Fig. 3.1
Site of action of NSAIDs
.
Originally thought of as possessing solely peripheral inhibition of prostaglandin production, more recent research indicates that NSAIDs have peripheral and central mechanisms of action [2, 16, 17]. 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 non-nociceptive stimuli (e.g., touch) [16, 18]. Peripheral inflammation induces a substantial increase in COX-2 [19] 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 [20]. 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 [21]. Additionally, the pro-inflammatory 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 PGE2, 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 [22]. 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 [22, 23]. At present, 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 PGE2 [22].
There appear to be two forms of input from peripheral-inflamed tissue to the CNS. The first is mediated by electrical activity in sensitized nerve fibers innervating the inflamed area, which signals the location of the inflamed tissue as well as the onset, duration, and nature of any stimuli applied to this tissue [21]. This input is sensitive to peripherally acting COX-2 inhibitors and to neural blockade with local anesthetics [24]. The second is a humoral signal originating from the inflamed tissue, which acts to produce a widespread induction of COX-2 in the CNS.
Pharmacokinetics
NSAIDs are most often administered enterally, but intravenous, intramuscular, rectal, and topical preparations are available. NSAIDs are highly bound to plasma proteins, specifically to albumin (>90 %), and therefore, only a small portion of the circulating drug in plasma exists in the unbound (pharmacologically active) form. The volume of distribution of NSAIDs is low, ranging from 0.1 to 0.3 L/kg, suggesting minimal tissue binding [25]. Most NSAIDs are weak acids with pK as < 6, and since weak acids will be 99 % ionized two pH units above their pK a, these anti-inflammatory medications are present in the body mostly in the ionized form. In contrast, the coxibs are nonacidic which may play a role in the favorable tolerability profile.
Absorption
NSAID’s pH profile facilitates absorption via the stomach, and the large surface area of the small intestine produces a major absorptive site for orally administered NSAIDs. Most of the NSAIDs are rapidly and completely absorbed from the gastrointestinal tract, with peak concentrations occurring within 1–4 h. The presence of food tends to delay absorption without affecting peak concentration [10]. Ketorolac is one of the few NSAIDs approved for parenteral administration, but most NSAIDs are not available in parenteral forms in the United States. Recently, injectable ibuprofen has been approved as an injectable formulation for pain and fever. Parenteral administration may have the advantage of decreased direct local toxicity in the gastrointestinal tract, but parenteral ketorolac tromethamine does not decrease the risk of adverse events associated with COX-1 inhibition. Topical NSAIDs possess the advantage of providing local action without systemic adverse effects. These medications, such as diclofenac epolamine transdermal patch (Flector®) and diclofenac sodium gel (Voltaren®) are formulated to traverse the skin to reach the adjacent joints and muscles and 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, in part, determines the distribution too because they are ionized at physiologic pHs. In areas with acidic extracellular pH values, NSAIDs may accumulate (inflamed tissue, gastrointestinal tract, kidneys) [24]. Additionally, the unbound drug is generally considered responsible for pharmacological effects, and the apparent volume of distribution (Vd/F), determined after oral administration, is usually 0.1–0.3 L/kg, which approximates plasma volume [25]. This high-protein binding places only a small portion in the active, unbound form. However, some NSAIDs (i.e., ibuprofen, naproxen, salicylate) have activity that is concentration-dependent because their plasma concentration approaches that of plasma albumin and the Vd/F increases with dose [24]. The high-protein binding (>90 %) of the NSAIDs has particular relevance in the state of hypoalbuminemia or decrease albumin concentrations (e.g., elderly, malnourished). A greater fraction of unbound NSAIDs are present in the plasma which may enhance efficacy, but also increase toxicity.
Elimination
The major metabolic pathway for elimination of NSAIDs is hepatic oxidation or conjugation. The half-lives of NSAIDs vary as active metabolites may be present or the metabolite is the active form when liberated from the prodrug. Also, the elimination of the NSAIDs may determine the dosing frequency as NSAID plasma elimination half-lives vary widely from 0.25 to 70 h [24]. Renal excretion of unmetabolized drug is a minor elimination pathway for most NSAIDs accounting for less than 10 % of the administered dose.
