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INTRODUCTION

Even under the best circumstances, surgery is controlled trauma. Suboptimal treatment of acute pain in the perioperative period can result in adverse short-term and long-term patient outcomes: insufficient acute perioperative pain control can lead to neuronal sensitization, which can subsequently result in chronic postoperative pain. The inability to control postoperative pain causes an increase in sympathetic tone, which leads to vasoconstriction and end-organ damage, a decrease in intestinal motility, which leads to increased nausea and vomiting, an impairment of immune function, increases in length of hospital stay and health care costs, and chronic regional pain syndrome.^1-4

Pathophysiology of pain

The subjective and emotional sensations of pain initiate at the site of tissue injury. Nociceptive nerves detect mechanical, chemical, or thermal changes in the injured tissue. This painful stimulus is then transduced by the nociceptors into action potentials and transmitted to the dorsal root ganglion via 2 types of afferent neurons: unmyelinated C fibers and myelinated A fibers. These first-order afferent nerve fibers continue propagating the action potential to the dorsal horn of the spinal cord, subsequently releasing synaptic glutamate and activating second-order afferent neurons. The pain stimulus is then relayed to the thalamus via the ascending spinothalamic tract; from there, it is sent to the somatosensory and limbic cortices of the brain. Sensory and affective pain discrimination, respectively, occur in these locations. The dorsal horn of the spinal cord is the primary site for the integration of the peripheral nociception and descending modulatory input.^1-6

Tissue injury, even in a controlled setting, results in the release of multiple inflammatory mediators, including histamine, bradykinin, prostaglandins (PGs), serotonin, nerve growth factor, leukotrienes, and 5-hydroxytryptamine. These mediators act either directly or indirectly on presynaptic first-order afferent neurons to intensify the noxious stimulus; they increase the concentrations of neurotransmitters such as calcitonin gene-related peptide, substance P, and cholecystokinin. The resulting inflammatory "soup" modulates numerous pain pathways that impact the development of peripheral sensitization ^1-7. Peripheral and central sensitization is the phenomena that is secondary to damaged cells, at the site of injury release inflammatory pain inducing agents. These mediators include bradykinin, cytokines, prostaglandins, growth factors, and substance P, that act either directly or indirectly on presynaptic first-order afferent neurons to intensify the sensation produced by a noxious stimulus⁷.

The development of central sensitization, which can take place immediately after surgery or up to several weeks after surgery, is influenced by multiple factors: preoperative pain, intraoperative tissue injury, and postoperative inflammatory processes. PGs and substance P can modulate central sensitization within the dorsal root ganglion; N-methyl-D-aspartate (NMDA) receptors that are activated in the spinal cord and higher brain centers also play an important role in central sensitization. Further, the up-regulation of cyclooxygenase (COX)-2 in the spinal cord can potentiate central sensitization.^1-6

Inflammatory-mediated hyperalgesia is usually a transient process that resolves with adequate pain treatment. However, continuing, unrelieved pain produces multifaceted functional, structural, chemical, and neuronal changes through a mechanism called neural plasticity. Neural plasticity generates pathologic pain that persists long after the recovery period of the initial painful injury. The phenomena of neural sensitization and plasticity highlight the significance of the multifocal drivers of pain. Multimodal analgesia seeks to moderate these diverse influencers of pain.^1,4,6-8

DEFINITION OF MULTIMODAL ANALGESIA

Due to an increased understanding of the nature and complexity of acute postoperative pain, as well as the desire to move away from opioid-based pain regimens, a multimodal approach is often chosen to treat this pain. This concept of pain management was first introduced by Kehlet and Dahl in 1993.⁷ Strictly, multimodal analgesia is defined as the administration of 2 or more drugs that act by different mechanisms for providing analgesia. These drugs may be administered via the same route or by different routes.⁸ A broader definition of multimodal analgesia relates a balanced approach to treating postoperative pain by combining adjuvants, analgesics, opioids, and regional techniques.^1,2 One goal of multimodal analgesia is to provide superior postoperative pain control through the simultaneous modulation of several pain pathways while minimizing the undesired adverse effects of excessive narcotic consumption, which can cause nausea, vomiting, sedation, ileus, respiratory depression, pruritus, and increased length of hospital stay.^1,6 A second objective of multimodal analgesia is to lessen dependence on opioid medications and, subsequently, decrease the incidence of opioid-related adverse events.⁷ This second goal is especially fitting, given the social context of the recent release of the Centers for Disease Control and Prevention (CDC) guidelines for safe opioid prescribing, which state that one of the greatest risks for opioid addiction is the use of opioid medications.⁹

Benefits of multimodal analgesia

The benefits of multimodal analgesia are a direct result of achieving the goals of multimodal analgesia and of not using postoperative pain treatment regimens that are anchored by opioid medications.

Improved postoperative pain relief

Jiang et al¹⁰ performed a meta-analysis of 21 randomized controlled trials (RCTs) involving approximately 1800 patients (1500 patients who underwent total knee arthroplasty [TKA] and 300 who underwent total hip arthroplasty [THA]) who were given periarticular multimodal drug injections (PMDIs) for postoperative pain control. The results of the analysis provided low-moderate quality evidence that PMDI provided better pain relief than traditional methods of pain relief in patients who underwent TKA or THA. In another study, Nakai et al¹¹ randomly divided 60 patients undergoing TKA into 3 groups of 20 patients per group: Group A did not receive multimodal therapy, Group B received an injection of a multimodal cocktail, and Group C received a local periarticular injection of a multimodal cocktail. (Different medications were used in Group B and Group C.) Group C had the best postoperative pain control, but patients in Groups B and C had significantly better postoperative pain control than patients in Group A. An RCT of patients undergoing lumbar decompression was performed to compare postoperative pain control with an opioid alone (morphine) compared with a preemptive multimodal analgesic regimen. The patients who received the multimodal postoperative pain regimen had lower visual analog scores (VAS) of pain at all time points.¹²

