Variations in treatment effects between drug trials are usually attributed to different patient characteristics, variations in outcome assessment, and random error. We have previously hypothesized that part of the variation in treatment effects between drug trials might be caused by differences in nonspecific factors. In a randomized clinical trial, we aimed to investigate whether experimentally induced expectancy can modify the analgesic effect of tramadol relative to placebo in chronic pain patients. In a 2 x 2 factorial, randomized, placebo-controlled, double-blind trial, chronic pain patients attending a chronic pain outpatient clinic were randomized to receive a single oral dose of 50 mg tramadol or placebo, and they were further randomized to receive positive or neutral information, verbally expressed by the physician, regarding the expected analgesic effect of the drug. Pain intensity was measured using a 10 centimeter visual analogue scale at baseline, and 0.5, 1, 2, 4, 6, and 8 hours after baseline. The one-hour pain intensity difference, calculated as the sum of pain intensity differences between baseline and 0.5 and 1 hour, was taken as main outcome measure. The one-hour sum of pain intensity differences of 28 patients treated after positive expectation and randomized to tramadol was 1.4 cm, while in 27 patients randomized to placebo, it was 0.8 cm. This corresponds with an analgesic effect of tramadol relative to placebo of 0.6 cm (95% confidence interval [CI], -0.5 cm to 1.8 cm). The 28 patients in the neutral expectancy group who were randomized to tramadol reported a 1.4 cm decrease on the sum of pain intensity differences, while 28 patients in the placebo group reported a 0.9 cm decrease. This corresponds with an analgesic effect of tramadol relative to placebo of 0.5 cm (95% CI, -0.9 cm to 1.8 cm). The 0.1 cm difference (0.6 cm - 0.5 cm) in analgesic effect between positive and neutral expectancy group was not statistically significant (95% CI, -0.7 cm to 1.0 cm). This trial did not discern a significant difference in the analgesic effect of tramadol between a positive and neutral expectancy group. This means that the phenomenon either does not exist, or we had an inappropriate model to demonstrate it. Regardless, this study demonstrates the type of quality trial that should be done to find out which non-specific factors, such as information regarding the expected effect, can modify treatment effects.