Opioids in breast cancer: Between analgesia and modulation of tumour progression

Preclinical investigations consistently demonstrate that activation of μ-opioid receptors and δ-opioid receptors promote proliferation, migration, angiogenesis, epithelial-mesenchymal transition, acquisition of cancer stem cell phenotypes, and chemoresistance. Conversely, selected opioids with atypical pharmacological profiles, including tramadol, nalbuphine, and dezocine, as well as antagonists of opioid receptors such as naloxone, naltrexone, and low-dose naltrexone, exhibit antineoplastic and immunomodulatory properties, frequently mediated through noncanonical pathways such as the opioid growth factor-opioid growth factor receptor axis. Clinical findings remain inconclusive: perioperative opioid administration has been variably associated with an increased risk of recurrence, whereas tramadol use has correlated with improved survival outcomes. Notably, while some reports suggest signs of potential risk, other perioperative studies, including large cohorts and randomized trials, have shown neutral or even favourable associations, underscoring heterogeneity across study designs and tumour biology. Interactions between opioids and immunotherapeutic strategies appear particularly critical, as opioids may diminish the efficacy of immune checkpoint inhibition by impairing cytotoxic T lymphocyte activity and natural killer cell function. Taken together, opioids embody a dual role as irreplaceable analgesics and potential modulators of breast cancer progression. Future research requires rigorously designed, prospective, biomarker-driven clinical trials that integrate molecular signatures, receptor expression profiles, and immunological endpoints to determine whether opioid therapy represents a therapeutic liability, an opportunity, or both within contemporary breast cancer management.