Approximately one-third of buprenorphine is metabolized predominantly by cytochrome P450 3A4 in the liver, yielding the active metabolite norbuprenorphine – about 40 times less potent [
1]. It is known from animal studies that norbuprenorphine possesses an analgesic effect and has high affinity for δ-receptors [
36,
37].
Nevertheless, the contribution of norbuprenorphine to the central clinical effect of buprenorphine is questionable as norbuprenorphine is less lipophilic and thereby does not readily cross the blood–brain barrier, at least after acute administration [
38,
39]. On the other hand, a study in sheep demonstrated that norbuprenorphine might contribute to the central effect of buprenorphine. In that study, significant respiratory depression was demonstrated after administration of norbuprenorphine [
40]. In the present study, norbuprenorphine was measurable in the plasma after 24hr and stayed stable over the treatment period. Nevertheless, the measured plasma concentration of norbuprenorphine was three times lower than the measured plasma concentration of buprenorphine. Both drugs were detectable over the period of time where blood samples were collected. The contribution of norbuprenorphine to the analgesic effect after transdermal administration of buprenorphine could not be distinguished in the present study and might not be of importance in the present study.