Combination therapies of an alpha-2 adrenergic receptor agonist and an alpha-2 adrenergic receptor antagonist at a concentration effective to potentiate but not antagonize a therapeutic effect of the alpha-2 adrenergic receptor agonist are provided. Also provided are methods for use of these combination therapies in potentiating the therapeutic effects of alpha-2 adrenergic receptor agonists, inhibiting development of acute and/or chronic tolerance to alpha-2 adrenergic receptor agonists and treating conditions treatable by alpha-2 adrenergic receptor agonist therapy in a subject. In addition, a method for reversing alpha-2 adrenergic receptor agonist tolerance and/or restoring therapeutic effect of an alpha-2 adrenergic receptor agonist in a subject via administration of an alpha-2 adrenergic receptor antagonist at a concentration effective to potentiate, but not antagonize, the therapeutic effect of the alpha-2 adrenergic receptor agonist is provided.