A guide to regional analgesia for Total Knee Arthroplasty.

Regional analgesia has been introduced successfully into the postoperative pain management after total knee arthroplasty, reducing pain scores, opioid use and adverse effects. Combination of regional analgesia techniques is associated with better pain management and lower side effects than single regional techniques. Adductor canal block provides good analgesia and considerably lower detrimental effect in muscular strength than femoral nerve block, enhancing surgical recovery. Infiltration techniques may have equivalent analgesic effect than epidural analgesia and peripheral nerve blocks, however there should be awareness of dose dependent toxicity. Novel long-acting local anesthetics role for regional analgesia is still to be determined, and will require larger randomized trials to support its advantage over traditional local anesthetics.

Introduction

Total knee arthroplasty (TKA) is a widely used method to treat end-stage osteoarthritis and other disabling knee conditions, and its demand is expected to increase to more than 1 million procedures by the year 2030 in the United States.[1-3] Therefore, increasing value of TKA has been an area of enhanced interest.[3] Among the changes in practice in the last decade, we have seen a steady decrease in hospital length of stay (LOS), and a shift towards outpatient surgery.[3,4] In 2018 the U.S. Centers for Medicare & Medicaid Services (CMS) finalized the 2018 Medicare Outpatient Payment System rule that removed TKA from the Medicare inpatient-only list of procedures. Altogether, the safety and general feasibility of cost-effective strategies across different TKA patient populations constitutes an area of increased interest and value.[5] One of the facets that continues to require improvement is the relatively high incidence of postoperative severe pain, ranging from 10 to 36%, which produce dissatisfaction among patients after TKA, and increased hospital utilization.[6,7]

Different anesthetic approaches and combinations such us general anesthesia (GA), neuroaxial anesthesia (epidural or spinal) and/or peripheral nerve blocks have been used in TKA. GA, historically, has been associated to high rates of postoperative nausea, vomit and delirium.[8] On the other hand, neuroaxial anesthesia reduces nausea, vomiting, cardiovascular and pulmonary complications and overall mortality when compared to GA.[9,10] Regional analgesia (RA) have been used to optimize pain management during the postoperative phase of TKA.[11] Most RA techniques use local anesthetics (LA), in lower concentration than anesthesia methods, to reduce pain and produce the least possible impairment in mobility.[12] Increased interest in RA has been mainly due to its improvement of pain management with relevant reduction in opioids consumption due to its opioid-sparing effect, decrease risk of addiction and opioid crisis.[13] Furthermore, RA can decrease opioid side effects such as urinary retention, constipation, nausea, vomiting, ventilatory depression and sedation which have resulted in lower LOS.[14] RA expanded its versatility when ultrasound improved the accuracy of LA administration.[15] Also, its role in decreasing risk of complications and LOS related to immobilization makes RA an ideal method for orthopaedic surgical procedures.[16] RA facilitates physical therapy by reducing postoperative pain. However, some techniques may reduce motor function which in turn can delay recovery times.

This review article will serve as a guide of classic and novel regional analgesic techniques used in the early postoperative period after TKA, comparing and discussing advantages and disadvantages among them in addition to present promising advances in this area. For the purpose of this review, we address anesthetic techniques as part of the intraoperative management and analgesic techniques as a component of multimodal analgesia for the perioperative care after TKA.

Anesthesia for TKA

TKA has been performed under two main anesthetic techniques: I) GA; and II) neuroaxial anesthesia. The use of intravenous and inhaled anesthetics drugs in GA, in addition to eliminating pain and consciousness, also prevents motor repose, autonomic and cardiovascular reflexes.[17] On the other hand, neuroaxial anesthesia utilizes local anesthetics to block sensory and motor nerves following a caudal direction from the spinal level the anesthetic was injected, with variable impact on autonomic nervous system.[18] Overall there are two main approaches to neuroaxial anesthesia used in TKA: A) Subarachnoid (intrathecal) anesthesia in which the needle is inserted at the subarachnoid space at L4/L5 lumbar interspace to administer opioids or LA; and B) Epidural anesthesia where epidural space is targeted by the needle. Unlike the subarachnoid space, the epidural space is septated and it contains fat, lymphatics, veins and nerve roots.[19] This non-continuous space may facilitate partial or unilateral effect during epidural anesthesia.[20]

