**6.2. Drug therapy**

**6.1. Regional analgesia techniques and multimodal analgesia**

96 Primary Total Knee Arthroplasty

induced by the surgery increase and serious risks may occur to the patients.

Despite improvements in pain management, approximately half of TKA (total knee arthroplasty) patients develop severe pain in the early postoperative period. Excessive tissue damage and complex innervation in TKA make pain control difficult. Femoral nerve, sciatic nerve, and obturator nerve are involved in the innervation of the knee joint. In major surgeries, such as TKA, changes occur in the endocrine system and central, peripheral, and sympathetic nervous systems. If postoperative analgesia is not achieved adequately, systemic responses

Conventional methods such as parenteral opioids, epidural analgesia, and femur blocks have been widely used to remove the pain associated with TKA [12]. In addition, the fascia iliaca block has recently been used more frequently to reduce the pain associated with TKA [13]. Comparing general anesthesia with neuraxial anesthesia in the patients with TKA, the risk of perioperative complications was significantly reduced in patients undergoing neuraxial anesthesia [14]. In another study, the risk of short-term complications in patients with TKA was higher in patients receiving general anesthesia than in patients receiving neuraxial anesthesia [15]. Neuraxial anesthesia was associated with the reduction of major complications. A recent meta-analysis has shown that there is a significant decrease in the incidence of postoperative surgical site infection in neuraxial anesthesia when compared to general anesthesia and neuraxial anesthesia in the patients with TKA and total hip arthroplasty (THA) [16]. The use of peripheral nerve block (PNB) also reduced the need for postsurgical critical care services [17]. Multimodal analgesia techniques are often used in the "fast-track" recovery protocols to improve pain relief. Mixture of local anesthetics and anti-inflammatory and opioid analgesics for periarticular infiltration has been used in the multimodal protocols. It can improve the pain score, reduce the total perioperative opioid consumption, enhance the early mobilization, and increase the patient satisfaction [18]. Several multimodal analgesics have been developed in clinical practice [19, 20] and paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, ketamine [21], alpha-2 adrenergic agonists [22], and corticosteroids have been used [23]. Periarticular drug injection is an attempt to apply a low-concentration, high-volume local anesthetic solution to the joint capsule and periarticular surrounding tissues to provide postoperative analgesia [24]. When used as a part of a multimodal analgesic protocol in patients undergoing TKA, femoral nerve blockade has been shown to reduce narcotic consumption and improve postoperative pain scores [25]. However, periarticular infiltration is usually insufficient to provide adequate analgesia in the anterior direction of the knee [26]. Periarticular infiltration analgesic protocols that infiltrate anterior, posterior, and medial compartments of the knee are reported to only last between 6 and 12 h [27]. Prolonged motor blockade, quadriceps muscle weakness, difficulty ambulating, and postoperative falls limit the utility of femoral nerve block (FNB) in the "fast track" rehabilitation protocols [28, 29]. In a study, Fascia iliaca block effectively reduced the amount of morphine used after TKA in the first 24 h. This study shows that the fascia iliaca block provides the same level of analgesia with the use of less morphine compared with the periarticular injection [30]. However, the fascia iliaca block requires as much as 40–50 mL of volume to achieve an effective result [31]. In another study, the analgesic efficacy of the fascia iliaca block was compared to the femur nerve block in the guideline

TKA operation is one of the most painful orthopedic procedures [43]. For this reason, it is difficult to provide adequate analgesia with a single drug or method. Multimodal analgesia methods will be more appropriate to reduce side effects and provide pain control. Multimodal analgesia is defined as providing more effective pain control by the combined use of various analgesic drugs and techniques that may have additive or synergistic effects targeting different pain mechanisms in the peripheral and/or central nervous system [44].

In multimodal pain management, patient education, preemptive oral medications, regional anesthesia methods, peripheral nerve blocks, local infiltrations, and postoperative rehabilitation are included. Most of the side effects seen in analgesia treatment are due to the parenteral opioid. One of the main goals of multimodal analgesia is to reduce the need for opioids.

