Advice from Professional Societies: Appropriate Use of NSAIDs

Advice from Professional Societies: Appropriate Use of NSAIDs Alexa Simon Meara, MD, Lee S. Simon, MD

bs_bs_banner Pain Medicine 2013; 14: S3 S10 Wiley Periodicals, Inc. Advice from Professional Societies: Appropriate Use of NSAIDs Alexa Simon Meara, MD,* and Lee S. Simon, MD *Division of Immunology and Rheumatology, Ohio State University Wexner Medical Center, Columbus, Ohio; Internal Medicine Residency, East Carolina University/Brody School of Medicine, Greenville, North Carolina; SDG LLC, Cambridge, Massachusetts, USA Reprint requests to: Alexa Simon Meara, MD, Department of Internal Medicine, Division of Rheumatology/Immunology, 480 Medical Center Drive, S2056, Columbus OH 43210, USA. Tel: 614-293-6869; Fax: 614-366-0980; E-mail: Alexa.meara@osumc.edu. Disclosures: Dr. Meara has nothing to disclose. Dr. Simon is or has been a consultant to Astrazeneca, NuvoResearch, Pfizer, Novartis, PLx Pharma, Hisamatsu, Dr Reddys, Cerimon, Bayer, Nicox, Wyeth, Asahi, Forest, Genzyme, Horizon, Pozen, ILPharma, Kowa, and Imprimis, Bayer Consumer, Sanofi. Abstract Objective. Non-steroidal anti-inflammatory drugs (NSAIDs) are some of the most commonly used medications due to their well-known analgesic, antiinflammatory, and antipyretic actions. Due to their known benefits and inherent risks, there have been multiple guidelines from national professional societies that suggest appropriate use to provide both maximum benefit and mitigate risk of adverse events, particularly in older individuals. Design. A literature search was undertaken using PubMed and search terms including pain, aging, treatment, non-steroidal anti-inflammatory drugs, arthritis, older patient, and guidelines. Practice guideline reviews were conducted from the following sources: American Geriatric Society, American College of Rheumatology, and the European League Against Rheumatism suggesting the appropriate and safer use of NSAIDs, along with references to guidelines product by Osteoarthritis Research International, the American Gastroenterological Association. Conclusions. Literature-based and professional society guidelines provides clinicians with means optimize efficacy and safety of NSAIDs in clinical practice. Summary recommendations are provided in this review. Key Words. NSAIDs; Adverse Events; GI Bleed; Cardiovascular Risk; Osteoarthritis; Gout; Ankylosing Spondylitis; Chronic Pain Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) are some of the most commonly used drugs in the United States due to their analgesic, antipyretic, and antiinflammatory properties. More than 70 million prescriptions have been written, and 30 billion over-the-counter usages have been noted [1]. NSAIDs have been around for over 200 years in various formulations, and over 20 different types are presently available in the United States including oral, intravenous, topical, and perrectum delivery [2]. Owing to the efficacy of the drugs, patients and practitioners have prescribed these drugs for a variety of disease states. However, NSAID use conveys significant risk both directly related to the mechanism of action as well as other idiosyncratic effects, and thus, guidelines have been developed to advise appropriate use of these drugs to help mitigate potential adverse events. These potential significant side effects include mucosal damage to the gastrointestinal (GI) tract, which includes ulcers and consequential bleeding, perforation or obstruction, renal dysfunction and resultant renal failure, and cardiovascular (CV) events as well as death. Despite the many available forms of NSAIDs, oral dosing is the most common route that is usually associated with chronic use and carries the most risk, particularly to the GI tract. Mechanism of Action of NSAIDs NSAIDs inhibit prostaglandin synthesis through inhibition of the cyclooxygenase enzyme (COX) subsequently decreasing both pain and inflammation. Synthesis of prostaglandins of the E series, predominately pro-inflammatory S3

Meara and Simon in nature, are suppressed [2]. Non-selective NSAIDs block both COX-1 and -2 downregulating both proinflammatory prostaglandins as well as concomitantly decreasing those prostaglandins that are considered housekeeping enzymes. These housekeeping enzymes maintain the lining of gastric and duodenal mucosa, physiological renal function, and other physiological functions of the body. In addition, non-selective NSAIDs inhibit thromboxane that alters the ability of platelets to aggregate through inhibiting the actions of COX-1 in the platelet [3]. The mechanism of action is illustrated in Figure 1. Selective COX-2 inhibition may also have some effects on physiological functions as well. The activity of COX-2 is predominantly upregulated in inflammatory states, states of intravascular volume depletion, and in the spinal cord and brain when there is a