237 TKA patients. Liposomal bupivacaine had longer postoperative walking distances and shorter mean stays than FNB (p-value <0.05).

Liposomal bupivacaine injection strategies may explain contradictory results. Bagsby et al. [21], retrospectively examined 150 TKA patients who received periarticular ropivacaine, morphine and epinephrine or liposomal bupivacaine (266 mg added to 30 mL normal saline to a total of 50 mL, needle gauge was not specified). Both cohorts used opiates similarly. Liposomal bupivacaine-injected patients reported greater VAS pain scores than multimodal patients during the hospital stay (4.9 vs. 4.4 points; p-value <0.04). Jain et al. randomly assigned 207 consecutive patients to receive periarticular liposomal bupivacaine (266 mg, diluted to 60 mL, 22-gauge needle), periarticular and morphine, or intra-articular and morphine. Three cohorts had similar 24-hour postoperative VAS scores. Liposomal bupivacaine releases over 72 hours. Alijanipour et al. randomised 162 patients to receive liposomal or periarticular free bupivacaine (266 mg, combined with 40 mL of normal saline and 0.5 mL of epinephrine 1 mg/mL, given with an 18-gauge needle). Postoperative pain, opioid consumption, KSS and 12-item Short Form Survey scores were similar (p-value >0.05). Early drug efficacy research may have been hampered by nonstandard methodologies. These experiments altered liposomal bupivacaine volume following dilution. Injection instructions were also lacking. Manufacturer recommends multisite injection and 20-gauge needle.

TKA studies have indicated liposomal bupivacaine analgesia. Despite some trials showing no difference in pain management, Khlopas suggests a learning curve for liposomal bupivacaine. Thus, a standard intraoperative injection protocol may improve discordant literature results. A phase 4, prospective, randomized, double-blind, controlled, parallel-group experiment with over 10 centers is comparing liposomal and conventional bupivacaine in TKA patients.

Peripheral Nerve Blocks

After TKA, FNBs, ACBs, femoral triangle blocks, obturator nerve blocks and sciatic nerve blocks have provided analgesia. These can be given as an infusion or an injection, which will be detailed.

Femoral Nerve Block

FNBs are a frequent peripheral nerve block for TKA analgesia. 60 Continuous blocks consume less opioids than single-shot blocks. 

Paul examined 23 randomized controlled trials comparing FNB and PCA opioids in TKA. Patients who received either a single-shot or continuous FNB had significantly reduced morphine consumption than those utilizing a PCA (20 and 15 mg; p-value <0.05) at 24 and 48 hours postoperatively (38 and 24 mg). Compared to PCA, single-shot and continuous FNB patients reported decreased pain scores at 24 (1.8 vs. 1.5 points) and 48 hours (1.5 vs. 1.3 points). FNB also outperforms epidural analgesia. Sakai compared FNB and epidural analgesia in 66 TKA patients. Compared to the epidural group, the FNB group had better knee range of motion (115 vs. 103 degrees; p-value <0.001) and quicker discharge (4 vs 5 days; p-value <0.002). Both groups had comparable resting VAS scores.

Studies have contrasted continuous and single FNBs. Choi et al. [22], randomised 168 TKA patients to continuous FNB, single FNB, or local infiltration analgesia. On POD 1, the continuous FNB and local infiltration groups had larger pain improvements than the single FNB group, but on POD 2, the groups had similar pain levels and opiate intake. Chan et al.65 randomised 200 TKA patients to compare single and continuous FNB to a control group (PCA) for postoperative pain. Continuous FNB patients had the lowest opioid intake (p-value <0.05), but there were no significant changes in VAS pain levels between the continuous and single FNB groups, although both were much lower than the PCA cohort.

FNBs may give good analgesia, although postoperative muscular weakness and falling risk have been observed. Jaeger found that 11 healthy volunteers had stronger quadriceps after ACBs than FNB. Compared to the placebo, the FNB decreased quadriceps muscular strength by 49%. Kwofie et al.34 found that quadriceps muscular strength decreased significantly (95 vs. 11%; p-value <0.05) compared to ACBs. These studies show that FNB may weaken muscles, increasing fall risk. Therefore, a fall prevention strategy should be implemented.

Sciatic Nerve Block

A sciatic nerve block and FNB can relieve posterior leg and knee pain.

A randomized trial by Abdallah et al. [23], showed that a sciatic nerve block plus FNB may improve pain alleviation. The FNB with a proximal or distal sciatic nerve block reduced severe knee pain (12 vs. 17 vs. 78%; p-value <0.001). These disparities lasted 6 hours post-operatively. It was found that no differences in pain levels between single-shot FNB with sciatic nerve block, single-shot FNB alone and continuous FNB. The combination block reduced morphine intake after TKA (11 vs. 16 mg; p-value <0.05).

Al-Zahrani et al. [24], reported no significant changes in pain levels or opioid use between continuous FNB with sciatic nerve block and epidural analgesia in 50 TKA patients. Adding sciatic nerve block to a FNB produces epidural-like analgesia, but motor paralysis may make ambulation difficult.

