Overdose Deaths Increased in Wave 4 of the Opioid Crisis, Coinciding with the COVID-19 Pandemic


The suggested wave 4 of the opioid crisis saw high opioid-involved overdose death rates in urban counties and high acceleration of overdose deaths in rural counties, indicating that the opioid crisis worsened during the COVID-19 pandemic.

Opioid-involved overdose deaths rates steadily increased in counties of every urbanicity type during wave 4 of the US opioid crisis, which coincided with the COVID-19 pandemic, according to a research letter published in JAMA Network Open.

Though all counties experienced an increase in deaths, counties of different urbanicities experienced different timing of acceleration of opioid-involved overdose deaths.

The theory of 3 overlapping waves of opioid-involved overdose deaths based on supply and demand was posited by Daniel Ciccarone, MD, MPH, professor of Family Community Medicine at UCSF, in an earlier study. Supply factors included iatrogenic and new illicit sources, while demand included social, cultural, and technological factors.

In approximately 2000, the first wave was prompted by physicians overprescribing opioid painkillers associated with mass addiction. The second wave involved heroin. In 2007, opioid-involved overdose deaths from heroin escalated and surpassed those from prescription opioids by 2015. Wave 3 involved illicit synthetic opioids, such as fentanyl. The use of these escalated after 2013.

Further evidence suggests a fourth wave, complicated by the addition of stimulants and the COVID-19 pandemic. To inform prevention and mitigation strategies, researchers conducted a cross-sectional study examining trends in opioid-involved overdose death rates in urban and rural US counties during the 4 waves.

They sourced data on opioid-involved overdose deaths from January 1, 1999, to December 31, 2020, from the CDC’s WONDER Database. Opioid-involved overdose deaths included those from 3147 counties and county equivalents categorized on a 6-point urbanicity scale. Analyses were conducted to determine death rates.

The findings showed that counties of every urbanicity type experienced statistically significant annual opioid-involved overdose death rate growth, with the largest differences in opioid-involved overdose death rates by urbanicity observed at the start and end of the study period. The initial rank order, which identified urban counties as having the highest rates and rural counties the lowest, reemerged by 2020.

Opioid-involved overdose death rates were higher in most urban counties during waves 1 and 4; however, acceleration rates were higher in most rural counties. Before 2000, opioid-involved overdose deaths were rare in rural communities, which lacked resources to treat opioid use disorders.

Restrictions on synthetic and semisynthetic opioids were associated with increased heroin use, contributing to wave 2, beginning around 2013. Researchers found that wave 2 was characterized by accelerated growth in opioid-involved overdose death rates.

Diverse trends were observed across urbanicity. Linear growth shifted to nonlinear growth in wave 3.

Opioid-involved overdose deaths from fentanyl increased by a factor of 12 from 2013 to 2019. With 4 years of substantial acceleration across all urbanicity types, both urban and rural counties were substantially impacted by this wave.

During wave 4, which coincided with the COVID-19 pandemic, there was marked growth across all urbanicity types. The opioid crisis worsened in all county types. Overall, opioid-involved overdose death rates increased steadily in counties of every urbanicity type, with distinct temporal wave patterns by urbanicity.

“The varied timing of acceleration by urbanicity suggests that policy makers should consider resources and socioeconomic and treatment needs of rural and urban communities as the opioid crisis evolves, particularly because urban outreach and treatment approaches may not work in rural areas,” the authors wrote.

These findings were consistent with the wave theory posed by Ciccarone, according to the authors.

The study had limitations. As death investigation systems vary by state, the data may undercount opioid-involved overdose deaths. Not all individuals who die of opioid-involved overdose have opioid use disorder.

Additionally, deaths in wave 4 are often a function of multiple drug interactions or inclusion of stimulants with synthetic opioids in the nonregulated, nonopioid drug supply. Some opioid-involved overdose deaths are the result of drug interactions or recreational use that may require nonrehabilitative interventions.


Post L A, Lundberg A, Moss C B, et al. Geographic trends in opioid overdoses in the US from 1999 to 2020. JAMA Netw Open. 2022;5(7):e2223631. doi:10.1001/jamanetworkopen.2022.23631

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