The Evolving Opioid Epidemic: Fentanyl, Fentanyl Analogues, and Other Drugs

By Iris Smith, Ph.D., M.P.H.

Although the dangers of opioids as well as it benefits were recognized as early as the 19th century, the global use of opioids both prescribed and illicit has increased significantly in the past 15 years.  Between 2005 and 2017 the national rate of opioid related hospitalizations increased 64% to 225 hospitalizations/100,000 populations.  The death rate in 2016 increased 27% from 2015.  Although opioid prescribing practices began to decline in 2012 in response to the increasing rate of overdose deaths, the use of illicitly obtained and synthetic opioids has continued to rise. The lower cost of production and relative ease of distribution of synthetic opioids has created what some experts refer to as the next “wave” of the opioid epidemic.1 Opioid use by pregnant women quadrupled from 1999 to 2014 and is now the most common reason for seeking drug treatment during pregnancy.  The incidence of neonatal addiction syndrome (NAS) increased 400% between 2000 and 2012.2, 3 Fentanyl (FEN), a synthetic opioid, has become the opioid most frequently implicated in overdose deaths, impaired driving incidents and NAS, as well as a major contributor to cocaine, methamphetamine and other drug-related deaths.  Most FEN and analogue fatalities reported in the US involve young white males (25-44), frequently intravenous drug users. Positivity rates for FEN have increased by 1850% among cocaine positive urine drug test results and 798% among methamphetamine tests.4  Because FEN is often combined with other drugs or used to produce counterfeit pills, users are often unaware that they have used it. 

While 90% of heroin enters the US from the southwestern border, smuggling of FEN and other synthetic opioids by migrants is likely negligible.5 Raw product and chemical precursors are smuggled into the US through transnational organizations to laboratories in China, some Caribbean countries and Canada. Mexican FEN is typically manufactured in clandestine laboratories, while Chinese FEN is often produced in more sophisticated facilities and is of higher quality.  The profit margin for a kilogram of processed FEN has been estimated at more than $1.5M.6

The increased use and distribution of FEN presents several challenges.  Although Naloxone is generally safe and effective in reversing respiratory depression caused by conventional opioids such as morphine and heroin, there are questions regarding its efficacy in treatment of FEN and its analogues.  The frequent use of synthetic opioids in combination with other drugs including stimulants also contributes to drug-related fatalities.  Compared with other opioids, overdose from FEN appears to result in distinct symptoms such as body and chest rigidity, dyskinesia and slow or irregular heartbeat, which may complicate the treatment of symptoms.Harm reduction strategies include the use of rapid test strips to detect the presence of FEN in urine at home or drug-checking services at supervised injection clinics. However, these approaches are still somewhat controversial and underutilized.



1 Ciaccarone D (2021). The Rise of Illicit Fentanyls, Stimulants and the Fourth Wave of the Opioid Overdose Crisis.  Current Opinions in Psychiatry; 34(4), pg. 344-350.,_stimulants_and_the.4.aspx /

2 Binswanter J (2019).  The United States Opioid Epidemic.  Seminars in Perinatology 43)3); 123-131.

3 Umaani R, Ali M, Dehele I, Paudyal V, Elnaem MH, Cheema. (2021) Causes, Nature and Toxicology of Fentanyl Analogues Associated Fatalities:  A systematic Review of Case Reports and Case Series.  Journal of Pain Research; 14, pg. 2601-2614.

4 Han Y, Yan W, Zheng Y, Zahid-Khan M, Yuan K, Lu L (2019).  The Rising Crisis f Illicit Fentanyl Use, Overdose and Potential Therapeutic Strategies.  Translational Psychiatry 9, pg. 282

5 Pergollizzi J, Magnusson P, LeQuang JAK, Breve F (2021).  Illicitly Manufactured Fentanyl entering the United States. Cureus 13(8).


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