Abstract
Nonsteroidal antiinflammatory drugs (NSAIDs) are among the oldest, most successful drugs known to modern medicine in the treatment of fever, pain, and inflammation. This class of drugs is the most common medications used by the general population for acute or chronic soreness and inflammation with more than 100 million prescriptions written annually in the United States.
The mechanism of action of NSAIDs is the inhibition of prostanoid production from arachnoid acid by either reversible or irreversible acetylation of cyclooxygenase (COX). Cyclooxygenase is present in at least two isoforms, COX-1 and COX-2, and it is the inhibition of COX-2 that primarily produces the analgesic effects of NSAIDs.
In the United States multiple NSAIDs are available with varying degrees of efficacy but all nonaspirin NSAIDS have US Food and Drug Administration label warning for increased risk of heart attack or stroke. Additionally in 2005 the FDA added a boxed warning to all prescription NSAIDs highlighting the potential for increased risk of cardiovascular events and the potential for life-threatening gastrointestinal bleeding associated with their use.
This chapter will provide an overview of the NSAIDs, as NSAIDs are pivotal in the amelioration of painful conditions.
Keywords
adverse events, black box warning, cyclooxygenase selectivity, dosing recommendations, postoperative analgesia
Nonsteroidal antiinflammatory drugs (NSAIDs) were first developed in the late 19th century, when salicylic acid was formulated by Kolbe and colleagues, and lead to the founding of the Heyden Chemical Company. In 1897 Felix Hoffman and Arthur Eichengrün developed acetylsalicylic acid (ASA), the acetylated form of salicylic acid. This new molecule, “Aspirin,” was patented by the Bayer Corporation and became the most widely used medication in the world. The early class of NSAIDs were salicylates (aspirin-like medications), which have been used to treat pain conditions for thousands of years, with the Ebers papyrus recommending the application of a decoction of the dried leaves of myrtle to the abdomen and back to expel rheumatic pains from the womb. In ancient Greece, Hippocrates recommended the juices of the poplar tree to treat eye diseases and those of willow bark to relieve the pain of childbirth and reduce fever. NSAIDs are among the oldest, most successful drugs known to modern medicine in the treatment of fever, pain, and inflammation. Annually, more than 111 million prescriptions were written for NSAIDs in the United States, accounting for approximately 60% of the US over-the-counter (OTC) analgesic market. In the United States it has been estimated that greater than 30 million people use NSAIDs daily. Approximately 43 million adults (19.0%) were regular aspirin users (took aspirin at least 3 times per week for more than 3 months) and more than 29 million adults (12.1%) were regular users of NSAIDs. Compared with 2005, when 12.1% were regular users of aspirin and 9.1% were regular users of NSAIDs. This was an overall increase of 57% in aspirin use and 41% in NSAID use. This volume of use and the increase represent substantial concerns, which are compounded by the results of telephone surveys indicating that up to 26% of nonprescription NSAID users take more than the recommended dose.
NSAIDs are a diverse group of compounds with analgesic, antipyretic, and antiinflammatory activity. In 1971 the molecular mechanism responsible for NSAID activity was discovered when John Vane demonstrated that ASA and other NSAIDs inhibited the activity of cyclooxygenase (COX) enzymes responsible for the conversion of arachidonic acid to prostanoids. The prototypical NSAID, aspirin, has been largely replaced by newer NSAIDs. This class of medications contains compounds that are often chemically diverse but are grouped together based on their therapeutic actions. Many of the NSAIDs used today are available as over-the-counter (OTC) products, with more than 14 million patients using NSAIDs for the relief of symptoms associated with arthritis alone.
Mechanism of Action
Prostaglandins are important in the regulation and generation of the inflammatory response, but they are also important in the regulation of thrombocyte aggregation, the induction of pain and fever, the regulation of vessel perfusion, and many other processes. These complex activities and interactions promote a range of diverse, and often opposing, physiologic and pathologic processes, including induction and resolution of the inflammatory response, protection of and damage to the gastrointestinal (GI) mucosa, promotion and inhibition of blood clotting and atherosclerosis, and renal control of blood pressure and renal disease. Their biosynthesis is significantly increased in inflamed tissue, and they contribute to the development of the cardinal signs of acute inflammation.
The mechanism of action of the NSAIDs is inhibition of prostanoid production from arachidonic acid by either reversible or irreversible acetylation of the COX ( Fig. 51.1 ). COX is present in at least two isoforms (COX-1 and COX-2) and is dispersed throughout the body. COX-1 is necessary for normal functions and is found in most cell types, mediating the production of prostaglandins, which are essential in the homeostatic processes in the stomach (gastric protection), lung, and kidney and in platelet aggregation. The inhibition of COX-1 isoform may be responsible for the adverse effects (AE) related to the nonselective NSAIDs. It is the COX-2 isoform that is induced by proinflammatory stimuli and cytokines, causing fever, inflammation, and pain; it is thus the target of antipyresis, antiinflammation, and analgesia by NSAIDs. COX-2, despite being the inducible isoform, is expressed under normal conditions in a number of tissues, which probably include brain, testis, and kidney. In inflammatory states, COX-2 becomes expressed in macrophages and other cells propagating the inflammatory process. The pain associated with inflammation and prostaglandin production results from the production of prostanoids in the inflamed body tissues; these sensitize nerve endings, leading to the sensation of pain.
