Opioid Tolerance in the Time of Fentanyl

"Using drug samples from the real-world illicit drug supply in the Los Angeles area, we found that one gram of a raw product understood to be “fentanyl” in fact contained a range of < 1 mg to almost 650 mg of fentanyl. Survey data from people who report recent, regular fentanyl use, report using about 1 g of raw product use per day on average, consistent with previous estimates (Ciccarone et al., 2024). Combining these parameters, we estimate that a typical consumer of illicit fentanyl uses the equivalent of almost 9000 milligrams of oral morphine daily, an extraordinary amount when considered in light of treatment guidelines that discourage doses in excess of 90 milligrams daily for the treatment of chronic pain (Dowell et al., 2016).

"It is generally recognized that as a result of tolerance, opioids have no set upper dose threshold, and that usage quantities can escalate rapidly among individuals with OUD who have ample access to opioids. It has also been previously described that the illicit market shift from heroin to illicit fentanyl drastically increased the potency of illicit opioid products, a key factor in skyrocketing rates of overdose and mortality (Ciccarone, 2017, Friedman and Shover, 2023). To our knowledge, this analysis represents the first effort to quantify these phenomena in estimated MME consumed per day among individuals consuming illicit opioids in the fentanyl era.

"The advent of community-based drug checking techniques provides a powerful opportunity to open the ‘black box’ of illicit drug products, and quantify drug contents with accuracy and precision (Bailey et al., 2023, Delaney et al., 2023). We find that the typical product sold in Los Angeles as fentanyl, and expected to be illicit fentanyl, is about 12.5% pure. One gram of this product, sold for approximately $100 USD in Los Angeles, would contain about 125 mg of active fentanyl, roughly 100-fold higher than a typical daily amount used for IV analgesia in an opioid-naïve adult. However, purity of illicit fentanyl samples in Los Angeles is also highly variable, ranging from 0.1% to almost 65% among quantified samples. A gram of illicit fentanyl could therefore contain from less than 180 MME to almost 120,000 MME. Assumptions about bioavailability, MME conversion factors, and the correlation between parameters, do influence the overall estimated dosage. However, under all plausible scenarios, individuals consuming illicit fentanyl in Los Angeles on average appear to be consuming MME ranges many orders of magnitude above clinical dosing regimens.

"This high—and highly variable—potency illustrates the impact of illicit fentanyl on the risk environment for people with OUD. The extraordinarily elevated overdose risk in the fentanyl era can be understood, in part, as a logical consequence of extreme variations in purity, wherein a gram of street product can vary wildly in its overall opioid content."