Peripherally Acting Analgesics

COX-1 is constitutively expressed and catalyzes the production of prostaglandins that are involved in numerous physiologic functions, including maintenance of normal renal function in the kidneys, mucosal protection in the gastrointestinal tract, and production of proaggregatory thromboxane A₂ in the platelets. COX-2 expression can be induced by inflammatory mediators in many tissues and has a role in the mediation of pain, inflammation, and fever. There has been speculation on the existence of a third isoform, COX-3, which would explain the mechanism of action of acetaminophen, a poor inhibitor of COX-1 and COX-2, but appears to have little relevance in humans. Evidence indicates that, in addition to peripheral blockade of prostaglandin synthesis, central inhibition of COX-2 may play an important role in modulating nociception.

COX-2 selective inhibitors (known as the coxibs) have less gastrointestinal toxicity than nonselective NSAIDs. However, increased cardiovascular risk has been associated with the use of this class of drugs.² They are used less frequently nowadays after withdrawal of rofecoxib and valdecoxib, following reports of excessive cardiac morbidity. Currently, celecoxib is the only COX-2 selective inhibitor available for clinical use. COX-2–selective inhibitors should be used cautiously in patients with underlying cardiovascular disease (see further discussion on “Cardiovascular Side Effects” section).

Coxibs may be a safer alternative to NSAIDs in the perioperative settings. Although nonspecific NSAIDs provide analgesic efficacy similar to coxibs, their use has been limited in the perioperative setting because of platelet dysfunction and gastrointestinal toxicity. The potential benefits of coxibs include improved quality of analgesia, reduced incidence of gastrointestinal side effects versus conventional NSAIDs, and no platelet inhibition. NSAIDs can be classified according to numerous characteristics, including COX selectivity, and chemical and pharmacologic properties

NSAIDs belong to a number of chemical families including acetic acids, oxicams, propionic acids, salicylates, fenamates, furanones, and coxibs (Table 9-1). All NSAIDs are weakly acidic chemical compounds and share similarities in pharmacokinetic properties.³ The volume of distribution of NSAIDs is low, ranging from 0.1 to 0.3 L/kg, suggesting minimal tissue binding. The plasma half-life of NSAIDs ranges from 0.25 to >70 hours, indicating wide differences in clearance rates. Hepatic or renal disease can alter NSAID protein binding and metabolism.⁴

Gastrointestinal absorption of NSAIDs occurs rapidly, usually within 15 to 30 minutes. After absorption, NSAIDs are more than 90% bound to albumin, which influences their distribution and drug-drug interaction potential. Hypoalbuminemia (e.g., due to alcoholic liver disease) can result in greater unbound drug and increased risk for NSAID-related adverse events.⁴ The liver metabolizes most NSAIDs, with subsequent excretion into urine or bile. Enterohepatic recirculation occurs when a significant amount of an NSAID or its conjugated metabolites are excreted into the bile and then reabsorbed in the distal intestine. Hepatic NSAID elimination is dependent on the free fraction of NSAID within the plasma and the intrinsic enzyme activity of the liver. NSAIDs are primarily eliminated by renal and biliary excretion. Reduced renal function prolongs NSAID half-life, and the dose should be lowered proportionally in patients with impaired kidney function.^3,4 Moderate to severe liver disease impairs NSAID metabolism, increasing the potential for toxicity.

Side Effects of Nonsteroidal Antiinflammatory Drugs

Platelet Function

Platelet aggregation and thus the ability to clot is primarily induced through an increase in thromboxane production following activation of platelet COX-1. There is no COX-2 isoenzyme in the platelet. NSAIDs and aspirin inhibit the activity of COX-1, but the COX-2–specific inhibitors (or COX-1–sparing drugs) have no effect on COX-1 and thus no effect on platelet function.⁵

Gastrointestinal Side Effects

NSAIDs are associated with a spectrum of upper gastrointestinal complications, ranging from endoscopic ulcers in 10% to 30% of patients to serious ulcer complications in 1% to 2% of patients, including perforation and bleeding.^6,7 Lower gastrointestinal tract complications are less well characterized.^8,9

