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Metabolite Contributions to Opioid Response and Tolerance Tolerance also may result from the production of metabolites that accumulate in the systemic circulation over time, penetrate the site of action, and interfere with pharmacologic response whether by competing with the parent compound for receptor binding (e.g., antagonists or partial agonists) or by down-regulating the responsivity of the receptor system or downstream events

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However, ongoing research is needed to better understand how these findings translate to human health outcomes