#### *6.2.1. Nonsteroidal anti-inflammatory drugs*

Tissue inflammation in TKA surgery triggers the production of PGs that play a role in acute postoperative pain. NSAIDs reduce central sensitization by inhibiting central and peripheral prostaglandin synthesis. It may be effective for 2 weeks when inflammation continues in the postoperative period. Ketorolac is a nonselective COX inhibitor and has oral, parenteral, ophthalmic, and nasal forms. It is used in moderate and severe postoperative pain management after major surgeries [45]. It reduces opioid consumption when used as a part of multimodal pain management [46]. The use of NSAIDs can cause gastritis or peptic ulcer formation and impair platelet aggregation, renal function, and wound healing. For this reason, there are concerns about their use in the perioperative period. Preemptive use of selective COX-2 (cyclooxygenase) inhibitors (celecoxib and rofecoxib) has been shown to reduce postoperative pain scores in the knee surgeries [47]. The use of selective COX2 inhibitors in TKA surgeries has been shown to reduce opioid consumption, provide early onset of physical rehabilitation, and reduce nausea and vomiting [48]. Similarly, diclofenac or ketorolac administered in a single dose in joint arthroplasty patients reduced morphine consumption by 29% compared to placebo [49].

**1.** Mu (μ) receptors: specific morphine agonist. It is stimulated by morphine and is responsi-

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**4.** Delta (d) receptors: beta-endorphin and encephalin are specific agonists. It is influential on

**1.** Natural opioids: phenanthrene derivatives: codeine, morphine, and thebaine. Benzyliso-

**2.** Synthetic opioids: phenylpiperidine derivatives (fentanyl, sufentanil, and meperidine), benzomorphan derivatives (pentazocine and phenazocine), diphenylpropyl or methadone derivatives (methadone and d-propoxyphene), and morphinan derivatives (levorphanol). **3.** Semisynthetic opioids: dihydromorphone/morphinone, heroin, and thebaine derivatives

Morphine contains the basic properties of the majority of the structures of the opioids. The effects of morphine in the central nervous system, analgesia, euphoria and sedation. The most important effect of morphine on the central nervous system therapeutically is analgesia.

Analgesia provided by systemic opioids often accompanies side effects such as sedation, nausea, pruritus, urinary retention, and constipation. However, they continue to be an important part of severe postoperative pain management [69]. They can be used intramuscularly, intravenously, orally, rectally, sublingually, subcutaneously, epidurally, or intrathecally. If patients are able to use the oral route, oral administration is recommended. Side effects of oral opioids are less frequent and are mostly related to the gastrointestinal system. Intravenous patientcontrolled analgesia (PCA) should be preferred if the parenteral route is used. Intravenous opioid PCA is recommended for bolus application with appropriate lock interval without basal infusion. In the postoperative period, it is usually administered via intravenous PCA for the first 24–48 h and then is used as oral agents [44]. Oral opioids have immediate release and controlled release forms [70]. Rapid-release patients are effective in the treatment of moderate and severe postoperative pain, but are impractical because they need to be reapplied every 4 h. Since postoperative pain is continuous at the beginning, analgesics should be used regularly especially in the first 24 h. Long-acting oxymorphone and oxycodone have been shown to be effective in postoperative analgesia in TKAs [71, 72]. Especially morphine and fentanyl are frequently used for postoperative analgesia in ТKА cases. The application of intrathecal morphine and fentanyl is very effective in postoperative pain control. In a study conducted, 0.2 mg and 0.3 mg intrathecal morphine administration was shown to be effective for postoperative analgesia [73]. Other studies have been done to support this study. The use of 0.5 mg intrathecal morphine has been shown to be more reliable and more effective than injections of 0.2 mg [74].

**2.** Kappa (k) receptors: they are responsible for spinal analgesia and sedation.

**3.** Sigma (s) receptors: responsible for dysphoria and hallucinations.

ble for supraspinal analgesia.

Classification of opioids:

(etorphine).

motor integration and urine function.

quinoline derivatives: papaverine.

