Nonsteroidal Anti-inflammatory

Aka: Nonsteroidal Anti-inflammatory, Non-Steroidal Antiinflammatory, Non-Opioid Analgesics, NSAID, Oxicam NSAID, Oxicam, Acetic Acid NSAID, Propionic Acid NSAID, Fenamate NSAID

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II. Indications

  1. Analgesia
  2. Antpyretic
  3. Antiinflammatory

III. Contraindications

  1. Hypersensitivity (including Allergic Triad)
  2. Peptic Ulcer Disease
  3. Anticoagulation or other significant bleeding risks
  4. Cardiovascular disease (esp. post-CABG)
  5. Pregnancy (esp. first and third trimester)
  6. Lactation of newborns (may provoke Hyperbilirubinemia)

IV. Mechanism

  1. Blocks Cyclooxygenase (COX)
  2. COX Enzyme converts Arachidonic Acid to PGG2
  3. COX1 Enzyme
    1. Location
      1. Gastric mucosa and intestinal mucosa
      2. Platelets
      3. Renal
      4. Vascular endothelium
    2. Inhibition Effects
      1. Predisposes to gastric or intestinal ulcers
      2. Predisposes to bleeding (anti-Platelet adhesion)
      3. No anti-inflammatory effect
      4. Renal effects
        1. Fluid retention
        2. Decreased Glomerular Filtration Rate (GFR)
  4. COX2 Enzyme
    1. Location
      1. Brain
      2. Renal (ascending tubule, Macula densa)
      3. Adenoma (colon)
      4. Cytokine-induced (inflammation related)
    2. Inhibition Effects
      1. Anti-inflammatory action
      2. Analgesic action
      3. Predisposes to Renal Injury in Hypovolemia
      4. Decreased malignant potential of Colonic Polyps
      5. May have benefit in Alzheimer's Disease

V. Precautions

  1. Peptic Ulcer risk, nephrotoxicity, and Cardiovascular Risk are FDA black box warnings

VI. Medications: Non-Opioid Alternatives to NSAIDs

  1. Acetaminophen (Tylenol)
  2. Non-acetylated Salicylate
  3. Low dose Prednisone (Rheumatoid Arthritis)
  4. Single joint local Corticosteroid Injection
  5. Topical NSAID (e.g. Diclofenac Gel)
  6. Lidocaine Patch
  7. Capsaicin Topically

VII. Medications: COX2 Selective NSAIDs

  1. More COX2 Selective
    1. Celecoxib (Celebrex) 200 mg PO qd-bid
    2. Rofecoxib (Vioxx)
      1. No longer available in the United States due to Cardiovascular Risks
  2. Relatively COX2 Selective
    1. Nabumetone (Relafen)
    2. Etodolac (Lodine)

VIII. Medications: Acetic acids

  1. Partially COX2 selective (less GI adverse effects)
    1. Etodolac (Lodine) 200-400 mg orally twice to three times daily
      1. Etodolac 400 mg is superior to Aspirin 650 mg
    2. Etodolac XL (Lodine XL) 400-1200 mg orally daily
    3. Nabumetone (Relafen) 1000 mg orally daily to twice daily
  2. Indoles
    1. Indomethacin 25-50 mg orally (or rectally) three times daily
    2. Sulindac (Clinoril) 150-200 mg orally twice daily
    3. TolmetinSodium (Tolectin) 200-600 mg orally three times daily
  3. Pyrrolo-pyrroles: Parenteral NSAID
    1. Ketorolac Tromethamine (Toradol)
      1. Ketorolac 10 to 30 mg IV (or 30 to 60 mg IM)

