ICJR REWIND: What Should Be in the Mix for Perioperative Pain Management in TJA?
Adequate pain control has been correlated with faster rehabilitation following joint replacement surgery and improved measures of patient satisfaction. This article, originally published on March 22, 2018, reviews the evidence for multimodal therapy in the preoperative, intraoperative, and postoperative periods.
Andrew M. Pepper, MD; John J. Mercuri, MD, MA; Omar A. Behery, MD, MPH; and Jonathan M. Vigdorchik, MD
Total joint arthroplasty (TJA) is an inherently painful surgical procedure. Up to 60% of patients who undergo total knee arthroplasty (TKA) report having severe postoperative pain; another 30% report moderate pain.  Optimizing pain control for patients undergoing TJA is not only crucial for patient well-being, but it is also increasingly important in today’s value-based patient care. As such, orthopaedic surgeons need a predictable, evidence-based, and cost-effective protocol for perioperative analgesia that maximizes pain management while minimizing side effects from the analgesics used.
Adequate pain control has been correlated with faster rehabilitation and improved measures of patient satisfaction, such as health-related quality-adjusted life years, return to work, and overall satisfaction. [1,2] It is also associated with reduced risk of readmission, a shorter length of stay, and a reduced risk of complications, such as myocardial infarction, pneumonia, venous thromboembolic disease, and chronic pain syndromes. All these advantages synergistically decrease costs and improve the quality of care, thereby increasing the value of the care provided.
During surgery, local tissue trauma initiates a local and system inflammatory cascade.  Relevant mediators include bradykinin, prostaglandins, substance-P, and histamine. The patient experiences direct nerve and soft tissue trauma, as well as indirect factors such as temperature changes.
With respect to the nervous system, the afferent pain signals are first carried by unmyelinated C-fibers and myelinated A-fibers to the dorsal root ganglion. In the ganglion, the fibers synapse in the dorsal horn and the signal continues to rise through the neurons of the spinothalamic tract. These spinothalamic neurons, which carry ipsilateral pain signals and contralateral temperature signals, ultimately arrive in the supra-spinal central nervous system, where the signals are interpreted and modulated.
At each stage of the pathway, surgeons have the opportunity to intervene.  Local anesthetics, anti-inflammatory drugs, cyclooxygenase-2 (COX-2) specific inhibitors, and cryotherapy can all work at the surgical site. Local anesthetics also have a role in the spinal cord, along with opioids, alpha agonists, and N-methyl-D-aspartate antagonists. The supra-spinal central nervous system can be targeted with opioids, alpha agonists, centrally acting analgesics such as acetaminophen, and anti-inflammatory drugs.
In the knee, 4 major nerves supply sensory innervation: 
- Femoral nerve
- Obturator nerves
- Tibial distribution of the sciatic nerve
- Peroneal distribution of the sciatic nerve
The concentration of nociceptor fibers is also important to consider,  with elevated nociceptor density in the fibrous capsule, collateral and cruciate ligament insertions, lateral retinaculum, infrapatellar fat pad, periosteum, and subchondral bone.
The hip has multiple sources of innervation: 
- The lumbar plexus generates the lateral femoral cutaneous nerve, the femoral nerve, and the obturator nerve.
- The obturator nerve has an articular branch to the hip joint, which is responsible for the phenomenon of referred pain to the knee.
- The sacral plexus also contributes to periarticular branches of the sciatic nerve.
The concentration of nociceptor fibers in the hip is likely highest in the labral base, the hip capsule, and the ligamentum teres.  However, there are admittedly little objective data on hip nociceptor density.
Approach to Pain Management
Multimodal pain management was introduced by Kehlet and Dahl in 1993.  The term refers to the use of multiple agents that affect different regions of the nociception pathway. The goal is to achieve improved pain control with less reliance on opioids, which decreases associated opiate side effects.
The adoption of multimodal pain management has been shown to: 
- Reduce opioid usage
- Improve pain scores
- Increase patient satisfaction
- Enhance early recovery
- Facilitate earlier hospital discharge
The following discussion reviews the evidence for multimodal therapy in the preoperative, intraoperative, and postoperative periods.
