New insights into the use of currently available non-steroidal anti-inflammatory drugs

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs), which act via inhibition of the cyclooxygenase (COX) isozymes, were discovered more than 100 years ago. They remain a key component of the pharmacological management of acute and chronic pain. The COX-1 and COX-2 isozymes have different biological functions; analgesic activity is primarily (although not exclusively) associated with inhibition of COX-2, while different side effects result from the inhibition of COX-1 and COX-2. All available NSAIDs, including acetaminophen and aspirin, are associated with potential side effects, particularly gastrointestinal and cardiovascular effects, related to their relative selectivity for COX-1 and COX-2. Since all NSAIDs exert their therapeutic activity through inhibition of the COX isozymes, strategies are needed to reduce the risks associated with NSAIDs while achieving sufficient pain relief. A better understanding of the inhibitory activity and COX-1/COX-2 selectivity of an NSAID at therapeutic doses, based on pharmacokinetic and pharmacodynamic properties (eg, inhibitory dose, absorption, plasma versus tissue distribution, and elimination), and the impact on drug tolerability and safety can guide the selection of appropriate NSAIDs for pain management. For example, many NSAIDs with moderate to high selectivity for COX-2 versus COX-1 can be administered at doses that maximize efficacy (~80% inhibition of COX-2) while minimizing COX-1 inhibition and associated side effects, such as gastrointestinal toxicity. Acidic NSAIDs with favorable tissue distribution and short plasma half-lives can additionally be dosed to provide near-constant analgesia while minimizing plasma concentrations to permit recovery of COX-mediated prostaglandin production in the vascular wall and other organs. Each patient's clinical background, including gastrointestinal and cardiovascular risk factors, should be taken into account when selecting appropriate NSAIDs. New methods are emerging to assist clinicians in the selection of appropriate NSAIDs and their doses/schedules, such as biomarkers that may predict the response to NSAID treatment in individual patients.

Keywords: cyclooxygenase inhibitors; cyclooxygenase selectivity; diclofenac; pain therapy; pharmacodynamics; pharmacokinetics.

Figures

Figure 1

Mechanism of action of NSAIDs. Notes: COX-1 and COX-2 catalyze conversion of arachidonic acid into the intermediate metabolite PGH2, which is the rate-limiting step of prostanoid formation. The activity of different prostanoids in a tissue depends on the cell type–specific expression of their receptors and on their biosynthesis. tNSAIDs and coxibs act by selectively inhibiting COX-1–dependent and/or COX-2–dependent prostanoid biosynthesis.,– Abbreviations: COX, cyclooxygenase; cPGES, cytosolic PGE2 synthase; CRTH2, chemoattractant receptor–homologous molecule expressed on T helper 2 cells; DP, PGD2 receptor; EP, PGE receptor; FP, PGF receptor; GI, gastrointestinal; H-PGDS, hematopoietic PGD synthase; IP, PGI2 receptor; L-PGDS, lipocalin-type PGD synthase; mPGES, membrane-associated PGE2 synthase; PG, prostaglandin; PGFS, PGF synthase; PGIS, PGI2 synthase; tNSAIDs, traditional non-steroidal anti-inflammatory drugs; TP, TX receptor; TxA2, thromboxane A2; TXS, thromboxane synthase.

Figure 2

Selectivity of NSAIDs for COX-1 and COX-2. Notes: (A) Relationship between inhibition of TxA2 in vivo and inhibition of COX-1 activity ex vivo is non-linear. (B) Conversely, the relationship between inhibition of prostacyclin in vivo and inhibition of COX-2 activity ex vivo is linear., (C) Relative COX-1/COX-2 selectivity of NSAIDs at their IC50 is shown, where higher values (>1) indicate greater selectivity for COX-2, while lower values (<1) indicate greater selectivity for COX-1.,,,– Figures 2B and 2C reprinted from García Rodríguez LA, Tacconelli S, Patrignani P. Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population. J Am Coll Cardiol. 2008;52(20):1628–1636, with permission from Elsevier. Abbreviations: ASA, acetylsalicylic acid; COX, cyclooxygenase; IC50, half-maximal inhibitory concentration; NSAID, non-steroidal anti-inflammatory drug; PGI-M, 2,3-dino-6-keto-prostaglandin F1α; TxA2, thromboxane A2.

