Rx Opioid Misuse Rare in Children with Sickle Cell Disease

By Pat Anson, PNN Editor

Children with sickle cell disease show no signs of misusing or becoming addicted to opioids after being treated for an acute pain crisis, according to a new study.

Sickle cell disease is a genetic disorder that causes red blood cells to form in a crescent or sickle shape, which creates painful blockages in blood vessels – known as a vaso-occlusive crisis (VOC) -- that can lead to seizures, strokes and organ failure. About 100,000 Americans live with sickle cell disease, primarily people of African or Hispanic descent.

In a retrospective cohort study involving 725 children with sickle cell disease (SCD), researchers at Georgia State University found “no concerning patterns of long-term or increasing use of opioids” within 3 years of their first opioid prescription.

A VOC is a life-threatening condition that is the most common reason for an SCD patient to visit a hospital or emergency room. Guidelines for emergency VOC treatment call for opioids and other analgesics to be administered with one hour. However, due to the stigma associated with opioids and fears of addiction, many SCD patients face long delays before receiving treatment, as well as discrimination and suspicion that they are seeking opioids to get high.

The study findings, published in JAMA Pediatrics, found little evidence to justify those fears. In the 725 children who were studied – all under the age of nine – only one pattern of low opioid use was found.  Most of the children used opioids sparingly, with only one in four (25.4%) having an opioid prescription for codeine or hydrocodone filled for them within five days of being discharged from a hospital after a VOC.

Researchers say more studies are needed to determine whether the limited use of opioids shows the effectiveness of nonopioid pain management or highlights “an unintended and potentially harmful treatment access problem” caused by opioid phobia.

"Because of the opioid epidemic, it's important to make sure that people understand that when giving prescriptions for children with sickle cell disease, you aren't creating folks who are going to misuse opioids," lead author Angela Snyder, PhD, of the Georgia Health Policy Center at Georgia State University, told MedPage Today.

In 2020, a report by the National Academies of Sciences, Engineering, and Medicine called for major changes in the way sickle cell disease is treated in the United States, including an end to the discrimination and stigma that many sickle cell patients face.

'Growing Pains' in Childhood Linked to Migraine

By Pat Anson, PNN Editor

Did you experience “growing pains” as a child? An unusual ache or throbbing in your legs that occurred late in the day and kept you awake at night?

The Mayo Clinic says there’s no evidence that a growth spell actually causes physical pain, and that any discomfort may be caused by a low pain threshold or even psychological issues.

But a small new study suggests something else may be going on: Brazilian researchers say children who have growing pains are significantly more likely to develop migraines – just as their parents did.  Migraine can be hereditary, and if one or both parents have migraine, there’s a 50-75% chance that their children will also.

“In families of children with growing pains, there is an increased prevalence of other pain syndromes, especially migraine among parents,” wrote lead author Raimundo Pereira Silva-Néto. PhD, a neurology professor at Federal University of Delta do Parnaibal. “Children with migraine have a higher prevalence of growing pains, suggesting a common pathogenesis; therefore, we hypothesized that growing pains in children are a precursor or comorbidity with migraine.”

With parental authorization, Silva-Néto and his colleagues followed 78 children between 5 and 10 years of age, who were born to mothers being treated for migraine at a headache clinic. Their findings were published in the journal Headache.

After five years, about half of the children reported growing pains in their lower limbs. Headaches occurred in 76% of those children, with many meeting the criteria for migraine without aura. By comparison, only 22% of the children who did not have growing pains had headaches.

Lower limb pain was reported most often in the calf muscles (70%), usually lasted more than 30 minutes, and occurred more frequently at night.

That nocturnal connection intrigued the researchers, who noted that previous studies have found that sleepwalking, nightmares, and restless leg syndrome also occur more frequently in children who have migraines.   

“There is no definitive explanation for the nocturnal patterns of growing pains, nor for the overlap with sleep disturbances; however, the authors believe the hypothesis of a common pathogenesis with migraine,” researchers concluded. “Pain in the lower limbs of children and adolescents, commonly referred to as GP (growing pains) by pediatricians and orthopedists, may reflect a precursor/comorbidity with migraine.”

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. In addition to headache pain, migraine can cause nausea, blurriness or visual disturbances, and sensitivity to light and sound. About one in five teens suffer from migraine.

Little Evidence Opioid Use by Children Leads to Addiction

By Pat Anson, PNN Editor

Healthcare providers have become more cautious in recent years about giving opioid pain medication to children, fearing that even short-term use could lead to a lifetime of addiction or even a fatal overdose.

But in a review at the University of Alberta, pediatric researchers found little evidence to support a link between short-term opioid use in childhood and opioid use disorder (OUD) later in life.

“We actually didn’t find a lot of evidence to directly answer our question,” said senior author Michele Dyson, PhD, assistant professor of pediatrics in the Faculty of Medicine & Dentistry and associate director of the Alberta Research Centre for Health Evidence.

