OBJECTIVES: To evaluate the tolerability of oral long-acting opioids (LAOs) in patients treated for chronic pain. Opioid analgesia is the mainstay of treatment for moderate to severe chronic pain. While highly effective in relieving pain, it is limited by adverse events (AEs), especially gastrointestinal and central nervous system events. AEs may result in additional treatment costs and discontinuation of therapy, compromising pain management. METHODS: A systematic review of English-language literature published through February 2009 was performed. Randomized controlled trials comparing commonly used oral schedule II LAOs with placebo or another opioid were included. Data on pain measures and pre-specified AEs (nausea, vomiting, somnolence, constipation, headache, pruritus, and dry mouth) were collected from each study. For descriptive statistics, treatment-arm data on tapentadol, oxycodone, oxymorphone, morphine, hydromorphone, and placebo were pooled across trials. Direct and indirect meta-analyses were performed to compare AE rates of individual LAOs with placebo and with tapentadol. RESULTS: Seventy-one published studies met the inclusion criteria. Tapentadol was associated with the lowest incidence of AEs across the 5 LAOs, with the exception of headache and dry mouth. The AE incidences for tapentadol, oxycodone, oxymorphone, morphine, hydromorphone, and placebo were: nausea: 19.5%, 32.5%, 38.8%, 29.7%, 33.5%, and 8.4%, respectively; vomiting: 7.9%, 16.1%, 19.9%, 15.5%, 15.1%, and 2.4%; somnolence: 10.2%, 24.8%, 18.3%, 33.6%, 50.4%, and 3.7%; constipation: 14.1%, 34.7%, 26.9%, 43.2%, 27.6%, and 6.1%; headache: 13.3%, 11.3%, 9.7%, 3.8%, 5.7%, and 10.4%; pruritus: 5.2%, 16.6%, 15.7%, 20.1%, 20.8%, and 1.5%; and dry mouth: 6.8%, 11.8%, 10.0%, 31.4%, and 2.6% (placebo), with no data for hydromorphone. Indirect meta-analyses further revealed a significantly favorable tolerability profile of tapentadol when compared to oxycodone, oxymorphone, and morphine. CONCLUSIONS: Opioid-associated AEs are common, but the incidence varied across the LAOs reviewed. Indirect meta-analyses suggest that tapentadol has a better tolerability profile than other LAOs.