Prenatal Use of Acetaminophen Linked to Early Puberty

By Pat Anson, PNN Editor

The daughters of women who took acetaminophen during pregnancy tend to start puberty early, according to a new study by Danish researchers.  

The study is the latest indication that prenatal use of acetaminophen – more commonly known as paracetamol outside the U.S. -- can have long term effects on children.

Researchers at Aarhus University studied health data on about 100,000 Danish women who provided detailed information about their use of acetaminophen during pregnancy.

Nearly 16,000 children born to those mothers between 2000 and 2003 were followed from the age of eleven and throughout puberty, with surveys every six months about different aspects of their development.

The study, published in the American Journal of Epidemiology, found that girls on average entered puberty between one-and-a-half and three months earlier if their mothers took the over-the-counter pain reliever for more than 12 weeks during pregnancy.

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"We found a 'dose-response' correlation. That is to say, the more weeks with paracetamol during pregnancy, the earlier puberty in girls, but not in boys," says lead author Andreas Ernst, a PhD student from the Department of Public Health at Aarhus University.

"While entering puberty one-and-a-half to three months earlier may seem unimportant, when taken together with the frequent use of paracetamol during pregnancy, our findings ought to make people take notice. Our results are certainly not the decisive factor that should change current practice, but the perception of paracetamol as 'the safe and harmless choice' during pregnancy ought to be challenged."

Early puberty development increases the risk of serious diseases in adulthood, such as obesity, diabetes, cardiovascular diseases and testicular and breast cancer.

The use of acetaminophen (paracetamol) has been increasing worldwide and studies have found that over half of pregnant women in the U.S. and European Union use the pain reliever at least once during their pregnancy. It is the active ingredient in Tylenol, Excedrin, and hundreds of pain medications.

Previous research has shown that prenatal use of acetaminophen is associated with slow language development, autism and attention deficit problems in young children.

Over 50 million people in the U.S. use acetaminophen each week to treat pain and fever. The pain reliever has long been associated with liver injury and allergic reactions such as skin rash. The FDA label for products containing acetaminophen warns 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.  

In its 2016 opioid prescribing guidelines, the CDC recommends acetaminophen as an alternative to opioid pain medication. The guideline only briefly mentions that acetaminophen is involved in hundreds of overdose deaths annually and can cause liver problems.

The CDC guideline does warn pregnant women -- at length -- that opioids can cause birth defects, poor fetal growth, still births and neonatal opioid withdrawal syndrome.

Patients at Ohio Hospital Have Surgery Without Opioids

By Pat Anson, PNN Editor

Would you want to go through a major surgery without the use of opioid pain medication?

Patients at an Ohio hospital are getting acetaminophen, gabapentin and nonsteroidal anti-inflammatory drugs (NSAIDs) to manage their pain before and after colorectal operations – and their surgeons say the treatment results in better patient outcomes.

“Over 75 percent of our elective colorectal patients underwent surgery without requiring narcotic analgesics postoperatively, including after discharge,” says Sophia Horattas, MD, of Cleveland Clinic Akron General Hospital.  “During this time period our patient satisfaction scores improved as well as patients' perceptions of pain control.”

All eight general surgeons at Akron General adopted the non-opioid treatment protocol in 2016, applying it to patients who had elective colon operations. Prior to surgery, the patients were all educated about pain management, non-opioid analgesics, and the risks associated with opioids.

Researchers evaluated 155 of the patients and presented their findings this week at the American College of Surgeons Clinical Congress in Boston.

Overall, 83 percent (128) of the patients did not need opioid medication after their operations. Among those who did, use of opioids before surgery was often an indicator that they would want them again. Nine of the 15 patients who had prior experience with opioids used them again after surgery.

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Among the remaining 140 patients who did not use opioids before surgery, 85 percent (119) did not need opioid medication for pain relief.

The researchers found that patients who used opioid painkillers typically spent more time in the hospital; an average of 2.7 days vs. 2.3 days for the non-narcotic group.

