King’s College London research, published today in Clinical Toxicology, sheds light on the UK’s growing synthetic opioid problem.

The presence of nitazenes on the unregulated drug market has risen steeply in the last seven years – prompting UK and international bodies to issue public health warnings about their use.

Nitazenes are a class of synthetic opioids which can have potencies of up to 500 times that of heroin. They can be readily manufactured at low cost. These potent synthetic opioids were originally synthesised for use in humans as analgesics but their development was halted due to extreme potencies.

While the National Crime Agency (NCA) reported 333 fatalities linked to nitazenes in 2024, researchers believe that the number of deaths has been underreported as concerns have been raised by toxicologists regarding their stability in postmortem blood samples. This means they are likely being missed by postmortem toxicology tests.

Testing this theory, researchers used anesthetised animal models to find that on average only 14% of nitazene present at the time of overdose was present when tested under real-world pathology and toxicology sample handling conditions.

The team then used modelling to reveal a 33% excess in drug deaths in Birmingham in 2023, using data from the UK National Programme on Substance Use Mortality (NPSUM) based at King’s College London. They believe that a credible explanation for at least some of these excess deaths may be due to the non-detection of nitazene that degraded prior to toxicology testing being performed. It typically takes around a month for blood samples to be analysed by toxicologists.

Dr Caroline Copeland, Senior Lecturer in Pharmacology & Toxicology at King’s College London, said: “If nitazenes are degrading in post-mortem blood samples, then we are almost certainly undercounting the true number of deaths that they are causing. That means we’re trying to tackle a crisis using incomplete data. When we don’t measure a problem properly, we don’t design the right interventions – and the inevitable consequence is that preventable deaths will continue.

“Understanding how nitazenes degrade, and what they degrade into, is critical. If we can identify these breakdown products and where degradation is occurring, we will be able to detect deaths more accurately and respond more effectively. Better science leads to better surveillance, and better surveillance will save lives.

“This research shows that the harm caused by nitazenes is likely being significantly underestimated. Because these drugs degrade in post-mortem blood, we may be missing up to a third of the deaths they are involved in, meaning public health responses are being designed and funded for only two-thirds of the real problem.

“Behind this undercount are people dying suddenly from extremely potent opioids, families left without answers, and communities facing a growing but largely hidden toll.”

Previous research suggested a potential link between paracetamol use in the first year of life and later eczema, asthma and other diseases.

“Our study found that paracetamol and ibuprofen are incredibly safe to use in young children,” says lead researcher Professor Stuart Dalziel, Cure Kids Chair of Child Health Research at Waipapa Taumata Rau, University of Auckland, and Paediatrician at Starship Children’s Hospital.

Dalziel says paracetamol and ibuprofen are the most common medicines prescribed or bought over the counter for babies worldwide.

“These results give parents and health professionals high confidence to continue to use these important medications.”

Almost 4,000 babies across New Zealand participated from birth, with half randomised to ensure their parents provided paracetamol and half to ensure their parents  provided ibuprofen when the infants required medication for fever or pain relief in the first year of life.

The researchers asked parents at regular intervals whether their children had eczema or asthma symptoms, or bronchiolitis. They also checked prescribing and hospital records.

The results for the first year of data have now been analysed and published in the leading journal The Lancet Child & Adolescent Health.

Eczema affected about 16 percent of babies given paracetamol and 15 percent of those given ibuprofen. Bronchiolitis occurred in about five percent of babies in both groups. These differences were not significant. Serious side effects were rare, and none was caused by the medications.

The study found no association between either medication and eczema or bronchiolitis and confirmed that both drugs were safe to use.

It is the first randomised controlled trial – considered the gold standard for research – to address this question.

This paper is part of a longer project dubbed the ‘Paracetamol and Ibuprofen in the Primary Prevention of Asthma in Tamariki (PIPPA Tamariki) study’.

PIPPA Tamariki is the largest trial ever conducted in children in New Zealand, and participants are being followed from birth to age six.

The researchers will soon publish findings on the same children at age three, and later at age six.

The long-term objective of the study is to test whether there are any links between paracetamol and specific conditions that can only be accurately diagnosed once children reach school age.

“We know that two‑thirds of children who are wheezy at age three years don’t develop asthma by age six,” says Dalziel.

“Thus we need to wait until school age to ultimately test if paracetamol in the first year of life causes asthma.”

