Fig. 1

Trial design. The effects of a single oral dose of four different treatments (lacosamide, pregabalin, tapentadol, placebo) on EEG-derived biomarkers of nociceptive processing will be assessed in four separate study periods separated by at least 1 week. In each study period, five blood samples will be taken to model the pharmacokinetic (PK) profiles of the chosen drugs in plasma (P), peripheral nerves (N), spinal (S), and brain (B) compartments (theoretical PK curves shown in gray). After the induction of a hyperalgesic state at the left forearm using HFS, the biomarkers will be assessed at four time-points shown in light red: before drug administration, and at three different times after drug administration, close to the expected maximum drug concentration and at relevantly lower drug concentrations. The biomarkers will be derived from measures of LEPs and PEPs elicited by laser and pinprick stimulation of the sensitized and contralateral non-sensitized limb, and measures of the spectral content of ongoing EEG. Patient-reported outcomes will be used to assess subject expectations (expectation PROMs) and state (state PROMs). Hyperalgesia testing (light blue) will be used to assess and compare the HFS-induced hyperalgesia across study periods and across the different BioPain RCTs