INTRODUCTION — More than 20 different nonsteroidal antiinflammatory drugs (NSAIDs) are available commercially, and these agents are used worldwide for their analgesic antipyretic and antiinflammatory effects in patients with multiple medical conditions. NSAIDs, including aspirin, do not generally change the course of the disease process in those conditions, where they are used for symptomatic relief.
The pharmacology and mechanisms of action of the NSAIDs will be reviewed here. The therapeutic variability and approach to the clinical use of NSAIDs, including their use in combination with other medications and in patients with comorbid conditions, the adverse effects of NSAIDs, an overview of cyclooxygenase (COX)-2 selective NSAIDs, and the mechanisms relevant to aspirin, its toxicities, and its uses in the rheumatic diseases are described in detail separately. (See "NSAIDs: Therapeutic use and variability of response in adults" and "Nonselective NSAIDs: Overview of adverse effects" and "Overview of COX-2 selective NSAIDs" and "Aspirin: Mechanism of action, major toxicities, and use in rheumatic diseases".)
PHARMACOLOGY — There are more than 20 different nonsteroidal antiinflammatory drugs (NSAIDs), from six major classes determined by their chemical structures, available for use worldwide. These drugs differ in their dose, drug interactions, and some side effects (table 1). Most NSAIDs are absorbed completely, have negligible first-pass hepatic metabolism, are tightly bound to serum proteins, and have small volumes of distribution.
NSAIDs undergo hepatic transformations variously by CYP2C8, 2C9, 2C19 and/or glucuronidation. Half-lives of the NSAIDs vary but in general can be divided into "short-acting" (less than six hours, including ibuprofen, diclofenac, ketoprofen and indomethacin) and "long-acting" (more than six hours, including naproxen, celecoxib, meloxicam, nabumetone, and piroxicam). Patients with hypoalbuminemia (due, for example, to cirrhosis or active rheumatoid arthritis) may have a higher free serum concentration of the drug.
Assessment of toxicity and therapeutic response to a given NSAID must take into account the time needed to reach the steady state plasma concentration (roughly equal to three to five half-lives of the drug). The pathogenesis of symptomatic peptic ulcer disease caused by exposure to NSAIDs is mainly a consequence of systemic (post-absorptive) inhibition of gastrointestinal mucosal cyclooxygenase (COX) activity. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity".)
Like other drugs, NSAIDs with a longer half-life tend to have greater enterohepatic circulation of active metabolites.
MECHANISMS OF ANALGESIA AND ANTI-INFLAMMATORY EFFECTS
Cyclooxygenase inhibition — The primary effect of NSAIDs is to inhibit cyclooxygenase (COX; prostaglandin synthase), thereby impairing the ultimate transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes (figure 1) [1]. The extent of enzyme inhibition varies among the different NSAIDS, although there are no studies relating the degree of COX inhibition with antiinflammatory efficacy in individual patients [2,3].
Cyclooxygenase enzymes — Two related isoforms of the COX enzyme have been described [4,5]: COX-1 (PGHS-1) and COX-2 (PGHS-2). The COX-1 and COX-2 isoforms possess 60 percent homology in those amino acid sequences apparently conserved for catalysis of arachidonic acid [6-10]. A splice variant derived from the COX-1 gene has been described, but the relevance of this isoform is still unclear.
The degree to which a particular NSAID inhibits an isoform of cyclooxygenase may affect both its activity and toxicity; there are important differences in the regulation and expression of these enzymes in various tissues:
●COX-1 – COX-1 is expressed in most tissues but variably. It is described as a "housekeeping" enzyme, regulating normal cellular processes (such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function), and is stimulated by hormones or growth factors.
An enzyme originally termed COX-3 is a splice variant of COX-1 denoted COX-1b; the role of this enzyme is unclear and remains controversial [11,12]. The mRNA for COX-1b appears to be expressed at a high level in the central nervous system, with transcripts accounting for 5 percent of COX mRNA in some studies; it has also been found in the heart [13,14].
