Pain and fever are common in early pregnancy and the options to manage them have been limited. Studies have raised safety concerns regarding acetaminophen while data on the safety of NSAIDs—which include widely used medications such as ibuprofen, diclofenac, and naproxen—has remained inconclusive.

The new study used data from the Southern Israeli Pregnancy Registry (SiPREG) to analyze 264,858 singleton pregnancies between 1998 and 2018, of which 20,202 (7.6%) were exposed to NSAIDs during the first trimester—most commonly ibuprofen (5.1%), diclofenac (1.6%), and naproxen (1.2%). Major congenital malformations were identified from linked clinical, hospitalization, and termination records. The researchers adjusted risks for maternal and pregnancy characteristics including maternal age, ethnicity, diabetes, obesity, folic acid use, and the reason for NSAID use.

NSAID exposure was not associated with major congenital malformations overall (8.2% vs. 7.0% in unexposed pregnancies; matched adjusted relative risk = 0.99), nor with malformations in specific organ systems including the cardiovascular, musculoskeletal, central nervous system, gastrointestinal, and genitourinary systems. No association was observed for any individual drug, and dose-response analyses found no significant link between cumulative NSAID exposure and birth defect risk.

“Our results provide reassuring evidence that NSAID use in early pregnancy is not associated with major birth defects,” the authors say. “These findings can help both pregnant women and physicians make informed decisions about managing pain and fever in early pregnancy.”

Dr. Daniel adds, “We used data from SiPREG, a large pregnancy registry in southern Israel that tracks medication use and pregnancy outcomes, including birth defects identified not only at birth, but also in pregnancy terminations and during the first year of life.”

“We examined whether common pain relievers from the NSAID group, such as ibuprofen, are linked to birth defects. We found no increased risk overall or for specific types of birth defects.”

Dr. Ariel Hasidim notes, “One of the most interesting parts of this research was finding a careful way to deal with gaps in real-world data. One key issue was that some people may have used common medicines like ibuprofen without it being recorded, which could affect the results. We tackled this head-on by using a special analysis to see whether and how this missing information might have influenced our findings.”

Paper available in PLOS Medicine: https://plos.io/4mGgtZ9

Citation: Hasidim AA, Ben Shitrit I, Idan D, Michael T, Levy A, Pariente G, et al. (2026) First-trimester nonsteroidal anti-inflammatory drugs exposure and risk of major congenital malformations: A retrospective register-based cohort study. PLoS Med 23(5): e1005063. https://doi.org/10.1371/journal.pmed.1005063

Author countries: Israel

Funding: The author(s) received no specific funding for this work.

The authors of the new PLOS Medicine study found that among people taking gabapentinoids, adding benzodiazepines was associated with a doubling in the risk of hospitalisation for drug poisoning, while adding opioids was associated with a 30% increase in risk.

The research revealed that gabapentinoids are often started as medication during periods of already heightened vulnerability to drug poisoning, which may be when someone is experiencing worsening symptoms and is seeking out additional medications.

The researchers found that the risk of poisoning can subside after someone starts taking gabapentinoids, but the elevated risk can persist for months, suggesting that gabapentinoids might not be an effective solution to reduce drug poisoning risks.

Gabapentinoids – drugs such as gabapentin and pregabalin – are widely prescribed for conditions such as epilepsy, nerve pain, and anxiety disorders, and are increasingly prescribed for pain relief as an alternative to opioids. They are now the seventh most commonly prescribed medication in the US, and a previous UCL study reported that across 65 countries, their usage increased by more than fourfold from 2008 to 2018.*

The authors say their findings suggest that clinicians should exercise more caution in prescribing gabapentinoids, and should be particularly vigilant around the risks of prescribing them alongside other medications.

Lead author Dr Kenneth Man (UCL School of Pharmacy) said: “Prescription rates for gabapentinoids have been increasing rapidly in recent years, as they are seen as a safe alternative to opioids. While they can be effective for pain relief and do have better perceived safety profiles than opioids, there are still substantial risks that clinicians and patients should be mindful of.”

The researchers reviewed data from people who had been prescribed a gabapentinoid between 2010 and 2020 in the UK, and searched for cases of hospitalisations for drug poisoning both before, during or after prescription of a gabapentinoid, while also reviewing what other medications people had been prescribed.

They focused their analysis on 16,827 people who had had at least one drug poisoning hospitalisation, which constituted just under 2% of the entire group of people who had been prescribed a gabapentinoid during the study period. The analysis incorporated up to 10 years of data for each individual, so that researchers could compare drug poisoning risks to times when the same person was not being prescribed a gabapentinoid.

The researchers included a range of different types of poisoning cases, both intentional and accidental, without excluding those who were taking more than the prescribed dosage or otherwise misusing a medication. Symptoms of drug poisoning may at times include loss of consciousness, breathing difficulties or seizures.