Specific Medications
Salicylates
Aspirin
Acetylsalicylic acid (ASA) is the most widely used analgesic, antipyretic, and anti-inflammatory agent in the world and remains the standard for which all other NSAIDs are compared. Aspirin inhibits the biosynthesis of prostaglandins by means of an irreversible acetylation and consequent inactivation of COX; thus, aspirin inactivates COX permanently. This is an important distinction among the NSAIDs because aspirin’s duration action is related to the turnover rate of cyclooxygenases in different target tissues. The duration of action of other NSAIDs, which competitively inhibit the active sites of the COX enzymes, relates more directly to the time course of drug disposition [26]. Platelets are devoid of the ability to produce additional cyclooxygenase; thus, thromboxane synthesis is arrested.
Propionic Acid
Naproxen
Naproxen is a nonprescription NSAID, but a newly formulated controlled-release tablet is available (Naprelan®). It is fully absorbed after enteral administration and has a half-life of 14 h. Peak concentrations in plasma occur within 4–6 h. Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels, naproxen is greater than 99 % albumin-bound. Naproxen is extensively metabolized to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Most of the drug is excreted in the urine, primarily as unchanged naproxen. Naproxen has been used for the treatment of arthritis and other inflammatory diseases. Metabolites of naproxen are excreted almost entirely in the urine. About 30 % of the drug undergoes 6-demethylation, and most of this metabolite, as well as naproxen itself, is excreted as the glucuronide or other conjugates.
Ibuprofen
Ibuprofen is one of the most widely used NSAIDs after ASA, and N-acetyl-p-aminophenol (APAP) in OTC is used for the relief of symptoms of acute pain, fever, and inflammation. Ibuprofen is rapidly absorbed from the upper GI tract, with peak plasma levels achieved about 1–2 h after administration. Ibuprofen is highly bound to plasma proteins 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. and mild-to-moderate pain conditions [27]. Ibuprofen at a dose of 1,200–2,400 mg/day has a predominately analgesic effect for mild-to-moderate pain conditions, with dose of 3,200 mg/day only recommended under continued care of clinical professionals. Even at anti-inflammatory doses of more than 1,600 mg/day, renal side effects are almost exclusively encountered in patients with low intravascular volume and low cardiac output, particularly in the elderly [28]. The effectiveness of ibuprofen has been demonstrated in the treatment of headache and migraine, menstrual pain, and acute postoperative pain [29–31]. The recent injectable formulation will gain increased use for acute pain and fever.
Ketoprofen
The pharmacological properties of ketoprofen are similar to other propionic acid derivative, although the different formulations differ in their release characteristic. Not available in the United States, the optically pure (S) enantiomer (dexketoprofen) is available which is rapidly reabsorbed from the gastrointestinal tract, having a rapid onset of effects. Additionally, capsules release drug in the stomach, whereas the capsule pellets (extended release) are designed to resist dissolution in the low pH of gastric fluid but release drug at a controlled rate in the higher pH environment of the small intestine. Peak plasma levels achieved about 1–2 h after oral administration for the capsules and 6–7 h after administration of the capsule pellets. 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 parent drug, and this may be important in persons with renal insufficiency. The extended release ketoprofen is not recommended for the treatment of acute pain because of the release characteristics. Individual patients may show a better response to 300 mg daily as compared to 200 mg, although in well-controlled clinical trials patients on 300 mg did not show greater mean effectiveness. The usual starting dose of ketoprofen is 50 or 75 mg with immediate release capsules every 6–8 h or 200 mg with extended release capsules once daily. The maximum dose is 300 mg daily of immediate release capsules or 200 mg daily of extended release capsules. Ketoprofen has shown statistical superiority over acetaminophen on the time-effect curves for pain relief and pain intensity difference in the treatment of moderate or severe postoperative pain and acute low back pain [32–34].