Controversial results have been published comparing GA and neuroaxial anesthesia. While some authors found advantages in neuroaxial anesthesia over GA such as reduction in short-term complications[21] including less blood transfusion[22] and surgical site infections[23], others failed to find differences other than lower LOS on neuroaxial anesthesia.[24] In addition, epidural techniques are associated with higher incidence of urinary retention, pruritus and hypotension, compared to anesthetic regional techniques.[25] Its higher incidence of side effects along with its technical complexity compared to spinal block, makes epidural anesthesia prone to obsolescence for TKA. A recent nationwide database study found that patients who undergo total joint arthroplasty with spinal anesthesia experience fewer 30-day complications and were less likely to have a non-home discharge than those with GA.[10] A large 2019 meta-analysis named the International Consensus on Anaesthesia-Related Outcomes after Surgery group (ICAROS), which analyzed 94 studies comparing neuroaxial vs GA in hip and knee arthroplasty, suggests the use of neuroaxial anesthesia for knee arthroplasty based on reduction in infections, deep venous thrombosis, blood transfusions, pulmonary and renal complications; evidence level: low, weak recommendation.[26]

Postoperative pain management contributes greatly to achieve enhanced recovery after surgery (ERAS) goals.[27] Recognition of the sensory innervation of the knee plays a key factor on regional analgesia, discussed in Regional analgesia uses different nerve block techniques as part of the multimodal analgesia arsenal to favor ERAS.[28]Techniques are presented in two different chronologic groups: 1) Classic Techniques; and 2) Novel Techniques.

Classic Techniques

Neuroaxial Analgesia

This method uses LA or opiates through a subarachnoid or epidural access to relief pain after TKA, applying single shot or continuous (catheter) technique. Continuous subarachnoid analgesia is associated with better hemodynamic stability, pain management, and less nausea and vomit than single shot technique in lower limb surgery[29]. Single shot epidural analgesia is limited to brief pain relief (<6 hours)[25] compared to 48 hours with standard epidural catheters and 6 weeks with tunneled epidural catheters[30].Neuroaxial techniques are frequently associated with hypotension, urinary retention and pruritus[25]; major complications such as spinal infections, bleeding, nerve damage, wrong route and cardiovascular collapse and respiratory depression have to be considered[30]

One metanalysis found no difference on analgesic effect in neuroaxial techniques compared to peripheral nerve blocks for TKA.[31] However, neuroaxial analgesia was associated with higher incidence of hypotension, urinary retention, nausea and vomiting.[31] On the other hand, researchers found that local infiltration provides better analgesia management than either subarachnoid[32] or epidural analgesia[33] for TKA. In favor of reducing opioid use, epidural analgesia provides superior pain control than intravenous opioids.[34,35] Advantages, disadvantages and contraindications of postoperative regional analgesic techniques for TKA are discussed in .

Table 2.

Regional Analgesia for TKA

Analgesic Procedure	Advantages	Disadvantages	Contraindications
Intrathecal analgesia	• Relatively easy technique• Bilateral analgesic effect for bilateral TKA	• Effect in sympathetic innervation (urinary retention and hypotension )• Respiratory depression related to intrathecal opioid use• Pruritus• Unnecessary bilateral block• Risk of infection and nerve damage• Delays mobilization	• Elevated intracranial pressure• Infection on the injection site• Risk of hypotension (hypovolemia)• Thrombocytopenia or coagulopathy
Femoral nerve block	• Easy access with or without ultrasound guidance• Excellent analgesia• Good predictable course of catheter with ultrasound guidance	• Delays mobilization• High risk of falls	• Patient inability to positioning• Allergy to LAs• Preexisting coagulopathies (endogenous or iatrogenic)• Active infection on the injection site• If no USG guidance, anatomic anomalies• affecting physical• landmarks identification• Pre-existing neuropathies affecting the distribution of the block
Sciatic nerve block (posterior)	• Analgesia on the posterior aspect of the knee• Adjuvant effect on anterior compartment blocks	• Relatively deep block• Requires prone/ semiprone position• Delays mobilization
Adductor canal block(ACB)	• Allows early mobilization and recovery time• Continuous technique provides the highest analgesic effect[73] • Higher opioid-sparing effect than LAI[78,79] • Easy ultrasound guide access[68]	• Tunneling is required in some cases
iPACK	• Adjuvant analgesic effect on ACB• Analgesia on the posterior aspect of the knee• Minimal impact on mobilization	• Limited to single shot technique• Short analgesic effect• Risk of foot drop
Local anesthetic infiltration (LAI)	• Easy intraoperative administration• Adjuvant analgesic effect• Minimal impact on mobilization	• Increased risk of toxicity[101] • Short analgesic effect• Risk of infections with intraarticular catheter
Genicular nerve block	• No risk of toxicity (no LA use)	• Requires Fluoroscopic and trained staff• USG guidance still in investigation• Scarce clinical evidence	• Bleeding diathesis• Infection at the site
Cryoanalgesia	• No risk of toxicity (no LA use)	• Unpredictable analgesic duration• Risk of permanent sensory and motor block• Scarce clinical evidence	• Raynaud syndrome• Cryoglubulinemia• Bleeding disorders• Active infection on the injection site[120]

