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Nonopioid Analgesics
The term nonopioid analgesics seems to imply a motley group of agents self-consciously trying to establish their parity with their famously potent cousins: the opioid family. With contemporary understanding of the complexities of both acute and chronic pain, the importance of a multimodal approach to pain management pharmacotherapy has emerged, and the former outcasts have slowly been incorporated into the armamentarium of the anesthesiologist.
With the exception of the nonsteroidal antiinflammatory drugs (NSAIDs), most nonopioid analgesics have stumbled awkwardly from other specialties such as psychiatry and neurology into the field of pain medicine. As the specialty of pain medicine learned that opioids were not a panacea for all chronic pain conditions because of their long-term inefficacy, toxicities, and a propensity for misuse, greater emphasis was placed on nonopioid analgesics either as first-line treatment or as an adjunct to opioids.
In March 2016 the Centers for Disease Control and Prevention (CDC) released guidelines for prescribing opioids in chronic pain. While these guidelines were directed at primary care physicians, all medical providers have likely felt the effects of the far-reaching effort to curb what has become known as an epidemic of opioid misuse and overdose. Paramount among these recommendations is the role of nonopioid analgesics in treating chronic pain, as evidenced by the first of 12 guidelines:
Nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain. Clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate.
Because of the pharmacologic heterogeneity of nonopioid analgesics, this chapter is broadly divided into two sections: one describing NSAIDs and another describing drugs used for treatment of neuropathic pain. An additional section discusses emerging developments of various drugs with potential utility in the perioperative and chronic pain population.
NSAID History
NSAIDs have been used for millennia in the form of the prototypical agent, aspirin. Hippocrates wrote about using powdered willow bark for pain and fever in the fifth century bc . In the late 18th century, Stone isolated salicylic acid from willow, myrtle, and a number of other plants. However, it was not until early in the 20th century that Hoffmann, a chemist with Bayer Pharmaceuticals, discovered acetylsalicylic acid and marketed aspirin for fever, pain, and inflammation. It was not until later in the 20th century that aspirin became the generic name for this compound. Aspirin continues to be an important drug, but now more for its antiplatelet activity than for its original indications.
The newer NSAIDs were released in the 1960s, the first being indomethacin, closely followed by ibuprofen. Since then several dozen agents have been released in the United States and elsewhere, competing for a lucrative commercial market. Over time, some of these agents have been withdrawn because of major toxicities, including hepatotoxicity, nephrotoxicity, and blood dyscrasias. The recent voluntary withdrawal of the blockbuster drug rofecoxib (Vioxx) generated considerable controversy and media coverage amid concerns of increased cardiovascular risk.
Despite these controversies, NSAIDs remain very useful and widely used drugs for their analgesic and antipyretic effects. In the management of postoperative pain, NSAIDs are probably underused despite good evidence for their safety and efficacy.
Nonsteroidal Antiinflammatory Drugs and Acetaminophen
Basic Pharmacology
Structure-Activity Relationships
Nonsteroidal antiinflammatory agents are a diverse group of drugs broadly categorized into salicylates, acetic acid derivatives, propionic acid derivatives, oxicam derivatives, and the cyclooxygenase (COX)-2 selective agents ( Fig. 19.1 ). All act by blocking prostaglandin synthesis, both in the periphery and in the central nervous system (CNS).
Mechanism
Prostaglandins are lipid-based compounds derived enzymatically from fatty acids that have important physiologic functions, including the mediation of the inflammatory response, the transduction of pain signals, and a central pyretic effect. The primary source of prostaglandins in humans is arachidonic acid, a 20-carbon polyunsaturated essential fatty acid that is, in turn, derived from cell membrane phospholipids. The NSAIDs act by inhibiting COX enzymes that catalyze the conversion of arachidonic acid to prostaglandins, thromboxanes, and prostacyclin ( Fig. 19.2 ).
The COX enzymes are now known to exist as three isoforms: COX-1, COX-2, and COX-3. COX-3 is a splice variant of COX-1 and is now recognized as the once elusive enzyme inhibited by acetaminophen. However, controversy still exists about the existence of COX-3 inhibition in humans and the mechanism by which acetaminophen-mediated analgesia occurs. COX-1 and COX-2 are the isoforms targeted by the traditional NSAIDs, while the more selective COX-2 inhibitors preferentially block COX-2. COX-1 is considered to be the constitutive enzyme (often called the housekeeping enzyme ), generating prostanoids involved in normal physiologic functioning such as gastrointestinal mucosal protection and hemostasis. COX-2, on the other hand, has low baseline expression but is inducible during physiologic stress by agents including proinflammatory cytokines, neurotransmitters, and growth factors.