Research indicates that NSAIDs, originally thought to possess solely peripheral inhibition of prostaglandin production, have peripheral and central mechanisms of action. Peripherally, prostaglandins contribute to hyperalgesia by sensitizing nociceptive sensory nerve endings to other mediators (such as histamine and bradykinin) and by sensitizing nociceptors to respond to nonnociceptive stimuli (e.g., touch). Peripheral inflammation, as a result of tissue injury, results in the release of inflammatory mediations, inducing a substantial increase in COX-2 and prostaglandin synthase expression in the central nervous system. Centrally, prostaglandins are recognized to have direct actions at the level of the spinal cord enhancing nociception, notably the terminals of sensory neurons in the dorsal horn. Both COX-1 and COX-2 are expressed constitutively in dorsal root ganglia and spinal dorsal and ventral gray matter, but inhibition of COX-2 and not COX-1 reduces hyperalgesia. Additionally, the proinflammatory cytokine interleukin-1beta (IL-1β) plays a major role in inducing COX-2 in local inflammatory cells by activating the transcription factor NF-κB. In the central nervous system (CNS) IL-1β causes increased production of COX-2 and prostaglandin E2 (PGE 2 ), producing hyperalgesia, but this is not the result of neural activity arising from the sensory fibers innervating the inflamed tissue or of systemic IL-1β in the plasma. Peripheral inflammation possibly produces other signal molecules that enter the circulation, crossing the blood-brain barrier, and act to elevate IL-lβ, leading to COX-2 expression in neurons and nonneuronal cells in many different areas of the spinal cord. Evidence suggests that interleukin 6 (IL-6) triggers the formation of IL-1β in the CNS, which in turn causes increased production of COX-2 and PGE 2 .
The analgesic effects of NSAIDs are primarily due to inhibition of the COX-2 isoform. Structurally, NSAIDs differ in their intrinsic ability to inhibit COX-1 and COX-2, with individual NSAIDs tending to be more selective for one COX enzyme than the other. The inhibition of the two COX isoforms by NSAIDs may be assessed by calculation of the concentration of a drug causing 50% inhibition (IC 50 ) of the COX-2 and COX-1 and expressing the two values as a ratio. A ratio of 1.0 indicates a nonselective NSAID, whereas a ratio less than 1 is considered more selective for COX-1. NSAIDs with a COX selectivity ratio greater than 1 are considered more potent COX-2 inhibitors. NSAIDs are used therapeutically at doses that produce more than a 50% reduction in prostanoid formation, and the analgesic therapeutic plasma concentration is directly correlated with the IC 80 . Comparing the COX-2 and COX-1 IC 50 values as a ratio provides an estimate of an NSAID’s selectivity but does not indicate the actual ratio of inhibition of COX-2 to COX-1 achieved in vivo at commonly prescribed NSAID doses. Comparison of the potencies of the NSAIDs against COX-1 and COX-2 at the IC 80 value therefore appears more appropriate. In fact, IC 80 values of COX-2 inhibition of 22 different COX inhibitors have been found to correlate directly with the analgesic/antiinflammatory plasma concentrations of different COX inhibitors.
Pharmacokinetics
Pharmacokinetic variables such as absorption, distribution, metabolism (biotransformation), and elimination, along with the dose delivered may contribute to plasma concentrations achieved after drug administration. These variables are considered a central determinant of the therapeutic and adverse responses associated with the administration of NSAIDs. NSAIDs are most often delivered enterally, but intravenous (IV), intramuscular (IM), rectal, intraocular, and topical preparations are available. In general, COX inhibitors are lipid-soluble, weakly acid drugs that bind extensively to plasma proteins, with albumin as the major binding protein. NSAIDs comprise a heterogeneous group of compounds in several chemical classes ( Table 51.1 ). This chemical diversity yields a broad range of pharmacokinetic characteristics. Although there are many differences in the kinetics of NSAIDs, they have some general properties in common. All but one of the NSAIDs are weak organic acids as given; the exception, nabumetone, is a ketone prodrug that is metabolized to the acidic active drug.
