Pill Pushing©

The Best of Pill Pushing - Fentanyl - It's what's in your heroin - (8/24/2018)

By Dr. Ron Gasbarro 

Society at the time 
The year was 1960. It is known as the "Year of Africa" because of major events on that continent, particularly the independence of 17 African nations from the United Kingdom, France, Italy, and Belgium. In 1960, the world population surpassed the 3 billion mark (by 2024, it is projected to pass the 8 billion milestone) [US Census Bureau, 2010]
Actress (One Day at a Time) Valerie Bertinelli and U2 singer-songwriter Bono were born that year, while actor (Gone with the Wind) Clark Gable died at age 59, and rockabilly singer (Summertime Blues) Eddie Cochran was killed in an auto accident at age 21. Comedienne Lucille Ball filed for divorce from husband Desi Arnaz after 19 years of marriage. The divorce ended the I Love Lucy franchise. Rock’n’Roll icon Elvis Presley returned home from Germany, after being away on military duty for 2 years. The US Food and Drug Administration announced that it approved birth control as an indication for Searle's Enovid, previously only prescribed for menstrual cramps, making it the world's first approved oral contraceptive pill. Domino's Pizza was founded. Following the admission of the State of Hawaii as the 50th state in August 1959, the new 50-star Flag of the United States was first officially flown over Philadelphia.  The television animated sitcom, The Flintstones premiered on ABC (Wilma!!). The eighth Olympic Winter Games were played in Squaw Valley, California. Hurricane Donna killed 50 people in Florida and New England. The US launched the first weather satellite, TIROS-1. And in 1960, the drug fentanyl was first developed for the management of postoperative pain. 
The drug in question – Fentanyl 
According to the National Institute on Drug Abuse, fentanyl is a powerful synthetic opioid analgesic that is similar to morphine but is 50 to 100 times more potent [Volpe, 2011; Higashikawa, 2008]. Also, according to the Drug Enforcement Agency (DEA), fentanyl is approximately 25 to 50 times more potent than heroin [DEA, 2016]. Like most other opioids, fentanyl is a schedule II prescription drug, meaning that it is a substance that has a high potential for abuse which may lead to severe psychological or physical dependence [DEA, 2017]. The drug is typically used to treat patients with severe pain or to manage pain after surgery [Nelson, 2009]. It is also sometimes used to treat patients with chronic pain who are physically tolerant to other opioids [Volpe, 2011]. In its prescription form, fentanyl is known by such brand names as Actiq®, Duragesic®, and Sublimaze®[DEA, 2015].  Street names for illicit fentanyl or for fentanyl-laced heroin include Apache, China Girl, China White, Dance Fever, Friend, Goodfella, Jackpot, Murder 8, TNT, and Tango and Cash [DEA, 2015].
In a manner similar to that of heroin, morphine, and other opioid drugs, fentanyl works by binding to the body's opioid receptors (mu receptors), which are found in areas of the brain that control pain and emotions [Gutstein, 2006]. When opioid drugs bind to these receptors, they can boost dopamine levels in the brain's reward areas, producing a state of euphoria and relaxation. The effects of this drug resemble those of heroin and include euphoria, drowsiness, nausea, confusion, constipation, sedation, tolerance, addiction, respiratory depression and arrest, unconsciousness, coma, and death.
Fentanyl was first made in 1960 by Paul Janssen, founder of the drug company Janssen Pharmaceutica [Stanley, 1992], following the medical development of meperidine, marketed as Demerol, another synthetic opioid analgesic several years earlier which entered medical use as a general anesthetic in the 1960s. Following this, many other fentanyl analogs were developed and introduced into medical practice, including sufentanil, alfentanil, remifentanil, and lofentanil. In the mid-1990s, fentanyl was introduced for palliative use with the fentanyl transdermal patch, followed in the next decade by the introduction of the fentanyl lollipop, dissolving sublingual tablets, and sublingual spray, all of which are absorbed through the skin inside the mouth. As of 2012, fentanyl was the most widely used synthetic opioid in medicine [UN, 2015]

