Commentary on Stam et al.: The substantial and dynamic contribution of opioid potency to total overdose risk

A mere 30 years ago, opioid overdose was considered an inevitable consequence of opioid use. People who use drugs, service providers and investigators leveraged lived experience and research findings to serve the lie to this fatalistic misconception and create a field of overdose prevention that is now a major component of how many countries respond to substance use. Naloxone provision, medications for opioid use disorder (MOUD) and safe consumption spaces are prototypical interventions in this domain. However, our ability to measure the impacts of these interventions remains nascent. Stam et al. [1] provide a significant contribution to that evolution by examining overdose rates by day at a supervised injecting facility.

There are multiple contributors to opioid overdose and overdose mortality rates. Using Norman Zinberg's construct of drug, set and setting, we can identify diverse potential factors (Figure 1) [2]. Addressing these in reverse order, ‘setting’ refers to the environment within which opioid use occurs. The illegal status of street opioids creates an unregulated market that is notoriously unstable, stigmatized [3], under constant pressure from law enforcement [4] and associated with other socio-economic pressures such as poverty, housing crises and structural racism. Issues as simple as using opioids in an unfamiliar place may lower one's tolerance to the drug [5], and interventions to improve on environmental factors include better access to naloxone, MOUD and safe consumption spaces [6]. ‘Set’, or one's internal conditions, is most often thought of as opioid tolerance [7]. Recent abstinence has long been associated with opioid overdose and maintaining a tolerance to opioids with MOUD is among our most effective prevention interventions. Data from anesthesiology research also demonstrate a clear genetic contribution to opioid overdose risk [8], and co-morbid health conditions such as cardiovascular and pulmonary disease contribute some amount to risk [9]. Suicidality, thought of as a spectrum of behavior from negligence to planned self-harm, is a factor with the latter contributing to approximately 15% to 20% of opioid overdose events [10]. Mental health disorders and personal trauma also contribute [2].

‘Drug’ factors contributing to overdose include polypharmacy, with sedating substances raising risk for opioid overdose by negating the protection of opioid tolerance [11]. Route of administration is also relevant, as injecting heroin is associated with a 4-fold higher rate of overdose than sniffing or smoking the drug [12], leading some harm reduction programs to encourage transitions from injecting to smoking. Although such a transition appears less protective for people using fentanyl, emerging data suggest an approximately 15% reduction in overdose risk when fentanyl is exclusively smoked instead of injected [13]. Supervised injection sites have previously established that heroin is approximately twice as risky as prescription opioids with regard to overdose and fentanyl is approximately four times as risky as heroin [14]. Moreover, Darke et al. [15] long ago determined that both potency and variations in potency of heroin were moderately associated with overdose risk. Stam et al.’s [1] data suggest that the actual contribution of potency may be much greater, with up to a 10-fold difference in one's overdose risk on days when more people are overdosing, presumably representing days when opioids are either more potent or undergoing substantial variation in potency. No other factor has been documented to have such influence on overdose risk.

Most notably, however, this estimate comes from a region without substantial fentanyl sold on the street. Throughout North America, opioid overdose mortality consistently increased by 4- to 5-fold as fentanyl replaced heroin as the dominant street opioid [16]. Models of the effectiveness of naloxone in reducing opioid overdose mortality are highly sensitive to the prevalence of fentanyl use; naloxone programming that reaches nearly all people using opioids would be expected to reduce heroin and fentanyl overdose mortality by 26% and 12%, respectively [16]. Given the universal increase in mortality rates wherever fentanyl comes to replace other opioids, this weakened response to evidence-based interventions likely extends to MOUD, safe consumption spaces and other overdose prevention strategies. The potency and variability in potency of fentanyl is so extreme, relative to heroin, that it may overwhelm other risk factors, leaving less room for extant prevention interventions to have a meaningful impact.

Our ability to influence and predict opioid overdose patterns remains limited. Stam et al. [1] remind us of the power the street opioid market has over this tragic outcome and the importance of not promising more than public health can deliver. The proportional impact of potency and variable potency on overdose risk is likely not static, but dynamic, depending on the available opioids. Additional research and a new era of mathematical modeling of overdose are needed to improve our ability to predict overdose patterns and better estimate the impact of prevention interventions.

None.