peripheral painful stimulus. The American Geriatric Society (AGS), the American College of Rheumatology (ACR), and the European League Against Rheumatism (EULAR) have developed guidelines for the appropriate usage of these drugs due to the concerns regarding both mechanism-driven and idiosyncratic adverse events. These guidelines are briefly discussed in this review. Guidelines for optimal treatment of patients with osteoarthritis (OA), gout, ankylosing spondylitis (AS), and other forms of musculoskeletal pain will also be discussed. In the context of rheumatoid arthritis (RA), NSAIDs are palliative for symptoms but have not been shown to alter the natural history of the disease; as a result reference to NSAID use in RA will be included in guidelines related to treating other forms of chronic musculoskeletal pain. Phospholipase A2 COX-1 Constitutive Arachidonic A2 Non selective NSAIDS block GI protection ( Prostaglandin) Platelet aggregation ( thromboxane) The American Gastroenterological Association (AGA) has issued guidelines regarding the use of concomitant gastroprotective agents in the treatment of patients who require treatment with chronic NSAID therapy, and the American Journal of Cardiology has published an analysis of CV risk associated with the chronic use of NSAIDs. Comments from these guidelines have also been included in this review. Adverse Effects of NSAIDs Although there are many potential adverse effects associated with the use of NSAIDs, several are more common than others. This section will briefly review GI, CV, and renal potential effects, and possible mitigation steps are discussed in the various available treatment guidelines. GI Effects Potential GI adverse events are due to systemic inhibition of prostaglandin synthesis. The result is a decrease in the protective barriers associated with the gastric and duodenal mucosa. Patients subsequently are at risk for developing gastric and duodenal ulcers, as well as GI bleeding and scarring that can lead to obstruction and perforation. The risk factors associated with increased incidence of GI-related adverse events with use of NSAIDs include the longer duration of NSAID usage, higher dosage, increased age over 60, past history of peptic ulcer disease of any cause, history of alcohol use, concomitant use of glucocorticoid, and/or anticoagulants as well as those patients who are frail and sicker are more at risk [4]. corticosteroids block COX-2 Inducible PGE2 ( Prostaglandin) Inflammation Pain Selective NSAIDs only block Figure 1 Mechanism of action non-steroidal anti-inflammatory drugs (NSAIDs) [3]. COX = cyclooxygenase; GI = gastrointestinal; PGE2 = Prostaglandin E2. S4

With the development of selective NSAIDs, the COX-2 selective inhibitors were initially thought to have no to little effect on the GI tract. However, multiple studies including large prospective GI outcome studies, such as VIGOR (rofecoxib), TARGET (lumiracoxib), CLASS (celecoxib), CONDOR (celecoxib), and GI REASONS (celecoxib), and the MEDAL (etoricoxib) trials [5 9] in which over 84,000 patients have been studied for at least 6 months, have demonstrated that the COX-2 selective inhibitors damage the GI mucosa less than the comparator nonselective NSAIDs. More recently, combinations of non-selective NSAIDs, naproxen with a proton pump inhibitor (Vimovo) or highdose famotidine combined with ibuprofen (Duexis), have been developed showing a decrease of endoscopic upper GI damage when studied in randomized, blinded, prospective trials of at least 6 months in duration [10 12]. These newly available drugs have decreased gastric and duodenal ulcers by about 50%, but large GI outcomes studies have not been done [10 12]. The AGA updated their guidelines to reflect these studies by strongly recommending concomitant use of gastroprotective drugs including misoprostol (which is limited by diarrhea symptoms), proton pump inhibitors, and high-dose H2 blockers with NSAID usage [13]. Another GI symptom, dyspepsia, however not lifethreatening, is one of the major factors for patient nonadherence to NSAID treatment. Concomitant use of either proton pump inhibitors or famotidine has been associated with a decreased incidence of this symptom complex. Each of the guidelines to be discussed later urges caution if the patient is over 75 years old due to the significantly elevated GI adverse events in this age group. In addition, in patients with a known history of peptic ulcer disease or gastritis, NSAIDs should be avoided or gastroprotective drug concomitantly provided regardless of whether a nonselective or selective drug is chosen. Cardiac Adverse Events Both non-selective and selective NSAID use is associated with an increased risk for hypertension, stroke, myocardial infarction, and death. Several prospective trials have demonstrated there may be up to a fivefold increased risk for CV thrombotic complications