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. 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]
  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-Narcotic alternatives to NSAIDs

VII. Preparations: COX2 Selective NSAID

  1. Celecoxib (Celebrex) 200 mg PO qd-bid
  2. Rofecoxib (Vioxx) is no longer available in the United States due to cardiovascular risks

VIII. Preparations: Acetic acids

  1. Partially COX2 selective (less GI adverse effects)
    1. Etodolac (Lodine) 200-400 mg PO bid-tid
      1. Etodolac 400 mg superior to Aspirin 650 mg
    2. Etodolac XL (Lodine XL) 400-1200 mg qd
    3. Nabumetone (Relafen) 1000 mg PO qd-bid
  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. Acetylsalicylic acid (Aspirin) 500-1000 mg q4-6 hours
  2. Trisalicylate (Trilisate) 1000-1500 mg q8-12 hours
  3. Diflunisal (Dolobid) 500 mg q8-12 hours
    1. Superior and longer acting than Aspirin 650 mg
    2. Superior and longer acting than Acetaminophen 650 mg
  4. Salsalate (Disalcid)
  5. Sodium Salicylate (Uracil 5)
  6. 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 orall daily
  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 Misoprostel)
      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)

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Ontology: Anti-Inflammatory Agents, Non-Steroidal (C0003211)

Definition (MSH) Anti-inflammatory agents that are non-steroidal in nature. In addition to anti-inflammatory actions, they have analgesic, antipyretic, and platelet-inhibitory actions.They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins. Inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects.
Definition (NCI_NCI-GLOSS) A group of drugs that decrease fever, swelling, pain, and redness.
Definition (NCI) Anti-inflammatory agents that are not steroids. In addition to anti-inflammatory actions, they have analgesic, antipyretic, and platelet-inhibitory actions. They are used primarily in the treatment of chronic arthritic conditions and certain soft tissue disorders associated with pain and inflammation. They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins. Inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects. Certain NSAIDs also may inhibit lipoxygenase enzymes or phospholipase C or may modulate T-cell function. (MeSH)
Definition (CSP) agents that counteract or suppress inflammation and are not steroids; most have in addition analgesic, antipyretic, and platelet-inhibitory actions; they act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins: inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects.
Concepts Pharmacologic Substance (T121)
MSH D000894
SnomedCT 283009002, 363586009, 16403005, 372665008
LNC LP157711-5, MTHU045310
English Agents, Non-Steroidal Anti-Inflammatory, Agents, Nonsteroidal Anti-Inflammatory, Agents, Nonsteroidal Antiinflammatory, Anti Inflammatory Agents, Non Steroidal, Anti Inflammatory Agents, Nonsteroidal, Anti-Inflammatory Agents, Nonsteroidal, Antiinflammatory Agents, Non Steroidal, Antiinflammatory Agents, Nonsteroidal, Non Steroidal Anti Inflammatory Agents, Non-Steroidal Anti-Inflammatory Agents, Nonsteroidal Anti Inflammatory Agents, Nonsteroidal Anti-Inflammatory Agents, Nonsteroidal Antiinflammatory Agents, NSAIDs, Non-steroid anti-inflam. drug, ANTI INFLAMM AGENTS NONSTEROIDAL, AIANS, ANTIINFLAMMATORY AGENTS NONSTEROIDAL, NSAIA, ANTIINFLAMM AGENTS NON STEROIDAL, NON STEROIDAL ANTI INFLAMM