“Patient education played a large role in protocol compliance, and patient satisfaction improved as they were able to avoid prolonged fasting, achieve improved pain control without the side effects of narcotic analgesia, and be discharged home earlier,” said Horrattas.

For pre-emptive analgesia before surgery, patients received one dose of acetaminophen, gabapentin, and the NSAID celecoxib (Celebrex).  In the operating room, patients received a nerve block and underwent anesthesia with the non-opioid pain relievers ketamine and lidocaine.   

Surgeons at Akron General have since adopted the non-opioid protocol for other major abdominal operations, such as bariatric procedures, gynecological and genital/urinary tract procedures, and liver and gall bladder operations.

“One of the great things about our protocol is its reproducibility.  Once we developed our program, we found that it could be standardized across departments with consistently reproducible results,” said Horattas.

Akron General’s protocol is similar to guidelines adopted by the American Pain Society (APS) for postoperative pain care. The APS also encourages the use of non-opioid medications such as acetaminophen, NSAIDs, gabapentin (Neurotin) and pregabalin (Lyrica).  

Akron General gets below average ratings for patient satisifaction from Hospital Compare, a Medicare survey that asks patients about their experiences during a recent hospital stay. The hospital received only two of a possible five stars, which places it in the bottom third of hospitals nationwide. Only 68% of Akron General’s patients said they would definitely recommend the hospital.

According to Healthgrades, 3 percent of the patients died after a colorectal surgery at Akron General, which is slightly below the national average for that procedure.

Opioid Addiction Rare After Surgery

In recent years, many hospitals have shifted away from routinely giving patients opioids during and after major surgeries -- even though it is rare for patients to become chronic opioid users.

A large Canadian study found that only 0.4% of elderly patients that were prescribed opioids while recovering from a heart, lung, colon, prostate or hysterectomy operation were still using them a year after their surgeries.

Another large study published this year in the British Medical Journal found similar results. Only 0.2% of patients who were prescribed opioids for post-surgical pain were later diagnosed with opioid dependence, abuse or a non-fatal overdose.

Long-term opioid use after dental surgeries is also rare. A recent study published in JAMA found that only 1.3% of teens and young adults who were given opioids after wisdom teeth removal were still being prescribed opioids months after their initial prescription.

The vast majority of patients still prefer opioids and perceive them as the most effective form of pain relief after surgery. In a recent survey of over 500 adults who were scheduled to have surgery, researchers at Thomas Jefferson University Hospital in Philadelphia found that 77% expected opioids, 37% expected acetaminophen, and 18% expected a NSAID for pain relief.

"Patients often assume they will receive opioids for pain, believing they are superior, and therefore may pressure physicians to prescribe them after surgery," said lead author Nirmal Shah, DO, an anesthesia resident at Thomas Jefferson University Hospital.

"But research shows opioids often aren't necessarily more effective. Clearly, we need to provide more education to bridge that gap and help patients understand that there are many options for pain relief after surgery, including other pain medications such as acetaminophen and ibuprofen."

Study Finds Many Treatments for Back Pain Ineffective

By Pat Anson, Editor

Lower back pain is the world’s leading cause of disability, affecting about 540 million people at any given time. With so many people suffering, you'd think there would be a consensus on the best way to treat or at least manage low back pain.

And you'd be wrong.

In a series of reviews appearing in The Lancet medical journal, an international team of researchers found that low back pain is usually treated with bad advice, inappropriate tests, risky surgeries and painkillers -- often against treatment guidelines.

“The majority of cases of low back pain respond to simple physical and psychological therapies that keep people active and enable them to stay at work,” says lead author Professor Rachelle Buchbinder of Monash University in Australia. “Often, however, it is more aggressive treatments of dubious benefit that are promoted and reimbursed.”

Buchbinder and her colleagues say low back pain is best managed in primary care, with the first line of treatment being education and advice to exercise, stay active and continue to work. Instead, a high number of low back pain patients are treated in emergency rooms, encouraged to rest and stop work, referred for scans or surgery, and prescribed painkillers.

