Learning Objectives/Outcomes: After participating in this CME/CNE activity, the provider should be better able to:

1. Describe the history of pain management in total joint arthroplasty and chronic persistent pain syndrome.

2. Evaluate the consequences of inadequate pain control.

3. Classify multimodal analgesia and preemptive analgesic techniques, listing the commonly used perioperative medications.

4. Identify mechanisms of pain processing.

Many medications are used in acute perioperative pain management, and a complete review is beyond the scope of this article. However, 4 medications have emerged as the most commonly used and effective medications in the treatment of acute perioperative pain control: celecoxib, gabapentin, subanesthetic ketamine, and acetaminophen. This review is geared toward perioperative providers, including anesthesiologists and certified registered nurse anesthetists, surgeons, and internists involved in the perioperative care of the surgical patient.

History of Pain Management in Total Joint Arthroplasty

Pain management in the early postoperative period has historically been known to be undermanaged. In the early 2000s, pain control was identified as inadequate in a large number of patients.1 Approximately 70% of patients experienced moderate to severe pain perioperatively. Of these, almost 25% of patients experienced mild to severe adverse side effects due to the use of opioids. In 2002, reports such as these led to the formation of an American Society of Anesthesiologists Special Task Force, composed of expert academic and private practice physicians, to devise practice guidelines for acute pain management in the perioperative setting. These guidelines were updated in.

Traditionally, perioperative pain management for total joint arthroplasties included general anesthesia with opioids. General anesthesia is a known cause of postoperative pulmonary complications, postoperative nausea and vomiting, and postoperative cognitive dysfunction, among other complications. Furthermore, in many instances, use of opioids alone does not provide optimal pain control and often may predispose patients to the above-mentioned side effects. Thus, acute perioperative pain management eventually transitioned to neuraxial blocks for pain management.

Although neuraxial blocks were an improvement from the use of general anesthesia with opioids for joint surgeries, these blocks also presented their own set of complications, including severe pain as the blocks dissipated, problems with concurrent anticoagulation use, and falls in the postoperative period. Issues such as these resulted in moving toward using peripheral nerve blocks and multimodal analgesia for postoperative pain control with either general anesthesia or neuraxial blocks in joint surgeries.

Consequences of Inadequate Pain Control

Suboptimal pain control in the perioperative period may lead to an increase in sympathetic tone, resulting in vasoconstriction and possibly end-organ damage. Decreased gastric motility, impaired immune function, prolonged length of hospital stay, rising health care costs, and chronic persistent postoperative pain syndrome are additional consequences of inadequate pain control. Not the least of these adverse effects is an adverse perception of pain management personnel.

Elderly patients are especially at risk due to adverse effects from escalating doses of opioids, including a greater propensity for respiratory depression postoperatively, hypotension, dizziness, confusion, and delirium. A final consequence may be development of a chronic persistent postoperative pain syndrome.

But how does one define when and if a chronic persistent postoperative pain syndrome has developed? Many criteria must be included, such as the degree of pain postsurgery, preexisting pain conditions and their impact on quality of life, the development of pain that lasts at least 2 months with signs and symptoms of chronic neuropathic pain. Other causes of pain such as cancer and infection must be excluded.3

Furthermore, certain factors may predispose patients to develop chronic persistent postoperative pain syndrome. These factors are divided into 3 main categories and include preoperative factors, surgical factors, and postoperative factors. Preoperative factors include preexisting pain, repeat surgery, psychological vulnerability, and work-related injuries. Surgical factors are listed as the type of surgery, surgical approach, and risk of nerve injury due to surgery. Lastly, postoperative factors include the severity of early postoperative pain, the need for postoperative radiation or chemotherapy, and neuroticism or psychologic vulnerability.

Thus, issues such as these have led to the popularity of increasing the use of nonopioid medications for perioperative pain control as part of the multimodal approach to pain control. Because treatment of chronic persistent pain syndrome is challenging, use of multimodal and pre-emptive analgesia perioperatively is crucial. Several opioid alternative medications are currently used, including cyclooxygenase-2 (COX-2) inhibitors, gabapentin, acetaminophen, and subanesthetic ketamine. Part of the plan for postoperative pain management must also include multimodal analgesic techniques and preemptive pain plans.

Multimodal Analgesia

Multimodal analgesia modulates various pain pathways while simultaneously decreasing unwanted side effects and providing optimal pain relief.4 Adverse side effects of opioids include nausea, vomiting, sedation, ileus, respiratory depression, and itching. Opioid-alternative medications are administered in the preoperative period and continued throughout the perioperative period, thereby becoming an integral part of preemptive analgesia.

