This is a series of studies in healthy volunteers to assess the potential for adverse
interactions between St. John's wort (SJW) extract and two narcotic (opioid) pain
medications: oxycodone and fentanyl. In the case of oxycodone, we are interested in whether
SJW treatment promotes the metabolism of oxycodone, such that it lowers the effectiveness of
standard doses of oxycodone in treating pain problems. For the fentanyl study, we will
investigate whether SJW treatment will interfere with the delivery of fentanyl to the brain
and diminish it's effectiveness to relieve pain. There is evidence to suggest that SJW
treatment may increase the activity of a transporter protein, named P-glycoprotein (Pgp), in
the blood-brain barrier (BBB) that protects the brain from exposure to drugs and other
dietary and environmental toxins.
Extract of St. John's wort (SJW: Hypericum perforatum) has gained widespread popularity as
an over-the-counter, natural antidepressant. Until recently, SJW was thought to be well
tolerated and relatively safe. Within the past year, adverse metabolic interactions have
been reported between SJW and several narrow therapeutic index drugs, notably cyclosporine,
indinavir and digoxin. The interactions are now recognized to involve induction of two drug
disposition mechanisms: cytochrome P450 3A4 enzyme and the active efflux pump,
P-glycoprotein, both leading to profound reductions in blood or plasma drug concentration
that compromises the therapeutic efficacy of the affected drug. Natural and synthetic
opioids are the first-line agents for the palliative treatment of severe pain that results
from cancer and cancer treatment. It is well recognized that depression is a co-morbid
condition of severe and poorly controlled cancer-related pain. Given the widespread
recognition of St. Johns wort as a mood enhancer and natural antidepressant, cancer pain
patients receiving opioid analgesics may well turn to this herbal preparation for relief of
The overall objective of this research proposal is to investigate if significant
interactions occur between two widely used opioid analgesics -- oxycodone and fentanyl and
St. John wort extract through laboratory-based studies in healthy volunteers. The studies
will assess the potential clinical significance of the interactions with respect to opioid
analgesia efficacy and side effects, and provide scientific insights into the
pharmacokinetic mechanisms underlying any observed interactions.
The oxycodone arm of the study is designed to 1) investigate the induction of
CYP3A4-mediated N-demethylation which is the major detoxification pathway for oxycodone, and
2) resolve the inductive effects of SJW on intestinal and hepatic CYP3A4 through intravenous
and oral administrations of a CYP3A-specific, in vivo catalytic probe -midazolam.
The fentanyl arm of the study is designed to 1) assess the effects of SJW on the brain
uptake and efflux kinetics of fentanyl through pharmacokinetic-pharmacodynamic (PK-PD)
modeling of miotic response over time during and following intravenous infusion of the
opioid, and 2) To evaluate the changes in analgesia and side effects of fentanyl upon
pretreatment with SJW that may have resulted from induction of Pgp at the BBB.
Overall, the proposed research will provide a definitive assessment of the potential and
clinical significance of adverse interactions between SJW and opioids in the context of
cancer pain therapy.
Healthy male and female volunteers of all ethnic origins, within 25% of ideal body weight,
between ages of 21 and 45 who are literate and proficient in the English language.