The non-selective activation of central and peripheral opioid receptors is a major shortcoming of currently available opioids. Targeting peripheral opioid receptors is a promising strategy to preclude side effects. Recently, we showed that fentanyl-derived mu-opioid receptor (MOR) agonists with reduced acid dissociation constants (pK(a)) due to introducing single fluorine atoms produced injury-restricted antinociception in rat models of inflammatory, postoperative and neuropathic pain. Here, we report that a new double-fluorinated compound (FF6) and fentanyl show similar pK(a), MOR affinity and [S-35]-GTP gamma S binding at low and physiological pH values. In vivo, FF6 produced antinociception in injured and non-injured tissue, and induced sedation and constipation. The comparison of several fentanyl derivatives revealed a correlation between pK(a) values and pH-dependent MOR activation, antinociception and side effects. An opioid ligand's pK(a) value may be used as discriminating factor to design safer analgesics.