Kratom and Oxycodone

Rationale

Oxycodone is a well-established semi-synthetic opioid agonist commonly used to treat moderate to severe pain.1 Like other opioids, oxycodone has a high risk for  side effects such as sedation and respiratory depression. Respiratory depression, in particular, is a leading cause of death due to opioid overdose. Side effects of oxycodone can become more of concern when its metabolism is inhibited, leading to increased oxycodone exposure even when used appropriately.1   As such, awareness of factors that can increase oxycodone blood concentrations in the body, including concomitant drugs and natural products is critical.2,3

Kratom (Mitragyna speciosa) is a tropical tree native to Southeast Asia that has been advocated for management of pain, opioid withdrawal, and anxiety due to its stimulant and opioid-like effects. These effects are dose dependent with stimulant effects being prominent at low doses and opioid effects dominating at higher doses. The majority of these effects are a result of its active constituents mitragynine and 7-hydroxymitragynine.4,5   Although historically utilized in Asia, it has recently become more popular in the US. According to the American Kratom Association, it is estimated that 10-16 million people use kratom as an opioid alternative as well as for recreational purposes and to ameliorate opioid withdrawal.6 The natural product’s increase in popularity has led to its listing on the US Drug Enforcement Administration’s (DEA) “Drugs of Concern” due to its sedative and addiction potential; however this was later retracted due to public opposition.7

While kratom poses potential safety concerns related to pharmacodynamic interactions  with select prescription medications, the primary focus of this review is its involvement in pharmacokinetic interactions with prescription medications.8 Ref Research indicates that kratom can inhibit the metabolism of certain medications, potentially leading to elevated blood drug concentrations and severe adverse effects.9 Based on these observations, it is imperative to evaluate the evidence for the potential metabolic inhibitory effects of kratom to minimize the risk of interactions between kratom and oxycodone.

Algorithm

Explanation

Oxycodone undergoes extensive metabolism by multiple metabolic pathways. Its main metabolic pathway is CYP3A; however, it is metabolized by CYP2D6 to a lesser extent. Product labeling for Oxycodone indicates that use of concomitant CYP3A4 and CYP2D6 inhibitors causing an increase in oxycodone concentration and increase in opioid effects.3  Kratom has the potential to inhibit the activity of cytochrome P450s (CYPs), mainly CYP3A4 and CYP2D6. Such inhibition is mediated in part by the abundant alkaloid mitragynine.10 Potential interactions with substrates of these CYPs can lead to potential clinically significant interactions with prescription medications. Accordingly, understanding the supporting evidence for potential kratom-drug interactions described in the literature.

A study published in 2020 investigated the effects of mitragynine on three major cytochrome P450s, specifically CYP2C9, CYP2D6, and CYP3A4. Mitragynine exhibited concentration-dependent inhibition of all three enzymes, with the most pronounced effect observed for CYP2D6.11 A 2021 study showed similar results, as mitragynine and three kratom extracts displayed concentration-dependent inhibition of CYP2C9, CYP2D6, and CYP3A in human liver microsomes (HLMs). At the minimum tested concentration (2 μg/mL), the kratom extracts inhibited CYP2D6, CYP2C9, and CYP3A by 44% to 64%, 24% to 29%, and 15% to 23%, respectively. Mitragynine at its lowest tested concentration (1 μM)  inhibited the same three enzymes (CYP2D6, CYP2C9, and CYP3A) by 57%, 21%, and 26%, respectively. In addition to testing concentration inhibition in HLMs, the three kratom extracts along with mitragynine were also evaluated for their inhibition potential in human intestinal microsomes (HIMs). The study found the kratom extracts at their lowest tested concentrations inhibited CYP3A by 24-25% and 9%, respectively. Lastly, the study found two interesting results from IC50 shifts experiments they conducted. The first is that mitragynine was found to be a strong competitive inhibitor of CYP2D6; the second was that mitragynine showed time dependent inhibition of CYP3A activity. Hanapi et al. reported similar trends showing that mitragynine inhibited CYP2D6, CYP2C9, and CYP3A4, with IC50 values of 0.45±0.33 mM, 9.70±4.80 μM and 41.32±6.74 μM, respectively.12

Aside from the invitro studies showing the inhibitory potential of kratom, there are two potentially risk modifying factors to highlight. The first is the age of patients receiving oxycodone. According to the product labeling for oxycodone, pharmacokinetics studies involving elderly patients ( over 65 years of age) showed increased plasma concentrations due to decreased clearance of oxycodone. It further states respiratory depression as the chief risk for elderly patients treated with opioids. The second risk modifying factor is the renal function of the patient. Since oxycodone is significantly excreted by the kidney, there may be an increase in the risk of adverse reactions due to increased concentrations of oxycodone within in the body.3