Comparison among postoperative analgesic techniques for TKA. All thechniques are rarely associated with infectious complications. Neuroaxial procedures are related with 1.1- 2.5 infections per 100.000 neuroaxial blocks. Risk factors of infectious complications in peripheral nerve blocks are: ICU hospitalization, duration of catheter more than 48 hrs, lack of antibiotic prophilaxis, catheters in the femoral region and number of catheter dressing changes are considered risk factors of infectious complications in peripheral nerve blocks.

Three in one Block

Described by Winnie et al.[36], its original purpose was to block the lumbar plexus retrogradely using high amounts of LA (>20ml). This technique uses a single shot local anesthetic to target the 3 main nerve branches from the lumbar plexus: femoral, lateral femoral cutaneous, and obturator nerves. Moreover, Rosenblatt[37] described that a catheter can be placed into the femoral sheath to extend the analgesic effect during the postoperative period. There is a lack of evidence comparing three in one block on its two variations: single shot and continuous administration of LA. However, it is well documented that a single shot administration of LA can provide a sensitive block for more than 24 hours.[38] Additionally, one shot three in one block reduces morphine consumption after knee surgery.[39,40]

Three in one catheter was promoted due to its similar analgesic effect and lower risk when compared to epidural catheter. Three in one block is an alternative to avoid classic side effects related to epidural analgesia.[41] The use of catheter in three in one block allows continuous administration of the local anesthetics, increasing the analgesic effect in the femoral or saphenous nerves.[42]

There are few studies comparing three in one block against other regional analgesic techniques. Besides, none of them were for knee surgeries. Comparisons were made in femur fractures surgeries. One study compared three in one block vs fascia iliaca block which uses an anterior approach variation of the femoral nerve and the lateral femoral cutaneous nerve. Researchers found that both techniques provide adequate analgesia but fascia iliaca block presented faster and more uniform nerve blockade.[43]

Nowadays, one in three block is not frequently used as before. One of the causes is its non- homogeneous effect in all three main lumbar plexus branches. Studies have shown just a 4% success rate in terms of achieving the obturator nerve block, relating to the poor analgesic effect on the medial aspect of the knee.[44] In fact, researchers proposed to change the term of this technique to two in one block due to its almost no effect in the obturator nerve. Also, the unpredictability of the course of the catheter placed without ultrasound guidance decreases its success rate.[45]

Femoral nerve Block

Described in 1952[46], femoral nerve block (FNB) can provide sufficient analgesia to the anterior aspect of the thigh including motor blockade of the muscles in the anterior compartment. It can be combined with sciatic and obturator nerve block to allow anesthesia for knee surgeries. FNB was initially performed blindly, by inserting a needle 1-1.5 cm laterally to the femoral artery pointing it to the midpoint of the inguinal ligament. In recent years clinicians prefer to use ultrasonography (USG) to enhance technique accuracy.[47]