Similarly, developmental disorders such as autism and attention deficit hyperactivity disorder (ADHD) are more accurately diagnosed as children get older.

Lead author Dr Eunicia Tan, a senior lecturer at the University of Auckland and emergency physician at Middlemore Hospital, says, “Ultimately, the study will provide important evidence regarding the link between paracetamol use and asthma, eczema, hay fever, and developmental disorders, such as autism and ADHD.”

The study was funded by the Health Research Council of New Zealand and Cure Kids and run by the University of Auckland and the Medical Research Institute of New Zealand, Wellington.

In this case, gabapentinoids — which include gabapentin (Neurontin) and pregabalin (Lyrica) — may cause leg swelling, leading doctors to suspect heart failure and then prescribe diuretics that can cause kidney injury, light headedness, and falls.

Researchers tracked the medical records of 120 older veterans, most of whom were male and were long-term users of five or more medications. All had taken gabapentinoids, followed by loop diuretics, which are prescribed for fluid buildup, a possible symptom of heart failure.

“Gabapentinoids are non-opioids, and prescribers associate them with a relatively favorable safety profile,” Michael Steinman, MD, a professor of Medicine at UCSF and senior author of the study said, noting that these prescriptions have almost doubled in a decade. “Patients taking them should regularly check in with their doctor to assess whether this is the best treatment for them and consider other options, including non-drug alternatives that might be more appropriate.”

Following gabapentinoids, the patients developed swelling in the legs or feet, but only 4 of the veterans’ physicians considered the drugs as the culprit, while 69 considered other causes. This included heart failure, and another condition called venous stasis in which abnormal blood flow puts pressure on veins, sometimes leading to ulcers. Although none of the veterans had these conditions in the year before they started taking gabapentinoids, just one doctor discontinued the drug. Close to 1 in 5 patients underwent imaging to rule out life-threatening conditions that the doctors suspected were the cause of their leg swelling.

All of the physicians, including those who suspected gabapentinoids as the cause, prescribed loop diuretics, such as Lasix. Within two months, 28 patients had symptoms that may have been due to the new drugs, such as worsening kidney functioning, dizziness, and blurred vision, and low sodium or potassium, which can disrupt critical body functions. Six were hospitalized or evaluated in the Emergency Department.

“Gabapentinoids may be prescribed at unnecessarily high doses or for conditions that they may not help,” said Matthew Growdon, MD, an assistant professor of Medicine at UCSF who is the first author of the paper. “In these cases, doctors should consider not prescribing these drugs — or giving lower doses to lessen the risk of prescribing cascades and other side effects.”

Journal: JAMA Network Open

Co-Authors: Please see the paper

Funding: National Institute on Aging (R03AG078804, K76AG088411, R03AG082859, P30AG044281, P01AG066605, 2K24AG049057, P01AG066605, R33AG086944); National Center for Advancing Translational Sciences (KL2TR001870); VA Center for Medication Safety in Aging and VA National Center for Patient Safety.

Disclosures: Steinman received honoraria from the American Geriatrics Society and royalties from UpToDate.

The work which was led by Anick Bérard, a Canadian researcher, points to methodological inadequacies in previous reviews and studies. It offers reassurance for pregnant women, public health agencies, and healthcare providers in alignment with recommendations from the Centers for Disease Control and Prevention (CDC), American College of Obstetricians and Gynecologists (ACOG), and The Society of Obstetricians and Gynecologists of Canada (SOGC).

Paracetamol/acetaminophen is the most commonly used over-the-counter pain reliever during pregnancy, taken in an estimated 70% of all pregnancies. In 2021, a commentary about a possible increased risk of NDDs in children exposed to acetaminophen in utero was published, leading to substantial concerns in the general population and among prescribers. However, this publication—as well as a subsequent narrative review by the same group of researchers—was met with criticism of its methodology, choice and quality of studies considered, and lack of mechanistic data.

Acetaminophen exposure during pregnancy is difficult to assess in epidemiological studies because it is available over the counter without a prescription and is used as needed. Hence, there is inconsistency between studies regarding the risk of NDDs associated with its use in pregnancy.