Opioid-sparing effects

In the study by Jiang et al,¹⁰ patients who were prescribed a PMDI regimen used less opioid medication than those who did not receive PMDIs. Mathiesen et al¹³ compared multimodal pain treatment with historical controls in patients who experienced multilevel spine surgery. The patient population included 40 consecutive patients who underwent multilevel spinal surgery and 40 historical controls who had comparable surgeries. The multimodal treatment included acetaminophen (APAP), nonsteroidal anti-inflammatory drugs (NSAIDs), gabapentin, dexamethasone, S-ketamine, and epidural pain treatment; the historical controls received patient-controlled analgesia (PCA) with morphine. The patients who received multimodal analgesia had a significantly lower use of opioid medication.¹³ In the study of patients undergoing lumbar decompression, patients receiving the multimodal pain medications had a 58% decrease in morphine use.¹² Jebaraj et al¹⁴ performed a systematic review of RCTs in which intravenous (IV) APAP was added to the postoperative pain regimen of patients undergoing orthopedic surgery. The review concluded that orthopedic postoperative pain protocols that contained IV APAP decreased opioid use by 46%.¹⁴

Decreased length of hospital stay

A retrospective study compared the use of a multimodal analgesia protocol in 200 total joint arthroplasty (TJA) patients to traditional postoperative pain control. Multimodal analgesia was associated with a significant decrease in length of hospital stay. The patients prescribed multimodal analgesia had an average length of stay of 2.5 days, and the patients in the traditional treatment group had an average length of stay of 3.1 days (p = 0.002).¹ Hansen et al¹⁵ evaluated a multimodal analgesia protocol and compared IV APAP and IV opioid medication with IV opioid medication alone. In a retrospective analysis of a central database between January 2009 and June 2015, approximately 500,000 orthopedic surgery patients were identified for the study. One-third of the study population received postoperative pain management with combination IV APAP and IV opioids and the remaining two-thirds received IV opioids starting on the day of surgery and continuing up to the second post-operative day. Patients who received IV APAP had a significantly shorter length of hospital stay. The decrease in hospital stay resulted in decreased hospital costs of more than $600 per patient.¹⁵

Decreased levels of nausea and vomiting

In the study of patients undergoing TKA or THA, Jiang et al¹⁰ observed less postoperative nausea and vomiting (PONV) in patients who were prescribed PMDIs for postoperative pain than in patients in the control group, who did not receive PMDIs.¹⁰ In the trial by Mathieson et al,¹³ the patients administered multimodal analgesia experienced less nausea than patients in the control group.¹³

STRATEGIES FOR MULTIMODAL ANALGESIA

Multimodal analgesia regimens are successful when they combine medications with different and complimentary mechanisms of action. In this way, the regimens provide increased pain relief, decreased pain perception, reduced occurrence of adverse side effects, and decreased length of postoperative hospital stay.^1,2,8,16,17 Such a balanced approach for the treatment of postoperative pain with a combination of adjuvant medications, analgesic non-opioid medications, opioid medications, and regional techniques attenuates the multiple drivers of postoperative pain. The final result is an additive or synergistic analgesia that is designed to decrease the use of postoperative opioid medications and decrease adverse medication-related events.^4,5,8,16,17 Table 1 lists the multiple components that could be utilized in a medication regiment for of multimodal analgesia.^1,7,13,16-22

Table 1: Components of Multimodal Analgesia1,7,12,16-22

Neural axial blockade Intrathecal, epidural medications Peripheral nerve blocks Transversus abdominis plane blocks Paravertebral blocks Local infiltration Intra-articular Incisional Systemic Nonsteroidal anti-inflammatory drugs/Cyclooxygenase-2 inhibitors Acetaminophen Gabapentinoids Ketamine α-2 agonists Magnesium Dexamethasone Opioid medications

Preemptive analgesia

Preemptive analgesia is initiated before surgery; its objective is to exert a preventive effect on pain perception and reduce nociceptive transmission of postoperative pain through the inhibition of central pain perception, which can lead to central sensitization.^{1-7,11-14,16,17} Preemptive analgesia uses medications with analgesic and antihyperalgesic properties whose durations of effect are longer than the expected durations of the medications. The theory of preemptive analgesia is rooted in preventing the production of inflammatory chemicals that are released during a painful stimulus, thereby circumventing the sensitization of central and peripheral nociceptive pain receptors. Sensitization of these nerve fibers decreases the pain threshold, which adds to the development of hypersensitivity to innocuous stimuli occurring during the postoperative period. Continued stimulation of these nerve fibers can result in chronic neuropathic pain. However, the prevention of this continued sensitization can improve a patient's postoperative pain, which can then reduce the risk for the development of chronic neuropathic pain.^1,7,16-18  

Preemptive analgesia usually includes medications that are easy to administer, have short onsets of action, and have an adverse effect profile that will not compromise the planned surgical procedure; medications may include NSAIDs, COX-2 inhibitors, pregabalin, gabapentin, and APAP. The medications are administered in the preoperative holding area 1 to 2 hours before incision.^7,8,17,18

Neural axial blockade

Neural axial blockade (NAB) includes epidural and spinal blocks administered as a single bolus, as well as a continuous infusion or in PCA delivery systems.^1,7,12,16-19 Opioids used for NAB provide superior analgesia than systemic opioids. The onset, potency, and duration of neuraxial opioids are determined by the lipophilicity or hydrophilicity of the medication. Fentanyl, a lipophilic opioid, provides rapid onset of analgesia, with limited distribution to the cerebrospinal fluid, and rapid clearance within 1 to 4 hours. Morphine and hydromorphone, which are hydrophilic opioids, have longer onsets on action (i.e., approximately 30 minutes) than lipophilic opioids and durations of action of up to 6 hours.^1,7,16-19 However, the lipophilic opioids are associated with a higher frequency of side effects such as pruritus, nausea, and vomiting, as well as delayed respiratory depression.^1,7,8,16-19