The good, the bad, and the ugly 
Fentanyl has enabled millions of people to undergo major surgery. It is the most commonly used painkiller during surgery. Fentanyl is used to dull airway reflexes and to minimize coughing while the breathing tube is placed into the trachea. It prevents pain from the surgeon’s scalpel while the brain is under anesthesia. It is also the analgesic that allows one to wake from anesthesia without feeling pain in the recovery room. 
Before fentanyl existed, morphine and other similar, relatively weak opioids were used that were insufficient for the type of major surgery that happens today [Edwards, 2016]. To treat major surgical pain, morphine is not only too weak but also slow and, once given, lasts a long time, possibly delaying consciousness. In addition, morphine causes histamine release in the body, resulting in cardiovascular side effects like hypotension (low blood pressure).
The precision and timing of modern surgery required a painkiller that was fast-acting, potent enough to blunt pain from a scalpel, stable enough not to cause cardiovascular problems, and short-acting enough to enable removal of the breathing tube once the surgery was over. In the hands of an anesthesiologist, who is licensed to prescribe and dispense fentanyl in the operating room, the drug is safe, even given its potency. Unmonitored, as it essentially causes a person to stop breathing, it can easily lead to death.
Did someone say death?
While the powerful opioid is invaluable in surgery and a godsend to severe, chronic pain patients, on the street, it kills. Fentanyl has become very popular in the sales of illicit street drugs as either a cutting agent or direct substitution for heroin or in the manufacturing of counterfeit oxycodone pills. Other illicit drugs such as cocaine and methamphetamine have been found to contain fentanyl or an ever stronger fentanyl analog [Edwards, 2016]. This may be an intentional mix on the part of the drug trafficker or may be as a result of an accidental cross-contamination as the drug trafficker may be selling fentanyl and other illicit drugs. These are not like the good old days when you could trust your neighborhood pusher to give you what you asked for. Just ask Prince, whose so-called Vicodin® was really fentanyl in disguise. Well, we cannot ask him because it killed him. 
Legally made, but diverted, fentanyl transdermal patches were designed for pain relief that can last up to 72 hours due to their controlled dosage time-release system. Illegal users tend to extract the contents of these and take much higher dosages in short spaces of time. According to US government figures, 1,013 people died between 2005 and 2007 as a result of illegal fentanyl analogs manufactured in Mexico [CDC, 2008]. These overdose deaths were most pronounced among addicts in Chicago, Philadelphia, and Detroit. Most of the overdoses were due to dealers cutting heroin with fentanyl. Why are illicit drug manufacturers cutting perfectly good heroin with fentanyl? Synthetic fentanyl can be made for pennies, whereas heroin requires intensive labor in the form of farming. One gram of pure synthetic fentanyl can equal about 7,000 doses on the street [CDC, 2008].The “outbreak” was contained after law enforcement officials shut down an illegal fentanyl lab in Toluca, Mexico. But the containment did not last long. 
In 2016, The Centers for Disease Control and Prevention (CDC) issued a health advisory to warn of its dangers, as deaths from synthetic opioids, mainly fentanyl, rose to 5,500 in 2014. The death rate of synthetic opioids, which includes fentanyl, increased by 72.2% from 2014 to 2015, with a total of 9,580 deaths [Rudd, 2016]. Synthetic opioid death rates (other than methadone) increased across all demographics, regions, and numerous states. Rates increased in all regions—107% in the Northeast, 95% in the Midwest, 56% in the South, and 13% in the West. Recent state reports have indicated that increases in synthetic opioid-involved deaths have been associated with the number of drug products obtained by law enforcement testing positive for fentanyl but not fentanyl prescribing rates. These reports indicate that increases in synthetic opioid-involved deaths are being driven by increases in fentanyl-involved overdose deaths, which are likely due to illicitly manufactured fentanyl [Gladden, 2016; Peterson, 2016]. The drug is so powerful that victims have been found with the needle in their arm, dying midway through an injection. 