| Medication (Generic) Name | Proprietary (Trade) Name | t ½ (h) | Percent Protein Bound (%) | Usual 24-Hour Adult Dose Range | Adult Daily Dose and Frequency | Comments | |
|---|---|---|---|---|---|---|---|
| Dosage | Schedule | ||||||
| Salicylates | |||||||
| Aspirin | Multiple | 2–3 | ∼90 | 2.4–4 g | 600–1500 mg | qid | Irreversible inhibitor of cyclooxygenase, cardioprotective, caution when used in combination with anticoagulants, associated with Reye syndrome in children |
| Buffered/enteric | Bayer, Bufferin, Ecotrin, multiple others | 2.4–4 g | 600–1500 mg | qid | |||
| Propionic Acid Derivatives | |||||||
| Naproxen | Naprosyn, others | 14 | 99 | 750 mg–1.0 g | 250, 375, 500 mg | bid | |
| Naproxen sodium | Aleve, Anaprox | 14 | 99 | 550–1100 mg | 275–550 mg | bid | — |
| Ibuprofen | Motrin, Advil, others | 6 | 99 | 1.2–2.4 g (pain) 2.4–3.2 g (inflammation) | 200–800 mg Maximum 3200 mg | qid qid | Available without prescription, parenteral formulation |
| Parenteral | Caldolor | ∼2 | 99 | 3.2 g | 400–800 mg | Every 6 h | |
| Ketoprofen | Orudis, Oruvail | 2–4 | 99 | 225 mg | 50–75 mg | qid | |
| Oxaprozin | Daypro | 40–60 | 99 | 1.2 g | 1.2 g | Once daily | |
| Acetic Acid Derivatives | |||||||
| Diclofenac | Voltaren | 1–2 | 99 | 150–200 mg | 50 mg 75 mg | bid–qid | Accumulates in synovial fluid, multiple formulations |
| Diclofenac/misoprostol | Arthrotec | 1–2 | 99 | 150–200 mg misoprostol should not exceed 800 μg | 50 mg/200 μg 75 mg/200 μg | bid–qid | Gastroprotective, contraindicated in pregnancy |
| Gel | Voltaren gel (1%) | 99 | 32 g | 2–4 g | qid | Decreased systemic absorption | |
| Patch | Flector patch (1.3%) | 12 | 99 | 360 mg | 1 patch (180 mg) | bid | Decreased systemic absorption |
| Etodolac | Lodine | 7 | 99 | 400–1000 mg | 200–300 mg | bid, tid | 15–20 mg/kg per 24 h |
| Indomethacin | Indocin Indocin SR, multiple others | ∼4 | 90 | <200 mg | 25–50 mg SR: 75 mg; rarely >150 mg | bid or tid | Limited use because of high side-effect profile in elderly |
| Ketorolac | Toradol | 4–6 | 99 | Oral not >40 mg/day Parenteral 30–60 mg, then 15–30 mg | Oral: 10 mg q6h for not >5 days total | qid | Limit use duration (<5 days), may precipitate renal failure in elderly or hypovolemic patients, efficacious in treating postoperative pain |
| Nabumetone | Relafen | 24 | 99 | 1.0–1.5 g | 500–750 mg | bid | Gastroprotective prodrug that is converted into the active molecule |
| Anthranilic Acid Derivatives | |||||||
| Mefenamic acid | Ponstel | 3–4 | 99 | 1.0 g | 250 mg | qid | Limit use duration <7 days |
| Oxicam | |||||||
| Meloxicam | Mobic | 15–20 | 99 | 7.5–15 mg | 7.5 mg (OA) 15 mg (RA) | bid qd | COX-2 selectivity at 7.5-mg dose |
| Coxibs (COX-2–Selective NSAIDs) | |||||||
| Celecoxib | Celebrex | 6–12 | 97 | 200 mg | 100–200 mg 400 mg—acute pain | Once daily or bid | Gastroprotective |
| Aniline Derivative | |||||||
| Acetaminophen | Tylenol, others | 2 | 20–50 | 2–4 g | 325–650 mg 650 mg–1 g | q4h qid | Hepatotoxicity in many combination medications; therefore patient education is needed |
There are various classifications of NSAIDs including chemical structure (e.g., salicylic acids, acetic acids), the t1/2 delineated by those shorter (<6 hours) or longer half-lives (>10 hours) and following the development of the selective COX-2 inhibitors, the classification into traditional NSAIDs (tNSAIDs) COX-2–selective NSAIDs. Traditional NSAIDs inhibit both COX-1 and COX-2, and COX-2–selective NSAIDs preferentially inhibit COX-2. Initially, only “coxibs” (e.g., celecoxib) were deemed COX-2–selective NSAIDs but the use of blood assays assessing COX-1 activity, thromboxane, COX-2 activity, and prostaglandin levels the degree of selectivity for COX-2 can be expressed in the inhibitory concentration (IC 50 ) ratios for COX-1/COX-2. The aforementioned IC 50 is a means of comparing NSAID potency; however, more than 50% inhibition is required to achieve analgesia. It has been shown that 80% inhibition (IC 80 ) correlates with plasma levels that produce clinically relevant analgesia and that the IC 80 may be a better measure of selectivity. The IC 80 estimates the actual ratio of inhibition of COX-2 to COX-1 achieved in vivo at commonly prescribed NSAID doses ( Fig. 51.2 ).
Absorption, Distribution, and Elimination
Absorption
Most NSAIDs are rapidly absorbed following oral ingestion, and peak plasma concentrations usually are reached within 2–4 hours. The presence of food tends to delay absorption without affecting peak concentration. Antacids, commonly prescribed to patients on NSAID therapy, variably delay but rarely reduce absorption. Most interaction studies performed with proton pump inhibitors (PPIs) suggest that relevant changes in NSAID kinetics are unlikely. Ketorolac, paracetamol, diclofenac, and ibuprofen are the few NSAIDs approved for parenteral administration, but most NSAIDs are not available in parenteral forms in the United States. Parenteral administration may have the advantage of decreased direct local toxicity in the GI tract, but parenteral ketorolac tromethamine, for example, does not decrease the risk of adverse events associated with COX-1 inhibition. Multiple NSAIDs can be formulated or compounded for transdermal delivery. These topical NSAIDs purport to have the advantage of providing local action without systemic AE. These medications, such as diclofenac in a transdermal patch, gel and topical solution, are formulated to traverse the skin to reach the adjacent joints and muscles and there exert therapeutic activity.
