Opioid use disorder and overdose is a growing concern worldwide.[3]World Health Organization. Opioid overdose. 2023 [internet publication].
https://www.who.int/news-room/fact-sheets/detail/opioid-overdose
In the UK, a total of 2551 drug poisoning deaths in 2023 involved opioids, which represented nearly half of all drug poisoning deaths (46.8%; increasing to 60.7% once deaths that had no drug type recorded were excluded). This was 12.8% higher than in 2022 (2261 deaths).[4]Office for National Statistics. Deaths related to drug poisoning in England and Wales: 2023 registrations. Oct 2024 [internet publication].
https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/bulletins/deathsrelatedtodrugpoisoninginenglandandwales/2023registrations
In the US, provisional data shows overdose deaths involving opioids are decreasing. In 2023, there were an estimated total of 110,037 drug overdose deaths, of which 83,140 involved opioids. In 2024, the estimated total overdose deaths was 80,391, with 53,743 involving opioids. Although these numbers are still very high, this decrease marks the lowest levels of overdose deaths since 2019.[5]Centers for Disease Control and Prevention. National center for health statistics: U.S. overdose deaths decrease almost 27% in 2024. May 2025 [internet publication].
https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2025/20250514.htm
New synthetic opioids (NSO) emerged on the illicit drug market in the second half of the 2000s and have become increasingly widespread. The most popular and the largest NSO subgroups are high-potency fentanyl and its analogues.[6]Zawilska JB, Adamowicz P, Kurpeta M, et al. Non-fentanyl new synthetic opioids - an update. Forensic Sci Int. 2023 Aug;349:111775.
http://www.ncbi.nlm.nih.gov/pubmed/37423031?tool=bestpractice.com
During 2016, the rate of synthetic opioid overdose deaths (other than methadone) exceeded those of heroin overdose deaths for the first time in the US (6.2 per 100,000 population vs. 4.9 per 100,000 population, respectively).[7]Seth P, Scholl L, Rudd RA, et al. Overdose deaths involving opioids, cocaine, and psychostimulants - United States, 2015-2016. MMWR Morb Mortal Wkly Rep. 2018 Mar 30;67(12):349-58.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877356
http://www.ncbi.nlm.nih.gov/pubmed/29596405?tool=bestpractice.com
During 2019-2022, US overdose deaths involving illegally manufactured fentanyls more than doubled, from an estimated 35,473 in 2019 to 73,838 in 2022.[8]National Institute on Drug Abuse. Drug overdose deaths: facts and figures. Aug 2024 [internet publication].
https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates#Fig3
[9]Centers for Disease Control and Prevention. National center for health statistics: provisional drug overdose death counts for specific drugs. Jan 2025 [internet publication].
https://www.cdc.gov/nchs/nvss/vsrr/prov-drug-involved-mortality.htm
Carfentanil, a fentanyl analogue 100 times more potent than fentanyl, has recently re-emerged in the US drug supply, and was linked to 238 deaths in 2024 (January to June), up from 29 deaths in 2023 (January to June).[10]Centers for Disease Control and Prevention. Morbidity and mortality weekly report (MMWR): detection of illegally manufactured fentanyls and carfentanil in drug overdose deaths - United States, 2021-2024. Dec 2024 [internet publication].
https://www.cdc.gov/mmwr/volumes/73/wr/mm7348a2.htm
Data from public health and law enforcement agencies also indicate widespread adulteration of cocaine with fentanyl and its analogues.[11]Centers for Disease Control and Prevention. Rising numbers of deaths involving fentanyl and fentanyl analogs, including carfentanil, and increased usage and mixing with non-opioids. HAN no. 413. July 2018 [internet publication].
https://emergency.cdc.gov/han/han00413.asp
[12]Drug Enforcement Administration. (U) Deadly contaminated cocaine widespread in Florida. Feb 2018 [internet publication].
https://www.dea.gov/sites/default/files/2018-07/BUL-039-18.pdf
The mixture of stimulants, such as cocaine and methamphetamines, with fentanyl is driving what experts call the opioid epidemic's ‘fourth wave’. The percent of US overdose deaths involving both fentanyl and stimulants increased from 0.6% in 2010 to 32.3% in 2021. By 2021, stimulants were the most common drug class found in fentanyl-involved overdoses in every state in the US.[13]Friedman J, Shover CL. Charting the fourth wave: geographic, temporal, race/ethnicity and demographic trends in polysubstance fentanyl overdose deaths in the United States, 2010-2021. Addiction. 2023 Dec;118(12):2477-85.
