By combining drugs with different mechanisms of action, synergistic effects may be achieved. The aim of the present experimental pain study was to combine paracetamol with dextromethorphan for synergistic effects. Furthermore, the reproducibility of the pain assessment methods was evaluated. Eighteen volunteers completed all periods in a three-way cross-over study. Pain stimuli were assessed at baseline and 1, 2 and 3 hr after dosing. The aim was to compare the pain-alleviating effect of 1 g paracetamol, 1 g paracetamol plus 30 mg dextromethorphan and placebo in response to a number of different stimuli in a human experimental volunteer model of skin and muscle pain. Repeated electrical stimulation of skin and muscle (temporal summation) modelled central integration and intramuscular hypertonic saline mimicked musculoskeletal pain. The method provided statistically stable pain recordings between repetitions on the same day and between days (all P > 0.05). Between repetitions on the same day, all tests were reproducible within the participants (intra-class correlation > 0.60). Between days all tests, except muscular pain pressure threshold, were reproducible within the participants (intra-class correlation > 0.60). There were no statistical differences (all P > 0.05) between paracetamol compared to placebo, and between the effect of paracetamol and dextromethorphan compared to placebo. The acute pain models were not sufficiently sensitive to detect an analgesic effect of paracetamol or the combination with dextromethorphan. The selected dose of dextromethorphan was low as the aim was to use commonly used doses, and a higher dose of dextromethorphan is most likely needed to attenuate the selected pain measures.