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 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.”

Published in the journal Social Science & Medicine, the study indicates that people’s theoretical willingness to accept money in exchange for enduring pain offers a more reliable way to measure discomfort than conventional ‘self-reported’ measures of pain levels such as number scales or visual charts.

In a series of experiments involving more than 300 participants, volunteers aged between 18 and 60 were exposed to mild painful stimuli and asked either to rate the intensity on a numerical scale or to indicate how much financial compensation they would require to repeat the experience. The experiment also included an analgesia study of people experiencing the same painful stimuli but with one group receiving a placebo and the other the pain relief cream.

The results revealed that the monetary measure:

• distinguished more clearly between different levels of pain,
• detected the effects of pain relief more consistently, and
• enabled more meaningful comparisons across individuals.

The familiar “rate your pain from one to ten” question is widely used in clinical and research settings, but its limitations are well known. Individuals interpret the scale differently, making it difficult to compare results across people or groups. By contrast, the authors of the study say that putting a price on pain creates a shared frame of reference.

Professor Carlos Alós-Ferrer, from Lancaster University Management School explained: “We’ve all been asked to rate our pain from one to ten—but one person’s three might be another’s five, and those numbers can shift with experience. Our research proposes a better way: turning pain into money—not to commodify suffering, but to create a scale we can all share.

“Different people still will put a different price on the same pain, but there is no problem interpreting the question. As a result, measurements are more precise and the shift from low to high levels of pain is clearly reflected in the monetary scale. This makes it useful for clinical trials to study the effectiveness of painkillers and treatments, because participants are randomly assigned to different groups.”

The authors of the study say that refining pain self-reported measurement is important because inaccurate pain measurements can lead to inadequate pain management for example in an emergency, a reduction in quality of life for those with longer term conditions, as well as imposing a considerable burden on health care systems. For example, more than US $600 billion are spent annually in the USA to treat pain, surpassing the cost of treating heart disease and diabetes. The authors suggest that their method provides a complementary approach to reliably measure experienced pain across individuals and could open the door to future research improving pain measurement and management.

Image: More than US $600 billion are spent annually in the USA to treat pain

View more Credit: “pills” by Oregon State University is licensed under CC BY-SA 2.0.

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.

Prior research shows that upward of 70% of pregnant women use acetaminophen during pregnancy to control pain or reduce fever. The drug, which is the active ingredient of many pain-relief medications, is one of the few considered safe to take during pregnancy by the U.S. Food and Drug Administration.

The new findings suggest, however, that doctors should reconsider prescribing medications with acetaminophen to mothers during pregnancy, the researchers said.

“Most of the prior studies asked women to self-report whether they had taken Tylenol or anything that contained acetaminophen,” said lead author Brennan Baker, a researcher at Seattle Children’s Research Institute. Baker also works in the lab of Dr. Sheela Sathyanarayana, a UW Medicine pediatrician.

“This medication was also approved decades ago, and may need reevaluation by the FDA,” said Sathyanarayana, the paper’s senior author.  “Acetaminophen was never evaluated for fetal exposures in relations to long-term neurodevelopmental impacts.”

Acetaminophen is widely used during pregnancy, with 41–70% of pregnant individuals in the United States, Europe and Asia reporting use. Despite acetaminophen’s classification as low risk by regulatory agencies such as the FDA, accumulating evidence suggests a potential link between prenatal acetaminophen exposure and adverse neurodevelopmental outcomes, including ADHD and ADHD autism spectrum disorder, the researchers noted.

This research tracked a cohort of 307 women from 2006 to 2011, who agreed to give blood samples during their pregnancy.  The researchers tracked plasma biomarkers for acetaminophen in the samples.

The children born to these mothers were followed for 8 to 10 years. Among the women who did not use acetaminophen during pregnancy, the rate of ADHD was 9%, but for the women who used acetaminophen, the ADHD rate among their offspring was 18%.

Acetaminophen metabolites were detected in 20.2% of maternal plasma samples. Children whose mothers had these biomarkers present in their plasma had a 3.15 times higher likelihood of an ADHD diagnosis compared with those without detected exposure.

The association was stronger among daughters than sons, with the daughters of acetaminophen-exposed mothers showing a 6.16 times higher likelihood of ADHD while the association was weaker and nonsignificant in males. Researchers did not know why the association was stronger in females.

The investigators’ analysis used data from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) research cohort, which comprised 1,031 pregnant individuals in Memphis, Tenn., who were enrolled between 2006 and 2011.

By happenstance, and not by design, the study cohort included only Black women, Baker said, adding that the results could be generalized to woman and children of any race or ethnicity.