Risk factors for NSAID-associated gastrointestinal complications include high NSAID dose, older age, Helicobacter pylori infection, a history of prior ulcer, and concomitant use of low-dose aspirin, anticoagulants, or corticosteroids.^10,11 Therefore, it is generally recommended that patients with gastrointestinal risk factors should be treated with COX-2–selective agents or nonselective NSAIDs with gastrointestinal protective cotherapy.^12,13

Cardiovascular Side Effects

NSAIDs are associated with an increased risk of cardiovascular adverse events such as myocardial infarction, heart failure, and hypertension. COX inhibition is likely to disturb the balance between COX-2–mediated production of proaggregatory thromboxane in platelets and antiaggregatory prostaglandin I₂ in endothelial cells. COX selectivity alone is not sufficient to define the risk of NSAID-associated cardiovascular complications. Based on two studies, the Vioxx Gastrointestinal Outcomes Research (VIGOR)¹⁴ study and the Adenomatous Polyp Prevention on Vioxx (APPROVe) study,¹⁵ rofecoxib was withdrawn from the market in 2004. Valdecoxib was subsequently withdrawn in 2005 due to a fourfold increase in the incidence of myocardial infarction.

The cardiovascular safety of nonselective NSAIDs has been under recent investigation. A meta-analysis of randomized trials found that high-dose ibuprofen and high-dose diclofenac were associated with a moderately increased risk of vascular events compared with placebo, similar to that observed with COX-2–selective agents; the risks associated with naproxen, although they cannot be completely excluded, appeared to be substantially lower.¹⁶

Studies are lacking on the long-term effects of nonselective NSAIDs on gastrointestinal and cardiovascular systems, which limit our understanding of the true benefits and risks of NSAIDs over the long term. To reduce the cardiovascular risks, the American Heart Association recommends that all NSAIDs should be used at their lowest effective dose. When NSAID therapy is required for patients at risk of cardiovascular complications, naproxen is recommended as the NSAID of choice.¹⁷ A recent meta-analysis of the vascular and upper gastrointestinal effects of NSAIDs confirms that diclofenac and ibuprofen raise risk of major vascular events as much as coxibs. Naproxen has no effect on vascular outcomes but does increase upper gastrointestinal complications.¹⁸

Renal Side Effects

The effects of the NSAIDs on renal function include changes in the excretion of sodium, changes in tubular function, potential for interstitial nephritis, and reversible renal failure due to alterations in filtration rate and renal plasma flow. Prostaglandins and prostacyclins are important for maintenance of intrarenal blood flow and tubular transport. All NSAIDs, except nonacetylated salicylates, have the potential to induce reversible impairment of glomerular filtration rate; this effect occurs more frequently in patients with congestive heart failure; established renal disease with altered intrarenal plasma flow including diabetes, hypertension, or atherosclerosis; and with induced hypovolemia, salt depletion or significant hypoalbuminemia.^19,20 Avoiding perioperative use of NSAIDs in patients with hypovolemia from any cause is an important means of minimizing renal injury.

Liver Side Effects

The use of aspirin was associated with reduced risk of developing hepatocellular carcinoma and of death due to chronic liver disease, whereas non-aspirin NSAID use was only associated with reduced risk of death due to chronic liver disease.²¹ Paradoxically, elevations in hepatic transaminase levels and liver failure have been reported with some of the NSAIDs.²²

Pulmonary Side Effects

Many adverse reactions attributed to NSAIDs are due to inhibition of prostaglandin synthesis in local tissues. For example, patients with allergic rhinitis, nasal polyposis, and/or a history of asthma, in whom all NSAIDs effectively inhibit prostaglandin synthetase, are at increased risk for anaphylaxis.²³ The use of selective COX-2 inhibitors as an alternative to aspirin and other NSAIDs has been suggested for patients with aspirin-exacerbated respiratory disease. The highly selective COX-2 inhibitor etoricoxib has been shown to be tolerated in most but not all patients tested.²⁴ An oral provocation test is therefore recommended before prescribing etoricoxib for patients with aspirin-exacerbated respiratory disease.²⁴

