Forgotten opioid has resurfaced as lethal street drug
Vanderbilt University Medical Center
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Co-author Shravani Durbhakula, MD, associate professor of Anesthesiology, Division of Pain Medicine at Vanderbilt University Medical Center.
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Nitazenes — a class of highly potent synthetic opioids — are rapidly emerging as a major contributor to the overdose crisis, according to a Pain Medicine review published today by authors from Vanderbilt University Medical Center and the University of Pittsburgh Medical Center.
Originally developed in the 1950s but never approved for clinical use, these substances are over 20 times more potent than fentanyl and hundreds to thousands of times more potent than morphine.
They can come in liquid, pills or powder form and have been found in substances sold via social media and on the illicit drug market since 2019.
Created as a potential pain reliever but never approved for medical use in humans or studied in a clinical trial, nitazenes are an illegal Schedule I drug that can be difficult to detect with standard drug tests and are often mixed into counterfeit pills or other street drugs.
“For patients, especially those with opioid use disorder or those exposed to illicit substances, nitazenes pose a serious and often hidden threat,” said co-author Shravani Durbhakula, MD, associate professor of Anesthesiology, Division of Pain Medicine at Vanderbilt University Medical Center.
“Because these drugs may not show up on routine toxicology screens, clinicians could miss a critical piece of the diagnosis during overdose treatment. Patients may also need higher or repeated doses of naloxone to reverse their effects,” she said.
The Tennessee State Unintentional Drug Overdose Reporting System (TN SUDORS) identified a total of 92 nitazene-involved fatal drug overdoses among Tennessee residents from 2019-2023.
In Tennessee, naloxone was administered in only one in three deaths involving nitazenes, and in all nitazene-involved deaths the drug was laced with other substances, most commonly fentanyl and methamphetamine.
“Many people consuming nitazenes don’t even know they’re taking them,” Durbhakula said. “These substances are often adulterants in pills sold as other opioids, making public education more important than ever.
“We also want to stress that this is not just a drug issue; it is a public health emergency. Addressing it will require collaboration between clinicians, public health officials, law enforcement and community organizations to implement harm-reduction strategies, support addiction treatment, and raise awareness about these evolving threats,” she added.
The authors recommend expanding access to new test strips that can detect nitazenes and for at-risk patients to have access to take-home naloxone, addiction treatment and education about counterfeit pills.
“Nitazenes are an emerging class of synthetic opioids that are even more potent than fentanyl and often undetected by routine drug tests,” said corresponding author Ryan Mortman, MD, a resident in the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh Medical Center.
“Their rapid spread in the illicit drug market, combined with the difficulty of reversing overdoses, underscores the urgent need for public awareness, early recognition, and expanded access to harm-reduction tools such as naloxone,” he said.
Co-author Trent Emerick, MD, associate professor of Anesthesiology and Perioperative Medicine and Bioengineering at the University of Pittsburgh’s School of Medicine, said next steps are to generate human clinical data to better understand nitazenes’ effects, especially long-term health impacts, metabolism and response to treatments like naloxone.
"The opioid crisis continues to evolve, and a thorough understanding of the mechanisms and risks of nitazenes is crucial for pain physicians, anesthesiologists and other providers,” Emerick said.
Journal
Pain Medicine
Article Title
Nitazenes: Are Pain Physicians Aware of the Risks?
Article Publication Date
14-Sep-2025
Researchers: Targeted efforts needed to stem fentanyl crisis
Study details high death tolls, economic loss in some states
A new study illuminates how some areas of the country have been hit much harder than others by the fentanyl epidemic, which took more than 70,800 lives in 2022 alone.
The research calls attention to a need for focused, coordinated efforts to prevent overdose deaths in the places where deaths from the opioid are rampant, said lead author Thomas Wickizer, a professor emeritus in The Ohio State University College of Public Health.
The study appears in the journal Health Affairs Scholar.
“We can look at this map and see there are certain areas which are experiencing this at an extremely dire rate, and energy and resources, including financial investments, should be shifted toward the areas with the greatest potential impact,” Wickizer said.
“There’s no fentanyl epidemic in South Dakota or Wyoming or Nebraska. But in Kentucky, West Virginia, New England, Ohio … there’s this intense concentration and it’s taking a huge toll.”