Preoperative or pre-emptive analgesia was first described by Wall in 1988. [2,7] The concept is to prevent the biochemical cascade of pain before it starts. It is suggested that medications should be administered anywhere from 1 to 24 hours prior to surgery. Agents such as celecoxib and oxycodone have been recommended by expert opinion.  Suggestions include 400 mg of celecoxib the day before surgery and 20 mg of extended-release oxycodone 1 hour before surgery.
Rofecoxib, although no longer commercially available, was shown in a randomized, double-blind, placebo-controlled trial to reduce opioid consumption, pain, vomiting, and sleep disturbance after TKA.  It was also associated with improved knee range of motion. Current thinking is that celecoxib might have a similar effect because like rofecoxib, as it is also a selective COX-2 inhibitor.
Despite good evidence that pre-emptive analgesia is efficacious, there are some limitations to our knowledge regarding its use in the perioperative period. First, optimal timing of pre-emptive analgesia is unknown, and no clear recommendation is available. In addition, there is no clear recommendation for which agents should be included in a pre-emptive analgesic regimen. [2,8,9].
Intraoperative analgesia begins with the induction of anesthesia – general, neuraxial, or peripheral nerve block. [1,11] General anesthesia is associated with cardiac and respiratory complications and typically should be avoided in patients with cardiopulmonary disease. Neuraxial anesthesia has fewer cardiopulmonary side effects than general anesthesia, and patients also benefit from reduced surgical time, decreased incidence of deep venous thrombosis,  and less postoperative nausea and vomiting.
General anesthesia offers potential benefits for same-day discharge, however, as it does not delay throughput while waiting for neurologic function to recover. Neuraxial anesthesia has other potential pitfalls, including misplacement of injection/catheter placement, nerve injury, and associated hypotension. And despite the noted benefits of neuraxial anesthesia, the evidence that it decreases intraoperative blood loss, mortality, or length of stay after surgery is limited.  Renewed interest and research in “short-acting spinal anesthesia” has provided evidence that such neuraxial techniques may provide safe alternatives to general anesthesia without limiting discharge. 
A peripheral nerve block in combination with sedation is another anesthesia option for TKA, which also avoids the potential cardiopulmonary complications associated with general anesthesia. The use of peripheral nerve blocks, including femoral nerve blocks, has been studied in conjunction with TKA, and in a meta-analysis of randomized trials, was found to achieve comparable analgesia to epidural anesthesia but with a more favorable side-effects profile overall.  However, the rate of permanent neurologic injury may be slightly higher with peripheral nerve blocks than with spinal or epidural anesthesia.  One study found no difference in pain during postoperative physiotherapy for a continuous infusion versus a single-dose peripheral femoral nerve block. 
Intraoperative Administration of Analgesics
One of the major intraoperative interventions that can improve pain control is the use of periarticular injections (PAI) of local analgesic agents.  In general, PAI has a low risk profile and provides significant benefit as a component of a multimodal pain regimen. These injections have been shown to:
- Improve visual analog pain scores
- Decrease opioid utilization
- Improve short-term range of motion
Diluted solutions of the injected agents also further minimize the risk profile.  Such risks include toxicity of local injection and adjacent nerve injury/temporary palsy, as well as the theoretical risk of infection at injection sites, although this has not been demonstrated in the literature. [15, 16]
A variety of techniques can be used for PAI, with little consensus regarding the ideal technique. One technique that has gained support recently is posterior capsular infiltration in TKA. A recent study, however, found no difference in visual analog pain scores in the first 24 hours postoperatively, morphine usage, blood loss, or length of stay between patients who did and who did not receive a posterior capsular infiltration during TKA.  Therefore, it appears that posterior capsular infiltration does not provide added analgesic benefit and does not warrant the potential risk of popliteal neurovascular injury. 
The use of local anesthetics in PAI has a verified benefit in pain control, with a low risk profile.  The mechanism of action for these drugs is reverse blockade of voltage-gated changes in nociceptors, which results in a decreased transmission of pain signals. Amide-linked anesthetics such as bupivacaine and ropivacaine may also block potassium channels, which can lead to a more intense nerve blockade.