Distribution
The majority of NSAIDs are weakly acidic, highly bound to plasma proteins (albumin), and lipophilic. The relatively low pH of most NSAIDs determines in part their distribution as they are ionized at physiologic pHs. In areas with acidic extracellular pH values, NSAIDs may accumulate (inflamed tissue, GI tract, kidneys). NSAIDs can be classified as acidic or nonacidic based on their chemical structure, and the acidity of the drug can have an effect on its distribution. NSAIDs with acidic functional groups (e.g., diclofenac, ibuprofen, ketoprofen) and with a high degree of protein binding have been shown to selectively accumulate and persist at sites of inflammation, whereas nonacidic NSAIDs (e.g., acetaminophen, celecoxib, rofecoxib) tend to be distributed homogenously throughout the body. The high protein binding (≥90%) of the NSAIDs has particular relevance in the elderly population. The elderly tend to have decreased concentrations of serum albumin, resulting in higher free fractions of NSAIDs in the blood. Although such elevated free fractions may enhance efficacy, they can also increase toxicity. Conditions that alter plasma protein concentration may result in an increased free drug fraction with potential toxic effects. Highly protein-bound NSAIDs have the potential to displace other drugs (e.g., warfarin) if they compete for the same binding sites, resulting in an increased plasma concentration of the displaced molecule.
Elimination
The major metabolic pathway for elimination of NSAIDs is hepatic oxidation or conjugation. The cytochrome P450 (CYP) system is the enzymatic catalyst for the oxidative biotransformation NSAIDs; hepatic biotransformation followed by renal excretion is the principal route of elimination of the majority of NSAIDs. NSAIDs may have active metabolites altering their half-lives, as active metabolites may be present or the metabolite is the active form when liberated from the prodrug. Also, elimination of the NSAID may determine the dosing frequency, as NSAID plasma elimination half-lives vary widely from 0.25 to 70 hours. Acidic NSAIDs with short plasma half-lives (e.g., diclofenac, ibuprofen, ketoprofen) may be associated with tolerability benefits compared with drugs with long plasma half-lives because of their rapid clearance from the plasma and nontargeted tissues, allowing for the recovery of COX activity in other tissues (e.g., production of vasoprotective prostanoids by endothelial COX-2) even while the drug continues to actively inhibit COX-2 at sites of inflammation. The plasma elimination half-lives of NSAIDs vary considerably, from 1 to 4 hours (ibuprofen, diclofenac) to greater than 12 hours (piroxicam, naproxen, and meloxicam). Drugs with short half-lives possess a fast onset of action and short duration of action. Drugs with long half-lives or those formulated for sustained release may have a longer duration of action but may also be associated with increased side effects, such as an NSAID-related gastropathy.
Specific Medications
There are multiple NSAIDs available in the United States and even more are available outside of the United States. Table 51.1 provides information on chemical class, pharmacologic data, and therapeutic dosages. The US Food and Drug Administration (FDA) has strengthened an existing label warning that all nonaspirin NSAIDs have an increased risk for heart attack or stroke. The following included selected representatives of different classes of NSAIDs.
Salicylates
Aspirin: This is the most common salicylate. It is an ester derivative of salicylic acid with medicinal properties similar to those of salicylic acid without having the bitter taste or producing the significant GI irritation of the latter. Aspirin competitively and irreversibly inhibits COX activity. This is an important distinction from all the NSAIDs because the duration of aspirin’s effects is related to the turnover rate of COXs in different target tissues. The duration of effect of nonaspirin NSAIDs, which competitively inhibit the active sites of the COX enzymes, relates more directly to the time course of drug disposition. The importance of enzyme turnover in relief from the action of aspirin is most notable in platelets, which, being anucleate, have a markedly limited capacity for protein synthesis. Thus this inhibition of platelet COX-1 lasts for the lifetime of the platelet. Aspirin will irreversibly block and permanently arrest the production of thromboxane A2 (TXA 2 ), thus inhibiting platelet aggregation for the duration of the platelets’ life cycle and making aspirin a cardiovascular (CV) protective agent. Salicylates also displace other NSAIDs, such as naproxen and phenylbutazone, from plasma binding sites, thus increasing the free concentrations of those drugs and increasing the risk of toxicity. Of note, salicylates have been associated with Reye syndrome, a potentially lethal pediatric disorder that produces seizures and coma. Therefore salicylates should be avoided in children with viral illnesses and associated fever.
Aspirin has three therapeutic dosage ranges: The low range (<300 mg/day) is effective in reducing platelet aggregation, intermediate doses (300–2400 mg/day) have antipyretic and analgesic effects, and high doses (2400–4000 mg/day) are used for an antiinflammatory effect. The maximum recommended daily dose of aspirin for adults and children above 12 years of age is 4 g. Although aspirin is regarded as the standard against which other drugs should be compared for the treatment of rheumatoid arthritis, many clinicians favor the use of other NSAIDs perceived to have better GI tolerability.