The research team studied data from 2022, when more than 70,800 people died of unintentional overdoses, a 31-fold increase over the 2,139 U.S. fentanyl deaths a decade before. The numbers have skyrocketed as fentanyl — which is 50 to 100 times more potent than morphine — has become more widely available.
Because it is relatively cheap to illegally manufacture, smuggle and distribute, and because it can be made to mimic the looks of prescription medications, fentanyl has become a powerful and deadly actor in the international drug trade.
“This is the worst manmade epidemic in U.S. history,” Wickizer said.
In 2022, West Virginia’s toll, at 75 per 100,000 deaths, was 15 times greater than that of South Dakota. Other areas with high fentanyl mortality rates included Washington, D.C., (58), Kentucky (45) and Ohio (42).
The study also attaches an economic loss to those deaths — adding another layer of understanding to the harm fentanyl deaths cause not just to individuals and families, but to society.
The research team estimated the nationwide toll in 2022 was at least 2 million years of life lost, corresponding to an economic loss on the order of $57 billion to $67 billion. They estimated that Ohio incurred the largest economic loss, with $3 billion in losses based on more than 3,900 deaths in 2022.
“These economic loss measures are another way to illustrate the brutality of the drug on people’s lives, on their communities. There is such a tremendous amount of pain and loss,” Wickizer said.
Local, state or regional efforts to combat the fentanyl epidemic may be more valuable than national approaches, the study authors said.
“It’s also important to recognize this cuts across different sectors. If you’re going to be successful, you need to engage public health, health care, law enforcement, social services, schools and others,” Wickizer said.
A model in Cuyahoga County, Ohio — home to Cleveland — may serve as inspiration for others looking to save lives due to fentanyl overdoses, said Rachel Mason, study co-author and an Ohio State PhD student in health services management and policy.
The Cuyahoga County program, funded by the Alcohol, Drug Addiction and Mental Health Services Board, was among 72 Mason and Wickizer surveyed in 2023.
There, fentanyl test strips were once considered drug paraphernalia. Now, they’re made available through a county-level program with multiple partners, she said. Along with harm reduction efforts including strips that allow drug users to test for fentanyl, the county’s successful program included social marketing to make people aware that drugs — anything from Adderall to heroin — could contain the opioid.
Other researchers who worked on the study are Evan Goldstein and Nasser Sharareh of the University of Utah’s School of Medicine.
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Journal
Health Affairs
IU researchers find that opioid pain meds prescribed during pregnancy do not cause increased risk of autism or ADHD
Indiana University
An Indiana University study brings a comprehensive new perspective to a growing body of evidence suggesting that mild to moderate use of prescribed opioid pain medications during pregnancy does not cause an increased risk for autism spectrum disorder (ASD) or attention-deficit/ hyperactivity disorder (ADHD) in children. The study explores documented associations between prescribed opioid pain medications during pregnancy and the increased risk for the two neurodevelopmental disorders. It concludes that other factors, rather than fetal exposure to opioid pain medications, may explain the increased risk for autism and ADHD in the children of individuals who received opioid prescriptions during pregnancy.
This study “helps provide more information to pregnant individuals and their physicians who are trying to make complex decisions about how to best manage pain during pregnancy,” said first author Emma Cleary, a graduate student in the lab of the study’s co-principal investigator, Professor Brian D’Onofrio in the Department of Psychological and Brain Sciences.
“While they are not able to rule out small increased risks for autism and ADHD with high amounts of exposure, which were rare in our data,” Cleary observed, “the results suggest that there is no causal effect of prescribed opioid analgesics on the risk for these two common neurodevelopmental disorders.”
The study’s findings further suggest, as co-author Ayesha Sujan, a postdoctoral fellow at Stanford University School of Medicine, noted, “that the observed associations between prenatal exposure to opioid analgesics and two major neurodevelopmental disorders—autism and ADHD—are largely driven by factors leading up to opioid analgesic use rather than the opioid exposure itself.”
Study data and designs
The study drew on the extensive data from Swedish population-based registers, including more than 1.2 million births in Sweden from 2007 to 2018 when analyzing risk of ASD, among whom 4.4% were exposed to prescribed opioid medications during pregnancy. Analyses of ADHD risk included more than 900,000 births from 2007 to 2015.
