Perioperative Pain Management

Opioid Analgesics

Adequate analgesia achieved with systemic opioids is frequently associated with side effects, including sedation, nausea, and pruritus. However, despite these well-defined side effects, opioid analgesics remain an integral component of postoperative pain relief. Systemic opioids may be administered by intravenous, intramuscular, and oral routes. Some analgesic regimens employ intravenous PCA for 24 to 48 hours postoperatively, with subsequent conversion to oral agents. The PCA device may be programmed for several variables, including bolus dose, lockout interval, and background infusion ( Table 25.1 ). The optimal bolus dose is determined by the relative potency of the opioid; insufficient dosing results in inadequate analgesia, whereas excessive dosing increases the potential for side effects, including respiratory depression. Likewise, the lockout interval is based on the onset of analgesic effects; too short of a lockout interval allows the patient to self-administer additional medication before achieving the full analgesic effect (and may result in accumulation/overdose of the opioid). A prolonged lockout interval will not allow adequate analgesia. The optimal bolus dose and lockout interval are not known, but ranges have been determined. Varying settings within these ranges appears to have little effect on analgesia or side effects. Although most PCA devices allow the addition of a background infusion, routine use in adult opioid-naïve patients is not recommended. However, a background opioid infusion may have a role in the treatment of opioid-tolerant patients. Because of variation in patient pain tolerance, PCA dosing regimens may have to be adjusted to maximize the benefits and minimize the incidence of side effects.

Adverse effects of opioid administration can cause serious complications in patients undergoing major orthopedic procedures. In a systematic review, Wheeler and associates reported gastrointestinal issues (nausea, vomiting, and ileus) in 37%, cognitive effects (somnolence and dizziness) in 34%, pruritus in 15%, urinary retention in 16%, and respiratory depression in 2% of patients receiving PCA opioid analgesia. Given the effectiveness and availability of adjunctive methods of postoperative pain control (i.e., peripheral blocks, periarticular injections), the many negative side effects of PCA analgesia have led to a significant decline in its use.

Oral opioids ( Table 25.2 ) are available in immediate-release and controlled-release formulations. Immediate-release oral opioids are effective in relieving moderate to severe pain, but they must be administered as often as every 4 hours. When these medications are prescribed “as needed” (prn), there may be a delay in administration and a subsequent increase in pain. Furthermore, interruption of the dosing schedule, particularly during the night, may lead to an increase in the patient's pain. Adverse effects of oral opioid administration are considerably less compared with those of intravenous administration and are mainly gastrointestinal in nature.

A controlled-release formulation of oxycodone (OxyContin) has been shown to provide therapeutic opioid concentrations and sustained pain relief over an extended time period. This longer-acting opioid formulation may be beneficial in patients with chronic pain or more extensive surgeries. Because pain decreases substantially over the first 24 to 36 hours, the routine use of controlled-release opioid formulations is no longer recommended. Recent focus on the excessive amount of opioids prescribed in the United States has prompted physicians to search for alternative analgesic options and multimodal combinations to decrease the amount of opioids prescribed.

Tramadol (Ultram) is a centrally acting analgesic that is structurally related to morphine and codeine (but is not truly an opioid). Its analgesic effect is manifest through binding to the opioid receptors and blocking the reuptake of both norepinephrine and serotonin. Tramadol should be used with caution in patients taking certain antidepressant medications (e.g., selective serotonin reuptake inhibitors) affecting the levels of these two neurotransmitters. Tramadol has gained popularity because of the low incidence of adverse effects, specifically, respiratory depression, constipation, and abuse potential. Thus, tramadol may be used as an alternative to opioids in a multimodal approach to postoperative pain, specifically in patients who are intolerant to opioid analgesics.

Nonopioid Analgesics (Acetaminophen and Nonsteroidal Antiinflammatory Drugs)

The addition of nonopioid analgesics reduces opioid use, improves analgesia, and decreases opioid-related side effects. The multimodal effect is maximized through selection of analgesics that have complementary sites of action. For example, acetaminophen acts predominantly centrally, while other nonsteroidal antiinflammatory drugs (NSAIDs) exert their effects peripherally.

The mechanism of analgesic action of acetaminophen has not been fully determined. Acetaminophen may act predominantly by inhibiting prostaglandin synthesis in the central nervous system. Acetaminophen has very few adverse effects and is an important addition to the multimodal postoperative pain regimen, although the total daily dose must be limited to 4000 mg. An intravenous formulation is currently available; although it is more expensive, it may be beneficial for patients who are unable to take medications by mouth. It is important to note that many oral analgesics are an opioid-acetaminophen combination. In these preparations, the total dose of opioid will be restricted to the acetaminophen ingested.

NSAIDs have a mechanism of action through the cyclooxygenase (COX) enzymatic pathway and ultimately block two individual prostaglandin pathways. The COX-1 pathway is involved in prostaglandin E ₂ –mediated gastric mucosal protection and thromboxane effects on coagulation. The inducible COX-2 pathway is mainly involved in the generation of prostaglandins included in the modulation of pain and fever but has no effect on platelet function or the coagulation system. In general, NSAIDs block both COX-1 and COX-2 pathways. Traditionally, NSAIDs have been viewed as peripherally acting agents. However, a central analgesic effect may occur through inhibition of spinal COX.

The introduction of specific COX-2 inhibitors represented a breakthrough in the treatment of pain and inflammation. However, despite their efficacy, two (rofecoxib [Vioxx] and valdecoxib [Bextra]) of three COX-2 inhibitors were voluntarily removed from general use because of an increased relative risk for cardiovascular events, such as heart attack and stroke, after 18 months of treatment. Celecoxib (Celebrex) is currently the only COX-2 inhibitor available in the United States, although the US Food and Drug Administration (FDA) has requested that safety information be included regarding potential cardiovascular and gastrointestinal risks of all selective and nonselective NSAIDs except aspirin ( https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-warning-non-aspirin-nonsteroidal-anti-inflammatory ).

Numerous NSAIDs have been used in the perioperative management of pain; both oral and intravenous routes exist. An intravenous dose of ketorolac 10 to 30 mg was found to have similar efficacy to 10 to 12 mg of intravenous morphine. In surgical patients, ketorolac reduces opioid consumption by 36%. Because of the potential for serious side effects, ketorolac should be used for 5 or fewer days in the adult population with moderate to severe acute pain.

Major side effects limiting NSAID use for postoperative pain control (renal failure, platelet dysfunction, and gastric ulcers or bleeding) are related to nonspecific inhibition of the COX-1 enzyme. Advantages of COX-2 inhibitors include lack of platelet inhibition and a decreased incidence of gastrointestinal effects. All NSAIDs have the potential to cause serious renal impairment. Inhibition of the COX enzyme may have only minor effects in the healthy kidney but can lead to serious side effects in elderly patients and those with a low-volume condition (blood loss, dehydration, cirrhosis, or heart failure). Therefore, NSAIDs should be used cautiously in patients with underlying renal dysfunction, specifically in the setting of volume depletion due to blood loss. Similar to the COX-2 inhibitors, NSAIDs interfere with the inhibitory COX-1 effect of aspirin on platelet activity and may counter its cardioprotective effects.

The effects of NSAIDs on bone formation and healing are of concern to the orthopedic population. Although data are conflicting, evidence from animal studies suggests that COX-2 inhibitors may inhibit bone healing. Thus, adverse effects of COX-2 inhibitors must be weighed against the benefits. Until definitive human trials are performed, it is reasonable to be cautious with the use of COX-2 inhibitors, especially when bone healing is critical.