There are other salicylate NSAIDs; these include but are not limited to diflunisal, choline magnesium trisalicylate, and salsalate.
Proprionic Acid
Propionic acid derivatives are traditional nonselective COX inhibitors. This class included ibuprofen, ketoprofen, naproxen, and oxaprozin.
Ibuprofen: Ibuprofen is one of the most widely used NSAIDs and one of the first to be available without a prescription (≤200 mg). It is rapidly absorbed from the upper GI tract with peak plasma levels achieved about 1–2 hours after administration. Ibuprofen is highly plasma protein–bound and has an estimated volume of distribution of 0.14 L/kg. Ibuprofen is primarily hepatically metabolized (90%) with less than 10% excreted unchanged in the urine and bile. The half-life is approximately 2 hours (2 ± ½ hour); the lack of active metabolites, OTC availability, and low toxicity potential support the use of ibuprofen in febrile and mild to moderate pain conditions. As an acidic NSAID with high protein binding, its persistence in the synovial fluid more than in the plasma allows continued antiinflammatory and analgesic activity after plasma levels have declined. Ibuprofen at a dose of 1200–2400 mg/day has a predominately analgesic effect for mild to moderate pain conditions, with a dose of 3200 mg/day recommended only under the continued care of clinical professionals. Even at antiinflammatory doses of more than 1600 mg/day, renal side effects are almost exclusively encountered in patients with low intravascular volume and low cardiac output, particularly in the elderly. The effectiveness of ibuprofen has been demonstrated in the treatment of headache and migraine, menstrual pain, and acute postoperative pain. Ibuprofen is available in OTC form, by prescription, and in combination with opioid medications, decongestants, and antihistamines. As a parenteral formulation, it has shown efficacy in postoperative pain reduction in multiple studies. Ibuprofen, consistent with other NSAIDs, has a boxed warning from the FDA for increased risk of serious CV thrombotic events, myocardial infarction, and stroke.
Naproxen: Naproxen is a nonprescription NSAID that first became available as a prescription-only medication but it has now become available OTC. However, a controlled-release tablet (Naprelan) is available by prescription only. Naproxen is fully absorbed after enteral administration and has a half-life of 14 hours. Peak concentrations in plasma occur within 2–4 hours and are somewhat more rapid after the administration of naproxen sodium. It is fully absorbed after enteral administration and has a half-life of 14 hours, but steady-state serum levels require more than 48 hours. Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels, naproxen is more than 99% albumin-bound, but this may be increased in the elderly in relation to the decrement in renal function. Naproxen has been formulated in combination, including the fixed-dose combination of sumatriptan/naproxen sodium (Treximet), approved for the acute treatment of migraine-type headaches. In contrast to other tNSAIDS, naproxen has been shown to be unassociated with an increased risk of major vascular events. A meta-analysis of over 600 clinical trials comprising more than 300,000 participants revealed a dose-related risk of major cardiovascular events with NSAIDs (tNSAIDS and coxibs) but not with naproxen. An ongoing study (completion 2016), the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) study, will provide further data on the comparative CV safety of celecoxib, ibuprofen, and naproxen.
Ketoprofen: The pharmacologic properties of ketoprofen are similar to other propionic acid derivatives, although the different formulations differ in their release characteristics. Peak plasma levels were achieved at about 1–2 hours after oral administration, with a half-life of approximately 2 hours. Ketoprofen has high plasma protein binding (98%–99%) and an estimated volume of distribution of 0.11 L/kg. Ketoprofen is conjugated with glucuronic acid in the liver, and the conjugate is excreted in the urine. The glucuronic acid moiety can be converted back to the parent compound. Thus the metabolite serves as a potential reservoir for the parent drug, which may be important in persons with renal insufficiency. Ketoprofen is available by prescription in multiple dose formulations (i.e., immediate release and extended release). The usual starting dose of ketoprofen is 50 or 75 mg with immediate-release capsules being administered every 6–8 hours or 200 mg with extended-release capsules being given once daily. The maximum dose is 300 mg/day of immediate-release capsules or 200 mg/day of extended-release capsules. Ketoprofen has a comparatively short half-life, potentially minimizing activity at COX-2, allowing COX-2 recovery; however, ketoprofen is associated with increased side effects (e.g., mild gastropathy). Although not approved by the FDA for transdermal prescription issuance, ketoprofen has been formulated for transdermal application. The topical application facilitates a reduction in systematic concentration while local (site of application) concentrations remain therapeutic. Transdermal application of ketoprofen has provided more efficacy than placebo at reducing pain in patients with a variety of painful soft tissue/musculoskeletal conditions.
Other Propionic Acid Derivatives
Fenoprofen, flurbiprofen, and oxaprozin are additional propionic acid derivatives. All of these medications except oxaprozin have similar pharmacologic properties, including time to peak plasma levels, protein binding, and half-life. Oxaprozin has a time to peak concentration of 3–4 hours and a half-life of 40–60 hours (see Table 51.1 ). Oxaprozin diffuses readily into inflamed synovial tissues after oral administration and is capable of inhibiting both anandamide hydrolase in neurons and NF-kappaB activation in inflammatory cells, which are crucial for the synthesis of proinflammatory and histotoxic mediators in inflamed joints.
