What You Should Know About Tylenol and Autism

By Mark Louie Ramos

Claims from the Trump White House about links between use of the painkiller acetaminophen – often sold under the brand name Tylenol in the U.S. – during pregnancy and development of autism have set off a deluge of responses across the medical, scientific and public health communities.

As a father of a child with level 2 autism – meaning autism that requires substantial support – and a statistician who works with such tools as those used in the association studies cited by the White House, I find it useful to think about the nuances of association versus causation in observational studies. I hope that this explanation is helpful to parents and expecting parents who, like me, are deeply invested in the well-being of their children.

Association Is Not Causation, But…

Most people have heard this before, but it bears repeating: Association does not imply causation.

An often-cited example is that there is a very strong association between ice cream sales and incidents of shark attacks. Of course, it goes without saying that shark attacks aren’t caused by ice cream sales. Rather, in the summertime, hot weather drives more appetite for ice cream and beach time. The increased number of people at the beach does, in turn, cause the likelihood of shark attacks to increase.

Yet pointing this out on its own is neither intellectually satisfying nor emotionally appeasing when it comes to real-life medical concerns, since an association does suggest potential for a causal relationship.

In other words, some associations do end up being convincingly causal. In fact, some of the most consequential discoveries of the past century in public health, like the links between smoking and lung cancer or the human papillomavirus (HPV) and cervical cancer, started out as findings of very strong association.

So when it comes to the issue of prenatal acetaminophen use and autism development, it is important to consider how strong the association found is, as well as the extent to which such an association could be considered causal.

Establishing Causal Association

So how do scientists determine if an observed association is actually causal?

The gold standard for doing so is conducting what are called randomized, controlled experiments. In these studies, participants are randomly assigned to receive treatment or not, and the environment where they are observed is controlled so that the only external element that differs among participants is whether they received treatment or not.

In doing this, researchers reasonably ensure that any difference in the outcomes of the participants can be directly attributed as being caused by whether they received the treatment. That is, any association between treatment and outcome can be considered causal.

Yet oftentimes, conducting such an experiment is impossible, unethical or both. For instance, it would be highly difficult to gather a cohort of pregnant women for an experiment and extremely unethical to randomly assign half of them to take acetaminophen, or any other medication for no particular reason, and the other half not to.

So when experiments are simply infeasible, an alternative is to make some reasonable assumptions on how observational data would behave if the association was causal and then see if the data aligns with these causal assumptions. This can very broadly be referred to as observational causal inference.

Parsing What the Studies Mean

So how does this apply to the current controversy over the potential for acetaminophen use during pregnancy to affect the fetus in a way that could result in a condition like autism?

Researchers who try to understand causal roles and links between one variable and potential health outcomes do so by considering: 1) the size and consistency of the association across multiple attempts to estimate it, and 2) the extent to which such association has been established under observational causal inference frameworks.

As early as 1987, researchers have been working to measure possible associations between acetaminophen use during pregnancy and autism. A number of these studies, including multiple large systematic reviews, have found evidence of such associations.

For instance, a 2025 review of 46 studies that examined association between acetaminophen use and an array of neurodevelopmental disorders, including autism, identified papers with five positive associations between acetaminophen and autism.

In one of those studies, which examined 73,881 births, the researchers found that children who were exposed to acetaminophen prenatally were 20% more likely to develop borderline or clinical autism spectrum conditions. Another examined 2.48 million births and reported an estimated association of only 5%.

Both of those are weak associations. For context, estimations of increased lung cancer risk from smoking in the 1950s were between 900% to 1,900%. That is, a smoker is 10 to 20 times more likely than a nonsmoker to develop lung cancer. By comparison, in the two autism studies above, a pregnant woman who takes acetaminophen is 1.05 to 1.20 times more likely than one who does not take the drug to have a child who would be later diagnosed with autism.

Not All Studies Are Created Equal

It’s also important to keep in mind that many factors can affect how well a study is able to estimate an association. In general, larger sample sizes provide both greater power to detect an association if one does exist, as well as improved precision over estimating the value of the association.

This does not mean that studies with smaller sample sizes are not valid, only that from a statistical perspective, researchers like me place greater confidence in an association drawn from a larger sample size.

Once an association – even a small one – is established, researchers then must consider the extent to which causation can be claimed. One way to do this is through what’s called dose-response. This means looking at whether the association is higher among women who took higher doses of acetaminophen during pregnancy.

The study mentioned above that looked at 2.48 million births shows an example of dose-response. It found that pregnant women who reported taking higher doses have higher autism risk.

Another way to examine possible causality in this context is to analyze sibling outcomes, which that same paper did. Researchers looked at whether associations between acetaminophen and autism persisted within families with more than one child.

For example, in a family with two children, if the mother used acetaminophen during one pregnancy and that child was later diagnosed with autism, but she did not use it during the other pregnancy and that child was not diagnosed, then this strengthens the causal claim.

Conversely, if acetaminophen was used during the pregnancy of the child who was not diagnosed with autism and not used during the pregnancy of the child who was, then that weakens the causal claim. When this was included in the analysis, the dose-response disappeared, and in fact the overall 5% increased risk mentioned before likewise disappeared. This weakens the claim of a causal relationship.

At present, there is clearly not enough evidence to establish a causal association between prenatal acetaminophen use and autism.

Yet as a parent who wonders if my daughter will ever be able to write her name, or hold a job or raise kids of her own, I understand that such explanations may not appease the fears or concerns of an expecting mother who is suffering from a fever.

Naturally, all of us want absolute certainty. But that’s not possible when it comes to acetaminophen use, at least not at this time.

Your doctor will be able to provide you with much sounder advice than any existing study on this topic. Your OB-GYNs are very likely aware of these studies and have much better judgment as to how these results should be considered in the context of your personal medical history and needs.

Researchers, meanwhile, will continue to dig deeper into the science of this critically important issue and, hopefully, provide greater clarity in the years to come.

Mark Louie Ramos, PhD, is an Assistant Research Professor of Health Policy and Administration at The Pennsylvania State University.

His research experience includes statistical development and multidisciplinary projects involving large datasets such as the United Kingdom Biobank, the National Health and Nutrition Examination Survey, and the United States Military Health System. He has taught mathematics and statistics subjects for over 20 years.

This article originally appeared in The Conversation and is republished with permission.

How Opiophobia Paved the Way for Tylenol Hysteria

By Crystal Lindell

The dirty little secret about alternatives to opioids is that they are all mostly bullshit.

They’re expensive, sometimes outright dangerous, and perhaps worst of all, ineffective.

So when doctors are telling you that you don’t need opioids to treat your pain, what they are really saying is that you don’t need pain treatment at all.

And that’s exactly the message that people are getting from the Trump administration’s recent guidance to avoid taking Tylenol while pregnant.

Specifically, the administration is now advising women not to use acetaminophen — which goes by the brand name Tylenol — for pain and fever during pregnancy due to claims that it raises the risk of their babies developing autism. 

Aside from the fact that science behind this claim is not definitive, the other major problem is that there is no safe alternative to acetaminophen that a woman can take for pain and fever while pregnant. Over-the-counter pain relievers like aspirin and ibuprofen can damage the kidneys of unborn babies.

President Trump admitted as much during the press conference about the new guidance, putting the onus on pregnant women to “tough it out” by not taking Tylenol

“Sadly, first question, what can you take instead? It's actually, there's not an alternative to that,” Trump said. “And as you know, other medicines are absolutely proven bad. I mean, they've been proven bad, the aspirins and the Advils and others, right?

“But if you can't tough it out, if you can't do it, that's what you're going to have to do. You'll take a Tylenol, but it'll be very sparingly.”

That’s a genuinely inhumane response to the pain pregnant women often endure, because what he’s really saying is that you just should not treat pain while pregnant. It’s also on-brand messaging for an opiophobic country that’s been dismissing everyone’s pain for almost a decade now.

As it turns out, when you tell people that their pain doesn’t deserve to be treated by opioids, then it’s a quick path to the idea that pain shouldn’t be treated by other substances, be they cannabis or kratom or Tylenol. 

In the end, it all really comes down to a fundamental question of whether or not pain is worthy of treatment.

And unfortunately, for many healthcare professionals and government officials, the answer is a resounding “no.” They do not believe that pain is worthy of treatment – as long as it’s not their pain. Because, make no mistake, when these types of policies come out, that’s exactly who they apply to: other people.

They know that they themselves will get to use opioids if and when the time comes that they need them for their own pain. And they don’t expect to have a pregnancy themselves, so of course they don’t care if pregnant women can’t have their pain treated.

It's why Trump can so dismissively say "there's no downside in not taking it." He means there is no downside to him if you don’t take Tylenol.

But for pregnant women, there most certainly is a downside. Failing to treat fever and significant pain can pose serious risks to both the mother and baby, resulting in miscarriages, birth defects, depression, infections and high blood pressure.

