OBJECTIVES: To assess the cost-effectiveness of tapentadol PR compared to opioids (morphine, oxycodone, transdermal buprenorphine [TDB] and transdermal fentanyl [TDF]) for the treatment of severe chronic non-cancer pain from the societal perspective in Portugal. METHODS: A one year Markov transition state model with monthly cycles was built. Four health states were defined: ‘no withdrawal and no adverse events treated’, 'occurrence of adverse events (AEs) with need for medical treatment', 'withdrawal due to AEs', and ‘withdrawal due to lack of efficacy'. If patients did not adequately respond to treatment or withdraw, switching to alternative second line opioid (morphine, hydromorphone, TDB or TDF) was considered. Third line therapy was the absorption state. Data regarding efficacy, tolerability and utility values (EQ-5D) were derived from clinical trials and published literature. Switch rates to subsequent opioid therapies and resource consumption were estimated by clinical experts. Costs were calculated from the societal perspective. Direct costs were calculated based on official Portuguese prices/tariffs, indirect costs derived from the National Health Survey. One-way and probabilistic sensitivity analyses were conducted. RESULTS: Mean annual total costs per patient amounted to 3793 € for morphine, 3,804€ for TDF, 3891 € for TDB, 3964 € for oxycodone, and 4117 € for tapentadol. Total QALYs generated were 0.6102 (morphine), 0.6062 (TDF), 0.6026 (TDB), 0.6096 (oxycodone), and 0.6287 (tapentadol). The resulting ICERs (€/QALY gained) for tapentadol yield 7,995 versus oxycodone, 8,685 versus TDB, 13,943 versus TDF, and 17,547 versus morphine. Varying costs, probabilities, and utilities by ±50%, ±10%, and ±10%, respectively, resulted in an ICER range from tapentadol being dominant (vs. oxycodone) to 26,000 €/QALY gained (vs. morphine). CONCLUSIONS: To improve pain relief and quality of life in patients with severe chronic pain tapentadol appears to be the favourable and cost-effective treatment option from the societal perspective in Portugal.