#### *6.2.2. Paracetamol*

It is nonopioidand and non-NSAID analgesic. It inhibits prostaglandin synthesis in the CNS and plays a role in preventing central sensitization. There is a minimal effect on peripheral PG synthesis. Unlike NSAIDs, the anti-inflammatory effect is poor, and there are no negative effects on platelet function and gastric mucosa. It has been shown that 1 g intravenous paracetamol provides rapid and effective analgesia in major orthopedic surgeons [50]. Paracetamol can be administered 1 g/day four times. When combined with paracetamol and NSAIDs, better analgesia is achieved when both drugs are used alone [51].

#### *6.2.3. Glucocorticoids*

Glucocorticoids have strong anti-inflammatory effects. Corticosteroids are thought to be an important component because of their local anti-inflammatory effects and their ability to reduce the local stress response in the operation [52]. There have been many studies on corticosteroids, and conflicting evidence has been obtained about their benefits [53–58]. Some studies have shown that postoperative pain is improved with corticosteroids [53–56] but other studies do not benefit [57, 58]. In another study, postoperative pain level was lower in the corticosteroid group than that in the noncorticosteroid group in first 24 h [59]. In a metaanalysis, dexamethasone, a long-acting glucocorticoid, has been shown to reduce postoperative pain and opioid consumption [60]. In one study, it was shown that preoperative single dose iv 40 mg dexamethasone reduced dynamic pain scores [61]. Another study showed that dexamethasone administered as a part of multimodal analgesia in 269 patients undergoing TKA reduced postoperative pain and bulimia and did not increase wound complications [62]. In contrast to these studies, patients with a periarticular injection with high- and low-dose corticosteroids were compared and found no improvement in postoperative pain level [58]. Surgical techniques such as the surgical approach and the use of pneumatic turniken may be effective on early postoperative pain [63, 64]. One of the most commonly used corticosteroids for periarticular injection is methylprednisolone [52, 57, 65–67].

#### *6.2.4. Opioids*

Opioids have been used to provide analgesia and relieve anxiety for centuries. Opioid receptors are found in many regions of the CNS. These receptors are located in the central nervous system, cerebral cortex, hypothalamus, thalamus, midbrain extrapyramidal area, substantia gelatinosa, and sympathetic preganglionic nerves. Places with the highest concentration of these receptors are structures and pathways associated with pain [68].

The first opioid receptors were found in 1973. Later, endogenous opioids were found. There are four types of receptors. These include mu (μ), kappa (k), sigma (s), and delta (d) receptors. Opioids show their effect by linking their receptors.


Classification of opioids:

nausea and vomiting [48]. Similarly, diclofenac or ketorolac administered in a single dose in joint arthroplasty patients reduced morphine consumption by 29% compared to placebo [49].

It is nonopioidand and non-NSAID analgesic. It inhibits prostaglandin synthesis in the CNS and plays a role in preventing central sensitization. There is a minimal effect on peripheral PG synthesis. Unlike NSAIDs, the anti-inflammatory effect is poor, and there are no negative effects on platelet function and gastric mucosa. It has been shown that 1 g intravenous paracetamol provides rapid and effective analgesia in major orthopedic surgeons [50]. Paracetamol can be administered 1 g/day four times. When combined with paracetamol and

Glucocorticoids have strong anti-inflammatory effects. Corticosteroids are thought to be an important component because of their local anti-inflammatory effects and their ability to reduce the local stress response in the operation [52]. There have been many studies on corticosteroids, and conflicting evidence has been obtained about their benefits [53–58]. Some studies have shown that postoperative pain is improved with corticosteroids [53–56] but other studies do not benefit [57, 58]. In another study, postoperative pain level was lower in the corticosteroid group than that in the noncorticosteroid group in first 24 h [59]. In a metaanalysis, dexamethasone, a long-acting glucocorticoid, has been shown to reduce postoperative pain and opioid consumption [60]. In one study, it was shown that preoperative single dose iv 40 mg dexamethasone reduced dynamic pain scores [61]. Another study showed that dexamethasone administered as a part of multimodal analgesia in 269 patients undergoing TKA reduced postoperative pain and bulimia and did not increase wound complications [62]. In contrast to these studies, patients with a periarticular injection with high- and low-dose corticosteroids were compared and found no improvement in postoperative pain level [58]. Surgical techniques such as the surgical approach and the use of pneumatic turniken may be effective on early postoperative pain [63, 64]. One of the most commonly used corticosteroids