Respiratory depression is the most significant adverse event associated with hydrophilic opioids such as morphine and hydromorphone: it can happen as late as 24 hours after the administration of the opioid. Epidural NAB has been shown to decrease early postoperative VAS pain scores. Patients who receive intrathecal NAB have been shown to have substantially lower VAS scores and lower PCA requirements. Although a local anesthetic and an opioid work synergistically, to date, no analgesic combination is preferred as the most effective and universally applicable recipe for specific neuraxial analgesia.^1,16-19

Peripheral nerve blocks

The use of a peripheral nerve block (PNB), either as a single injection or as a continuous infusion of a long-acting anesthetic through an indwelling catheter, has been found to decrease acute postoperative pain in patients undergoing orthopedic procedures. While many studies have reported that the use of PNBs decreases postoperative opioid use, recent guidelines for the treatment of perioperative pain have concluded that the data for PNBs is equivocal.^1,7,8,16-19 There are 3 methods of accomplishing PNBs for TJA: psoas compartment block (complete lumbar plexus), fascia iliaca block (femoral, obturator, and partial lateral femoral cutaneous nerves), and femoral nerve block (femoral and partial lateral femoral cutaneous nerves).⁷

In addition to decreasing postoperative opioid use, PNBs are advantageous because their unilateral nature enables early ambulation following TJA. (Patients who undergo TJA and do not receive PNBs tend to initially rely on the contralateral limb for ambulation.) Long-acting anesthetic agents provide the longest duration of action and, because of this characteristic, are the most commonly used medications for PNB.^1,7,16-19

Possible adverse events of PNB use include nausea, vomiting, pruritis, nerve injury, bleeding, and infection. A unique disadvantage of continuous PNB is motor weakness. The presence of motor weakness increases the potential fall risk. The use of a protective nerve brace can be used to decrease the chance of falls secondary to limb weakness.^7,16-19 Nerve palsy has been reported with PNB, though the incidence is low (between 0.22% and 0.5%). The most severe systemic complications arising from PNB use are the rare occurrences of seizure and cardiac arrest; the combined incidence of these complications is less than 0.03%. The use of lipid emulsion as a treatment for PNB systemic toxicity, combined with the use of local anesthetics with a larger margin of safety such as ropivacaine, and the use of ultrasound to guide the injections has decreased the incidence of PNB side effects.^7,18

Systemic medications for multimodal analgesia

Administering local anesthetics or nerve blockades does not eliminate the need for systemic pain control after surgical procedures. Several systemic medications comprising multiple mechanisms of action can be administered via various routes of administration as part of multimodal analgesia in the perioperative setting.

Acetaminophen

A recent set of guidelines for the treatment of acute pain in the postoperative setting strongly encourages the use of APAP as part of a multimodal analgesic postoperative protocol.⁸ The mechanism of action of APAP-mediated pain relief is not completely understood, but APAP quickly crosses the blood-brain barrier and most of the mechanisms involved in analgesia are believed to take place in the central nervous system (CNS). APAP centrally inhibits PGs via the COX pathway. APAP has been demonstrated to strengthen the descending serotonergic inhibitory pain pathways, initiate indirect activation of cannabinoid CB1 receptors, act as an agonist of transient receptor potential cation channel subfamily V member 1, serve as a central antinociceptor, and reduce nitric oxide pathways via NMDA or substance P.^1,20-22 Even though APAP inhibits COX-1 and COX-2 enzymes, APAP has low peripheral anti-inflammatory activity, limited gastrointestinal (GI) effects, and a clinically insignificant impact on platelet function, which distinguishes it from NSAIDs.^20,21

APAP is available in rectal, oral, and IV formulations around the world. APAP peak plasma concentrations are achieved 3.5 to 4.5 hours after rectal administration, 45 to 60 minutes after oral administration, and within 15 minutes after IV infusion. Rectal formulations are an appropriate choice in the setting of PONV, but these preparations have been associated with lower bioavailability and increased interpatient variability compared with oral formulations. (Oral bioavailability of APAP is 85% to 93%.) Early plasma concentrations of APAP after rectal administration may vary, resulting in subtherapeutic concentrations of less than 10 mg/mL for up to 1 to 1.5 hours^20-22.

The dose of APAP for oral and IV administration to adult and adolescent patients weighing at least 50 kg is 1 g every 4 to 6 hours, up to a maximum of 4 g/day or a dose of 650 mg every 4 hours (3,900 mg/day)^20,21. In the recent years the maximum daily dose of APAP has come under heavy scrutiny, and some experts recommend no more than 3 g/day of APAP²². For most patients, the shortest dosing interval is 4 hours, but for patients with severe renal impairment (i.e., creatinine clearance of 30 mL/min or lower), the minimum duration between doses is 6 hours. For patients weighing less than 50 kg and for children and newborns, a weight-based dose of 10 to 15 mg/kg of APAP should be administered.

The roles of IV versus oral APAP in postoperative pain control have yet to be fully elucidated.^20-22 IV APAP is the administration route of choice if a patient cannot tolerate the administration of oral medications. IV APAP allows for convenient administration with a rapid onset of pain relief that may be particularly useful in the postoperative setting.^{1,7,12,14,16-22} The onset of pain relief after IV APAP occurs within 15 minutes in adult patients. This rapid onset may offer a clinical benefit compared to oral dosing, which has an onset ranging from 30 to 90 minutes: in clinical situations in which rapid onset of action is desired or when the patient is unable to reliably tolerate oral intake, an IV formulation of APAP may be preferred.²¹