As the name implies, preemptive analgesia begins before the start of surgery. It aids in preventing both peripheral and central nervous system nociceptors sensitization by preventing the production of inflammatory neurotransmitters. The rationale implies that sensitization of nerve fibers lowers pain threshold, resulting in hypersensitivity to external stimuli in the perioperative period and the development of chronic neuropathic pain. By blocking this pathway, anesthesia and pain providers can improve the overall analgesia experience for the patient, resulting in improved outcomes and decreased incidence of development of chronic neuropathic pain.

Mechanism of Pain Processing

There are 4 main sites of pain processing: peripheral nociceptor (nerve endings), nerve and dorsal root ganglion, the dorsal horn of the spinal cord, and the brain and brainstem5 (Figure 1). Drugs act at several sites along this pathway.

Figure 1. The several sites along the pain pathway are indicated and the sites at which different drugs act. A variety of drugs acts at various anatomic locations along the pain-signaling pathway. Ketamine modulates pain at the dorsal horn of the spinal cord.

How Each Medication Contributes to Pain Management

Cyclooxygenase-2 Inhibitors

Multimodal analgesia has been gaining popularity over the past several years. A variety of medications are used, one of which includes COX-2 inhibitors, which reduce pain and inflammation, as do other nonsteroidal anti-inflammatory drugs (NSAIDs). COX-2 inhibitors have been championed over COX-1 inhibitors because of the favorable side effect profile. COX-2 inhibitors work peripherally and prevent prostaglandin production. They have a decreased risk of gastric ulcers, decreased risk of platelet dysfunction, and decreased risk of renal injury compared with COX-1 inhibitors/NSAIDs.4 However, some COX-1 inhibitors such as Arthrotec (diclofenac and misoprostol) have been used successfully in the perioperative period with minimal adverse side effects. And although there has been concern regarding cardiovascular complications associated with COX-2 inhibitors, doses of up to 400 mg per day have not been shown to produce adverse cardiovascular effects.

Multiple studies have supported their use, including large meta-analyses. One such study of 8 randomized controlled trials included 571 patients undergoing total knee replacement. The patients received COX-2 inhibitors preoperatively. Results showed lower pain scores per visual analogue scales (VAS), improved range of motion, less opioid consumption, and decreased opioid adverse effects in up to 3 days postoperatively, as compared with those patients who did not receive COX-2 inhibitors preoperatively.6

In another randomized, double-blind, placebo-controlled study of 107 patients undergoing total knee arthroplasty, patients were given 200 mg of celecoxib twice a day for 6 weeks postoperatively. Results indicated a decrease in the number of narcotic pill consumption in the celecoxib group (76.3 +/- 55 vs 138 +/- 117) (P = 0.003).6 VAS pain scores were also lower at 3, 6, and 12 weeks postoperatively in the celecoxib group. Furthermore, a greater degree of knee flexion was noted in the celecoxib group up to 1 year postoperatively as measured by the American Knee Society Scores and the Oxford Knee Score scales used at 3 and 6 weeks postoperatively. The American Knee Society Score describes patients' functional outcomes before and after total knee arthroplasty. It assigns a number to pain score, alignment, and contracture. The Oxford Knee Score scale is the United Kingdom's version of the American Knee Society Score.

Although there has been concern regarding cardiovascular complications associated with COX-2 inhibitors, doses of up to 400 mg per day have not been shown to produce adverse cardiovascular effects.

Gabapentinoids

Gabapentin has also been proven to be beneficial when used as part of multimodal analgesia perioperatively. Although gabapentin has a structure similar to [gamma]-aminobutyric acid, it does not act on this receptor. Instead, it works by decreasing stimulus-induced hyperexcitability of the posterior horn neurons. Gabapentinoids also possess an antihyperalgesic effect via postsynaptic binding of gabapentin to the [alpha] 2-[delta] subunit of the dorsal horn-neuron voltage-gated calcium channels. A resulting decrease in calcium entry into nerve endings leads to decreased neurotransmitter release.7

Gabapentin was initially used as an antiepileptic for partial seizures in the 1990s. However, since then, multiple studies have shown its efficacy in a variety of other settings, including the perioperative setting.

