The invention provides pharmaceutical compositions comprising macromolecular gastrointestinal enzyme-labile opioid prodrugs, co-formulated with small-molecule and/or macromolecular gastrointestinal enzyme inhibitors. The macromolecular constructs are minimally absorbed from the GI tract, and can produce non-linear pharmacokinetic profiles of the delivered opioid agonist following oral ingestion. An optional macromolecular opioid antagonist may also be present in compositions of the invention to discourage tampering by potential abusers.