Enduring untreated pain can wear you down in ways you can’t even predict. It will destroy your sleep, steal your hope, and even make you mean. When it’s your pain, you’ll do anything to make it stop.

Pain is a medical condition on its own, and “toughing it out” is not an effective treatment. Until we as patients and voters demand better, I fear both the government and our healthcare system will continue chipping away at the pain treatments we still have — until there is literally nothing left but silent prayers and fleeting wishes.

Trump: ‘Don’t Take Tylenol If You’re Pregnant’

By Pat Anson

The Trump administration is advising women not to use acetaminophen (Tylenol) for pain and fever during pregnancy due the risk of their babies developing autism. About two-thirds of expectant mothers in the United States use acetaminophen.

Speaking at the White House, President Trump and Health and Human Services Secretary Robert F. Kennedy also linked childhood immunization shots to rising rates of autism, which now affects about 1 in 31 American children.

“They pump so much stuff into those beautiful little babies, it's a disgrace. I don't see it. I think it's very bad. They're pumping -- it looks like they're pumping into a horse. You have a little child, a little fragile child and you get a vat of 80 different vaccines, I guess, 80 different blends and they pump it in,” Trump said in a rambling statement that veered from Tylenol to vaccines and back again.

“And I will say there are parts of the world that don’t take Tylenol. I mean, there’s a rumor. And I don’t know if it’s so or not, that Cuba, they don’t have Tylenol because they don’t have the money for Tylenol and they have virtually no autism.”

Cuba does in fact have autism, although at low rates. It also has limited supplies of acetaminophen, which is known as paracetamol outside the U.S.

Acetaminophen is one of the most widely used over-the-counter pain relievers in the world, and medical professionals generally consider it one of the safest ways to relieve pain and fever. High fevers during pregnancy have been associated with birth defects and miscarriages, while poorly treated pain can lead to depression, insomnia and other harms to pregnant women.

The FDA warns expectant mothers not to take other over-the-counter pain relievers, such as aspirin and ibuprofen, because they can damage the kidneys of unborn babies.

The UK’s National Health Service (NHS) maintains that it is safe for pregnant women to use paracetamol. “Paracetamol is the first choice of painkiller if you're pregnant or breastfeeding. It's been taken by many pregnant and breastfeeding women with no harmful effects in the mother or baby,” the NHS says on its website.

Kenvue, the maker of Tylenol, also disputes any link between acetaminophen and autism.

“We believe independent, sound science clearly shows that taking acetaminophen does not cause autism. We strongly disagree with any suggestion otherwise and are deeply concerned with the health risk this poses for expecting mothers,” the company said in a statement.

In recent years, a handful of studies have linked the use of acetaminophen by pregnant women to autism, Attention-Deficit Hyperactivity Disorder (ADHD), and hyperactivity in children, although the evidence is not conclusive. A large 2021 study in Europe found that women who took acetaminophen while pregnant were 19% more likely to have children with autism.

“Today, the FDA will issue a physicians’ notice about the risk of acetaminophen during pregnancy and begin the process to initiate a (warning) label change. HHS will launch a nationwide public service campaign to inform families and protect public health,” Kennedy said.

“HHS wants to encourage physicians to exercise their best judgment and the use of acetaminophen for fevers and pain in pregnancy by prescribing the lowest effective dose for the shortest necessary duration and only when treatment is required.”    

‘Outright Lies and Dangerous Advice’ 

The FDA’s current warning label for acetaminophen cautions people about the risk of liver damage and other side effects, but does not specifically warn pregnant women about using the pain reliever. The agency said in 2015 that the evidence was “too limited” to justify such a warning.  

“The announcement on autism was the saddest display of a lack of evidence, rumors, recycling old myths, lousy advice, outright lies and dangerous advice I have ever witnessed by anyone in authority in the world claiming to know anything about science,” Arthur Caplan, PhD, founding head of the Division of Medical Ethics at NYU’s Grossman School of Medicine told The New York Times.

One of the reasons autism rates have risen in the U.S. is that its definition changed. Once considered extremely rare, a task force added Asperger’s syndrome to the list of autistic conditions, which resulted in a surge of new cases. Over the next decade, autism rates surged from 1 in 2,500 children to 1 in 31.

“The rapid rise in autism cases is not because of vaccines or environmental toxins, but rather is the result of changes in the way that autism is defined and assessed — changes that I helped put into place,” Dr. Allen Frances, a psychiatrist who led the task force, wrote in a recent op/ed in The New York Times.

“Our intentions were good, but we underestimated the enormous unintended consequences of adding the new diagnosis. The resulting explosion in cases included many instances of overdiagnosis — children were labeled with a serious condition for challenges that would better be viewed as a variation of normal. It also sowed the seeds of conspiracy theories and anti-vaccine beliefs as people wondered how to explain the rising cases.”

An FDA statement today also cautioned about drawing too many conclusions about links between autism and acetaminophen.

“It is important to note that while an association between acetaminophen and neurological conditions has been described in many studies, a causal relationship has not been established and there are contrary studies in the scientific literature,” the FDA said in a press release.

“It is also noted that acetaminophen is the only over-the-counter drug approved for use to treat fevers during pregnancy, and high fevers in pregnant women can pose a risk to their children. Additionally, aspirin and ibuprofen have well-documented adverse impacts on the fetus.”

It’s Rare for Chronic Pain Patients to Overdose on Opioids

By Neen Monty

The Penington Institute is an Australian non-profit public health and drug policy research organization. Its core mission is to study drug use “in a safe, considerate and practical way. We seek solutions, not scapegoats. We strive for positive outcomes, not negative stereotypes.”

A most worthy cause.

Each year, Penington releases Australia’s Annual Overdose Report, the country’s most comprehensive study of overdose trends and impacts. I am not against the work of the Penington Institute. On the contrary, they serve a very necessary purpose and have a noble goal.

However, for several years running, they have demonized chronic pain patients and twisted the statistics to inflate the harms of prescription opioids. And this is generally what I write about. To correct the record.

Here’s the download page to Penington’s 2025 report. It documents how many overdoses and what substances were involved. The report relates to data from the 2023 calendar year. Paging through it, something jumped out at me immediately.

Naturally, I jumped straight to the ‘Opioids’ section. There is a table, with key facts. One of these key facts is:

“From 2019-2023, there were 163 unintentional drug-induced deaths involving pharmaceutical opioids as the sole drug type.”

That’s an average of nearly 33 people who died accidentally every year when pharmaceutical opioids were the sole drug type. 33 people. In a country with 27.4 million people.

Does that sound like an opioid crisis to you? Does that sound like a reason to deny tens of thousands of patients access to safe and effective pain relief?

Do you know what immediately occurred to me when I realised that less than 50 people per year die from prescription opioid overdose?

I remembered this 2023 report from the Therapeutic Goods Administration (Australia’s version of the U.S. Food and Drug Administration), justifying their changes to paracetamol scheduling. That’s acetaminophen for those of you in the U.S.

Paracetamol pack sizes were reduced to 16 tablets per packet and supermarkets could only sell two packs per person. Larger packs were only available at pharmacies, and some required a pharmacist’s approval.

Do you know why they made paracetamol harder to get?

Because 50 Australians were dying every year from paracetamol overdoses, with rates of intentional overdose highest among adolescents and young adults.

There was an outcry when the changes came into effect. Chronic pain patients were again being harmed by policy because a different patient group was overdosing.

Because 50 people die of paracetamol overdoses per year in Australia.

Do you get what I am saying?

Paracetamol is still available over-the-counter in Australia, albeit in smaller pack sizes. And yet opioids are almost impossible to access.

Fewer Australians die from prescription opioid overdoses than from paracetamol overdoses. This was true long before any changes were made in opioid scheduling in 2020, making opioids much harder to get.

Opioid prescribing was already declining in 2020, so there was no need to change opioid prescribing practices. Certainly no medical need. In fact, this policy change caused a great deal of harm to those who live with constant, severe pain, and has had no benefits. For anyone.

Please think about it. Reflect upon it. Make it make sense. How is this anything other than a witch hunt?

Paracetamol kills more people than prescription opioids, yet it’s still available over the counter. And doctors are torturing people who live with painful, progressive and incurable diseases, by denying us access to safe and effective pain relief.

Because 33 people die of prescription opioid overdoses every year. While 50 people die of paracetamol overdoses.

Does Australia have an opioid crisis? No.

Does Australia have a prescription opioid crisis? Also no!

We never had a prescription opioid crisis. And we were never heading for one. Prescription opioid overdoes have been falling in Australia since 2018. Check the statistics.

Unlearn what you have been told and learn the true statistics.

There was no need to make changes in 2020. Yet those changes caused interminable suffering to people who live with constant, severe pain from illness or injury.

Most chronic pain patients are still suffering. Many have died.

Does this seem fair to you? Does this seem right? Does it seem reasonable?