●COX-2 – COX-2 is a highly regulated enzyme that is constitutively expressed in the brain, kidney, bone, and probably in the female reproductive system, but which is undetectable in most other tissues [15]. Its expression is increased during states of inflammation, or experimentally in response to mitogenic stimuli. As an example, growth factors, phorbol esters, and interleukin (IL)-1 stimulate the expression of COX-2 in fibroblasts, while endotoxin serves the same function in monocytes/macrophages [5,16].
Another distinguishing characteristic of COX-2 is that its expression is inhibited by glucocorticoids [17]. This observation may contribute to the significant antiinflammatory effects of the glucocorticoids. The efficacy and safety of selective COX-2 inhibitors are discussed in further detail separately. (See "Overview of COX-2 selective NSAIDs".)
COX-2 has an important role in the inflammatory process, although the effect of COX-2 inhibition on inflammation is not completely understood:
●COX-2 knockout mice are less susceptible to inflammation in some models than intact mice, but responses differ depending upon the model of inflammation employed for study [18-20].
●COX-1 knockout mice show less ulceration after the administration of indomethacin than intact mice, even though their gastric prostaglandin E2 levels are reduced by 99 percent [21].
●COX-2 may have antiinflammatory properties. Using an animal model of inflammation and carrageenin-induced pleurisy, one study showed that maximal COX-2 expression coincided with inflammatory resolution and was associated with minimal prostaglandin E2 synthesis [22].
●Human T lymphocytes express the COX-2 isoenzyme where it may serve a role in both the early and late events of T-cell activation, such as the production of IL-2, tumor necrosis factor (TNF)-alpha, and interferon-gamma [23].
●Although selective COX-2 inhibition may produce less gastric toxicity, there has been concern that COX-2 inhibition could delay healing of gastric erosions or ulcers and may enhance injury in an inflamed tissue, as in an experimental model of colitis [24-26]. These observations may have clinical importance in patients with inflammatory bowel disease in whom nonselective NSAIDs can exacerbate the disease. (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults".)
A clinically significant delay in healing of ulcers was not observed in the clinical trials of celecoxib, which is considered a relatively selective inhibitor of COX-2 at usual therapeutic doses. However, approximately 40 percent of the patients included in the trials were required to be free of ulcers prior to study entry. Thus, the effect of celecoxib on ulcer healing in patients with preexisting ulcer disease has not been well-established.
Some older NSAIDs are also relatively selective for the COX-2 receptor at low doses. Nabumetone, for example, appears to be a more effective inhibitor in some experimental systems of COX-2 than COX-1 [27]. Etodolac also inhibits the COX-2 isoform more than COX-1 (10 to 1 ratio) [28,29].
Further discussion relating to COX-2 inhibitors is presented elsewhere. (See "Overview of COX-2 selective NSAIDs".)
Studies with salicylates — In a human whole cell system, salicylates are very potent inhibitors of both COX-1 and COX-2, with the latter inducible form being more sensitive to the effects of the drug than the constitutive enzyme [30]. However, salicylates barely inhibit the COX enzyme in pure cell-free enzyme systems, and their effects are not measurable in cell membrane systems. Although the nonacetylated salicylates are not good prostaglandin synthesis inhibitors in vitro, clinical studies have shown that these drugs (such as salsalate) may be as effective as other NSAIDs with respect to their antiinflammatory effects in patients with RA [31]. The effects of aspirin are described in more detail separately. (See "Aspirin: Mechanism of action, major toxicities, and use in rheumatic diseases".)
The effects of acetylsalicylic acid on COX-2 activity are very different from the effects on COX-1 [32]. Acetylated COX-1 and COX-2 cannot form the intermediate products of prostaglandin synthesis. However, acetylated COX-2 retains the capacity to alter arachidonic acid to form 15(R)-hydroxyeicosatetraenoic acid (15R-HETE), while acetylated COX-1 does not. 15R-HETE has unknown biochemical effects, but it may be important as a modulator of proliferation since it is a product of an inducible enzyme during states of inflammation [32]. This effect on proliferation may have several interesting ramifications, including the use of aspirin for the prevention of colon cancer. (See 'Apoptosis' below and "NSAIDs (including aspirin): Role in prevention of colorectal cancer".)