Mothers often are advised to turn to acetaminophen, the primary agent in Tylenol, rather than ibuprofen, which is more likely to adversely affect the fetal kidney or heart, Baker said.

“(Acetaminophen) is really the only option to control fever or pain during pregnancy,” he said.

So, what is a mother to do?

“There is obviously more work that needs to be done in this area,” he said. “And we need to continually update our guidance.”

For example, he suggested, during prenatal visits, patients should discuss the dosage of a drug that contains acetaminophen or talk about what pain it is intended to help manage, he said. Another drug class, such as triptans, is safe and effective for managing migraines, he added.

More work needs to be done to find out if some people can tolerate acetaminophen during pregnancy with no ill effects on the fetus while others cannot, he said.

He added that research findings on the effects of the drug and its potential risks during pregnancy have not been consistent.

One study recently released in Sweden, showed no link between maternal acetaminophen use and ADHD in their children; while another study out of Norway, did in fact find a link. The study out of Sweden, however, relied on self-reported data, Baker noted.

“The study out of Sweden, however, reported that only 7% of pregnant individuals used acetaminophen,” Baker noted. “And that study could have underestimated the exposure.

“I think it goes back to how the data was collected,” he added. “The conflicting results means that more research is needed.”

Medical societies and the FDA should update guidance on the use of acetaminophen as safety data emerges, Sathyanarayana said.

The study found that less than 3 percent of pain medications prescribed to the athletes who played in one or both of the two seasons were for opioids. Slightly more than 86 percent of the pain medications were nonsteroidal anti-inflammatory agents (NSAIDs) such as ibuprofen, naproxen, diclofenac or celecoxib – which are currently the preferred first-line pain medication recommended for pain.

“NFL athletes are exposed to very physical contact and to the development of pain during or after games due to injuries. There’s always been a concern from a safety and health perspective about what are they using to treat their pain,” said Regenstrief Institute and Indiana University School of Medicine researcher-clinician Kurt Kroenke, M.D., a study co-author and national leader in the field of medical symptoms.

“The good news is of all medicines prescribed to league players for pain, opioids account for only 3 percent. Moreover, only 10 percent of NFL athletes received even a single prescription for an opioid during a one-year period. I think there’s been much greater attention to what can be done in the training room for NFL athletes for their injuries and pain that doesn’t rely on medicines.”

Dr. Kroenke is a consultant to the National Football League-National Football League Players Association (NFLPA) Joint Pain Management Committee, whose members are appointed by the NFL and the NFLPA. The committee’s goals are to address the challenges of pain management for current NFL players and to facilitate research to better understand and improve potential alternative treatments.

A total of 3,142 players had a signed contract with at least one NFL team during the 2021 season. 14,903 prescriptions for pain medications issued to 2,207 of these men by either a team doctor or external medical providers were entered into the monitoring program database.

During the 2022 season, there were 14,880 prescription pain medications, slightly fewer than the prior year, issued to 2,189 players (out of a slightly larger population of 3,152 with signed contracts) entered into the monitoring program database.

In 2021 and 2022 a total of 576 players were prescribed opioid medications, indicatingthat most players (more than 90 percent) did not receive any opioid prescriptions.

Opioid prescriptions for NFL players in 2021 and 2022 contrast significantly with the findings of a survey of retired NFL players, reported in 2011, which showed that 52 percent had used prescription opioids during their career and of those who had used opioids, 71 percent reported misuse.

Since that time, Centers for Disease Control and Prevention (CDC) guidelines for prescribing opioids have changed significantly to reduce risks of opioid use disorder, overdose and death.

In 2019 the NFL and the NFLPA established the prescription drug monitoring program to track prescriptions of scheduled substances and other prescription medications. 2021 and 2022 were the first two years of standardized and robust data in this centralized electronic medical record system.

“The NFL-NFLPA Pain Management Committee is always looking to improve the health and safety of the players, and the Prescription Drug Monitoring Program aims to do that by educating medical staffs about their prescribing habits. We are encouraged by these early results but we hope to limit opioid prescriptions even further in the future,” said paper co-author Kevin Hill, M.D., MHS, director of the Division of Addiction Psychiatry at Beth Israel Deaconess Medical Center, an associate professor of psychiatry at Harvard Medical School and co-chair of the NFL-NFLPA Joint Pain Management Committee.

“Professional football is a very physical sport. But anyone who watches professional hockey or NBA basketball or big league soccer and even college and high school sports, realizes how these players also are prone to injuries and pain,” said Dr. Kroenke. “I think how we treat pain safely, using opioid pain medications very infrequently, applies across all sports.”