“If opioids are used as indicated, they can be a safe and effective strategy for pain management,” she said. “In some cases, they really are part of the best treatment plan to manage a child’s pain.”

Dyson and her colleagues reviewed 21 observational studies involving nearly 50 million patients under the age of 18 who were exposed to opioids for less than 14 days. Most of the studies were considered low quality and did not look at the duration of opioid use.

One study did show a potential link between short-term exposure and later abuse. But researchers concluded the findings overall were not definitive because they did not specify duration of exposure or lacked a control group. Their findings are reported in the journal Pediatrics.

“There is limited evidence to determine if short-term therapeutic exposure to opioids in childhood is
definitively associated with future nonmedical opioid use or development of an OUD; however, this review suggests a link between lifetime therapeutic opioid use (unknown duration) and nonmedical opioid use. The existing evidence on risk factors for nonmedical opioid use or OUD after short-term therapeutic exposure is unclear,” researchers concluded.

Conflicting Advice

Whether opioid medication is appropriate for children is a controversial issue. Earlier this year, the World Health Organization (WHO) released new guidelines recommending that opioids only be used for children who are dying or seriously ill and not expected to recover.

Like the Alberta study, a WHO advisory panel found little good quality research on how to treat childhood pain, but recommended that children with chronic pain be treated with physical therapy and psychological interventions such as cognitive behavioral therapy.  

An international study in The Lancet came to a very different conclusion, warning that opioid prescribing guidelines intended for adults are being “inappropriately applied to young people.” Because of the stigma associated with opioids, researchers said childhood pain was often untreated or poorly treated, leading to chronic pain, disability and other negative consequences in adulthood.

“Health-care professionals, young people, and parents continue to hold misconceptions and believe myths about opioid use in pediatric patients, whereby the media depicts opioids as the villain and the underlying reason for substance misuse,” researchers said. “Opioids have their place in pediatric pain medicine.”

That finding is at odds with a 2018 warning from the U.S. Food and Drug Administration, which said that cough and cold medications containing opioids pose “serious risks” to children and should no longer be prescribed to patients younger than 18.

A recent study found that opioid misuse is relatively rare in U.S. adolescents and young adults. Less than 1% of those who filled an opioid prescription for the first time overdosed or developed opioid use disorder within the next 12 months.

The conflicting advice can be confusing to both parents and providers.

“Parents see stories about overdoses in the news and are afraid for their children, while physicians and prescribers are also worried because they don’t know what the evidence is,” says Dyson. “Health-care providers don’t want to cause harm, and at the same time, they still want to be able to treat pain appropriately.”

Dyson and her team at the University of Alberta have developed a series of infographics to help physicians, parents and young people recognize that opioid pain relievers are sometimes needed.

One such graphic plainly states: “Opioids don’t have to be scary!”

View fullsize

UNIVERSITY OF ALBERTA INFOGRAPHIC

“While we can’t say for sure that a short-term prescription for pain is linked with misuse, there is some evidence that that could happen,” she explained. “There is likely some risk, but it needs to be balanced with the harms of stigmatizing opioid use and under-treating pain, which comes with its own significant short- and long-term consequences.”

Cannabis Poisoning Calls Rise, Particularly for Children

By Pat Anson, PNN Editor

A new analysis of calls to U.S. poison control centers suggests that more regulation is needed of cannabis products to protect consumers – and children in particular — from adverse health consequences.

Researchers found a significant increase in cannabis-related calls to poison centers from 2017 to 2019, about half of them from a healthcare facility.

Most of the 28,630 calls involved someone ingesting cannabis flower or buds, but a growing number involved manufactured cannabis products such as edibles, vaporized liquids and concentrates. About a third of the calls were considered serious.

Cannabis-Related Calls to U.S. Poison Control Centers

JAMA NETWORK OPEN

Most of the calls about manufactured cannabis products involved underage children. Twenty-seven percent involved children under the age of 10 and about a third (34.5%) involved youths between 10 and 20 years of age. Edibles were involved in about two-thirds of those calls.

“Children may be at particular risk for exposure to edible products, such as cookies or candy,” wrote lead author Julia Dilley, PhD, Oregon Health Authority, in JAMA Network Open.

“Although we did not see more serious health outcomes for manufactured product exposures compared with plant products overall, most cannabis plant exposures involved polysubstance use, whereas most cases for manufactured products were for those products alone, suggesting that exposure to manufactured products alone may be relatively more likely to generate adverse events.”

Dilley and her colleagues say cannabis products are riskier for children because they may not know they are consuming THC (tetrahydrocannabinol), the psychoactive ingredient in cannabis. Even when they are labeled, research has found that the amount of THC in cannabis products is often inaccurate.

