We previously reported that a multifunctional opioid/neuropeptide FF receptor agonist, DN-9, achieved peripherally restricted analgesia with reduced side effects. To develop stable and orally bioavailable analogues of DN-9, eight lactam-bridged cyclic analogues of DN-9 between positions 2 and 5 were designed, synthesized, and biologically evaluated. <i>In vitro</i> cAMP assays revealed that these analogues, except <b>7</b>, were multifunctional ligands that activated opioid and neuropeptide FF receptors. Analogue <b>1</b> exhibited improved potency for κ-opioid and NPFF<sub>2</sub> receptors. All analogues exhibited potent, long-lasting, and peripherally restricted antinociception in the tail-flick test without tolerance development after subcutaneous administration and produced oral analgesia. Oral administration of the optimized compound analogue <b>1</b> exhibited powerful, peripherally restricted antinociceptive effects in mouse models of acute, inflammatory, and neuropathic pain. Remarkably, orally administered analogue <b>1</b> had no significant side effects, such as tolerance, dependence, constipation, or respiratory depression, at effective analgesic doses.