However, this schema is acknowledged to be an oversimplification in that there are exceptions to this rule: for example, COX-2 is constitutively expressed in the kidney and CNS, and COX-1 can be induced by certain stress conditions in nerve tissue. Although both enzymes are structurally similar and act basically in the same fashion, their respective gene expression profiles and selective inhibition can determine NSAID side effects and toxicity.
Metabolism
The primary mode of NSAID elimination is by hepatic biotransformation by cytochrome P450 (CYP 450)-mediated oxidation or glucuronide conjugation. Renal excretion of unmetabolized drug is much less important, accounting for less than 10% of the administered dose. Biliary excretion has been described for certain NSAIDs, although this route plays a small role. Because NSAIDs share common metabolic pathways, nuances relating to metabolism are not a basis for therapeutic decisions regarding the appropriate NSAID for a given patient.
Clinical Pharmacology
Pharmacokinetics
NSAIDs are weak acids with pK a values typically lower than 5, and therefore they exist mostly in the ionized form at physiologic pH. NSAIDs, except aspirin, which is 50% to 80% bound, are highly bound to plasma proteins, primarily albumin. NSAID half-lives vary significantly between drugs ( Table 19.1 ). Because oral NSAIDs are often prescribed for long-term use, a focus of modern NSAID development has been to design compounds that are relatively long-acting to facilitate improved patient compliance.
TABLE 19.1
Summary of Nonsteroidal Antiinflammatory Drugs and Acetaminophen
| Drug | Common Trade Name | Half-Life (hr) | Protein Binding (%) | Typical Daily Dose Range | Typical Dosing Schedule | Typical Pediatric Dosing (mg/kg per 24 hr) | Notes |
|---|---|---|---|---|---|---|---|
| Acetaminophen/paracetamol | Tylenol, Panadol Ofirmev (IV) |
2 | 20–50 | 2–4 g | 325–650 mg q4hr | 10–15 mg/kg q6–8 hr prn | No antiinflammatory effect |
| Propionic Acid Derivatives | |||||||
| Fenoprofen | Nalfon | 2–3 | 99 | 1.2–2.4 g | 300–600 mg qid | NA | |
| Flurbiprofen | Ansaid | 2 | 99 | 200 mg | 100 mg bid | NA | |
| Ibuprofen | Motrin, Advil, Brufen, others | 6 | 99 | 1.2–2.4 g | 400–800 mg qid | 7.5–10 mg/kg qid | Higher doses sometimes used for inflammatory conditions; maximum dose 3200 mg/day |
| Ketoprofen | Orudis | 2–4 | 99 | 225 mg | 75 mg tid | NA | |
| Naproxen | Naprosyn | 14 | 99 | 750–1000 mg | 250–375 mg bid | 5–10 mg/kg bid | |
| Naproxen sodium | Alleve, Anaprox | 14 | 99 | 550–1100 mg | 275–550 mg bid | 5–10 mg/kg bid | |
| Fenamates | |||||||
| Diclofenac | Voltaren | 1–2 | 99 | 150–200 | 50 mg tid 75 mg bid |
2–3 mg/kg per 24 hr | Hepatotoxicity rarely reported. Also has topical formulations |
| Tolmetin | Tolectin | 5 | 99 | 600–1800 mg | 200–600 mg tid | 20–30 mg/kg per 24 hr as 3–4 doses | |
| Ketorolac | Toradol | 4–6 | 99 | IV: 60 mg/day a | 30 mg first dose; then 15 mg q6hr a | IV: 0.5 mg/kg per day, single dose only | a Half the dose if age >65 yr or weight <50 kg |
| Enolic Acid Derivatives (Oxicams) | |||||||
| Meloxicam | Mobic | 15–20 | 99 | 7.5–15 | 7.5–15 mg qd | NA | Higher dose typically used for rheumatoid arthritis Intermediate COX-1 and COX-2 selectivity |
| Piroxicam | Feldene | 40–50 | 99 | 20 mg | 10–20 mg qd | NA | |
| Nabumetone | Relafen | 24 | 99 | 1000–1500 mg | 500–750 mg bid | NA | |
| Acetic Acid Derivatives | |||||||
| Etodolac | Lodine | 7 | 99 | 400–1200 mg | 200–400 mg tid/qid | 15–20 mg/kg/24 hr | |
| Indomethacin | Indocin, others | 2–5 | 90 | 100–200 mg | 25–50 mg TID/QID | 2–4 mg/kg/24 hr | |
| Sulindac | Clinoril | 8–16 | 99 | 400 mg | 150–200 mg | bid/tid | |
| COX-2 selective NSAID | |||||||
| Celecoxib | Celebrex | 6–12 | 97 | 200 mg | 100–200 mg qd/bid | 3 mg/kg bid | 400 mg/day used for acute pain |
bid, Twice daily; COX, cyclooxygenase; IV, intravenous; NA, nonsteroidal antiinflammatory drug; prn, as needed; q, every; qd, every day; qid, four times daily; tid, three times daily.
