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New Insights Into the Use of Currently Available Non-Steroidal Anti-Inflammatory Drugs Journal of Pain Research Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW New insights into the use of currently available non-steroidal anti-inflammatory drugs Kay Brune1 Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs), which act via inhibition of the Paola Patrignani2 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 1Department of Experimental and Clinical Pharmacology and COX-2 isozymes have different biological functions; analgesic activity is primarily (although Toxicology, Friedrich-Alexander not exclusively) associated with inhibition of COX-2, while different side effects result from University Erlangen-Nuremberg, Erlangen, Germany; 2Department of the inhibition of COX-1 and COX-2. All available NSAIDs, including acetaminophen and Neuroscience, Imaging and Clinical aspirin, are associated with potential side effects, particularly gastrointestinal and cardiovascular Sciences, Center of Excellence on effects, related to their relative selectivity for COX-1 and COX-2. Since all NSAIDs exert their Aging, G d’Annunzio University, Chieti, Italy 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 associ- ated side effects, such as gastrointestinal toxicity. Acidic NSAIDs with favorable tissue distribu- tion 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 appro- priate 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, pharmacody- namics, pharmacokinetics, pain therapy Introduction Pain represents a major public health problem worldwide,1–3 with chronic pain affecting Correspondence: Kay Brune 4 Department of Experimental and approximately 27% of the adult population in Europe and more than 100 million adults Clinical Pharmacology and Toxicology, in the United States.1 Undertreated acute pain can be associated with an increased risk Friedrich-Alexander University Erlangen- of deleterious health consequences (eg, delayed wound healing, immune dysfunction, Nuremberg, Krankenhausstraße 9, D-91054 Erlangen, Germany cardiovascular problems related to the stress response, and respiratory problems, such Tel +49 913 1852 2292 as pneumonia) and the development of chronic pain.5 In addition, unrelieved chronic Email [email protected] erlangen.de severe pain can negatively impact an individual’s quality of life, day-to-day functioning, submit your manuscript | www.dovepress.com Journal of Pain Research 2015:8 105–118 105 Dovepress © 2015 Brune and Patrignani. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/JPR.S75160 permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Brune and Patrignani Dovepress sleep quality, interpersonal relationships, and work productiv- 2004.10 However, traditional NSAIDs, which inhibit COX-2 ity, and is associated with a substantial economic burden.1,6 without sustained inhibition of platelet COX-1, may also be There are two major options for the pharmacological associated with an increased risk of cardiovascular events, management of pain: non-steroidal anti-inflammatory drugs particularly at high doses.11,20–23 (NSAIDs), which act via inhibition of cyclooxygenase (COX) Although novel compounds are being developed isozymes, and opiate/opioid analgesics.7,8 NSAIDs, which (eg, COX-inhibiting nitrous oxide donors) to improve safety are among the most widely used medications worldwide,9,10 and tolerability, it is unlikely that an ideal oral NSAID that are often preferred because of their low abuse potential, avoids all potential side effects will be available in the near robust efficacy, and long history of clinical use.11 Guidelines future.11,24 Thus, strategies are needed to reduce the risks for pain management tend to be specific to medical condi- associated with currently available NSAIDs. Drug choice tions or settings. Current guidelines for chronic low back should be driven by the clinical and demographic features pain and osteoarthritis generally recommend the use of oral (eg, age) of the patient, and the lowest effective dose of drug acetaminophen (or topical NSAIDs for osteoarthritis) for should be used for the shortest period of time25 to reduce the first-line pain management, with other oral NSAIDs recom- risk of cardiovascular and gastrointestinal side effects related, mended in the first-line or second-line setting depending at least in part, to drug exposure.11 on the specific guideline; some guidelines also recommend The development of whole-blood assays of COX isozyme opioids, although typically not as first-line therapy.8,12–15 inhibition in vitro has proved useful for differentiating NSAIDs It has, however, recently been shown that acetaminophen based on their pharmacodynamic features, such as COX-2 is not measurably effective in acute low back pain (ie, not versus COX-1 selectivity (ie, experimental COX isoenzyme more effective than placebo).16 Other work in patients with selectivity),26–28 while ex vivo assessment after NSAID dos- osteoarthritis demonstrated that ibuprofen was associated ing allows evaluation of COX isozyme selectivity achieved at with greater improvements compared with acetaminophen circulating drug levels. Additionally, the use of biochemical in measures of osteoarthritis pain, function, and quality markers of COX isozyme inhibition in vivo, such as the assess- of life.17 Acetaminophen and other oral NSAIDs are also ment of major enzymatic urinary metabolites of the parent recommended for acute pain, such as postoperative pain prostanoid, permits assessment of the actual inhibition of pros- management.7 tanoid biosynthesis following NSAID dosing. The use of these The first non-opioid analgesics (phenazone, paracetamol, biomarkers of COX inhibition have provided a mechanistic and aspirin) were found by serendipity more than 100 years interpretation of the efficacy, adverse events, and interindi- ago.18 Later, systematic research identified their mode of vidual variability associated with NSAID treatment.21,22,29–31 action as inhibition of prostanoid production.18 The devel- This review provides an overview of these and other opment of animal models of pain and inflammation led to key aspects that differentiate orally administered NSAIDs, the discovery of a host of new NSAIDs (eg, diclofenac, ibu- with a focus on the role of these factors in establishing the profen, ketoprofen, naproxen), many of which were acidic, safety and tolerability of individual NSAIDs for analgesia. highly protein-bound compounds that generally showed Characterization of the pharmacokinetic and pharmacody- similar therapeutic effects and side effects related to their namic differences between these compounds and their rela- inhibitory activity on prostanoid synthesis.18 tionship with the administered oral dose may allow for better NSAIDs inhibit prostanoid biosynthesis through their tailoring of NSAID therapy to individual patient needs. activity on the COX enzymes COX-1 and COX-2.19 The two COX isoforms (COX-1 and COX-2) have different func- Mechanism of action of NSAIDs: tions, and the inhibition of these isoforms results in different COX-1 and COX-2 inhibition therapeutic effects and side effects.11 Efforts to avoid the gas- The anti-inflammatory, analgesic, and antipyretic activities of trointestinal side effects associated with COX-1 inhibition11 NSAIDs are mediated by their inhibition of prostanoid bio- led to the development of selective COX-2 inhibitors called synthesis.11,32,33 Prostanoids are synthesized from arachidonic “coxibs”, which were designed to inhibit COX-2 while spar- acid, a fatty acid present in cell membranes as a phospholipid ing COX-1 at therapeutic doses.18 Evidence of increased ester.11,19,32 COX isozymes convert arachidonic acid first to risk of myocardial infarction and
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