Oxaprozin
In contrast to the other propionic acid derivatives, oxaprozin peak plasma levels are not achieved until 3–6 h after an oral dose and its half-life of 40–60 h allows for once-daily administration [35]. Oxaprozin is highly bound to plasma proteins and has an estimated volume of distribution of 0.15 L/kg. Oxaprozin is primarily metabolized by the liver, and 65 % of the dose is excreted into the urine and 35 % in the feces as metabolites. 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 synthesis of pro-inflammatory and histotoxic mediators in inflamed joints [36–38].
Acetic Acid
Diclofenac
Diclofenac has COX-2 selectivity, and the selective inhibitor of COX-2 lumiracoxib is an analog of diclofenac. Its potency against COX-2 is substantially greater than that of indomethacin, naproxen, or several other NSAIDs and is similar to celecoxib [10]. Diclofenac is rapidly absorbed after oral administration, but substantial first-pass metabolism of only about 50 % of diclofenac is available systemically. After oral administration, peak serum concentrations are attained within 2–3 h. 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 35 % as bile conjugates. Diclofenac is available in two enteral formulations, diclofenac sodium and diclofenac potassium. Diclofenac potassium is formulated to be released and absorbed in the stomach. Diclofenac sodium, usually distributed in enteric-coated tablets, resists dissolution in low-pH gastric environments, releasing instead in the duodenum [39]. Hepatotoxicity, elevated transaminases, may occur, and measurements of transaminases should be measured during therapy with diclofenac. Other formulations of diclofenac include topical gels (Voltaren® Gel) and transdermal patches (Flector® Patch). Additionally, diclofenac is available in a parenteral formulation for infusion (Voltarol® Ampoules), and more recently, a formulation for intravenous bolus has been developed (diclofenac sodium injection [DIC075V; Dyloject®]). Uniquely, diclofenac accumulates in synovial fluid after oral administration [40], which may explain why its duration of therapeutic effect is considerably longer than the plasma half-life of 1–2 h. Oral preparations have been shown to provide significant analgesia in the postoperative period for adults experiencing moderate or severe pain following a surgical procedure [41].
The transdermal application of diclofenac has also shown efficacy in the treatment of musculoskeletal disorders including ankle sprains, epicondylitis, and knee osteoarthritis [42, 43]. The advantage of the transdermal formulation is the lack of appreciable systemic absorption and accumulation of the medication at the site of application, thereby providing local pain relief. In comparison to enteral delivery, topical application of diclofenac provides analgesia by peripheral activity and not central mediation.
Etodolac
Etodolac has some degree of COX-2 selectivity conferring less gastric irritation compared with other NSAIDs [44]. The analgesic effect of full doses of etodolac is longer than that of aspirin, lasting up to 8 h. After oral administration, peak serum concentrations of 16 and 25 mg/L are attained within 2 h of administering 200 and 400 mg, respectively. Etodolac is highly bound to plasma proteins and has an estimated volume of distribution of 0.4 L/kg. Etodolac is excreted primarily in the urine, and 60 % of a dose is recovered within 24 h. Greater than 60 % of the metabolites are hydroxylated with glucuronic conjugation. The half-life of etodolac is approximately 7 h in healthy subjects. When compared with other NSAIDs, etodolac 300 and 400 mg daily has tended to be more effective than aspirin 3–4 g daily and was similar in efficacy to sulindac 400 mg daily [10]. Clinical doses of 200–300 mg twice a day for the relief of low back or shoulder pain have been equated to analgesia with naproxen 500 mg twice a day [45]. In postsurgical pain, etodolac 100–200 mg was approximately equivalent to aspirin 650 mg in providing pain relief, although etodolac had a longer duration of action [46].
Indomethacin
It is a nonselective COX inhibitor introduced in 1963, but has fallen out of favor with the advent of safer alternatives. Indomethacin is a more potent inhibitor of the cyclooxygenases than is aspirin, but patient intolerance generally limits its use to short-term dosing. Oral indomethacin has excellent bioavailability. Peak concentrations occur 1–2 h after dosing. Indomethacin is 90 % bound to plasma proteins and tissues. The concentration of the drug in the CSF is low, but its concentration in synovial fluid is equal to that in plasma within 5 h of administration [10]. Complaints associated with gastrointestinal irritation are common, including diarrhea, and ulcerative lesions are a contraindication to indomethacin use. Indomethacin has FDA approval for closure of persistent patent ductus arteriosus, but side effect profile limits other uses.
