Naloxone and Naltrexone as Potential Adjuvants for Vaccination Against Intracellular Pathogens: A Narrative Review

BACKGROUND: Adjuvants potentiate adaptive immunity by enhancing antigen-specific immune responses, yet many exhibit high toxicity for clinical use. Naloxone (NLx) and naltrexone (NLt) opioid receptor antagonists have emerged as promising adjuvants in preclinical vaccination models against intracellular pathogens. OBJECTIVE: This narrative review synthesizes evidence from 2000 to 2025 evaluating NLx/NLt as adjuvants against bacterial, viral, and parasitic infections, while examining proposed immunoregulatory mechanisms. METHODS: A comprehensive search of Web of Science, PubMed, Scopus, ScienceDirect, and ProQuest employed Boolean operators combining: (vaccine OR vaccination) AND (adjuvant) AND (naloxone OR naltrexone OR NLx OR NLt OR "opioid receptor antagonist") AND ("immune response" OR "cellular immunity" OR "Th1"). RESULTS: Key findings demonstrate that NLx/NLt monotherapy or combinatorial use with Alum consistently, enhanced Th1 polarization and cellular immunity, Elevated pathogen clearance and protection rates, synergistically overcame Alum's Th2 bias. Mechanistically, μ-opioid receptor (MOR) antagonism disrupts tonic immunosuppression, reversing opioid-mediated inhibition of dendritic cell maturation, IL-12 production, and cytotoxic T-cell function. CONCLUSIONS: This immunorestorative action positions NLx/NLt as strategic adjuvants for vaccines targeting intracellular pathogens requiring robust cell-mediated immunity. Future horizons include combinatorial platforms (e.g. DNA vaccines + low-dose naltrexone) and clinical translation.