Part I: Missouri’s Fentanyl Poisonings Rise to Record Levels

Abstract

Missourians are dying of fentanyl poisoning at an unprecedented rate. We identified growth areas in Missouri for fatal fentanyl encounters in rural and western counties. Though the deaths occur for a multitude of reasons, a growing trend adds to the surge in fentanyl fatalities: poisonings from counterfeit pills. The tablets are often labeled with brand names for alprazolam or oxycodone, but may contain only fentanyl at a dangerous level. Teenagers find counterfeit pills all too easily via social media. Believing they have found an easy way to obtain a quick high or relief of minor pain and anxiety, they take the pill alone in their bedroom, with no possibility of reversing a fatal fentanyl dose. There is a wide range of respiratory depression from illicit drugs containing fentanyl. We reviewed the physiologic respiratory response to drugs containing fentanyl that varies with genetics and the unpredictable amount of fentanyl contained in illicit drugs.

Several Trends Drive Increase in Fentanyl–Related Deaths

In this article, we document the increase in fentanyl–related deaths in Missouri with new statistics. This report updates a previous report on fentanyl in Missouri.¹ The most important trend accounting for fentanyl–related deaths is the increased fentanyl content in illicit drugs. We spoke with Tom Van De Berg, MD, Medical Examiner for Greene County, about the increase in opioid–related deaths there from 62 in 2020 to 101 in 2021.² He stated: “Last year it really shot up for us. There is so much of it on the street.”

This persistent rise of fentanyl–related deaths in America began in 2014.³ Ben Westhoff, author of Fentanyl Inc., stated of fentanyl: “It’s so cheap to produce and it’s so powerful, that drug dealers began realizing it was a way to increase their profits.”⁴

Part I of this update on illicit fentanyl reports a record–breaking total of fentanyl fatalities in Missouri and a new pattern for those deaths. Dealers now deliver fentanyl to virtually any town in Missouri. A recent fatal case due to ingestion of just one–half of a counterfeit pill typifies a growing trend. Part I concludes with new research findings pinpointing the location of the lethal effect of fentanyl on respiration in the brainstem and explaining the variation in susceptibility to fentanyl toxicity.

Part II will document the critical change in fentanyl manufacturing—from a finished Chinese product to a Mexican product made from basic Chinese chemicals. Missouri statistics on narcotic prescriptions and significant harm reduction efforts will complete this two–part update on fentanyl in Missouri.

Missouri Opioid Fatalities in 2021: Rural Rates Rise; St. Louis City and County Decline

The result of the heavy influx of fentanyl–contaminated drugs from Mexican cartels, manufactured from basic Chinese chemicals, is apparent in recent statistics for opioid–related fatalities in Missouri. Provisional data from the Bureau of Health Care Analysis and Data Dissemination, Missouri Department of Health and Senior Services (MO DHSS), give a total of 1,581 opioid overdose deaths for Missouri residents in 2021.⁵ This represents a significant increase from the 1,375 fatalities recorded in 2020.⁶

Figure 1 shows the opioid death rate per 100,000 for counties that recorded five or more deaths from provisional data available May 20, 2022.⁷ Counties not reporting data or with four or fewer deaths are shown in gray. St. Louis City still leads the state in opioid death rates at 86 per 100,000 population, followed closely by Dent County, which had 83 per 100,000 population (12 opioid deaths in Dent County, population 14,421). In descending order, the six counties that follow the top two counties, with opioid fatality rates between 45–69 deaths per 100,000 population, are Crawford, Washington, Phelps, St. Francois, Jefferson, and Warren. This data from 2021 demonstrates a rise in fatalities for many counties outside the urban fringes, especially along the Interstate–44 corridor.

Figure 1.

Lethal opioid overdoses in Missouri, rate per 100,000, statistics from MO DHHS. Percent changes from 2020 to 2021 are noted in + or – percent. Gray areas: statistics not available. For counties with a “+%” notation, statistics are incomplete; the minimum percentage increase is noted. ⁷

St. Louis City and County demonstrated a fall in opioid death rates from 2020 to 2021—the first decline observed in these areas in years. The growth rates were high in some western counties such as Jackson and Greene counties, although both have a far lower opioid fatality rate than St. Louis City and even lower than many rural counties. Overall, the Interstate–44 corridor is the predominant pattern observed in counties with the highest opioid death rates and the highest percentage increases in Missouri opioid fatalities.

