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NSAID Selection Tool - Guidance on available agents

Instructions

Use this tool to navigate the various nonsteroidal anti-inflammatory drugs (NSAIDs) to determine which drugs should be considered if a patient fails to respond to a particular drug or class of drugs.  The six classes are listed below along with the drugs in each class.  Also review the background information below this tool. For example, patients with both high cardiovascular risk factors and high gastrointestional risk factors should not be treated with an NSAID. There are also several conditions that would limit the use of NSAIDs such as current GI bleed, uncontrolled hypertension, etc. 

Patients that fail to achieve sufficient pain relief or experience side effects related to a particular class may respond to an alternative class.  It is assumed that an adequate trial with the current class was completed (at least 2 weeks) and that the dosages used were within the therapeutic range for the given condition.

Multiple boxes can be checked if a patient has had experience with multiple drugs from more than one class. Once a box is checked, it removes the drugs from that class for consideration. The program will then
generate dosing guidelines for the remaining drugs with comments to help guide the selection of a new drug.

Select all drug classes that did not produce an adequate response

Salicylates

Aspirin
Diflunisal
Salsalate
  Acetic acid derivatives
Diclofenac
Etodolac
Indomethacin
Ketorolac
Nabumetone
Sulindac
Tolmetin
  Enolic acid (Oxicam) derivatives
Meloxicam:
Piroxicam:
  Propionic acid derivatives
Ibuprofen: 
Naproxen:
Ketoprofen:  
Fenoprofen:
Flurbiprofen: 
Oxaprozin:
  Anthranilic acid derivatives (Fenamates)
Mefenamic acid:
  Selective COX-2 inhibitors (Coxibs)
Celecoxib


Additional options

Enabling the option below will considerably reduce the number of available drugs that meet the selected requirements.
List only those drugs that have a lower risk of gastrointestinal
 (GI) effects e.g. lower bleeding risk:



Reducing the risk of GI toxicity:

  1. Switch to alternative agents if possible such as acetaminophen or other Non-NSAID analgesics.
  2. Add a PPI:   
    Omeprazole 20mg qd OR
    Lansoprazole 15 mg qd  OR
    Esomeprazole: 20-40 mg qd OR
    pantoprazole: 20-40 mg qd
  3. Consider adding Misoprostol: 200 mcg tid-qid - often associated with intolerable abdominal discomfort and diarrhea
  4. Switch to a selective COX-2 inhibitor
Does the patient have musculoskeletal symptoms with known cardiovascular
disease or risk factors for Ischemic Heart Disease? 
  
 

Background Info  top of page

         Nonsteroidal anti-inflammatory drugs (NSAIDs) have several benefits when it comes to managing pain and inflammation and are effective for numerous acute and chronic conditions (Examples include: ankylosing spondylitis, low back pain, dental pain, dysmenorrhea, acute gout, headache, migraine, osteoarthritis, psoriatic arthritis, and rheumatoid arthritis). 

Multiple NSAID classes are available based on the chemical structure (e.g. propionic acid, acetic acid derivatives, etc.). These agents can have significant differences in the mechanism of action (degree of prostaglandin-mediated and nonprostaglandin-mediated actions), possible toxicities, pharmacokinetics, pharmacodynamics, and metabolism.

Variability:
Individual responses to a particular NSAID can vary greatly, although when equipotent dosages are used, the clinical efficacy of a particular NSAID will likely be similar to other NSAIDs. Toxicity is one area where the variability can be significant. For example, some individuals will experience GI distress with one agent but not with another. Other side effects or adverse effects may also be related to a particular agent while other NSAIDs do not cause the same effects.

Purpose of this program:
The main reason for this program is that it provides quick access to the six major classes of NSAIDs. Each class has differences in their biochemical and physiological effects that may ultimately determine the efficacy of a particular class.  Other factors such as the absorption, distribution, and metabolism are less important in determining the efficacy of a particular agent, however may play a greater role in possible toxicities.

