[en] Highlights: • Opioids are important pain-relieving drugs but also carry a risk of harmful side effects. • Decreasing the pK_a of the opioid amine group promotes selective binding in inflamed tissue. • Fluorinated morphine derivatives are calculated to have lower pK_a’s for pH -specific binding. Opioids such as morphine are important pain-relieving drugs but also carry a risk of harmful side effects including addiction. Morphine is active in both healthy and inflamed tissue, however, decreasing the pK_a of the biochemically-active amine group can promote selective binding in the more acidic conditions of inflamed tissue and reduce harmful side effects associated with opioids. Herein, we explore the impact of fluorination on the pK_a of fluoromorphine derivatives to identify which will bind selectively in inflamed tissue. Theoretical pK_a values are determined at the M06-2X(SMD)/aug-cc-pVDZ level of theory by calculating the $\mathrm{\Delta }{\mathit{\text{G}}}_{\mathit{aq}}$ values for the amine deprotonation reactions.