FNB can be performed as a single anesthetic shot or using a catheter for continuous analgesia. Several meta-analyses comparing single shot vs. continuous FNB have contradictory findings. While some declare lower morphine consumption[48] and lower pain scores after TKA in the continuous method[49], others found no difference with the single-shot method.[50,51] Elderly patients may benefit from the combination of FNB and GA. One study reported decreasing intraoperative and postoperative analgesic use, recovery and extubation times in patients with advanced ages who underwent TKA under GA plus FNB.[52] When compared against epidural analgesia, FNB has no impact on the sympathetic innervation and produces less incidence of urinary retention.[53]

On the other hand, this method has substantial effect on mobility. Researchers have found that FNB, single shot or catheter, decreases the motor strength of the quadriceps muscle, increases recovery time and risk of falls compared to adductor canal block (ACB) [54,55]. Moreover, there is no difference in pain control between FNB and ACB.[56,57] However, FNB showed superior analgesic effect against local infiltration. On a randomized control trial, 194 patients received FNB or infiltration for TKA, the FNB group had significantly lower amount of opioid use compared to the infiltration group.[58]

Sciatic Nerve Block

The classic posterior approach was first described in 1923 by Labat. There have been several other variations described, some are the anterior approach, parasacral and subgluteal modifications. Nowadays, ultrasound guided sciatic nerve block is commonly used. USG identifies the sciatic nerve in between the greater trochanter and the ischial tuberosity, the nerve lies over quadratus femoris beneath the gluteus maximus. SNB is more a complement than an absolute analgesic resource for knee surgeries. SNB contribute with analgesic effect to the posterior aspect of the knee where FNB has no influence. Evidence shows that SNB increases the analgesic effect during the first 12 postoperative hours in patients who received FNB for TKA[59], but also can deteriorates postoperative mobilization.[60] Researchers have made efforts to predict the need of SNB as additional pain management in those patients who received FNB for TKA[61]. Factors associated with a higher probability of postoperative SNB requirements were: younger age, lower BMI, depression, short surgical procedures under peripheral nerve blocks and infiltration anesthesia.

SNB has also been compared to local infiltrations when an additional block to FNB is needed for TKA. Some authors have claimed better analgesic effect, reduction on opioid use, nausea and vomiting events for the combination of FNB plus SNB in comparison to FNB plus local infiltrations.[62,63] Although, some other investigators found no difference in pain control between these two strategies[64]. In addition, SNB can be used in combination with ACB. Investigators found lower postoperative pain scores at rest and in movement when ACB plus SNB technique was compared to ACB alone[65].

Adductor Canal Block

Van der Wal et al. in 1993, described ACB as a transartorial approach, using landmarks to block the saphenous nerve.[66] Unlike FNB, this technique achieves more sensorial than motor block. The Adductor canal (AC) contains distal branches of the femoral nerve such as the saphenous nerve, the obturator nerve as well as sensory and motor branches for the quadriceps muscle. Nowadays, ultrasound is commonly used to identify the AC ().[67] In supine position, the leg is externally rotated and the probe is positioned at the midpoint of the thigh on its medial aspect. The superficial femoral artery is used as a reference, the AC is located anterolaterally to the artery. The needle is advanced and a particular “pop” indicates that the tip pierced the vastoadductor membrane, which is the roof of the adductor canal. A single dose of local anesthetic is injected or a catheter is placed. In practice, clinicians prefer tunneling the AC catheter due to its proximity to the surgical field. Although, tunneling the AC catheter may increase the time of the procedure, it decreases the risk of intraoperative dislodgement.[68]

Figure 1.

Adductor canal block. The needle (yellow arrows) is injecting local anesthetic (blue area) which is spreading into the adductor canal. In the proximities, the superficial femoral artery (FA) is anterior to the superficial femoral vein (FV). The Sartorius muscle (SM) is more superficial.