The study did not distinguish between medical and recreational cannabis. Interestingly, the rate of calls to poison centers from states where cannabis is legal was slightly higher than those where cannabis is still illegal, suggesting that legalization does not increase the level of safety.  

“Market factors may drive the industry to continue developing novel products, which could present additional health risks. Applying regulatory controls to market-driven innovations in potency and additives is key. Novice cannabis users are often advised to ‘start low, go slow’; this guidance may be equally applicable to regulating new retail cannabis markets and products,” researchers said.

Some cannabis companies are intentionally marketing their products as candy and snacks to make them more attractive to children. The Food & Wine website reports the Wrigley Company recently filed three lawsuits against cannabis manufacturers, alleging they produced THC-spiked products that resemble Wrigley candies such as Skittles, Life Savers and Starbursts   

“We take great pride in making fun treats that parents can trust giving to their children and children can enjoy safely," a Wrigley spokesperson told Reuters. "We are deeply disturbed to see our trademarked brands being used illegally to sell THC-infused products."

One cannabis company, THC Living, recently took a “snortable” cannabis candy off the market after complaints on social media. According to Leafly, the packaging and marketing of “Cannabis Bumps” were designed to make the powdered candy look like cocaine. Each package contained a hefty dose of 600mg of THC.    

WHO Guideline Only Recommends Opioids for Children Who Are Dying

By Pat Anson, PNN Editor

The World Health Organization (WHO) has released new guidelines on the treatment of chronic pain in children, recommending that prescription opioids only be used for children who are dying or seriously ill and not expected to recover.

The 56-page guideline calls access to pain management a “fundamental human right,” while at the same time warning that “evidence of the effectiveness and safety of opioids is completely lacking in children.”

The guideline emphasizes the use of physical and psychological pain therapies, while taking a cautious approach to opioids. Morphine is only recommended for children in palliative care and those with “life-limiting” conditions for which there is no cure and “an early death is expected.”

“Children who are appropriately prescribed morphine for chronic pain in the context of end-of-life care or in children with life-limiting conditions, may require morphine for the management of intercurrent, acute or breakthrough severe pain,” the guideline states.

“Time-limited use of morphine in these contexts should be at the lowest appropriate dose and duration possible and must be regularly reviewed in order to ensure the fewest possible adverse events. Healthcare providers and caregivers need to perform frequent and repeated reassessments of pain and other symptoms, and the principles and relevant guidelines for acute pain management should be followed, including having an opioid stopping plan.”

The new recommendations for children between 0 and 19 years of age are a marked departure from previous WHO guidelines for chronic pain, which said that opioids “are known to be safe and there is no need to fear accidental death or dependence.”

Those guidelines were withdrawn in 2019, after two U.S. congressmen accused the United Nation’s health agency of being “corruptly influenced” by opioid manufactures.  A coalition of palliative care organizations objected, saying WHO caved-in to political pressure.

“We are extremely concerned that the withdrawal of these guidance documents will lead to confusion and possible extreme measures that will hinder access to patients with legitimate medical needs,” the coalition said in a joint statement. “Lack of availability and limited access to these medications for legitimate medical treatment is a human rights violation.”

‘Very Low Certainty’ of Evidence

Most of the recommendations made by a WHO advisory panel – the Guideline Development Group (GDG) — are vague, conditional and based on “very low certainty” of evidence. One of GDG’s members was Andrew Kolodny, MD, a psychiatrist and addiction specialist who founded Physicians for Responsible Opioid Prescribing (PROP), an anti-opioid activist group.

Despite an admitted “paucity of high-quality research” on how to treat pain in children, the GDG recommended that children be treated from a “biopsychosocial perspective” that incorporates physical therapy and psychological interventions such as cognitive behavioral therapy.  

“Children with chronic pain and their families and caregivers must be cared for from a biopsychosocial perspective; pain should not be treated simply as a biomedical problem,” the GDG said.

There is surprisingly little discussion in the guideline about the risks and benefits of non-opioid drugs such as acetaminophen. Some of the recommendations border on platitudes, such as treatment being “child and family-centered” and “tailored to the family’s values, cultures, preferences and resources.”

One area where the GDG is adamant is the importance of treating childhood pain to prevent it from becoming a lifetime problem.

“Exposure to chronic pain in early life may have implications for the incidence, severity and duration of chronic pain, and may be associated with long-term, maladaptive neurological changes,” the guideline warns.

“Chronic pain in childhood is associated with progression of pain into adulthood and potentially predisposes these children to other chronic health problems in later life. The negative impacts of chronic pain also extend to family members who report a higher burden of care and a detrimental effect on family function. As such, chronic pain during childhood has a very significant negative impact on the child over their life course as well as their wider family unit, making appropriate diagnosis and management essential.”  

The GDG said large, multi-center trials are needed to examine the safety and efficacy of virtually all pain management therapies. Additional research is also needed for children suffering from cancer pain and those with developmental and intellectual disabilities.