Hypersensitivity Reactions

Hypersensitivity reactions to NSAIDs do rarely occur, and they are more common in individuals with nasal polyps or asthma. Allergic reactions include bronchoconstriction, rhinitis, and urticaria. Recent data suggest a role of altered COX-2 regulation associated with the aspirin-intolerant asthma/rhinitis syndrome.²³ Because of the potential for cross-reactivity, avoidance of all NSAIDs is recommended. In rare cases, NSAIDs have been implicated in causing aseptic meningitis and, in children, Reye syndrome.²⁵

Idiosyncratic Adverse Effects

Typical nonspecific reactions include skin rash and photosensitivity, aseptic meningitis, tinnitus, hearing loss, and neutropenia. The effect of prostaglandin inhibition may result in premature closure of the ductus arteriosus. Acetylsalicylic acid (ASA) has been associated with small for gestational age neonates and neonatal bruising; however, it has been used for many years in the treatment of patients who require NSAIDs while pregnant.²⁶ The most common toxicities associated with NSAIDs are gastrointestinal, cardiovascular, and renal and are related primarily to COX inhibition and decreased synthesis of prostaglandins.

Drug-Drug Interactions

Drug-drug interactions with NSAID therapy may result from their pharmacodynamic or pharmacokinetic interactions. Nonselective NSAIDs affect other antiplatelet agents via additive inhibition of platelet aggregation. The result is an increased bleeding risk with the concomitant use of NSAIDs and other antiplatelet agents.^25,27

Significant drug-drug interactions have been documented with use of NSAIDs and lithium. NSAIDs decrease lithium clearance and increase serum lithium concentrations by inhibiting renal prostaglandin production and altering intrarenal blood flow.^25,27,28 Data are conflicting regarding the drug-drug interaction potential of angiotensin-converting enzyme (ACE) inhibitors and NSAIDs.²⁹

Concurrent administration of digoxin and NSAIDs can decrease renal clearance of digoxin, increase plasma drug concentration, and potentiate digoxin toxicity. NSAIDs interact with anticonvulsant agents such as phenytoin and valproic acid by displacing the anticonvulsants from their protein-binding sites, which increases the free drug concentration. Combination use of corticosteroids and aspirin can increase renal clearance of salicylate and significantly decrease plasma salicylate concentrations.^27,28

NSAIDs can be used in selected critically ill patients but should be used judiciously because of the potential for toxic adverse events, particularly renal toxicity in hypovolemic patients. The lowest effective dose of the NSAID should be used for the shortest duration indicated. Appropriate clinical and laboratory follow-up is necessary.

Acetaminophen

Acetaminophen (Tylenol, also known as paracetamol, N-acetyl-p-aminophenol, and nAPAP) is a popular antipyretic and analgesic found in many over-the-counter and prescription products. Acetaminophen is antipyretic and analgesic but has little, if any, antiinflammatory action. Acetaminophen is the leading cause of acute liver failure in the United States, and nearly half of acetaminophen-associated cases are due to unintentional overdose.

Acetaminophen has a central analgesic effect that is mediated through activation of descending serotonergic pathways. Debate exists about its primary site of action, which may be inhibition of prostaglandin synthesis. The mechanism of action has been debated. In animal models, it has been seen to inhibit COX-3. At the spinal cord level, it has been shown to antagonize neurotransmission by N-methyl-D-aspartate (NMDA), substance P, and nitric oxide pathways.

Oral acetaminophen has excellent bioavailability. Acetaminophen is suitable for analgesic or antipyretic uses; it is the first-line analgesic in osteoarthritis and particularly valuable for patients in whom aspirin is contraindicated (e.g., those with peptic ulcer disease, aspirin hypersensitivity, and children with febrile illness). The conventional oral dose of acetaminophen is 325 to 650 mg every 4 to 6 hours; total daily doses should not exceed 4,000 mg (2,000 mg per day for chronic alcoholics). In efforts to reduce the incidence of hepatotoxicity, a U.S. Food and Drug Administration (FDA) advisory panel recommended in 2009 a lower maximum daily dose of acetaminophen of 2,600 mg and a decrease in the maximum single dose from 1,000 mg to 650 mg.