In 1 study, gabapentin was administered 1.2 g per day 1 hour before coronary artery bypass graft surgery and continued 2 days postoperatively.8 Results showed that postoperative pain scores at days 1, 2, and 3 were significantly lower in the gabapentin group than in the placebo group. Other studies have indicated its benefits in orthopedic surgeries. Significantly lower pain scores were obtained at 2 hours postoperatively in patients who received preemptive gabapentin undergoing internal fixation of the tibia under spinal block.9

Yet another study examined the effects of gabapentin on acute postoperative pain and morphine intake in patients undergoing spine surgery.10 Gabapentin 1200 mg given 1 hour before incision resulted in lower pain scores at 1, 2, and 4 hours postoperatively. In addition, morphine consumption was lower in the gabapentin group than in the placebo group, leading to the added benefit of lower incidence of postoperative nausea and vomiting because of opioids.10

It is important to note that abrupt cessation of gabapentin may result in withdrawal symptoms similar to those seen in alcohol withdrawal, including irritability, agitation, anxiety, palpitations, and diaphoresis within 24 to 48 hours.8

Pregabalin has also been known to provide excellent analgesia when used as part of a multimodal analgesia plan in lieu of gabapentin. Although it is more potent than gabapentin and can reach optimal cerebrospinal fluid levels faster than gabapentin, cost remains an issue with pregabalin. Thus, gabapentin is used more commonly in perioperative pain management.

Acetaminophen

Use of acetaminophen as part of multimodal analgesia has been on the rise for the past few years. This drug has been in use for more than 100 years as an analgesic and an antipyretic. Studies over the past decade have confirmed its efficacy as a pain reliever in the perioperative period while simultaneously allowing the decrease in the amount of opioids consumed and the risk of adverse side effects of opioids.11 The IV form of acetaminophen has been used in Europe since 2002. However, it was not introduced into the United States until January 2011. Although the mechanism of action is not completely understood, acetaminophen is thought to work via centrally mediated pathways. It is also thought to be a cannabinoid receptor agonist, COX-2 isoenzyme inhibitor, and an agonist of the transient receptor potential cation channel, subfamily V, member 1, a central antinociceptor.11

A major benefit of acetaminophen is that 1000 mg of IV acetaminophen has been shown to be as effective as morphine 10 mg given intravenously. Its use is favored over the oral and rectal routes because the IV form reaches peak cerebrospinal fluid concentration quickly. In addition, IV acetaminophen has been used effectively in all phases of the perioperative period and is not dependent on delayed absorption, which is noted in oral administration.

Pharmacokinetics demonstrate that serum therapeutic levels of acetaminophen needed for optimal effect are 16 and 10 [mu]g/mL in adults and children respectively.11 When given intravenously, analgesic effects are achieved within 15 minutes of administration, with the peak effect reached within 1 hour. The duration of effect lasts approximately 4 to 6 hours. Although time to reach peak effect with the IV formulation is approximately 15 minutes, it requires 45 to 75 minutes to reach peak effect when given orally. Time to reach peak effect is even longer if acetaminophen is administered rectally. The median time to reach maximum plasma concentration (or T_max) for rectal administration is 3 to 4 hours. Advantages of the IV route as compared with the oral and rectal routes are shown in Figures 2 to 4.

Figure 2. Mean plasma acetaminophen concentration-time curves after IV, oral, and per rectum administration of 1000 mg (n = 7 for oral; n = 6 for IV/per rectum). (Reprinted with permission from

Figure 3. Mean cerebrospinal fluid acetaminophen concentration-time curves after IV, oral, and per rectum administration of 1000 mg. (Reprinted with permission from

Figure 4. The EC

Multiple studies have shown evidence to support the use of acetaminophen in the perioperative period as part of a multimodal analgesia regimen. Not only does it provide effective perioperative pain control, it also allows providers to decrease the amount of opioids needed in the perioperative period, thereby reducing the adverse side effects of the opioids.

Ketamine

Ketamine has recently gained popularity as part of a multimodal analgesia regimen. Use has been on the rise in the perioperative period for several reasons. It is a phencyclidine derivative, which was initially referred to as CI-581. Ketamine was initially used as an anesthetic agent in the early 1960s with its first documented use in the late 1960s.12 It has traditionally been used as an induction agent in hemodynamically unstable patients; however, over the past few years, research has supported its use in the perioperative period because of its ability to prevent chronic pain.

Ketamine has multiple street names, including Special K, vitamin K, and Kit Kat, to name a few. It exerts its action via the N-methyl-D-aspartate (NMDA) receptor. It is an NMDA receptor antagonist, and at anesthetic doses, leads to multiple central nervous system effects resulting in a dissociative state.