Former President Trump withdrew the United States from WHO last year in a dispute over its handling of the COVID-19 pandemic. President Biden reversed that decision on his first day in office.  

Lancet Study Calls for Improvements in Pediatric Pain Care

By Pat Anson, PNN Editor

An international study by The Lancet has found that childhood pain often goes untreated, unrecognized and poorly managed, leading to chronic pain, disability and other negative consequences in adulthood.

The report by the Lancet Child and Adolescent Health Commission, led by the Centre for Pain Research at the University of Bath, found that too many children live with pain — even in developed countries — and calls for improvements in pediatric pain care, including diagnosis, pain management, social support and psychological treatment.

"Among health-care professionals, it is easy to agree that no child should experience pain if that pain can and should be prevented, avoided, or successfully treated,” said lead author Emma Fisher, PhD, a Versus Arthritis fellow at the University of Bath.

“In practice, however, we know there is ample evidence that children frequently experience preventable pain, and that in high-income settings, with advanced health-care systems and highly educated and regulated health professionals, children and young people experience pain that often goes unnoticed, unreported, or is not responded to, across healthcare including in the Emergency Department, post-surgical care, and in tertiary care.”

Childhood Pain ‘Swept Under the Carpet’

The report provides several examples of childhood pain not being recognized or treated adequately, such as what happened to Caitriona Roberts of Belfast, Northern Ireland. At age 12, she went to her doctor with pain and swelling in her ankle. Initially written-off as 'just a sprain' that would go away, she would spend the next six months living in almost constant pain, until she was referred to a specialist who diagnosed her with juvenile idiopathic arthritis, an autoimmune condition.

Now 28, Roberts has learned how to live and manage the disease. She helped researchers prepare The Lancet report.

"I think this issue has been swept under the carpet for too long. Still today, over 15 years on from my diagnosis with arthritis, I find people, including medical professionals, unaware of the condition or its effects on my day-to-day life. And when I speak to other young people, I find that sadly, very little seems to have changed in terms of how they experience pain or the support they receive,” Roberts said.

Researchers say up to 10% of young people experience chronic pain into early adulthood, with conditions such as arthritis, other types of musculoskeletal pain, recurring abdominal pain, and headaches.  

"This really matters, both for those experiencing pain and those around them but also across wider society. We know that chronic pain experienced in childhood is likely to feed through to adulthood and this has long-term health and economic costs associated,” said Fisher.

She called on providers and policymakers “to sit up and listen to the fact that too many of our young people are in pain and need help."

Myths About Opioids

One obstacle to getting that help is the stigma associated with opioid pain medication, particularly in the United States and Canada, where researchers say guidelines intended to control opioid use in adults are being “inappropriately applied to young people.”

“Substance use disorders and pain medication are both conflated in policy and in the media's portrayal of the North American opioid crisis,” the report found. “Through this media, public views have been influenced to consider opioids as drugs of addiction rather than pain medicine.  

“Health-care professionals, young people, and parents continue to hold misconceptions and believe myths about opioid use in pediatric patients, whereby the media depicts opioids as the villain and the underlying reason for substance misuse. Opioids have their place in pediatric pain medicine. In the context of the oversupply of opioids, childhood pain can usefully be considered a risk factor for long-term harmful exposure to opioids.”

More Than Growing Pains

The report found that improvements in pediatric pain care have come slowly. The last major intervention in the field came in the 1980’s, when it was recognized for the first time that babies experienced pain. Up until that point, a number of routine and major operations, including heart surgery, were carried out on babies without anesthetics.

"Parents tell us about the struggle they have convincing their GP that their child's illness is more than growing pains,” said Zoe Chivers, Head of Services at Versus Arthritis, which funded the report. “While the focus, attention, and dedication in providing quality services to children is consistently in place for conditions like cancer it's woefully absent for childhood arthritis and chronic pain.

"As a society we need to understand that dismissal of arthritis comes at high price and that adults and children living in pain with the condition should no longer be expected to pay it."

The study has four key goals: to make childhood pain matter, to make it understood, to make it visible, and to make it better. One recommendation is to make routine vaccinations less painful and stressful for children, such as allowing parents to be present during the injections and using topical analgesics.

"For many parents and children, a trip to the doctors for routine inoculations will be a stressful and painful experience. This does not have to be the case - we know how we can make the experience less painful for young people, but we're not doing it. This is just another example of how pain has been accepted as an everyday feature of growing up," said Fisher.

Over-the-Counter Pain Relievers Involved in Growing Number of Suicides

By Pat Anson, PNN Editor

One of the reasons opioid prescriptions have been reined in over the last few years is concern that some patients may use the drugs to take their own lives. One study estimates that up to 30% of fatal opioid overdoses are suicides.