“Pain Medication Data from the 2021 and 2022 National Football League Prescription Drug Monitoring Program” is published in Current Sports Medicine Reports, a publication of the American College of Sports Medicine.

Authors and affiliations as listed in the paper:

Hill, Kevin P. MD, MHS^1,2; Kroenke, Kurt MD, MACP³; Wasserman, Erin B. PhD⁴; Mack, Christina PhD, MSPH⁴; Ling, Geoffrey S.F. MD, PhD^5,6; Mayer, Thom MD⁶; Solomon, Gary S. PhD^7,8; Sills, Allen MD, FACS^7,8

¹Division of Addiction Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA

²Department of Psychiatry, Harvard Medical School, Boston, MA

³Indiana University School of Medicine and Regenstrief Institute, Indianapolis, IN

⁴IQVIA, Research Triangle Park, NC

⁵National Football League Players Association, Washington, DC

⁶Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD

⁷National Football League, New York, NY

⁸Department of Neurological Surgery, Vanderbilt University School of Medicine, Nashville, TN

Kurt Kroenke, M.D., MACP  

In addition to his role as a research scientist with the William M. Tierney Center for Health Services Research at Regenstrief Institute, Dr. Kroenke is an Indiana University Indianapolis Chancellor’s Professor and a professor of medicine at the Indiana University School of Medicine.

In the first study of its kind in the UK, Louise Norton and Dr Bridget Dibb from the University of Surrey investigated the experiences of patients dependent on medication for chronic pain. Pharmacological treatment for chronic pain usually involves potentially addictive substances such as non-steroidal anti-inflammatory drugs, gabapentinoids, and opioids. Increased prescription levels of such pain relief medications have been associated with heightened levels of overdose and misuse.

Dr Bridget Dibb, Senior Lecturer in Health Psychology at the University of Surrey, said:

“An increasing number of people are experiencing chronic pain, which can interfere with their daily life and lead to depression and anxiety. Medication can help alleviate pain and return a sense of normalcy to a person’s life; however, there is a risk of dependence, which can potentially cause damage to vital organs, including the liver and kidneys.

“The first step to tackle this problem is to learn more about a person’s experience, how they perceive their dependence and how they interact with others, including the medical profession.”

To learn more, interviews were carried out with nine participants who had become dependent on pain medication. Participants spoke about how their dependence on pain medication resulted in them feeling not fully present and removed from their lives due to the side effects of the treatment. Many also expressed frustration about the lack of alternative treatment options available on the NHS to manage their pain, with medications being too readily prescribed.

The majority of participants also spoke about their negative interactions with medical professionals, with some attributing the cause of their dependence on them.  Many believed a lack of continuity between doctors led to missed opportunities in spotting their dependence, enabling it to continue.

Louise Norton added:

“Relationships with medical professionals substantially affect the experiences of those with painkiller dependence. Doctors can often be seen as authority figures due to their expertise and so patients may be apprehensive to question their treatment options. However, through providing patients with thorough information, doctors can enable more shared-decision making in which patients feel better supported and equipped to manage their chronic pain.”

Researchers noted participants felt stigmatised when speaking with others about their dependence due to a lack of understanding about their reliance to prescribed pain medications. Such interactions left participants feeling ashamed and critical of themselves.

Dr Dibb added:

“Those with a dependence on prescription painkillers not only have to navigate their reliance on the medication but the shame and guilt associated with such a need. Combining this with feelings of being misunderstood and ignored by medical professionals, they have a lot of emotional needs to be managed alongside their physical pain. To prevent this from happening medical professionals need to be more vigilant when prescribing medication and ensure that their patients are fully aware of the risk of dependence before they begin treatment.”

This study was published in the journal Pain and Therapy.

The research is published May 3 in the journal Nature.

Painkilling drugs such as morphine and oxycodone, as well as illegal street drugs such as heroin and fentanyl, activate what are known as mu opioid receptors on nerve cells. Those receptors relieve pain but also cause euphoria — the feeling of being high — and that feeling contributes to addiction. An alternative strategy is to target another opioid receptor, called the kappa opioid receptor. Scientists attempting to make drugs that target only the kappa receptor have found that they also effectively relieve pain, but they can be associated with other side effects such as hallucinations.

Researchers at the Center for Clinical Pharmacology at Washington University School of Medicine and the University of Health Sciences & Pharmacy, also in St. Louis, have identified the potential mechanisms behind such hallucinations, with the goal of developing painkillers without this side effect. Using electron microscopes, they identified the way that a natural compound related to the salvia plant selectively binds only to the kappa receptor but then causes hallucinations.