Many studies that have investigated the efficacy of liposomal bupivacaine for PAI, with somewhat mixed results. One high-volume center reported a significant decrease in opioid usage up to POD2, greater achievement of physical therapy milestones, decreased length of stay, and more discharges to home among patients who received liposomal bupivacaine in their PAI.  A recent meta-analysis and systematic review, however, showed no improvement with liposomal bupivacaine over conventional PAI with local anesthetics and found that the use of liposomal bupivacaine was cost prohibitive. 
PAIs can also contain sympathetic nervous system modulators, such as epinephrine and clonidine: 
- Epinephrine is a non-specific alpha- and beta-adrenergic agonist and vasoconstrictor that helps to decrease absorption of peripherally administered medications, thereby potentiating the intensity and duration of other local agents to inhibit nociceptive action potentials.
- Clonidine is an alpha-2 adrenergic agonist that appears to have multifactorial adjunctive effects when administered peripherally. Through its action on alpha-2 receptors, clonidine causes weak vasoconstriction after peripheral application. Through yet-to-be-determined mechanisms, clonidine has been shown to potentiate the intensity and duration of peripherally administered local anesthetics and inhibit nociceptor action potentials in unmyelinated nerves.
These sympathetic nervous system modulators may carry risks: Epinephrine can theoretically cause skin necrosis, and clonidine has been noted to cause hypotension and bradycardia. 
Limited data support the use of opioids in PAI. In a randomized, double-blind, placebo-controlled trials, 5 mg of morphine was included in a multimodal cocktail with bupivacaine and betamethasone.  This cocktail was found to reduce the need for oral opioids and improve pain scores. However, another recent randomized controlled trial found no advantage in terms of postoperative pain relief when morphine was added to PAI in patients undergoing bilateral TKA.  The opioid receptor density in the peripheral tissues in low, and limited data can support the effectiveness of opioids in PAI. 
Non-steroidal anti-inflammatory drugs used in PAI work through a similar mechanism as enteral or parenteral agents: They prevent the production of pro-inflammatory mediators such as prostaglandins.  Including agents such as ketorolac and injecting the cocktail periarticularly is equivalent to a traditional intramuscular injection.
Corticosteroids are often included in PAI,  and they act directly on nuclear receptors to block production of pro-inflammatory molecules. They have also been shown to potentiate the effect of other medications in the cocktail. Corticosteroids have documented efficacy in non-operatively treating osteoarthritis, but their efficacy as part of a surgical cocktail is unclear. There are theoretical concerns with wound drainage, periprosthetic joint infection, and delayed wound healing, but the evidence on the clinical application of these drugs in PAI is limited.
A recent meta-analysis demonstrated wide heterogeneity in studies of PAI in TJA patients.  Therefore, the optimal drugs and dosages that should be in the optimal PAI cocktail remain unclear.
Although PAI with local anesthetics can reduce postoperative pain, additional modalities can be used in the postoperative period to improve pain control. Postoperative cryotherapy, for example, has demonstrated minimal side effects and quicker hospital discharge after TJA, with reduced requirement for morphine-equivalent pain medication.  Cryotherapy works through vasoconstriction to reduce local inflammation, local tissue metabolism, and nerve conduction velocity. When combined with compressive dressings, cryotherapy can promote additional vasoconstriction and prevent edema. There is a theoretical risk of delayed wound healing with aggressive cryotherapy use, but this has not been clinically demonstrated. 
The traditional mainstay of postoperative pain management has been enteral and parenteral analgesics. Opioids in both forms are powerful analgesics, are used widely, and are part of most postoperative multimodal pain management regimens. However, used alone, opioids have limited pain control potential, and in excessive doses, they carry the risk of constipation, abdominal pain, nausea, drowsiness, altered mentation, and respiratory depression. Therefore, opioids must be used in conjunction with other agents to optimize pain control while limiting side effects.