But the risk of suicide is greater with over-the-counter (OTC) pain relievers. According to an analysis of nearly 550,000 calls to U.S. poison control centers from 2000 to 2018, the number of suicide calls involving acetaminophen, ibuprofen and other OTC analgesics rose 57 percent.

Children between the ages of 6 and 19 accounted for about half of those calls, and females represented 73% of cases among individuals of all ages.

“Because they are easy to purchase and can help alleviate a variety of symptoms, many families have over-the-counter pain relievers readily available in their homes, often in large quantities,” said Alexandra Funk, PharmD, co-author of the study and director of the Central Ohio Poison Center at Nationwide Children’s Hospital.

“Unfortunately, the easy access to these medications is likely a big part of the reason that they are used in suicide attempts and deaths. The fact that they are being used more often with more serious outcomes is cause for concern.” 

The study, published in Pharmacoepidemiology and Drug Safety, found that nearly half (48%) of the OTC analgesic calls to poison control centers involved acetaminophen alone, followed by ibuprofen (33%), and aspirin (19%). Acetaminophen accounted for nearly two-thirds (65%) of the 1,745 deaths that were reported.

Rates of suicide-related cases involving acetaminophen and ibuprofen increased significantly during the study period, while the rate of aspirin cases decreased. About a third of the calls involved exposure to multiple substances, and those cases were twice as likely to result in hospitalization or death.

“The top three substance categories associated with suicide-related exposures in the US are antidepressants, OTC analgesics, and antipsychotics, and of these, OTC analgesics are the only one readily available without a prescription or other restrictions,” researchers found. “With suicide-related exposures involving OTC analgesics increasing in the US, more effective interventions are clearly needed to reduce injuries and deaths from this cause.”

One way to reduce the risk if suicide is to regulate the sale of OTC pain relievers by requiring single dose packaging – also known as blister packs. Rather than emptying a bottle of pills, each individual tablet would have to be punched out of the package.

“Because suicidal ingestion is often a highly impulsive act, this would deter overdoses by limiting the amount of medication that can be extracted at one time,” said Gary Smith MD, senior author of the study and director of the Center for Injury Research and Policy at Nationwide Children’s Hospital. “In addition, the U.S. should follow the lead of other countries that have successfully reduced suicidal ingestions of these medications by limiting the package size and quantity that can be purchased by an individual at one time.”

According to another recent study of calls to poison control centers, gabapentin (Neurontin) and the muscle relaxer baclofen are also involved in a growing number of suicides and attempted suicides.  

Suicide is the 10th leading cause of death in the U.S. Over 48,000 Americans took their own lives in 2018.

Should Children Be Prescribed Cymbalta?

By Pat Anson, PNN Editor

The Food and Drug Administration has quietly expanded the use of an antidepressant to treat fibromyalgia in pediatric patients between 13 to 17 years of age – despite the known risk of suicidal behavior by children on antidepressant drugs.  

Cymbalta (also known by its generic name, duloxetine) is a serotonin and norepinephrine reuptake inhibitor (SNRI) made by Eli Lilly that was first approved by the FDA as a treatment for depression in 2004.

In the years that followed, Cymbalta’s use greatly expanded as it was also approved as a treatment for anxiety, diabetic neuropathy, chronic musculoskeletal pain and fibromyalgia in adults.

The approvals came with a major caveat: a black box warning label that specifically cautioned patients and providers that “Cymbalta is not approved for use in pediatric patients” because it could increase the risk of suicidal thinking and behavior in children.

2007 Cymbalta warning label

So why is the FDA now approving the use of Cymbalta by children?  

The federal agency issued no press release when it sent a letter to Eli Lilly on April 20 notifying the company that it was approving its longstanding request to allow Cymbalta to be prescribed for juvenile fibromyalgia. Lilly itself has made no public announcement about the approval.

Health and Human Services Secretary Alex Azar, who oversees the FDA, was President of the U.S. division of Eli Lilly from 2012 to 2017, a period when the cost of Cymbalta doubled.

‘No New Safety Concerns’

The FDA’s approval of Cymbalta for pediatric cases appears to be based on a single placebo-controlled study -- sponsored by Eli Lilly -- in which 184 children with juvenile fibromyalgia were given duloxetine, placebo or a combination of the two over the course of 39 weeks.

Eli Lilly not only funded the study, but its employees designed it, collected data, conducted the analysis, and wrote the article that reported on its findings, which was published last year in the journal of Pediatric Rheumatology.

While the study did not show that duloxetine was significantly better than placebo, patients taking the drug did show a modest improvement in pain severity. Notably, Eli Lilly researchers also said they found “no new safety concerns” about duloxetine.

Which doesn’t mean there were no safety concerns, it just means they didn’t find any new ones. Duloxetine is well known to have side effects in adults, such as fatigue, nausea, mood swings and weight gain.

