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Breast cancer has the greatest epidemiological impact in women. Opioids represent the most prescribed analgesics, both in surgical time and in immediate postoperative period, as well as in chronic pain management as palliative care. We made a systematic review analyzing the literature’s evidence about the safety of opioids in breast cancer treatment, focusing our attention on the link between opioid administration and increased relapses. The research has been conducted using the PubMed database. Preclinical studies, retrospective and prospective clinical studies, review articles and original articles were analyzed. In the literature, there are several preclinical in vitro and in vivo studies, suggesting a possible linkage between opioids administration and progression of cancer disease. Nevertheless, these results are not confirmed by clinical studies. The most recent evidence reassures the safety of opioids during surgical time as analgesic associated with anesthetics drugs, during postoperative period for optimal cancer-related pain management and in chronic use. Currently, there is controversial evidence suggesting a possible impact of opioids on breast cancer progression, but to date, it remains an unresolved issue. Although there is no conclusive evidence, we hope to arouse interest in the scientific community to always ensure the best standards of care for these patients.