Figure 3

Average inhibition of whole-blood COX-2 activity (A) and COX-1 activity (B) by NSAIDs. Inhibition was observed over 8 hours following dosing with different NSAIDs. Note: Reproduced with permission from Van Hecken A, Schwartz JI, Depré M, et al. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol. 2000;40(10):1109–1120. ©1999–2014 John Wiley & Sons, Inc. Abbreviations: BID, twice-daily dosing; COX, cyclooxygenase; NSAID, non-steroidal anti-inflammatory drug; PGE2, prostaglandin E2; QD, once-daily dosing; TID, dosing three times per day; TxB2, thromboxane B2.

Figure 4

NSAID concentration in inflamed tissue/synovial fluid and plasma. Notes: For an acidic, rapid-release NSAID, the concentration of drug peaks quickly in the plasma after dosing, then declines rapidly, while the concentration in the synovial fluid peaks with some delay and declines slowly. At therapeutic dosing levels, this could result in persistent therapeutic activity (inhibition of hyperalgesia-inducing prostaglandins) in the absence of high plasma concentrations, as drug levels in the synovial fluid exceed the concentration required for 80% inhibition of COX-2 activity (the level of inhibition required for full analgesic efficacy,, shown in blue shading), while potentially allowing for a period of recovery of the blood/vasculature and other central organs (eg, kidney, shown in green shading)., This figure shows the approximate changes in plasma and tissue/synovia concentrations after multiple twice-daily dosing (Day 8 is shown in this example). The red arrows beneath the x axis indicate dosing times. Abbreviations: COX, cyclooxygenase; NSAID, non-steroidal anti-inflammatory drug.

Figure 5

Predicted annual absolute risks of major vascular events or upper gastrointestinal complications with long-term, high-dose therapy. Notes: Risks (±1 standard error) are shown for (A) coxib, (B) diclofenac, (C) ibuprofen, and (D) naproxen for patients with the specified predicted annual risk of a major vascular event (left panels) or an upper gastrointestinal complication (right panels). The predicted annual risk of upper gastrointestinal complications is lower for NSAIDs with greater COX-2 selectivity (eg, coxibs and diclofenac), while the risk of major vascular events is comparable between these drugs. Naproxen, which has no COX-2–specific selectivity, shows some cardioprotective effects but more gastrointestinal toxicity. Reproduced from Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769–779. Permission conveyed through Copyright Clearance Center, Inc. Abbreviations: COX, cyclooxygenase; NSAIDs, non-steroidal anti-inflammatory drug; pa, per annum; SE, standard error.

Figure 6

Determinants and sources of variability in the individual response to an NSAID. Notes: There are a number of factors that influence the likelihood of experiencing GI or CV adverse events associated with NSAID use. The pharmacokinetics and pharmacodynamics of the drug may be affected by genetic factors (eg, differences in expression of drug-metabolizing enzymes). In addition, individual clinical and demographic characteristics may affect the therapeutic activity and tolerability of the NSAID. Adapted with permission from Patrono C, Patrignani P, García Rodríguez LA. Cyclooxygenase-selective inhibition of prostanoid formation: transducing biochemical selectivity into clinical read-outs. J Clin Invest. 2001;108(1):7–13. Permission conveyed through Copyright Clearance Center, Inc. Abbreviations: ASA, acetylsalicylic acid; COX, cyclooxygenase; CV, cardiovascular; CYP, cytochrome enzymes; GI, gastrointestinal; NSAID, non-steroidal anti-inflammatory drug; PU, peptic ulcer; SNP, single-nucleotide polymorphism.