The researchers estimated risks based on the dose range and duration of cumulative exposure during pregnancy. By analyzing the data from a variety of perspectives, the study also accounted for a range of possible confounding factors. When comparing children exposed to opioid medication to unexposed children, results suggested increased risk with higher doses, similar to what was observed in previous studies. However, when they statistically adjusted for factors such as parental age and psychiatric conditions, and used a narrower set of comparison groups to that account for shared characteristics between the groups, the observed risks decreased. Notably, when comparing exposed children to unexposed children whose birthing parent had been prescribed opioids in the year before conception but not during pregnancy, the increased risk for autism and ADHD in the exposed children was markedly diminished. Similarly, the risk for these neurodevelopmental conditions disappeared when comparing differentially exposed siblings. These designs provide a strong test of the causal effects of these medications because they enabled the researchers to hold constant some of the shared characteristics of individuals who are prescribed opioids around the time of pregnancy and the genetic and environmental factors common to siblings.
The paper, titled “Prescribed opioid analgesic use in pregnancy and risk of neurodevelopmental disorders in children: A retrospective study in Sweden,” was published on September 16 in the journal PLOS Medicine.
As Cleary explained, “The way we take our findings together, is that yes, initially, we observe this increased risk for high dose and low doses. But as we increase our adjustment for various sources of potential bias, adjusting for proxies of socio-economic status, mental health history of parents, characteristics of the pregnancy, diagnoses of painful conditions, previous opioid pain medication use, and genetics and environmental factors in the sibling comparisons, we’re able to account for many of these things that potentially could confound our associations. And when doing so, the risks that we initially observe go away. As previous studies have explored, these background characteristics would make you both more likely to be exposed to prescribed opioids and increase risk of ASD and ADHD.”
One of the study’s innovative features was the use of text-mining algorithms, a novel technique previously used by some of the authors to study ADHD medication use but not yet applied to prescribed opioid use. This technique enabled the researchers to take into account the written instructions on each prescription and thereby consider the possible variations in how patients actually took the medications. “With these pharmacy-based dispensations,” said Cleary, “there’s always some uncertainty, but with text-mining of the ‘as needed dosages’ or prescriptions with a range, such as 1-3 pills a day, we were able to test different possible versions of exposure – and across those analyses we found converging results.”
The study also entailed work across several fields and disciplines. As D’Onofrio added, “This is a great example of how collaborations among researchers, clinicians, and data engineers can leverage large datasets to help answer key clinical questions, especially when it is not feasible to conduct randomized controlled trials.”
Takeaways and future directions
The findings ultimately provide greater clarity for those seeking to treat pain during pregnancy insofar as they suggest that opioid pain medication does not cause substantial increased risk of autism and ADHD. Yet, the findings also beg the question: What are the underlying causes of increased risk for autism and ADHD in this group of children and how can they be addressed?
“We need more explanation,” said Cleary. “It could be the pain and underlying pathophysiological processes, it could be genetics. But people who may be more likely to be prescribed an opioid, may also need more support to help manage symptoms throughout their pregnancy.”
More research is needed to explain the workings of these factors. And yet, as her co-author Sujan added, “the results elucidate the critical need to provide pregnant individuals experiencing pain with psychosocial support and evidence-based pain management tools, both pharmaceutical and non-pharmaceutical.”
Other researchers include Martin E. Rickert, IU Department of Psychological and Brain Sciences; Franziska Fischer, Karolinska Institutet, Stockholm, Sweden; Tyra Lagerberg, Karolinska Institutet and Warneford Hospital, University of Oxford, Oxford, United Kingdom; Zheng Chang, Karolinska Institutet; Paul Lichtenstein, Karolinska Institutet; Patrick D. Quinn, IU School of Public Health; and Anna Sara Öberg, Karolinska Institutet and Harvard University T.H. Chan School of Public Health.
This research was supported by the National Institute on Drug Abuse of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Journal
PLOS Medicine
Method of Research
Data/statistical analysis
Subject of Research
People
Article Title
Prescribed opioid analgesic use in pregnancy and risk of neurodevelopmental disorders in children: A retrospective study in Sweden
Article Publication Date
16-Sep-2025
Prescribed opioid pain medications during pregnancy likely aren’t associated with increased risk of autism, ADHD
Study of more than 1 million Swedish children finds increased risk can be attributed to other factors
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Person holding silver blister pack.
view moreCredit: cottonbro studio, Pexels (CC0, https://creativecommons.org/publicdomain/zero/1.0/)
Previous studies have suggested that children exposed to opioid pain medications while in the womb have higher rates of autism spectrum disorder (ASD) and attention- deficit/hyperactivity disorder (ADHD), but a new study finds that any increased risk could be explained by other factors. Emma N. Cleary of Indiana University Bloomington, USA, and colleagues published these findings on September 16th in the open-access journal PLOS Medicine.
