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Fentanyl is a powerful opioid anesthetic and analgesic, the use of which has caused an increasing public health threat in the United States and elsewhere. Fentanyl was initially approved and used for the treatment of moderate to severe pain, especially cancer pain. However, recent years have seen a growing concern that fentanyl and its analogs are widely synthesized in laboratories and adulterated with illicit supplies of heroin, cocaine, methamphetamine, and counterfeit pills, contributing to the exponential growth in the number of drug-related overdose deaths.

Fentanyl was first developed in 1960 by Paul Janssen as a potent opioid anesthetic and analgesic. At the time, fentanyl was the fastest-acting opioid discovered to date and more powerful than morphine (50–100 times) and heroin (30–50 times). Transdermal, intravenous, and transbuccal fentanyl administration and several other drugs with chemical structures that are similar to fentanyl have been developed, approved, and used for surgical anesthesia and the management of severe cancer pain and perioperative pain, eventually becoming the most often used synthetic opioid in clinical practice. Since 1979, fentanyl and its analogs have been synthesized in laboratories and sold as heroin substitutes or mixed with other illicitly sourced drugs, leading to an increase in fentanyl-related overdose deaths

Based on data from the National Vital Statistics System, 599,255 drug overdose deaths occurred from 1979 to 2016 in the United States, and the overall mortality rate has seen exponential growth. Fentanyl-related overdose deaths predominantly occurred in the northeastern United States, mostly affecting younger people (20–40 years of age), and grew sharply since 2013.

Rapid death from ingesting fentanyl has become increasingly more common. Its high potency, fast onset of action, and duration of the desired effect may be particularly important contributing factors to the higher risk of overdose deaths and social consequences. Fentanyl has become a major contributor to cocaine-related fatal overdoses. The rate of fentanyl-related overdose deaths increased 55% between 2015 and 2017 in New York city. Synthetic opioids are also increasingly detected in illicit supplies of heroin, methamphetamine, and counterfeit pills.
Moreover, the number of fatal overdoses from synthetic opioids, primarily fentanyl and its analogs, was 19,547 in 2016 in the United States, and this rate increased by 88% per year from 2013 to 2016.

Deaths that were attributable to illicit fentanyl use were first reported in the early 1980s and occurred sporadically in the United States. A surge in the occurrence of fentanyl-related fatalities among illicit drug users occurred in 2006. A total of 1013 deaths in six states occurred from April 4, 2005, to March 28, 2007. Since then, the prevalence of opioid-related mortality has increased persistently, and the number of reported fentanyl-related deaths more than doubled (from 2628 to 5544) between 2012 and 2014. The rate of fentanyl-related overdose deaths increased from <15% in 2010 to ~50% in 2017 in Marion County, Indiana. The presence of fentanyl and its analogs has become a central contributor to the increase in the number of opioid-related overdose deaths. Preliminary estimates of opioid overdose deaths in the United States in 2016 revealed that fentanyl and its analogs have contributed to nearly half of opioid overdose deaths. Moreover, the number of deaths that were attributable to illicitly manufactured fentanyl and its analogs nearly quadrupled between July 2015 and June 2017 in Montgomery County, Ohio. Heroin-positive cases declined while methamphetamine-positive cases increased in these victims. Fentanyl is ~30–50 times more potent than heroin, and smaller volumes of heroin and other drugs that are adulterated with fentanyl can produce powerful effects with lower production costs. The opioid crisis is likely attributable to illicitly manufactured fentanyl and its analogs around the world, especially when they are mixed with heroin and other drugs, and the route of administration. A high risk of overdose and deaths was found among this vulnerable population that exhibited high fentanyl exposure, thus highlighting the pressing need to develop appropriate harm-reduction strategies, Despite the beneficial clinical anesthetic and pain-relieving effects of fentanyl, the frequent use of fentanyl primarily affects the central nervous system (CNS) and gastrointestinal, cardiovascular, and pulmonary systems and can cause several side effects. Fentanyl has rewarding effects and thus high abuse potential. Its repeated use leads to the development of tolerance and drug dependence. Analyses of adverse-event reporting systems in the United States, Europe, and the United Kingdom have shown that cases of fentanyl-related misuse, abuse, dependence, and withdrawal steadily increased between 2004 and 2018, resulting in prolonged hospitalization or death. Other mental disorders, such as depression, insomnia, and suicidality, can also occur with fentanyl abuse, contributing to relapse and a higher risk of respiratory depression or overdose death. The treatment of these mental disorders may help prevent fentanyl-related fatalities and achieve abstinence. In conclusion, the crisis of opioid-related overdoses, especially fentanyl and its analogs, is a major threat to both individual and public health. Respiratory depression, cardiovascular effects, and neuropsychiatric symptoms are associated with fentanyl overdose and lethality. *pieces collected from