Most NSAIDs are rapidly absorbed following oral administration, with peak plasma concentrations generally reached within 2 to 3 hours. Factors affecting gastric emptying can profoundly affect the time course of the clinical effects of NSAIDs. In part because of the variability in the time course of oral absorption, the use of rectal NSAIDs is popular in Europe for the management of postoperative pain and has the added advantage of being possible even when oral intake is not. Ketorolac and ibuprofen are the only parenteral NSAIDs currently available in the United States, but intravenous diclofenac and parecoxib are available elsewhere. Parenteral administration is advantageous in renal colic because of its more rapid onset than with oral administration, but it has demonstrated no obvious advantage over oral administration for any other indication.
Pharmacodynamics
Therapeutic Effects
NSAIDs are widely used for their analgesic properties, particularly when pain has an inflammatory component such as in certain rheumatologic conditions. Tissue trauma results in cell membrane disruption and release of arachidonic acid, the substrate for COX enzymes, and consequently a rise in local prostaglandin (PG) concentrations. These prostanoids, particularly PGE 2 , result in sensitization of nociceptors to mechanical stimuli and other chemical mediators such as bradykinin, leading to increased nociceptor firing and pain perception. COX enzyme activity has also been identified in the CNS, including the dorsal horn of the spinal cord, and it is postulated that COX inhibition also provides a central analgesic mechanism.
The antipyretic effect of the NSAIDs is very predictable and has utility in the treatment of fever, both in adults and children. Perioperatively, NSAIDs are indicated in a multimodal analgesic approach, and the American Society of Anesthesiologists (ASA) recent practice guidelines for acute pain management in the perioperative setting encourage the use of NSAIDs unless contraindicated. A less common NSAID indication (indomethacin is typically used) is in the prevention of ductus arteriosus closure when this would be detrimental in certain neonatal congenital heart conditions where an ongoing right-to-left shunt is desired before corrective surgery. Fig. 19.3 provides an overview of the pharmacodynamic effects of NSAIDs, including both therapeutic and adverse effects.
Adverse Effects
NSAIDs have a number of nonspecific adverse effects, including rash and gastrointestinal upset (e.g., dyspepsia, abdominal pain, and diarrhea), that are not related to their targeted mechanism. Other adverse effects are manifest in multiple organ systems, reflecting the widespread expression of the COX enzymes.
Cardiovascular Effects
All NSAIDs, and not just the COX-2 selective agents, can increase the risk of serious cardiovascular thrombotic events such as myocardial infarction and stroke. The mechanisms underlying these adverse effects are complicated but likely include an imbalance between the prothrombotic and vasoconstricting activity of thromboxane A 2 (TXA 2 ), and the antithrombotic and vasodilatory effects of prostacyclin (PGI 2 ), thereby favoring deleterious thromboxane effects. In addition, NSAIDs increase blood pressure in a dose-dependent fashion, which may also be linked to the increased cardiovascular risks associated with their use. Prolonged administration of COX-2–selective NSAIDs can cause adverse events through inhibition of PGI 2 , including development of hypertension and the promotion of thrombus development in a ruptured plaque. Recent reviews of both nonselective NSAIDs and COX-2 inhibitors have found that nonselective NSAIDs and celecoxib carry little risk of ischemic stroke, whereas rofecoxib and valdecoxib (both discontinued) are associated with significant risk. However, the cerebrovascular safety of nonselective NSAIDs has been questioned in other studies, suggesting that all NSAIDs should be used with caution in patients with high risk for cerebrovascular disease.
The perioperative administration of NSAIDs, especially the COX-2 selective agents for short-term use, has been subject to some controversy owing to their possible role in increasing morbidity after cardiac surgery. However, a recent meta-analysis of studies using parecoxib and valdecoxib compared with placebo in noncardiac surgery concluded that there were no differences in cardiovascular events between groups.