Adductor Canal Block

ACB provides TKA analgesia and quadriceps muscle function better than FNB. ACB may provide superior analgesia and reduced opioid usage than placebo and FNB. Jenstrup randomised 75 TKA patients to receive an ACB with 0.75% ropivacaine or placebo in a double-blind trial (saline). At 24 hours postoperatively, the ropivacaine group had lower VAS scores (40 vs. 60 points) and morphine use (40 vs 56 mg) than the placebo group. It randomized 40 TKA patients to receive a single bupivacaine ACB injection or saline. The bupivacaine group had a significantly reduced resting pain burden (p-value <0.009) and used less opioids postoperatively (48 vs. 60 mg; p-value = 0.03). ACB preserves muscle strength better than FNBs, even though other investigations have shown lower muscle function than placebo. 

ACBs may allow quicker ambulation than FNBs. Shah and Jain [25], randomized 100 TKA patients to ACB or FNB. The ACB group had a faster timed up and go test (51 vs. 180 seconds; p-value <0.05) than the FNB block, although pain assessments were similar. The earlier trials showed that ACB may relieve pain like FNB while retaining motor function. Nerve blocks may also reduce opioid use.

Current Multimodal Analgesic Regimens

Recently, multimodal analgesic regimens have been used to address several pain pathways and reduce narcotic use. Ranawat et al. [26]. recommended continuous postoperative epidural analgesia, adjuvant FNB and morphine PCA to reduce postoperative pain.

Lavie et al. [27]. recommended preoperative cryneurolysis for 5 days, an ACB on operation day, intraoperative periarticular bupivacaine with epinephrine injections and postoperative planned acetaminophen, celecoxib, pregabalin and hydrocodone/acetaminophen. In total hip and knee arthroplasties, Parvataneni used pre-emptive celecoxib and oxycodone, intraoperative bupivacaine, morphine sulphate and methylprednisolone and postoperative ketorolac, celecoxib, oxycodone and acetaminophen. This approach reduced pain scores compared to FNB and PCA on PODs 1–3 (p-value <0.05). 55% of the multimodal cohort went home, compared to 20% in the control group.

In conclusion, numerous multimodal analgesia regimens have been devised by combining effective drugs. Different centers proposed and analyzed these regimens; therefore, they cannot be compared. Prospectively compare multimodal therapy in the same patient group.

Novel Techniques 

Liposomal Bupivacaine Nerve Blocks: Liposomal bupivacaine can be administered intraoperatively but not peripherally. FNB with liposomal bupivacaine following TKA moderately reduced average pain and opioid use in the first 72 hours after surgery compared to placebo in two-part clinical research designed to fulfil FDA analgesic agent approval standards. Wang et al. [28]. examined 341 TKA patients who received an ACB with liposomal bupivacaine or a ropivacaine pain ball. At 36 hours postoperatively, the liposomal bupivacaine group had lower pain scores (3.1 vs. 4l points; p-value <0.001) and decreased opioid use (115 vs 173 mg; p-value <0.08). Both groups had similar stay lengths and costs. For an interscalene brachial plexus block, 52 adult patients were randomized to receive either 5 mL of 0.25% bupivacaine immediately followed by 10 mL of liposomal 133 mg (n 1/4 26) or 15 mL of conventional 0.25% BUP. The Modified Brief Pain Inventory short form measured greatest pain in the first postoperative week. Secondary outcomes were analgesic satisfaction, surgical arm functionality, sleep duration, time to first opioid (tramadol) request, opioid consumption (mEq), sensory–motor block features and side effects. Liposomal bupivacaine added to normal bupivacaine in interscalene brachial plexus blocks may reduce pain and improve patient satisfaction in the first week after major shoulder surgery, even with multimodal analgesia.

Cryoneurolysis

Postoperative pain management now includes cryoneurolysis. Terminal nerves are cold-treated [29]. In rats, degeneration occurred distant to the freezing location, preserving the anatomical structure [30]. Nerve endings regenerate 6 weeks after therapy. Dasa et al. [31] compared 50 patients who received percutaneous freezing of the infrapatellar branch of the saphenous nerve and femoral cutaneous nerve before TKA versus 50 who did not. The cryoneurolysis cohort had fewer patients with lengths of stay over 2 days (6 vs. 67%; p-value <0.0001). The therapy group also consumed 45% less narcotics within 12 weeks postoperatively (2,069 vs. 3,764 mg; p-value <0.0001). Cryoneurolysis also reduced the Knee Injury and Osteoarthritis Outcome Score symptom subscale scores more than the control group at 6 and 12 weeks postoperatively (p-value <0.004).

Due to subjectivity and patient variability, TKA pain control is difficult. Thus, a single analgesic regimen is difficult to create. We compared perioperative analgesia methods in this analysis. Periarticular injections are effective with few side effects. Interventional pain management may increasingly involve liposomal bupivacaine and/or its combinations. A multimodal perioperative strategy including periarticular or perineural injections is most effective for pain management and postsurgical recovery and rehabilitation. 1,69 Liposomal bupivacaine is being studied for its efficacy and safety in peripheral nerve blocks, with promising results in postoperative analgesia [32].

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