ACB’s main advantage over previous techniques is its low impact on muscular strength. Numerous publications show that ACB has less detrimental effect on the quadriceps strength compared to FNB. In particular, ACB is associated with earlier mobilization and recovery times with equivalent pain scores compared to FNB.[57,69,70] Similarly, researchers found that ACB in volunteers reduced 8% of quadriceps strength compared to 49% in FNB.[71] A recent meta-analysis found that continuous ACB deteriorates less the quadriceps strength compared to continuous FNB and it is associated with better rehabilitation outcomes.[72] Moreover, researchers have compared single shot ACB and ACB catheter. Multiple studies show that continuous ACB provides better analgesia, less postoperative opioid use and shorter rehabilitation periods compared to single-shot ACB [73-76]. However, some others found that the superiority of ACB catheter over ACB single-shot was only presented after the second postoperative day when presumably the single dose of LA has worn off[72,77]. Other advantages have also been described for ACB. ACB presents less postoperative opioid consumption than local infiltrations technique after TKA; however, both provide equivalent pain control and impact on muscle strength.[78,79] A recent meta-analysisreviewed a substantial number of randomized controlled trials comparing different RA techniques for TKA.[80] Continuous ACB showed a solid superiority over other techniques, results are summarized in .

Table 3.

Comparison of Regional Analgesia techniques in TKA

ComparisionA vs B	Rest VAS at 24 h	Rest VAS At 48h	Total OMEQC	ROM
ACB vs PAI	A≃B	A≃B	A>>>B*	A≃B
ACB + PAI vs PAI	A>>B*	A≃B	A>>>B*	A>>>B*
ACB + PAI vs ACB	A>>B*	A≃B	A≃B	A≃B
cACB vs ACB	A>>B*	A>>>B*	A>>>B*	A>>>B*
LB vs PAI	A≃B	A≃B	A≃B	A≃B

Comparasion of weighted mean difference (WMD) (accumulative differences of studies weighted by the sample size) of studies with the same clinical outcomes and interventions. Two posoperative analgesic strategies (A vs B) after TKA were compared. Evaluating visual analoge scale (VAS) at rest, 24h and 48h posoperatively, total oral morphine equivalents consumption (OMEQC) and Range of Motion (ROM) are explained as no difference (A≃ B), small superoirity (A>B), moderate superiority (A>>B), large superiority (A>>>B) by the magnitude of the WND ( 0, 0-0.2, 0.2-0.8, >0.8 respectivily). ACB, adductor canal block; cACB, continuous adductor canal block; PAI, periarticular infiltration; LB, Liposomal Bupivacaine.

p value was <0.05

Adapted from Journal of Clinical Anesthesia Volume 68, February 2021, 11009.

Novel Techniques

Infiltration between the popliteal artery and capsule of knee (iPACK) block

iPACK block was developed by Sinha in 2012. The aim of iPACK block is to control the pain at the posterior aspect of the knee after TKA without causing foot drop.[81] This technique can block important genicular nerves such as articular branches of tibial and common peroneal nerves, posterior branches of the obturator nerve, and medial genicular nerve.[82] The needle is inserted in a trajectory from anteromedial to posterolateral at the distal metaphyseal level of the femur in between the shaft of the femur and the popliteal artery ().[83] iPACK block is used mostly in conjunction with FNB and its advantages are still been studied. Multiple researchers suggest that iPACK block can enhance the analgesic effect, lower opioid consumption, and ambulation time of ACB. [84-87] iPACK block was found to be superior to periarticular infiltrations when it was required to improve the effect of ACB.[88] Authors have reported a low incidence of foot drop after iPACK block[89], hypothetically due to spread of the LA to the tibial and peroneal nerves. There are some concerns regarding the trajectory of the needle; for example, some authors intuit an unintentional saphenous nerve injury related to its thinness, which makes it difficult to identify even with the use of USG.[90]

Figure 2.

iPACK. The local anesthetic is distributed transversally between the Popliteal Artery (PA) and the Femur.

Local Anesthetic Infiltration (LAI)

This technique consists of a systematic intraoperative administration of LA in the periarticular and intraarticular tissues of the knee. There is no consensus to guide the best use of LAI[91], often surgeons perform this technique using plain LA or combination of analgesic medications. Generally, the cocktail comprehends a high volume (150-170 mL) of a mixture of 0.2% ropivacaine or 0.125% levobupivacaine plus ketorolac and epinephrine.[92] The systematic injection occurs in 3 phases during a period of 1 hour to decrease risk of toxicity. First, the posterior capsule is infiltrated with the mix, then deep tissues around the medial and lateral collateral ligaments and wound edges; and subsequently, the subcutaneous tissue is injected. Also, an intraarticular catheter can be placed for additional administration of LA during the postoperative period. Researchers have seen better short term pain control when the intraarticular catheter was inserted compared to single-shot LAI.[93] However, the same researchers suggest considering the risk of infection related to the intraarticular catheter. Compression bandage plays a key factor to extend the analgesic effect of LAI.[94].