In 2005, a consensus statement issued by the Food and Drug Administration (FDA) Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee concluded that COX-2 selective agents are important treatment options for pain management and that the preponderance of data demonstrates that the cardiovascular risk associated with celecoxib is similar to that associated with commonly used, older, nonselective NSAIDs. The committee also concluded that short-term use of NSAIDs does not appear to increase cardiovascular risk and that rigorous scientific studies are needed to characterize the longer-term cardiovascular risks of these therapies. With respect to the longer-term use of NSAIDs, a careful risk-benefit analysis should be performed, particularly in those already at risk for cardiovascular events.
Bone Healing
Bone healing is dependent on an inflammatory response involving numerous cytokines, including interleukin (IL)-1, IL-6, tumor necrosis factor, and fibroblast growth factor, so it is not surprising that agents that disrupt normal cytokine function can impair bone homeostasis and repair. There are convincing animal data that nonselective and COX-2 inhibitor NSAIDs inhibit bone healing. This inhibition of healing response has been used therapeutically to prevent heterotrophic bone formation after arthroplasty. In a rat model of femoral fracture healing, celecoxib or rofecoxib delayed fracture healing compared with indomethacin. At 8 weeks postoperatively, there was still evidence of the original fracture in these two groups.
However, human data on possible detrimental effect of NSAID use in the perioperative period are conflicted and controversial. The issue of bone healing and NSAIDs has been addressed mostly in the spinal fusion literature. Successful spinal fusion surgery demands a robust bone healing process, so spine surgeons place great importance on mitigating all risk of nonunion with measures such as smoking cessation and NSAID avoidance. A retrospective analysis of 288 patients who underwent instrumented spinal fusion from L4 to the sacrum demonstrated a five times higher nonunion rate when ketorolac was used in the immediate postoperative period. In contrast, another retrospective study found that, in 405 consecutive patients who underwent primary lumbar spinal fusion, a subset of patients who had ketorolac 30 mg intravenously every 6 hours for 2 days had similar fusion rates to a group that had no NSAIDs. A recent meta-analysis of five retrospective studies explored the relation of ketorolac dose and successful spinal fusion rates and concluded that high-dose ketorolac (>120 mg/day) might be associated with poor outcomes, whereas standard dose ketorolac (<120 mg/day) was not. In the absence of any prospective or randomized studies, and realizing that bony nonunion is a high-morbidity outcome, use of perioperative NSAIDs in spinal fusion cases should be considered carefully, particularly when other risk factors for poor bone healing (e.g., smoking) exist. In nonspine orthopedic surgery, there is good evidence of NSAID analgesic efficacy and no significant association with compromised bone healing.
Allergy and Hypersensitivity
All NSAIDs, including aspirin, can induce hypersensitivity reactions of two general types, both likely related to the inhibition of prostaglandin synthesis. Provocation of asthmatic attacks in patients with vasomotor rhinitis and nasal polyposis is likely related to inhibition of normal production of the bronchodilator PGE 2 . NSAIDs also rarely induce the syndrome of urticaria and angioedema related to inhibition of prostaglandin effects that normally stabilize histamine stores in mastocytes and inhibit the inflammatory response. In susceptible individuals, this unchecked inflammation can result in spontaneous degranulation of mastocytes with release of histamine in the respiratory tract and skin, which leads to bronchoconstriction and urticaria. This process is COX-1 mediated, and therefore COX-2 selective NSAIDs may be used, but with caution, in NSAID-intolerant patients.
Gastrointestinal Toxicity
The long-term use of oral NSAIDs inhibits production of prostaglandins that maintain normal gastrointestinal mucosal integrity and results in gastric and colonic mucosal damage, including erosion and ulceration. In addition, oral NSAIDs can cause local irritation, and when erosion and/or ulceration is present, hemostasis is compromised by COX-1 inhibition. This constellation of physiologic derangements results in a spectrum of gastrointestinal problems, ranging from mild gastritis to peptic ulceration with perforation.
The morbidity and mortality of NSAID use is a significant public health problem, although it appears to be abating in recent years, likely because of the more widespread use of proton pump inhibitors, rather than the use of COX-2 inhibitors. Risk factors identified for the development of NSAID-induced ulcers include advanced age, history of previous ulcer, concomitant use of corticosteroids, higher doses of NSAIDs (including the use of more than one NSAID), concomitant administration of anticoagulation agents, serious systemic disorders, cigarette smoking, consumption of alcohol, and concomitant infection with Helicobacter pylori . Short-term use of NSAIDs in the perioperative period carries little risk of mucosal injury, although intolerance or nausea can be an issue in patients given NSAIDs on an empty stomach.
