NSAIDs Overview. Souraya Domiati, Pharm D, MS

NSAIDs Overview Souraya Domiati, Pharm D, MS

Case A 32 years old shows up into your pharmacy asking for an NSAID for his ankle pain He smokes1 pack/day His BP is 125/75mmHg His BMI is 35kg/m2 His is on no medication except for aspirin 81mg/day as a cardioprotective since his father had died of an STEMI at age of 50 years. What are your recommendations?

Outline Prevalence of use Classification Mechanism of action Uses Major side effects Choice of NSAID

Prevalence Amongst the most used drug worldwide with an estimation of over 20 million people using this class of medication daily In Lebanon Out of the 446 studied sample 300 (68.8%) patient used NSAIDS and 136 (31.1%) were non-users Age group User of NSAIDs Non user of NSAIDS OR CI P Total 18-39 111 33 2.23 1.3-2.82 0.00 144 40-59 121 58 1.38 0.58-2.25 0.20 179 >60 68 45 - - - 113 Total 300 136 - - - 436 Raj Majithia, David A. Johnson, Michael J. Ryan, F. Taylor Wootton, Jeff Willis, Kelvin Hornbuckle, Whitney Brooks. (2013). Underreported use of non-steroidal anti-inflammatory drugs in an outpatient gastroenterology practice: a prospective office-based Survey. Gastroenterology Insights ; volume 5:e3 Sarah El Sayegh, Ahmed El Mallah, Amal Galal, Souraya Domiati. (2015). How much do consumers really know about non-steroidal anti-inflammatory drugs? A Community Pharmacy-Based Survey Study

Nonsteroidal Anti-inflammatory Drugs Classification Goodman& Gilman s The Pharmacologic Basis of Therapeutics 12ed

Mechanism of action

Acetaminophen (Paracetamol) Works mainly on COX-3 is a weak anti-inflammatory drug Effective as an antipyretic and analgesic agent at typical doses that partly inhibit COXs.

Aspirin

Some pharmacokinetics characteristics Most NSAIDs are rapidly absorbed following oral ingestion Peak plasma concentrations: 2-3 hours.

Some Pharmacokinetics characteristics Food intake may delay absorption and sometimes decreases systemic availability Antacids variably delay, but rarely reduce, absorption. Relevant changes in NSAID kinetics are unlikely seen with PPI.

Some Pharmacokinetic characteristics Plasma t 1/2 varies considerably among NSAIDs. ibuprofen, diclofenac, and acetaminophen have relatively rapid elimination (t 1/2 of 1-4 hours), Piroxicam has a t 1/2 of 50 hours t 1/2 of COX-2 selective NSAIDs also varies 6-12 hours for celecoxib, 20-26 hours for etoricoxib

Some Pharmacokinetic characteristics Hepatic biotransformation Renal excretion Route of elimination Not recommended in advanced Hepatic Renal disease disease

Uses Fever All have this property but the most common used agents are the ones with rapid onset of action

Uses Premature Labor NSAIDS are used as tocolytic agent Indomethacin, Ketolac and Sulindac Patent Ductus Arteriosus IV Indomethacin, IV Ibuprofen

Uses Inflammation and Pain Pain mediated by inflammation is the one much more likely to be relieved by NSAIDs than other types of pain Osteoarthritis Rheumatoid arthritis Gouty arthritis

Uses Inflammation and pain In Rheumatoid arthritis, osteoarthritis or gouty arthritis the analgesic and anti-inflammatory activity of all NSAIDs and aspirin are similar at equipotent doses. The selection of a specific NSAID should be based on tolerability, previous response, and cost. Some patients respond to one NSAID better than to another. If an insufficient response is achieved with one NSAID, another agent from the same or a different chemical class should be tried.

Uses Acute pain Dysmenorrhea pain arising from the hollow viscera usually is not relieved by NSAIDs except menstrual pain Migraine attacks

Side effects Immunologic reactions Hepatic injury Renal side effect Cardiovascular side effects Gastro-intestinal side effects

Side effects Hepatic Injury 2007 The Health Canada withdraws lumiracoxib from the market due to concern regarding its liver toxicity.

Renal side effects Side Effects

Side Effects Cardiovascular side effects Ischemic cardiovascular disease heart failure Increased blood pressure Possible atrial fibrillation Stroke risk depends on the agent, dose and COX-2 selectivity

Side Effects Cardiovascular side effects normally Traditional NSAIDs Selective COX-2 Aspirin

Side Effects 2004 Rofecoxib (Vioxx ) was withdrawn from the market due to its cardiovascular side effects 2005 FDA advisory committee recommended the suspension of valdecoxib (Bextra ). 2007 Etoricoxib received a nonapprovable letter from the FDA due to safety concerns of an increased risk of cardiovascular events.

Side Effects Cardiovascular Side effects Celecoxib was allowed to remain in the market place, but with a black box warning indicating a risk of adverse cardiovascular events.

Side Effects Cardiovascular side effects 2011 Meta-analysis Major cardiovascular events were significantly increased compared with placebo for high-dose diclofenac (adjusted rate ratio [ARR] 1.41, 95% CI 1.12-1.78) and for the coxibs (ARR 1.37, 95% CI 1.14-1.66) A similar, but statistically non-significant, increase in risk was observed with high-dose ibuprofen (ARR 1.44, 95% CI 0.89-2.33). The use of high-dose naproxen did not result in a significant increase in major cardiovascular events (ARR 0.93, 95% CI 0.69-1.27) or coronary events. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011; 342:c7086.