“The safety profile of duloxetine observed in this study was similar to that observed in previous pediatric duloxetine trials of other indications, as well as in duloxetine trials in adults with FM (fibromyalgia). Nausea, headache, vomiting, and decreased appetite were the most frequently reported AEs (adverse events) in the present study, which are similar to those reported previously in adult population with FM,” wrote lead author Himanshu Upadhyaya, Global Lead Physician in Psychiatry at Eli Lilly.

But a closer look at the study findings – which anyone can see for themselves at clinicaltrials.gov – shows that 6 children taking duloxetine exhibited alarming signs of self-harm. There were two attempted suicides and one intentional drug overdose. One child intentionally injured himself and two had suicidal thoughts. Three other children on duloxetine experienced depression, hallucinations and a seizure.

Granted, nine children in total isn’t that many – but in a small study with 184 participants, it’s concerning – especially when no one in the placebo group had the same behavior or symptoms, according to study results posted on the government-run website.

However, in their published findings in Pediatric Rheumatology, Eli Lilly researchers downplayed the suicidal thinking and other side effects associated with duloxetine, saying they were “not significantly different” than those of children on placebo. The two attempted suicides aren’t even mentioned.

“In the present study, the suicidal ideation events reported with duloxetine were not significantly different from placebo-treated patients. Similar results were reported previously, including the exposure-adjusted analysis of suicidal ideation events, which have not shown any significant difference between duloxetine and placebo,” researchers said.

“None of the SAEs (serious adverse events) reported were considered to be study drug-related and none have led to study discontinuation. There were no deaths reported during the study. There were no significant differences between groups in suicide-related behaviors or ideation.”

Eli Lilly went to great lengths to conduct the study. Its researchers said it took almost 7 years and significant recruitment efforts to find enough children to participate with parental approval. Most of the participants were in the United States, but some were recruited as far away as India and Argentina.

Suicide has long been associated with duloxetine, going back to its earliest clinical trials. A 19-year college student participating in one study killed herself in 2004, four days after being taken off the drug. Four other patients who took duloxetine during clinical trials also committed suicide, although Eli Lilly said at the time there was no evidence directly linking those deaths to the drug.

Withdrawal ‘Brain Zaps’

A common complaint of patients who take duloxetine is how quickly they become addicted and what happens when they stop taking the drug. Many complain of severe withdrawal symptoms such as mood swings, nausea, fatigue and electric-like sensations called “brain zaps.”

PNN columnist Crystal Lindell went through withdrawal when she started weaning herself off Cymbalta in 2015. Her column on that experience (see “How I took Myself Off Cymbalta”) has become a reference point for hundreds of patients trying to get off the drug.

Crystal thinks expanding the use of Cymbalta to include pediatric patients is not a good idea.

“I would urge extraordinary caution when it comes to giving Cymbalta to teenagers,” Crystal says. “When I was first given Cymbalta about seven years ago, I was 29. At that time, the doctor told me I may be too young to take it because it was known to cause suicidal thoughts in young people. He advised me to be in touch with him if that starts to happen. And I was much older than the age group they just approved to take this drug.  

“I hope doctors will be more cautious about giving Cymbalta to teenagers than they have been about giving it to adults. I always advise readers to listen to their doctor first and foremost, but don't be shy about pressing them on which medications they prescribe you. Ask them about side effects and withdrawal so that you can feel comfortable about what you’re taking.”

The FDA’s new warning label for Cymbalta still cautions about suicidal thinking and behavior in children, but no longer warns that the drug is not approved for use by pediatric patients.

NEW CYMBALTA WARNING LABEL

Duloxetine’s checkered history is well known at the FDA. The agency’s adverse events reporting system has recorded over 33,500 serious cases involving duloxetine since 2007, most of them classified as psychiatric disorders. Over 3,900 of those adverse events resulted in death.

Although Eli Lilly’s patent on duloxetine expired years ago, Cymbalta remains a top money-maker for the company. Cymbalta sales during the first quarter of 2020 were up 28% from a year ago to more than $210 million.

In addition to treating juvenile fibromyalgia, Cymbalta could be repurposed in other ways to boost sales for Eli Lilly. Over 300 clinical studies are underway to explore the use of duloxetine to treat a smorgasbord of other conditions, including shingles pain, cancer pain, surgical pain, post-traumatic stress disorder, attention deficit disorder, and cocaine addiction.

In short, a drug with risky side effects that was originally developed to treat depression is being used for health conditions it was never intended to treat. And more could be added to the list.

How Children Process Pain

By Dr. Lynn Webster, PNN Columnist

No one saw it happen. My three-and-a-half-year-old granddaughter was in the basement by herself when she broke her arm. My guess is that she was jumping on the couch or standing on the back of it. Either way, the accident left her screaming and crying -- a natural response to being frightened and injured.

