We investigated a possible interaction between topic analgesic treatment and treatment expectation on pain at the behavioral and neuronal level by combining topical lidocaine-prilocaine treatment with an expectancy manipulation in a 2-by-2 within-subject design (open treatment, hidden treatment, placebo, control). 32 healthy subjects received heat pain stimuli on capsaicin pretreated skin and rated their experienced pain during functional magnetic resonance imaging. This allowed us to separate drug- and expectancy-related effects at the behavioral and neuronal level and to test whether they interact during the processing of painful stimuli. Pain ratings were reduced during active treatment and were associated with reduced activity in the anterior insular cortex. Pain ratings were lower in open treatment compared to the hidden treatment and related to reduced activity in the anterior insular cortex, the anterior cingulate cortex, the secondary somatosensory cortex and the thalamus. Testing for an interaction revealed that the expectation effect was significantly larger in the active treatment conditions compared to the no-treatment conditions and was associated to signal changes in the anterior insular cortex, the anterior cingulate cortex and the ventral striatum. In conclusion, this study shows that even in the case of a topic analgesic, expectation interacts with treatment at the level of pain ratings and neuronal responses in placebo-related brain regions. Our results are highly relevant in the clinical context as they show (i) that expectation can boost treatment and (ii) that expectation and treatment are not necessarily additive as assumed in placebo controlled clinical trials.