‘Given the significant methodological challenges in this area, additional individual studies will inevitably suffer the same limitations as are already present in published studies,’ explains Dr Bérard of the University of Montreal and CHU Sainte-Justine, Montréal, Quebec, Canada. ‘An integrative approach, summarising the present state of knowledge and quantifying specific methodological areas of biases, as our study does, is needed in order to have a significant impact in future studies performed as well as on the causal effect of acetaminophen use during pregnancy on the risk of specific NDDs.’

Dr Bérard and an international group of experts in the field conducted a comprehensive search of major bibliographic databases and grey literature to identify human studies evaluating the association between prenatal acetaminophen exposure and the risk of NDDs in offspring. Sixteen studies retrieved met eligibility criteria.

The authors conclude that the observed increase in risk is likely not causal and can be explained by inherent biases and underlying genetic factors. They recommend further studies to examine this association more robustly.

Commenting on the study, noted expert in the field Dr David Coghill, University of Melbourne, said it was a landmark piece of work that highlights the importance of good science and strong methods. ‘The findings of no association between acetaminophen [paracetamol] use during pregnancy and the risk of autism and ADHD in the child are not unexpected. These new findings support the position of professional organisations and regulatory bodies around the world that women should continue to use acetaminophen during pregnancy and do so without fear. The fact that they contradict the recent announcements by the US government must be acknowledged and acted on.’

“We are commonly asked in youth addiction treatment how long to stay on medication and how strictly it must be taken to provide protection,” said lead and corresponding author Scott Hadland, MD, MPH, MS, chief of Adolescent and Young Adult Medicine at Mass General Brigham for Children. “Our findings suggest that maintaining high adherence for at least a year substantially reduces overdose risk. It’s a clear message to clinicians, families and youth that longer treatment saves lives.”

The study analyzed data on 11,649 youth aged 13-26 who initiated buprenorphine in Massachusetts between 2014 and 2020. Using the Massachusetts Public Health Data Warehouse—a comprehensive statewide dataset linking medical, pharmacy, and mortality records—the team identified four patterns of medication use: high adherence for 12 months (24%), low adherence for 12 months (28%), discontinuation after 3-9 months (16%), and discontinuation in under 3 months (33%).

Compared to youth with high adherence for 12 months, those who stopped within 3-9 months had an 82% higher risk of opioid overdose, while those who stopped in under 3 months had a 76% higher risk. Youth who were on medication for 12 months but had low adherence had a 46% higher risk. Youth who stayed on medication for a year and had high adherence also had lower rates of emergency department visits and hospitalizations.

While buprenorphine is the only medication approved for opioid use disorder in adolescents under 18, many families and youth elect to discontinue treatment after just weeks or months once they see improvements. However, the study’s findings show that consistent, year-long use likely provides the greatest protection against overdose and other serious outcomes.

“Opioid use disorder is a condition that can come and go over the course of several years,” said Hadland. “Staying on treatment longer—even when things feel better—may prevent relapse and save a young person’s life.”

The study underscores the importance of helping youth adhere to treatment, including through the use of long-acting injectable buprenorphine and providing enhanced support for youth with co-occurring mental illness or housing instability.

“Amid the fentanyl era, short-term treatment is simply not enough,” said Hadland. “Clinicians, insurers, and health systems should do everything possible to help young people continue medication for at least a year or longer. This is a key step toward reducing youth overdose deaths.”

Authorship: In addition to Hadland, authors include Simeon D. Kimmel, Shapei Yan, Amy L. Bettano, Wei-Hsuan Lo-Ciganic, Sarah M. Bagley, Jessica B. Calihan, Heather E. Hsu, and Marc R. Larochelle.

Disclosures: Hadland is a member of the editorial board of Pediatrics. Lo-Ciganic has received grants from Merck Sharp & Dohme and Bristol Myers Squibb, holds a pending patent (U1195.70174US00), and has been compensated by Teva Pharmaceuticals for consulting services unrelated to this work. Kimmel reports receiving consulting fees from the Massachusetts Department of Public Health’s Bureau of Substance Addiction Services.

Funding: The study was funded by the National Institute on Drug Abuse (K23DA045085, R01DA057566, K18DA059913, and related grants). Coauthors included researchers from Boston Medical Center, the Massachusetts Department of Public Health, and the University of Pittsburgh.

Paper cited: Hadland SE et al. “Buprenorphine Treatment Duration and Adherence among Youth and Subsequent Health Outcomes” Pediatrics DOI: 10.1542/peds.2025-071147

The researchers say confidence in the findings of existing evidence reviews and studies on this topic is low to critically low, and suggest that any apparent effect seen in previous studies may be driven by shared genetic and environmental factors within families.