An intravenous (IV) preparation of acetaminophen is currently available for clinical use. Optimal analgesia for moderate to severe postoperative pain cannot be achieved using a single agent alone.³⁰ IV paracetamol provides around 4 hours of effective analgesia for about 37% of patients with acute postoperative pain.³¹ With its inherent safety and demonstrated efficacy, IV acetaminophen can prove to be an asset in managing perioperative pain.

Current evidence suggests that a combination of paracetamol and an NSAID may offer superior analgesia compared with either drug alone.³²

Acetaminophen is well tolerated and has a low incidence of gastrointestinal side effects. However, acute overdosage can cause severe hepatic damage, and the number of accidental or deliberate poisonings with acetaminophen continues to grow. Chronic use of <2 g per day is not typically associated with hepatic dysfunction, but overuse of acetaminophen-containing narcotic and over-the-counter combination products marketed in the United States has led to heightened awareness of the possibility of toxicity.

The pharmacology of acetaminophen overdose, including its time course and treatment is interesting and important to understand. Damage to the liver results from one of acetaminophen’s metabolites, N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI leads to liver failure by depleting the liver’s natural antioxidant glutathione and directly damaging liver cells, leading to liver failure. Treatment is aimed at removing the paracetamol from the body and replacing glutathione. Activated charcoal can be used to decrease absorption of acetaminophen in those who present, soon after ingestion of, an overdose. Acetylcysteine is administered as an antidote and acts as a precursor for glutathione and can neutralize NAPQI directly. Patients treated early after ingestion have a good prognosis.

Acetylsalicylic acid (Aspirin)

Aspirin is the oldest and most widely used medicinal compound in the world. It is considered separately from the NSAIDs due to its predominant use in the treatment of cardiovascular and cerebrovascular diseases. Aspirin is found in hundreds of over-the-counter medicines worldwide, and remains at the forefront of medicine, with newly discovered applications for the prevention and treatment of several life-threatening diseases. Aspirin is a derivative of salicylic acid. Aspirin and salicylate are rapidly metabolized in the plasma (e.g., by plasma esterases), erythrocyte, and liver, to salicylate in vivo.³³

Aspirin has several different approved uses. Aspirin acts as a general analgesic by blocking the action of the COX enzymes and thus prevents the production of prostaglandins. Aspirin effectively treats headaches, back and muscle pain, and other general aches and pains. In addition, aspirin produces inhibition of COX and thus prostanoid synthesis³⁴ and also protein kinase.³⁵ However, these are not necessarily the most likely mechanisms.³⁶ Aspirin irreversibly inactivates COX, leading to prolonged inhibition of platelet aggregation.

Overdose

The mechanism of NSAID toxicity in overdose is related to both their acidic nature and their inhibition of prostaglandin production. The severity typically depends on the dose ingested and the salicylate concentration that correlates with the degree of acid–base disturbance.^29,37 Salicylate levels of 300 to 600 mg/L are associated with mild toxicity, 600 to 800 mg/L with moderate toxicity, and greater than 800 mg/L with severe toxicity. For nonselective NSAIDs, plasma concentrations are not commonly measured because the half-life of many of these agents is relatively short.³⁷

Symptoms include nausea, vomiting, abdominal pain, tinnitus, hearing impairment, and CNS depression (Table 9-2); with higher dose aspirin ingestion, metabolic acidosis, renal failure, CNS changes (e.g., agitation, confusion, coma), and hyperventilation with respiratory alkalosis due to stimulation of the respiratory center. The presence of acidemia permits more salicylic acid to cross the BBB.³⁸ With other nonselective NSAID ingestions, symptoms are similar.^37–39