Several meta-analyses have compared the efficacy of LAI against other postoperative analgesic strategies. LAI is associated with superior analgesic effect than epidural analgesia[33] with lower incidence of nausea and vomiting and a wider range of articular motion.[95] In the case of FNB, there was a similar effect in pain control compared to LAI.[96] Importantly, periarticular infiltration technique was superior to FNB in avoiding muscle weakness.[97] Other studies have questioned the benefit to adding LAI to the ACB. While some have found benefit in the combination to reduce pain and opioid consumption[98], others have not seen a clinical difference.[99] Reports about complications related to this technique point to the dose and speed in which the infiltrations were administrated [92,100]. A high dose of adrenaline in LAI given in a short period of time can cause high blood pressure with ST and T wave alterations.[100]

Genicular Nerve Block

This method uses radiofrequency ablation (RFA) of the genicular nerves (knee joint nerves). Although, RFA was primarily investigated to cure intractable pain due to advanced cancer in the '60s[101] and to treat pain from the spinal facet joints since the '70s[102], nowadays is also used for non-surgical treatment in advanced osteoarthritis of the knee.[103] Most recent applications include postoperative chronic pain management after TKA.[104] With fluoroscopic guidance, pain physicians use needles to target the periosteal areas at the superior lateral, superior medial, inferior medial borders of the knee. A high-frequency current travels throughout the needle until its tip where it causes neurolysis to the surrounded nerves.[103]

Despite its wide use in other areas, there is limited evidence supporting RFA for pain management after TKA. One of the first cases reported is a 48-year-old male with persistent severe pain after TKA, using both fluoroscopic and ultrasound guidance, the genicular block was performed. The patient reported significant improvement in pain scores; muscular strength and range of motion at 3 months follow up.[105] Later on, similar results were described in another case report 104. A recent study showed promising results in the use of ultrasound to guide the genicular nerve block for TKA.[106] One randomized clinical trial compared the genicular nerve block against local anesthetic and corticoid therapy in patients with persistent pain after TKA[107]. Similar pain reduction and improvement in physical function were obtained in both groups, portraying genicular nerve block with RFA as an alternative to conventional treatment. However, more studies are needed to fully include this technique as an option for postoperative pain management after TKA.

Long-acting Anesthetics

Pain after TKA is directly associated with low mobilization which in turn is related to high morbidity and prolonged hospital stay.[108] Pain management needs to be assured during the postoperative period for a considerable time after TKA. Consequently, duration of the action of LA is one of the key features in RA for TKA. LA with high affinity for proteins present longer anesthetic effect. Lipid solubility is another factor associated with prolonged anesthetic effect. Lipid-soluble LA can remain longer in the proximity of the neural membranes in a more continual release.[109] Also, adjuvants increase the duration of LA; some of them are alpha 2 agonists, steroids, magnesium and the vasoconstrictors. Ropivacaine and bupivacaine are the two most frequently used long-acting LA. In recent years the liposomal version of bupivacaine has drawn the attention of physicians due to its promising longer effect. Performance of different LA is illustrated in .[110]

Table 4.

Local Anesthetics Performance in Peripheral Nerve Blocks

Anesthetic	Onset (minutes)	Duration of Anesthesia (hours)	Duration of Analgesia (hours)	Toxicity considerations*
2% lidocaine	10 - 20	2 - 5	3 - 8	High CNS toxicity in neuroaxial anesthesia
1.5% mepivacaine	10 - 20	2 - 5	3 - 10
0.2% ropivacaine	15 - 30	n/a	5 - 16	Lower myotoxicity
0.5% ropivacaine	15 - 30	4 - 12	5 - 24
0.25% bupivacaine	15 - 30	n/a	5 - 26	Higher myotoxicity, neurotocicity and cardiotoxicity (tachycardia and ventricular fibrilation)Chondrotoxic
0.5% bupivacaine (+epi)	15 - 30	5 - 15	6 - 30