Regulatory bodies, clinicians, pregnant women, parents, and those affected by autism and ADHD should be informed about the poor quality of the existing reviews and women should be advised to take paracetamol when needed to treat pain and fever in pregnancy, they add.

Paracetamol (acetaminophen) is the recommended treatment for pain and fever in pregnancy and is considered safe by regulatory agencies worldwide.

Existing systematic reviews on this topic vary in quality, and studies that do not adjust for important factors shared by families or parents’ health and lifestyle cannot accurately estimate the effects of exposure to paracetamol before birth on neurodevelopment in babies.

To address this uncertainty, researchers carried out an umbrella review (a high-level evidence summary) of systematic reviews to assess the overall quality and validity of existing evidence and the strength of association between paracetamol use during pregnancy and the risks of autism or ADHD in offspring.

They identified nine systematic reviews that included a total of 40 observational studies reporting on paracetamol use during pregnancy and the risk of autism, ADHD, or other neurodevelopmental outcomes in exposed babies.

Four reviews included meta-analysis (a statistical method that combines data from several studies to give a single, more precise estimate of an effect).

The researchers used recognised tools to carefully assess each review for bias and rated their overall confidence in the findings as high, moderate, low, or critically low. They also recorded the degree of study overlap across reviews as very high.

All reviews reported a possible to strong association between a mother’s paracetamol intake and autism or ADHD, or both in offspring. However, seven of the nine reviews advised caution when interpreting the findings owing to the potential risk of bias and impact of unmeasured (confounding) factors in the included studies.

Overall confidence in the findings of the reviews was low (two reviews) to critically low (seven reviews).

Only one review included two studies that appropriately adjusted for possible effects of genetic and environmental factors shared by siblings, and accounted for other important factors such as parents’ mental health, background, and lifestyle.

In both these studies, the observed association between exposure to paracetamol and risk of autism and ADHD in childhood disappeared or reduced after adjustment, suggesting that these factors explain much of the observed risk, say the researchers.

They acknowledge some limitations. For example, the included reviews differed in scope and methods, they were unable to explore the effects of timing and dose, and their analyses were limited to autism and ADHD outcomes only.

However, they say this overview brings together all relevant evidence and applies established methods to assess quality, and shows “the lack of robust evidence linking paracetamol use in pregnancy and autism and ADHD in offspring.”

They conclude: “The current evidence base is insufficient to definitively link in utero exposure to paracetamol with autism and ADHD in childhood. High quality studies that control for familial and unmeasured confounders can help improve evidence on the timing and duration of paracetamol exposure, and for other child neurodevelopmental outcomes.”

That first paper on the collective experience of more than 1,800 trial patients found that the combination of ibuprofen and acetaminophen provided better pain relief than hydrocodone with acetaminophen for the first two days after surgery and greater satisfaction over the post-operative period. The new subgroup analysis, published in JAMA Network Open, demonstrated that the results held for both male and female patients.

“We wanted to determine whether the pain medication’s effects were consistent in males and females separately,” said Janine Fredericks Younger, an associate professor at Rutgers School of Dental Medicine and lead author of the analysis. “And what we found is that in both subgroups (males and females), the non-opioid was superior for that first day and night, and then no worse than the opioid for the rest of the post-op period.”

The trial that produced both papers, funded by an $11 million grant from the National Institutes of Health, compared patients who received 400 milligrams of ibuprofen (Advil, Motrin) combined with 500 milligrams of acetaminophen (Tylenol) against those who got 5 milligrams of hydrocodone with acetaminophen.

The gender-specific analysis was particularly important because women consistently report higher pain levels after surgery, raising questions about whether pain medications work differently for each sex.

“There’s obviously different biological mechanisms, different hormones involved,” said Cecile Feldman, dean of Rutgers School of Dental Medicine and senior author of both studies. “But results confirm that the analgesic effect for both groups is the same.”

The researchers deliberately enrolled equal numbers of men and women from the start, allowing them to conduct robust subgroup analyses. Patients across five universities tracked their pain twice daily for nine days using electronic diaries, rating not just pain but also sleep quality, ability to perform daily activities and overall satisfaction.

