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  • Review Article
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Using pharmacokinetic principles to optimize pain therapy

Nature Reviews Rheumatology volume 6, pages 589–598 (2010)Cite this article

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Abstract

Cyclo-oxygenase (COX) inhibitors are widely used to relieve musculoskeletal pain. These agents block the production of prostaglandins (PGs) at sites of inflammation by inhibiting the activity of two COX enzymes necessary for PG production and normal organ homeostasis. Inhibition of PG production at sites unrelated to pain is associated with adverse drug reactions (ADRs). The degree of analgesic efficacy, as well as the incidence and the localization of ADRs, are critically influenced by the pharmacokinetics (absorption, distribution and elimination) of these drugs. Ideally, sufficient and permanent inhibition of COX enzymes should be achieved in target tissues, with minimal ADRs. To minimize underdosing or overdosing, which result in therapeutic failure or ADRs, the COX inhibitor with the most appropriate pharmacokinetic properties should be selected on the basis of a thorough pharmacokinetic–pharmacodynamic analysis. In this Review, the pharmacokinetics of the prevailing COX inhibitors will be discussed and enigmatic aspects of these intensively used drugs will be considered.

Key Points

  • Cyclo-oxygenase (COX) inhibitors comprise substances with a broad spectrum of pharmacokinetic characteristics

  • Rapid onset of analgesia requires administration of COX inhibitors with fast absorption, such as solutions or uncoated tablets with salts of the respective compound

  • Among the COX inhibitors, only acidic compounds are currently considered to accumulate in the inflamed joint (deep compartment) and to confer long-term inhibition of COX2 when given at therapeutic doses

  • To achieve acute analgesic effects and to avoid toxic drug accumulation following long-term use, administration of a suitable initial loading dose followed by a smaller maintenance dose should be considered

  • Only >95% COX1 inhibition in platelets confers a clinically relevant inhibition of platelet aggregation; moreover, correlation analyses suggest that 80% COX2 inhibition is necessary for pain relief

  • Overdosing increases the incidence of adverse effects, but does not enhance analgesia

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Figure 1: The pathway of prostanoid synthesis and the role of the COX enzymes.
Figure 2: Discordant dose-response relationships between aspirin and the inhibition of platelet COX1 or analgesia related to COX2 inhibition.
Figure 3: Distribution of acidic and nonacidic COX inhibitors.
Figure 4: Doubling the dose of a COX2 inhibitor already eliciting full COX2 inhibition does not produce additional pharmacological effects but rather enhances dose-related ADRs.
Figure 5: Simulation of the pharmacokinetic profile of a short half-life (ibuprofen, t50: 2 h) and long half-life (etoricoxib, t50: 24 h) COX-inhibitor.

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Authors and Affiliations

  1. Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany

    Kay Brune & Bertold Renner

  2. Institute of Toxicology and Pharmacology, University of Rostock, Schillingallee 70, Rostock, 18057, Germany

    Burkhard Hinz

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Contributions

K. Brune, B. Renner and B. Hinz researched the data for the article and K. Brune and B. Hinz provided a substantial contribution to discussions of the content. K. Brune and B. Hinz wrote the article and K. Brune, B. Renner and B. Hinz contributed to review and/or editing of the manuscript before submission.

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Correspondence to Burkhard Hinz.

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K. Brune is a consultant for Aventis, Bayer, Merck and Novartis, and is on the speakers bureau and receives grant/research support from these companies. B. Renner receives grant/research support from GlaxoSmithKline and Merck Sharp & Dohme. B. Hinz is a consultant for Novartis, is on the speakers bureau for Merck Sharp & Dohme and Novartis, receives grant/research support from Bayer and Merck Sharp & Dohme, Mundipharma Pfizer and Sanofi.

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Brune, K., Renner, B. & Hinz, B. Using pharmacokinetic principles to optimize pain therapy. Nat Rev Rheumatol 6, 589–598 (2010). https://doi.org/10.1038/nrrheum.2010.141

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