So while there is a lot of debate about why drug overdose deaths have dropped in the last 12-18 months, that discussion has missed two equally important points — first, that drug overdose deaths are still a major preventable cause of death in the U.S., and second, that nonfatal drug overdoses, along with other sequelae of substance use disorder more broadly, is a huge source of preventable costs to society in general, and the U.S. healthcare system specifically.
For the last 20 years, the prime directive for healthcare work with people who inject drugs has been “keep the person alive.” That directive calls for the use of any and all harm reduction approaches, including the following:
- Naloxone distribution
- Fentanyl test strips for cocaine users
- Supervised Injection Facilities
- Syringe and needle access programs (SNAPs)
- Low barriers to access medications for Opiate Use Disorder (MOUD)
Countering the above efforts are largely supply-side trends. These include growth in the illicit drug supply of xylazine, a nonopioid veterinary sedative that can greatly increase the danger to users of fentanyl as well as cocaine and other drugs. In mid-2023, U.S. drug seizures from 38 states by Phase II of the Drug Enforcement Administration’s Operation Overdrive found xylazine in nearly 40% of the samples. Equally concerning are the growth of nitazenes, a class of synthetic opioids that is increasing in some parts of the U.S., and ketamine, a dissociative anesthetic with a number of legitimate medical uses (and more that are being actively developed). Ketamine (along with the possibility of supplies of other drugs being identified to buyers as ketamine) is appearing in the illegal drug supply, but so far, well below 1% of all overdose death reports detect this drug in the victim. From 2019 to 2023, the percent increased from 0.3% to 0.5%, so it bears monitoring.
In a 2017 research paper by legendary economist Alan B. Krueger, strong correlation was found between opiate prescribing and workers, particularly “prime-age men.” Krueger found that the rise in opioid prescriptions could account for as much as 43% of the decline in the male labor force participation from 1999-2015. Far from improving functioning, opiate prescribing has reduced the quality of life and productivity of this important section of the American workforce. Fortunately, new pain management guidelines in response to these findings have reduced opioid prescribing and the community burden created by unused, stolen or diverted opioid drugs. The DEA’s Theft/Loss Reporting Database has found that the number of unaccounted-for opioid doses declined from 12.9 million in 2010 to about 4 million in 2023. However, books like Dreamland by Sam Quinones and other official law enforcement reports have documented how the illicit opioid supply pivoted from prescription opioids to heroin, and most recently to fentanyl.
Which brings us to the relative reduction in overdose deaths that we are welcoming most recently. So far, the major drivers of this change are unclear. The reliability that this trend will continue is also unknown. Until actionable data appears giving us insight into why this trend is occurring, we should consider the efforts that might at least correlate with reduced overdose death rates.
Supply and Trafficking-associated Interventions
According to the DEA’s 2024 National Drug Threat Assessment, bulk quantities of fentanyl precursors are procured from China by particular Mexican drug cartels that manufacture the drug in Mexico and then transport it into US communities in partnership with a web of US-based illicit drug wholesalers. The DEA has discovered a number of these networks using the most common social media platforms to coordinate their operations. Law enforcement efforts have also targeted the financing of these operations through prosecution of money laundering rings.
For the last 35 years, fatal drug overdoses were dominated by the impact of opioids. However, non-opioid drugs are steadily increasing in appearance in fatal overdose testing reports. Leading the trend are psychostimulants (e.g. methamphetamine) and cocaine.
While cocaine trafficking into the US has been a trend for the last 40 years, the appearance of cocaine in overdose reports, often with fentanyl together, is a new and disturbing phenomenon. Could this trend mean that law enforcement and healthcare industry efforts to reduce the supply of opioids in the community has finally resulted in a sustainable reduction in fatal overdose risk in the U.S.?
Interventions Focused on People who Inject Drugs
Naloxone distribution has been one of the most consistently effective methods of reducing opioid overdose death risk. In a 2022 study published in JAMA Network Open, researchers who distributed an extra 10,000 naloxone kits annually over three years to people who inject drugs in the highest-risk areas of Rhode Island reported an estimated 25% reduction in overdose death risk over the 3-year study period. The authors estimated that the intervention strategy reduced opioid overdose deaths (OODs) by 73.4 over the study period, costing $27,312 per OOD averted. One of the key elements of this study was the active identification of areas at highest risk for OODs, followed by very active distribution of naloxone kits in those areas. This was compared to simply making naloxone kits available for members of the public to request or purchase, or focusing on areas generally associated with illicit opioid or stimulant use without specifying the use of substances via the injection route.
Other studies have repeatedly demonstrated that any naloxone distribution reduces OODs in a community, and higher numbers of naloxone kits distributed in a community has a significantly larger impact on OODs than smaller numbers. So it is likely that naloxone distribution is playing a role in the recent reduction of OODs. However, there are three significant limitations to the future utility of naloxone distribution.