In addition, at subanesthetic doses ketamine possesses centrally mediated analgesic effects, and therefore plays an important role in pain processing. Anesthetic dose is 1.0 mg/kg or more intravenously. Subanesthetic dosing for ketamine is 0.3 mg/kg or less intravenously. The NMDA receptor works primarily in the dorsal horn of the spinal cord. The steps leading up to central sensitization are as follows: tissue injury -> glutamate release in dorsal horn -> glutamate binds to NMDA receptors -> NMDA receptors activated -> intracellular processes activated -> resulting in altered behavior -> central sensitization. The end result is chronic pain.

Central sensitization is also referred to as "wind-up" phenomena (Figure 5).

Figure 5. Site and mode of action of ketamine. The activated primary nociceptive afferent from the periphery releases glutamate at the second-order sensory neuron in the dorsal horn of the spinal cord. The glutamate binds to NMDA receptors. Ketamine blocks the NMDA receptor, which attenuates the development of central sensitization and opioid tolerance and hyperalgesia. Reprinted with permission from Mayo Clinic, Phoenix, Arizona.

Although there has been concern regarding side effects with the use of subanesthetic ketamine, most of these have been mild and well tolerated by patients. The drug is associated with a low incidence of mild psychomimetic symptoms, nystagmus, and double vision when administered in subanesthetic doses. However, there are some contraindications to its use because of its metabolism. Therefore, the clinician may choose to avoid its use in patients with renal or hepatic insufficiency.

Specific medical conditions where subanesthetic ketamine is not suitable include high-risk coronary artery or vascular disease, uncontrolled hypertension, increased intracranial and intraocular pressure, psychosis, sympathomimetic syndrome, recent liver transplantation, porphyria, and globe injuries. Subanesthetic ketamine has been used successfully in painful procedures, opioid-tolerant patients, those with opioid-induced hyperalgesia, surgery with high risk of developing chronic postsurgical pain syndrome, and any time there is a desire or need to minimize the use of perioperative opioids.

Multiple studies have supported the use of ketamine in perioperative multimodal analgesia. For example, the authors of a systematic review of 70 studies in which IV perioperative ketamine was given concluded that IV ketamine significantly decreased postoperative opioid needs, and also increased the time to the first operative narcotic requirement.5

Yet another such study included 101 patients and reported a 37% decrease in morphine use over a 48-hour period in opioid-tolerant patients undergoing spine surgery.13

Furthermore, a meta-analysis of 14 studies compared 2 groups of patients.14 One group acted as placebo control and the other group received perioperative IV ketamine. Results demonstrated that subanesthetic doses of ketamine resulted in a 25% and 30% decrease in risk of persistent postsurgical pain at 3 and 6 months, respectively. Promising results such as these have given way to protocols in place for use of perioperative ketamine and continuing a subanesthetic infusion for 48 hours postoperatively with excellent outcomes. In fact, centers such as the University of Pittsburgh Medical Center and Mayo Clinic in Florida and Arizona have also begun implementing such practices.

The question of appropriate dosing of subanesthetic ketamine in perioperative pain management is still controversial, however. Although there are no set recommendations in regard to dosing of ketamine, most experts advocate injecting a bolus of ketamine at induction, followed by serial doses or, in some cases, an infusion.

Extensive research on the ideal timing and dosing of ketamine has been conducted.15 Recommendations conclude that ketamine should be dosed preincision as a bolus, and then followed by either an infusion or serial boluses. Indeed, ketamine use in the perioperative period has been shown to be an effective way of decreasing narcotic needs and side effects associated with their use, while also decreasing the risk of chronic pain.

Conclusion

Evidence supports the use of multimodal analgesia in the perioperative period. Multiple modalities are employed in this technique, including regional blocks, periarticular injections, and a variety of nonopioid medications, with excellent results including shorter length of hospital stay, reduced number of adverse side effects, and improved patient satisfaction. Medications should be dosed 1 to 2 hours before surgery in the preoperative period and continued for 48 to 72 hours postoperatively.

* Dosing recommendations are as follows:

* Celecoxib: 200 mg orally.

* Gabapentin: 300 mg orally.

* Acetaminophen: 1000 mg IV or orally.

* Ketamine: 15 to 20 mg IV bolus with induction of anesthesia followed by serial boluses or infusion for 24 hours.

All 4 of the above-listed medications are administered preoperatively in the recommended doses (in no preferential order) as part of a multimodal analgesia strategy for total joint procedures.

References