Long-term cancer survivors develop special health issues and specific needs. Chronic pain, whether the consequence of their cancer or as a side effect of treatment, is one of their most prevalent concerns. We conducted a review of the English-language literature on long-term cancer survivorship and chronic opioid therapy, with the objective of determining the efficacy, safety and tolerability in this group of patients. Practical management recommendations are made on the basis of this review. Pain syndromes encountered in the long-term cancer survivors are diverse. Opioid receptor pathways possess complex and pleiotropic functions and continuous over-activation may lead to de novo endocrinopathies, immunosuppression, neurocognitive impairment, or cell cycle disturbances with potential clinical connotations. However, there are insufficient data to support evidence-based decision making with respect to patient selection, doses, administration, monitoring and follow-up. Data about long-term treatment effectiveness and safety are limited and often aggravated by the overlapping of several diseases prevalent among long-term cancer survivors, as well as chronic opiate-induced toxicity. Chronic opioid therapy is frequent in long-term cancer survivors, and may negatively affect the immune system, and produce health problems such as endocrinopathies, osteoporosis, neurological or cardiopulmonary effects, alterations of cell cycle kinetics, abuse and addiction. This review highlights the need for specialized teams to treat chronic pain in long-term cancer survivors from an integrative perspective.