Marked tolerance can develop to the acute pharmacologic effects, with the exception of miosis and constipation. The mechanism of opioid tolerance development may involve receptor uncoupling. Antagonists of glutamate N-methyl-daspartate (NMDA) receptors (eg, ketamine), as well as δ-receptor antagonists, are reported to block opioid tolerance. Although there is cross-tolerance between different opioid agonists, it is not complete. This provides the basis for “opioid rotation,” whereby analgesia is maintained (eg, in cancer patients) by changing from one drug to another.