associated with use of higher dose and chronic use of the NSAIDs in patients with arthritis and patients with recurrent colonic polyps [14 18]. In general, the discussed guidances all suggest that NSAIDs should be avoided in patients with known active ischemic heart disease, cerebrovascular disease, and moderate-to-severe heart failure. Due to the prostaglandin inhibitory action of NSAIDs, patients over 75 are 1.7 times likely to develop hypertension [19]. All patients with known hypertension should be carefully followed for worsening hypertension while taking NSAIDs and especially those Professional Societies Advice on NSAID Usage patients already known to be hypertensive and on antihypertension medications. Renal Effects NSAID induced renal toxicity is a result of the constriction of the renal arterial system by NSAID inhibition of prostaglandin synthesis. This decrease in renal plasma flow potentially causes direct kidney damage, which is further exacerbated in those patients who are already volumedepleted for whatever reason. This constrictive effect of decreased intravascular volume is amplified by NSAIDs inhibiting prostaglandin generation that in turn blocks the vasodilatation of the renal arterial system. NSAIDs also cause fluid retention possibly due to the enhanced effect on antidiuretic hormone, which reduces free-water excretion and can worsen hypertension [2]. The fluid retention effects are increased by certain antihypertensive medications including angiotensin-converting enzyme inhibitors. Kidney allergic effects are also described, which may lead to interstitial nephritis of unclear cause. In general, the guidelines all suggest that patients with creatinine clearances less than 30 ml/min should not be treated with these drugs. Glomerular filtration rate decreases with age, and thus renal side effects due to NSAIDs are seen more often in elderly patients. Drug-Drug Interaction As patients age the number of different medications prescribed and taken increases. Clinicians should be careful about bleeding risk when patients are prescribed warfarin, clopidogrel, or aspirin together with NSAIDs. Patients should know that NSAIDs combined with glucocorticoids may potentiate the GI adverse events [4]. Summary of the AGS, ACR, and EULAR NSAID Treatment Guidelines Guidelines for NSAID use developed by AGS were deemed important since 23.5% of all hospitalizations related to drug adverse events are the result of NSAID use in patients over 65 year old [20]. Overall, this is a significant cause of morbidity and associated increased healthcare costs [20]. It is estimated that one quarter of adverse drug events (ADEs) in the primary care setting could have been prevented by application of such treatment guidelines [4]. The AGS guidelines reflect the ACR and EULAR guidelines in the usage of NSAIDs. These guidelines also reflect the AGA and ACJ guidelines for the general usage of NSAIDs. ACR and EULAR have not developed specific guidelines for use of NSAIDS; however, they have included information regarding the use of these drugs in specific disease state treatment guidelines. All of these treatment guidelines agree in general that the overall first choice for a systemic analgesic for any type of musculoskeletal pain is acetaminophen (or paracetamol), and the dose is typically up to 4 g/day. If the symptoms are not controlled or acetaminophen is contraindicated, then NSAIDs should be considered next. NSAIDs should S5

Meara and Simon be used at the smallest possible dose for the shortest period of time to treat the patients pain. However, chronic inflammatory musculoskeletal disease patients often need these drugs chronically at significant anti-inflammatory doses. Thus, the chosen NSAID should be concomitantly prescribed with a gastroprotective agent, particularly if the patient has any or a combination of the earlier mentioned risk factors for GI adverse events. The other guidelines provided by the ACR and EULAR are dedicated to treatment recommendations of specific indications or diseases. Each disease state and use of NSAIDs in that circumstance will be discussed. Specific Disease Treatments OA NSAIDs, although known to be good analgesic and antiinflammatory drugs, are not associated with altering the natural disease of OA or RA as they have not been shown to alter X-ray progression in either disease process. Conversely, patients with AS using higher dosed NSAIDs have shown benefit with decreased structural progression of the disease as demonstrated by serial X-ray. In gout, NSAIDs are used to provide both an acute benefit of decreasing pain and inflammation during an acute attack as well as providing a prophylactic effect of prevention of the next attack at relative low doses and are recommended to prevent gout flares when urate lowering therapy is initiated [21]. The AGS guidelines provide a central concept adopted by the ACR and