IX. Medications: Salicylates

  1. See Salicylate
  2. Acetylsalicylic Acid (Aspirin) 500-1000 mg every 4-6 hours
  3. Trisalicylate (Trilisate) 1000-1500 mg every 8-12 hours
  4. Diflunisal (Dolobid) 500 mg every 8-12 hours
    1. Risk of Acute Interstitial Nephritis
    2. Compared with Aspirin, lower risk of Gastrointestinal Bleeding, Tinnitus
  5. Salsalate (Disalcid)
  6. Sodium Salicylate (Uracil 5)
  7. Sodium thiosalicylate (Tusal)

X. Medications: Propionic Acids

  1. Ibuprofen (Motrin)
    1. Ibuprofen 400 mg comparable to Tylenol #3
  2. Naproxen (Naprosyn) 500 mg q12 hours
    1. Naproxen 500 mg superior to Aspirin 650
  3. Naproxen Sodium (Anaprox) 550 mg q12 hours
    1. NaproxenSodium 550 mg superior to Aspirin 650
  4. Flurbiprofen (Ansaid) 200-300 mg/day divided twice to four times daily
  5. Fenoprofen (Nalfon) 200 mg q4-6 hours
    1. Similar to Aspirin (but more potent)
    2. Avoid in Renal Insufficiency
    3. Increased genitourinary adverse effects (e.g. Dysuria, Hematuria, nephropathy)
    4. Decreased gastrointestinal adverse effects
  6. Ketoprofen (Orudis) 25-75 mg q6-8 hours
    1. Ketoprofen 25 mg comparable to Ibuprofen 400 mg
    2. Ketoprofen 50 mg more potent than Tylenol #3
  7. Oxaprozin (Daypro) 1200 mg orally daily

XI. Medications: Oxicams

  1. General
    1. Long half life (once a day dosing)
  2. Meloxicam (Mobic) 7.5 to 15 mg orally daily
    1. Despite being touted as more COX-2 specific, still has moderate gastrointestinal adverse effects
      1. See NSAID Gastrointestinal Adverse Effects
  3. Piroxicam (Feldene) 20 mg orally daily (or divided twice daily)
    1. Additional mechanisms beyond inhibition of Prostaglandin synthesis
      1. Inhibits Neutrophil aggregation
      2. Inhibits Lysosome enzyme release

XII. Medications: Fenamate

  1. Anthranilic Acid
    1. Meclofenamate (Meclomen) 50-100 mg PO q4-6 hours
      1. Comparable to Aspirin
      2. Diarrhea occurs in up to 35% of patients
    2. Mefenamic Acid (Ponstel)
      1. Dysmenorrhea: Initial 500 mg orally, then 250 mg orally every 6 hours for up to 1 week
  2. Acetic Acid: Diclofenac (Voltaren, Arthrotec)
    1. Precaution
      1. Other NSAIDs are preferred over Diclofenac
      2. Diclofenac is not recommended
        1. Cardiovascular Risk (similar to vioxx)
        2. Hepatotoxicity risk
        3. Increased GI toxicity risk
      3. References
        1. (2013) Presc Lett 20(7):42
    2. Oral
      1. DiclofenacPotassium (Cataflam) 50 mg orally every 8 hours (Comparable to Aspirin)
        1. Faster absorption (hence faster onset) than DiclofenacSodium (Voltaren)
      2. Diclofenac XR 100 mg orally daily
      3. Arthrotec (50 mg Diclofenac with 200 mcg Misoprostol)
      4. Zorvolex 18 or 35 mg orally every 8 hours
        1. Released in 2014 as expensive, lower dose version of DiclofenacPotassium 50 mg
        2. No evidence of improved safety or similar efficacy to the lower priced, higher dose (50 mg) tablet
        3. Recommendations are still to use other systemic NSAIDs instead of Diclofenac
        4. (2014) Presc Lett 21(2): 9
    3. Topical
      1. Diclofenac Gel (Pennsaid)
      2. Flector Patch (applied to most painful area every 12 hours)