Opioids are commonly prescribed to help manage pain during pregnancy, but it is unclear whether opioid exposure in utero increases a child’s risk of neurodevelopmental disorders like ASD and ADHD. In the new study, researchers looked for connections between the dose and duration of opioid exposure during pregnancy, and the child’s risk of later being diagnosed with these two conditions.
Researchers looked at rates of ASD in more than 1.2 million children born in Sweden between 2007 and 2018, and rates of ADHD in more than 900,000 children born between 2007 and 2015, along with their level of exposure to opioid pain medications during pregnancy. They saw that while 2.0% of the unexposed children had ASD by age 10, 2.9% of children exposed to a low dose of opioids and 3.6% of children exposed to a high dose were diagnosed with the condition. Rates of ADHD followed a similar trend. However, when the researchers used statistical methods and different comparisons to consider confounding by genetic and environmental factors that might be obscuring the relationship between opioids and neurodevelopmental disorders, the increased risk disappeared.
The researchers cautioned that their study did not look at the impact of extremely high doses and long durations of opioids, since their dataset did not include such information due to Swedish opioid prescription practices. However, overall, the findings provide little evidence that exposure to prescribed opioid pain medications during pregnancy substantially increases a child’s risk for autism and ADHD at the levels they studied.
Emma N. Cleary says, “We wanted to conduct this study to help provide more information for pregnant individuals and their physicians who are trying to make complex decisions about how to best manage pain during pregnancy. Pregnant individuals and their physicians must weigh the importance of managing painful conditions with concerns about potential consequences of fetal exposure to prescribed opioid pain medications. These concerns include potential impacts on child neurodevelopment. These decisions are made even more difficult due to insufficient data on the safety of these medications during pregnancy. While this study is not able to rule out small increased risks with high amounts of exposure, the results suggest that there is not a causal effect of prescribed opioid analgesics on risk for two common neurodevelopmental disorders, providing more data to support decision-making.”
Co-author Ayesha C. Sujan adds, “We are excited to share our findings because we believe that they have important clinical implications. Our findings suggest that the observed associations between prenatal exposure to opioid analgesics and two major neurodevelopmental disorders—autism and ADHD—are largely driven by factors leading up to opioid analgesic use rather than the opioid exposure itself. Our results, therefore, elucidate the critical need to provide pregnant individuals experiencing pain with psychosocial support and evidence-based pain management tools. These can include both pharmaceutical and non-pharmaceutical approaches.”
In your coverage, please use this URL to provide access to the freely available paper in PLOS Medicine: https://plos.io/4md1kNM
Citation: Cleary EN, Sujan AC, Rickert ME, Fischer F, Lagerberg T, Chang Z, et al. (2025) Prescribed opioid analgesic use in pregnancy and risk of neurodevelopmental disorders in children: A retrospective study in Sweden. PLoS Med 22(9): e1004721. https://doi.org/10.1371/journal.pmed.1004721
Author countries: United States, Sweden, United Kingdom
Funding: Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health (T32DA024628-15 [ENC] and R01DA048042 [Principle investigators: BMD and ASO], URL: NIDA.NIH.GOV | National Institute on Drug Abuse (NIDA)). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Journal
PLOS Medicine
Method of Research
Observational study
Subject of Research
People
COI Statement
Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: ENC declared that research reported in this publication was supported by the National Institute on Drug Abuse (NIDA) of the National Institutes of Health under award number T32DA024628-15; BMD and ASO declared that they have received a grant from NIDA to support the work under award number R01DA048042. FF reported that she is an employee of Quantify Research AB, providing consultancy services to pharmaceutical companies and other private and public organizations and institutions. ZC declared that he received speaker fees from Takeda Pharmaceuticals, outside the submitted work. The authors have declared that no interests have a financial stake in the results of the current study and no other competing interests exist.
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