Does any of this seem like good policy?

To be clear, I am not saying that opioids should be available over-the-counter. Please do not twist my words to imply that.

Opioids for severe, daily pain should be managed as they were before 2020. By general practitioners who know their patients well.

There should be no dose ceilings because there is no evidence that dose ceilings reduce overdoses and death. GPs are more than capable of prescribing an appropriate dose and duration to manage severe chronic pain.

Instead, chronic pain patients in Australia are forced to go to a pain management specialist, who barely knows them and rarely understands their pain.

People who live with severe, daily pain from disease and injury have a right to pain relief. We need help.

And this year’s Penington report shows that we are not the ones who are overdosing.

It is time to restore access to safe and effective pain relief for those who desperately need it. Chronic pain kills far more often than the opioids prescribed for chronic pain do. Patients die from heart attacks, strokes, hypertension, and other stress-induced conditions when their pain is not treated.  

The true cause of most overdose deaths is polypharmacy: multiple drugs, both legal and illegal, that are often mixed with alcohol.

Targeting people who live with painful, progressive and incurable diseases and injuries, denying us access to pain medication, is never going to reduce overdoses by illicit drug users. They are two different patient populations.

It is not chronic pain patients who are overdosing.

Neen Monty is a patient advocate in Australia who lives with rheumatoid arthritis and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), a progressive neurological disease that attacks the nerves.

Neen is dedicated to challenging misinformation and promoting access to safe, effective pain relief. She has created a website for Pain Patient Advocacy Australia to show that prescription opioids can be safe and effective, even when taken long term. You can subscribe to Neen’s newsletter on Substack, “Arthritic Chick on Chronic Pain.”

Most Treatments for Low Back Pain Don’t Work

By Crystal Lindell

While I’ve struggled with relatively mild lower back pain for years now, a few months ago I threw my back out for the first time. I literally could not get out of bed on my own, and I spent almost a week on the couch recovering while my lower back spasmed. 

It was horrible, and even my usual pain relief methods and doses of pain meds did not help much. In the end, for me, it was mostly just time and rest that seemed to help the most. 

Now a new study confirms just how difficult it is to treat low back pain. 

In fact, only about 10 percent of treatments for low back pain actually work, according to new research published this week in the journal BMJ Evidence-Based Medicine. 

The study by an international team of researchers looked at 301 placebo-controlled clinical trials for 56 different treatments for low back pain. The team found that most non-surgical and non-interventional treatments did not work. Those that did work provided only small analgesic effects better than a placebo.

Specifically, they found that NSAIDs were the only treatment that worked for acute low back pain, while five treatments for chronic low back pain provided relief: exercise, spinal manipulative therapy (chiropractic), taping, antidepressants, and transient receptor potential vanilloid 1 agonists, which are topical patches like Qutenza (capsaicin).  

As for the treatments that did not work, the researchers found that three treatments for acute low back pain – exercise, glucocorticoid injections, and paracetamol (acetaminophen) – and two treatments for chronic low back pain (antibiotics and anaesthetic drugs) were ineffective. 

They didn’t have enough good quality evidence for the remaining treatments to determine if they worked or not. 

For acute low back pain, 10 non-pharmacological treatments had “low to very low certainty evidence” that they actually worked, including: acupuncture, behavioral health education, extracorporeal shockwave, heat, laser and light therapy, massage, mobilization, osteopathic, spinal manipulative therapy, and transcutaneous electrical nerve stimulation (TENS). 

They also found that 10 pharmacological treatments had inconclusive evidence about their effectiveness for acute low back pain, including: cannabinoids, colchicine, immunoglobulin, muscle relaxants, muscle relaxants + NSAIDs, nucleoside, opioids, ozone injections, pyrazolone derivatives, and topical rubefacients.

For chronic low back pain, over three dozen treatments had inconclusive evidence to support their efficacy, which included everything from bee venom and TENS to dry cupping and muscle relaxants.

The bottom line is that there’s not much evidence to support the use of many treatments that are commonly prescribed and promoted for lower back pain — even the ones recommended in medical guidelines.

“Our review did not find reliable evidence of large effects for any of the included treatments,” researchers concluded. “There are also common treatments for which no placebo-controlled trials have been conducted despite being commonly recommended in clinical practice guidelines.”

The study ends as many often do, with a plea for more high-quality evidence to give patients and doctors real choices and effective options for treating back pain. 

“While we would like to provide more certain recommendations for where to invest and disinvest in treatments, it is not possible at this time,” researchers said.

NSAIDs Preferred for Acute Dental Pain

By Pat Anson, PNN Editor

Nonsteroidal anti-inflammatory drugs (NSAIDs) taken alone or in combination with acetaminophen are recommended as first-line treatments for managing short-term acute dental pain in adults and adolescents aged 12 and older, according to a new guideline developed by the American Dental Association (ADA).

Opioid analgesics should only be used when NSAIDs and acetaminophen are insufficient to reduce pain or when NSAIDs are contradicted, according to the ADA guideline, which also warns dentists to avoid “just-in-case” opioid prescribing.    

“Providing prescribing guidelines for acute dental pain management is an important step towards improving patient treatment and outcomes,” Marta Sokolowska, PhD, deputy center director for substance use and behavioral health at the FDA's Center for Drug Evaluation and Research, said in a press release. “We hope this clinical practice guideline will reduce the risk of opioid addiction, overdose and diversion.”

Opioids were once routinely prescribed to dental patients after a surgical tooth extraction or even a simple toothache. In 1998, dentists wrote 15.5% of all prescriptions for immediate release opioids in the United States. Many of those prescriptions are now considered high risk because the daily dose was over 50 MME (morphine milligram equivalents) or the amount prescribed exceeded a 3-day supply.

After reviewing 82 clinical trials involving tooth extractions, the ADA’s guideline panel found that NSAIDs were more effective than opioids in reducing post-operative pain.

“When managing acute dental pain, there are several reasons to consider alternatives to opioids. First, evidence suggests that opioids may not be the best approach to managing what is often inflammation-related acute dental pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) would target the source of the pain, whereas opioids would not,” the guideline cautions.

Only in “rare instances” when pain control is inadequate with NSAIDs does the guideline recommend low doses of oxycodone or hydrocodone, in combination with acetaminophen. Opioids can also be used when NSAIDs are contradicted due to health issues, such as a patient having cardiovascular problems or a bleeding ulcer.

“When opioids are prescribed, clinicians should obtain informed consent from the patient (or the parent or guardian in the case of minors) with detailed information about potential opioid undesirable effects. This is particularly critical in adolescents and young adults who are at increased risk of subsequent misuse and substance use disorder even after a single prescription,” the guideline says.

This is the second of two ADA guidelines on acute dental pain management. A previous set of recommendations for pediatric patients under the age of 12 was published in 2023. It also recommends NSAIDs and acetaminophen as preferred analgesics. Opioids such as codeine and tramadol are not recommended for children under any circumstances.

The risk of long-term opioid use after a tooth extraction is relatively rare. A 2018 study of over 70,000 teens and young adults who had their wisdom teeth removed found that only 1.3% were still being prescribed opioids months after their initial prescription by a dentist.

Migraine Sufferers Rank Triptans as Most Helpful Medication

By Pat Anson, PNN Editor

A large new study that compared the effectiveness of acute migraine medications found that triptans are two to five times more helpful than ibuprofen and acetaminophen in treating migraine attacks. Triptans were also found to be more effective than Excedrin migraine, opioids, and other non-steroidal anti-inflammatory drugs (NSAIDs).

The study used a unique methodology, gathering data on over 3 million migraine attacks reported by over 278,000 people in the US, UK and Canada who used a smartphone app during a six-year period. The Migraine Buddy app allows users to monitor the frequency of their migraine attacks, triggers and symptoms, and rate how “helpful” or “not helpful” their medications are.

“There are many treatment options available to those with migraine. However, there is a lack of head-to-head comparisons of the effectiveness of these treatment options,” said lead author Chia-Chun Chiang, MD, a neurologist who specializes in Headache Medicine and Vascular Neurology at the Mayo Clinic. “These results confirm that triptans should be considered earlier for treating migraine, rather than reserving their use for severe attacks.”

Chiang and his colleagues looked at a total of 25 medications among seven drug classes. Different dosages and medication combinations were combined in their analysis. Newer drugs that inhibit calcitonin gene-related peptides (CGRP) were excluded because they were not in wide enough use during the study period.

How Patients Rated Effectiveness of Acute Migraine Drugs

NEUROLOGY

The study findings, published in the journal Neurology, ranked several triptans (eletriptan, zolmitriptan, sumatriptan, rizatriptan, naratriptan, almotriptan and frovatriptan) as the most helpful medications, with about 75% effectiveness.

By comparison, acetaminophen (paracetamol) was helpful only 37% of the time.