“Since 2002, scientists have been trying to learn how this small molecule causes hallucinations through kappa receptors,” said principal investigator Tao Che, PhD, an assistant professor of anesthesiology. “We determined how it binds to the receptor and activates potential hallucinogenic pathways, but we also found that other binding sites on the kappa receptor don’t lead to hallucinations.”

Developing new drugs to target these other kappa receptor binding sites may relieve pain without either the addictive problems associated with older opioids or the hallucinations associated with the existing drugs that selectively target the kappa opioid receptor.

Targeting the kappa receptor to block pain without hallucinations would be an important step forward, according to Che, because opioid drugs that interact with the mu opioid receptor have led to the current opioid epidemic, causing more than 100,000 overdose deaths in the U.S. in 2021.

“Opioids, especially synthetic opioids such as fentanyl, have contributed to far too many overdose deaths,” Che said. “There’s no doubt we need safer pain-relieving drugs.”

Che’s team, led by first author Jianming Han, PhD, a postdoctoral research associate in Che’s laboratory, found that a class of signaling proteins called G proteins cause the kappa opioid receptor to activate several different pathways.

“There are seven G proteins linked to the kappa receptor, and although they are very similar to each other, the differences between the proteins may help explain why some compounds can cause side effects such as hallucinations,” Han said. “By learning how each of the proteins binds to the kappa receptor, we expect to find ways to activate that receptor without causing hallucinations.”

The function of the G proteins has largely been unclear until now, particularly the protein that activates the pathway lined to hallucinations.

“All of these proteins are similar to one another, but the specific protein subtypes that bind to the kappa receptor determine which pathways will be activated,” Che said. “We have found that the hallucinogenic drugs can preferentially activate one specific G protein but not other, related G proteins, suggesting that beneficial effects such as pain relief can be separated from side effects such as hallucinations. So we expect it will be possible to find therapeutics that activate the kappa receptor to kill pain without also activating the specific pathway that causes hallucinations.”

Han J, Zhang J, Nazarova AL, Bernhard SM, Krumm BE, Zhao L, Lam JH, Rangari VA, Majumdar S, Nichols DE, Katritch V, Yuan P, Fay JF, Che, T. Ligand and G protein selectivity in kappa opioid receptor. Nature, May 3, 2023.

The study was funded with support from the National Institute of General Medical Sciences and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH). Grant numbers: R35 GM143061 and R01 NS099341.

The research was conducted by a multidisciplinary team led by Professor Shoham Choshen-Hillel from the Hebrew University of Jerusalem (HU)’s School of Business Administration and Federmann Center for the Study of Rationality, HU Psychology Department’s Dr. Anat Perry, and Dr. Alex Gileles-Hillel from Hadassah Medical Center and HU.

In the first part of the study, 67 doctors were given empathy assessment tasks in the morning and asked to respond to simulated patient scenarios.  These doctors were either at the end of a 26-hour shift or just beginning their workday. The study found that doctors who recently completed night shift showed less empathy for patient’s pain. For example, these physicians’ exhibited decreased emotional responses to pictures of people in pain and consistently scored their patients low on pain assessment charts.

In the second part of the study, the researchers looked at actual medical decisions made by emergency room doctors in the United States and Israel.  In all, they analyzed 13,482 discharge letters for patients who came to the hospital in 2013-2020 with a chief complaint of pain (headache, back pain, etc.).  Across all data sets, physicians were 20-30% less likely to prescribe an analgesic during nightshifts (compared to daytime shifts) and prescribed fewer painkillers than were generally recommended by the World Health Organization. “They’re tired and therefore they’re less empathic to patients’ pain.  When we looked at ER doctors’ discharge papers, we found that they prescribed fewer painkillers,” Choshen-Hillel explained.

This bias remained significant even after adjusting for patients’ reported level of pain, patient and physician’s demographics, type of complaint, and emergency department characteristics.  “Our takeaway is that nightshift work is an important and previously unrecognized source of bias in pain management, likely stemming from impaired perception of pain. The researchers explain that even medical experts, who strive to provide the best care for their patients, are susceptible to the effects of a nightshift,” Perry noted.

Looking ahead, the researchers suggest implementing more structured pain management guidelines in hospitals.  Another important implication relates to physician work structure, and the need to improve physicians’ working schedules. “Our findings may have implications for other workplaces that involve shiftwork and empathic decision-making, including crisis centers, first responders, and the military. In fact, these results should probably matter to all people who are sleep-deprived,” added Gileles-Hillel.