Pharmacokinetic/Pharmacodynamic Relationships of Transdermal Buprenorphine and Fentanyl in Experimental Human Pain Models

: Pharmacokinetic/pharmacodynamic (PK/PD) modelling can be used to characterize the relationship between dose regimen of opioids, plasma concentration and effect of opioids, which in turn can lead to more rational treatment regimens of pain. The aim of this study was to investigate the concentration–effect relationship for transdermal buprenorphine and fentanyl in experimentally induced pain. Twenty‐two healthy volunteers were randomized to receive transdermal patches with fentanyl (25 μg/hr, 72 hr), buprenorphine (20 μg/hr, 144 hr) or placebo. The experimental pain tests were pressure at the tibial bone, cutaneous thermal stimulation, cold pressor test (conditioning stimulus (3 ± 0.3°C cold water), nerve growth factor–induced muscle soreness and intradermal capsaicin‐induced hyperalgesia and allodynia. Experiments were carried out at baseline, 24, 48, 72 and 144 hr after application of patches. Time‐course of placebo was described first and was afterwards added to the description of the time‐courses of buprenorphine and fentanyl. This was either described by zero (no drug effect), linear or Emax model concentration–effect relationships. Time‐dependent changes in pain measures in the placebo arm were described by linear or quadratic functions. The time‐course of fentanyl and buprenorphine plasma concentrations was complex but could be represented by cubic spline interpolation in the models. Buprenorphine significantly attenuated bone‐associated pain, heat pain, nerve growth factor–induced soreness and cold pressor pain. Fentanyl significantly attenuated cold pressor pain for the administered dose regimens. Although the PK/PD relationship for both drugs could be described with similar models, tissue‐differentiated analgesic effects between buprenorphine and fentanyl was shown.