“Our results strongly support the use of triptans, the first class of migraine-specific medication for the acute treatment of migraine,” researchers reported. “In practice, NSAIDs and acetaminophen are generally the first-line medications utilized for mild to moderate headache, and migraine-specific medications are often reserved for moderate to severe migraine attacks, which could potentially result in under-utilization of triptans or delayed treatment during migraine attacks.”

Participants found NSAID’s more effective than acetaminophen, with ketorolac helpful 62% of the time, indomethacin helpful 57% of the time, diclofenac helpful 56% of the time and ibuprofen helpful 42% of the time.

Excedrin migraine was effective only about half the time, about the same as tramadol and codeine. Opioids are usually not recommended for migraine because they’ve been associated with medication overuse headache.

“For people whose acute migraine medication is not working for them, our hope is that this study shows that there are many alternatives that work for migraine, and we encourage people to talk with their doctors about how to treat this painful and debilitating condition,” said Chiang.

Migraine affects about 39 million people in the United States and is the second leading cause of disability worldwide, according to the American Migraine Foundation.  

Another recent study that compared migraine prevention drugs found that two medications usually used to treat depression and high cholesterol are just as effective as the new CGRP inhibitors. Amitriptyline is a tricyclic antidepressant, while simvastatin is a statin. Both drugs are used off-label for migraine prevention and cost substantially less than CGRP drugs.

Tylenol on Trial: Does Acetaminophen Cause Autism and ADHD?

By Teresa Carr, Undark Magazine

More than 100 families of children with autism and attention deficit hyperactivity disorder are suing companies that market acetaminophen, the pain reliever in Tylenol and an array of other medications. Tylenol-maker Johnson & Johnson, as well as major retailers that use acetaminophen in their store-brand products, knew about research linking prenatal use of acetaminophen to neurodevelopmental disorders in children, the families claim, and should have included warnings on product labels.

The court filings reveal mothers wracked with guilt, convinced that by taking an over-the-counter pain reliever, they caused their child’s disability. In case after case, these women say that if they had thought acetaminophen could possibly harm their baby, they would have minimized their use of the drug — or not taken it at all.

It’s hardly an open-and-shut case. Most of what is known about acetaminophen and pregnancy comes from a type of study that sifts through data looking for correlations between prenatal exposures and developmental disorders. Scientists have been fighting amongst themselves over how much weight to give these studies, which were not designed to prove that a given factor — in this case, acetaminophen — caused ADHD or autism.

The debate reached a boiling point in 2021, when a group of international scientists declared that the current research, limited as it is, warrants stronger warnings about the use of acetaminophen during pregnancy. In a consensus statement published in Nature Reviews Endocrinology, the scientists called for “precautionary action” through focused research and increased awareness of the drug’s potential risks. Ninety-one scientists, clinicians, and public health professionals from around the world signed on.

That statement was the “galvanizing incident” for the lawsuits, said Ashley Keller, a founding partner at the legal firm Keller Postman LLC and one of the lawsuits’ lead attorneys.

‘An Outlier Opinion’

But there’s a hitch: The consensus statement does not, in fact, reflect the views of many experts or of any major medical organization. The same Nature journal published three rebuttals signed by numerous professional groups as well as individual researchers and clinicians. These critics wrote that the consensus statement used flawed data to exaggerate potential harms of acetaminophen and downplayed the drug’s essential role for treating fever and pain.

Johnson & Johnson has seized on those criticisms in its defense. The consensus statement “is an outlier opinion of a small group whose position has been rejected by their own medical organizations and every regulatory body to address the issue,” company spokesperson Melissa Witt told Undark in an email. Giving credence to theories not based in sound science, she said, could harm millions of pregnant women.

This debate over how to interpret the acetaminophen science lies at the heart of the lawsuits, and the answer has profound implications, both for individuals and for public health. Acetaminophen is one of the most common drugs in the world, and in the United States, up to 65 percent of all expectant mothers use it. The cases have been consolidated in the Southern District of New York. If the litigation proceeds to trial, attorneys expect tens to hundreds of thousands of families to join in.

It’s a shame that questions linger about the safety of a drug that’s been around for 70 years, said Christina Chambers, a professor of pediatrics at the University of California, San Diego and lead investigator for a series of studies on exposures during pregnancy for the Organization of Teratology Information Specialists, a professional society that provides advice on using medications during pregnancy and breastfeeding.

In an interview with Undark, Chambers expressed doubts about the consensus statement, saying that if acetaminophen has any effect on fetal development, that effect is likely to be modest. Still, she added, “What this accumulated data calls for is to do better study.”

Top Selling Pain Reliever

Acetaminophen was discovered in 1878, according to an FDA history of groundbreaking medications. But it wasn’t until the early 1950s that researchers demonstrated that the compound worked as well as the two popular pain relievers of the time — aspirin and acetanilide — with fewer side effects. In 1955, drugmaker McNeil gained FDA approval and launched Tylenol Elixir for Children, advertising it “for little hotheads.”

Four years later Johnson & Johnson acquired McNeil, and, in 1975, began aggressively marketing an “extra strength” 500-milligram version of the drug to adults. By the early 1980s, Tylenol was the top-selling pain reliever in the U.S.

Acetaminophen is now used in more than 600 over-the-counter and prescription medications, including combination products for sleep, cough, cold, and allergy.

Acetaminophen is one of the most common drugs in the world, and in the United States, up to 65 percent of all expectant mothers use it.

Today, new medications typically undergo toxicity testing in animals before researchers study their safety and effectiveness in humans, but like many older drugs, acetaminophen didn’t undergo as thorough of a process. “Back in ’55 we weren’t doing preclinical testing for reproductive safety,” said Chambers.

Scientists do know that, in most cases, acetaminophen is the safest way for pregnant women to relieve fever and pain. “Not treating a fever — especially a high fever — can have consequences,” continued Chambers.

Strong data from lab animal and human studies have associated a high fever at certain points in pregnancy with an increased risk of birth defects and other fetal abnormalities. And, while it’s an understudied area, she said, chronic pain is associated with depressive symptoms, insomnia, and other harms to the mother and could adversely affect her pregnancy.

Some common over-the-counter drugs treat both fever and pain, such as nonsteroidal anti-inflammatory drugs like aspirin, ibuprofen (Advil), and naproxen (Aleve), but the FDA warns against using any of these after 20 weeks of pregnancy because these drugs can damage the unborn babies’ kidneys.

Meanwhile, other painkillers have their own drawbacks. Babies exposed to opioids during the first trimester of pregnancy are at increased risk for birth defects of the brain, spine, and spinal cord. In addition, studies show that regular use of opioids during pregnancy increases the risk of poor fetal growth, preterm delivery, stillbirth, and neonatal opioid withdrawal syndrome.

Medicinal cannabis may address pain, and some women might think of it as a natural and, therefore, safe alternative. But there’s very little data available on short- and long-term outcomes for mothers and babies exposed to the potent products available today, said Chambers. Recent studies suggest that cannabis increases the risk of preterm birth and smaller babies, but it’s hard to tease out the effects from other factors. She described the drug’s legalization and increased societal acceptance as “a huge experiment happening now.”

“So, what are you left with?” she asked.

In 1975, Johnson & Johnson began aggressively marketing extra-strength Tylenol to adults. In this 1983 commercial, the product is touted as the most potent pain reliever that can be bought without a prescription:

Rising Rates of Autism and ADHD  

For pregnant people experiencing fever or pain, acetaminophen is widely viewed as the best option. But can it also harm the fetus?

To begin answering this question, researchers have analyzed preexisting datasets of health information, looking for associations between acetaminophen use during pregnancy and neurodevelopmental problems in children. Such research is referred to as observational, and while it can be useful, this approach can’t typically prove causality.

Autism rates have climbed steadily since the Diagnostic and Statistical Manual of Mental Disorders, or DSM, first established it as a distinct disorder in 1980. In 2000, 1 in 150 children were diagnosed with autism by the age of eight according to the Centers for Disease Control and Prevention; by 2020, the number had risen to 1 in 36.

ADHD rates increased as well, though not as sharply. In 2019, 6 million children between the ages of 3 and 17 (9.8 percent) had received a diagnosis of ADHD, compared to 4.4 million children in 2003, according to CDC data from a national survey of parents.

Many experts attribute the bulk of that increase to greater awareness and broadening definitions of the disorders. Factors such as improved survival for premature infants and a trend toward starting families later may also play a role, as both prematurity and older parents are associated with increased risk for neurodevelopmental disorders.

In the early 2010s researchers additionally became interested in whether acetaminophen, so commonly used by pregnant people, could affect fetal development.

In 2014, after a couple of observational studies suggested a possible link, the Food and Drug Administration began a formal process to track data on the issue. The findings from the agency’s initial review of the evidence, based on limited and contradictory data, were inconclusive according to a Drug Safety Communication published the following year.

Since then, researchers from several countries, including the U.S., have published a steady stream of observational research. In 2021, an international group of researchers came together to review the evidence and craft a consensus.