Opioids have been used to provide analgesia and relieve anxiety for centuries. Opioid receptors are found in many regions of the CNS. These receptors are located in the central nervous system, cerebral cortex, hypothalamus, thalamus, midbrain extrapyramidal area, substantia gelatinosa, and sympathetic preganglionic nerves. Places with the highest concentration of

The first opioid receptors were found in 1973. Later, endogenous opioids were found. There are four types of receptors. These include mu (μ), kappa (k), sigma (s), and delta (d) receptors.

NSAIDs, better analgesia is achieved when both drugs are used alone [51].

for periarticular injection is methylprednisolone [52, 57, 65–67].

these receptors are structures and pathways associated with pain [68].

Opioids show their effect by linking their receptors.

*6.2.2. Paracetamol*

98 Primary Total Knee Arthroplasty

*6.2.3. Glucocorticoids*

*6.2.4. Opioids*


Morphine contains the basic properties of the majority of the structures of the opioids. The effects of morphine in the central nervous system, analgesia, euphoria and sedation. The most important effect of morphine on the central nervous system therapeutically is analgesia.

Analgesia provided by systemic opioids often accompanies side effects such as sedation, nausea, pruritus, urinary retention, and constipation. However, they continue to be an important part of severe postoperative pain management [69]. They can be used intramuscularly, intravenously, orally, rectally, sublingually, subcutaneously, epidurally, or intrathecally. If patients are able to use the oral route, oral administration is recommended. Side effects of oral opioids are less frequent and are mostly related to the gastrointestinal system. Intravenous patientcontrolled analgesia (PCA) should be preferred if the parenteral route is used. Intravenous opioid PCA is recommended for bolus application with appropriate lock interval without basal infusion. In the postoperative period, it is usually administered via intravenous PCA for the first 24–48 h and then is used as oral agents [44]. Oral opioids have immediate release and controlled release forms [70]. Rapid-release patients are effective in the treatment of moderate and severe postoperative pain, but are impractical because they need to be reapplied every 4 h. Since postoperative pain is continuous at the beginning, analgesics should be used regularly especially in the first 24 h. Long-acting oxymorphone and oxycodone have been shown to be effective in postoperative analgesia in TKAs [71, 72]. Especially morphine and fentanyl are frequently used for postoperative analgesia in ТKА cases. The application of intrathecal morphine and fentanyl is very effective in postoperative pain control. In a study conducted, 0.2 mg and 0.3 mg intrathecal morphine administration was shown to be effective for postoperative analgesia [73]. Other studies have been done to support this study. The use of 0.5 mg intrathecal morphine has been shown to be more reliable and more effective than injections of 0.2 mg [74]. Intrathecal morphine is less hydrophobic than other opioids, has a longer duration in the cerebrospinal fluid, and provides very good postoperative analgesia [75]. On the other hand, another study reported that morphine should not be used even in small doses due to these side effects [76]. Opioids are known to produce more effective and long-lasting anesthesia when used with local anesthetics. Opioids are known to produce more effective and long-lasting anesthesia when used with local anesthetics [77, 78]. In a study of TKA cases, we compared the use of intrathecal morphine and fentanyl for postoperative analgesia and found that fentanyl provided more effective postoperative analgesia [79]. Long-acting opioids (LAO) are often used for malignant, nonmalignant, and different pain treatments. A lot of work about LAO (oxycodone, morphine) has been done in this regard. In a study on LAO, there was a decrease in pain while there was an increase in vomiting and sedation [80]. After the use of LAO (oxycodone), the rehabilitation of patients was found to be better in TKA cases [81]. In the studies performed, intravenous PCA and oxycodone were compared and there was no difference in pain [82], and no difference in pain after LAO (oxycodone) used after total joint arthroplasty [83].

