1. Evaluate the benefits and drawbacks of pre-emptive analgesia

Pre-emptive analgesia is the theory that treating pain prior to a noxious insult, such as surgery, can reduce the physiological consequences of the injury more effectively than if treated afterwards [1]. It is hypothesized that pre-emptive analgesia provides better pain control by preventing the peripheral and central changes that occur in response to an injury and may reduce the resulting sequelae, such as chronic pain syndromes. Effective pre-emptive analgesia would demonstrate a decreased need for analgesics beyond the effects of the pre-emptive treatment and a lower incidence of persistent pain syndromes [2]. This is of particular concern in certain surgeries, including total knee replacement, that are often complicated by chronic pain [3]. The theory of pre-emptive analgesia has been well demonstrated in animal models; yet studies in humans have not been as conclusive. Studies that support the use of pre-emptive analgesia show reductions in pain scores, total opioid use, and chronic pain with an increased time to first analgesic request after surgery [4].

Pre-emptive analgesia is based on an understanding of the complex cascade of pain-modulating substances released in response to tissue injury. Peripheral nerve fibers are activated by tissue damage, and initiate a cascade of signals that temporarily or permanently alter peripheral and central pain pathways [5]. Tissue injury causes localized inflammation stimulating release of pain-modulating substances. These pro-pain modulating substances cause further peripheral sensitization and amplify pain impulses to future injury. As pain impulses persist unabated, they act on wide dynamic range (WDR) neurons in the CNS that are responsible for conducting both nociceptive and non-nociceptive sensory signals. This physiologic change to the WDR neurons results in central pain, allodynia, and other chronic pain syndromes [5–6].

As suggested above, central pain sensitization results from an incisional phase (acute tissue injury) and an inflammatory phase (reaction to injury) that may last for several days. The ability of each phase to permanently alter central pain pathways depends on the duration of the phase, suggesting that the inflammatory phase predominates. Effective pre-emptive analgesia therefore must cover the entire time that a noxious stimulus is present, and extend postoperatively to cover the inflammatory phase.

Early animal models indicated pre-emptive analgesia was an effective strategy for surgical pain. Woolf and Wall. demonstrated decreased systemic morphine requirements to prevent development of dorsal horn hyperexcitability compared to the amount needed to reverse established central changes [7]. This suggested that pain treatment is facilitated when analgesics are given before the insult. Unfortunately, human trials have been less encouraging. A meta-analysis comparing preoperative and postoperative analgesic strategies concluded that pre-emptive epidural, local anesthetic(LA) infiltration, and non-steroidal anti-inflammatory drug (NSAID) administration decreased analgesic consumption and time to first analgesic request [8]. However, pain scores were unchanged in the epidural group and neither N-methyl-D-aspartate (NMDA) antagonists nor opioid administration showed efficacy [8]. Conversely, ketamine, dextromethorphan [9], and gabapentin [10] have shown promise as treatments that interrupt changes to central pain pathways. Furthermore, aside from risks and side effects inherent to individual agents, pre-emptive analgesia has very few risks.

2. Examine whether outcomes are altered by increased pain in the acute postoperative period

Adequate postoperative pain control is a complex challenge and untreated pain is associated with worsened outcomes, especially after major orthopedic surgeries [3, 11–12].

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  Chronic pain: The severity of acute postoperative pain is a significant predictor of chronic pain in many surgeries including limb amputations and thoractomies [13]. Chronic pain is reduced at six months with pre-emptive use of LA administration via continuous nerve block or thoracic epidural. In addition to perineural LAs, inflammatory responses may also be reduced by NSAID and steroid administration. While opioids effectively suppress the inflammatory response intraoperatively, they are not as effective postoperatively, which may explain why opioid administration has not shown improvements in chronic pain.

  
  
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  Function: Several important outcomes after total knee surgery (such as acute pain, range of motion, ambulation, stiffness, and overall function) are improved with the use of a continuous femoral nerve catheter. However, these effects are only seen while the catheter is used and do not appear to be present once it is removed [14].

  
  
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  Pulmonary complications: Poor postoperative analgesia may reduce ambulation and increase opioid use thereby increasing the risks of thromboembolic events, atelectasis, respiratory depression, and hypoxemia. However, improved pulmonary outcomes have only been demonstrated with utilization of epidurals for major upper abdominal surgeries. This effect is increased with thoracic epidurals for longer than 24 hours. Data that pulmonary complications are improved with other analgesic strategies in the setting of other surgeries are lacking. Although data are scarce, certain patient populations (i.e., obese, severe obstructive sleep apnea) may be more susceptible to pulmonary complications from high opioid use [13].