AGENTS, NONSTEROIDAL ANTIINFLAMMATORY AGENTS, nonsteroidal antiinflammatory agent, NSAIDS, nonsteroidal anti-inflammatory drugs (medication), nonsteroidal anti-inflammatory drugs, nsaid, nsaids, nonsteroidal anti-inflammatory drugs (NSAIDs), Anti-Inflammatory Agents, Non-Steroidal, Non-steroidal anti-inflammatory drug (substance), Non-steroidal anti-inflammatory product, Non-steroidal anti-inflammatory product (substance), Nonsteroidal antiinflammatory drugs, Nonsteroidal anti-inflammatory agents, nonsteroidal anti-inflammatory drug, NSAID, NSAID - Non-steroidal anti-inflammatory drug, Non-steroidal anti-inflammatory drug, Non-steroidal anti-inflammatory agent (product), Non-steroidal anti-inflammatory agent (substance), Non-steroidal anti-inflammatory agent, Non-steroidal anti-inflammatory agent, NOS, Nonsteroidal Antiinflammatory Drug, Nonsteroidal Anti-inflammatory Drugs
French Antiinflammatoires non stéroïdiens, Agents antiinflammmatoires non stéroïdiens, Anti-inflammatoires non stéroïdiens, Agents anti-inflammatoires non stéroïdiens, Médicaments antiinflammatoires non stéroïdiens, AINS
Swedish Antiinflammatoriska medel, icke-steroida
Spanish antiinflamatorio no esteroide, agente antiinflamatorio no esteroide, antinflamatorio no esteroide (producto), antinflamatorio no esteroide, agente antiinflamatorio no esteroide (sustancia), agente antinflamatorio no esteroide (sustancia), droga antinflamatoria no esteroide, agente antiinflamatorio no esteroide (producto), Fármacos Antiinflamatorios no Esteroideos, Antiinflamatorios no Esteroideos, antinflamatorio no esteroide, producto (sustancia), antinflamatorio no esteroide, producto, Fármacos Semejantes a la Aspirina, Agentes Antiinflamatorios no Esteroideos, Fármacos Antirreumáticos no Esteroideos, Agentes Semejantes a la Aspirina, Agentes Antirreumáticos no Esteroideos, AINE, agente antinflamatorio no esteroide, antiinflamatorio no esteroide (producto), antiinflamatorio no esteroide (sustancia)
Czech antiflogistika nesteroidní, NSAID
Finnish NSAID
Italian NSAIDs, Farmaci antinfiammatori non steroidei
Russian ANALGETIKI PROTIVOVOSPALITEL'NYE, NESTEROIDNYE PROTIVOVOSPALITEL'NYE SREDSTVA, PROTIVOREVMATICHESKIE SREDSTVA NESTEROIDNYE, PROTIVOVOSPALITEL'NYE SREDSTVA NESTEROIDNYE, ANTAGONISTY SINTEZA PROSTAGLANDINA, ASPIRINOPODOBNYE SREDSTVA, АНАЛГЕТИКИ ПРОТИВОВОСПАЛИТЕЛЬНЫЕ, АНТАГОНИСТЫ СИНТЕЗА ПРОСТАГЛАНДИНА, АСПИРИНОПОДОБНЫЕ СРЕДСТВА, НЕСТЕРОИДНЫЕ ПРОТИВОВОСПАЛИТЕЛЬНЫЕ СРЕДСТВА, ПРОТИВОВОСПАЛИТЕЛЬНЫЕ СРЕДСТВА НЕСТЕРОИДНЫЕ, ПРОТИВОРЕВМАТИЧЕСКИЕ СРЕДСТВА НЕСТЕРОИДНЫЕ
Japanese 非ステロイド系抗リウマチ剤, 抗炎症性鎮痛薬, 抗リウマチ剤-非ステロイド系, 鎮痛薬-抗炎症性, 非ステロイド系抗炎症薬, 非ステロイド系抗リウマチ薬, 鎮痛消炎薬, 抗炎症剤-非ステロイド系, 抗炎症性鎮痛剤, 鎮痛剤-抗炎症性, 消炎鎮痛剤, 鎮痛消炎剤, 非ステロイド抗炎症剤, 非ステロイド消炎薬, 非ステロイド系消炎剤, 非ステロイド系消炎薬, 非ステロイド系抗炎症剤, アスピリン様剤
Croatian ANTIFLOGISTICI, NESTEROIDNI
Polish Leki przeciwzapalne niesteroidowe, NLPZ, Środki aspirynopodobne, Leki przeciwreumatyczne niesterydowe, Niesteroidowe leki przeciwzapalne, Leki przeciwbólowe przeciwzapalne
Norwegian NSAID, Non-Steroidal Anti-Inflammatory Drugs, Ikke-steroide antiinflammatoriske midler, COX-hemmere
Portuguese Anti-Inflamatórios não Esteroides, Fármacos Anti-Inflamatórios não Esteroides, Fármacos Semelhantes à Aspirina, Agentes Anti-Inflamatórios não Esteroides, Agentes Similares à Aspirina, Fármacos Antirreumáticos não Esteroides
German Antiphlogistika, nichtsteroidale, Entzündungshemmende Mittel, nichtsteroidale, Nichtsteroidale entzündungshemmende Mittel