The replacement of heroin for fentanyl in the illicit opioid supply has potentially reduced the effectiveness of naloxone as a rescue agent in two ways. First, the increased affinity of fentanyl for the mu opioid receptor and the lipid solubility of the drug means that higher concentrations of naloxone are sometimes required to displace fentanyl from the opioid receptors. Therefore a single administration of naloxone may not be adequate to rescue a victim experiencing an overdose. Second, the use of high dose fentanyl raises the risk of fentanyl-induced chest wall rigidity, also known as Wooden Chest Syndrome. While rare, the condition can occur without warning and is often fatal outside of an operating room environment. Since the condition is related to excess noradrenergic outflow from the locus coeruleus to the spinal cord, opioid receptor blockade is less likely to reverse the condition, though successful case reports of this intervention do exist.
Lastly, the growth of xylazine in the illicit opioid supply will reduce the effectiveness of naloxone going forward since xylazine is a highly dangerous alpha-2 adrenergic agonist without any opioid stimulation by itself.
Studies of the benefits of fentanyl test strips toward reducing OODs in people who inject drugs generally as well as cocaine users specifically, are not yet strongly consistent nor large enough to make meaningful statements about this intervention. As the percent of fentanyl in the illicit opioid supply grows, the impact of test strips in the population that injects opioids specifically is likely to wane. In the studies that have been done, there has been an association between people who inject drugs accepting an offer of test strips and other related harm-reduction behaviors such as reducing the frequency and amount of injection drug use.
Supervised Injection Facilities (SIFs) provide monitored settings where people who inject drugs can safely use those drugs. Such locations have been opening in many countries around the world such as Canada, Australia and France. The first sites in the U.S. opened in New York City in late 2022. Studies of these sites suggest that they reduce overdose risk in the vicinity of the SIF, and are not associated with increases in drug use or drug crime. Like most harm-reduction strategies, including a relatively small focus on skills in motivational interviewing and referral for treatment into the staff training reduces the time people who use these services take before entering into SUD treatment. Unfortunately, efforts to open new SIFs in different communities around the nation have encountered resistance from local and federal regulators. So considering the nearly-nationwide reduction in overdose deaths observed by state and federal agencies, it is unlikely that SIFs have had a measurable impact on this trend occurring very far from the few U.S.-based SIFs.
Could Syringe and Needle Access Programs (SNAPs) reduce OODs? Looking at such programs directly, there is little reason to believe that providing people who inject drugs with cleaner and safer injection equipment would reduce OODs. However, studies do support some effectiveness in SNAPs toward encouraging people who inject drugs to enter SUD treatment programs, which could reduce OODs indirectly. Nonetheless there are other reasons to support SNAPs, such as reducing the spread of blood-borne infections in communities and reducing needle stick injuries in first responders.
Finally, there are efforts to improve the availability of SUD treatment generally, and medications used for OUD specifically. To this end, and pursuant to a change in federal law, the DEA eliminated the federal waiver system that required buprenorphine prescribers to maintain a second DEA number solely for use in the office-based treatment of OUD with buprenorphine. Obtaining a waiver required the completion of a specific CME-based training program provided by a limited number of educational providers, as well as a number of other requirements that were often cited by physicians and other prescribers as barriers to obtaining the waiver. Since the elimination of the waiver system, some states have retained their own specific rules on buprenorphine prescribing, including waiver training requirements for prescribers, counseling and other services requirements even for patients in long-term recovery, ongoing CME requirements, dosing limits, dosage form limits, as well as requirements specific to Medicaid recipients.
A 2023 Journal of Addiction Medicine review supported the elimination of dosing limits in particular, citing research that associated higher doses with better treatment retention and adherence, fewer positive test results for opioids and cocaine, and the relatively low risk of overdose death due to diverted buprenorphine compared to the higher risk of trafficked fentanyl, including cocaine laced with fentanyl.
Looking at the evidence base of all three FDA-approved medications to treat OUD (methadone, buprenorphine and naltrexone), strong evidence exists to support the notion that the use of medications has a significant impact on treatment adherence and retention, positive drug tests, and other endpoints that are associated with OOD.
So would the further elimination of state-based restrictions and barriers to the use of medications for OUD lead to further reductions in OOD? The totality of the evidence suggests the answer is “yes,” but realize that the factors impacting OOD risk are complex in each state, especially in communities within each state. How interventions are implemented matters. The more interventions focus on helping the population of people who inject drugs, the more impactful the results. The general availability of SUD treatment (including, but not limited to medications) and naloxone kits are likely the most impactful interventions of those discussed above. What happens to the illicit drug supply in terms of xylazine, nitazines, fentanyls (including carfentanyl) and other substances in both the illicit opioid supply and the cocaine supply will also determine whether the current trends in OODs continue.