Given the recent surge in illegally-made fentanyl, the CDC Injury Center is analyzing synthetic opioids (other than methadone) separately from other prescription opioids. This new analysis can provide a more detailed understanding of the increase in different categories of opioid deaths from previous years. Using this analysis, in 2015 there were more than 15,000 deaths involving this more limited category of prescription opioids (an increase in this category of 443 deaths since 2014), equivalent to about 42 deaths per day [Rudd, 2016]. Changing the way deaths are analyzed seems to result in a decrease in deaths involving prescription opioids. But, this new number is likely an undercount of deaths related to prescription opioids because it does not include deaths that are associated with pharmaceutical fentanyl, tramadol, and other synthetic opioids that are used as legitimate pain relievers.
Regardless of the analysis strategy used, prescription opioids continue to be involved in more overdose deaths than any other drug, and all the numbers are likely to underestimate the true burden given the large proportion of overdose deaths where the type of drug is not listed on the death certificate. The findings show that two distinct but interconnected trends are driving America’s opioid overdose epidemic: a 15-year increase in deaths from prescription opioid overdoses, and a recent surge in illicit opioid overdoses driven mainly by heroin and illegally-made fentanyl [CDC, 2015]. Both of these trends continued in 2015.
The impact on society
Many users underestimate the potency of fentanyl. The dosage of fentanyl is a microgram, one-millionth of a gram, similar to just a few granules of table salt. But this epidemic is getting more horrific, thanks to one of fentanyl’s analogs - carfentanil. 
The DEA has issued a public warning to the public and law enforcement nationwide about the health and safety risks of carfentanil. Carfentanil is a synthetic opioid that is 10,000 times more potent than morphine and 100 times more potent than fentanyl, which itself is 50 times more potent than heroin.  The DEA, local law enforcement, and first responders have recently seen the presence of carfentanil, which has been linked to a significant number of overdose deaths in various parts of the country. Improper handling of carfentanil, as well as fentanyl and other fentanyl-related compounds, has deadly consequences. Police and first responders have been trained not to touch carfentanil with their bare hands and to wear surgical masks. 
Carfentanil is a Schedule II substance under the Controlled Substances Act and is used as a tranquilizing agent for elephants and other large mammals.  The lethal dose range for carfentanil in humans is unknown.  However, as noted, carfentanil is approximately 100 times more potent than fentanyl, which, itself, can be lethal at the 2-milligram range, depending on the route of administration and other factors. Side effects of carfentanil are similar to those of fentanyl, which include itching, nausea and respiratory depression, which can be life-threatening. Fentanyl analogs have killed hundreds of people throughout Europe and the former Soviet republics since the most recent resurgence in use began in Estonia in the early 2000s, and novel derivatives continue to appear [Mounteney, 2015]. Expect this drug to kill many more people.  
Where the drug is now
Can we do without medications like fentanyl altogether? Right now, we cannot do without opioids entirely [Edwards, 2016]. We would need potent alternatives with limited side effects. The alternative tools we have are insufficient to enable us to quit opioids cold turkey.
A transition plan of sorts has developed in the medical community where we use multiple non-opioid pain medications in combination with non-medication treatments, such as mindfulness, behavioral therapy, and education to minimize the need for opioids. In many instances, these creative efforts have enabled opioid-free options for specific major surgeries. The good news is that the demand for change has reached the top levels of government, hospitals and patient organizations. Money for research and education is being made available. New laws are being enacted. A revolution in pain management is necessary and, hopefully, imminent.