At the time, it wasn’t clear if she was seriously hurt. But my daughter said she behaved very differently after previous falls left her with minor bumps and bruises.

In a recent column, "Teaching Children How to Cope With Pain," I wrote about how parents should respond to children when they injure themselves. Experiencing pain is part of life, and children develop their own reactions based on an almost infinite number of factors.

As adults, we tend to think about the physical trauma pain causes. We pay scant attention to how the young brain processes injuries or the images created in their minds as a result of them.

Children’s brains are unable to process trauma in the way adults do. This is due in part to the limited verbal ability young children have to express what they are feeling.

Still, they do integrate the experience of pain. And hopefully the lessons they learn about managing pain during childhood help them cope with pain when they reach adulthood.

Imagery and drawing are ways to help children effectively process their pain. The symbolic meaning of an image can be very revealing. Sigmund Freud described how imagery can reflect the feelings, attitudes and qualities of our environment.

Hermann Rorschach famously built on that idea to develop the Rorschach (or inkblot) test. The concept of the Rorschach test is that through drawing or interpreting images, children can convey the emotional loads they carry.

The first collection of children’s drawings of pain was published in 1885, well before Rorschach developed his test. It appeared in an article written by art reformer Ebenezer Cookie and illustrated how the stages of children’s development corresponded to the clarity of their drawings.

All trauma has the potential to affect a child’s development and perspective. This does not mean that all trauma damages the brain or renders a child unable to manage stress. In fact, trauma is a life experience that children must learn to manage without compromising their emotional development. That sets the stage for being able to handle pain effectively as they mature.

Velcro or Teflon

In his book “Hardwiring Happiness: The New Brain Science of Contentment, Calm, and Confidence,” neuropsychologist Rick Hanson says, “Your brain was wired in such a way when it evolved, it was primed to learn quickly from bad experiences but not so much from the good ones.”

That explains why traumatic memories so often stick in our brains while positive memories seem to slip away.

“It’s an ancient survival mechanism that turned the brain into Velcro for the negative, but Teflon for the positive,” Hanson concludes.

On the day of my granddaughter's injury, my daughter called and asked for help. Fortunately, my wife and I live nearby, so I rushed over immediately. Even before I entered her home, I began to wonder whether the injury my granddaughter experienced would be more Teflon than Velcro.

Usually when I arrive, my granddaughter calls my name and races to give me a hug. That didn't happen on the day she fell. Instead, she was clinging to her mother, who was trying and failing to console her and "make it all better."

It was obvious to me that my granddaughter had a fracture and needed to be taken to the emergency room.

After the orthopedic surgeon treated and cast her arm, my granddaughter experienced minimal pain. It was a bump in the road she would one day forget. Or would she? And should she?

Two weeks later, my granddaughter was at preschool, where the class was studying cloud formations. Each student was asked to draw clouds and explain what their Rorschach images meant to them.

Below, you can see my granddaughter's drawing, which she made by applying blobs of ink to the paper and folding it in half. Her interpretation of that image was that the clouds were “my broken bones.”

The separation of the clouds might have been the projection Freud would have expected from a child with a recent injury where bones were separated and had to be mended. 

It reinforced the lesson for me that young children are always processing and interpreting the events of their lives. These experiences create images and memories that are a part of their developing brains and personalities. 

Although my granddaughter is only three and a half, she is already forming her adult interpretation of pain, one layer at a time. Whether her experience will be more Teflon than Velcro, only time will tell.

Lynn R. Webster, MD, is a vice president of scientific affairs for PRA Health Sciences and consults with the pharmaceutical industry. He is author of the award-winning book, “The Painful Truth,” and co-producer of the documentary, “It Hurts Until You Die.” You can find him on Twitter: @LynnRWebsterMD.

This column is for informational purposes only and represent the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

Acetaminophen Linked to Hyperactivity and Behavior Problems in Children

By Pat Anson, PNN Editor

A new study is adding to the growing body of evidence linking maternal use of acetaminophen to hyperactivity and other behavioral problems in children. Acetaminophen – which is more commonly known as paracetamol outside the U.S. – is the world’s most widely used over-the-counter pain reliever.

British researchers have been following over 14,000 children born in 1991 and 1992 who are enrolled in the Avon Longitudinal Study of Parents and Children. The children’s health, cognitive skills, temperament and behavior were regularly evaluated as they grew older.

Children with mothers who regularly used acetaminophen in mid to late pregnancy were more likely to be hyperactive, less adaptable and to have conduct problems in their pre-school years. The attention and hyperactivity issues appear to lessen by age 7, although boys exposed to the drug were more likely to have conduct problems until age 9.

“We have shown that paracetamol consumption between 18 and 32 weeks gestation was associated with adverse trends in pre‐school child behaviour, but the associations were no longer present by the end of primary school (age 10‐11 years). Boys appeared to be more susceptible than girls to possible behavioural effects of the drug,” researchers reported in the journal Paediatric and Perinatal Health.