Hemostatic Effects
Platelets, lacking a nucleus and the ability to generate new proteins like COX, are particularly susceptible to the effects of COX inhibitors. Aspirin irreversibly acetylates COX enzymes and inhibits platelet aggregation for the 10- to 14-day life span of the platelet. Other nonselective NSAIDs reversibly inhibit COX, causing only transient reduction in TXA 2 formation. Consequently, inhibition of platelet activation resolves after most of the drug is eliminated. For example, a single 300- to 900-mg dose of ibuprofen can inhibit platelet aggregation for 2 hours after administration, and the effect is largely dissipated by 24 hours. Overall, with the exception of aspirin, NSAIDs cause transient, dose-dependent, and modest bleeding time abnormalities, which often do not exceed normal limits. However, clinical studies have revealed some significant issues with perioperative hemostasis and nonselective NSAID use. In total hip arthroplasty, patients taking nonselective NSAIDs had more intraoperative and postoperative blood loss than those who did not. Despite concern on the part of many ear, nose, and throat surgeons regarding the use of NSAIDs for pain control after pediatric tonsillectomy, a thorough meta-analysis of studies addressing this concern failed to find any significant association between NSAIDs and perioperative bleeding requiring return to the operating room. Importantly, the COX-2 enzyme has not been identified in platelets, so the COX-2 inhibitors are not thought to have deleterious antiplatelet effects.
Renal Toxicity
Aspirin and all other NSAIDs, including COX-2 inhibitors, can transiently decrease renal function in selected patients, resulting in hypertension, edema, and even acute renal failure. These effects occur more often in patients with underlying renal disease and in those with intravascular volume depletion. Renal perfusion and glomerular filtration are closely regulated by renal prostaglandin synthesis, particularly in the fluid-depleted state. Inhibition of this system is the postulated mechanism of NSAID-induced sodium ion (Na + ) retention and renal dysfunction. In the perioperative setting, NSAIDs seldom cause clinically significant renal impairment, but should be withheld in patients who are significantly volume depleted, have intraoperative oliguria, or have preexisting renal impairment.
Other Toxicities
Aspirin and diclofenac are the most potentially hepatotoxic NSAIDs and should be avoided in patients with preexisting hepatic failure. NSAIDs have been implicated in hypersensitivity-induced aseptic meningitis, generally manifesting with meningeal signs commencing within weeks of starting therapy. It is a diagnosis of exclusion after ruling out an infectious cause of the meningeal irritation.
Drug Interactions
Hypoalbuminemia increases the free fraction of NSAIDs in the plasma, thus affecting their distribution and elimination. The high degree of serum protein binding increases interaction risk with other highly protein bound drugs. In clinical practice, however, this is rarely significant, and NSAIDs can be used safely in conjunction with other agents commonly used in perioperative practice. One exception is the potential for nephrotoxicity when NSAIDs are used concomitantly with other potentially nephrotoxic drugs such as the aminoglycosides, radiographic contrast media, and diuretics. Nonselective NSAIDs should be used with caution in patients who have been using other platelet-inhibiting drugs or anticoagulants.
Special Populations
Renal Failure
In general, NSAIDs are avoided in patients with renal failure. The use of NSAIDs in patients with preexisting renal insufficiency can have deleterious effects as discussed earlier. Renal failure influences NSAID kinetics by reducing renal excretion of the drugs and metabolites normally eliminated in the urine and by affecting their distribution and biotransformation. All NSAIDs are very highly bound to plasma proteins, and hemodialysis will not likely increase elimination of these agents. No dosage adjustments are therefore necessary for hemodialysis patients receiving NSAIDs.
Liver Disease
The majority of NSAIDs have low hepatic clearance, so mild to moderate liver disease should theoretically not interfere with their oral bioavailability. Because NSAIDs are so avidly protein-bound, alteration of liver albumin synthesis would be expected to cause alterations in the unbound drug fraction in plasma. Diclofenac has been the agent most implicated with hepatic dysfunction and should be avoided in patients with liver disease.
Older Age
Advanced age is an independent risk factor for both cardiovascular disease and NSAID gastropathy, so NSAIDs should be used with additional caution in this population. However, the opioid-sparing effects of NSAIDs in the postoperative period make NSAIDs an attractive pain management adjunct, particularly when concerns exist regarding oversedation, delirium, or respiratory depression in older patients receiving opioids. In older adults, the relatively high lipid solubility of NSAIDs, potentially decreased plasma protein levels, and reduced renal function all contribute to an increased likelihood of toxicity. Therefore the lowest effective dose of NSAID should be administered, with frequent follow-up (sometimes including renal function tests) for assessment of side effects or toxicity.
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