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“In many countries, painkillers that have limited positive effect are routinely prescribed for low back pain, with very little emphasis on interventions that are evidence based such as exercises," adds co-author Professor Nadine Foster of Keele University in the UK.

"As lower-income countries respond to this rapidly rising cause of disability, it is critical that they avoid the waste that these misguided practices entail."

Low back pain mostly affects adults of working age in lower socioeconomic groups. People with physically demanding jobs, physical and mental comorbidities, smokers, and obese individuals are at greatest risk of reporting low back pain. 

Most people with new episodes of low back pain recover quickly, but recurrences are common. It’s also important to rule out more serious causes of back pain, such as cancer, arthritis and spinal fractures. In a small proportion of people, low back pain can become chronic and disabling.

The Lancet authors say patients should avoid harmful and useless treatments, and doctors need to address widespread misconceptions about their effectiveness. For example, there is limited evidence to support the use of opioids for low back pain, and epidural steroid injections and acetaminophen (paracetamol) are not recommended at all.

The authors recommend counseling, exercise and cognitive behavioral therapy as first-line treatments for short-term low back pain, followed by spinal manipulation, massage, acupuncture, meditation and yoga as second line treatments.

“Millions of people across the world are getting the wrong care for low back pain. Protection of the public from unproven or harmful approaches to managing low back pain requires that governments and health-care leaders tackle entrenched and counterproductive reimbursement strategies, vested interests, and financial and professional incentives that maintain the status quo,” said co-author Professor Jan Hartvigsen of University of Southern Denmark.

“Funders should pay only for high-value care, stop funding ineffective or harmful tests and treatments, and importantly intensify research into prevention, better tests and better treatments.”

The findings in The Lancet series are similar to those reported in other medical journals. A 2016 study published in JAMA Internal Medicine found that regular exercise and education reduce the risk of developing lower back pain by as much as 45 percent.

Another study in JAMA found that opioid medication provides only modest short-term relief for low back pain. Previous studies published in the British Medical Journal and The Lancet also found little evidence that acetaminophen was effective in treating low back pain.

Overuse of Acetaminophen Increases During Flu Season

By Pat Anson, Editor

Acetaminophen is a key ingredient in hundreds of over-the-counter pain relievers and cough, cold and flu medicines – from Excedrin and Tylenol to Theraflu and Alka-Seltzer Plus.

Recent guidelines released by the UK’s National Institute for Health Care Excellence (NICE) even recommend acetaminophen (paracetamol) for treating sore throat pain.

But a large new study warns that too many cold and flu sufferers take too much acetaminophen – which has long been associated with liver damage and allergic reactions such as skin rash.

Researchers at the University of Pittsburgh and Boston’s University’s Slone Epidemiology Center surveyed nearly 14,500 U.S. adults about their use of acetaminophen in the preceding 30 days. The study, which was sponsored by Johnson & Johnson, was conducted over a five-year period, from 2011 to 2016.

Investigators found that 6.3% of acetaminophen users exceeded the recommended maximum adult daily dose of 4,000 mg on at least one day during a week that they used acetaminophen.

Usage patterns grew during the cold and flu season. The odds of taking more than 4,000 mg of acetaminophen increased to 6.5% compared to 5.3% during the off-season.

This was primarily due to increased use of over-the-counter medications designed to treat upper respiratory cold and flu symptoms.

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"This is the first multi-year, year-round study that includes detailed data on how consumers used acetaminophen medications," said Saul Shiffman, PhD, of Pinney Associates and the University of Pittsburgh. "The study findings suggest the importance of educating consumers about acetaminophen and counseling them about appropriate use and safe dosages of these medications.

"Getting this message out is especially important during cold/flu season, when people may be more likely to treat illness symptoms with acetaminophen combination products, sometimes without even realizing they contain acetaminophen."