UPDATE 2018 - Often laced into popular illicit drugs, synthetic opioids are killing more people than heroin or OxyContin® [Jones, 2018]. Synthetic opioids, particularly illicit fentanyl, contributed to more US deaths by overdose in 2016 than prescription opioids, according to a new analysis. Synthetic opioids, a category distinct from heroin and prescription drugs like Vicodin® or OxyContin®, were listed as contributing to 19,413 deaths in 2016, 2,000 more than were connected to prescription opioids, according to an analysis published May 1, 2018, in JAMA Psychiatry. The numbers represent the first time this decade that synthetic opioids were found to have contributed to more overdose deaths than prescription versions. The data also shows a dramatic shift from 2010 to 2016, during which the portion of all opioid-related deaths involving synthetic opioids rose from 14% to 46%

Ron Gasbarro, PharmD is a registered pharmacist, medical writer, and principal at Rx-Press.com. Visit him at www.rx-press.com.


Centers for Disease Control and Prevention. CDC health advisory: Increases in fentanyl drug confiscations and fentanyl-related overdose fatalities. HAN Health Advisory. October 26, 2015. Available at: http://emergency.cdc.gov/han/han00384.asp    Accessed January 30, 2017.


Centers for Disease Control and Prevention (CDC). Nonpharmaceutical fentanyl-related deaths – multiple states, April 2005-March 2007. MMWR Morb Mortal Wkly Rep. 2008;57:793-6.


Controlled Substances Act. Vol 21 CFR 1308.21. Available at: http://www.deadiversion.usdoj.gov/21cfr/cfr/1308/1308_12.htm. Accessed January 30, 2017.


Drug and Chemical Evaluation Section, Office of Diversion Control, Drug Enforcement Administration. Fentanyl fact sheet. March 2015. http://www.deadiversion.usdoj.gov/drug_chem_info/fentanyl.pdf.


Edwards DA. Fentanyl: Widely used, deadly when misused. Alternet.org; 2016. Available at: www.alternet.org/drugs/fentanyl-widely-used-deadly-when-misused Accessed January 28, 2017.  


Garnock-Jones KP. Fentanyl buccal soluble film: A review in breakthrough cancer pain. Clin Drug Investig. 2016;36:413-9. 
Gladden RM, Martinez P, Seth P. Fentanyl law enforcement submissions and increases in synthetic opioid-Involved overdose deaths - 27 states, 2013-2014. Morb Mortal Wkly Rep. 2016;65:837-43.
Gutstein H, Akil H. Opioid Analgesics. In: Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 11th ed. Columbus, Ohio: McGraw-Hill; 2006.
Higashikawa Y, Suzuki S. Studies on 1-(2-phenethyl)-4-(N-propionylanilino) piperidine (fentanyl) and its related compounds. VI. Structure-analgesic activity relationship for fentanyl, methyl-substituted fentanyls and other analogues. Forensic Toxicol. 2008;26:1-5.


Jones CM, Einstein EB, Compton WM. Changes in synthetic opioid involvement in drug overdose deaths in the United States, 2010-2016. JAMA. 2018;319:1819-21.
Mounteney J, Giraudon I, Denissov G, Griffiths P. Fentanyls: Are we missing the signs? Highly potent and on the rise in Europe. Int J Drug Policy. 2015;26:626-31.
Nelson L, Schwaner R. Transdermal fentanyl: Pharmacology and toxicology. J Med Toxicol. 2009;5:230-41. 
Peterson AB, Gladden RM, Delcher C, Spies E, Garcia-Williams A, Wang Y, et al. Increases in fentanyl-related overdose deaths - Florida and Ohio, 2013-2015. Morb Mortal Wkly Rep. 2016;65:844-9.
Rudd RA, Seth P, David F, Scholl L. Increases in drug and opioid-involved overdose deaths — United States, 2010–2015. MMWR Morb Mortal Wkly Rep. ePub: 16 December 2016. Available at: https://www.cdc.gov/mmwr/volumes/65/wr/mm655051e1.htm.  Accessed January 30, 2017.
Stanley TH. The history and development of the fentanyl series. J Pain Symptom Manage. 1992;7(3 Suppl):S3-7.
United Nations. International Narcotics Control Board. Narcotic Drugs Stupéfiants Estupefacientes 2014; 2015. Available at: www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2014/Narcotic_Drugs_Report_2014.pdf  Accessed January 28, 2017. 
United States Census Bureau. World Population: 1950–2050. September, 2016. Available at: https://www.census.gov/population/international/data/idb/worldpopgraph.php Accessed January 30, 2017.
US Drug Enforcement Agency. DEA Public Affairs. Public safety alert from Drug Enforcement Administration: counterfeit hydrocodone tablets containing fentanyl. April 1, 2016. Available at: https://www.dea.gov/divisions/sf/2016/sf040116.shtml  Accessed January 29, 2017.
Volpe DA, Tobin GAM, Mellon RD, et al. Uniform assessment and ranking of opioid Mu receptor binding constants for selected opioid drugs. Regul Toxicol Pharmacol. 2011;59:385-90.

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