A Cochrane review examining APAP compared to placebo for postoperative pain demonstrated that the number needed to treat for 1 patient to achieve at least at 50% reduction in pain after a single dose (1 g) of APAP is 4.6.²² A recent review of the literature of IV APAP for postoperative pain in patients undergoing orthopedic surgeries stated that 5 trials showed significant decreases in postoperative opioid use after administration of IV APAP. The same review stated that 6 clinical trials reported decreased pain scores when APAP was included in a postoperative multimodal pain protocol.¹⁴ In the retrospective review discussed previously, the addition of APAP to a postoperative pain protocol decreased hospital stays and lowered hospital costs.¹⁵

APAP has limited potential for drug-drug interactions. Medications that inhibit or induce hepatic enzyme cytochrome P450 2E1 may alter the metabolism of APAP: medications that inhibit this enzyme may increase APAP's hepatotoxic potential, but the clinical significance of consequences of these drug-drug interactions have not been established. The clinical significance of APAP-ethanol interactions is complex: alcohol intake induces hepatic cytochromes, yet alcohol acts as a competitive inhibitor of the metabolism of APAP. The concurrent use of probenecid decreases APAP clearance, but, again, the clinical significance of these effects remains to be fully discerned. Previous reports, as well as professional experience, suggest that APAP may increase the risk for developing liver damage in patients receiving (or those who received in the past) hepatic enzyme-inducing medications. Nevertheless, a review of the literature of patients taking APAP and barbiturates and/or antiseizure medications demonstrated scant evidence to support this assertion.²¹

NSAIDs and COX-2 inhibitors

The same guidelines for the treatment of acute pain in the postoperative setting that encourage the use of APAP also strongly encourage the use of NSAIDs as part of a multimodal analgesia postoperative regimen.⁸ Tissue damage during surgery causes the release of arachidonic acid from membrane phospholipids. Arachidonic acid is ultimately metabolized to PGs, which, in turn, decrease the pain threshold in peripheral nociceptors.^7,19-22 The COX enzymes mediate this metabolism: COX-1 is the most abundant isoform of COX found in most tissues and it mediates renal homeostasis, platelet aggregation, and preservation of the GI mucosa; COX-2 is primarily expressed in the brain and kidneys, but it is also expressed at the site of tissue injury due to the actions of cytokines and growth factors. These enzymes produce the PGs responsible for pain modulation.⁷ At the site of tissue injury, PGs sensitize first-order afferent neurons to bradykinin; in the dorsal root ganglion, PGs potentiate the release of excitatory substances: glutamate and substance P. PGs also affect glycinergic inhibition of primary afferent neurons.^7,22

NSAIDs act to reversibly, or irreversibly, inhibit COX-1 and COX-2, which ultimately prevents the conversion of arachidonic acid into PGs and thromboxane A2.^1,7,16-22 The COX-1 pathway, which is ubiquitous throughout the body, mediates PGE2-driven gastric mucosal protection and thromboxane effects on coagulation. The COX-2 enzyme, which is an inducible pro-inflammatory molecule, is chiefly involved with generation of PGs that modulate pain and fever, but it has no effect on the anticoagulation cascade or platelet function.^1,7,22 Most COX-1 and COX-2 inhibitors have excellent bioavailability, are significantly and tightly bound to plasma proteins, are metabolized by the liver, and are eliminated via renal excretion.^{1,7,12,16-18,20-22} For optimal results and pain control in the postoperative setting, NSAIDs should be administered on a scheduled, around-the-clock basis instead of on an as-needed basis.^17,22

Numerous studies describe the benefits of including COX-1 or COX-2 inhibitors in a multimodal analgesia protocol.^{1,6,7,12,16-22} The use of NSAIDs as part of postoperative pain control has been shown to decrease opioid medication use by up to 20% to 30%. Effective analgesia is achieved with both COX-2 selective inhibitors and nonselective NSAIDs, and greater pain relief is achieved with a longer duration of therapy. A recent meta-analysis of 17 studies comparing the use of NSAIDs to the use of opioid pain management alone showed decreased pain scores and lower opioid consumption when adjunct NSAIDs were administered to patients undergoing lumbar spine surgery.¹² A meta-analysis of 8 RCTs evaluated a total of 571 patients undergoing TKA who were prescribed perioperative COX-2 inhibitors; the perioperative use of COX-2 inhibitors resulted in lower VAS scores, greater range of motion, less opioid consumption, and a lower incidence of opioid-related adverse effects. An RCT of 107 patients undergoing TKA who were prescribed 200 mg of celecoxib (a COX-2 selective inhibitor) twice daily for 6 weeks postoperatively demonstrated significantly lower VAS pain scores.  Additionally there was less total postoperative opioid medication use in the treatment group that was prescribed celecoxib: 76.3 ± 55 tablets of opioid medication in the celecoxib group versus 138 + 117 tablets of opioid medication in the group that did not receive the COX 2 inhibitor¹

However, NSAIDs are not without risks. Renal failure, platelet dysfunction, and gastric ulcers or bleeding are associated with the nonspecific inhibition of the COX-1 enzyme and are the primary adverse events that limit the use of NSAIDs.^{1,6,7,12,16-22} A Cochrane review challenged the concept that NSAIDs have a deleterious effect on renal function in the perioperative period: a total of 23 trials were reviewed that included a total of 1459 patients. The review noted that NSAIDs caused a clinically insignificant transient reduction in renal function in the early postoperative period in patients with normal preoperative renal function. Therefore, NSAIDs should not be withheld from adults with normal preoperative renal function because of concerns about postoperative renal impairment.¹⁷ Advantages of the COX-2 inhibitors are the lack of platelet inhibition and a low incidence of GI effects.^{1,6,7,12,16-22} According to available research investigating the short-term use of NSAIDs, it appears that renal and cardiovascular side effects are uncommon in patients without renal or cardiac risk factors.¹⁹

A unique adverse event of NSAIDs used in perioperative pain management in patients undergoing orthopedic surgeries is the increased risk of pseudoarthrosis (also called nonunion). A retrospective study illustrated significantly increased nonunion rates of 17% in patients who received intramuscular ketorolac compared with 4% in patients who received no NSAIDs postoperatively. However, a meta-analysis of 5 retrospective comparative studies demonstrated an increased risk of nonunion with the use of high-dose ketorolac after spinal fusion but no detrimental effects of short-term use of NSAIDs such as ketorolac, diclofenac, celecoxib, or rofecoxib at standard recommended doses.¹² Therefore, the effects of NSAIDs and COX-2 inhibitors on bone formation and healing are inconsistent in the orthopedic population.