XIII. Adverse Effects

  1. See NSAID Gastrointestinal Adverse Effects
  2. See NSAID Renal Adverse Effects
  3. Bleeding risk
    1. Reversible inhibition of Platelet aggregation
    2. Associated with standard NSAIDs (esp. Naprosyn)
    3. COX2 Inhibitors have minimal effect on bleeding
    4. Avoid in patients with Thrombocytopenia and other Platelet disorders
    5. Stop Aspirin 7-10 days before procedures
    6. Stop NSAIDS five half-lives prior to the procedure
      1. Stop Ibuprofen 2 days before the procedure
      2. Stop Naprosyn 2-3 days before the procedure
      3. Stop Piroxicam (Feldene) 10 days before the procedure
  4. Headache
  5. CNS effects (esp. Indomethacin)
  6. Hepatotoxicity (esp. oral Diclofenac)
  7. Musculoskeletal effects
    1. May delay healing in Tendinopathy
    2. Increased malunion risk in long bone Fractures (Femur Fracture, Tib-Fib Fracture, Humerus Fracture), Odds Ratio 2
      1. NSAIDs blunt inflammatory response which is key to laying down new bone
      2. Indomethacin may be higher risk for nonunion than other nsaids
      3. Chronic NSAID use prior to Fracture also increases the risk of nonunion
      4. Jeffcoach (2014) J Trauma Acute Care Surg 76(3): 779-83 [PubMed]
    3. Longerterm use >3 days has been associated with an increased risk of nonunion or delayed union
      1. Ali (2020) Trauma 22(2): 94-111 [PubMed]
      2. Wheatley (2019) J Am Acad Orthop Surg 27(7): e330-36 [PubMed]
    4. However other human trials have not found significant delayed Fracture healing
      1. Marquez-Lara A (2016) JBJS Rev 4(3):e4. [PubMed]
      2. Li Q (2011) Spine 36:e461-8 [PubMed]
      3. Dodwell (2010) Calcif Tissue Int 87:193-202. [PubMed]
      4. (2017) Presc Lett 24(2): 9
      5. DePeter (2017) J Emerg Med 52(4): 426-32 +PMID:27751698 [PubMed]
    5. Bone healing in children <11 years old also does not appear to be affected by NSAIDs
      1. Choo (2021) Children 8(9): 821 [PubMed]
    6. Major orthopedic groups recommend NSAID use after Fracture over Opioids
      1. Theoretical risk of non-union with NSAIDS is far overshadowed by the real risk of Opioid Use Disorder in the U.S.
      2. Murphy (2023) Trauma Surg Acute Care Open 8(1): e001056 [PubMed]
  8. Cardiovascular/cerebrovascular risk (interferes with Aspirin anti-Platelet effects)
    1. Avoid NSAIDs in patients with vascular disease (risk increases within days of use)
    2. Avoid all NSAIDs and COX2 Inhibitors in the post-CABG period
    3. Risk of fluid retention and Congestive Heart Failure exacerbation
    4. Counters antiplatelet activity of Aspirin
    5. Take Aspirin 2 hours before or 8 hours post-Ibuprofen
    6. Take Aspirin 36 hours after last Naproxen
    7. Naprosyn (Naproxen) may be associated with less Cardiovascular Risk than other NSAIDs
    8. Celebrex may also be associated with less Cardiovascular Risk than NSAIDS (despite Vioxx history)
      1. Ruschitzka (2017) Eur Heart J +PMID:29020251\ [PubMed]
    9. Increased risk with Diclofenac and to a lesser extent Ibuprofen
    10. Limit NSAID to lowest dose and shortest duration
    11. (2013) Lancet 382(9894):769-79 +PMID:23726390 [PubMed]
    12. Bally (2017) BMJ 357:j1909 +PMID:28487435 [PubMed]
    13. Steinhubl (2005) Am College Card 45:1302 [PubMed]
  9. Hypertension
    1. On average NSAIDs increase Blood Pressure 5 mmHg, in part related to fluid retention
    2. Blood Pressure increase is more common in Diabetes Mellitus, Congestive Heart Failure, Kidney or liver disease
    3. Associated with daily use (intermittent use is unlikely to have an effect)
    4. Decreases efficacy of Antihypertensives
      1. Calcium Channel Blockers are less affected by NSAID induced Blood Pressure increases
  10. Allergic Reaction
    1. Allergic Reaction (IgE mediated)
      1. Avoid all NSAIDs unless otherwise allowed via formal allergy evaluation
    2. Pseudoallergic reaction
      1. COX reaction, often associated with Asthma, Nasal Polyps, Allergic Rhinitis
      2. Assume true Allergic Reaction first and do not retrial with any NSAID until allergy evaluation
    3. Intollerance to side effect
      1. Distinguish and offer counter measures or alternative NSAID
    4. References
      1. Orman and Hayes in Herbert (2017) EM:Rap 17(3): 8-9

