By Adegboyega Oyemade, MD, FAPA

Funding/financial disclosures. The author has no conflict of interest relevant to the content of this letter. No funding was received for the preparation of this letter.

Innov Clin Neurosci. 2018;15(11–12):11–12

Dear Editor:

Fentanyl was created in 1960 as an intravenous surgical anesthetic (Sublimaze®, Janssen Pharmaceuticals Inc.), which is 50 to 100 times more potent than morphine and was rarely used except in operating rooms. In the 1990s, a new transdermal fentanyl skin patch (Duragesic®, Janssen Pharmaceuticals Inc.) was developed to treat chronic pain, and its use increased rapidly due to its effectiveness and potency in managing pain. Other forms of fentanyl have also been developed (e.g., lozenges, buccal forms, sublingual tablets, sublingual spray, and nasal sprays).1,2 Carfentanil, an analog of fentanyl, was developed in 1974 and is 10,000 times more potent than morphine. It was never intended for human use, but instead as a tranquilizer for large animals.3 The first known epidemic of overdose deaths attributed to a fentanyl analog (alpha-methylfentanyl) was in 1979 in California.2

The United States Centers for Disease Control and Prevention (CDC) reported that opioid overdose deaths in the United States increased by more than 20 percent from 2016 to 2017 (52,898–64,070), and that the unintentional use of illicitly manufactured fentanyl alone or in combination with heroin or cocaine, as well as counterfeit prescription tablets of oxycodone, hydrocodone, and alprazolam, have been cited as reasons for the spike in opioid overdose deaths.4,5 Fentanyl analogs, such as acetylfentanyl, furanylfentanyl, and carfentanil, have been increasingly detected in overdose deaths. Results from the CDC Enhanced State Opioid Overdose Surveillance (ESOOS) Program examining data from July to December 2016 from 10 states showed that fentanyl was detected in at least half of the opioid overdose deaths in 7 of  the 10 states studied. Carfentanil, furanylfentanyl, and acetylfentanyl were detected in over 10 percent of overdose cases in four states.6 Reports have noted that illicitly manufactured fentanyl mixed with heroin, with or without the user’s knowledge, was the driving force in many fentanyl overdoses.6 Another source of fentanyl overdose is reportedly from diversion of fentanyl-containing medicines, particularly transdermal patches. Fentanyl extracted from patches can be used orally, via transmucosal application, via rectal insertion, intravenously, insufflated, or inhaled after volatilization.5

Responders to fentanyl overdoses have described certain characteristics, namely an immediate blue discoloration of the lips, gargling sounds with breathing, stiffening of the body, seizure-like activities, foaming at the mouth, confusion, and strange affect. Additionally, in one study, 83 percent of the examined fentanyl overdose cases required at least two doses of naloxone for resuscitation.7 Fentanyl and its analogs are highly potent, of high lipophilicity, fast acting, and can lead to rapid loss of consciousness and death when overdosed. Studies of fentanyl-related overdose deaths reported that lack of norfentanyl, the major fentanyl metabolite, in the bloodstream signifies how rapidly death occurs, as this means there is not enough time for fentanyl to be metabolized into norfentanyl. Additionally, the rapid onset of chest wall rigidity has been noted as the one of the major causes of death.8,9

Naloxone is a competitive mu-opioid receptor antagonist medication used for reversal of an opioid overdose and can be administered intravenously, intramuscularly (IM), subcutaneously (SC), intranasally, inhalation through nebulization, and via an endotracheal tube. The Surgeon General’s advisory on naloxone, released on April 5, 2018, emphasized the need for increased access to naloxone as a public health response to the opioid overdose crisis. The growing number of overdose deaths led to the expansion of naloxone access. Initially, access was limited to healthcare providers and first responders, but it was later extended to non-medical bystanders. The naloxone products approved by the United States Food and Drug Administration (FDA) for use by bystanders includes the intramuscular autoinjector Evzio® (Kaléo, Inc.) in 2014 and intranasal Narcan® (Adapt Pharma) in 2015. The FDA recently approved a newer version of Evzio® that delivers 2mg of naloxone IM/SC, which is five times the initial dose of the old version. This was in response to the increasing number of opioid overdoses due to inadequate reversals, secondary to the highly potent opioids (i.e., fentanyl and its analogs).10 Several medication-assisted treatments approved to treat an opioid use disorder—buprenorphine-naloxone (Suboxone® [Indivior], Bunavail® [Biodelivery Sciences], Zubsolv® [Orexo Inc.], and generic forms), methadone, and the naltrexone/long-acting naltrexone injection, Vivitrol® (Alkermes)—have been the mainstay treatments for the last few years. However, recent long-acting formulations (i.e., Probuphine® buprenorphine implant [Titan Pharmaceuticals], which lasts six months and was approved in 2016; Sublocade® buprenorphine extended-release injection [Indivior], which is a monthly injection approved in 2017, and the pipeline of investigational buprenorphine weekly and monthly injections [CAM2038]), adds to the armamentarium of treatment options.

Legislative efforts are also being made to combat the opioid epidemic, such as improving access to treatment and increasing preventive measures, namely the Comprehensive Addiction and Recovery Act (CARA) bill (signed in 2016), the Opioid Crisis Response Act (OCRA) (signed in 2018), and the Synthetics Trafficking and Overdose Prevention Act (STOP) (also signed in 2018).


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