https://onlinelibrary.wiley.com/doi/10.1111/add.16318
http://www.ncbi.nlm.nih.gov/pubmed/37705148?tool=bestpractice.com
The opioid crisis has also become increasingly complicated due to the emergence of comixtures of synthetic opioids with other central nervous system depressants. This includes animal tranquilisers such as xylazine, and more recently, medetomidine, both associated with a growing number of fatalities in the US.[14]Kariisa M, Patel P, Smith H, et al. Notes from the Field: xylazine detection and involvement in drug overdose deaths - United States, 2019. MMWR Morb Mortal Wkly Rep. 2021 Sep 17;70(37):1300-2.
https://www.cdc.gov/mmwr/volumes/70/wr/mm7037a4.htm?s_cid=mm7037a4_w
http://www.ncbi.nlm.nih.gov/pubmed/34529640?tool=bestpractice.com
[15]U.S. Department of Justice; Drug Enforcement Administration. The growing threat of xylazine and its mixture with illicit drugs. Oct 2022 [internet publication].
https://www.dea.gov/sites/default/files/2022-12/The%20Growing%20Threat%20of%20Xylazine%20and%20its%20Mixture%20with%20Illicit%20Drugs.pdf
[16]Palamar JJ, Krotulski AJ. Medetomidine infiltrates the US illicit opioid market. JAMA. 2024 Nov 5;332(17):1425-6.[17]Centers for Disease Control and Prevention. Morbidity and mortality weekly report (MMWR): overdoses involving medetomidine mixed with opioids - Chicago, Illinois, May 2024. May 2025 [internet publication].
https://www.cdc.gov/mmwr/volumes/74/wr/mm7415a1.htm
From 2019 to 2022, among 21 jurisdictions in the US (including 20 states and the District of Columbia), the monthly percentage of illegally manufactured fentanyl-involved deaths with xylazine detected increased 276%, from 2.9% to 10.9%.[18]Centers for Disease Control and Prevention. Morbidity and mortality weekly report (MMWR): illicitly manufactured fentanyl-involved overdose deaths with detected xylazine - United States, January 2019-June 2022. Jun 2023 [internet publication].
https://www.cdc.gov/mmwr/volumes/72/wr/mm7226a4.htm
Many non-fentanyl NSOs are now also becoming increasingly prevalent on the illegal drug scene.[6]Zawilska JB, Adamowicz P, Kurpeta M, et al. Non-fentanyl new synthetic opioids - an update. Forensic Sci Int. 2023 Aug;349:111775.
http://www.ncbi.nlm.nih.gov/pubmed/37423031?tool=bestpractice.com
Nitazenes and nitazene analogues (e.g., benzimidazole opioids) have been found as contaminants in street heroin and cocaine as well as black market vaping liquids and fake prescription drugs purchased online. New forms of nitazenes are emerging, with one believed to be >300 times more potent than morphine and >45 times more than fentanyl.[19]Wise J. Nitazenes: toxicologists warn of rise in overdoses linked to class of synthetic opioids. BMJ. 2024 Nov 8;387:q2465.[20]Montanari E, Madeo G, Pichini S, et al. Acute intoxications and fatalities associated with benzimidazole opioid (nitazene analog) use: a systematic review. Ther Drug Monit. 2022 Aug 1;44(4):494-510.
http://www.ncbi.nlm.nih.gov/pubmed/35149665?tool=bestpractice.com
In the UK, the Office for Health Improvement and Disparities and the National Crime Agency confirmed through laboratory testing that there were 179 deaths involving one or more nitazenes occurring between June 2023 and May 2024.[21]Office for Health Improvement and Disparities. Research and analysis: deaths linked to potent synthetic opioids. Oct 2024 [internet publication].
https://www.gov.uk/government/publications/deaths-linked-to-potent-synthetic-opioids/deaths-linked-to-potent-synthetic-opioids#data-on-deaths-involving-potent-synthetic-opioids
Recent abstinence, resulting in loss of tolerance (e.g., during incarceration), increases the risk of overdose. Because of this, drug overdose is the most common cause of death of former inmates after prison release; the risk of death in the 2 weeks after release is 12 times that of the general population.[22]Binswanger IA, Stern MF, Deyo RA, et al. Release from prison - a high risk of death for former inmates. N Engl J Med. 2007 Jan 11;356(2):157-65.
http://www.ncbi.nlm.nih.gov/pubmed/17215533?tool=bestpractice.com