Studies with topical NSAIDs — Several NSAIDs are now available as topical formulations, and topical diclofenac became available in the United States without prescription (over the counter) during 2020. There is evidence that these agents are effective compared with placebo for several chronic painful conditions, including osteoarthritis [33]. Moreover, there are data demonstrating that these agents are absorbed and penetrate local tissues in the area of application [34]. Topical application of NSAIDs limits systemic absorption [34] and the associated side effects and drug interactions [35].
Accumulating data demonstrate good benefit and relative safety of topical NSAIDs compared with other analgesics, including oral NSAIDs. A thorough and well-done systematic review and meta-analysis of topical NSAIDs used for patients with osteoarthritis demonstrated very slight increases in risk compared with placebo for most NSAID-associated toxicities [36]. In addition to the relative safety of topical NSAIDs, they appeared to be as effective (or more effective) than many oral NSAIDs. In a network meta-analysis evaluating NSAIDs for patients with osteoarthritis, diclofenac gel and solution appeared at least as effective as (and possibly more effective than) several commonly used oral NSAIDs [37]. The use of topical NSAIDs for patients with knee osteoarthritis is discussed separately. (See "Management of knee osteoarthritis", section on 'Topical NSAIDs'.)
Non-prostaglandin-mediated effects — Several non-prostaglandin-mediated mechanisms of action have been postulated to explain the antiinflammatory actions of the nonacetylated salicylates, although aspirin (the only acetylated NSAID) is not thought to have antiinflammatory effects other than those related to inhibition of prostaglandin synthesis; these observations may also apply, to a varying degree, to the nonsalicylate NSAIDs [2,3]. As examples:
●Some of these effects appear to be related to the physicochemical property of NSAIDs that enables them to insert into biological membranes and disrupt important interactions necessary for cell function (eg, transmembrane anion transport, oxidative phosphorylation, and uptake of arachidonate).
●Neutrophil function is inhibited by nonacetylated salicylates and other nonsalicylate NSAIDs in vitro. As an example, NSAIDs interfere with the neutrophil-endothelial cell adherence that is critical for the ability to respond to inflammation. NSAIDs decrease the expression of L-selectin, which removes a crucial step in the migration of granulocytes to sites of inflammation [38].
The role of these non-prostaglandin-mediated processes in clinical inflammation remains unclear. Despite the fact that nonacetylated salicylates have shown equal antiinflammatory efficacy when compared with acetylsalicylic acid in patients with rheumatoid arthritis [39], there is no clear evidence that COX inhibition is not achieved at the doses of drug required to achieve an antiinflammatory response [2,3,40].
NSAIDS have also been demonstrated in vitro to inhibit nuclear factor (NF)-kappaB-dependent transcription, leading to inhibition of inducible nitric oxide synthetase (iNOS) [41]. NOS, once induced by cytokines and other proinflammatory mediators, produces NO in large amounts, thereby leading to increased inflammation (including vasocongestion, cytotoxicity, and vascular permeability) [42]. Therapeutic levels of aspirin inhibit expression of iNOS and the subsequent production of nitrite in vitro [41]. Sodium salicylate and indomethacin have no such effects at pharmacologic doses, although, at suprapharmacologic dosages, sodium salicylate also inhibits nitrite production [41].
The inhibition of NF-kappaB by salicylates may be responsible for the capacity of salicyl salicylate (salsalate) to reduce levels of HbA1c and to improve other markers of glycemic control in patients with type 2 diabetes; such studies were based, in part, on the observation that NF-kappaB is activated by obesity and promotes insulin resistance and risk for type 2 diabetes and cardiovascular disease [43].
Apoptosis — A novel effect of NSAIDs has been described involving prostaglandin inhibition. Prostaglandins inhibit apoptosis (programmed cell death) in vivo; NSAIDs, therefore, establish a more normal cell cycle in the inflammatory state via inhibition of prostaglandin synthesis [44]. An important extension of these observations may be the association between the use of aspirin, and perhaps other NSAIDs, and a reduced risk of colorectal cancer. (See "NSAIDs (including aspirin): Role in prevention of colorectal cancer".)
