Volume 180 issue 7 of the British Journal of Pharmacology is a themed issue on advances in opioid pharmacology at the time of the opioid crisis. In last week’s PAAD (March 21, 2023), Vidya and I discussed how, based on its pharmacology, fentanyl was different than other mu-agonist opioids like morphine. In today’s PAAD we will discuss why combining benzodiazepines with oxycodone can be so deadly. For regular readers of the PAAD, this shouldn’t be a surprise. I’ve been advocating for months for co-prescribing intranasal naloxone whenever outpatients at high risk of respiratory depression or opioid abuse are discharged home. Patients at high risk include patients with sleep disordered breathing, teenagers either as the patient or living in the patient’s home, or patients of any age discharged home on both oxycodone and any benzodiazepine. All of us who have practiced “It’s OK anesthesia” in the elderly patient undergoing cataract surgery have experienced that sinking experience when fentanyl is followed by just a bit of midazolam. Suddenly, the patient loses consciousness and stops breathing. Additionally, in patients of all ages we’ve known that the combination of oxycodone and any benzodiazepine is equally dangerous. But why? In today’s PAAD, a pharmacologic explanation for this oxycodone- benzodiazepine drug-drug interaction is presented. It’s an eye opener!
An important disclaimer: As you will shortly see, one of the active metabolites of oxycodone is oxymorphone. In fact, oxymorphone is 2-3 times more potent than oxycodone. Endo pharmaceuticals manufactures oxymorphone under the brand name is Opana. As way of full disclosure, I was a consultant to ENDO when oxymorphone was being developed as both an immediate and extended release oral preparation (around 2005-2015). Myron Yaster MD
Original article
Roland Lawson, Petra Čechová, Eliès Zarrouk, James Javellaud, Václav Bazgier, Michal Otyepka, Patrick Trouillas, Nicolas Picard, Pierre Marquet, Franck Saint-Marcoux, Souleiman El Balkhi. Metabolic interactions of benzodiazepines with oxycodone ex vivo and toxicity depending on usage patterns in an animal mode. Br J Pharmacol. 2023 Apr;180(7):829-842 PMID: 34855983
As way of background, “diazepam is biotransformed to either nordazepam by CYP2C19 or CYP3A4, or temazepam by CYP3A4. Both nordazepam and temazepam are in turn hydroxylated and N-demethylated, respectively, into oxazepam, an active metabolite.(Note: from MY: Serax the brand name for oxazepamwhich is a benzodiazepine that was (is?) often used in patients with liver failure because it does not require liver metabolism for its effects or excretion.) Oxycodone is known to be biotransformed into noroxycodone and oxymorphone by CYP3A4 and 2D6, respectively. The former N-demethylation pathway (oxycodone to noroxycodone) represents 47% of the transformation of oxycodone. The minor metabolite, oxymorphone can also be biotransformed by CYP3A4 into noroxymorphone”.1 Oxymorphone is an active metabolite, is 2-3 times more potent than oxycodone, and has 40-fold higher affinity to μ-opioid receptors than oxycodone.2 Usually, the amount of oxymorphone produced from oxycodone metabolism is insignificant. On the other hand, if the metabolism pathway favors CYP2D6 as will occur with benzodiazepine co-administration, more oxymorphone will be produced than “normal”. Although not discussed in the article, the effects of CYP2D6 phenotypes could also modify the effect of oxycodone in CYP2D6 poor metabolizers and oxymorphone in ultra metabolizer phenotypes, with reduced need for oxycodone for similar analgesia. Just think how CYP2D6 affects codeine metabolism.
This study was conducted in mice and in silico. “In mice, in acute conditions, both diazepam and diclazepam (a designer drug used illicitly mostly in Europe) inhibited the metabolism of oxycodone. In chronic conditions and at pharmacologically equivalent doses, diclazepam drastically enhanced the production of oxymorphone, an active metabolite. In silico, the affinity of benzodiazepines was higher than oxycodone for CYP3A4, inhibiting oxycodone metabolism through CYP3A4. Oxycodone metabolism is likely to be diverted towards CYP2D6”1 and thereby increases the production of oxymorphone. Thus, “acute doses of diazepam or diclazepam result in the accumulation of oxycodone, whereas chronic administration induces the accumulation of oxymorphone, the toxic, active metabolite. This suggests that overdoses of opioids in the presence of benzodiazepines are partly due to metabolic interactions, which in turn explain the patterns of toxicity dependent on usage”.1 This is demonstrated in the following figure from the paper.
Hopefully future studies will look at these drug-drug-interactions with other benzodiazepines and mu-agonist opioids at clinically relevant doses.
PS from Myron: When taking Board qualifying exams and you see CYP 2D6, the answer historically is codeine metabolism to morphine. However, as of today, you know oxycodone is also metabolized by the 2D6 (and 3A4) pathways.
References
1. Lawson R, Čechová P, Zarrouk E, et al. Metabolic interactions of benzodiazepines with oxycodone ex vivo and toxicity depending on usage patterns in an animal model. British journal of pharmacology. Apr 2023;180(7):829-842. doi:10.1111/bph.15765
2. Klimas R, Witticke D, Elin Fallah S, Mikus G. Contribution of oxycodone and its metabolites to the overall analgesic effect after oxycodone administration. Expert Opin Drug Metab Toxicol. May 2013;9(5):517-28. doi:10.1517/17425255.2013.779669