Acetic Acid Derivatives
Acetic acid derivatives are traditional, nonselective COX inhibitors. This class includes diclofenac, etodolac, ketorolac, tolmentin, sulindac and indomethacin.
Indomethacin: Indomethacin is a potent nonselective COX inhibitor introduced in 1963. It was widely used as an antiinflammatory medication but has fallen out of favor with the advent of safer alternatives. The tendency toward AE of indomethacin compared with other commercially available NSAIDs has limited its indication and duration of use. In the United States it is available only by prescription. Oral indomethacin has excellent bioavailability, with peak concentrations occurring 1–2 hours after dosing. Indomethacin is 90% bound to plasma proteins and tissues. The half-life in plasma is variable, perhaps because of enterohepatic cycling, but averages about 2.5 hours. Complaints associated with GI irritation are common, including diarrhea, and ulcerative lesions are a contraindication to indomethacin use. A meta-analysis of 280 placebo-controlled trials of NSAIDs showed that indomethacin posed an “intermediate risk” of GI irritation, with coxibs posing a lower risk and medications such as ketorolac posing the highest risk. In addition to gastropathy, indomethacin is associated with central nervous system adverse events, with severe frontal headache occurring in 25%–50% of patients who take the drug for long periods. Dizziness, vertigo, light-headedness, and mental confusion may also occur. Indomethacin is available in enteral and parenteral formulation and is indicated for the treatment of acute mild to moderate pain. Parenteral indomethacin has an indication for the closure of persistent patent ductus arteriosus, but its side effect profile limits other uses of the parenteral formulation.
Etodolac: Etodolac has some degree of COX-2 selectivity, conferring less gastric irritation compared with other NSAIDs. After oral administration, peak serum concentrations are attained within 2 hours. Etodolac is highly bound to plasma proteins, with an estimated volume of distribution of 0.4 L/kg. It is excreted primarily in the urine, and 60% of a dose is recovered within 24 hours. The half-life of etodolac is 6–8 hours irrespective of dosage form; therefore it attains steady state quickly with only a modest degree of accumulation with chronic administration. Etodolac is available by prescription; in a review of nine studies (1459 participants), etodolac showed usefulness as an analgesic in postoperative pain, with efficacy similar to single dose paracetamol 1000 mg and celecoxib 200 mg. Additionally, in providing relief of postsurgical pain, etodolac 100–200 mg was approximately equivalent to aspirin 650 mg, although etodolac had a longer duration of action. Etodolac 600 mg/day showed substantially better gastroduodenal tolerability than ibuprofen (2.4 g/day), indomethacin (200 mg/day), or naproxen (1 g/day). A review of etodolac safety data from more than 3000 patients enrolled in double-blind and open-label clinical trials and from more than 8000 patients taking etodolac in postmarketing surveillance studies found that the rates of abdominal pain and dyspepsia were similar to those with several other NSAIDs and that GI ulceration occurs in less than 0.3% of patients taking etodolac.
Nabumetone: Nabumetone is a ketone prodrug with weak COX inhibitory activity in vitro; in vivo, however, it undergoes hepatic biotransformation to the active component, 6-methoxy-2-naphthylacetic acid (6-MNA), which is a relatively selective COX-2 inhibitor that has antiinflammatory and analgesic properties. Nabumetone is highly bound to plasma proteins and has an estimated volume of distribution of 0.68 L/kg. Nabumetone is excreted primarily in the urine and has a half-life of approximately 20–24 hours, achieving substantial concentrations in synovial fluid. The long plasma half-life of 6-MNA and its persistence in synovial fluid facilitate a once-daily dosage regimen. Compared with other NSAIDs, nabumetone has tended to show efficacy and tolerability in the treatment of arthritis, but studies are lacking in the treatment of acute postoperative pain. Nabumetone compares favorably with other NSAIDs with respect to its renal and GI AE profile. The most frequent AE are those commonly seen with COX inhibitors; they include diarrhea, dyspepsia, headache, abdominal pain, and nausea. In common with other COX inhibitors, nabumetone may increase the risk of GI AE, but studies have reported incidents equal to other COX-2 selective inhibitors but considerably lower than for nonselective COX inhibitors. This has been attributed mainly to the nonacidic chemical properties of nabumetone but also to its COX-1/COX-2 inhibitor profile.
