The landscape of pain management over the last 3 decades has cycled from the opiophobia of the late 80s and early 90s through opiophilia and back again.1 Notable pit stops along the way included “pain as the fifth vital sign,” the acceptance of opioid use in chronic noncancer pain, and the advent of “The Opioid Crisis.” 

There has been a definitive decline in the rate of opioid prescribing, yet the CDC reports of opioid related deaths continue to rise.2 As it stands today, illicit opioids, specifically illicit fentanyl/fentanyl analogs, top the charts in opioid related deaths. Between 2015 and 2016, heroin and illicit fentanyl contributed to 35,000 opioid related deaths, and prescription drugs accounted for fewer than 15,000.1  In the July/August 2018 issue of Practical Pain Management, researchers explored the idea that the key to revealing  the veracity of how the opioid epidemic has evolved may lie in the logistics of overdose death reporting, and the pharmacology and pharmacokinetics of prescription and illicit fentanyl.2

In the article "Fentanyl: Separating Fact from Fiction," fentanyl and fentanyl analogs are divided into 3 groups; pharmaceutical fentanyl, pharmaceutical fentanyl derivatives and illicit fentanyl. Pharmaceutical fentanyl is a full mu-opioid receptor agonist with a potency 50-100 times greater than morphine.2 It is a substrate of cytochrome P450 3A4 (CYP3A4), which makes it prone to drug-drug interactions and pharmacogenomic variability due to genetic polymorphisms. Fentanyl is metabolized by CYP3A4 to the inactive molecule, norfentanyl. Depending on the formulation, the kinetics and elimination half-life of pharmaceutical fentanyl vary with half-life ranges from 3.65 hours to 27 hours with consideration to continuous release formulations.2 Otherwise, fentanyl itself has a very short half-life closer to the 3-hour range.

There are 3 fentanyl derivatives approved for use in humans: alfentanil, remifentanil and sufentanil. All 3 are limited in use to the inpatient setting and alfentanil and remifentanil are rarely seen as drugs of abuse. Sufentanil, however, has been detected in combination with other illicit drugs in overdose victims along with a fourth fentanyl derivative, carfentanil, which is approved only for use as a tranquilizing agent in large mammals.2 This drug is 100 times more potent than fentanyl and is being found with increasing frequency in the serum of overdose decedents.2

The illicit fentanyl compounds or, nonpharmaceutical fentanyl, are a moving target in terms of street availability and illicit synthesis. This group is comprised of compounds that are illegally altered to create new products which can evade current tests and medical examiners. Illicit fentanyl has been detected as the sole ingredient in drug overdoses, in combination with legally obtained substances (such as legitimate prescriptions, alcohol or over the counter products) and in combination with other licit and illicit substances.

According to the CDC morbidity and mortality weekly report, only 3 states reported detecting carfentanil in overdose deaths during the second half of 2016, but by the end of the first half of 2017, 7 states had reported overdose deaths associated with carfentanil.3 In the same timeframe, the number of counties in which overdose deaths with carfentanil present occurred increased from 54 to 77 with Ohio reporting the highest numbers of carfentanil overdose deaths.3 Between October 2016 and February 2017. the number decreased slightly in proportion with an increase in acrylfentanyl and furanylfentanyl (both forms of nonpharmaceutical fentanyl) deaths.2,3 

Further complicating the landscape, the DEA reports that fentanyl and its analogues are often produced in China and then shipped internationally where they are mixed into the heroin supply or combined with other non-opioid drugs and pressed into a tablet form.This practice partially explains why overdoses with these substances are often misidentified as heroin overdoses or pinned on other prescription opioids present in the body at the time of the overdose.

The reporting of these overdoses often neglects important pharmacological insight into drug metabolism and leads to erroneous documentation.2 When these overdoses are documented as caused by fentanyl or fentanyl analogs, a common misconception follows whereby it is assumed that prescription fentanyl was the cause of these overdoses and further blame is pushed onto prescribers and prescription opioids. As the authors reported, diagnosis codes used for opioid overdose do not differentiate between licit and illicit opioids nor do they capture the nuance of polysubstance overdose.2

As a potential bright spot in the effort to shed full light on the true causes of opioid drug overdoses, the state unintentional overdose reporting system (SUDORS) aims to collect information on all substances that contributed to death as well as “all substances for which the decedent tested positive”.3 This database has been receiving reports since August 2017, and as of August 2018, 32 states and District of Columbia are contributing data.3 This is important because the multitude of substances, licit and illicit, that may be present in the body at the time of overdose death could all be considered for their potential contribution. Further, the CDC's Project—Improving the Quality and Timeliness of Data on Drug Overdose Deaths has joined medical examiners, coroners, public health experts and health IT to expedite their processes with the goal of having 90% of drug-related death records made available for public health surveillance and decision-making within 90 days of death.5 It seems that this effort could be further improved with the addition of a pharmacist to the team to fully appreciate the pharmacological and pharmacokinetic complexities of today’s opioid overdose.  

Overall, prescription fentanyl is rarely abused or obtained illegally in comparison to other opioids, such as morphine, oxycodone, and hydrocodone. It is especially important for practicing pharmacists to consider the implications of illicit fentanyl, to separate them from illicit fentanyl analogues that can be up to 1000x more potent than prescription fentanyl, and to educate providers and the community on the differences.


This article was co-written with Amelia L. Persico, PharmD, MBA. Dr. Persico is a graduate of Albany College of Pharmacy & Health Sciences and Union Graduate College. She has practiced as a community pharmacy manager and is currently a PGY1 Pharmacy Resident at the Stratton Veterans Administration Medical Center in Albany, New York.



Information provided is the sole work of the authors, and the stated opinions or assertions do not reflect the opinions of employers, employee affiliates, or any pharmaceutical companies listed. It was not prepared as part of the authors’ duties as federal employees. 

References
  1. Mark R Jones; et al. A Brief History of the Opioid Epidemic and Strategies for Pain Medicine. Pain Ther 2018 June; 7(1):13-21.
  2. Bettinger, J; et al. Fentanyl: Separating Fact from Fiction. PPM 6Aug2018;18(5). https://www.practicalpainmanagement.com/treatments/pharmacological/opioids/fentanyl-separating-fact-fiction. Accessed October 2, 2018.
  3. O’Donnell, Julie, R. Matthew Gladden, Christine L. Mattson, Mbabazi Kariisa. Notes from the field: Overdose Deaths with Carfentanil and Other Fentanyl Analogs Detected-10 States, July 2016-June 2017. MMWR, CDC. https://www.cdc.gov/mmwr/volumes/67/wr/mm6727a4.htm. October 29, 2018.
  4. Knierim, PE. Tackling Fentanyl: The China Connection. 9 Sep 2018. Department of Justice DEA. https://www.dea.gov/. Accessed October 12, 2018.
  5. CDC. Project- Improving the Quality and Timeliness of Data on Drug Overdose Deaths. CDC website. https://www.cdc.gov/surveillance/projects/improving-data-on-drug-overdose-deaths.html. Accessed October 17, 2018.