Despite the high burden of pain experienced by hospitalised infants there are few analgesics with proven efficacy. Testing analgesics in infants is experimentally and ethically challenging and minimising the number of infants required to demonstrate efficacy is essential. EEG-derived measures of noxious-evoked brain activity can be used to assess analgesic efficacy, however, as variability exists in infant’s responses to painful procedures, large sample sizes are often required. Here we present a novel experimental paradigm to account for individual differences in baseline nociceptive sensitivity which can be used to improve the design of analgesic trials in infants. The paradigm is developed and tested across four studies using clinical, experimental and simulated data (99 infants). We provide evidence of the efficacy of both gentle brushing and paracetamol, substantiating the need for randomised controlled trials of these interventions. This work provides an important step towards safe, cost-effective clinical trials of analgesics in infants.