Ketorolac: Ketorolac is an NSAID with activity at COX-1 and COX-2 enzymes, thus blocking prostaglandin production. After oral administration, peak serum concentrations are attained within 0.5–1 hour. Ketorolac is highly bound to plasma proteins and has an estimated volume of distribution of 0.28 L/kg. Ketorolac is excreted primarily in the urine and has a half-life of approximately 5–6 hours in healthy subjects. Since its approval, it has drawn more favor as a potent analgesic agent because of its moderately effective antiinflammatory effects. Multiple studies have investigated the analgesic potency of ketorolac; in animal models, the analgesic potency has been estimated to be between 180 and 800 times that of aspirin. Compared with morphine, ketorolac 30 mg IM has been shown to be equivalent to IV morphine 2–4 mg, 12 mg morphine IM, and 100 mg meperidine IM. Ketorolac is available for enteral, ophthalmic, and parenteral administration. An intranasal formulation (Sprix) is available for use in the United States. This may be more effective than administration by oral routes in providing improved absorption, avoidance of first-pass effects, GI AE, and improved patient compliance. It has been observed that the mean values for total body clearance were decreased by about 50% and that the half-life was approximately doubled in patients with renal impairment compared with healthy control subjects. Ketorolac may precipitate or exacerbate renal failure in hypovolemic patients, the elderly, or especially those with underlying renal dysfunction. Ketorolac is recommended for limited use (3–5 days).
Diclofenac: Diclofenac was introduced in 1973 and has become the most widely prescribed NSAID. It is available by prescription in many formulations (enteral, parenteral, transdermal, and ophthalmic). It has COX-2 selectivity and its potency against COX-2 is substantially greater than that of indomethacin, naproxen, or several other NSAIDs; it is similar to celecoxib. Diclofenac is rapidly absorbed after oral administration but may vary between different salt formulations. Substantial first-pass metabolism occurs; only about 50%–60% of diclofenac is available systemically. After oral administration, peak serum concentrations are attained within 2–3 hours but may vary secondary to differences in GI pH, partial precipitation of the dose in the acidic conditions in the stomach, variable timing in gastric emptying, and enterohepatic circulation. Diclofenac is highly bound to plasma proteins and has an estimated volume of distribution of 0.12 L/kg. Diclofenac is excreted primarily in the urine (65%) and as bile conjugates (35%). Uniquely, diclofenac accumulates in inflamed tissues and synovial fluid after oral administration, which may explain why its duration of therapeutic effect is considerably longer than its plasma half-life of 1–2 hours. Diclofenac administered as the sodium salt was detectable in synovial fluid for up to 11 hours following administration of a 50-mg enteric-coated tablet and up to 25 hours following administration of a 100-mg slow-release tablet. Diclofenac sodium, usually distributed in enteric-coated tablets, resists dissolution in low-pH gastric environments, releasing instead in the duodenum. Diclofenac potassium is more water-soluble and was considered to provide more rapid dissolution and faster absorption with the aim of releasing the active drug in the stomach to permit rapid uptake and prompt pain relief. Topical preparations are available with the purpose of limiting systemic exposure, reducing the AE, but providing localized analgesia and pain reduction. Topically, diclofenac has a much smaller total systemic absorption (approximately 3%–5%) than oral diclofenac products and less than 10% of the C max achieved following oral administration. On the other hand, interstitial concentrations of diclofenac in muscle tissue are usually higher after topical treatment than after oral administration of NSAIDs. The injectable formulations of diclofenac have been developed, with Dyloject receiving FDA approval for moderate pain, principally postoperative pain. Diclofenac has been formulated in fixed-dose combinations including diclofenac sodium-misoprostol (Arthrotec), for patients at high risk for developing NSAID-induced gastric ulcers, erosion, or similar complications.
Anthranilic Acid
Mefenamic acid: Arthranilic acid, also known as mefenamic acid, is a weak organic acid. Peak plasma levels are attained in 2–4 hours and its elimination half-life is approximately 2 hours. More than 90% has been reported to be bound to albumin; it has an estimated volume of distribution of 1.06 L/kg. The mechanism of action, like that of other NSAIDS, is the inhibition of prostaglandin synthesis. In addition, however, mefenamic acid appears to reduce the activity of prostaglandins, possibly by binding to and blocking prostaglandin receptors on cells in a dose-dependent fashion. Mefanamic acid is available by prescription and has potential utility in its ability to affect smooth muscle and decreasing uterine resting pressure. It also has a dose-dependent effect for relaxing tonic uterine contraction. Its use in clinical medicine has declined, since mefenamic acid may offer no clinical advantage over other NSAIDs.
Oxicam
Meloxicam: Oxicam, or meloxicam, is an enolic acid derivative that has relative COX-2 selectivity. Meloxicam has high plasma protein binding (99%) and an estimated volume of distribution of 0.1–0.2 L/kg. Its terminal elimination half-life is approximately 20 hours, making it suitable for once-daily dosing. Its steady-state drug plasma concentrations are reached within 3–5 days. Although there is little evidence for the efficacy of this drug in the postoperative setting (lack of data), meloxicam has shown efficacy in the treatment of osteoarthritis. Additionally, an oral formulation of meloxicam (SoluMatrix) has been developed, aimed at decreasing the dose-related risk for serious GI, CV, and renal adverse events associated with NSAIDs.
Cyclooxygenase-2 Inhibitors
All NSAIDs are COX-2 inhibitors with varying degrees of COX-1 activity. The inhibition of the constitutive COX-1 isoform can be described as a side effect of NSAID use and the inhibition of COX-2 as the purposeful intent. Inhibition of COX-1 can alter homeostatic functions, such as protection of the GI mucosa and platelet activation. The COX-2 inhibitors as a class were developed to decrease the risk of injury to the GI tract associated with the inhibition of COX-1 activity while taking advantage of the COX-2 inhibition resulting in antiinflammatory, analgesic, and antipyretic properties. Approved by the FDA in 1998, celecoxib was the first selective COX-2 inhibitor indicated for the treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and acute pain conditions. Two other coxibs were developed and brought to market, but owing to an increased risk of CV side effects, rofecoxib and valdecoxib were withdrawn. To date, celecoxib is the only coxib approved by the FDA for use in the United States, although others are available for use in Europe (e.g., etoricoxib, parecoxib, lumiracoxib).
