Antihistamines are frequently used to treat allergy symptoms (1). Misuse of antihistamines has been documented primarily in adolescents and young adults (2); however, antihistamine involvement in overdose deaths has not been widely studied. Among the various antihistamine subtypes, the first-generation H1 subtype can cause anticholinergic effects, including strong sedation (3) that might be exacerbated when co-used with other sedative drugs (e.g., opioids).* Diphenhydramine, a common over-the-counter first-generation H1 antihistamine, has been combined with opioids as an adulterant† in illicit drug supply (4) and can be used to reduce opioid-related side effects (e.g., itchy skin because of histamine release from opioid use).

Provisional estimates indicate that synthetic opioids, including illicitly manufactured fentanyl (IMF), were involved in approximately two thirds of an estimated 108,174 overdose deaths in the United States during the 12 months ending in April 2022.* Previous analyses have identified para-fluorofentanyl, a schedule I† illicit fentanyl analog, in drug overdose deaths in eight states from late 2020 through June 2021 (1–3). Limited data suggest that para-fluorofentanyl is likely similar to or slightly less potent than IMF (3,4); however, its role in the illicit drug market and its impact on the opioid overdose crisis has not been widely studied. To better understand monthly trends in drug overdose deaths involving para-fluorofentanyl in the United States, CDC analyzed overdose death data from the State Unintentional Drug Overdose Reporting System (SUDORS).

During May 2020-April 2021, the estimated number of drug overdose deaths in the United States exceeded 100,000 over a 12-month period for the first time, with 64.0% of deaths involving synthetic opioids other than methadone (mainly illicitly manufactured fentanyls [IMFs], which include both fentanyl and illicit fentanyl analogs).* Introduced primarily as adulterants in or replacements for white powder heroin east of the Mississippi River (1), IMFs are now widespread in white powder heroin markets, increasingly pressed into counterfeit pills resembling oxycodone, alprazolam, or other prescription drugs, and are expanding into new markets, including in the western United States(†) (2). This report describes trends in overdose deaths involving IMFs (IMF-involved deaths) during July 2019-December 2020 (29 states and the District of Columbia [DC]), and characteristics of IMF-involved deaths during 2020 (39 states and DC) using data from CDC's State Unintentional Drug Overdose Reporting System (SUDORS). During July 2019-December 2020, IMF-involved deaths increased sharply in midwestern (33.1%), southern (64.7%), and western (93.9%) jurisdictions participating in SUDORS. Approximately four in 10 IMF-involved deaths also involved a stimulant. Highlighting the need for timely overdose response, 56.1% of decedents had no pulse when first responders arrived. Injection drug use was the most frequently reported individual route of drug use (24.5%), but evidence of snorting, smoking, or ingestion, but not injection drug use was found among 27.1% of decedents. Adapting and expanding overdose prevention, harm reduction, and response efforts is urgently needed to address the high potency (3), and various routes of use for IMFs. Enhanced treatment for substance use disorders is also needed to address the increased risk for overdose (4) and treatment complications (5) associated with using IMFs with stimulants.

Xylazine is a drug used in veterinary medicine as an animal sedative with muscle relaxant and analgesic properties (1). It is not approved by the Food and Drug Administration for use in humans, in whom it acts as a central nervous system depressant and can cause respiratory depression, slowed heart rate, and hypotension (2). When used as a toxic adulterant in illicitly produced opioids such as fentanyl or heroin (3), xylazine might potentiate sedation and respiratory depression, increasing the risk for fatal overdose. In addition, because xylazine is not an opioid, it does not respond to opioid reversal agents such as naloxone; therefore, if illicit opioid products containing xylazine are used, naloxone might be less effective in fully reversing an overdose. Several states have reported increases in xylazine-involved overdose deaths; however, the prevalence of xylazine involvement in drug overdose deaths (overdose deaths) has not been extensively studied, particularly in the United States (4). To better understand the impact of xylazine adulteration on the evolving drug overdose epidemic in the United States, CDC analyzed unintentional and undetermined intent overdose death data from the State Unintentional Drug Overdose Reporting System (SUDORS) in 38 states and the District of Columbia (DC).*,†