The use of acetaminophen (paracetamol) is even more pronounced in France, according to a new study published in the British Journal of Clinical Pharmacology.

There was a 53% increase in the use of paracetamol in France between 2006 and 2015, and 1000 mg tablets of paracetamol (which are not available in the United States) are now the most-used drug among French adults. There is also a trend towards larger doses. Consumption of 1000 mg tablets increased by 140 percent in France over the ten-year study; while consumption of 500 mg tablets decreased by 20 percent.

Compared to other countries in Europe, France ranked first in paracetamol usage and third in the consumption of mild opioids such as tramadol and codeine. The French use of strong opioids such as morphine was among the lowest in Europe.

"To our knowledge, this is the first published study analysing consumption trends for both non-opioids and opioids over the last decade in France. Long-term surveillance over the past 10 years has highlighted quantitative and qualitative changes in analgesic consumption patterns in France," said study co-author Philippe Cavalié, PhD, of the French National Agency for Medicines and Health Products Safety.

"The very widespread analgesics consumption that we have documented raises the concern of overuse and misuse, as well as addiction to opioids."

The U.S. Food and Drug Administration asked drug makers in 2011 to limit acetaminophen doses to 325 mg per tablet or capsule. The FDA also requires a “Boxed Warning” label – the agency’s strongest warning – to call attention to serious risks.

Over 50 million people in the U.S. use acetaminophen each week for pain and fever – many unaware of the risk of liver injury and allergic reactions. Over 50,000 emergency room visits each year in the U.S. are blamed on acetaminophen overdoses, including 25,000 hospitalizations and 450 deaths.

For more information about acetaminophen and how to avoid overdosing, visit KnowYourDose.org.

Is JAMA Opioid Study Based on Junk Science?

By Pat Anson, Editor

You may have read about a research study published this week in the Journal of the American Medical Association (JAMA), which compared the effectiveness of opioid and non-opioid medications in treating chronic pain. 

The yearlong study of 240 patients found that opioids were not superior to pain relievers like acetaminophen and ibuprofen in treating chronic back pain or hip and knee pain caused by osteoarthritis.  Pain improved for 41% of the patients who took opioids, compared to 54% in the non-opioid group.  

It’s an interesting study – one of the few to look at the effectiveness of any pain relievers long term – but some critics are questioning the study’s methodology and the alleged anti-opioid bias of its lead author, Erin Krebs, MD, a researcher for the Department of Veterans Affairs.

First let’s look at some of the news coverage the study is getting.

“Opioids Don’t Treat Chronic Pain Any Better Than Ibuprofen” reads the headline in Newsweek, an article that never mentions the JAMA study was limited to patients with back pain or osteoarthritis.

“Opioids Don’t Beat Other Medications for Chronic Pain” was the headline in NPR.com, while the Chicago Tribune went with “Opioids no better than common painkillers for treating chronic pain.”

The Tribune article included a quote from one of the co-authors of the CDC opioid guidelines. "The fact that opioids did worse is really pretty astounding," said Roger Chou, MD. "It calls into question our beliefs about the benefits of opioids."

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Notice the news coverage strongly suggests that opioids are ineffective for all types of chronic pain – not just back pain and osteoarthritis.  Patients living with chronic pain from arachnoiditis, trigeminal neuralgia or some other intractable pain condition would probably disagree about that. And they'd find the idea of taking ibuprofen laughable, if not infuriating. But no one asked for their opinion.

Also unmentioned is that opioids are usually not prescribed for osteoarthritis or simple back pain, which are often treated with NSAIDs and over-the-counter pain relievers.

So, what JAMA has published is a government funded study designed to look at a treatment (opioids) that most people with back pain and arthritis never actually get.

“You've been had by anti-opioid advocates disguising their advocacy as science.  Krebs is well known in professional circles for this kind of distorted advocacy junk science,” wrote patient advocate Red Lawhern, PhD, in a comment submitted to the Philadelphia Inquirer after it published a misleading headline of its own, “Prescription opioids fail rigorous new test for chronic pain.”

