The patient is currently taking mitragynine
Interaction found with [oxycodone hydrochloride 10 mg oral capsule]
| CrCl Function (ml/Min) | ||||
| Kidney failure | Severely decreased | Moderately to severely decreased | Mildly to moderately decreased | Normal to high |
Consider alternative pain medications such as NSAIDs or acetaminophen. If an opioid is indicated, can consider hydromorphone, oxymorphone, and morphine as their metabolism is not dependent on CYP3A4 and CYP2D6.
Oxycodone is a substrate of CYP2D6 and CYP3A4. Concomitant use with kratom can lead to potentially severe adverse events such as respiratory depression due to inhibition of these key enzymes. Factors such as renal function and age can affect the potential severity of any adverse effects. The risk of a serious adverse event may be reduced by minimizing additional risk (e.g. nephrotoxin use) or discontinuing the offending natural product.
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.1 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.2 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 CYP2D6.3 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.4
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.1
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.5
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