On every measure, the over-the-counter combination matched or beat the opioid. Patients taking the non-opioid medications reported better sleep quality and less interference with daily activities. Those who received opioids were twice as likely to call back requesting additional pain medication.

“The results actually came in even stronger than we thought they would,” Feldman said. “We expected to find the non-opioid to be non-inferior, so that at least it was no worse than opioids. We were surprised to see that it was actually superior.”

Dental procedures are a common entry point for opioid exposure. Dentists wrote more than 8.9 million opioid prescriptions in 2022, ranking among the nation’s leading prescribers of the drugs.

“There are studies out there to show that when young people get introduced to opioids, as many have via wisdom tooth extraction, there’s an increased likelihood that they’ll eventually use them again, and then it can lead to addiction,” said Fredericks Younger, noting that opioid overdoses kill more than 80,000 Americans annually.

The research focused on the extraction of impacted wisdom teeth, which requires cutting into gums and sometimes removing bone, making it one of the most painful dental procedures. The Food and Drug Administration uses this as a standard model for testing pain medications because it reliably produces moderate to severe pain for about 48 hours.

Feldman said the results, showing the superiority of the over-the-counter medication to opioids, likely apply to other dental procedures but cannot be automatically generalized to surgeries in other parts of the body. She would like to see similar studies conducted for a range of procedures, particularly those for orthopedic injuries, which frequently result in opioid prescriptions for high school and college athletes.

Despite mounting evidence, many dentists continue writing “just in case” opioid prescriptions for patients who are told to start with over-the-counter medications. The next phase of research will examine why these prescribing patterns persist.

“How can we now, with the evidence and the knowledge that we have, eliminate these prescriptions from being written?” Fredericks Younger said.

The findings align with American Dental Association recommendations to avoid opioids as first-line pain treatment. Feldman said the study’s results leave little room for doubt.

“We feel pretty confident in saying that opioids should not be prescribed routinely for dental procedures,” she said. “Our non-opioid combination really should be the analgesic choice.”

In the early 2000s, use of prescription opioids to treat acute and chronic noncancer pain increased substantially in Canada, and with it came a rise in opioid-related harms. The availability of more opioid products, coupled with aggressive marketing of these drugs, contributed to these early increases in Canada and in other countries.

Many initiatives have been introduced with the goal of reducing these harms throughout the country, including policy changes, a focus on continuing medical education for evidence-based prescribing, and a national Canadian guideline for opioid prescribing published in 2017.

With these changes, a need has emerged for national information on prescription opioid use in Canada and how this varies in different parts of the population. Researchers aimed to help fill this gap with a study of opioid prescribing in 6 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, and Quebec) between 2018 and 2022. The number of people newly starting opioids declined 8% during the study period, and the total number of people accessing opioids declined 11%. In 2022, across Canada, approximately 1.8 million people started an opioid to manage pain for the first time. However, the rate of opioid prescribing varied among provinces, ranging from 55 new opioid starts per 1000 people in Ontario to 63 per 1000 people in Alberta.

“[T]he interprovincial variations in our findings may indicate differences in the implementation of prescribing guidelines, underscoring the need for coordinated national strategies and ongoing evaluation of their effects on patient outcomes,” writes Dr. Tara Gomes, a researcher in the Ontario Drug Policy Research Network at St. Michael’s Hospital, Unity Health Toronto, with coauthors.

Annual rates of new prescriptions were higher for females, older adults, and people living in lower-income neighbourhoods and rural regions. Codeine was most usually prescribed in most provinces, with the exception of Quebec, where people were more commonly dispensed morphine and hydromorphone. Oxycodone dispensing decreased over time, although in Ontario over one-quarter of opioids prescribed were still for oxycodone in 2022.

The authors caution that although lower rates of opioid prescribing may reflect doctors’ efforts to ensure safe and appropriate prescribing, a balance is needed to ensure that people are not left without pain relief or cut off from medications without appropriate supports and coordination of care.

“Importantly, although these recommendations intended to promote safer opioid prescribing, improper implementation can lead to rapid dose tapering, abrupt opioid discontinuation, and reluctance to initiate patients on opioids when clinically indicated. In some cases, these changes have led to patients seeking access to opioids from the unregulated drug supply, which are inherently more harmful,” write the authors.

The researchers suggest that clinicians engage in conversations with patients to ensure shared decision-making, and assess pain levels and ability to function.

