Five Things to Know about Fentanyl on National Fentanyl Awareness Day 2023

By Leigh Wedenoja

Fentanyl is involved in nearly 70 percent of all overdose deaths and fentanyl overdose is one of the leading causes of death for Americans under 50. Fentanyl is a synthetic opioid with a number of different analogs, some of which are approved by the US Food and Drug Administration (FDA) to treat extreme pain and others that are fully illicit. Fentanyl is particularly dangerous due to both its potency and the large number of fentanyl analogs, all of which have different potency levels ranging from 50 to 100 times the strength of morphine. This makes the fentanyl content of a drug unpredictable, which can lead users to unintentionally ingest too much. According to the Drug Enforcement Administration (DEA), fentanyl is ubiquitous, either sold on its own as a powder or tablet or mixed with other drugs like heroin or cocaine.

Overdose deaths are at an all-time high and they are primarily driven by fentanyl, which accounts for nearly 80 percent of overdose deaths in New York State. Despite this high rate of death, there are proven treatment and harm reduction methods to reduce overdose deaths and combat opioid-use disorder (OUD). Unfortunately, those harm reduction and treatment methods are specific to opioids and are thus less effective for people who use fentanyl in combination with non-opioid drugs. Methamphetamine and cocaine supplies are routinely found to be contaminated by fentanyl, and fentanyl becomes even more deadly when combined with other central nervous system depressants like prescription tranquilizers or the veterinary tranquilizer xylazine.

This year, May 9th has been designated National Fentanyl Awareness Day. The campaign was created to raise awareness of the risks associated with the potent synthetic opioid fentanyl. The day is sponsored by a large group of public and private entities, including the DEA, substance-use disorder (SUD) treatment and support groups, advocates, think tanks, and social media companies.

In light of this effort to broaden awareness of the dangers of fentanyl, this blog highlights five facts about the fentanyl overdose crisis, including evidence-based methods for harm reduction and treatment from our previous research and our recently updated Overdose Mortality Dashboard.

  1. Overdose fatalities are at an all-time high and are primarily driven by fentanyl

Overdose fatalities have increased dramatically since the early 2000s, initially due to the expanded availability and perceived safety of prescription opioids such as OxyContin. As the dangers of prescription opioids became clearer and diversion pathways for legal prescription drugs were shut down, heroin grew in popularity as a substitute. The modern overdose crisis, which now kills over 100,000 people each year, accelerated dramatically with the introduction of fentanyl into the heroin supply in 2016. In 2021, 106,699 people died from a drug overdose.

There was a further rapid increase in overdose mortality from 2019 to 2020, largely driven by the COVID-19 pandemic, which disrupted substance-use healthcare, harm reduction programs, and drug trafficking pathways, all of which, in combination with pandemic stress, increased the probability of lethal overdose. We discuss the intersection of the COVID-19 pandemic and the drug overdose epidemic in the “Epidemic in a Pandemic” series.

Before 2006, deaths from fentanyl overdoses were virtually unknown and from 2006 until 2015, fentanyl was found to be a contributor in 8 to 13 percent of deaths. The large-scale introduction of fentanyl into the heroin and opioid supply began in 2016 and can be tracked through overdose deaths. That year, fentanyl was present in 46 percent of all overdose deaths in the US. The fentanyl mortality rate continued to spike; by 2020, 76 percent of overdose deaths involved fentanyl. In New York in 2021, 79 percent of overdose deaths—nearly four in five—involved fentanyl.

  1. Illicit stimulants like methamphetamine and cocaine are more lethal when combined with fentanyl

Previously, we have written about the surge in overdose deaths associated with methamphetamine and cocaine. Cocaine and methamphetamine are both stimulant drugs, which cause a more energetic high than opioids and increase energy, heart rate, and alertness rather than decrease them. Both methamphetamine and cocaine have been involved in previous overdose crises. Solid cocaine—also called “crack” or “crack-cocaine”—largely emerged in eastern cities and its use sharply rose between 1985 and 1989. Methamphetamine, in contrast, emerged in the western United States in the late 1990s and early 2000s.

Cocaine and methamphetamine overdoses are a national problem and every state has seen an increase in both since 2010. However, cocaine remains more common on the east coast and methamphetamine remains more common on the west coast. For example, despite a 1,200 percent increase in the number of methamphetamine-related deaths in New York from 2011 to 2021, cocaine-related overdose deaths are still nearly four times higher than those from methamphetamine (2,289 to 599). California, by contrast, has substantially more methamphetamine overdose deaths compared to cocaine overdose deaths, with 6,030 methamphetamine-associated deaths in 2021 and only 1,446 cocaine-associated deaths.

One reason why fentanyl-adulterated stimulants are so dangerous is because stimulant users are less likely to be aware of the opioid harm reduction methods. People who believe they have only ingested cocaine or methamphetamine may not be aware of the signs of an opioid overdose and are unlikely to carry naloxone (brand name, Narcan), which can immediately reverse the effects of the opioid.

  1. Fentanyl itself becomes more lethal if used with central nervous system depressants like xylazine and Xanax

Over the past few years, health practitioners, policymakers, and the media have increasingly identified the dangers of polysubstance use—most commonly mixing fentanyl with other central nervous system depressants like muscle relaxants, barbiturates, benzodiazepines, and alcohol. Unlike fentanyl-adulterated cocaine and methamphetamine where the fentanyl becomes more lethal because it has a very different effect than the user’s primary drug, the mixture of fentanyl and tranquilizers is more lethal because both drugs are central nervous system depressants and magnify each other.

