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Significance Many assume that morphine tolerance is a continually progressive response, based mainly upon preclinical studies typically lasting a week or less. Yet, clinicians have long appreciated the ability to manage cancer pain in patients with stable opioid doses for months, implying that extended dosing may eventually stabilize the level of tolerance. To reconcile these differences, we examined tolerance over 6 wk and show that extended morphine dosing leads to progressive tolerance for 3 wk that then stabilizes for up to 6 wk and is associated with increases in the abundance of mu opioid receptor splice variant mRNA levels of as much as 300-fold.

Stabilization of morphine tolerance with long-term dosing: Association with selective upregulation of mu-opioid receptor splice variant mRNAs