4 grams per day. However, when used long term, many experts recommend a maximum of 3 grams per day, and even lowering this to 2 grams per day in older patients, patients who have or are at risk of liver disease such as those with alcohol use disorder or malnourishment, and patients with organ dysfunction (Solomon, 2021a; Tauben & Stacey, 2021b). While acetaminophen does not appear to interact with platelet function or increase the risk of bleeding, it is known to interact with warfarin, and may require more frequent INR monitoring. Nonselective non-steroidal anti-inflammatory agents (NSAIDS) Nonselective non-steroidal anti-inflammatory agents (NSAIDs) decrease pain and inflammation by blocking cyclooxygenase (COX), thereby decreasing production of prostaglandins. There are two isoforms of cyclooxygenase, COX-1 and COX-2. COX-2 is upregulated in inflammatory states and is involved in the produc - tion of prostaglandins; COX-1 is found in most tissues and regu- lates normal cellular processes such as gastric protection, platelet aggregation, kidney function, and vascular homeostasis. Nonse- lective NSAIDs block both COX-1 and COX-2, leading to anti-in- flammatory effects as well as adverse reactions (Solomon, 2021b). NSAIDs medications are a mainstay of treatment in musculoskel- etal pain with an inflammatory component, such as menstrual cramps or muscle sprains. More than 17 million Americans use NSAIDs on a daily basis, making them one of the most commonly used classes of medications in the world (Solomon, 2021a). How- ever, the efficacy of these medications in pain without ongoing inflammation, such as low back pain, is low (Tauben & Stacey, 2021b). Examples of nonselective NSAIDs and their typical dosages used for analgesia include (Solomon, 2021a): ● Naproxen, 250-550mg every 12 hours. ● Ibuprofen, 400mg every 4 to 6 hours. ● Ketoprofen, 50mg every 6 hours or 75mg every 8 hours. ● Flurbiprofen, 50 to 100mg every 6 to 12 hours. ● Oxaprozin, 1200mg once daily. ● Diclofenac, 50mg every 8 hours. ● Etodolac, immediate release 200 to 400mg every 6 to 8 hours, or extended release 400 to 1000mg daily. ● Indomethacin, immediate release 25 to 50mg every 8 to 12 hours, or controlled release 75mg once or twice daily. ● Sulindac, 150 to 200mg every 12 hours. A variety of side effects are associated with NSAIDs; the risk of developing side effects is increased with high, frequent dosing or longer durations. Gastrointestinal effects, such as dyspepsia, pep- tic ulcer disease, and bleeding, are more likely in patients over 60, those with a prior history of a gastrointestinal event, those taking high doses of NSAIDs, or those taking glucocorticoids, an- tiplatelet drugs, or anticoagulants. Gastrointestinal effects may be reduced by taking the drug with food, milk or antacids. Adverse effects on the kidneys can include worsening of underlying hyper- tension, electrolyte and fluid abnormalities, and an increased risk Selective COX-2 inhibitors A focus of drug development in the early 1990s was to create a product that selectively inhibits COX-2, targeting prostaglandin production without affecting the various cellular processes that rely on COX-1. This led to the development of several products, most of which have been removed from the market due to an in- creased risk of adverse cardiovascular events. There is one prod- uct that remains available in the US – celecoxib (Solomon, 2021b). It is typically given in doses of 200mg daily or 100mg every 12 hours (Solomon, 2021a). Celecoxib has similar efficacy to NSAIDs in terms of analgesia and anti-inflammatory effects. It is associated with a reduction in gas - tric toxicity compared to NSAIDs, and little to no effects on inhib- iting platelet function, allowing for increased use in patients with bleeding disorders and those at risk for gastrointestinal bleeding. ● Meloxicam, 7.5 to 15mg once daily. ● Piroxicam, 10 to 20mg once daily.
It also interacts with isoniazid and other agents that induce the CYP450 enzyme system (Solomon, 2021a). Healthcare Consideration: Acetaminophen is found in a num- ber of prescription and over the counter products. Patients should be counseled to be aware of the acetaminophen con- tent of other products they are taking, and to avoid exceeding their daily limit (Solomon, 2021a). of acute renal failure and renal cell cancer. Patients with existing glomerular disease, hypercalcemia, renal insufficiency, or volume depletion conditions are at an increased risk of developing acute renal failure (Solomon, 2021a). Both chronic and short-term use are associated with an increased risk of myocardial infarction or stroke, and NSAIDs can exacer- bate heart failure. This risk can be minimized by using the low- est effective dose for the shortest duration possible. Hepatic en- zymes can be elevated by NSAIDs, but liver failure is rare. Other rare side effects include anaphylaxis, pulmonary effects such as bronchospasm or pulmonary infiltrates, neutropenia, tinnitus, and life-threatening rashes such as Stevens-Johnson syndrome (Solo- mon, 2021a). NSAIDs have antiplatelet effects that can be beneficial in some patients, such as using aspirin for cardiac prophylaxis in patients with coronary heart disease. However, these effects can create issues in patients with preexisting platelet deficits or when con - sidering surgery. For most NSAIDs, platelet function normalizes within 3 days of discontinuation, suggesting that NSAIDs should generally be discontinued at least 3 days prior to surgery. The an- tiplatelet effects of NSAIDs can be exacerbated when combined with other antiplatelet agents or anticoagulants, increasing the risk of bleeding. Therefore, NSAIDs should be avoided if possible in patients taking blood thinning agents. Certain antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) also appear to have antiplatelet effects, so combination with NSAIDs can in- crease the risk of gastrointestinal bleeding (Solomon, 2021a). Oral NSAIDs should be avoided in patients with GI bleeding, platelet dysfunction, difficult to control hypertension, hypona - tremia, cirrhosis, and creatinine clearance less than 60mL/min. NSAIDs should be used cautiously in older adults, due to the in- creased risk of adverse effects. Lower doses and limited durations are preferable to mitigate these risks. Topical NSAIDs, such as diclofenac gel or patches, can be considered in these patients to reduce the risk of adverse reactions (Solomon, 2021a). Pregnant patients should avoid NSAIDs if possible in order to avoid the risk of adverse pregnancy outcomes. There is limited information on the use of NSAIDs in lactation, but ibuprofen ap- pears to be the preferred agent in these patients since it is only excreted into the breast milk in very small amounts and has the most information available on its safety (Bermas, 2021). However, like NSAIDs, celecoxib is associated with an increased risk of adverse cardiovascular events, including stroke, myocardial infarction, heart failure, and death. This increased risk is seen in patients with and without pre-existing cardiovascular disease. This risk can be minimized by using the lowest effective dose for the shortest duration possible. In addition, celecoxib can cause acute renal failure, though it appears to be associated with 40% few- er renal events when compared with ibuprofen. The risk of acute kidney injury is increased in patients with chronic kidney disease, those who are volume-depleted due to as aggressive diuresis or heart failure, and those with severe hypercalcemia (Solomon, 2021b).
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