“We all sat down and said, it’s time to put all this together; we’ve done reviews, there’s more and more evidence,” said lead author Ann Bauer, an epidemiologist at the University of Massachusetts Lowell. “We all felt that it was time for women to have this information.”

Of the 29 observational studies involving 220,000 mother-child pairs, 26 linked prenatal use of acetaminophen to neurodevelopmental disorders including ADHD, autism, language delays, lower IQ, and cerebral palsy among others. Sixteen studies showed a more-pronounced effect with longer-term use of the drug.

Bauer pointed out that a handful of observational studies published after the consensus statement also suggest an association.

The group conceded that the observational data is imperfect. The positive association could stem from other factors, such as heredity or the condition that prompted the woman to take the drug. Still, the researchers concluded that the combined weight of the data was strong enough to warrant warning labels on acetaminophen and for health care professional to caution women against indiscriminate use of the drug. Society should act now, they wrote, “not wait unequivocal proof that a chemical is causing harm to our children.”

In science, it’s always possible to find something wrong with individual studies, said David Møbjerg Kristensen, a professor of molecular biology at Roskilde University in Denmark, one of the consensus authors. “But it’s more when you have all the studies lining up that you begin to be concerned,” he said.

‘Irresponsibly Published’

But other experts say that it’s misleading to stack up profoundly limited data and conclude that, as a whole, it carries more weight.

The paper from Bauer’s team was “irresponsibly published,” said Nathaniel DeNicola, an obstetrician-gynecologist based in Orange County, California, who helped review the evidence for the American College of Obstetricians and Gynecologists. “It did not reflect the preponderance and overall weight of the data, and it did not reflect the clinical context.”

DeNicola, who has expertise in environmental exposures and health policy, pointed out that consensus authors didn’t include numerous reviews, including those from major medical organizations, that drew different conclusions. Both ACOG and the Society for Maternal-Fetal Medicine, for example, found no clear evidence that acetaminophen causes fetal developmental issues and no reason to change current medical advice and practice.

In the end, neither did the FDA. In 2018, the agency brought the issue before its Medical Policy and Program Review Council, which provides oversight and direction of policies. The council found the available data didn’t warrant changes on acetaminophen labels or updates to the existing safety communication, wrote FDA press officer Charlie Kohler in an email to Undark.

While the agency continues to monitor the issue, it closed the formal tracking process in 2020 said Kohler, because extensive reviews failed to turn up solid evidence of a link between the drug and neurodevelopmental issues.

The gold standard for understanding the effect of a medication is to randomly assign one group to take the drug and another to get a placebo, with neither researchers nor participants knowing who got what until the end of the study. However, those randomized clinical trials rarely include pregnant women because of potential risks to the fetus. As a result, acetaminophen researchers rely on observational studies and laboratory experiments, including those that test the effects of the drug on experimental animals.

It can be difficult, however, to study neurodevelopmental problems in these animals. For one, researchers wouldn’t diagnose ADHD or autism in a mouse, though some research finds that mice exposed to acetaminophen in the womb are more likely to have problems with learning, memory, motor skills, and social behavior. Additionally, the biological mechanisms that lead to a diagnosis in humans are complex and not well understood, said Kristensen, so researchers don’t know what to exactly look for when they study the brains of laboratory animals.

Research in test tubes and lab animals does show that acetaminophen affects several chemical systems involved in brain development. “The compound is doing multiple different things during development at specific time points when the fetus is vulnerable,” said Kristensen. But whether these factors contribute to neurodevelopmental problems, he added, is unclear. Kristensen said that he expects to publish data within the next year or so that could help clarify the connection.

It’s also hard to know what to make of the observational research, which has numerous limitations, according to DeNicola. Many of the studies rely on women’s recall of having taken acetaminophen, which can be faulty weeks and even months later, he said. And instead of a clinical diagnosis of a child’s developmental or behavior disorder, studies often depend on assessments by parents and teachers, which sometimes differ.

One of the biggest issues with the observational research is failing to adequately control for other factors that cause autism and ADHD, particularly heredity, said Per Damkier, head of research in clinical pharmacology at the University of Southern Denmark and a co-author of a consensus rebuttal by the European Network of Teratology Information Services. (Teratology is the study of diseases and conditions that are congenital, or present at birth.) Based on data from Western countries, researchers estimate that up to 80 percent of autism and up to 90 percent of ADHD results from genes children inherited from their parents. If you don’t account for that huge factor, he said, “you inevitably will come up with misleading results.”

For example, a 2017 Pediatrics study included in the original consensus review found that the father’s use of acetaminophen increased a child’s risk of ADHD just as much as the mother’s use during pregnancy. While the researchers theorize that acetaminophen could have altered how the fathers’ genes work, Damkier said that the more likely explanation is that the analysis didn’t sufficiently adjust for heredity.

The pain or illness that prompts a woman to take a pain reliever may also skew the data. In their consensus rebuttal, authors from the Organization of Teratology Information Specialists point to the OTIS’ long-running MotherToBaby study, which found that compared to pregnant women who use acetaminophen for short periods, those who take it longer term report having more mental health conditions, including depression and anxiety, and are more likely to take antidepressants — all factors studies suggest are associated with ADHD and autism in children.

In a 2020 study, epidemiologist Reem Masarwa, then a postdoctoral fellow at McGill University in Montreal, and colleagues explored whether confounding factors such as heredity and maternal illness could be biasing acetaminophen research.

The group reanalyzed data from a meta-analysis Masarwa had published two years earlier, which had found a 35 percent increased risk of ADHD in children exposed to prenatal acetaminophen. This time the researchers stringently adjusted for parental ADHD and migraines in the mother.  The ADHD risk nearly disappeared.

‘There’s Something Biological Going On’

The consensus authors cite two studies that overcome the limitation of relying on a mother’s memory of acetaminophen use. The first, a 2019 study, tested umbilical cord blood for traces of acetaminophen and the second, published in 2020, measured acetaminophen in babies’ first bowel movement. Both found that the higher the prenatal exposure to acetaminophen, the greater the chance of a child receiving a physician diagnosis of a neurodevelopmental disorder.

“The beautiful thing about the new studies coming out is that the better the study, the stronger the associations,” said Kristensen. “Suddenly, you can see dose response, which is something we always look for because that argues that there’s something biological going on.”

However, both of those studies have drawbacks as well. Acetaminophen only lingers in the blood for a few hours, so the implication of the cord-blood study is that a single dose right before birth could have a dramatic effect on a child’s brain. Many experts find that result implausible.

Testing a newborn’s bowel movement may be a better measure as it is thought to reflect the mother’s use of acetaminophen during the last two trimesters of pregnancy. But as with some other observational studies, the researchers didn’t account for why the mother took the drug in the first place.

Plaintiff attorney Ashley Keller said that his first responsibility is to help his clients win compensation. In addition, he said, there’s also a public health issue at stake in that the women need full information to make informed decisions.

In April, U.S. District Judge Denise Cote, who is presiding over the pre-trial proceedings, took the unusual step of inviting federal regulators to provide an opinion on whether the science warrants adding a warning to acetaminophen labels about an association between prenatal exposure and ADHD and autism.

The FDA declined to comment on whether the agency would weigh in by the end of July as requested by Judge Cote.

Claiming that FDA regulations and federal laws prevent them from changing Tylenol labels, Johnson & Johnson is pushing for a dismissal. The company continues to evaluate the science and has not seen any evidence that acetaminophen use during pregnancy causes fetal development issues, Witt, the company spokesperson, wrote in an email. “Leading medical organizations agree with the current product label which clearly states, ‘If pregnant or breast-feeding, ask a health professional before use.’”

Bauer said the lawsuits are helping get the word out about the accumulating research on acetaminophen’s risks. Up until now, she said, a lot of women have viewed the drug as “completely innocuous,” something to take “whenever they are in discomfort.” Others disagree. DeNicola said that the women he sees in his practice are conscientious about using acetaminophen.

One thing everyone agrees on is the recommendations for acetaminophen use, said DeNicola: “Use it only where indicated in the lowest dose for the shortest duration.” So, for pain or fever that means taking one pill, one time, to see if symptoms ease, he said.

Another point of real consensus is the need for more research. Bauer said that several groups are looking at possible mechanisms for how acetaminophen could affect development. “As far as the epidemiology, there’s a pretty perfect study that could be done,” she said, pointing out that, with smartphones, women can easily record what they take and why. “But it’s going to take us many, many years is the problem.”

“Something that is potentially this important for, not just fetal, but for childhood brain development should be studied,” DeNicola said. “And it should be studied in a real way.” For example, he would like to see studies that use blood tests and other measures throughout pregnancy to accurately track exposures not just to acetaminophen, but also to environmental substances of greater concern to fetal development, such as industrial chemicals. And, since a baby’s brain continues to develop after birth, studies should account for use of acetaminophen in childhood — a glaring omission from most of the current research, said DeNicola.

