Newly Published
Perioperative Medicine  |   November 2019
Influence of St. John’s Wort on Intravenous Fentanyl Pharmacokinetics, Pharmacodynamics, and Clinical Effects: A Randomized Clinical Trial
Author Notes
  • From the Department of Anesthesia and Operative Services, Madigan Army Medical Center, Tacoma, Washington (M.J.L.); the Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina (E.D.K); the Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (M.J.L., D.D.S.); and the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington (M.C.K.-R., K.S., D.D.S.).
  • Submitted for publication June 3, 2019. Accepted for publication October 25, 2019.
    Submitted for publication June 3, 2019. Accepted for publication October 25, 2019.×
  • Correspondence: Address correspondence to Dr. Loughren: Department of Anesthesia and Operative Services, Madigan Army Medical Center, 9040A Jackson Ave., Joint Base Lewis-McChord, Washington 98431. michael.j.loughren.civ@mail.mil. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Pain Medicine / Pharmacology / Opioid
Perioperative Medicine   |   November 2019
Influence of St. John’s Wort on Intravenous Fentanyl Pharmacokinetics, Pharmacodynamics, and Clinical Effects: A Randomized Clinical Trial
Anesthesiology Newly Published on November 26, 2019. doi:https://doi.org/10.1097/ALN.0000000000003065
Anesthesiology Newly Published on November 26, 2019. doi:https://doi.org/10.1097/ALN.0000000000003065
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • The popular herbal medicine, St. John’s wort, is a potent inducer of several cytochrome P450 enzymes, including CYP3A4, which plays a role in the metabolism of fentanyl. St. John’s wort may also influence the expression of P-glycoprotein, which can alter the movement of drugs across the blood–brain barrier.

What This Article Tells Us That Is New:

  • The pharmacokinetics and pharmacodynamics (pupillary diameter over time) were examined in volunteers before and after treatment with St. John’s wort. No differences were seen, suggesting that this herbal medication does not influence the clinical behavior of fentanyl.

Background: Patients often use complementary and alternative herbal medicines, hence, potential exists for adverse herb–drug interactions. Fentanyl is metabolized by hepatic CYP3A4 and considered transported by blood–brain barrier P-glycoprotein. Both disposition processes could be upregulated by the herbal St. John’s wort. This investigation evaluated effects of St. John’s wort on fixed-dose and apparent steady-state IV fentanyl pharmacokinetics, pharmacodynamics, and clinical effects.

Methods: Healthy volunteers received a fentanyl fixed-dose infusion and an individually tailored target controlled infusion on separate days, before and after 30-day St. John’s wort (300 mg thrice daily; n = 8) or placebo control (n = 8) in a randomized parallel-group design. Fentanyl plasma concentrations, pupil diameter, analgesic response to experimental pain (cold pressor), subjective side effects, and cognitive effects were measured. Plasma fentanyl concentrations and changes in pupil diameter were subjected to pharmacokinetic–pharmacodynamic modeling.

Results: St. John’s wort did not alter fentanyl pharmacokinetics. Clearance (l/min) before and after St. John’s wort (1.13 ± 0.29 and 1.24 ± 0.26, respectively) or placebo (0.96 ± 0.28 and 1.12 ± 0.27, respectively) were not different. St. John’s wort also did not affect fentanyl pharmacodynamics as measured by pupil constriction after fixed-dose and tailored fentanyl infusions. EC50 (ng/ml) was 1.1 ± 0.7 and 1.4 ± 0.9 before and after St. John’s wort versus 1.2 ± 0.8 and 1.4 ± 1.7 before and after placebo. Effect site equilibration time, T½,ke0 (min), was 12.8 ± 5.3 and 11.3 ± 6.4 before and after St. John’s wort versus 11.4 ± 6.4 and 11.1 ± 5.6 before and after placebo. St. John’s wort had no influence on analgesia, cognitive performance, or somatic cognitive–affective effects of fentanyl.

Conclusions: St. John’s wort did not alter fentanyl pharmacokinetics, pharmacodynamics or clinical effects, suggesting no effect on hepatic clearance or blood-brain barrier efflux. Patients taking St. John’s wort will likely not respond differently to IV fentanyl for anesthesia or analgesia.