Polysubstance Use and Naloxone

A new phase of the fentanyl crisis in America

Historically, the opioid epidemic in this country has been described as having three “waves.”¹ Now, however, we appear to be entering a fourth.¹ Dominated by the combined use of opioids and stimulants, the fourth wave of the US opioid overdose epidemic may ultimately be just as deadly as the three preceding it.^1-3 Read on to learn more about the fourth wave of the opioid overdose epidemic, polysubstance use, “speedballing” (a dangerous form of polysubstance use) and why this new chapter of the US opioid overdose crisis poses such a significant threat to public health.^1-3

The current state of the American opioid overdose crisis

Although it makes headlines on what seems like a daily basis, the opioid overdose crisis in this country, sadly, is not news.⁴ In spite of a small decrease in the number of opioid overdose fatalities estimated to have occurred in 2023, the increase in the death rate over time remains shocking—32.6 deaths per 100,000 in 2022 compared to 8.2 deaths per 100,000 in 2002.^5,6

The first three waves of opioid overdose deaths

From 1999 until 2021, nearly 645,000 Americans died from opioid-related overdoses.⁴ The Centers for Disease Control and Prevention (CDC) examined the data related to the different types of opioids associated with these fatalities and identified three distinct waves of opioid-related deaths:^1,4

• Wave 1: The first wave started with increased opioid prescribing in the 1990s.⁴ As a result of this shift, overdose deaths involving prescription opioids (natural and semi-synthetic opioids and methadone) began to rise.⁴
• Wave 2: The second wave of opioid overdose deaths began in 2010, with rapid increases in heroin-related overdose fatalities.⁴
• Wave 3: The third wave started in 2013, with significant increases in overdose deaths involving synthetic opioids, especially those involving illegally made fentanyl.⁴

A deadly fourth wave of opioid overdose

What distinguishes the fourth wave of the US opioid overdose epidemic from the first, second and third waves is the rapid increase in the number of overdose deaths involving multiple substances.¹ Illegal drugs commonly combined in this latest rash of fatalities are synthetic opioids like fentanyl and fentanyl analogs and stimulants like cocaine and methamphetamine.⁷

Double trouble: fentanyl and stimulants

Polysubstance use involves taking more than one drug at a time.^1,8 People who chronically use fentanyl or heroin, for example, may add a stimulant to offset the feelings of fatigue that can be associated with opioids.² This form of polysubstance use, also known as “speedballing,” is especially risky.² Stimulants can cause vasoconstriction of blood vessels and increase the need for oxygen, while opioids do just the opposite—they can actually slow down breathing so less oxygen is available.² The stress on the body resulting from this combination of substances can increase the likelihood that a person suffers an overdose.²

Polysubstance risk isn’t always intentional

While some people are aware they are using a combination of opioids and stimulants, this is not always the case.⁸ Unintentional polysubstance use can happen when a person takes drugs that have been mixed or cut with other substances (ie, synthetic opioids like fentanyl) without their knowledge.⁸ Speedballing, for example, has become difficult to avoid in recent years because of the widespread contamination of cocaine and methamphetamine with fentanyl.^2,9 In 2022, synthetic opioids (other than methadone) were involved in:^10,11

• 75% of cocaine-involved deaths
• 68% of benzodiazepine-involved deaths
• 68% of stimulant-involved deaths
• 63% of all psychostimulant*-involved deaths
• 47% of antidepressant-involved deaths

*Psychostimulants with abuse potential, primarily methamphetamine.

Risk factors for polysubstance use

According to one study, characteristics that may increase a person’s risk of polysubstance use include:^12,13

• Age (the risk of polysubstance use is higher in younger people)
• Lower levels of education
• Unemployment
• Being white
• Living with a disability
• Anxiety
• Depression and other mood disorders
• Severe tobacco or alcohol use

Genetics, a family history of substance abuse, stress, trauma and access to illegal drugs have the potential to contribute to polysubstance use as well.¹²

Signs of polysubstance use

The signs of polysubstance use may vary depending on the substances involved.¹² A person engaging in polysubstance use may:¹²

• Mix or use greater amounts of substances to achieved the desired effect
• Experience withdrawal symptoms (ie, insomnia, digestive issues) after stopping drug use
• Appear intoxicated, with symptoms that can lead to trauma injuries (ie, falls, accidents)
• Suffer overdose
• Have health problems (i.e., alcohol-related liver damage, seizures, addiction with chronic pain)

The craving and urge to use substances, the obsession with using, and planning drug use can change people’s priorities and the way they interact with others.¹² Those who engage in polysubstance use may also experience psychological changes and mental health issues, including:¹²

• Mood swings
• Changes in behavior
• Anxiety, depression or isolation

How you can help

If you have a friend or loved one who is struggling with substance use, there are things you can do to help:

• Educate yourself—Contacting the Substance Abuse and Mental Health Services Administration (SAMHSA) National Helpline at 1-800-662-4357 for information on support and treatment facilities in your area is one place to start.^14,15
• Carry naloxone—Keep naloxone on hand in case of an opioid overdose emergency.^16,17 Kloxxado^® (naloxone HCl) nasal spray 8mg is a widely available, easy-to-use intranasal naloxone product that could save the life of someone experiencing a life-threatening opioid overdose.¹⁶ Narcan^® is another intranasal naloxone product.¹⁷ The main difference between Kloxxado^® and Narcan^® is that each dose of Kloxxado^® contains 8 mg of naloxone, while each dose of Narcan^® contains 4 mg of naloxone.^16,17 A recent study showed that 78% of opioid overdose reversals involve at least 8 mg of naloxone.¹⁸
• Be patient—The goal may be recovery, but it’s important to be prepared for relapse.¹⁴ Although some people achieve long-term recovery on the first attempt, others may try multiple times over a number of years before they are successful.¹⁴

Kloxxado^® is a registered trademark of Hikma Pharmaceuticals USA Inc.

All other registered trademarks are the property of their respective owners.

Please see the Full Prescribing Information and Medication Guide for Kloxxado^® for complete product details.

NOTE: This article was not written by a medical professional and is not intended to substitute for the guidance of a physician. These are not Hikma’s recommendations, but rather facts and data collected from various reliable medical sources. For a full list of resources and their attributing links, see below.

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