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

Figures & data

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.^19,88–90
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.^19,44 (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.^{19,27,42,47–52} 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.²¹
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 F_1α; 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.⁵⁴
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,^55,60 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).^57,60 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.²⁰
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.³¹
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.

Table 1 Risk factors for NSAID gastrointestinal and cardiovascular side effects

Risk factors for GI side effects

• Advanced age (ie, ≥65 years of age)

• History of peptic ulcers

• History of upper GI bleeding

• Serious comorbid medical conditions

• Concomitant Helicobacter pylori infection

• Concomitant use of corticosteroids and/or selective serotonin reuptake inhibitors

• Concomitant use of antiplatelet therapy (eg, aspirin, clopidogrel) and other anticoagulants

• Use of high NSAID doses

• Cigarette smoking

• Alcohol consumption

Risk factors for CV side effects

• Unstable angina

• Myocardial infarction

• Recent bypass surgery

• Recent placement of a cardiovascular stent

• Use of high NSAID doses

• Hypertension

• Heart failure

Note: Data supported by several studies.^{23,25,84,86,87}

Abbreviations: CV, cardiovascular; GI, gastrointestinal; NSAID, non-steroidal anti-inflammatory drug.

Table 2 Prevention strategies in patients with cardiovascular and/or gastrointestinal risk factors treated with NSAIDs

General rules

• Use the lowest effective NSAID dose for the shortest period of time

• Immediate-release NSAID formulations are preferred, with repeated administration as necessary

• Avoid concomitant therapy with corticosteroids, low-dose aspirin, or other antiplatelet/anticoagulation agents

• Limit use of NSAIDs with the highest GI toxicity (eg, ketorolac, piroxicam, and ketoprofen)

• Test for Helicobacter pylori infection in patients with prior ulcer history and eradicate if present

Use of prevention strategies

GI risk factors

• Low risk: intermediate or highly COX-2–selective NSAID (standard dose) alone, or nonselective NSAID + gastroprotectant therapy (eg, PPI, misoprostol)

• One or two risk factors: intermediate or highly COX-2–selective NSAID + gastroprotectant therapy (eg, PPI, misoprostol)

• History of ulcer bleeding

○ Highly COX-2–selective NSAID + gastroprotectant therapy (eg, PPI, misoprostol)

○ Avoid nonselective NSAIDs (eg, naproxen)

○ Eradicate H. pylori infection

Previous CV events or risk for CV events (patients under treatment with low-dose aspirin)

• Low risk for GI events: nonselective NSAID (naproxen) + gastroprotectant therapy (eg, PPI); aspirin and naproxen should be administered at different times to mitigate (but not completely avoid) interference with aspirin’s antiplatelet effect

• High risk for GI events (history of ulcer bleeding)

○ Avoid the use of NSAIDs (including nonselective and intermediate or highly COX-2–selective NSAIDs)

○ Eradicate H. pylori infection

○ Avoid use of ibuprofen, as it may interfere with aspirin’s antiplatelet effect

○ Substitution of aspirin with other antiplatelet therapy (clopidogrel) is not recommended

Note: Data supported by several studies.^23,86,87

Abbreviations: CV, cardiovascular; GI, gastrointestinal; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor.

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