Side Effects Cardiovascular side effects Meta-analysis of 754 RCTs 2013 Use of COX-2 inhibitors compared with placebo increased serious CV events, RR=1.37 (95% CI 1.14 to 1.66) Diclofenac also increase CV events, RR=1.20 (95%CI 0.94 to 1.54) Naproxen (1000mg daily) is associated with fewer CV events than COX-2 inhibitors Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; 382:769.

Side Effects Cardiovascular side effects According to 16 of the 25 advisers queried by FDA Data is not conclusive that Naproxen is associated with a lower risk of cardiovascular thrombotic events 2017 PRECISION Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen

Mamdani M, Juurlink DN, Lee DS, et al. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet 2004; 363:1751. Gislason GH, Rasmussen JN, Abildstrom SZ, et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med 2009; 169:141. Heart Failure Side Effects In an observational study of 36,354 patients who received at least one prescription of an NSAID following a first hospitalization for HF There was a dose-dependent increase in risk of death, which was highest with diclofenac, celecoxib, and rofecoxib (adjusted hazard ratio [HR] 2.08, 95% CI 1.95-2.21; HR 1.75, 95% CI 1.63-1.88; and HR 1.70, 95% CI 1.58-1.82). High doses of ibuprofen (>1200 mg daily) and naproxen (>500 mg daily) were also associated with an increased risk of death (adjusted HR 1.31 and 1.22, respectively), but lower doses were not.

Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials. JAMA 2006; 296:1619 Side Effects Arrhythmia In a population-based, case-control study from Denmark involving 2925 cases of newly diagnosed atrial fibrillation or flutter and 21,871 controls the use of COX-2 selective NSAIDs was associated with an increase in risk of atrial arrhythmia compared with controls (incidence risk ratio [IRR] 1.27, 95% CI 1.20-1.34).

Side Effects Hypertension All nonsteroidal anti-inflammatory drugs (NSAIDs) in doses adequate to reduce inflammation and pain can increase blood pressure in both normotensive and hypertensive individuals The average rise in blood pressure is 3/2 mmhg but varies considerably

Side Effects Gastro-intestinal side effects Range from dyspepsia to severe ulcer and bleeding

Side Effects Gastro-intestinal side effects depends on the selectivity of the agents the risk factors directly related to the patient taking NSAID

Side effects Patients at increased risk for NSAID GI TOXICITY High risk 1. History of a previously complicated ulcer, especially recent 2. Multiple (>2) risk factors Moderate risk (1 2 risk factors) 1. Age >65 years 2. High dose NSAID therapy 3. A previous history of uncomplicated ulcer American Journal of gastroenterology Guidelines for Prevention of NSAID- Related Ulcer Complications 4. Concurrent use of aspirin (including low dose) corticosteroids or anticoagulants Low risk 1. No risk factors H. pylori is an independent and additive risk factor and needs to be addressed separately

Recommendations

Alternatives having less side effects Promising alternatives Licofelone (ML3000), a 5-LOX, COX-1 and COX-2 inhibitor, is recently developed NO-NSAID

New Diclofenac submicron particle capsules have been developed using SoluMatrix technology to provide analgesia at lower doses than available solid oral dosing forms.

Case A 32 years old shows up into your pharmacy asking for an NSAID for his ankle pain He smokes1 pack/day His BP is 125/75mmHg His BMI is 35kg/m2 His is on no medication except for aspirin 81mg/day as a cardioprotective since his father had died of an STEMI at age of 50 years. What are your recommendations?

Case Is Aspirin indicated? According to the U.S. Preventive Services Task Force Recommendation Aspirin is not recommended for men age less than 45 CHD risk depending on age, diabetes, total cholesterol, HDL, Blood pressure and smoking is =2%

GI Risk Patients at increased risk for NSAID GI TOXICITY High risk 1. History of a previously complicated ulcer, especially recent 2. Multiple (>2) risk factors Moderate risk (1 2 risk factors) 1. Age >65 years 2. High dose NSAID therapy 3. A previous history of uncomplicated ulcer American Journal of gastroenterology Guidelines for Prevention of NSAID- Related Ulcer Complications 4. Concurrent use of aspirin (including low dose) corticosteroids or anticoagulants Low risk 1. No risk factors H. pylori is an independent and additive risk factor and needs to be addressed separately

Choice of the dosage form Oral Rectal IM Topical

Choice of the dosage form Depend on the patient case Site of pain Intensity of pain Guidelines American College of Rheumatology 2012 Recommendations Pharmacologic recommendations for the initial management of hand OA We conditionally recommend that health professionals should use one or more of the following: Topical capsaicin Topical NSAIDs Oral NSAIDs, including COX-2 selective inhibitors Tramadol We conditionally recommend that health professionals should not use the following: Intraarticular therapies Opioid analgesics We conditionally recommend that persons age 75 years should use topical rather than oral NSAIDs. In persons age < 75 years, technical Expert Panel expressed no preference for using topical rather than oral NSAIDs.

Case Stop Aspirin Give

References Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; 382:769. Caughey GE, Cleland LG, Penglis PS, et al. Roles of cyclooxygenase (COX)-1 and COX-2 in prostanoid production by human endothelial cells: selective up-regulation of prostacyclin synthesis by COX-2. J Immunol 2001; 167:2831. Cheng Y, Austin SC, Rocca B, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 2002; 296:539. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011; 342:c7086.

Mamdani M, Juurlink DN, Lee DS, et al. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet 2004; 363:1751. Gislason GH, Rasmussen JN, Abildstrom SZ, et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med 2009; 169:141. Hall D, Zeitler H, Rudolph W. Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure. J Am Coll Cardiol 1992; 20:1549. Heerdink ER, Leufkens HG, Herings RM, et al. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med 1998; 158:1108. Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials. JAMA 2006; 296:1619.