Membrane-stabilizing agents and calcium channel α-2-d ligands (gabapentanoids)

Although the exact mechanism of actions of gabapentin and pregabalin are unknown, it is widely believed that these agents inhibit the α-2-δ-1 and α-2-δ-2 subunits of voltage-gated calcium channels on neuronal cells to decrease the amount of voltage-gated calcium channels trafficked outwards to the cellular membrane.^{1,7,12,17,19,22} This causes a subsequent decrease in the release of the neurotransmitters glutamate, norepinephrine, serotonin, dopamine, and substance P into the synaptic cleft.¹⁹ These medications may help to decrease central sensitization to pain.¹

The use of gabapentin for postoperative pain control in orthopedic surgeries has demonstrated mixed results. A recent systematic review and meta-analysis investigating the efficacy of gabapentin and pregabalin in postoperative pain management of lumbar spine surgery analyzed 7 high-quality trials. This meta-analysis described significant postoperative pain reduction and decreased opioid medication use with the use of either gabapentin or pregabalin compared with placebo treatment. The analysis reported few notable adverse effects.¹² A meta-analysis of RCTs assessing gabapentin use after THA showed improved postoperative pain control and decreased opioid medication requirements in patients prescribed gabapentin postoperatively. However, in another study, the use of gabapentin as part of a THA postoperative multimodal pain regimen did not lower pain scores or adverse events or improve range of motion.²²

Recently, 2 meta-analyses investigated the use of pregabalin in multimodal postoperative pain control in TKA patients. In the first study, 6 trials that enrolled a total of 769 patients assessed VAS pain scores after TKA with rest or mobilization at 24 and 48 hours. Perioperative use of pregabalin decreased pain at 24 and 48 hours at rest. In addition, pregabalin use was associated with decreased postoperative opioid doses.²³The second meta-analysis included 7 randomized trials to evaluate the efficacy of pregabalin after total knee replacement. The analysis demonstrated that pregabalin decreased pain at 24 and 48 hours with rest, decreased postoperative opioid use, and increased knee flexion. However, the use of pregabalin did not decrease pain at 72 hours postoperatively.²⁴

Despite positive outcomes reported in these analyses, several studies offer no evidence of benefit of the perioperative use of membrane-stabilizing medications such as gabapentin and pregabalin as part of multimodal analgesia regimens. These investigations did not demonstrate any decreases in acute pain or reductions in opioid medication use between the patients who received gabapentanoids and control patients.¹⁹

Multiple investigations and trials of gabapentin and pregabalin illustrated that these agents decreased PONV.^{1,12,19,22-24} However, the use of these agents is not without risk. The most common adverse events associated with these membrane-stabilizing agents are sedation, dizziness, somnolence, peripheral edema, and CNS effects.^1,7,19,22-24

Pregabalin is a more potent medication and has less variable absorption than gabapentin. The use of gabapentin and pregabalin for multimodal analgesia is considered an off-label use.^1,12,17,22 The doses of gabapentin and pregabalin employed in studies evaluating their utility in perioperative pain control were standard doses that are recommended by the manufacturers and the United States (U.S.) Food and Drug Administration (FDA). The doses of gabapentin used in these studies were 300 to 1200 mg, and the doses of pregabalin were 75 to 600 mg.^{1,12,17,19-24}

NMDA antagonists

Several NMDA antagonists are available as anesthetics and can be used in multimodal pain control. These agents inhibit the action of NMDA at the NMDA receptor.

Ketamine. Ketamine, which is traditionally used as an anesthetic agent, is a racemic mixture of R and S enantiomers.²² The S or levo enantiomer is approximately 4 times more potent than the R or dextro enantiomer. The S enantiomer has fewer adverse CNS effects and a shorter duration of action than the R enantiomer.^2,5,6,22

The primary mechanism of action of ketamine is the noncompetitive inhibition of NMDA receptors in the CNS and spinal cord.^5,6,20,22 Therefore, ketamine's actions reduce the presynaptic release of glutamate and improve opioid-induced hyperalgesia and pain tolerance.^5,6,20 Additionally, ketamine is theorized to weakly interact with m- and k-opioid receptors. However, when employed at high doses, ketamine can have local anesthetic properties related to the inhibition of neuron sodium channels. Ketamine may also possess anticholinergic activity due to its inhibition of nicotinic and muscarinic receptors.^5,6 When used intraoperatively, subanesthetic doses of ketamine may attenuate the actions of opioids and volatile anesthetic-induced hyperalgesia.²² Orthopedic surgery patients with a past medical history of substance abuse, chronic pain patients who are opioid-tolerant, and/or patients who are currently taking opioid agonist/antagonist combinations or partial agonists such as buprenorphine may particularly benefit from the unique properties of ketamine.^5,6

A systematic review of more than 70 studies of IV ketamine used for postoperative pain control demonstrated decreased postoperative opioid use for pain control. Surgery patients who were also being treated with chronic opioid therapy were prescribed intraoperative ketamine at a dose of 10 mcg/minute; these patients demonstrated less post-surgical opioid use and lower pain intensity than patients who did not use ketamine.²²

The adverse effects of ketamine are dose dependent, with higher doses of ketamine being associated with an increased incidence of adverse events. The adverse events are primarily related to the CNS and include vivid dreams, hallucinations, dysphoria, and anxiety.^5,6,22 Benzodiazepines are commonly given with high doses of ketamine to attenuate the psychomotor effects associated with ketamine.^5,6