Fatal drug overdose statistics presented here represent all fatalities from opioids and are taken from ICD–10 coding for drug overdose deaths on death certificates and combined with available toxicology data.⁸ The opioid drug category includes both natural and synthetic opioids. The latter category includes fentanyl, fentanyl analogs, and other synthetic narcotics such as U–47700. This drug is known as “pink,” “pinky,” or “U4” and is associated with an increasing number of fatal opioid overdoses.^{9, 10}

These fatal overdose totals are preliminary and subject to death–certificate reporting error. A combination of drugs (e.g., opioids and methamphetamines) sometimes contributed to fatal outcomes. Nora Volkow, MD, of the National Institute on Drug Abuse (NIDA) stated: “Unfortunately, comprehensive toxicological testing is not performed in many cases, or the results are not recorded on death certificates, so the reported numbers of fatal opioid overdoses and overdoses due to fentanyl might not capture the full scope of the epidemic.”¹¹

Poisonings From Lethal Counterfeit Pills

Libby Davis of Shawnee, Kansas, the mother of sixteen–year–old Cooper Davis, told us how her son died. Cooper and three friends bought two light–blue pills with the label “Perc 30,” indicating that the pills contained 30 mg of oxycodone. Cooper and his friends traveled from Shawnee, Kansas to Missouri to meet a drug dealer through a contact they found on Snapchat.¹² Each of the friends agreed to take one–half pill. Mrs. Davis and her husband, Randy, knew nothing of this until they received a phone call from the police about Cooper. Libby Davis told us: “About six p.m., we got the call that every parent fears. The officer said: ‘Cooper is having a medical emergency. You need to get to this address as soon as you can.’ ”

Cooper’s parents stood in the driveway waiting for the EMTs to give an update. The team had been attempting to resuscitate Cooper for 40 minutes. After a change in his EKG reading that gave the EMTs hope, they brought him out of the house to transfer him to the hospital. Cooper’s parents were alarmed to see Cooper under a mechanical compressor pumping his chest, part of an intense effort to revive their son. Following a prolonged resuscitation effort, his lungs began hemorrhaging, and the Davis couple agreed to suspend efforts to revive their son. The three teenagers who shared the pills with Cooper walked away unharmed.

Cooper’s death was front–page news. His parents told the Kansas City Star that as far as they knew, Cooper did not have any addiction or drug use other than marijuana. He took half a counterfeit pill and died.¹²

Libby and Randy Davis decided to begin an educational effort to counteract the rise in fatal fentanyl encounters. She told us that the word “overdose” carries the wrong message. Since the person is not seeking any amount of fentanyl, the event cannot be described as an overdose, but should instead be called a poisoning. She explained: “Teenagers with anxiety and depression are turning to self–medication. Pills have been normalized and these teenagers are trying to fix themselves. Curious teenagers decide to self–medicate and not bother their parents.” She added: “There is a stigma when we say ‘overdose,’ and the public thinks, not my family, not my kid. People aren’t listening if we call it an overdose. Let’s call it a poisoning. If they poisoned our milk supply, everyone would know.” She further stated: “This happens so suddenly, there is no time to learn from mistakes. How do you cure a kid’s curiosity?”

Fentanyl poisonings in Missouri from counterfeit pills rose sharply in 2021. Another sixteen–year–old, Ethan Everley, also from the Kansas City area, died of fentanyl poisoning from a counterfeit pill.¹³ “Social media is almost exclusively the way they get the pills,” said Morgan Gire, district attorney for Placer County, California, who filed murder charges against a dealer accused of killing 20–year–old Kade Webb.¹⁴ These recent reports continue a trend going back to at least 2015, when eight overdoses from counterfeit Xanax (alprazolam) pills were reported.¹⁵ The number of counterfeit pills seized by federal agents has soared—from 42,202 in the first quarter of 2018 to 2,089,186 in the fourth quarter of 2021.¹⁶ Reports vary, but according to one Drug Enforcement Agency (DEA) analysis, about 42 percent of these fake pills contain a lethal dose of fentanyl.¹⁷

The DEA released a public safety alert about the dangers of fake pills on September 27, 2021, their first public safety alert in six years. According to Andree Swanson of the DEA, the organization seized as many counterfeit pills in 12 months as they had in the previous 24.¹⁸ In their “One Pill Can Kill” campaign, the DEA cites the hazards of counterfeit pills.¹⁹ Drugs sold by counterfeiters, labeled as Xanax, Percocet, and Oxycontin knowingly contain fentanyl.¹⁹ An increasing number of deaths occur in opioid–naïve teenagers who use social media to find and take just one pill or part of a pill.