Celecoxib: Currently celecoxib is the only selective COX-2 inhibitor available in the United States. It is 30-fold more selective for COX-2 than COX-1, compared with 0.5-fold for ibuprofen, 0.7-fold for naproxen, 1.9-fold for indomethacin, 18-fold for meloxicam, 29-fold for diclofenac, and 267-fold for rofecoxib. Peak serum concentrations are attained 2–4 hours after administration. Celecoxib is highly bound to plasma proteins, is excreted primarily by hepatic metabolism, and has a half-life of approximately 11.2 and 15.6 hours. Additionally, NSAID-induced GI complications are among the most common serious drug-related adverse events, but celecoxib preferentially inhibits the inducible COX-2 isoform and not the constitutive COX-1 isoform, thus conferring a gastroprotective effect. When used for a long time, celecoxib has fewer side effects associated with the digestive system than other NSAIDs. There is no evidence to suggest that differences in the selectivity of these agents toward one COX isoenzyme is of importance with respect to analgesia, as currently all drugs used for analgesia are COX-2 inhibitors. Additionally there are no clear differences in efficacy for pain relief associated with different NSAIDs, although celecoxib was associated with a lower risk of ulcer complications compared with nonselective NSAIDs. Celecoxib, which has a relatively slow rate of absorption, can be administered at standard doses to effectively treat osteoarthritis pain, but it is “not ideal” for the treatment of acute pain, since it takes considerable time for absorption and often requires a loading dose to achieve clinically meaningful analgesia. Although celecoxib has been shown to be effective in treating acute postoperative pain, its primary indication is for the treatment of osteoarthritis and rheumatoid arthritis.
As stated earlier celecoxib is the sole selective COX-2 inhibitor available in the United States secondary to increased cardiovascular risk associated with the withdrawn rofecoxib and valdecoxib. The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) Study assessed the noninferiority of celecoxib compared to two most commonly prescribed traditional NSAIDs (ibuprofen & naproxen) with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Although the study recorded a high study discontinuation rate (69%), the findings suggest that modest-dose celecoxib was noninferior to ibuprofen or naproxen in regard to cardiovascular safety.
Acetaminophen
Acetaminophen (paracetamol, or APAP) is an analgesic and antipyretic medication that produces its analgesic effect by inhibiting central prostaglandin synthesis with minimal inhibition of peripheral prostaglandin synthesis. Acetaminophen and NSAIDs have important differences, such as acetaminophen’s weak antiinflammatory effects and its generally poor ability to inhibit COX in the presence of high concentrations of peroxides, as are found at sites of inflammation. It also does not have AE on platelet function or the gastric mucosa. After oral administration, peak serum concentrations are attained within 0.5–1.0 hour. A small portion of acetaminophen is bound to plasma proteins (20%–50%), and elimination from the body is primarily by the formation of glucuronide and sulfate conjugates in a dose-dependent manner. The half-life of acetaminophen is approximately 2–3 hours in healthy subjects. Acetaminophen is perhaps the safest and most cost-effective nonopioid analgesic when it is administered in analgesic doses.
The maximum daily dose in healthy adults is 4000 mg/day. The FDA has reduced the maximum daily dose of acetaminophen in fixed-dose prescription medications and OTC fixed-dose medications to no more than 325 mg per unit dose, but concern remains for fixed-dose OTC vitamins, minerals, other dietary supplements containing acetaminophen and the potential for toxicity by inadvertent cumulative exposure. In elderly persons, acetaminophen may be recommended as first-line therapy for pain, and tNSIADs should be used with caution because drug interactions and AE. Although often labeled as a first-line medication for pain attenuation, acetaminophen has shown minimal efficacy in treating osteoarthritis; it is ineffective in the treatment of low back pain but was shown to offer effective pain relief for about half of participants experiencing moderate to severe pain after surgery.
In 2010, the FDA approved the IV formulation of acetaminophen (OFIRMEV), indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. Prior to the approval of OFIRMEV, propacetamol, a water-soluble prodrug of acetaminophen, was available in Europe as a parenteral form yielding 0.5 g acetaminophen per 1 g of propacetamol. The use of IV acetaminophen has been studied in acute postoperative pain, revealing rapid and effective analgesia in patients with moderate to severe pain after surgery. In comparing enteral and parenteral acetaminophen, no clear indication exists for preferential prescribing of IV acetaminophen. One of the main clinical and practical advantages associated with IV administration is the faster onset of analgesia relative to an equivalent oral dose. In addition, IV administration is associated with more predictable pharmacokinetic and pharmacodynamic behavior. Another potential advantage of IV administration is avoidance of first-pass hepatic exposure through the portal circulation, which may reduce the potential for hepatic injury.
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