Herb-Opioid Interactions
Condition: Pain
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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 depressive symptoms.

      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.
    

Intervention name(s): St. John's Wort; oxycodone; fentanyl
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Fentanyl; Oxycodone
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Single
Primary purpose: Diagnostic
Keywords: opioid; St. John's wort; analgesia; metabolism; transporter