EULAR, and described in detail in Table 1. It is important to note that patients who possess risk factors as noted earlier for potential GI adverse events, all treatment guidelines recommend that gastroprotective therapy should be concomitantly provided whether the older patient is prescribed a non-selective NSAID or a selective COX-2 inhibitor. OA is a degenerative joint disease often associated with inflammation that can be progressive, which archetypally worsens with use and age, leading to loss of cartilage and bone consequently disrupting the joint. This is the most common form of arthritis in Western populations. It is estimated 10% of the Western populations is affected by hip OA, and 10% of patients over 55 years old are affected or disabled by knee OA [22,23]. ACR and EULAR have similar guidelines and reflect the AGS, the National Institute of Health and Clinical Excellence, and the Osteoarthritis Research International (OARSI) guidelines for the usage of NSAIDS in OA. The ACR recently updated the OA guidelines in 2012 for hand, hip, and knee OA pharmacological and non-pharmacological treatments. The recommendations are first to try non-pharmacological therapies, then add acetaminophen, and if unsuccessful consider NSAIDs. First, try topical NSAIDs to the symptomatic joint followed by the use of systemic NSAIDs at the lowest effective dose for the shortest period of time. The ACR summary uses the EULAR OA and OARSI Table 1 2012 American Geriatrics Society Beers Criteria for potentially inappropriate medication use in older adults [4] Medications Rational Recommendation Non-COX-selective NSAIDs, oral: Aspirin > 325 mg/day, i.e., Diclofenac Diflunisal Etodolac Fenoprofen Ibuprofen Ketoprofen Meclofenamate Mefenamic acid Meloxicam Nabumetone Naproxen Oxaprozin Piroxicam Sulindac Tolmetin Indomethacin and Ketorolac, includes parenteral Increases risk of GI bleeding and PUD in high-risk groups: Age > 75 Concomitant use with: Corticosteroids Anticoagulants Antiplatelet agents Use of proton pump inhibitor or misoprostol reduces risk* Increases risk of GI bleeding and peptic ulcer disease in high-risk groups (see above non-cox selective NSAIDs). Of all the NSAIDs, indomethacin has most adverse effects. Avoid chronic use unless other alternatives are not effective and patient can take gastroprotective agent (proton pump inhibitor or misoprostol) Avoid * Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 6 months and in approximately 2 4% of patients treated for 1 year. These trends continue with longer duration of use. COX = cyclooxygenase enzyme; GI = gastrointestinal; NSAID = non-steroidal anti-inflammatory drug; PUD = peptic ulcer disease. S6

Professional Societies Advice on NSAID Usage Table 2 American College of Rheumatology 2012 recommendations for the use of pharmacological therapies in osteoarthritis of the hand, hip, and knee [24] Pharmacological Recommendations for the Initial Management of Hand OA Pharmacological Recommendations for the Initial Management of Knee OA Pharmacological Recommendations for the Initial Management of Hip OA Use one or more of the following: Topical capsaicin Topical NSAIDs, including trolamine salicylate Oral NSAIDs, including COX-2 selective inhibitors Tramadol Should not use the following: Intraarticular therapies Opioid analgesics Recommend that persons age >75 years should use topical rather than oral NSAIDs. In persons age <75 years, the TEP expressed no preference for using topical rather than oral NSAIDs. No strong recommendations were made for the pharmacological management of hand OA. guidelines in the development of this update (Table 2) [22 25]. Gout Gout is caused by deposition of uric acid crystals within soft tissues and the joints activating the inflammasome that induces significant pain and profound inflammation. NSAIDs are primarily used in acute gout attacks to offset this pain and inflammation. ACR recently released in 2012 Use one of the following: Acetaminophen Oral NSAIDs Topical NSAIDs Tramadol Intraarticular corticosteroid injections Should not use the following: Chondroitin sulfate Glucosamine Topical capsaicin No recommendations regarding the use: Intraarticular hyaluronates Duloxetine Opioid No strong recommendations were made for the initial pharmacological management of knee OA. Use one of the following: Acetaminophen Oral NSAIDs Tramadol Intraarticular corticosteroid injections Should not use the following: Chondroitin sulfate Glucosamine No recommendation regarding the use: Topical NSAIDs Intraarticular hyaluronate injections Duloxetine Opioid analgesics No strong recommendations were made for the initial pharmacological management of hip OA. COX-2 = cyclooxygenase 2; NSAID = non-steroidal anti-inflammatory drug; OA = osteoarthritis; TEP = Technical Expert Panel. new acute and chronic gout treatment guidelines. The EULAR guidelines reflect the new ACR guidelines in