**6.3. Nonpharmacological techniques**

**6.4. Preemptive analgesia**

inflammatory injury [98].

**1.** Local anesthetics

**3.** COX-2 inhibitors

**6.5. Patient education**

scores decrease [100].

**5.** NMDA receptor antagonists

**4.** Opioids

Drugs used in preemptive analgesia:

**2.** Nonsteroidal anti-inflammatory drugs (NSAIDs)

nificant [94]. Routine use is therefore not recommended.

There have been many studies on surgical techniques and equipment, but most have had no or limited effect on postoperative analgesia. These studies focused on drains, surgical approaches, tourniquet use, prosthetic types, and reshaping of the patellar surface. A comparison of cooling and compression techniques with the control group showed that postoperative pain and morphine consumption were reduced [92]. The efficacy of TENS administration in postoperative analgesia after TDP was not demonstrated [93]. The results of cryotherapy are contradictory. The potential benefits of cryotherapy in a meta-analysis are not clinically sig-

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Analgesics are administered before painful stimulation to prevent peripheral and central sensitization. Preemptive analgesia inhibits peripheral sensitization and central sensitization. It should also prevent inflammatory and neuropathic pain types [95]. Local anesthetic infiltration, regional anesthesia methods, and drugs (NMDA receptor antagonists, opioids, COX-2 inhibitors, nonsteroidal anti-inflammatory drugs (NSAID), and local anesthetics) can be used for preemptive analgesia. According to a study, preemptive analgesia is statistically significant, although not clinically significant [96]. When preemptive analgesia is administered, it should be considered as a method of pathological pain as well as physiological conventional perioperative analgesia [97]. Preemptive analgesia is an effective method in clinical practice for the approach to postoperative pain involving incisional and

There are two major components of pain perception: the sensory discriminative component and the motivational affective component [99]. Emotional component is targeted with patient education. Patients and their relatives are informed, and their anxiety is reduced by eliminating their fears about the unknown; the realistic goals are identified, and a relationship is established with patients and their relatives; the patient satisfaction increases, and the pain

### *6.2.5. Gabapentinoids (gabapentin and pregabalin)*

Gabapentin has been shown to be effective in the treatment of herpetic neuralgia, neuropathic pain [84], and diabetic neuropathy [85]. These anticonvulsant drugs, which have been used for a long time in the management of chronic pain, have started to be used in acute postoperative analgesia in recent years. They may cause side effects such as sedation and dizziness. It has been shown that administration of pregabalin (300 mg preoperatively and 150–50 mg twice daily for the first 14 days postoperatively) reduces the incidence of opioid consumption and neuropathic pain development after TKA [86]. We also have studies showing that postoperative analgesia is reduced after the application of preoperative gabapentin and pregabalin in lower extremity surgeons [87, 88]. Another study has shown that gabapentin effectively reduces postoperative narcotics consumption and pruritus incidence [89]. In another metaanalysis trial, the use of pregabalin shows that it could improve pain control at 24 and 48 h with rest, reduce morphine consumption, and improve knee flexion level, as well as reduce nausea, vomiting, and pruritic event rate. However, pregabalin increased the incident rate of dizziness after total knee arthroplasty (TKA) and total hip arthroplasty (THA) but could not improve the pain control at 72 h with rest [90].

#### *6.2.6. Ketamine*

Ketamine is used by anesthetists for sedation and general anesthesia. With the detection of the N-methyl-d-aspartate receptor's role in nociceptive pain transmission and central sensitization, ketamine has begun to be used as a potential antihyperalgesic agent. Subanesthetic low doses of ketamine provide significant analgesic efficacy without psychomimetic side effects [45]. Low-dose ketamine has no adverse effects on respiratory and cardiovascular system and does not cause nausea-vomiting, urinary retention and constipation or postoperative ileus. In patients receiving TKA, low-dose ketamine infusion has been shown to reduce morphine consumption postoperatively (3 μg/kg per minute intraoperatively and 1.5 μg/kg per minute for 48 h) [91].