“I suggest that you retract your article.  In its present form, it is propaganda not fact,” said Lawhern, a co-founder of the Alliance for the Treatment of Intractable Pain (ATIP). “Opioids have never been the first-line medical treatment of choice in lower back pain or arthritis. That role is served by anti-inflammatory meds, some of them in the prescription cortico-steroid family.  NSAIDs have a role to play, recognizing that they are actively dangerous in many patients if taken at high doses for long periods.  Hundreds of people die every year of cardiac arrest or liver toxicity due to high-dose acetaminophen or ibuprofen.” 

Who is Erin Krebs?  

Dr. Krebs is an associate professor at the University of Minnesota Medical School and a prolific researcher at the VA Medical Center in Minneapolis.

She was also an original member of the “Core Expert Group” – an advisory panel that secretly drafted the CDC’s controversial opioid guidelines while getting a good deal of input from the anti-opioid activist group Physicians for Responsible Opioid Prescribing (PROP). The guidelines recommend that opioids not be prescribed for chronic pain.

Krebs also appeared in a lecture series on opioid prescribing that was funded by the Steve Rummler Hope Foundation, which coincidentally is the fiscal sponsor of PROP. 

Some of her previous opioid research has been controversial. In a study published last year in the Annals of Internal Medicine, Krebs reviewed 67 studies on the safety and effectiveness of opioid tapering. Most of the studies were of poor quality, but nevertheless Krebs came to the conclusion that pain levels and the quality of life of patients “may improve during and after opioid dose reduction.”

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“This review found insufficient evidence on adverse events related to opioid tapering, such as accidental overdose if patients resume use of high-dose opioids or switch to illicit opioid sources or onset of suicidality or other mental health symptoms,” wrote Krebs.

PROP founder Andrew Kolodny, MD, read the review and liked it, tweeting that “dangerously high doses should be reduced even if patient refuses.”

But forced opioid tapering is never a good idea, according to a top CDC official.

“Neither (Kreb’s) review nor CDC's guideline provides support for involuntary or precipitous tapering. Such practice could be associated with withdrawal symptoms, damage to the clinician–patient relationship, and patients obtaining opioids from other sources,” wrote Deborah Dowell, MD, a CDC Senior Medical Advisor, in an editorial also published in the Annals of Internal Medicine. 

As for Krebs’ contention that there is “insufficient evidence” of adverse events associated with opioid tapering, that notion may be put to rest next month when the VA releases a new study showing that tapering has led to a growing number of suicides by veterans.

In a summary of the findings, which will be presented at the Rx Drug Abuse & Heroin Summit, VA researchers report that “opioid discontinuation was not associated with overdose mortality, but was associated with increased suicide mortality.”  

Who and what should we believe in the neverending debate about opioids? PNN columnist Roger Chriss wrote about Krebs’ opioids vs. non-opioids study last year, when the initial reports of its findings came out. Roger said prescribing decisions are best left to physicians who know their patients’ medical conditions – not researchers, regulators or the news media.

“In reality, there is no ‘versus’ here. Opioids and NSAIDs are both valuable tools for chronic pain management. To pretend that one is inherently better than the other is to miss the essential point: Both work and should be available for use as medically appropriate,” Roger wrote. 

Do OTC Pain Relievers Dull Your Emotions?

By Pat Anson, Editor

Ibuprofen, acetaminophen and other over-the-counter pain relievers may do more than just dull your physical pain. They could also dull your emotional and cognitive senses, according to a new study.

Researchers at the University of California, Santa Barbara reviewed a small body of clinical studies that suggest OTC pain medications have an overlapping effect on us, both physically and emotionally.

One study, for example, found that acetaminophen makes people feel less empathy for others.

Research also found that women who took ibuprofen reported less social anxiety and hurt feelings after being excluded from a game or when writing about a time when they felt betrayed.

Yet another study found that acetaminophen lessens the discomfort of parting with a prized possession. When asked to set a selling price on an object they owned, individuals who took acetaminophen set prices that were cheaper than the prices set by individuals who took placebos.