Reactions to Local Anesthetics (LA) are rare and mostly are secundary to intravascular administration or absortion. Local toxicity (myotoxicity and neurotocicity) differ among LAs, bupivacaine > procaine > tetracaine >ropivacaine. Systemic reactions include, neurotoxicity(agitation,dizziness, myoclonic responses, nistagmus,disartria, muscle contractures, perioral parestesias, metallic taste,tinnitus, speech disorders, tonic-clonic seizures,respiratory depression (hypoxia, acidosis) and coma) and cardiotoxicity (tachycardia, hypertension (initially),hypotension and bradycardia (severe toxicity),miocardial depression and low cardiac output associated with arrhythmias (PR prolongation, branch blocks, ventricular ectopia, ventricular tachycardia, ventricularfibrilation, torsade de pointes, sinus arrest,asystole)

Adapted from Hadzic's Peripheral Nerve Blocks and Anatomy for Ultrasound-Guided Regional Anesthesia, 2nd 2. Local Anesthetics: Clinical Pharmacology and Rational Selection Jeff Gadsden

Pharmaceutic companies have modified bupivacaine in order to improve its performance. Levobupivacaine is less neurotoxic and cardiotoxic due to modifications made in the original structure of bupivacaine; but at the same time, it preserves its original potency and effect.[111] Liposomal bupivacaine (Exparel; bupivacaine liposome injectable suspension, Pacira Pharmaceuticals, Inc., Parsippany, NJ, USA) uses a multivesicular configuration to reduce the speed of degradation of bupivacaine (); in consequence, its analgesic duration is longer than plain bupivacaine achieving 72 hours of analgesia. The Food and Drug Administration (FDA) approved liposomal bupivacaine for intraoperative infiltrations and interscalene brachial plexus block.[112]

Figure 3.

—A) Scanning electron micrographic image of DepoFoam with bupivacaine; B) diagram representing the polyhedral, nonconcentric aqueous chambers filled with medication (with permission from Pacira Pharmaceuticals, Inc.).

A recent narrative review concluded that the current evidence does not support the routine use of liposomal bupivacaine over standard LA for postoperative pain management.[113] Specifically for TKA, liposomal bupivacaine has been studied both in peripheral nerve blocks and LAI analgesic techniques with controversial results. Some researchers found that liposomal bupivacaine is associated with high analgesic effectiveness in peripheral better pain scores at later time, reduction in morphine consumption and less nausea than plain bupivacaine for articular infiltrations.[114] Similarly, a recent meta-analysis showed that periarticular injection with liposomal bupivacaine is associated with faster functional recovery but no difference in pain scores was seen when compared with FNB.[115] However, another meta-analysis compared liposomal bupivacaine in periarticular injections for TKA with traditional LAs and found no clinical difference in pain reduction neither opioid consumption[116]. Although, the authors acknowledge the lack of studies with comparable procedures, which may limit their conclusions. Similarly, No clinical advantage was found when liposomal bupivacaine was compared to ropivacaine in ACB for TKA.[117]

Most recently, an investigational drug called HTX-011 (Heron Therapeutics, Inc. San Diego, CA, USA) has been studied. It is composed of bupivacaine and meloxicam in a bioerodible polymer. The purpose to include meloxicam is to decrease local inflammation to maintain a more physiological pH locally and decrease peripheral sensitization.[118] HTX-011 is directly applied around periarticular tissues not using a needle. Although, this Drug has not FDA approval, a phase 2b trial in total knee arthroplasty has finished. The researchers found superior reduction in pain scores in patients who received HTX-011 during TKA compared to periarticular injections with plain bupivacaine during the first 72 hours after surgery[119].