“The truth is … that opioids are less effective and less safe than many care to admit,” writes Dr. David Juurlink, an internist and researcher at Sunnybrook Research Institute and the University of Toronto, Toronto, Ontario, in a related commentary https://www.cmaj.ca/lookup/doi/10.1503/cmaj.251666 praising the continued decline in opioid prescribing.

Opioids can be effective when carefully prescribed, particularly for short periods. But, with long-term use, their effectiveness can wane and they can harm patients in ways that are hard to appreciate.

“Most clinicians have seen how well opioids can work when first given,” writes Dr. Juurlink. “But they are at their pharmacologic best in the initial days of treatment. Continue them for weeks, months, or years and the calculus becomes progressively less favourable.”

Juurlink urges thoughtful prescribing, which “begins with recognizing that all patients in pain fall into 1 of 3 mutually exclusive groups: those not yet on opioids, those taking opioids chronically (sometimes called ‘legacy patients’), and those with established addiction. The latter 2 groups overlap and are easily harmed by rapid dose reduction, but they can also be harmed by dose escalation. For such patients, when pain intensifies, nonopioid strategies are preferred. The first group, by contrast, has the most to gain from thoughtful opioid stewardship.”

In a new analysis, researchers explored the possible consequences of that reduction in costs through the eyes of those who make up the drug supply chain. The authors summarize potential long-term implications for the structure, conduct, and performance of the illegal opioid supply industry, as well as potential consequences for drug law enforcement organizations.

The analysis was conducted by researchers at Carnegie Mellon University, the University at Albany, the University of Arizona, and the University of Maryland. It is published in Global Crime.

The United States has had a substantial illegal opioid market for more than 50 years. Starting around 2000, a rise in prescriptions for opioids for pain management led to an additional market in diverted prescription opioids. And around 2015, illegally manufactured fentanyl entered the market, which spurred continued increases in fatal drug overdoses.

“Although there has been much research on these changes, few studies have considered the motivations for the rise in fentanyl from the perspective of the illegal drug traffickers,” says Jonathan P. Caulkins, professor of operations research and public policy at Carnegie Mellon’s Heinz College, the lead author.

The analysis begins by asking how fentanyl, a cheap, synthetic opioid, might affect supply and demand in a market previously dominated by heroin, a plant-based, semi-synthetic product that in North America is more expensive, less potent, and less lethal than fentanyl.

Fentanyl is much cheaper to produce than heroin, generating a supply shock in the market for illegal opioids that may have implications beyond the standard prediction that prices will drop and consumption will increase. In their analysis, the authors describe the shock of cheap production, showing why this might lead to proportionately smaller reductions in the retail price than in the import price of illegal opioids. Then they consider the implications for illegal opioid suppliers and supply, relying on knowledge about the idiosyncrasies of illegal drug markets.

The authors then assess effects on the demand side of the market; given the demand elasticities for illegal opioids, price reductions lead to only modest declines in expenditures and thus also in drug-related income-generating crime. They also consider possible implications for the ability of law enforcement to affect the market, addressing why high-level seizures of fentanyl become even less relevant than when heroin was the principal illegal opioid. Among the authors’ conclusions:

• The implications of fentanyl’s lower cost will be larger in Mexico’s high-level markets than in U.S. retail markets because the cost of the drug represents a smaller part of the cost of supply in U.S. retail markets. Hence, the market shift toward fentanyl may have less pronounced effects on crime, violence, and criminal incomes in the United States than on economic outcomes in Mexico.
• That asymmetric impact has implications for high-level interdiction and drug enforcement: Seizures at higher market levels are less valuable to law enforcement precisely because drugs are less costly for traffickers to replace.
• In Mexico, the shift to synthetic fentanyl represents a major loss of income for farmers who grew poppies.
• The health implications in the United States are enormous, with significantly increased rates of overdose.
• The spread of fentanyl has also led to changes in domestic markets beyond a drop in price, including more frequent adulteration of illegal opioids with other dangerous substances and the spread of counterfeit pills containing fentanyl. In addition, fentanyl has made the prospect of using illegal drugs scarier for drug consumers.

“In our analysis, we walk through potential implications for both the supply side and the demand side of the market,” notes Shawn D. Bushway, professor of public administration at University at Albany, who coauthored the article. “We believe our work is the first explicit economic analysis of potential effects of fentanyl on the illegal market for opioids.”