At the moment, no one is conducting exactly that type of study on acetaminophen.

However, FDA spokesperson Charlie Kohler said that agency is conducting a small study to see how people’s bodies absorb, metabolize, and excrete the drug. The agency is also planning a toxicology study in 2024, pending approval of funding.

And Chambers said that she is coordinating a study funded by the National Institutes of Health of about 8,000 mother-child pairs in 25 sites across the U.S. The Healthy Brain and Child Development Study will capture information on prenatal exposures, including to acetaminophen, and use brain imaging and standardized assessments to track brain development in children. Researchers will release data annually, so information on prenatal exposure to acetaminophen will begin to emerge in the next couple of years, she said.

If there’s anything good to come out of the controversy, it’s that every drug, over the counter or not, deserves rigorous research on safety, said Chambers — and society hasn’t invested in systematically doing that type of research. She pointed out that while the FDA requires new drugs to be assessed for safety during pregnancy, nobody has the resources of motivation to do that for old drugs like acetaminophen.

“And we need to stop that,” said Chambers. “We need to turn that wheel around, pay attention and do the work that needs to be done.”

This article was originally published by Undark, a non-profit, editorially independent online magazine covering the complicated and often fractious intersection of science and society. You can read the original article here.

Study Finds Non-Opioid Pain Relievers Effective for Arthroscopic Surgery

By Pat Anson, PNN Editor

Patients recovering from minimally invasive shoulder or knee surgery do just as well with non-opioid pain relievers as those who use opioids, according to a new study at McMaster University and Hamilton Health Sciences (HHS) in Canada.

The study, published by the Journal of the American Medical Association (JAMA), looked at 193 outpatients who had arthroscopic surgeries on their knees or shoulders at three hospitals in Hamilton, Ontario.

About half received standard care with opioids for postoperative pain, while the other half received naproxen and acetaminophen for pain, as well as pantoprazole, a medication normally used to treat heartburn and acid reflux. An emergency supply of opioids was available to both groups, if needed, for additional pain relief.

After six weeks, patients in the opioid group had used an average of 72.6 mg of opioids, compared to 8.4 mg in the opioid-sparing group. Two patients in the opioid-sparing group asked for opioid medication after discharge. Researchers say there were no significant differences in pain levels, patient satisfaction or adverse events between the two groups. 

“This study clearly shows that many of these surgical patients can be treated safely without opioid medications in a select population,” said lead author Olufemi Ayeni, MD, a professor of surgery at McMaster and an orthopedic surgeon at HHS. “Furthermore, by reducing the number of opioids prescribed, we can collectively reduce the development of a reservoir of unused medications that can cause harm to many in society.” 

Over the past decade, the number of arthroscopic surgeries has soared in North America. About one million arthroscopies are performed annually in the United States and 100,000 in Canada. Several studies, however, have that found arthroscopic surgeries provide only temporary relief from knee pain and do not improve function long term.

To be clear, there is no comparison between arthroscopies and highly invasive surgical procedures such as heart bypass surgery.  Arthroscopies are a type of “keyhole” surgery in which the surgeon makes a small incision and inserts a tiny camera and instruments to diagnose and repair damaged ligaments or joints. The procedure often takes less than an hour and patients are sent home the same day — so there is less need for pain medication.

A recent analysis of nearly half a million minimally invasive surgeries in the U.S. found that the number of opioid pills prescribed to patients fell by 50% since 2017. Hospitals are increasingly using acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), gabapentinoids and other non-opioids for post-operative pain.  

Most Americans are more worried about treating post-operative pain than they are about becoming addicted to opioids. A 2021 Harris poll found that nearly 8 out of 10 U.S. adults believe opioids are sometimes necessary to manage pain after surgery and 60% prefer opioids over OTC pain relievers.

Pregnant Women Raise Risk of Complications by Using OTC Pain Relievers

By Pat Anson, PNN Editor

Pregnant women who take over-the-counter pain relievers are one-and-a-half times more likely to have complications, including stillbirth and premature delivery, according to a large new study.

Researchers at the University of Aberdeen analyzed data from over 151,000 pregnancies in the UK from 1985-2015, looking for medical notes indicating the women used paracetamol (acetaminophen), aspirin or the non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac, naproxen and ibuprofen — either alone or in combinations.

The findings, recently published in BMJ Open, show a significantly higher risk of a preterm delivery, neonatal death, low birth weight and other health problems in babies born to mothers who used OTC pain relievers. Neural tube defects of the brain, spine or spinal cord were 64% more likely; while hypospadias, a birth defect affecting the penis, was 27% more likely.

“Over-the-counter analgesics consumption during pregnancy was associated with a substantially higher risk for adverse perinatal health outcomes in the offspring. The use of paracetamol in combination with other non-steroidal anti-inflammatory drugs conferred the highest risk,” wrote lead author Aikaterini Zafeiri, PhD. “The increased risks of adverse neonatal outcomes associated with non-prescribed, over-the-counter, analgesics use during pregnancy indicate that healthcare guidance for pregnant women regarding analgesic use need urgent updating.”

One of the more surprising aspects of the study is how use of the five analgesics by pregnant women grew dramatically over the 30-year study period.  In 1985, only 1.8% reported using one of the pain relievers. By 2015, that had grown to 70.6% -- with most of the increase coming in the last seven years of the study.

Although it is believed to be one of the largest and most comprehensive studies of its kind, the research was limited. The duration, dose and stage of the pregnancy when analgesics were consumed were not recorded. The health of the mothers and babies later in life was also not studied.

But given the substantial increase in analgesic use during pregnancy and the higher risk of complications, researchers say more caution is needed on use of the drugs.

“The ease of access to non-prescription painkillers, in combination with availability of misinformation as well as correct information through the internet, raises safety concerns,” said Zafeiri. “It should be reinforced that paracetamol in combination with NSAIDs is associated with a higher risk and pregnant women should always consult their doctor or midwife before taking any over-the-counter drugs. We would encourage a strong reinforcement of the official advice for pregnant women.”   

Previous studies have linked prenatal use of paracetamol to autism, hyperactivity and behavioral problem in children. Despite the findings, drug regulators in the UK and US maintain that it is safe for pregnant women to use paracetamol (acetaminophen).

“Paracetamol is the first choice of painkiller if you're pregnant or breastfeeding. It's been taken by many pregnant and breastfeeding women with no harmful effects in the mother or baby,” the UK’s National Health Service (NHS) says on its website.

The Food and Drug Administration also does not caution pregnant women about using acetaminophen. The agency said in 2015 that the evidence was “too limited” to justify such a warning.  

Meanwhile, drug regulators in Australia are so concerned about recent deaths involving paracetamol that they may restrict access to the drug. Australia’s Therapeutic Goods Administration (TGA) has commissioned a report by an expert panel on the risks of paracetamol misuse.

“While paracetamol has well established safety and toxicity profiles, the wide use is paralleled by a high prevalence of accidental and deliberate paracetamol poisoning in the community, in both adults and children,” the TGA said in a statement earlier this month.

“The TGA is aware of concerns, particularly of families and healthcare professionals of affected consumers of paracetamol, regarding the number of poisonings and deliberate overdoses from paracetamol obtained from general retail outlets, and whether current access restrictions are appropriate.”

Australia currently regulates the quantity and dose of paracetamol sold over-the-counter. The independent commission will consider if stricter buying limits should be imposed. 

FDA Warns Supplements for Pain Contain Undeclared Drugs

By Pat Anson, PNN Editor

The U.S. Food and Drug Administration is warning consumers not to purchase or use dietary supplements marketed for pain relief under the brand names “Artri King” or “Ortiga” due to potentially dangerous ingredients not listed on their labels. Use of the products has led to at least one death, according to the FDA.

The Artri King and Ortiga supplements are promoted as treatments for arthritis, muscle aches, osteoporosis, bone cancer and other painful conditions – and list ingredients such as glucosamine, turmeric and Omega 3. But FDA laboratory analyses found the supplements also contain undeclared drugs such as steroids, muscle relaxants and non-steroidal anti-inflammatory drugs (NSAIDs):

• Dexamethasone (a corticosteroid) is commonly used to treat inflammatory conditions. It can impair a person’s ability to fight an infection and at high doses can cause increased blood glucose levels, changes in blood pressure, damage to bones, psychiatric problems and adrenal dysfunction.

• Diclofenac sodium (a NSAID) can raise the risk of cardiovascular problems, such as heart attack and stroke; serious gastrointestinal damage, including bleeding, ulcers, and fatal tears of the stomach and intestines; and liver toxicity that can result in death or the need for a liver transplant.

• Methocarbamol (a muscle relaxant) can cause sedation, dizziness and low blood pressure.

