"Alongside their legitimate uses as medicines and in research, the fentanils also have a long history of illicit use as replacements for heroin and other controlled opioids. Between 1979 and 1988, more than 10 fentanils that had been made in illicit laboratories were detected on the drug market in the United States (Henderson, 1991). The first was alpha-methylfentanyl, followed by substances such as 3-methylfentanyl and 4-fluorofentanyl. Typically, they were sold as heroin or ‘synthetic heroin’.

"Over the 15-year study period, 335,123 opioid-related deaths in the United States met our inclusion criteria, with an increase of 345% from 9489 in 2001 (33.3 deaths per million population) to 42,245 in 2016 (130.7 deaths per million population). By 2016, men accounted for 67.5% of all opioid-related deaths (n = 28,496), and the median (interquartile range) age at death was 40 (30-52) years.

"Among the 42 249 opioid-related overdose deaths in 2016, 19,413 involved synthetic opioids, 17,087 involved prescription opioids, and 15,469 involved heroin. Synthetic opioid involvement in these deaths increased significantly from 3007 (14.3% of opioid-related deaths) in 2010 to 19,413 (45.9%) in 2016 (P for trend <.01). Significant increases in synthetic opioid involvement in overdose deaths involving prescription opioids, heroin, and all other illicit or psychotherapeutic drugs were found from 2010 through 2016 (Table).

The White House Council of Economic Advisers [CEA] released its analysis of the economic costs of illegal opioid use, related overdoses, and overdose mortality in November 2017. It reported a dramatically higher estimate than previous analyses, largely due to a change in methodology. Previous analyses had used a person's estimated lifetime earnings to place a dollar value on that person's life.

"Preliminary estimates of U.S. drug overdose deaths exceeded 60,000 in 2016 and were partially driven by a fivefold increase in overdose deaths involving synthetic opioids (excluding methadone), from 3,105 in 2013 to approximately 20,000 in 2016 (1,2). Illicitly manufactured fentanyl, a synthetic opioid 50–100 times more potent than morphine, is primarily responsible for this rapid increase (3,4). In addition, fentanyl analogs such as acetylfentanyl, furanylfentanyl, and carfentanil are being detected increasingly in overdose deaths (5,6) and the illicit opioid drug supply (7).

"Fentanyl is a synthetic opioid analgesic acting predominately at the μ-opiate receptor. It has historically been used as a pain reliever and an anaesthetic in both human and veterinary medicine and in terms of analgesic activity it is at least 80 times more potent than morphine. Fentanyl was first synthesized by Paul Janssen in 1960 and marketed as a medicinal product for treating pain. Subsequently, many fentanyl analogues were developed including sufentanil, alfentanil, remifentanil, and carfentanil.

"In 2014, alcohols, including ethanol and isopropyl alcohol, were involved in 15% of all drug overdose deaths and 17% of the drug overdose deaths that mentioned involvement of at least one specific drug. Table E shows the frequency of alcohol involvement among drug overdose deaths involving specific drugs.
"• Alcohol involvement was mentioned in 12%–22% of the drug overdose deaths involving fentanyl, heroin, hydrocodone, morphine, oxycodone, alprazolam, diazepam, or cocaine.

"In 2016, a total of 67,265 persons died of drug-induced causes in the United States (Tables 5, 6, 8, and I–1). This category includes deaths from poisoning and medical conditions caused by use of legal or illegal drugs, as well as deaths from poisoning due to medically prescribed and other drugs. It excludes deaths indirectly related to drug use, as well as newborn deaths due to the mother's drug use. (For a list of drug-induced causes, see Technical Notes.)

"Between 2008 and 2015, a total of 644 NPS had been reported by 102 countries and territories to the UNODC early warning advisory on NPS. The emergence of NPS was reported for the first time in 2015 in Kyrgyzstan and Mauritius. In 2015, the early warning advisory also registered the emergence of NPS in previous years in Belarus, Serbia, South Africa and Tajikistan. The majority of countries and territories that reported the emergence of NPS up to December 2015 were from Europe (41), followed by Asia (30), Africa (16), the Americas (13) and Oceania (2).

"Even though opioids have been controlled in the United States with regulations and restrictions, opioid utilization has been increasing at an unprecedented pace (1-10). Manchikanti et al (1), in an evaluation of opioid usage over a period of 10 years, showed an overall increase of 149% in retail sales of opioids from 1997 to 2007 in the United States, with an increase of 1,293% for methadone, 866% for oxycodone, and 525% for fentanyl.