The researchers found that people taking both a gabapentinoid and a benzodiazepine were four times more likely to be hospitalised with drug poisoning in the four weeks after starting gabapentinoid treatment, in comparison to when they were taking neither drug. Gabapentinoid combined with an opioid doubled the poisoning risk in the first four weeks, relative to taking neither drug.

Study participants were frequently taking gabapentinoids alongside other prescribed medications, with 89% taking them alongside opioids at some point in the study period, and 55% taking them alongside benzodiazepines for at least some time.

The highest risk of drug poisoning was found in the 90 days before the study participants began taking gabapentinoids, suggesting the prescription of gabapentinoids may sometimes have been linked to concerns about the effects of other medications.

The study’s first author, Dr Andrew Yuen (UCL School of Pharmacy), explained: “A clinician’s decision to prescribe gabapentinoids may sometimes be an attempt to minimise the risk of drug poisoning linked to opioids or other medications.

“While the risk of poisoning did decrease somewhat after patients began gabapentinoid treatment, they still faced an elevated risk of drug poisoning, which suggests that clinicians need to remain vigilant to the risks.”

Dr Kenneth Man added: “Our findings do not suggest that gabapentinoids are unsafe or should not be prescribed, but clinicians should be cautious when prescribing them, particularly if a patient is taking other medications as well, and clinicians should closely monitor patients who are taking them.”

The researchers say their findings are aligned with an announcement earlier this year from the UK’s medicines regulator, the Medicines and Healthcare products Regulatory Agency (MHRA), strengthening the warnings on gabapentinoids regarding addiction, dependence, withdrawal, and tolerance.**

The researchers say that it remains unclear if gabapentinoids can directly cause drug poisoning, and how that might occur, but there is evidence to suggest they might enhance the sedative effects of medications including opioids and benzodiazepines. There is also evidence of abuse potential, particularly for people with a history of substance abuse.

The study, supported by the NIHR UCLH Biomedical Research Centre, involved researchers in the UCL School of Pharmacy, the UCL Division of Psychiatry, UCLH, the University of Hong Kong, and Aston University.

* https://www.nature.com/articles/s41467-023-40637-8

** https://www.gov.uk/drug-safety-update/improving-information-supplied-with-gabapentinoids-pregabalin-slash-gabapentin-benzodiazepines-and-z-drugs

That is the key finding from a new Washington State University study showing that recurring inflammation linked to the disease can sensitize the nervous system, driving lasting pain.

The work helps explain one of the most frustrating aspects of endometriosis, a condition in which tissue similar to the uterine lining grows outside the uterus. It affects more than 10% of reproductive-aged women, or roughly 190 million people worldwide, and often causes severe pelvic pain and infertility.

In a paper published in the Journal of Clinical Investigation, WSU scientist Kanako Hayashi and collaborators found that repeated cycles of inflammation can trigger lasting changes in the brain, amplifying and sustaining pain over time.

“We’re showing that this is not just a local gynecological disease,” said Hayashi, a professor in WSU’s School of Molecular Biosciences. “Once the system is sensitized, the brain keeps responding, even if the original lesions are gone.”

Endometriosis has long puzzled researchers because pain does not reliably match the extent of disease. Some patients with widespread lesions report little discomfort, while others with minimal tissue growth experience debilitating symptoms.

“That mismatch tells us something more complex is happening,” Hayashi said. “It’s not just the lesions themselves. It’s how the body and the nervous system respond over time.”

To investigate, the research team designed a model that mimics repeated menstrual cycles. Most previous studies induced endometriosis-like conditions only once. Hayashi’s group instead introduced multiple cycles, simulating the repeated backflow of menstrual tissue called retrograde menstruation, thought to contribute to the disease.

Mice exposed to repeated cycles showed heightened sensitivity and lasting changes in the nervous system. Inflammation increased in the pelvic region, and signals traveled along nerve pathways to the spinal cord and brain, where researchers observed clear signs of neuroinflammation.

“That repeated stimulation acts like turning up the volume again and again,” Hayashi said. “Eventually, the system becomes hypersensitive. Even small signals can feel very painful.”

To strengthen the findings, the team also analyzed tissue samples from rhesus macaques with naturally occurring endometriosis through a collaboration with the Oregon National Primate Research Center. No primate experiments were conducted at WSU.

The results help explain why pain can persist even after lesions are removed. Once the brain’s pain-processing circuits are sensitized, they can continue to generate pain signals independently.

“It becomes a feedback loop,” Hayashi said. “The body is sending signals to the brain, and the brain is reinforcing those signals back to the body.”

The study also points toward new approaches for treatment. Rather than focusing only on removing lesions or suppressing hormones, therapies could target inflammation in the nervous system. In the study, both a commonly used hormonal drug and an immunomodulating compound reduced pain sensitivity and brain inflammation in the mouse model, even without shrinking lesions.

“We now have a system where we can follow the entire process from the beginning,” Hayashi said. “That gives us a powerful way to develop better treatments and, hopefully, detect the disease earlier.”

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.”