Magnesium. Magnesium is a noncompetitive NMDA antagonist; it acts to prevent extracellular calcium movement into cells and decreases central sensitization. Magnesium has also been shown to block glutamate and aspartate at the NMDA receptor. Magnesium can be administered intravenously in the perioperative period. Pooled data have shown that perioperative infusions of magnesium are associated with decreased postoperative pain and opioid use. These studies also demonstrated that IV infusions of magnesium can be used without clinically significant effects caused by toxic serum levels of magnesium.¹⁷ A recent systematic review of the literature illustrated that IV magnesium decreased IV opioid use by 25% in the first 24 hours postoperatively. Intrathecal administration combined with intrathecal morphine has demonstrated a synergistic effect secondary to magnesium's NMDA receptor blockade activity. Additionally, the combination of ketamine and magnesium has shown synergistic activity.^2,5,22 A recent meta-analysis demonstrated that magnesium infusions do lower acute pain scores postoperatively, which leads to opioid-sparing effects. When magnesium was continued as an infusion postoperatively, further improvements in pain scores and decreased opioid use were evident.^2,5 Adverse effects of magnesium include nausea, vomiting, diarrhea, hypotension, and arrhythmias.²²

Central-acting α-2 agonists

Clonidine and dexmedetomidine are centrally acting, presynaptic a-receptor agonists. These agents decrease central sympathetic outflow, which results in a sympatholytic effect and decreased norepinephrine release in the locus ceruleus and substancia gelatinosa.^2,6,19,22 Dexmedetomidine possesses a much higher affinity for the α-2 receptor than the a-1 receptor: it is 7 to 8 times more selective for the α-2 receptor than clonidine. However, dexmedetomidine is not yet approved by the FDA for spinal or epidural anesthesia.²² Clonidine can be given intrathecally, intravenously, orally, and topically. Dexmedetomidine can be administered intravenously.^2,19

A meta-analysis of clonidine and dexmedetomidine administered perioperatively showed that patients receiving either a-agonist agent had a morphine dose reduction at 24 hours, with dexmedetomidine providing a more pronounced opioid-sparing effect.^19,22 When administered intrathecally, clonidine can potentiate the sensory and motor block of local anesthetics by 30% to 50%. Additionally, perioperative dosing of dexmedetomidine can prolong the duration of both sensory and motor blocks in spinal anesthesia.²²

The most common adverse effects associated with these medications are dry mouth, drowsiness, dizziness, constipation, and sedation.^2,6,19,22 Clonidine can also produce cardiovascular effects such as hypotension, bradycardia, congestive heart failure, electrocardiographic abnormalities, and orthostatic symptoms.^19,22 In the Perioperative Ischemic Evaluation (POISE)-2 trial, low-dose clonidine administration was shown to increase the risk of clinically significant hypotension and nonfatal cardiac arrest.²² Dexmedetomidine produces hypotension and bradycardia at incidences of 17% and 26%, respectively.^19,22

For perioperative use, clonidine is prescribed for intrathecal administration in doses ranging from 15 to 45 mg. When utilized as an adjuvant to PNBs, the dose of clonidine for perioperative use is 0.5 to 1.0 mg/kg. Dexmedetomidine for procedural indications is administered as a loading dose of 1 mg/kg given over 10 minutes followed by a maintenance infusion of 0.2 to 0.6 mg/kg per hour.^2,6,22

Glucocorticoids

Dexamethasone, a glucocorticoid, produces an anti-inflammatory response by inhibiting activated glucocorticoid receptors and transcription factors such as nuclear factor-k B and activator protein-1, which are involved in pro-inflammatory gene expression.^19,22 As a result, glucocorticoids possess many varied mechanisms of action: they prevent the release of acid hydrolases from leukocytes, prevent leukocyte attachment to vessel endothelium, lower macrophage accumulation, decrease edema formation via blocking capillary walls, block histamine activity, reduce inflammation from endotoxins, inhibit the release of cytokines such as tumor necrosis factor-a, and decrease immunoglobin/complement concentrations.²² Together, these mechanisms can produce a significant positive effect on pain management and lessen systemic inflammation. Glucocorticoids limit pain mediators and directly block c-fiber transmission and potentiate endorphin release.^7,22 Dexamethasone, given preoperatively at a dose greater than 0.1mg/kg, lowers postoperative pain and subsequent opioid medication use. Placebo-controlled, randomized clinical trials have illustrated that preoperative methylprednisolone at high doses produced markedly decreased pain scores for up to 32 hours postoperatively, lowered postoperative immediate-release oral oxycodone use for the first 24 hours, and produced less fatigue during the day of surgery. However, these beneficial effects came at the expense of a restful night's sleep on the first postoperative night.⁷

Adverse effects of glucocorticoids include impaired wound healing, elevated glucose and insulin resistance, gastrointestinal ulcers, CNS effects such as restlessness and euphoria, osteoporosis, muscle wasting, fat redistribution, and the Cushing effect. However, these events do not appear to be clinically significant following a single preoperative dose of a glucocorticoid.^7,19,22

Opioid medications

Opioid medications are the cornerstone of moderate-to-severe postoperative pain control.⁷ Opioid medications bind μ-, δ-, and κ-opioid G protein-couple receptors in the nervous system. The primary sites of action of opioids are the dorsal horn of the spinal cord, brainstem, cortex, and portions of the peripheral nervous system. At the level of the damaged tissue, opioid receptors interact with nociceptors and prevent signal transduction. At the dorsal root ganglion, opioid medications imitate the actions of endogenous opioids on first- and second-order neurons by inhibiting the release of neurotransmitters, thereby hyperpolarizing the cell membrane. In the midbrain, opioid medications inhibit synaptic transmission of gaba-aminobutyric acid through the descending inhibitory pathways, facilitating the synaptic currents in these antinociceptive regulatory pathways.^7,19 The therapeutic profile versus the adverse-effect profile of opioids is determined by the balance of receptor activity. Effects such as analgesia, antitussive, and anti-shivering must be balanced with undesirable effects such as respiratory depression, nausea, vomiting, and decreased GI and urinary motility. Analgesic effects, euphoria, and sedation are mediated through m-receptor agonism; k- and d-receptor activation results in sedation and/or weak analgesia.⁷