Ketorolac
Ketorolac Tromethamine is a NSAID with activity at COX-1 and COX-2 enzymes thus blocking prostaglandin production. After oral administration, peak serum concentrations are attained within 1–2 h. 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 h in healthy subjects. Administration of ketorolac is available for enteral, ophthalmic, and parenteral delivery and is the only parenteral NSAID currently available in the United States. Ketorolac has been utilized to treat mild-to-severe pain following major surgical procedures including general abdominal surgery, gynecologic surgery, orthopedic surgery, and dentistry. Multiple studies have investigated the analgesic potency of ketorolac, and in animal models, the analgesic potency has be estimated to be between 180 and 800 times that of aspirin [47, 48]. When compared to morphine, ketorolac 30 mg intramuscular (IM) has been shown to be equivalent to 12 mg morphine IM and 100 mg meperidine IM [49]. It was observed that the mean values for total body clearance of ketorolac were decreased by about 50 % and that the half-life was approximately doubled in patients with renal impairment compared with healthy control subjects [50], and it may precipitate or exacerbate renal failure in hypovolemic, elderly, or especially those with underlying renal dysfunction. Therefore, ketorolac is recommended for limited use (3–5 days). Recently, intranasal route of administration of ketorolac (Sprix™) has been approved by the FDA for acute pain. The CSF penetration of this compound via the nasal route should be superior.
Nabumetone
Nabumetone is a prodrug, which undergoes hepatic biotransformation to the active component, 6-methoxy-2-naphthylacetic acid (6MNA), that has some degree of COX-2 selectivity conferring less gastric irritation compared with other NSAIDs [51]. 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 h in healthy subjects enabling single-daily dosing. When compared with other NSAIDs, nabumetone has tended to show efficacy [52] and tolerability in the treatment of arthritis [53, 54].
Anthranilic Acid
Mefenamic Acid
Peak serum concentrations are attained within 2–4 h and a half-life of 3–4 h. Mefenamic acid has been associated with severe pancytopenia and many other side effects. Hence, therapy is not to be for more than 1 week [55].
Meloxicam
The enolic acid derivative shows nonselectivity, except for meloxicam which shows relative COX-2 selectivity. For example, meloxicam shows dose-dependent COX selectivity, where 7.5 mg is more selective for COX-2 while at 15 mg meloxicam becomes less selective [56]. After oral administration, peak serum concentrations are attained within 5–10 h after administration. Meloxicam is highly bound to plasma proteins and has an estimated half-life of approximately 15–20 h in healthy subjects.
COX-2 Inhibitors
COX-2 inhibitors (celecoxib, rofecoxib, and valdecoxib) were approved for use in the United States and Europe, but both rofecoxib and valdecoxib have now been withdrawn from the market due to their adverse event profile. Recently, parecoxib and etoricoxib have been approved in Europe. The newest drug in the class, lumiracoxib, is under consideration for approval in Europe. Upon administration, most of the coxibs are distributed widely throughout the body with celecoxib possessing an increased lipophilicity enabling transport into the CNS. Despite these subtle differences, all of the coxibs achieve sufficient brain concentrations to have a central analgesic effect [57] and all reduce prostaglandin formation in inflamed joints. The estimated half-lives of these medications vary (2–6 h for lumiracoxib, 6–12 h for celecoxib and valdecoxib, and 20–26 h for etoricoxib). Likewise, the relative degree of selectivity for COX-2 inhibition is lumiracoxib = etoricoxib > valdecoxib = rofecoxib >> celecoxib [10].