A 17–year–old girl from Cameron, Missouri, Faith Richardson, died after taking illicit pills obtained in Chillicothe, Missouri.²⁰ A 34–year–old woman also from Chillicothe died in similar circumstances.²¹

Cooper Davis Died, and His Three Friends Were Unharmed: Variation in Response to Opioids

Fentanyl is a potent narcotic: 80–100 times as strong as morphine.^{22, 23, 24} Although the DEA gives 2 mg as a lethal dose of fentanyl, one toxicologist states, “Giving someone 500 mcg (0.5mg) would be seen as irresponsible if ordered in the hospital…The fatal dose of fentanyl in an opoid–naïve adult is likely less than 2000 mcg.” ²⁵

Fentanyl’s potency and low–price boosts profits for dealers who do not have to purchase more expensive drugs. The trouble ensues when cartels and drug dealers use crude methods to mix fentanyl, e.g. with a spoon.²⁶ As a result, The amount of fentanyl in illegal drugs as well as counterfeit pills is completely random—even from the same supply or supplier—which increases the probability of someone being poisoned or overdosing. One portion or pill may not contain fentanyl, while others from the same supply may.²⁷ Toxicology reports from counterfeit pills, when available, may show only fentanyl as the active opioid ingredient, though many limited tests may not detect fentanyl analogs. Cooper Davis’s toxicology report, for example, showed only fentanyl, caffeine, and naloxone; the opioid antagonist employed too late to save him.²⁸

In addition to the unpredictability of fentanyl exposure, variability in genetics, and therefore, varying kinetics of drug metabolism, heighten the risk of an overdose.^{29, 30, 31} The variation in effective analgesic opioid dose has been found in multiple clinical studies.^{29, 31} This effective clinical dose for analgesia depends on the variation in response to a given dose of opioids as well as the variation in individual response to painful stimuli.

Opioid effects are mediated by multiple opioid receptors including the μ–opioid receptor, coded by the Oprm1 gene.³² The activity of the μ–opioid receptor can differ significantly depending on the Oprm1 gene variant. The Oprm1 polymorphism A118A>G has been studied in a mouse model and in possible relation to opiate addictions in humans.^{33, 34, 35} The implication of these studies is that persons with this polymorphism have less of a response to opioids.

The most critical adverse effect of fentanyl, as well as all opioids, is respiratory depression mediated via the same μ–opioid receptor on a tiny cluster of neurons in the brainstem.^{32, 36, 37} These neuron clusters include the pre–Bötzinger complex, the parabrachial nucleus, and the Kolliker–Fuse nucleus.^{37, 38, 39} In–vivo work in the mouse model implicates the Kolliker–Fuse nucleus in apneic events at high opioid doses.³⁹ Experimental work by Bachmutsky et al. utilized mice with Oprm1 gene deletion from selected respiratory sites.⁴⁰ The researchers demonstrated contributions from all of these brainstem respiratory centers in opioid–induced respiratory depression.⁴⁰ Just 70–140 neurons in the brainstem were found to govern respiratory toxicity from opioids.⁴⁰

Oertel et al. demonstrated 118A>G carriers received less analgesia from alfentanil and that homozygous 118A>G carriers were protected from respiratory depression.⁴¹ The ARUP reference laboratory⁴² for the 118A>G allele test notes a wide variation among populations in the presence of a single 118A>G allele: African Americans 1.5–4%, Whites 11–14%, Hispanics 14–24%, and Asians 49–60%.^{33, 34, 35}

Fentanyl is metabolized by the CYP3A4/5 enzyme, rather than the combined CYP2D6 and CYP3A4/5 pathways used in metabolizing hydrocodone, oxycodone, and methadone.⁴³ The CYP3A5*3/*3 allele reduces the metabolism of fentanyl. Takashina et al. found a two–fold increase in fentanyl plasma concentration and a greater number of CNS adverse effects in patients homozygous for CYP3A5*3/*3 in comparison to CYP3A5 patients.⁴⁴ Barratt et al. analyzed CYP3A4 and CYP3A5 polymorphisms in cancer pain patients receiving transdermal fentanyl using stepwise linear regression.⁴⁵ Only 14% of the variability in serum fentanyl levels were accounted for by CYP3A4*22 and CYP3A5*3 variants, CYP3A inhibitors (i.e. drug–drug interactions), and variables relating to liver and kidney function implying other genetic differences may be important.⁴⁵ For example, the P–glycoprotein adenosine triphosphate (ATP)–binding cassette transporter, encoded by the ABCB1 gene, regulates transportation across the blood–brain barrier, controlling entry of drugs into the brain. Two studies showed that, because of effect on the P–glycoprotein transporter, patients with ABCB1 transport gene alleles had different fentanyl requirements for pain relief.^{44, 46}

We have reviewed new data showing that Missouri has record numbers of fentanyl poisonings. We discussed the growing instances of poisonings from counterfeit fentanyl pills. We also reviewed new basic science findings on the effects of opioids on the brainstem and how those effects vary significantly in the population. This concludes Part I of our two–part series: Missouri’s Fentanyl Poisonings Rise to Record Levels.