Opioid medications have been used postoperatively for centuries and they produce multiple positive effects for postoperative pain control. However, the liberal use of opioid medications in recent decades has led to an opioid use epidemic. The cost of indiscriminate opioid prescribing is sobering: an opioid overdose death occurs approximately every 30 minutes in the U.S.¹⁷ Recent CDC guidelines for safe opioid prescribing state that the use of opioid medications postoperatively places patients at risk for opioid addictions and, therefore, recommend a very small postoperative window of opioid medication use of 3 days.⁹

Oral administration of morphine, oxycodone, or hydrocodone or IV administration of morphine, hydromorphone, or fentanyl are the most common choices for opioids used in perioperative pain management. Oral administration may provide adequate analgesia compared with IV administration of opioid medications, and oral administration is associated with fewer adverse events than IV administration.^2,6,7 The CDC guidelines recommend the use of immediate-release opioids rather than sustained-release formulations, and they caution against the concurrent use of sustained-release and immediate-release opioid medications.⁹ Most multimodal analgesia protocols advocate for the use of immediate-release opioids for 48 hours after surgery, with around-the-clock dosing at a fixed schedule.⁷ The use of methods that allow patients to have greater direct control over their postoperative pain medication, such as a patient controlled pump intravenous administration, known as patient controlled analgesia (PCA),  has resulted in greater postoperative pain control, with fewer undesirable effects such as respiratory depression.^2,6,7,19

The adverse effects of opioid medications limit their widespread usefulness. Opioids affect multiple organ systems and pathways, including digestive, nociceptive, immune, hormonal, psychomotor, urinary, cardiac, respiratory, and musculoskeletal systems. Therefore, opioid medications produce a constellation of adverse effects, including nausea, vomiting, constipation, sedation, dizziness, respiratory depression, physical dependence, tolerance, immunosuppression, sexual dysfunction, depression, fatigue, decreased bone mineral density, sleep disturbance, urinary depression, and hypotension.^2,6,7,19

GUIDELINE RECOMMENDATIONS FOR MULTIMODAL ANALGESIA IN ORTHOPEDIC SURGERY

Given the quantity and variety of medications discussed, as well as the volume of research and evaluations of the use of the medications in multimodal analgesia, a concise, yet thorough, set of guidelines that direct perioperative pain management in orthopedic surgeries is warranted. The American Society of Anesthesiologists (ASA) Task Force on Acute Pain Management and the Korean Knee Society have published two of the most through guideline recommendations for postoperative pain control in orthopedic surgery.^8,25 The purpose of these guidelines is to: (1) facilitate the safety and effectiveness of acute pain management in the perioperative setting; (2) decrease the risks of adverse outcomes; (3) maintain patients' functional abilities, as well as physical and psychologic well-beings; and (4) enhance quality of life for patients with acute pain during the perioperative period.⁸ The Korean guidelines were developed on the basis of a systematic review of research evidence and the consensus opinions of a multidisciplinary working group of experts. The ASA guidelines were developed by a task force of 11 appointed members that consisted of anesthesiologists in private and academic practices from various geographic areas of the U.S. and 2 consulting methodologists from the ASA Committee on Standards and Practice Parameters. The ASA task force established guidelines by means of a 7-step process that reviewed and evaluated scientific evidence and opinion-based evidence, sought the opinions of experts outside the task force, and approved and re-evaluated recommendations. ⁸ This rigorous methodological process was similar to the CDC's process for developing guidelines for safe opioid prescribing.^9,25

The ASA guidelines state that consultants and ASA members strongly agree that, whenever possible, anesthesiologists should use multimodal pain management therapy. Further, these parties strongly agree that APAP should be considered as part of a postoperative multimodal pain management regimen and that COX-2 selective NSAIDs, nonselective NSAIDs, and gabapentaniods should be considered as part of a multifaceted, postoperative multimodal pain management regimen. Further, unless contraindicated, patients should receive an around-the-clock regimen of NSAIDs, COX-2 selective NSAIDs, or APAP.⁸

The Korean guidelines for pain control after orthopedic surgeries is not as extensive as its American counterpart, possibly reflecting the difference in procedures considered.^8,25 The Korean guidelines recommend the use of multimodal oral pain regimens as soon as oral administration of medications is possible after surgery. The guidelines reinforce that the combined use of medications with differing mechanisms of action produces maximum pain relief with reduced opioid consumption, which results in fewer adverse events and greater patient satisfaction. Similar to the ASA guidelines, the Korean guidelines advocate the use of APAP and COX-2 inhibitors.²⁵

Recommending appropriate multimodal regimens after THA or TKA

The ASA guidelines recommend 2 possible methods of multimodal analgesia. One approach is the use of 2 or more analgesic agents from different medication classes administered by a single route of administration rather than a single agent administered alone. For example, epidural or intrathecal opioids could be combined with local anesthetics or clonidine; IV opioids could be combined with clonidine, ketorolac, or ketamine; or oral opioids could be combined with NSAIDs, COX-2 selective inhibitors, or APAP. A second approach to multimodal analgesia is the use of 2 or more drug delivery routes instead of a single route. For example, epidural or intrathecal opioids could be combined with IV, intramuscular, oral, transdermal, or subcutaneous analgesics, or IV opioids could be combined with oral NSAIDs, COX-2 selective inhibitors, or APAP. Table 2 offers examples of multimodal regimens for orthopedic surgeries^26,27 and Table 3 offers an example of a  multimodal analgesia protocol where the medications utilized are based on the patient's postoperative pain.²⁸