The study, led by Feinuo Sun, UT Arlington assistant professor of kinesiology and the senior author of the paper in The Journal of Pain, investigated how state-level policies— including minimum wage laws, Medicaid coverage, other welfare programs and education levels—affect pain outcomes.

“For the first time, we examined the development of arthritis pain over 10 years and how state welfare policies shape these trends,” Dr. Sun said.

Arthritis pain has become more common over the last decade, now affecting an estimated 58.5 million Americans, according to the Centers for Disease Control and Prevention. Between 2011 and 2021, an additional 4.6 million people reported moderate to severe joint pain.

The study analyzed data from the Behavioral Risk Factor Surveillance System from 2011 to 2021, tracking arthritis-related pain over a full decade. This approach differs from previous research, which typically relied on cross-sectional data capturing only a single year.

Texas is among the states showing a significant increase in overall joint pain. Colorado saw the largest rise, with an average increase of 26.2%, followed by Hawaii, Nebraska, Kansas, North Dakota and Texas. Only four states—Montana, Wyoming, South Dakota and New York—showed a decreasing trend.

However, among the states with a significant increase in overall joint pain, Texas was the only one to see a decrease in the educational gap—meaning the difference in pain prevalence between adults with high and low education levels narrowed, Sun said.

“In Colorado, both the education gap and overall pain prevalence have risen, indicating that pain has been increasing most rapidly among adults with the lowest education levels,” she said. “In contrast, in Texas, the education gap narrowed while overall pain prevalence still increased, suggesting that the rise was primarily driven by growing pain prevalence among higher-educated adults.”

Identifying states with both rising pain prevalence and widening education gaps, Sun said, is a key takeaway from the study, as it highlights where interventions may be most needed.

Another important finding is the impact of Medicaid generosity in reducing both overall pain and disparities across education levels. The study found that states with more generous Medicaid programs not only have lower joint pain prevalence but also smaller education gaps in pain. The score for Medicaid generosity was measured across four dimensions: income eligibility, immigrant benefits, administrative burden and benefit levels.

“Medicaid generosity is a comprehensive measure of how accessible and beneficial the program is,” Sun said. “And we found that more generous Medicaid programs help reduce arthritis-related pain, particularly among adults with lower levels of education.”

Next steps for the research include exploring how individuals’ experiences with pain are influenced by changes in state-level policies, helping researchers better understand how geography and governance shape public health.

Tramadol is an opioid used to treat moderate to severe pain in adults. Some antidepressants that inhibit the CYP2D6 enzyme, called CYP2D6 inhibitors, can interfere with how the body metabolizes tramadol. When the CYP2D6 enzyme is blocked, tramadol is not metabolized properly and may build up in the body, potentially increasing the risk of side effects like seizures. Common CYP2D6-inhibiting antidepressants include fluoxetine, paroxetine and bupropion.

“We found a modest but measurable increase in the risk of seizures when tramadol was taken with antidepressants that inhibit the CYP2D6 enzyme,” said study author Yu-Jung Jenny Wei, PhD, of The Ohio State University in Columbus. “This risk was consistent whether the antidepressant or tramadol was started first.”

Researchers analyzed 10 years of Medicare data to identify 70,156 nursing home residents age 65 and older who had been prescribed both tramadol and an antidepressant.

They divided participants into two groups based on which drugs they took first. Of participants, 11,162 people took tramadol first and then an antidepressant with it, while 58,994 people took an antidepressant first and then added tramadol.

Seizure rates for people who took tramadol first were 16 seizures per 100 person-years, and for people who took antidepressants first, the rate was 20 seizures per 100 person-years. This means for every 100 people who used both tramadol and an antidepressant followed for one year, about 16 or 20 received a seizure diagnosis.

In both groups, researchers then compared seizure rates between those who took tramadol with CYP2D6-inhibiting antidepressants and those who took tramadol with antidepressants that do not inhibit the enzyme. In those who took tramadol first and added an antidepressant, the rate was 18 seizures per 100 person-years for those taking CYP2D6-inhibiting antidepressants compared to 16 seizures per 100 person-years in people taking other antidepressants. In those who took antidepressants first and added tramadol, the rate was 22 seizures per 100 person-years for those taking CYP2D6-inhibiting antidepressants compared to 20 seizures per 100 person-years in people taking other antidepressants.