Acetaminophen is a centrally acting analgesic and antipyretic. It lacks the systemic side effects of traditional non-steroidal anti-inflammatory drugs, and both parenteral and enteral administration have been proven efficacious in controlling pain.  A recent randomized, controlled trial also suggests that parenteral administration is efficacious when used intraoperatively, but this may not offer advantages over perioperative enteral use of acetaminophen.  The major drawback of acetaminophen use is hepatotoxicity at high doses, and, therefore, it may be contraindicated in patients with hepatic dysfunction.
Non-steroid anti-inflammatory drugs and COX-2 specific inhibitors are also an important part of the multimodal pain management protocol. These medications have anti-inflammatory, analgesic, and antipyretic mechanisms. They work by limiting prostaglandin production through the inhibition of cyclooxygenase enzymes. Multiple studies support their use to decrease pain, opioid consumption, and opiate-related side effects. [1, 8, 24] They have also been found to be effective when given preoperatively.  COX-2 selective medications have the added benefit of avoiding the side effects that occur with non-selective COX inhibitors, including effects on the gastric mucosa and increased acidification contributing to peptic ulcers. . There is theoretical risk of decreased osteointegration and fracture healing with the use of non-steroidal anti-inflammatory drugs, in addition to potential platelet inhibition and increased bleeding, but no significant evidence confirms these risks.
Enteral administration of neuromodulator medications such as gabapentin and pregabalin is a more recent addition to multimodal pain management.  These medications provide analgesia through anti-convulsant and neuropathic pathways, exerting their function at presynaptic voltage-gated calcium channels in the dorsal horn synapse. This decreases the excitatory signal release along the afferent pathway. Neuromodulator medications have been shown to decrease neuropathic pain and opioid consumption and increase postoperative range of motion in the joint,  although the evidence is limited. Side effects for these medications include confusion, sedation, and dizziness, which are potentially limiting to patient rehabilitation after TJA.
Tramadol is another enteral medication often considered perioperatively. It is a synthetic compound that acts centrally as both an opioid agonist and a monoamine uptake inhibitor. This has an effect on noradrenaline and serotonin pathways. In one study, tramadol was shown to decrease morphine consumption when used as part of a multimodal pain management protocol;  however, a randomized controlled trial showed it to be equivalent to placebo.  Despite this, there is limited thorough study on the true efficacy of tramadol in multimodal pain management regimens.
N-methyl-D-aspartate antagonists such as ketamine are another newer addition to postoperative multimodal therapy strategies . These compounds potentiate the effects of opioids and prevent hyperalgesic complications from uncontrolled pain. The role of ketamine is promising, but trials have only studied it in combination with pregabalin, which has demonstrated a minimal beneficial effect.  Studies have shown that magnesium decreases opioid requirement with no side effects, whereas ketamine decreases opioid requirements and pain levels. 
Transdermal opioid patches are an alternative for administering opioid pain medication following TJA. Their major benefit is the ease of use. The disadvantage of transdermal opioid patches is that they contribute to the overall cumulative opioid dose and the dangerous side effects of opioid when used in conjunction with enteral opioid medications. They also demonstrate variable delivery and dosage timing with other enteral and parenteral opioids. Therefore, unpredictable delivery and side effects make them difficult to support in multimodal pain management regimens.
Multimodal pain management is essential in improving outcomes and optimizing the patient experience surrounding TJA, with multiple available modalities – working through various mechanisms and targeting different aspects of the pain perception pathway – at each perioperative phase. However, the ideal pain management protocol remains elusive, and the currently available evidence is predicated on heterogeneous studies with varied results and outcomes.
Andrew M. Pepper, MD, and John J. Mercuri, MD, MA, are adult reconstruction fellows from the NYU Langone Orthopedic Hospital/Insall Scott Kelly, Department of Adult Reconstruction, New York, New York. Omar A. Behery, MD, MPH, is an orthopaedic surgery resident at the NYU Langone Orthopedic Hospital, New York, New York. Jonathan M. Vigdorchik, MD, is an Assistant Professor of Orthopaedic Surgery, Associate Fellowship Director in Adult Reconstruction, and Co-Director of Robotics in Orthopaedic Surgery at the NYU Langone Orthopedic Hospital, Department of Adult Reconstruction, New York, New York.
The authors have no disclosures relevant to this article.
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