Table 2: Examples of Multimodal Analgesia Protocols in Orthopedic Surgeries26,27
Total knee arthroplasty	Total hip arthroplasty
Preoperative*
Gabapentin 300 mg PO + celecoxib 200 mg PO + APAP 1g PO and Sustained-release oxycodone 10 to 20 mg PO	Gabapentin 300 mg PO + celecoxib 200 mg PO + APAP 1g PO
Intraoperative
Spinal anesthesia is preferred with 10 to 15 mg bupivacaine or Femoral nerve or adductor canal block with 20 to 30 mLs 0.2% ropivacaine with insertion of an indwelling catheter or Intraoperative periarticular mixture in a total volume of 100 mL: epinephrine 1 mg/mL; 0.5 mL ketorolac 30 mg/mL; 1 mL clonidine 100 μg/mL; 0.8 mL ropivacaine 5 mg/mL; 49.25 mL NS to qs to 100ml; plus intraoperative dose of 15 mg IV ketorolac once Consider ketamine/sciatic nerve blockade for patients with chronic pain, high opioid use, or intolerance to opioids	Spinal anesthesia is preferred with 10 to 15 mg bupivacaine or Intraoperative periarticular mixture in a total volume of 100 mL: epinephrine 1 mg/mL; 0.5 mL ketorolac 30 mg/mL; 1 mL clonidine 100 μg/mL; 0.8 mL ropivacaine 5 mg/mL; 49.25 mL NS to qs to 100ml; plus intraoperative dose of 15 mg IV ketorolac once Consider single-shot lumbar plexus or fascia iliaca block or ketamine 0.5 mg/kg for patients with chronic pain, high opioid use, or intolerance to opioids
Postoperative
PACU Continuous femoral nerve or adductor canal block infusion: 0.2% ropivacaine at 8 to 10 mL/h or APAP 1000 mg PO + oxycodone 10 mg PO PRN VAS pain score of 4 or greater Opioids PRN Floor APAP 1000 mg PO every 8 h around-the-clock or Sustained-release oxycodone 10 or 20 mg PO every 12 h or Gabapentin 300 mg PO every night at bedtime (Adjust dose for renal impairment) or Tramadol 50 mg PO every 6 h PRN mild pain (Use with caution in patients with history of seizures) or Immediate-release oxycodone 10 mg PO every 4 h PRN severe pain or Ketorolac 7.5 mg IV every 6 h × 2 doses (Start 6 h after surgery completed) or Hydromorphone 0.2 to 0.4 mg IV push every 2 h PRN breakthrough pain	PACU Continuous femoral nerve or adductor canal block infusion: 0.2% ropivacaine at 8 to 10 mL/h or APAP 1000 mg PO + oxycodone 10 mg PO PRN VAS pain score of 4 or greater Opioids PRN Floor APAP 1000 mg PO every 8 h around-the-clock or Sustained-release oxycodone 10 or 20 mg PO every 12 h or Gabapentin 300 mg PO every night at bedtime (Adjust dose for renal impairment) or Tramadol 50 mg PO every 6 h PRN mild pain (Use with caution in patients with history of seizures) or Immediate-release oxycodone 10 mg PO every 4 h PRN severe pain or Ketorolac 7.5 mg IV every 6 h × 2 doses (Start 6 h after surgery completed) or Hydromorphone 0.2 to 0.4 mg IV push every 2 h PRN breakthrough pain
*Administer 2 hours before procedure. Abbreviations: APAP = acetaminophen; IV = intravenous; NS = normal saline (sodium chloride 0.9%); PACU = post-anesthesia care unit; PO = by mouth; PRN = as needed; VAS = visual analogue scores of pain.

Table 3: Example of a Multimodal Analgesia Protocol that is Prescribed based on Patient Pain Level28
	Low-dose regimen (< 50 MED or opioid-naive patient)	Low-dose NPO regimen (< 50 MED or opioid-naive patient)
Level 1: Mild pain (VAS 1-3)	APAP 650 mg PO every 6 h* Celecoxib 100 mg PO BID Etodolac 400 mg PO BID Ibuprofen 400 mg PO every 6 h	APAP 650 mg PR every 6 h* APAP 1000 mg IV every 6 h* Ketorolac 15 mg IV every 6 h
Level 2: Moderate pain (VAS 4-7)	Level 1 drug plus 1 of the following: Tramadol 25 mg PO every 6 h Morphine 7.5 mg PO every 4 h Oxycodone 5 mg PO every 4 h	Level 1 drug plus 1 of the following: Morphine 4 mg IV every 4 h Hydromorphone 0.5 mg IV every 4 h
Level 3: Severe pain (VAS 8-10)	Level 1 drug plus 1 of the following: Oxycodone 10 mg PO every 4 h Morphine 4 mg IV every 4 h Hydromorphone 0.5 mg IV every 4 h	Level 1 drug plus 1 of the following: Morphine 6 mg IV every 4 h Hydromorphone 0.5 mg IV every 3 h
*Prescriber may select APAP + a nonsteroidal anti-inflammatory drug for mild pain. APAP = acetaminophen; BID = twice daily; IV = intravenous; MED = Morphine equivalent daily dose; NPO = nothing by mouth; PO = by mouth; PR = rectally; VAS = visual analogue scores of pain.

SUMMARY

Multimodal analgesia is the use of 2 or more medications with differing mechanisms of action to produce a synergistic or additive analgesic effect and fewer overall adverse effects. The U.S. is facing an ongoing crisis of prescription opioid abuse, so the ability to prescribe medications other than opioid medications is desired. Currently, guidelines are available from the CDC and ASA, as well as foreign medical societies, to help guide the development of multimodal protocols for the management of orthopedic postoperative pain. The use of multimodal analgesia and the initiation of oral medications as quickly as possible after surgery can decrease time in the hospital and, therefore, decrease health care costs and lower an orthopedic patient's risk of adverse events secondary to hospitalization.

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