For the symptomatic treatment of pain in patients with therapy-refractory rheumatoid arthritis (RA) and persisting pain opioids are indicated. However, there are no placebo-controlled studies on the efficacy and tolerance of opioids. Thus, in line to the criteria of evidence based medicine we have examined for the first time whether tilidine/naloxone is more effective than placebo in reducing pain. In a double-blind, randomized, placebo-controlled pilot study, the effect of tilidine/naloxone on the number of painful and swollen joints as well as on pain and sleep disturbances was examined. With regard to impact on quality of life the short form of the McGill pain questionnaire was used, with regard to tolerance, the number of adverse events was recorded. A total of 20 patients with rheumatoid arthritis was enrolled in the study. The data for 19 patients (13 male, 6 female, average age 58 years) were available for evaluation. In the tilidine/naloxone group 11 patients took on average 339 mg tilidine/naloxone per day while 8 patients received a placebo. After 6 weeks of treatment there were significant differences in favor of the verum group concerning intensity of pain (decrease from 7.2 to 3.9 measured on a visual analog scale, p = 0.05), number of painful joints (decrease from 14 to 8, p = 0.038), and quality of sleep (p = 0.04). Adverse events occurred in 9 patients (6 on tilidine/ naxolone vs. 3 on placebo). In the tilidine/naxolone group 5 patients finished the study prematurely (2 because of an insufficient effect and 3 because of side effects) as compared to 2 patients in the placebo group (insufficient effect). In conclusion, tilidine/naxolone led to a significant reduction of pain, improvement of quality of sleep and improvement of the general state in rheumatoid arthritis patients. In the verum group only 1 of 11 patients dropped out due to an opioid-typical side effect. For all other patients the reason for prematurely termination were adverse side effects for which an association with the medication was considered unlikely. Thus, tilidine/naxolone is well tolerated and effective in reducing pain in patients with rheumatoid arthritis.