To help ensure the differences were not due to other health issues, the researchers adjusted for factors such as pain levels, depression symptoms, physical function and cognitive ability.

After adjustments, for people who took tramadol first, seizure risk was 9% higher when taking it with a CYP2D6-inhibiting antidepressant compared to with an antidepressant that did not inhibit this enzyme. For those who took an antidepressant first and added tramadol, the risk was about 6% higher for people who took a CYP2D6-inhibiting antidepressant compared to people who took an antidepressant that did not inhibit the enzyme.

To test whether this interaction was specific to tramadol, the researchers repeated the analysis using hydrocodone, another opioid pain reliever that is unlikely to cause seizure risk when used with antidepressants. No increased seizure risk was observed with hydrocodone and CYP2D6-inhibiting antidepressants.

“These findings underscore the need for careful prescribing practices, especially for older adults with complex health conditions,” said Wei. “Doctors should be aware of potential seizure risks when prescribing tramadol with antidepressants, particularly CYP2D6 inhibitors. Given how commonly both are prescribed to older adults, these interactions may be more important than previously thought.”

A limitation of the study was that medication data came from prescription records, which did not confirm whether patients took the drugs as directed.

This research was supported by the National Institute on Aging.

And it likely increases the risk of serious side effects, including heart disease, the findings indicate, prompting the researchers to conclude that the potential harms of tramadol probably outweigh its benefits, and that its use should be minimised.

Tramadol is a dual action opioid widely prescribed for the treatment of moderate to severe acute and chronic pain. As such, it’s recommended in several medical guidelines for pain management, note the researchers.

Its use has surged in recent years, and it’s now among the most commonly prescribed opioids in the US, possibly because of its perceived lower risk of side effects and the widespread belief that it is safer and less addictive than other short-acting opioids, they add.

Although tramadol has been included in previous systematic reviews, none has provided a comprehensive assessment of tramadol’s efficacy and safety in a range of chronic pain conditions, they say.

In a bid to plug this knowledge gap, the researchers scoured research databases for randomised clinical trials published up to February 2025 that compared tramadol with placebo (dummy treatment) for patients with chronic pain, including cancer pain.

Nineteen clinical trials involving 6506 participants with chronic pain were eligible for inclusion in the analysis. Five looked at the impact of tramadol on neuropathic pain; nine focused on osteoarthritis; four looked at chronic low back pain; and one focused on fibromyalgia.

The average age of the trial participants was 58, but ranged from 47 to 69. Tablets were the primary formulation used; only one trial included topical cream. Length of treatment ranged from 2 to 16 weeks while length of follow up ranged from 3 to 15 weeks.

Pooled data analysis of the trial results showed that while tramadol eased pain, the effect was small and below what would be considered clinically effective.

Eight of the trials reported on the proportion of serious side effects arising after treatment during follow up periods of between 7 and 16 weeks.

Statistical analysis of these trials results indicated a doubling in the risk of harms associated with tramadol compared with placebo, mainly driven by a higher proportion of ‘cardiac events,’ such as chest pain, coronary artery disease, and congestive heart failure.

Use of tramadol was also associated with a heightened risk of some cancers, although the follow up period was short, making this finding “questionable,” say the researchers.

Pooled data analysis of all the trial results indicated that tramadol treatment was associated with a heightened risk of several milder side effects, including nausea, dizziness, constipation, and sleepiness.

The researchers acknowledge that the outcome results were at high risk of bias, but this increases the likelihood that the findings overestimate the beneficial effects and underestimate the harmful effects of tramadol, they suggest.

They point out: “Approximately 60 million individuals worldwide experience the addictive effects of opioids. In 2019, drug use was responsible for approximately 600,000 deaths, with nearly 80% of these fatalities associated with opioids and approximately 25% resulting from opioid overdose.

“In the United States, the number of opioid-related overdose deaths increased from 49,860 in 2019 to 81,806 in 2022. Given these trends and the present findings, the use of tramadol and other opioids should be minimised to the greatest extent possible.”

They conclude: “Tramadol may have a slight effect on reducing chronic pain (low certainty of evidence) while likely increasing the risk of both serious (moderate certainty of evidence) and non- serious adverse events (very low certainty of evidence). The potential harms associated with tramadol use for pain management likely outweigh its limited benefits.”