The six major classes are:

  1. Salicylates
  2. Propionic acid derivatives
  3. Acetic acid derivatives
  4. Enolic acid (Oxicam) derivatives
  5. Anthranilic acid derivatives (Fenamates)
  6. Selective COX-2 inhibitors

       

 Some toxicities are more likely to occur as the dose of a particular NSAID is increased.  A possible approach for patients that experience dose-limiting gastrointestinal effects include switching to a selective COX-2 inhibitor or adding a PPI or similar drug to the current nonselective NSAID regimen.  [Note: Although selective COX-2 inhibitors have a lower risk of  gastrointestinal toxicities, there may be a higher rate of cardiovascular adverse events. ]

Partial list of possible adverse effects include:

  1. Increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. Risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
  2. Can cause or worsen renal insufficiency.
  3. NSAID's cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines.
  4. Anemia, increased bleeding time.
  5. GI other: Anorexia, abdominal pain, dyspepsia, elevated liver enzymes, gross bleeding/perforation.

Generally avoid NSAID therapy if any of the following are present:

  1. GI bleeding
  2. Platelet dysfunction
  3. Moderate to severe renal insufficiency
  4. Uncontrolled hypertension
  5. Cirrhosis
  6. Reduced cardiac output
  7. Concomitant anticoagulant therapy
  8. Hypovolemia

          All patients should be screened initially to determine if NSAID therapy is appropriate and if the benefits of therapy exceed the risks. Patients who are at a high risk for cardiovascular, gastrointestinal or renal reactions should be treated with alternative agents.

Gastrointestinal (GI) side effects (trends):
Among the older NSAIDs, Ibuprofen is the least likely to cause adverse GI effects. Newer agents such as  etodolac, meloxicam, and nabumetone are also less likely to cause injury.

Worst offenders  (higher GI toxicity) include:

  1. Flurbiprofen
  2. Ketoprofen
  3. Ketorolac
  4. Oxaprozin
  5. Piroxicam

Lower risk of adverse GI events:

  1. Celecoxib
  2. Etodolac
  3. Ibuprofen
  4. Meloxicam
  5. Nabumetone

 

Damage to the GI tract is due primarily to inhibition of COX-1 which leads to:

  1. Decreased bicarbonate secretion
  2. Decreased mucosal blood flow
  3. Decrease epithelial mucus
  4. Decreased mucosal resistance to injury - Increased susceptibility to local effects of gastric acid, pepsin and bile acids.

NSAIDs can also damage the gastric mucosa directly. NSAIDs with longer half-lives or those available in sustained-release forms (e.g. diclofenac) are associated with an increased risk of adverse GI effects such as GI bleeding and perforation.  NSAIDs with shorter half-lives such as ibuprofen cause fewer adverse GI events (may permit recovery of critical COX enzyme functions), as well as a lower risk of developing impaired renal function.

Reducing the risk of GI toxicity:

  1. Switch to alternative agents if possible such as acetaminophen or other Non-NSAID analgesics.
  2. Add a PPI:  
    Omeprazole 20mg qd OR
    Lansoprazole 15 mg qd  OR
    Esomeprazole: 20-40 mg qd OR
    pantoprazole: 20-40 mg qd
  3. Consider adding Misoprostol: 200 mcg tid-qid - often associated with intolerable abdominal discomfort and diarrhea
  4. Switch to a selective COX-2 inhibitor

Cardiovascular risk factors present:  top of page

AHA's Stepped Care Approach to Pharmacologic Therapy for Musculoskeletal Symptoms With Known Cardiovascular Disease or Risk Factors for Ischemic Heart Disease:   (order of use) - Focus on agents with the lowest reported risk of cardiovascular events and progress to other agents based on the balance between benefit and risk.

  1. acetaminophen
  2. aspirin
  3. tramadol
  4. narcotic analgesics (short term)
  5. nonacetylated salicylates (e.g., diflunisal)
  6. ------------Increased risk below this line - additional considerations------
  7. Non COX-2 selective NSAIDs [Best bet: Naproxen]
  8. NSAIDs with some COX-2 activity
  9. COX-2 Selective NSAIDs [LEAST DESIRABLE]

 
Guidance from AHA includes (selections below horizontal line):

  1. Select patients at low risk of a thrombotic event
  2. Prescribe lowest dose required to control symptoms
  3. Add ASA 81 mg and PPI to patients at increased risk of thrombotic events
  4. Regular monitoring for possible adverse effects such as sustained hypertension, worsening renal function, edema, GI bleeding.

 Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation 2007;115:1634-42.
http://circ.ahajournals.org/content/115/12/1634

References   top of page

  1. Abraham PA, Keane WF. Glomerular and interstitial disease induced by nonsteroidal anti-inflammatory drugs. Am J Nephrol. 1984;4:1-6.
  2. Amabile CM, Spencer AP. Keeping your patient with heart failure safe: a review of potentially dangerous medications. Arch Intern Med. 2004;164:709-720.
  3. Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KA; American Heart Association. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007;115(12):1634-1642.
  4. April PA, Curran NJ, Ekohlm BP, et al: Multicenter Comparative Study of Salsalate (SSA) vs Aspirin (ASA) in Rheumatoid Arthritis (RA), Arthritis Rheumatism 30 (4 supplement): S93, 1987.
  5. Bhatt DL, Scheiman J, Abraham NS, et al, “ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risk of Antiplatelet Therapy and NSAID Use. A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents,” J Am Coll Cardiol, 2008, 52(18):1502-17.
  6. Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs--differences and similarities. N Engl J Med 1991; 324:1716.
  7. Deodhar SD, McLeod MM, Dick WC, et al: A Short-Term Comparative Trial of Salsalate and Indomethacin in Rheumatoid Arthritis. Curr. Med. Res. Opi; 5:185-188, 1977.
  8. Estes D, Kaplan K: Lack of Platelet Effect With the Aspirin Analog, Salsalate, Arthritis and Rheumatism, 23:1303-1307, 1980.
  9. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med. 1991;115:787-796.
  10. García Rodríguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs.Lancet. 1994;343:769-772.
  11. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ. 2005;330:1366-1372.
  12. Hochberg MC, Altman RD, April KT, et al, “American College of Rheumatology 2012 Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and Knee,” Arthritis Care Res (Hoboken), 2012, 64(4):465-74.
  13. Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology. 2001;120:594-606.
  14. Lanas A, García-Rodríguez LA, Arroyo MT, et al. Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. Gut. 2006;55(12):1731-1738.
  15. Morris HG, Sherman NA, McQuain C, et al: Effects of Salsalate (Non-Acetylated Salicylate) and Aspirin ( ASA) on serum Protaglandins in Humans. Ther. Drug Monit. 7:435-438, 1985.
  16. Patrignani P, Tacconelli S, Bruno A, Sostres C, Lanas A. Managing the adverse effects of nonsteroidal anti-inflammatory drugs. Expert Rev Clin Pharmacol. 2011;4(5):605-621.
  17. Regula J, Butruk E, Dekkers CP, et al: Prevention of NSAID-associated gastrointestinal lesions: a comparison study pantoprazole versus omeprazole.Am J Gastroenterol. 2006;101:1747-1755.
  18. Smolinske SC, Hall AH, Vandenberg SA, et al, “Toxic Effects of Nonsteroid Anti-inflammatory Drugs in Overdose. An Overview of Recent Evidence on Clinical Effects and Dose-Response Relationships,” Drug Saf, 1990, 5(4):252-74.
  19. Talley NJ, Evans JM, Fleming KC, et al. Nonsteroidal anti-inflammatory drugs and dyspepsia in the elderly. Dig Dis Sci. 1995;40:1345-1350.
  20. 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.
  21. Wilcox CM, Allison J, Benzuly K, et al. Consensus development conference on the use of nonsteroidal anti-inflammatory agents, including cyclooxygenase-2 enzyme inhibitors and aspirin [published correction appears in Clin Gastroenterol Hepatol. 2006;4(11):1421]. Clin Gastroenterol Hepatol. 2006;4(9):1082-1089.
  22. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med. 1999;340:1888-1899


Disclaimer

All calculations must be confirmed before use. The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgement. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.   Read the disclaimer
 

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