Much of this recent focus has been on xylazine which is a non-opioid tranquilizer only approved for veterinary use. Researchers believe that xylazine (and other tranquilizers) are combined with fentanyl for two primary reasons—tranquilizers can lengthen the high from opioids like fentanyl, and xylazine is not approved for human consumption so it does not have the same controlled substance precautions as other central nervous system depressants.

Mixing fentanyl with tranquilizers of any type increases its lethality and probability of overdose. Benzodiazepines, which include the brand names Xanax, Valium, and Klonopin, have a long history of contributing to opioid overdose fatalities and are themselves controlled substances with potential for abuse; doctors who prescribe them are required to enter prescriptions into the prescription monitoring program. In 2021, nearly 14 percent of opioid overdose deaths also involved benzodiazepines. Sedatives also increase the likelihood of nonlethal overdoses; a large-scale study of people exposed to opioids found that those exposed to both opioids and other tranquilizers were 20 to 60 percent more likely to overdose compared to those only exposed to opioids.

Although the combination of prescription benzodiazepines and opioids is far more widespread than the use of xylazine, xylazine presents additional risks beyond those of other tranquilizers. Unlike benzodiazepines, which are generally taken with opioids, xylazine has been mostly found mixed directly into fentanyl powder or pills at unpredictable doses. This adulteration has led the DEA to issue a public safety alert stating that xylazine has been found in 23 percent of seized fentanyl powder and 7 percent of seized fentanyl pills. Xylazine has also been shown to produce open and difficult-to-heal sores. The prevalence of xylazine-adulterated fentanyl has increased. Initially found on the east coast, it has now spread to almost every state.

Mixing opioids with other central nervous system depressants not only increases the probability of overdose but also the probability that an overdose will be lethal because tranquilizers are not affected by the opioid overdose reversing drug naloxone. Administering naloxone to a person who has ingested both fentanyl and a tranquilizer will reverse the effect of the fentanyl but not that of the tranquilizer, which can lead to death due to reduced heart rate and oxygen intake.

  1. Harm reduction methods for opioid-use disorder (OUD) can decrease fentanyl-involved deaths

People who use fentanyl, either intentionally or through adulteration of other drugs, are more likely to suffer a lethal overdose compared to people who use any other common illicit drug without fentanyl. Despite its higher lethality, fentanyl is still an opioid and opioid harm reduction and treatment methods have proven successful in preventing lethal overdoses in people who use fentanyl. It is important to draw a distinction between harm reduction and substance-use disorder (SUD) treatment. Harm reduction methods are intended to decrease the probability of overdose and death among people who actively use drugs and SUD treatment is intended to help people abstain from using those drugs.

Harm reduction policies have expanded dramatically as the death toll from the overdose epidemic has increased and there are two harm reduction programs that are especially valuable in addressing fentanyl. The first is the distribution and administration of naloxone. Naloxone is an FDA-approved medication that blocks opioid receptors and can immediately reverse an opioid overdose. It is available in both an injectable form and a nasal spray. The nasal spray has been available as a prescription drug since 2015 and as of March 29, 2023, it is available fully over the counter. Although it is too early to tell what the effects of over-the-counter naloxone will be, studies have found that increased availability and distribution of naloxone has reduced overdose deaths by 11 to 21 percent.

Unfortunately, naloxone is less effective in reversing overdoses that involve both opioids and non-opioid drugs. While naloxone will reverse the effect of a fentanyl overdose, it does not reverse or inhibit the effects of stimulants like cocaine and methamphetamine or tranquilizers like benzodiazepines and xylazine.

The second harm reduction method directly applicable to lethal fentanyl overdose is fentanyl test strips. As discussed above, one of the dangers of fentanyl is that its concentration—or even presence—is often unknown to the user. Fentanyl may be present in drugs sold as heroin or even in counterfeit prescription opioid pills. Fentanyl test strips have only recently become widely available and there is limited information on their effectiveness in reducing overdose deaths. However, early studies have shown that fentanyl test strips and positive results for fentanyl have caused people who use drugs to change their behavior and engage in less risk. Fentanyl test strips are now legal in 36 states, 16 of which legalized them in the past year. Fentanyl test strips are especially beneficial to users of non-opioid drugs such as methamphetamine and cocaine so they can know whether or not their drug supply has been adulterated by fentanyl.

  1. There are evidence-based effective treatments for people with SUD who use fentanyl

Medication-assisted treatment (MAT) is an effective treatment for OUD, which includes people who use fentanyl. The most common drugs used in MAT are methadone, buprenorphine, and naloxone. Methadone is generally administered on its own as a liquid, whereas naloxone and buprenorphine are used in conjunction most commonly under the brand name Suboxone. A less common FDA-approved MAT drug is naltrexone. Each of these drugs, and their combinations for MAT, have different benefits and drawbacks. Recommended practice is that people with SUD who want MAT should be offered all options.

MAT works by reducing or eliminating the physical symptoms of opioid withdrawal. These medications can be safe to use for months, years, or even a person’s lifetime if necessary to treat physical withdrawal symptoms. Best practices for MAT treatment involve combining medications with other treatment modalities like therapy, self-help groups, peer coaching, and other support systems, which address not only the physical triggers of SUD but also the mental, emotional, and social triggers.

Like the overdose reversal drug naloxone, MAT is only effective in treating the withdrawal symptoms of opioids, not other classes of drugs. There are no equivalent medications to treat cocaine, methamphetamine, or tranquilizer withdrawal. However, the additional treatment modalities recommended to be used in conjunction with MAT can be effective for treating SUD patients with polysubstance use.


Leigh Wedenoja is senior policy analyst at the Rockefeller Institute of Government