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. 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

III. Precautions

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

IV. Adverse Effects

  1. NSAID Gastrointestinal Adverse Effects
  2. 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. 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]
  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. Naprosyn (Naproxen) may be associated with less cardiovascular risk than other NSAIDs
    3. Celebrex may also be associated with less cardiovascular risk than NSAIDS (despite Vioxx history)
      1. Ruschitzka (2017) Eur Heart J +PMID:29020251\ [PubMed]
    4. Increased risk with Diclofenac and to a lesser extent Ibuprofen
    5. Take Aspirin 2 hours before or 8 hours post-Ibuprofen
    6. Take Aspirin 36 hours after last Naproxen
    7. Limit NSAID to lowest dose and shortest duration
    8. (2013) Lancet 382(9894):769-79 +PMID:23726390 [PubMed]
    9. Bally (2017) BMJ 357:j1909 +PMID:28487435 [PubMed]
    10. Steinhubl (2005) Am College Card 45:1302 [PubMed]
  9. Hypertension
    1. On average NSAIDs increase Blood Pressure 5 mmHg
    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. 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

V. Monitoring: Protocol for NSAID use in elderly

  1. Monitor Blood Pressure
  2. Labs: Obtain at baseline and q3-12 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]

VI. Preparations: 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. Preparations: 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. Meloxicam (Mobic)

VIII. Preparations: 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 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 PO/PR tid
    2. Sulindac (Clinoril) 150-200 mg PO bid
    3. Tolmetin Sodium (Tolectin) 200-600 mg PO tid
  3. Pyrrolo-pyrroles: Parenteral NSAID
    1. Ketorolac Tromethamine (Toradol)
      1. Ketorolac 30 mg IV or 60 mg IM

IX. Preparations: 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
  5. Salsalate (Disalcid)
  6. Sodium Salicylate (Uracil 5)
  7. Sodium thiosalicylate (Tusal)

X. Preparations: 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 bid-qid
  5. Fenoprofen (Nalfon) 200 mg q4-6 hours
    1. Similar to Aspirin
    2. Avoid in Renal Insufficiency
  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 qd

XI. Preparations: Oxicams

  1. General
    1. Long half life (once a day dosing)
  2. Meloxicam (Mobic) 7.5 to 15 mg orally daily
    1. More COX-2 Selective
  3. Piroxicam (Feldene) 20 mg qd

XII. Preparations: Fenamate

  1. Anthranilic Acid
    1. Meclofenamate (Meclomen) 50-100 mg PO q4-6 hours
      1. Comparable to Aspirin
  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. Diclofenac Potassium (Cataflam) 50 mg orally every 8 hours (Comparable to Aspirin)
        1. Faster absorption (hence faster onset) than diclofenac Sodium (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 Diclofenac Potassium 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. 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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