that NSAIDs relieve the pain in an acute gout flare with a number needed to treat of 3 [26,27]. There is no evidence to suggest that NSAIDs vs colchicine as compared with the effects of corticosteroids are better in the treatment of an acute gout flare. The choice is based on the practioner s assestment of the patient s comorbidities and to provide the least risk for potential ADEs. Figure 2 illustrates the algorithm for acute gout management. Corticosteroids Either intra-articular or 5 7 day oral taper Pain Figure 2 Management of acute gout [27]. NSAIDs = nonsteroidal anti-inflammatory drugs. Colchicine 1.2 mg followed by 0.6 daily until the pain subsides With normal renal function Relief NSAIDs Selective or non-selective NSAIDs of your choice Taken daily until the pain subsides S7

Meara and Simon First Line Exercise/Physical Therapy + NSAIDs ***Pain control Analgesics ***Pain and Disability Surgery AS Axial Disease Modifying Agents TNF blockers AS is a chronic inflammatory back arthritis associated with sacroiliitis and spondylitis that eventually leads to the development of ankylosis through the evolution of syndesmophytes. This disease is associated with peripheral arthritis, enthesitis, and anterior uveitis, and typically presents in early adulthood more commonly in men then women. There is about 1% prevalence [28,29]. The firstline pharmacological treatment for AS is NSAIDs within the EULAR treatment flow chart in Figure 3. These guidelines are 5 years old, and the ACR axial spondyloarthritis update is anticipated in the next year or so [28]. Higher dose NSAIDs have been shown to slow the progression of the disease and increase patient mobility. For those patients with known significant GI risk factors, concomitant gastroprotective agents should be used. In considering patients who have significant risk factors for adverse CV outcomes, then NSAIDs should not be used [28]. Chronic Pain/Musculoskeletal Pain Chronic pain is one of the most common complaints in the primary care setting, especially in the population above 65 years [30]. Back pain is the most common reason for people under 45 years to limit work and leads to decreases in economic productivity [31]. It is a top reason why patients visit their primary care provider. NSAIDs are shown to be beneficial for both acute and chronic nonspecific musculoskeletal pain due to the antiflammatory effects. NSAIDs are beneficial for symptomatic pain control in the chronic treatment of RA at the lowest dose and for the shortest period of time possible. In most fibromyalgia-related guidelines, NSAIDs are not the firstline treatment for this chronic pain syndrome. However, the ACR acknowledges that some patients may find some pain relief with NSAIDs [32]. Overall, NSAIDs of any type, either topical or oral, might be useful in the treatment of these chronic musculoskeletal painful syndromes. Conclusions Sulfasalazine Peripheral Disease Modifying Agents TNF blockers Corticosteroids Figure 3 Ankylosing spondylitis treatment algorithm [28]. ***These can be incorporated anywhere in the disease process. NSAIDs = non-steroidal anti-inflammatory drugs; TNF = tumor necrosis factor. treat painful symptoms and inflammation associated with disease states such as OA, gout, AS, or chronic musculoskeletal pain, but careful consideration must be paid to potential side effects in particular populations. Patients over 65 years old should be dosed appropriately, and attention should be paid to kidney function, CV status, and risk factors for GI adverse events. If dosed appropriately and followed closely, side effects can be mitigated to minimize morbidity and mortality. In general, because the adverse events associated with the use of NSAIDs are potentiated by longer duration of therapy, then the shortest possible duration is suggested and the lowest effective dose should be given. If topical NSAIDs can be used, which are associated with fewer systemic adverse events, these should be considered, particularly in the older population. References 1 U.S. Food and Drug Administration, Nonprescription Drugs Advisory Committee. Executive Summary. September 2002;19 20. 2 Simon LS. NSAIDs and COX-2 inhibitors in pain. In: Bajwas ZH, Warfield CA, eds. Principals and Practice of Pain Medicine, 2nd edition. New York: McGraw Hill; 2004:616 26. 3 Vane JR, Botting RM. New insights into the mode of action of anti-inflammatory drugs. Inflamm Res 1995;44(1):1 10. 4 The American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatric Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2012;60(4):616 31. 5 Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520 8. The ACR, EULAR, and the AGS all have developed extensive guidelines governing the use of NSAIDs to 6 Farkouh ME, Kirshner H, Harrington RA, et al. Comparison of lumiracoxib with naproxen and ibuprofen in S8

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