Although oral morphine is the gold standard in the front-line approach to moderate-severe cancer pain, transdermal opiates are largely used in clinical practice. Aims of our work were to review the evidences of literature supporting these different habits and to suggest an evidence-based criterion to guide clinical research and clinical practice. A systematic review of literature with meta-analysis of the safety data reported in randomized clinical trials comparing slow releasing oral morphine and transdermal opiates was performed using the random effect model. The quality of the evidences supporting the use of the different strategies and the strength of the recommendations was analyzed using the GRADE method. A significant advantage in favor of transdermal opiates was observed for constipation, urinary retention, need of laxative use and patient's preferences; a significant advantage in favor of slow releasing oral morphine was observed for diarrhea and sweating. The quality of the evidences supporting a front-line use of transdermal fentanyl was considered low, while those supporting the use of transdermal buprenorphine was considered very low. For the use oftransdermal fentanyl and for that oftransdermal buprenorphine a weak and a strong recommendation against their us as front-line treatment of moderate-severe cancer pain can be respectively obtained from the literature data. Transdermal opiates represent a safety and effective alternative to oral morphine against cancer pain, but they can not replace oral morphine as the gold standard first-line treatment of moderate-severe cancer pain.