  
  
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  Cardiac complications: Increased sympathetic signaling from uncontrolled pain may result in tachycardia and increased cardiac oxygen demand. This may cause severe morbidity and even mortality in vulnerable populations; therefore, optimal postoperative pain control is critical. The only analgesic strategy shown to reduce cardiac morbidity in lower extremity surgical patients is with epidural or epidural/opioid combinations. These studies suggest that reducing the sympathetic response to pain has a favorable effect on cardiac morbidity and that adequate coverage of surgical pain with peripheral nerve blocks or local infiltration may also result in improved cardiac outcomes [13].

  
  
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  Thromboembolic events: Acute postoperative pain may increase the incidence of thromboembolic events. Pain amplifies the inflammatory response to surgery creating a hypercoaguable state and inhibits ambulation thereby worsening venous stasis. Continuous epidurals after lower extremity surgery appear to reduce deep venous thrombosis. However, meta-analyses suggest that this does not clinically decrease pulmonary embolism risk [13–15].

  
  
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  Gastrointestinal complications: Postoperative ileus may prolong hospital stays and delay recoveries. Impaired gastric motility is attributed to opioid administration and inhibitory splanchnic autonomic reflexes. Strategies that minimize acute postoperative pain and subsequent opioid administration may reduce postoperative ileus. Thus far, only postoperative thoracic epidural use has reduced postoperative ileus [15].

  
  
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  Postoperative cognitive dysfunction: This affects 20% of patients undergoing non-cardiac surgery and is present up to three months after surgery in 10% of surgical patients. The etiology of postoperative cognitive dysfunction is multifactorial and relatively unknown. Several retrospective studies have not shown a difference in incidence based on anesthetic or analgesic technique. However, poorly controlled postoperative pain treated with opioids or other drugs with cognitive impairing side effects may have a negative impact on vulnerable populations [13].

  
  
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  Thirty-day mortality: One large retrospective study associated intraoperative neuraxial anesthesia for total knee replacements with an improvement in 30-day mortality [13]. No other studies show a similar effect for postoperative pain control.

  
  
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  Hospital length of stay: Poor acute postoperative pain control with its ensuing complications may result in increased hospital length of stay. However, most retrospective studies do not demonstrate any improvement in length of stay with better analgesia, likely because length of stay is determined by many other factors such as ambulation and drain removal [16].

3. Describe intraoperative analgesic techniques that can have opioid-sparing effects

Opioid-sparing anesthetic techniques have several advantages. These include reduced respiratory complications, nausea, vomiting, itching, and sedation, all of which can promote early discharge from the post-anesthesia care unit and participation in physical therapy. These advantages may also facilitate patient discharge; although this is difficult to demonstrate.

Several strategies exist to manage intraoperative pain for total knee arthroplasty. Neuraxial techniques, including subarachnoid and epidural anesthetics with or without a general anesthesia, are a reliable way to avoid intraoperative opioids. A large retrospective analysis of neuraxial vs. general anesthesia for total knee replacements showed that neuraxial techniques were associated with decreased pulmonary, cardiac, gastrointestinal, renal, infectious, and bleeding complications and even improvements in 30-day mortality [12]. While pain control was improved with the addition of intrathecal morphine, it did not have postoperative opioid-sparing effects in patients receiving a total knee replacement [17].

Blockade of the femoral and sciatic nerves has shown to effectively reduce opioid use intra- and postoperatively [18]. The classic femoral nerve block is associated with quadriceps weakness and the risk of patient falls [19]. Because of this, many practitioners prefer an adductor canal block, which targets the saphenous nerve, a branch of the femoral nerve. This approach is amenable to perineural catheters with similar analgesia and better quadriceps strength compared with femoral nerve blocks [20–21]. Lastly, local infiltration of analgesia (LIA) is a technique in which surgeons inject a mixture of local anesthetic, narcotic, NSAID, and sometimes steroid directly into the joint capsule. This technique has been shown to reduce morphine consumption and improve ambulation when compared with epidural anesthesia. The injectate varies greatly, and it is important to account for the large volume of local anesthetic injected when considering peripheral nerve blocks in the setting of LIA [22].

Other opioid-sparing strategies commonly used include administration of preoperative acetaminophen, celecoxib, and gabapentinoids. Intraoperative use of NMDA antagonists such as ketamine and magnesium may also be effective at treating CNS nociception changes associated with surgery.

Multimodal approaches using several of these techniques should be used to reduce their individual side effects and maximize the opioid-sparing advantages. Whichever strategy is utilized, it is important to discuss the approach with the surgeons to facilitate other goals of care and consider how interventions fit into the larger system.