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"In many ways, the reviewed findings are alarming," wrote lead author Kyle Ratner, PhD, an assistant professor of psychology at UC Santa Barbara. "Consumers assume that when they take an over-the-counter pain medication, it will relieve their physical symptoms, but they do not anticipate broader psychological effects.

“Are more regulations needed? Should warnings be expanded on drug labels? At this point, drawing strong conclusions from the existing studies would be premature. Nonetheless, policymakers might start thinking about potential public health risks and benefits.”

Ratner and his colleagues say one place to start is to further study the effects of OTC analgesics on pregnant women. Recent research has found higher rates of autism and attention deficit disorder (ADHD) in young children whose mothers used acetaminophen while pregnant.

Acetaminophen -- also known as paracetamol – is the world’s most widely used over-the-counter pain reliever. It is the active ingredient in Tylenol, Excedrin, and hundreds of other pain medications. Ibuprofen is also widely used and can be found in brand name products such as Motrin and Advil.   

“Found in medicine cabinets across the world and used multiple times per week by people of all ages, genders, and ethnic backgrounds, these drugs are woven into modern life. Policymakers should take note of existing findings but not rush to judgment,” said Ratner.

The study is published online in the journal Policy Insights from the Behavioral and Brain Sciences.

Acetaminophen May Slow Language Development

By Pat Anson, Editor

Another study has linked acetaminophen to learning difficulties in young children born to mothers who used the over-the-counter pain reliever during pregnancy.

Researchers at the Icahn School of Medicine in New York City say toddlers exposed to acetaminophen in the womb had a slower rate of language development at 30 months. The findings are consistent with other studies reporting higher rates of autism, attention deficit disorder (ADHD) and behavioral problems in children born to mothers who used acetaminophen while pregnant.  

Acetaminophen (paracetamol) is one of the most widely used pain relievers in the world. It is the active ingredient in Tylenol, Excedrin, and hundreds of other pain medications. Researchers say over half the pregnant women in the United States and European Union use the drug.

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“Given the prevalence of prenatal acetaminophen use and the importance of language development, our findings, if replicated, suggest that pregnant women should limit their use of this analgesic during pregnancy,” said senior author Shanna Swan, PhD, Professor of Environmental and Public Health at the Icahn School of Medicine at Mount Sinai.

“It’s important for us to look at language development because it has shown to be predictive of other neurodevelopmental problems in children.”

The study involved 754 women who enrolled in the Swedish Environmental Longitudinal, Mother and Child, Asthma and Allergy study (SELMA) during weeks 8-13 of their pregnancy. Researchers asked the women to report the number of acetaminophen tablets they took between conception and enrollment, and tested the acetaminophen concentration in their urine.

A delay in a child's language development, defined as the use of fewer than 50 words at 30 months of age, was measured by a nurse and a follow-up questionnaire filled out by the mothers.

Girls born to mothers with high exposure -- those who took acetaminophen more than six times in early pregnancy -- were nearly six times more likely to have language delay than girls born to mothers who did not take acetaminophen.

While the number of acetaminophen tablets and concentration in urine were associated with a significant increase in language delay in girls, there was only a slight increase in boys.  The findings suggest that acetaminophen use in pregnancy results in the loss of the well-recognized female advantage in language development in early childhood.

The study is published online in the journal European Psychiatry. Researchers will follow-up with the children and re-examine their language development at age seven.

A 2016 study of over 2,600 Spanish women linked acetaminophen to autism and attention deficit problems in their children. Studies in Denmark and New Zealand have also linked acetaminophen to a higher risk of ADHD.

Over 50 million people in the U.S. use acetaminophen each week to treat pain and fever. The pain reliever has long been associated with liver injury and allergic reactions such as skin rash. In the U.S. over 50,000 emergency room visits each year are caused by acetaminophen, including 25,000 hospitalizations and 450 deaths.