Artri King advertisement

The FDA urges consumers taking the supplements to immediately talk to a healthcare provider about safely discontinuing their use because suddenly stopping the undeclared drugs may be dangerous. The drugs may also interact with other medications a person is taking.

The FDA said it has received reports of adverse events, including liver toxicity and death, associated with the use of Artri Ajo King supplements since the agency issued its first warning on January 5, 2022. A second warning about Artri King was issued this week.

The FDA’s new warnings include Ortiga Mas Ajo Rey and Ortiga Mas Ajo Rey Extra Forte supplements, which are promoted as treatments for joint pain and arthritis.

Artri King and Ortiga sold their products on various websites, including Amazon, Walmart and E-Bay, as well as some retail stores, primarily targeting Spanish-speaking consumers.

Acetaminophen Warning Labels Ineffective

Sometimes warnings from government health agencies don’t have their intended impact. Such is the case for warnings from Health Canada about taking high doses of acetaminophen, a pain reliever widely used in over-the-counter medicines for headache, cough, cold and flu.

Product labels for acetaminophen were changed in Canada in 2009 to warn of the risk of possible liver damage. In 2016, the labeling was updated with additional information about safe dosing and to identify products containing acetaminophen.

But those changes did not decrease rates of hospitalization for acetaminophen overdoses, according to a new study published in CMAJ (Canadian Medical Association Journal).  In an analysis of more than 12 000 hospital admissions for acetaminophen overdoses in Canada between 2004 and 2020, researchers found the updated warning labels had little impact.

"We found that changes to acetaminophen labels that communicated the risks of overdose and the presence of acetaminophen in over-the-counter products did not affect rates of hospital admission for accidental acetaminophen overdose, ICU admission for accidental acetaminophen overdose and admission for acetaminophen overdoses involving opioids," writes lead author Dr. Tony Antoniou, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto.

Previous research has found that less than half of patients regularly read labels for over-the counter analgesics, and only 26% read the active ingredients before using them the first time. Acetaminophen is used in so many different products that consumers may be unaware how much they’re taking. As a result, up to 6% of patients exceed the maximum daily recommended dose.

The FDA warned U.S. consumers about the risk of acetaminophen causing liver injury in 2009. Five years later, the agency told manufacturers to stop selling drug products with more than 325 milligrams of acetaminophen per dose.

Those actions have done little to prevent adverse reactions to acetaminophen. According to the FDA’s Adverse Events Reporting System, nearly 2,800 adverse events involving acetaminophen were reported in 2009. By 2021, the number of adverse events had grown to over 15,000, a 440% increase. Over 27,000 drug deaths involving acetaminophen were reported from 2009 to 2021.

Fizzy Pain Relievers Are Bad for the Heart

By Pat Anson PNN Editor

Long-term use of the pain reliever acetaminophen has long been associated with liver, kidney, heart and blood pressure problems.  A new study has also found that some acetaminophen tablets are so loaded with salt that they significantly raise the risk of a heart attack or stroke in as little as one year.

At issue are dissolvable acetaminophen tablets that are mostly used to treat cold and flu symptoms, as well as minor aches and pains. The tablets quickly dissolve in water because of their high salt (sodium) content, creating a fizzy, effervescent drink that is absorbed more quickly in the digestive system than a standard tablet.

Some of the fizzy tablets contain as much as 440 milligrams of sodium per pill. A recommended daily dose of two tablets taken four times a day adds up to over 3,500 milligrams – more sodium than three McDonald’s Big Macs – and nearly double the daily amount recommended for healthy adults.

Since high salt content has long been associated with cardiovascular problems, a team of researchers looked at the health records of 300,000 people enrolled in Britain’s National Health Service who were prescribed acetaminophen (paracetamol) to see what impact the medications may have.

Their findings, recently published in the European Heart Journal, showed that patients with a history of high blood pressure (hypertension) taking fizzy acetaminophen tablets were up to 45% more likely to suffer a heart attack, stroke or heart failure within a year. Just one prescription for the tablets increased their risk of dying by 177 percent, and those with five or more prescriptions were 264% more likely to die.

The risk of a heart attack, stroke or death for patients without high blood pressure also rose with a prescription for fizzy acetaminophen, but to a lesser degree.

“The direct message from this study is clear—there are likely to be millions of people worldwide taking paracetamol on a daily basis in a ‘fast-acting’ effervescent or soluble formulation who are increasing their risks of cardiovascular disease and premature death,” wrote Aletta Schutte, PhD, and Bruce Neal, PhD, in an accompanying editorial.

“Fortunately, only a small proportion of paracetamol formulations contain sodium but, with ‘fast-acting’ and ‘fizzy’ medications increasing in popularity, the adverse effects of medication-related sodium intake look set to rise rather than fall.”

The risk isn’t limited to fizzy tablets with acetaminophen. Other effervescent medications containing aspirin, ibuprofen and even vitamins also contain high levels of sodium.  

With or without salt, long-term acetaminophen use can be risky. A recent study at the University of Edinburgh found that acetaminophen significantly raised the risk of heart disease and stroke in people with high blood pressure. Researchers said the increased risk of cardiovascular problems was similar to that seen with non-steroidal anti-inflammatory drugs (NSAIDs).

Acetaminophen is the most widely used over-the-counter pain reliever in the world — and is the active ingredient in Tylenol, Excedrin, and hundreds of pain medications. But a 2021 review found little or no evidence to support the use acetaminophen for most pain conditions.

Are NSAIDs Really Better Than Opioids for Post-Operative Pain?

By Pat Anson, PNN Editor

There have been a rash of recent studies promoting the use acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) over opioids for post-operative pain.

One such study at a Houston hospital led surgeons to conclude that patients were better off with Tylenol. "This study provides us with a strategy to successfully manage pain after surgery using over-the-counter pain medication,” said Min Kim, MD, head of thoracic surgery at Houston Methodist Hospital.  

But critics point out that most of the studies never examine how patients feel about the effectiveness of their pain treatment — focusing instead on the number of opioid pills and smaller opioid doses being prescribed. Pain relief was a secondary consideration, if it was considered at all.

A rare exception to that is a study recently published in the Canadian Medical Association Journal (CMAJ), which found that ibuprofen and other NSAIDs gave better post-operative pain relief than the opioid codeine. In a systematic review of 40 clinical trials involving over 5,000 patients who had outpatient procedures, researchers said patients who took NSAIDs had lower pain scores 6 and 12 hours after surgery than patients taking low doses of codeine.

"In all surgery types, subgroups and outcome time points, NSAIDs were equal or superior to codeine for postoperative pain," wrote lead author Matthew Choi, MD, Associate Professor of Surgery at McMaster University in Ontario. "We found that patients randomized to NSAIDs following outpatient surgical procedures reported better pain scores, better global assessment scores, fewer adverse effects and no difference in bleeding events, compared with those receiving codeine.

“These findings are of general importance to any clinician performing painful medical procedures. The various trials in our meta-analysis evaluated a range of procedures, different NSAID types and various degrees of acetaminophen coadministration.”

But critics say the McMaster study also has flaws. The claim that “all surgery types” and “a range of procedures” were included in the analysis is misleading at best. Most of the studies — 28 of the 40 that were analyzed — involved dental surgery, a fact that is not sufficiently disclosed. The rest of the outpatient procedures were for plastic surgery and orthopedic corrections – which can hardly be compared to more serious surgeries that require more pain relief and days or weeks of recovery, not just 6 to 12 hours.      

Another issue is the use of codeine as a research subject. Stefan Franzen, PhD, a chemistry professor at North Carolina State who has an extensive background in biomedical research, questions whether low doses of codeine should even be compared to NSAIDs.

“I question the premise that codeine is the drug that is or should be used by dentists,” said Franzen, author of “Patient Z,” a book the examines the criminalization of pain care. “I read a few papers not cited by this report and they too do not find a great efficacy for codeine. Part of this may be dose. Most commonly they are using 30-60 mg of codeine, which is 5-10 mg of morphine. Not very much if you have severe pain.

“Codeine may be a poor choice, but it may also be a straw man. Why not use tramadol, for example?”

‘Manipulated Data’

Patient advocate Bill Murphy also has doubts about the selection criteria used in studies touting the benefits of non-opioid pain relievers. He believes some researchers cherry-pick evidence to support a conclusion they’ve already reached.

“Opioid sparing post-op surgery programs are nothing more than an attempt to solve a non-problem and in doing so, patients suffer needlessly. The data produced from such programs are very often manipulated by those who designed the program in an obvious attempt to skew the results in favor of a program they endorsed,” said Murphy, who helped get legislation passed in New Hampshire to ensure that pain patients have access to opioid medication.

Murphy has advocated on behalf of patients at Portsmouth Regional Hospital, which has an “Enhanced Surgical Recovery” program that significantly reduced the use of opioids. Instead of Vicodin, patients get Neurontin or nerve blocks for pain relief.