The mechanism of this protective effect cannot be entirely attributed to inhibition of prostaglandin synthesis. The two prerequisites for the development of cancer are proliferation and the inhibition of apoptosis. One study found that sulindac decreased the size of adenomatous polyps in patients with familial adenomatous polyposis by increasing apoptosis rather than altering proliferation [45]. Celecoxib has also been shown to reduce the development of adenomas in patients with familial adenomatous polyposis and in patients with sporadic adenomatous polyps [46-48]. However, its use for this indication is not widely embraced because of concerns regarding the risk-benefit ratio for this agent at the doses used in these trials.
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Nonsteroidal antiinflammatory drugs (NSAIDs) (Beyond the Basics)")
SUMMARY
●All nonsteroidal antiinflammatory drugs (NSAIDs) are absorbed completely, have negligible first-pass hepatic metabolism, are tightly bound to albumin, and have small volumes of distribution. Half-lives of the NSAIDs vary but, in general, can be divided into "short-acting" (less than six hours) and "long-acting" (more than six hours) drugs. Patients with hypoalbuminemia (due, for example, to cirrhosis or active rheumatoid arthritis) may have a higher free serum concentration of the drug. (See 'Pharmacology' above.)
●The primary effect of NSAIDs is to inhibit cyclooxygenase (COX; prostaglandin synthase), thereby impairing the ultimate transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes. The extent of enzyme inhibition varies among the different NSAIDS, although there are no studies relating the degree of COX inhibition with antiinflammatory efficacy in individual patients. (See 'Cyclooxygenase inhibition' above.)
●Two related isoforms of the COX enzyme have been well characterized: COX-1 (PGHS-1) and COX-2 (PGHS-2). The COX-1 and COX-2 isoforms possess 60 percent homology in those amino acid sequences apparently conserved for catalysis of arachidonic acid. A splice variant derived from the COX-1 gene has been termed COX-3. The relevance of this isoform is still unclear. There are important differences in the regulation and expression of these enzymes in various tissues. (See 'Cyclooxygenase enzymes' above.)
●COX-1 is expressed in most tissues but variably. It is described as a "housekeeping" enzyme, regulating normal cellular processes (such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function) and is stimulated by hormones or growth factors. COX-2 is usually undetectable in most tissues; its expression is increased during states of inflammation, or experimentally in response to mitogenic stimuli. COX-2 is constitutively expressed in the brain, in the kidney, in bone, and probably in the female reproductive system; the expression of COX-2 is inhibited by glucocorticoids. Differences in the effectiveness with which a particular NSAID inhibits an isoform of COX may affect both its activity and toxicity. (See 'Cyclooxygenase enzymes' above.)
●Salicylates barely inhibit the COX enzyme in pure cell-free enzyme systems, and, in cell membrane systems, their effects are not measurable. However, in a human whole cell system, they are very potent inhibitors of both COX-1 and COX-2, with the latter inducible form being more sensitive to the effects of the drug than the constitutive enzyme. Although the nonacetylated salicylates are not good prostaglandin synthesis inhibitors in vitro, clinical studies have shown that these drugs (such as salsalate) may be as effective as other NSAIDs in patients with rheumatoid arthritis. (See 'Studies with salicylates' above.)
●Several non-prostaglandin-mediated mechanisms of action have been postulated to explain the actions of the nonacetylated salicylates; these observations may also apply, to a varying degree, to the nonsalicylate NSAIDs. These include disruption of interactions necessary for cell function through actions in cell membranes and inhibition of neutrophil function, including endothelial cell adherence, by nonacetylated salicylates and other nonsalicylate NSAIDs in vitro. NSAIDS have also been demonstrated in vitro to inhibit nuclear factor (NF)-kappaB-dependent transcription, leading to inhibition of inducible nitric oxide synthetase (iNOS). (See 'Non-prostaglandin-mediated effects' above.)