Lastly, a clinical trial is underway to understand how kratom affects the metabolism of oxycodone and how this potential pharmacokinetic interaction may alter the effects of oxycodone. The study will evaluate oxycodone as a dual cytochrome P450 substrate of CYP2D6 and CYP3A. Results from the study will further shape the clinical decision support algorithms involving this interaction.13

Artifacts for implementers

Click to view our experimental Kratom-Oxycodone CDS App

References

  1. Barrett JE, Shekarabi A, Inan S. Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments. Pharmacol Rev. 2023 Nov;75(6):1062-1118. doi: 10.1124/pharmrev.121.000506. Epub 2023 Jun 15. Erratum in: Pharmacol Rev. 2023 Dec 15;76(1):195. PMID: 37321860; PMCID: PMC10595024.
  1. Huddart R, Clarke M, Altman RB, Klein TE. PharmGKB summary: oxycodone pathway, pharmacokinetics. Pharmacogenet Genomics. 2018;28(10):230-237. doi:10.1097/FPC.0000000000000351
  2. OxyContin (oxycodone) extended-release tablets [prescribing information]. Stamford, CT: Purdue Pharma LP; October 2021. https://www.fda.gov/media/131026/download
  3. Garcia-Romeu A, Cox DJ, Smith KE, Dunn KE, Griffiths RR. Kratom (Mitragyna speciosa): User demographics, use patterns, and implications for the opioid epidemic. Drug Alcohol Depend. 2020 Mar 1;208:107849. doi: 10.1016/j.drugalcdep.2020.107849. Epub 2020 Feb 3. PMID: 32029298; PMCID: PMC7423016.
  4. Prozialeck WC, Jivan JK, Andurkar SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. J Am Osteopath Assoc. 2012;112(12):792–799. [PubMed: 23212430]
  5. Henningfield JE, Grundmann O, Babin JK, Fant RV, Wang DW, Cone EJ. Risk of death associated with kratom use compared to opioids. Prev Med. 2019 Nov;128:105851. doi: 10.1016/j.ypmed.2019.105851. Epub 2019 Oct 21. PMID: 31647958.
  6. Schimmel J, Amioka E, Rockhill K, Haynes CM, Black JC, Dart RC, Iwanicki JL. Prevalence and description of kratom (Mitragyna speciosa) use in the United States: a cross-sectional study. Addiction. 2021 Jan;116(1):176-181. doi: 10.1111/add.15082. Epub 2020 Apr 28. PMID: 32285981.
  7. Tanna RS, Tian DD, Cech NB, et al. Refined prediction of pharmacokinetic kratom-drug interactions: time-dependent inhibition considerations. J Pharmacol Exp Ther. 2021;376(1):64–73. [PubMed: 33093187]
  8. Tanna RS, Cech NB, Oberlies NH, Rettie AE, Thummel KE, Paine MF. Translating Kratom-Drug Interactions: From Bedside to Bench and Back. Drug Metab Dispos. 2023 Aug;51(8):923-935. doi: 10.1124/dmd.122.001005. Epub 2023 Jun 7. PMID: 37286363; PMCID: PMC10353077.
  9. Warner ML, Kaufman NC, Grundmann O. The pharmacology and toxicology of kratom: from traditional herb to drug of abuse. Int J Legal Med. 2016;130:127–38.
  10. Todd DA, Kellogg JJ, Wallace ED, et al. Chemical composition and biological effects of kratom (Mitragyna speciosa): in vitro studies with implications for efficacy and drug interactions. Sci Rep. 2020;10(1):19158. [PubMed: 33154449]
  11. Hanapi NA, Ismail S, Mansor SM. Inhibitory effect of mitragynine on human cytochrome P450 enzyme activities. Pharm Res. 2013;5:241–6.
  12. Evaluating a Potential Pharmacokinetic Kratom-oxycodone Interaction Concurrent with Clinical Endpoints. Identifier NCT05846451. U.S. National Library of Medicine. 2023-. https://classic.clinicaltrials.gov/ct2/show/study/NCT05846451 (accessed 2023-12-16).

Authorship

Author: Dr. Kojo Abanyie with input from Dr. Daniel Malone, Dr. Mary Paine, and Dr. Ainhoa Gomez Lumbreras

Email: koa27@pitt.edu

Date: March 25, 2024