XIV. Safety

  1. Safety in Lactation varies across NSAIDs
  2. Avoid NSAIDs in pregnancy outside the first part of the second trimester (13 to 20 weeks)
    1. Teratogenic in first trimester
    2. Risk of premature ductus arteriosus closure in the fetus in third trimester
    3. Most NSAIDs carry a legacy system Pregnancy Category B or C designation (aside from third trimester)
      1. However, many obstetricians avoid NSAIDs entirely in pregnancy (even in second trimester)
  3. Associated adverse effects in pregnancy
    1. Associated with increased Miscarriage risk when used around the time of conception
    2. Associated with first trimester congenital anomalies
      1. Hypoplastic Left Heart
      2. Tetralogy of Fallot
      3. Gastroschisis
      4. Spina bifida
      5. Interrante (2017) Ann Epidemiol 27(10): 645-53 [PubMed]
    3. Associated with fetal adverse effects after 20 weeks
      1. Fetal Kidney injury
      2. Oligohydramnios
      3. https://www.fda.gov/safety/medical-product-safety-information/nonsteroidal-anti-inflammatory-drugs-nsaids-drug-safety-communication-avoid-use-nsaids-pregnancy-20
    4. Associated with adverse effects after 30 weeks
      1. Premature ductus arteriosus closure
        1. Results in fetal Pulmonary Hypertension and fetal death
      2. Prostaglandins induce systemic and pulmonary vessel relaxation (including ductus arteriosus)
        1. NSAIDS inhibit Prostaglandin synthesis, resulting in Vasoconstriction
        2. NSAID induced Vasoconstriction may result in premature ductus arteriosus closure
      3. References
        1. Koren (2006) Ann Pharmacother 40(5): 824-9 [PubMed]

XV. Drug Interactions

  1. Loop Diuretics
    1. NSAIDS decrease efficacy
  2. Drug levels may be increased by NSAIDs as a class
    1. Cyclosporine
    2. Digoxin
    3. Lithium
    4. Methotrexate
    5. Phenytoin
  3. Anticoagulants (Warfarin, DOACs)
    1. Avoid in combination with NSAIDs (increased Hemorrhage risk, esp. Gastrointestinal Bleeding)

XVI. Monitoring: Protocol for NSAID use in elderly

  1. Monitor Blood Pressure
  2. Labs: Obtain at baseline and every 3-12 months
    1. Complete Blood Count (CBC)
    2. Creatinine
    3. Liver Function Tests
  3. Review of Systems for NSAID adverse effects
    1. Nausea or Vomiting
    2. Dark stools or bloody stools
    3. Dyspepsia
    4. Cognitive changes
  4. References
    1. Lipsky (2000) J Rheumatol 27:1338 [PubMed]

XVII. References

  1. (2000) Tarascon Pocket Pharmacopoeia
  2. Wolfe (1999) N Engl J Med 340:1888 [PubMed]
  3. (2000) Med Lett Drugs Ther 42(1085):73-8 [PubMed]

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