KEY POINTS
- Fentanyl in counterfeit pills or smoked alone or with methamphetamine are changing the overdose epidemic.
- Inexperienced (low-tolerance) fentanyl smokers, users or speedballers, are at high risk of overdose.
- Pre-existing Depression, COVID, heart disease, and liver disease lead to a greater risk of overdose death.
- Prevention and education are needed while NIDA supports developing vaccines and new medications.
The last heroin epidemic in the ‘70s and early ‘80s led to speedballing (combining heroin with cocaine). Freebasing was an alternative to intravenous use and its associated needle risks. It was replaced by crack cocaine, which was easier to mass-produce and distribute. The current epidemic started with prescription opioids and moved to heroin, then fentanyl, and lastly, speedballing. Fentanyl has flooded the U.S. and is extremely cheap — $10/gram. This new smoking overdose risk is moving from San Francisco throughout the rest of the country.
This new phase of the opioid overdose crisis focuses on young naïve users. They are sold fentanyl-laced opioid-pain pills, counterfeit Adderall, and other drugs attached to a Trojan horse of fentanyl. As for vapers and smokers, they speedball fentanyl with methamphetamine via fentanyl smoking. Difficulty injecting, fear of needles, hepatitis, and HIV risks, as well as fear of overdose, seemingly motivated this transition from injecting to smoking. Smoking encourages inhalation of large doses of fentanyl — approximately 50 mg of pure fentanyl per day.
When we studied crack, intranasal cocaine, and intravenous use of cocaine in the 1980s, we were surprised to discover smoking was equivalent to injection in speed to the brain. Taking pills orally has the slowest response but most users want to experience the drug’s effects as quickly as possible. Users may mistakenly believe they are “safe” from overdoses if they smoke drugs like fentanyl. Younger needle-adverse new users have learned to smoke and vape and are less fearful of smoking fentanyl. However, it is still very possible to overdose as smoking fentanyl today often means higher doses, plus smoking the previous smoker’s drugs piggy-backed, including fentanyl and meth residues.
Experts are concerned about more fentanyl overdoses among new smokers of fentanyl as the potency of the drugs and new users’ much lower tolerance (compared to that of experienced users) collide.
Agnostic Respiratory Stimulants Are Being Developed
Narcan (naloxone) was developed 50 years ago, has limitations, and is ideally suited to reverse heroin and morphine. It was not designed to treat fentanyl overdoses.
With fentanyl, the window of time for saving a person is much shorter than with heroin. Some drugs bind with a higher affinity to opioid receptors than others. When they bind with higher affinity, there’s a greater probability that the drugs “stick” to the binding site. Fentanyl is catalyzing the death epidemic because of its extremely high intrinsic efficacy and affinity for opioid receptors.
Shallow breathing, respiratory depression, and not breathing are major issues in overdoses. The fentanyl crisis, speedballing, and polysubstance ingestion with agents from multiple respiratory depressant classes cause respiratory chaos. Reversing them is difficult, creating an unmet need for treatment medicines stimulating breathing.
Experts are concerned because a fentanyl/fentanyl analog overdose requires swift, timely, and effective treatment, whether drugs were speedballed or used alone. Fentanyl overdoses are often catastrophic because of the rapidity of overdose onset and the very narrow window of time necessary for reversal. Direct comparisons are lacking but some early comparisons suggest the medication nalmefene has advantages in treating respiratory depression fentanyl overdoses.
A new paper directly compared intranasal naloxone vs. nalmefene for fentanyl overdose. The authors focused on respiratory depression and cardiac arrest. Using a validated translational animal model, the study quantitatively predicts opioid-induced respiratory depression and cardiac arrest. In this study, intranasal (IN) nalmefene significantly outperforms intranasal naloxone in reducing cardiac arrest rates following synthetic opioid overdoses. A single dose of IN nalmefene substantially reduced cardiac arrest incidence, whereas four doses of IN naloxone were required for similar outcomes. This research underscores the potential of IN nalmefene as a new, underutilized FDA-approved intervention to fight the synthetic opioid crisis.
However, it’s important to have more than simulations; a real and direct comparison in overdoses treated with intranasal Narcan or Opvee is needed. But this will take years. We desperately need the established Narcan distribution system and current inventories of naloxone at home and in the community to save lives. Theoretically, we could save more lives if nalmefene were added to the original large dose of intranasal administration of Narcan by EMTs — or at least, after naloxone alone has failed. This is an issue that should be studied.
References
Ciccarone D, Holm N, Ondocsin J, Schlosser A, Fessel J, Cowan A, Mars SG. Innovation and adaptation: The rise of a fentanyl smoking culture in San Francisco. PLoS One. 2024 May 22;19(5):e0303403. doi: 10.1371/journal.pone.0303403. PMID: 38776268; PMCID: PMC11111043.
Strauss DG, Li Z, Chaturbedi A, Chakravartula S, Samieegohar M, Mann J, Nallani SC, Prentice K, Shah A, Burkhart K, Boston J, Fu YA, Dahan A, Zineh I, Florian JA. Intranasal Naloxone Repeat Dosing Strategies and Fentanyl Overdose: A Simulation-Based Randomized Clinical Trial. JAMA Netw Open. 2024 Jan 2;7(1):e2351839. doi: 10.1001/jamanetworkopen.2023.51839. PMID: 38261323; PMCID: PMC10807299.
Skolnick P. Treatment of overdose in the synthetic opioid era. Pharmacol Ther. 2022 May;233:108019. doi: 10.1016/j.pharmthera.2021.108019. Epub 2021 Oct 9. PMID: 34637841.
Ivsins A, Bonn M, McNeil R, Boyd J, Kerr T. A qualitative study on perceptions and experiences of overdose among people who smoke drugs in Vancouver, British Columbia. Drug Alcohol Depend. 2024 May 1;258:111275. doi: 10.1016/j.drugalcdep.2024.111275. Epub 2024 Mar 29. PMID: 38581922; PMCID: PMC11088499.