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    Nonsteroidal Anti-inflammatory Drugs Dosing for Acute Musculoskeletal Pain

    Cardinal Presentations / Presenting Problems, Orthopedic

    Last Updated Aug 04, 2023
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    By John van Bockxmeer, Vishal Varshney, Anthony Lau, Catherine Zang

    Context

    • Tissue injury and inflammation results in peripheral mediator release and stimulation of nociceptors on peripheral nerve endings.
    • NSAIDs work by blocking cyclooxygenase enzymes, COX-1 and COX-2, which are responsible for producing prostaglandins that stimulate pain receptors. They are protein-bound and renally excreted.
      • Non-selective NSAIDs inhibit both COX-1 and COX-2 enzymes, posing a higher risk of gastrointestinal bleeding due to COX-1’s protective role in the stomach.
      • COX-2 inhibitors offer reduced gastrointestinal toxicity but may have a heightened risk of cardiovascular side effects compared to non-selective NSAIDs.
    • When the COX enzyme sites become saturated, surpassing the ceiling dose of an NSAID increases the concentration of unbound drug in the body, raising the risk of adverse events without providing additional therapeutic benefits.

    Diagnostic Process

    Patient specific factors to consider:

    • Consider alternative diagnoses and pain modalities, neuropathic and chronic nociplastic pain that require a modified approach.
    • Use a validated pain assessment score: numerical rating scale.
    • Have a patient-centered discussion and consider minimising NSAIDs if:
      • Age greater than 65 years old.
      • History of:
        • ulcer or gastrointestinal bleeding.
        • cardiovascular disease.
        • pediatric brittle asthma which may be precipitated by NSAIDs.
        • renal disease (acute kidney injury or chronic kidney disease) or factors predisposing to AKI such as dehydration or rhabdomyolysis.
        • sulfonamide allergy.
        • concurrent anticoagulant, antiplatelet, glucocorticoid, or SSRI use (increased bleed risk).

    Recommended Treatment

    Agent Selection, Dosing, and Duration

    • Mild to moderate pain: ibuprofen, naproxen, diclofenac.
    • Moderate to severe pain: ketorolac.
    • Maximum individual NSAID ceiling doses:
      • Ibuprofen: 400 mg PO
      • Naproxen: 440 mg PO (recommended dose: 250-375 mg PO BID)
      • Diclofenac: 50 mg PO
      • Ketorolac: 10 mg IM/IV (15 mg might be most practicable depending on vial size)
        • To minimize UGIB risk: < 65 y, maximum 10 mg/day, max duration: 5 days.
    • Duration of use: reassessment after 5 days.
    • Duration of action: based on trial data, patients should be informed that 70% of people will experience pain relief for at least 6 hours.
    • Higher daily doses of NSAIDs, particularly ketorolac, are associated with an increased risk of bleeding, including UGIB and/or perforation, beyond the above ceiling doses.

    Quality Of Evidence?

    Justification

    • There is level 1b evidence to support NSAID ceiling dosing (individual randomized control trials).
    • Studies suggest using the lowest effective dose of NSAIDs and not exceeding ceiling doses.
    • Different oral ibuprofen doses (400-800mg) showed comparable pain relief in randomised double-blinded trials for acute pain in adult ED patients (level 1b).
    • Diclofenac doses (50-100mg) showed similar efficacy for acute post-op pain (level 3a).
    • Ketorolac at various doses (10-90mg PO/IM/IV) demonstrated similar efficacy (level 2b, 1b).
    • Naproxen’s optimal ceiling dose remains uncertain, post-operative pain data found a NNT of 2.3 for 440mg dosing (level 4).
    • Ketorolac poses a higher dose-dependent risk of UGIB compared to other NSAIDs (level 4).
    • Although rarely used, Ketorolac administration beyond 5 days increases UGIB risk; limiting use to 10mg/day for 5 days in patients under 65 avoids increased UGIB risk. Ketorolac use for up to 6 days does not increase GI complications (level 4).
    Moderate-High

    Related Information

    Reference List

    1. Van Bockxmeer J, Varshney V, Lau A. Ceiling Doses of Ketorolac and Ibuprofen in Acute Pain Management [Internet]. UBC CPD; 2023 [cited 2023 Jun 5]. Available from: https://thischangedmypractice.com/ceiling-doses-nsaid-acute-pain-management/


    2. Motov S, Masoudi A, Drapkin J, et al. Comparison of Oral Ibuprofen at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2019;74(4):530-537. doi:10.1016/j.annemergmed.2019.05.037


    3. Motov S, Yasavolian M, Likourezos A, et al. Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2017;70(2):177-184. doi:10.1016/j.annemergmed.2016.10.014


    4. Strom BL, Berlin JA, Kinman JL, et al. Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. A postmarketing surveillance study. JAMA. 1996;275(5):376-382. doi:10.1001/jama.1996.03530290046036


    5. Ong CK, Lirk P, Tan CH, Seymour RA. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res. 2007;5(1):19-34. doi:10.3121/cmr.2007.698


    6. McQuay HJ, Moore RA. Postoperative analgesia and vomiting, with special reference to day-case surgery: a systematic review. Health Technol Assess. 1998;2(12):1-236.


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