Celecoxib
Currently, celecoxib is the only selective COX-2 inhibitor available in the United States. After oral administration, peak serum concentrations of celecoxib are attained 2–3 h after administration. Celecoxib is highly bound to plasma proteins, is excreted primarily by hepatic metabolism, and has a half-life of approximately 11 h in healthy subjects. Celecoxib does not interfere with platelet aggregation; thus, perioperative administration can be conducted as part of a multimodal analgesic regimen without increased risk of bleeding. Additionally, NSAID-induced GI complications are one of the most common drug-related serious adverse events, but celecoxib preferentially inhibits the inducible COX-2 isoform and not the constitutive COX-1 isoform thus conferring some gastroprotective effect.
Etoricoxib
Etoricoxib is a second-generation, highly selective cyclooxygenase 2 (COX-2) inhibitor with anti-inflammatory and analgesic properties [61]. It shows dose-dependent inhibition of COX-2 across the therapeutic dose range, without inhibition of COX-1, does not inhibit gastric prostaglandin synthesis and has no effect on platelet function [62]. Etoricoxib shows 106-fold selectivity for COX-2 over COX-1 [63], compared with 7.6-fold selectivity observed with celecoxib [62, 63].
Acetaminophen
Acetaminophen (paracetamol – APAP) is an analgesic and antipyretic medication that produces its analgesic effect by inhibiting central prostaglandin synthesis with minimal inhibition of peripheral prostaglandin synthesis [10, 11]. After oral administration, peak serum concentrations are attained within 0.5–3 h. A small portion of acetaminophen is bound to plasma proteins (10–50 %) and has an estimated volume of distribution of 0.95 L/kg. Acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. The half-life of acetaminophen is approximately 2–3 h in healthy subjects. As previously stated, acetaminophen and NSAIDs have important differences such as acetaminophen’s weak anti-inflammatory effects and its generally poor ability to inhibit COX in the presence of high concentrations of peroxides, as are found at sites of inflammation [10, 11] nor does it have an adverse effect on platelet function [12] or the gastric mucosa [11]. It is absorbed rapidly, with peak plasma levels seen within 30 min to 1 h, and is metabolized in the liver by conjugation and hydroxylation to inactive metabolites and has duration of action of 4–6 h [64, 65]. Paracetamol is perhaps the safest and most cost-effective non-opioid analgesic when it is administered in analgesic doses [66]. Paracetamol is available in parenteral form as propacetamol, and 1 g of propacetamol provides 0.5 g paracetamol after hydrolysis [67]. Propacetamol is widely used in many countries other than the United States and has shown to reduce opioid consumption by about 35–45 % [68] in postoperative pain studies [68, 69] including after cardiac surgery [70].
Safety, Toxicity, and Adverse Effects
Although NSAIDs are the most widely used OTC medications, with a long history of use, research, and medication advancements, NSAIDs remain as a source of adverse effects. NSAIDs not only share therapeutic actions but also similar adverse effects that include GI ulceration and bleeding, disturbance of platelet function, sodium and water retention, nephrotoxicity, and hypersensitivity reactions [71]. The adverse effects range from minor (e.g., nausea, gastric irritation, dizziness) to major (e.g., allergic reaction, gastrointestinal, renal and coagulation derangements, and delay in bone healing) in acute use. Chronic use of these medications may increase minor or major adverse effects. The three most common adverse drug reactions to NSAIDs are gastrointestinal, dermatological, and neuropsychiatric, the last one oddly not being age related [55, 72].
Gastrointestinal
Gastrointestinal bleeding is one of the most frequently reported significant complications of NSAID use. The effects of NSAIDs on gastric mucosa have been estimated to occur in 30–40 % of users [73]. NSAIDs affect the GI tract with symptoms of gastric distress alone and through actual damage with ulceration. Dyspepsia has been shown to have an annual prevalence with NSAID use of about 15 % [55]. One review estimated 7,000 deaths and 70,000 hospitalizations per year in the USA among NSAID users. Among rheumatoid arthritis patients, an estimated 20,000 hospitalizations and 2,600 deaths per year are related to NSAID GI toxicity [55, 74]. Evidence of the association between NSAIDs and gastropathy accrued in the 1970s with the increased use of endoscopy and the introduction of several new NSAIDs [55, 75].
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