“I was personally called in to advocate on behalf of several patients who were left to suffer in pain following surgery only to have staff assure them their pain was being well managed,” Murphy explained in an email. “Surgeons and nurses reported they were doing very well with Portsmouth Regional’s new protocol for managing post-op pain when in fact, they were not doing ‘very well’ at all.

“These patients were in horrible pain. Of the three I spoke with, none were ever provided any relief. I was with one patient as she was discharged. She was in tears and moved at a glacial pace due to pain as her son and I helped her into his vehicle outside. It was heartbreaking to watch. Her adult son was furious. I stayed in touch with each patient for several weeks afterwards. Each suffered greatly, one was not making any gains in physical therapy due to her lasting pain.”

In 2019, only 11% of patients were prescribed an opioid while at the Portsmouth hospital, and less than 6% were discharged with an opioid prescription. Murphy says the hospital’s policy inevitably leads to some patients with poorly treated pain.  

“What Portsmouth Regional Hospital’s ‘Enhanced Surgical Recovery’ program was doing is akin to making patients bite down on a piece of wood, grind it out, and then convince them the whole experience was for their own good,” says Murphy.    

Acetaminophen Use by Pregnant Women Raises Risk of Autism or ADHD in Children

By Pat Anson, PNN Editor 

A large new study in Europe is adding to the growing body of evidence that the use acetaminophen (paracetamol) by pregnant women raises the risk of their children having autism or Attention-Deficit Hyperactivity Disorder (ADHD)

Researchers at the University of Barcelona followed nearly 74,000 mothers and their children in the UK and five other European countries, finding that women who took the pain reliever while pregnant were 19% more likely to have children with Autism Spectrum Conditions (ASC) and 21% more likely to develop ADHD symptoms.

“Associations between prenatal acetaminophen and ASC and ADHD symptoms were consistently positive for both boys and girls albeit slightly stronger among boys,” researchers reported in the European Journal of Epidemiology.

Several previous studies have linked prenatal use of acetaminophen to autism, ADHD and hyperactivity in children, but this was by far the largest. Although the exact cause is unknown, it’s believed acetaminophen affects a baby’s brain development and growth, especially during the third trimester. The study found no evidence that acetaminophen raised the risk of autism and ADHD after the children were born.

Despite the findings, the UK’s National Health Service (NHS) maintains that it is safe for pregnant women to use paracetamol.

“Paracetamol is the first choice of painkiller if you're pregnant or breastfeeding. It's been taken by many pregnant and breastfeeding women with no harmful effects in the mother or baby,” the NHS says on its website.

The U.S. Food and Drug Administration also does not caution pregnant women about using acetaminophen. The agency said in 2015 that the evidence was “too limited” to justify such a warning.  

The University of Barcelona researchers are a bit more cautious, saying pregnant women should take acetaminophen “only when necessary.”

“Considering all evidences on acetaminophen use and neurodevelopment, we agree with previous recommendations indicating that while acetaminophen should not be suppressed in pregnant women or children, it should be used only when necessary,” they said.

Acetaminophen is the most popular pain reliever in the world, and is used by over half the pregnant women in Europe and the United States. It is the active ingredient in Tylenol, Excedrin, and hundreds of pain medications. Excessive use of acetaminophen can cause liver, kidney, heart and blood pressure problems. A recent study found little or no evidence to support its use for most pain conditions.  

Kolodny: NSAIDs ‘Just as Effective As Opioids’

By Pat Anson, PNN Editor

It’s fair to say that Dr. Andrew Kolodny is recognized as an expert in substance abuse. Koldony is board-certified in Psychiatry and Addiction Medicine, and for a few years was the Chief Medical Officer of Phoenix House, which operates a chain of addiction treatment centers. He now co-directs an opioid research program at Brandeis University.

Kolodny is also the founder of the anti-opioid activist group Physicians for Responsible Opioid Prescribing (PROP), has testified as a well-paid expert witness in opioid litigation, and is frequently quoted in the media about opioid painkillers, often calling them “heroin pills.”

But Kolodny is not board-certified in pain management and is not recognized as an “expert” in treating physical pain. So it was a bit of a surprise to hear him giving medical advice about over-the-counter pain relievers last week in a webinar held by the Partnership for a Drug-Free New Jersey.

"Many people don't know this, but the class of analgesic known as NSAIDs are as effective and in some cases more effective than opioids, even for excruciating painful conditions like renal colic. It's also called kidney stone pain. NSAIDs have been shown to be just as effective,” Kolodny said.  

Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen are widely used to treat minor pain and headaches, but they are not generally used for severe or chronic pain.  

We asked Mary Maston what she thought about Kolodny’s advice. She is an expert on kidney stone pain, having been born with a congenital disorder called medullary sponge kidney (MSK), which causes her kidneys to continually produce new stones.  

“The class of analgesic known as NSAIDs are as effective and in some cases more effective than opioids, even for excruciating painful conditions.”

— Dr. Andrew Kolodny

“I wholeheartedly disagree that NSAIDs are as effective and in some cases more effective than opioids,” Maston told us. “My first thought was, ‘I wonder if he's ever had a kidney stone?’ Ask any patient that has, whether they have MSK like me or not, and they will quickly tell you that over-the-counter NSAIDs do absolutely nothing for kidney stone pain. I have never encountered a single patient that has said they just took some Aleve and that took care of the pain even a little bit.” 

Kolodny was just getting started. He also recommended acetaminophen (Tylenol) as an alternative to opioids, and said it can be combined with ibuprofen (Advil) for even stronger pain relief. 

“Tylenol is not as strong a pain reliever as NSAIDs, but can for some people be very effective. And fortunately, you can actually combine a drug like Advil with a drug like Tylenol because they work differently. As long as a patient is able to take Tylenol and is able to take Advil, as long as they don't have a contradiction to taking those medications, they can even be combined,” Kolodny said. 

“The combination of Tylenol and Advil is actually first-line for wisdom tooth removal, even though in many cases dentists often still give drugs like hydrocodone or oxycodone to teenagers when their wisdom teeth come out. Tylenol and Advil combined gives better pain relief, with less side effects." 

“What he said about kidney stones is not correct. In fact, it’s cruel. What he said about tooth extractions is correct,” says Jeffrey Fudin, PharmD, an expert in pharmacology and pain management. “But encouraging expanded chronic NSAID use without preliminary discussion with a physician or pharmacist is bad and he is oversimplifying. Pain source, cause, quality and quantity all need to be assessed. 

“And he didn’t offer what should be done for those patients that can’t take NSAIDs due to medical disorders or who can’t tolerate them or they don’t work. What do we do, not treat them?” 

Risky Side Effects of OTC Drugs

NSAIDs and acetaminophen are widely used over-the-counter pain relievers, and both can have serious side effects. NSAIDs increase the risk of heart attacks and stroke, while excessive use of acetaminophen can cause liver, kidney, heart and blood pressure problems. A recent study found little or no evidence to support the use acetaminophen for most pain conditions.  

Kolodny, who does not speak with this reporter, briefly acknowledged some of those issues during the webinar. 

“Some patients have medical problems where they are not able to take an NSAID. And sometimes for severe acute pain there is a role for opioids. But that should always be very short-term use. Or if it's ever prescribed for a chronic pain condition, intermittent use, meaning not taken every day. Because when opioids are taken every day, quickly patients develop tolerance to the pain-relieving effect,” Kolodny said. 

“He makes it sound as though it’s either opioids or NSAIDS/acetaminophen,” Fudin said in an email to PNN. “There are lots of options that can be used instead of opioids or in addition to opioids other than NSAIDs/acetaminophen in an effort to combine multiple different pharmacological mechanisms permitting lower doses of several drugs.”

An over-the-counter pain reliever that combines ibuprofen and acetaminophen was recently introduced called Advil Dual Action, but it is marketed as a treatment for “minor aches and pains” such as headaches, toothaches and menstrual cramps. Nothing about severe pain, chronic pain or kidney stones.

“NSAIDs have been known to cause acute kidney failure in patients that have perfectly healthy kidneys, and my nephrologist says we don't want to tempt the gods,” says Mary Maston. “Once I explain this to ER doctors and anesthesiologists when I have surgery, they quickly nod and agree.”

Maston would like to see an end to one-size-fits-all approaches to pain care and for providers to treat patients as individuals. One way to do that is with CYP450 testing, which looks for enzymes that determine how effective a medication will be in a patient.

“I personally think it's time to stop cramming all patients into convenient little boxes and start making CYP450 tests mandatory for anyone who suffers with chronic conditions. It would take the guesswork out of prescribing, prevent patient suffering, and eliminate the stigma, abuse and neglect of chronic pain patients by their providers,” she said. 

Dr. Fudin would like to see Dr. Kolodny stay in his lane as a psychiatrist and addiction treatment doctor. 

“Would it be okay for a board-certified pain specialist professing to be an expert and to opine under those circumstances on best drugs for schizophrenia?” asked Fudin.