The aim of this study was to examine and compare the efficacy and safety of combining strong opioids (transdermal fentanyl) with weak opioids (codeine or tramadol) for the management of severe cancer pain. Forty six patients (25 male / 21 female) aged 42-80 years were studied. According to an eleven-grade numeric rating scale (NRS; 0 = no pain, 10 = severe pain), they all had severe steady pain intensity greater than 5 (NRS >5) despite treatment with weak opioids and adjuvant drugs, as proposed by the 2nd step of the World Health Organization (WHO) analgesic ladder, at the maximum tolerated doses. Enrollment to the 3rd step of the ladder and initiation of transdermal fentanyl (fentanyl-TTS) was decided and informed consent was obtained by all subjects. They were randomly divided into 3 groups: group F (n=15), which constituted the control group, received fentanyl-TTS alone, group C (n=17) received combined codeineacetaminophen (Lonalgal®) tablets in addition to fentanyl-TTS and group T (n=14) had tramadol capsules administered along with fentanyl-TTS. The above additional drugs were given at equipotent doses every 12 hours. All patients were informed so as to increase fentanyl-TTS dosage by 25μg/h/72h in cases of high steady pain intensity (NRS >4). Oral transmucosal fentanyl citrate was prescribed for possible acute pain episodes. A month later, the following parameters were recorded: pain intensity, final dosage of fentanyl-TTS, daily dosage of transmucosal fentanyl citrate, drug-related side effects and patients’ judgment of treatment. Statistically significant results were recorded for pain intensity at the end of the study (p<0.05) compared to pain intensity immediately before enrollment but without significant differences among the studied groups (p>0.05), as well as for mean final dosage of fentanyl-TTS in groups C (p<0.01) and T (p<0.05) compared to the relative dosage in group F. Favorable but not statistically significant (p>0.05) results were recorded for the rest of the endpoints apart from the adverse effects of the drugs used; nausea, vomiting and to a lesser extent constipation and somnolence were seen. In conclusion, the combination of either tramadol or codeine-acetaminophen with fentanyl-TTS were proven to be useful alternatives for long-term treatment of severe cancer pain for patients placed at the 3rd step of the WHO analgesic ladder, probably sparing the need for opioid switching or route rotation. Nevertheless, drug-related side effects were not limited. Moreover, due to lack of sufficient studied data we would not recommend any similar combinations for the management of severe cancer pain.