youThe US Centers for Disease Control and Prevention (CDC) estimates that 107,477 drug-related deathsThey occurred between August 2021 and August 2022, and most were attributed to the powerful synthetic opioid fentanyl. These provisional estimates reflect a modest decrease (2.57%) from the previous year, defying an increasing trend that has persisted for the past 20 years, where opioids have been the main driver of overdose deaths. Through its evolutions, the current opioid epidemic has proven to be a constantly moving target, and much remains to be learned to curb fentanyl exposure and overdose.
The origins of the current opioid epidemic are now well known. In the early 1990s, the liberal prescription of opioid pain relievers led to the wide availability and diversion of opioids such as oxycodone. Some of the people exposed to prescription opioids developed opioid abuse and dependence, what we now call opioid use disorder. Many of those affected started on prescription opioids and later switched to cheaper and increasingly pure heroin.
Consequently, in 2010, we began to see an increase in heroin-related overdose deaths. The sharp rise in opioid overdose death rates, coupled with the widening mortality gap among working-class white Americans, put opioid use disorder at the forefront of the national agenda. Billions in funding were allocated for treatment and research to combat the epidemic, and compassion for people with opioid use disorder was at an all-time high. However, the epidemic evolved again when the opioid market was flooded with fentanyl and its illicitly manufactured analogues. This transition has had an impact on key stakeholders in the opioid epidemic: people who use opioids, treatment providers, researchers, and harm reduction professionals.
In 2008, I began my postdoctoral training at Columbia University Medical Center in New York and observed the evolution of the opioid epidemic as a behavioral pharmacologist and harm reducer. With fentanyl increasingly becoming the opioid of choice and inevitable for many people who use opioids, it is clear that it has presented unique challenges in reducing the harms of opioid use disorder.
When asked why fentanyl is such a problem, the obvious answer is its potency. Fentanyl is generally considered to be 50 times more powerful than heroin, and some analogues, such as carfentanil, can be thousands of times more potent than heroin. With opioids, their “addictive” effects are pharmacologically intertwined with their risk of overdose. This means that the increased substance-induced euphoria and anxiolytic effects are accompanied by increased respiratory depression (the primary means by which opioid overdose is fatal).
Early in the overdose epidemic, there was a growing implementation of programs that sought to equip anyone who might overdose on opioids with the opioid antagonist: naloxone. Although naloxone can block the effects of fentanyl, there is evidence to suggest that there is less time to save someone from a fentanyl-related overdose compared to other opioids. The potency of fentanyl has led some naloxone distribution programs to modify practices, administering more than the standard two doses of naloxone. It also fuels an ongoing debate about the need for, and risks of, higher-dose formulations of naloxone. Some argue that higher-dose formulations of naloxone would be better for treating fentanyl-related overdoses. While others worry that fear of opioid withdrawal precipitated by naloxone reduces the likelihood that these formulations will be used, even in potentially life-saving situations. Finally, fentanyls are known to have adverse effects uncommon to other opioids. Chest wall rigidity, known as “wooden chest syndrome”, may contribute to fentanyl-induced effects on respiration and is not likely to respond to naloxone.
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In addition to increasing the risk of overdose, fentanyl has had other consequences for people who use substances. In the last five to 10 years, we have seen illicitly manufactured fentanyl increasingly used to increase the potency of heroin. This started in the US East Coast drug markets. heading west. In New York, fentanyl has largely replaced heroin in the illicit opioid market and is no longer a cutting agent, but the main component. At the start of the fentanyl epidemic, heroin users often expressed fear and took steps to avoid cutting heroin with fentanyl. Harm reduction professionals have attempted to support such efforts by providing fentanyl test strips to allow users to test their supply. However, the prevalence of fentanyl in many illicit markets now makes it impossible to avoid.
For opioid users, the resulting transition to physiological dependence on fentanyl has presented other challenges. Although more potent, fentanyl is shorter-acting than opioids like heroin and oxycodone, meaning people typically have to use it more frequently throughout the day to avoid withdrawal. In addition to the increased financial burden, taking fentanyl on more occasions makes it more difficult to always use sterile equipment, increasing the risk of exposure to blood-borne pathogens such as HIV and hepatitis C. It is also believed that the nature of short-acting fentanyl may be responsible for the increased use of the adulterant xylazine. Xylazine is an animal anesthetic, believed to cut off fentanyl’s supply to prolong its effects. Being a sedative, xylazine may increase the risk or severity of an opioid overdose. The presence of xylazine in illicit opioid supplies has been associated with an increase in serious injuries, some of which are extralocal, meaning that they occur at sites on the body other than the injection site. Further research is needed to establish a causal connection between xylazine adulteration and these injuries, which could be used to develop xylazine-specific harm reduction recommendations.
The use of buprenorphine, a drug used to treat opioid use disorder, has also been affected by the ubiquity of fentanyl. The unique pharmacology of fentanyl as leading prescribers to develop new ways to transition fentanyl-dependent patients to buprenorphine. Although fentanyl is short-acting, it is highly lipophilic, resulting in prolonged dissipation from the body. Therefore, there is much to learn about the withdrawal profile of fentanyl (ie, severity and duration), as it is not consistent with its pharmacodynamics. effects. Clinical researchers are also wrestling with the challenges of fentanyl dependence, as opioid maintenance and withdrawal management protocols, which have been used in clinical trials for years, are no longer effective.
Illicitly manufactured fentanyl is also increasingly adulterated in counterfeit pills sold online as prescription opioids or benzodiazepines. This may be contributing to rising opioid-related overdose rates among recreational users, particularly younger adults experimenting with these substances.
Finally, there is growing concern that the fear of fentanyl is causing us to go back down a dangerous legislative path. Some stateUnited States, like Oklahoma, are developing criminal penalties associated with fentanyl that are reminiscent of the draconian crack and cocaine sentencing laws. Mandatory life sentences and murder charges have been touted as ways to combat fentanyl distribution. Legislation of this type is unlikely to change the composition of the supply of illicit substances and will do nothing to reduce demand for opioids. While the frustration with the ongoing opioid epidemic and the dangers of fentanyl is understandable, we must move forward with scientifically supported methods to reduce the prevalence of substance use disorders and minimize the risk of overdose.
In Europe, mobile drug screening services at raves let partygoers know what they were using. Practices like this can help ensure a safer drug supply and can help reduce the risk of overdose among younger or “recreational” users. Safe consumption facilities also provide a means to reduce the risk of overdose among active users, along with increased access to naloxone. In fact, in March 2023, the US Food and Drug Administration approved the first over-the-counter naloxone formulation, Narcan. For those seeking treatment, our current FDA-approved medications remain the best way to mitigate the morbidity and mortality associated with opioid use disorder. In addition, researchers are developing new treatment approaches, such as opioid vaccines and other immunotherapies.
More empirical research is needed on various aspects of the fentanyl epidemic, and many dedicated people are working to get the answers needed to address this problem. But there is a long way to go, and with that in mind, we must also look forward, beyond fentanyl. Addiction epidemics can be cyclical in nature, and what we learn in our fight against fentanyl can help prepare us for what’s next.
If you or someone you know may have a substance use disorder, SAMHSA’s National Helpline (1-800 622-4357) is a free and confidential treatment, referral and information service.
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