Cryoanalgesia

Cryoanalgesia, also called cryoneurolysis, is a method to temporarily block nerves through very low temperatures. It was first described in 1961 using a probe with liquid nitrogen to create ice crystals which in turn produced severe endoneural edema disrupting neural conduction.[120] Nowadays, more complex and narrow-gauge probes using N2O or CO2 create an ice-ball with temperatures ranging from −70°C to −90°C to ablate the nerves reversely. Duration of the block is unpredictable due to the factors involved (temperature, time of exposure and nerve diameter) but usually is count in weeks or months. There is few clinical evidence about the use of cryoanalgesia in TKA. Five patients (Three with knee surgery and two with shoulder surgery) received cryoanalgesia postoperatively and the pain scores and opioid use was recorded. All patients described pain scores no more than 2 on a 0-10 scale and opioid consumption was lower compared to historic controls.[121] Furthermore, one retrospective study found that the addition of cryoanalgesia to the standard multimodal pain management five days before TKA reduces significantly length of stay and opioid consumption postoperatively.[122] Although, cryoanalgesia does not represent systemic toxicity, the risk of complete sensory and motor block along with its uncertain effect time may limit its use.

In summary, RA has been successfully incorporated into the postoperative analgesic arsenal for TKA. Evidence supports its roll to improve analgesic management and decrease opioids use. Chronologically, a more caudal approach has been developed in order to selectively target sensitive nerve branches and avoid motor impact. Although, some techniques are associated with deleterious effect on mobilization, novel techniques apparently bypass this disadvantage but still more evidence is needed to fully implement them. Combination of RA techniques can improve the analgesic effect. Pharmaceutics have also made efforts to improve the performance of LAs. New LAs have been promoted as longer duration drugs than previous ones but requires further proof with large randomized clinical trials. Cryoanalgesia is still unpredictable and represents an undiscovered field.

Conclusion

Orthopedic procedures, including TKA, demands a multimodal analgesic approach. This need to provide a diversified pain management comprises an advancement in the field, increasing interest and value in new analgesic techniques to improve patients’ outcomes and satisfaction.

Table 1.

Sensory Innervation of the Knee

Compartment	Nerves	Considerations	Joint Supply	Cutaneous Supply
Anterior	Femoral nerve	Crosses behind the inguinal ligament and lateral to the femoral artery and provides branches to innervate each muscular component of the quadriceps muscle (Vastus Medialis, intermedious and lateralis branches)	The vastus medialis to the medial collateral ligament, The vastus lateralis branches end at the quadriceps tendon without innervating the capsule of the knee	The vastus medialis to the superomedial aspect, The vastus Intermedius to the anterosuperior aspect of the knee
	Common fibular nerve	Provides articular (genicular) branches to knee, lateral superior, lateral inferior, recurrent.	Inferolateral capsule of the knee joint, proximal tibiofibular joint	Lateral aspect of the knee
	Saphenous nerve	Cutaneous branch of the Femoral nerveRuns into the adductor canal	Infrapatellar BranchDescending BranchAntero inferior capsule of knee joint	Medial and inferior aspect of the knee
Posterior	Tibial nerve	Branch of the Sciatic nerve, provides the posterior articular nerve.	Articular (genicular) branches to knee medial superior, medial inferior, middle and capsular branches	Medial portion of the capsule, retinaculum, collateral ligaments of knee joint proximal and distal tibiofibular joint
	Obturator nerve	Originates two main branches: anterior and posterior	Posterior branch to joint capsule, cruciate ligaments and synovial membrane	Anterior branch to medial aspect and mid-thigh
Plexuses	Contributors to the plexus		Sensory innervation
Peripatellar	Femoral nerve: medial, intermediate, lateral femoral cutaneous nerves Saphenous nerve: infrapatellar branch Retinacular nerves: medial (terminal branch of nerve to vastus medius), lateral (direct branch of sciatic nerve) Nerve to vastus intermedius		Skin anterior, superior, inferior, medial and lateral to patella; retinacula; collateral ligaments and capsule of knee joint
Subsartorial	Saphenous nerve: infrapatellar branch Obturator nerve: anterior division Medial femoral cutaneous nerve Nerve to vastus medius		Cutaneous to medial side of knee, retinaculum, collateral ligaments and capsule of knee joint
Popliteal	Tibial nerve Sciatic nerve Obturator nerve		Retinaculum, anterior and posterior cruciate ligaments, collateral ligaments and capsule of knee joint

Adapted from Pulsed radiofrequency of the composite nerve supply to the knee joint as a new technique for relieving osteoarthritic pain: a preliminary report. Pain Physician.2014;17(6):493-506.