Acetaminophen is used by over half the pregnant women in the United States and European Union. It is the active ingredient in Tylenol, Excedrin, and hundreds of pain medications.

Previous studies have linked maternal use of acetaminophen to asthma, autism and attention deficit disorder (ADHD) in children, as well as early puberty and slow language development in girls.

“Our findings add to a series of results concerning evidence of the possible adverse effects of taking paracetamol during pregnancy such as issues with asthma or behaviour in the offspring,” said lead author Professor Jean Golding of the University of Bristol.

“It reinforces the advice that women should be cautious when taking medication during pregnancy and to seek medical advice where necessary.”

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

“Paracetamol has been used routinely during all stages of pregnancy to reduce a high temperature and for pain relief. There's no clear evidence it has any harmful effects on an unborn baby,” the NHS says on its website.

The FDA’s 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.  

Teaching Children How to Cope with Pain

By Dr. Lynn Webster, PNN Columnist

Summer is upon us and so is trauma season. Emergency room visits for children with traumatic injuries can double during the summer. Potential injuries range from insect and animal bites to serious bicycle and ATV injuries.

This means parents will be on the front line, triaging each event to determine which injury needs medical treatment and which requires "only" emotional support.

A mother recently asked newspaper advice columnist Amy Dickinson about the best way to handle her toddler's pain. The mother was seeking suggestions from a stranger because she disagreed with her husband’s approach. She wanted to learn the "right" way to respond to her child's injuries.

The mother said she felt the need to provide the hurt child with ice packs and hugs, regardless of the extent of the injury, because that felt nurturing and productive.

On the other hand, the father thought his wife was making too big of a deal out of their child's pain. He believed that coddling children deprived them of the opportunity to grow into self-sufficient, resilient adults.

The columnist advised the mother that "tender gestures are an important part of parenting." Show your children that you care about their pain, Dickinson suggested, but don't turn each incident into a melodrama.

The mother's question grabbed my attention, because treating a child's pain is an omnipresent issue with far-reaching implications. By the time they reach age five, children have developed the way they will address adversity for the rest of their lives. Obviously, how a parent responds to a child’s injury -- their attitudes and behaviors -- is part of the culture that helps children form that foundation.

Options in Soothing a Child’s Pain

An overly doting, anxious parent can reinforce a hyperbolic response to pain that has little to do with the actual injury. A small "ouchie" can become a catastrophic event, and that may contribute to learned anxiety and the perception of greater pain.

On the other hand, ignoring an injury can lead to more aggressive attention-seeking behavior. Children need to know that an empathetic adult cares, even if the injury is relatively minor. Feeling safe positively influences a child's experience of adversity.

Children who have the emotional and cognitive ability to understand and determine their response to an injury generally suffer less. This is self-efficacy, and it allows the child to feel in control.

It's important to help children master their response to pain in age-appropriate ways. Of course, you comfort your pre-verbal children with a calm, measured voice and attitude. When children can communicate verbally, you can begin asking them whether their injury is a big one or small one. Then ask the children how they can make themselves feel better. This is how to nurture their resilience.

Accepting Pain

Experts who study why some people seem to handle pain better than others believe that acceptance plays a major role. There are two kinds of acceptance: acceptance with resignation and acceptance with resilience. 

Acceptance with resignation, or learned helplessness, steals hope more thoroughly than pain itself can do. A resigned person feels incapable of solving the problem and simply gives up.

Acceptance with resilience, on the other hand, makes it possible for a person to reinvent himself or herself to resolve the problem.

Children must learn how to accept pain with resilience so they can quickly, and without drama, move on from it. This requires a mutually caring relationship with the parent or guardian.

Big hurts, medium hurts, and small hurts may require different treatment, but not necessarily a different emotional response. Fundamentally, children must realize that everyday hurts are problems with solutions.

I recently watched my daughter instinctively demonstrate this behavior. My granddaughter, Gracie, fell and bumped her knee. The three-year-old began to cry. My daughter then asked Gracie: “is it a "big ouchie" or a "small ouchie?"

The question redirected Gracie’s attention. To my surprise, Gracie answered in a soft and shaky voice, “a small one.” Gracie received a hug from her mom and seemed to forget about the incident.

The Goal Is a Resilient Child

Pain is part of growing up. Parents cannot prevent injuries from occurring with their children, but they can model how to accept the injury with resilience.

To paraphrase Viktor Frankl, we have the power to choose our response to adversity. Relying on ourselves gives us control over our behaviors and happiness.

When parents can model self-efficacy without dismissing a child’s fears or insecurities; the result will be a resilient child who is able to experience pain as part of life, but not mistake it for life itself. 

Lynn R. Webster, MD, is a vice president of scientific affairs for PRA Health Sciences and consults with the pharmaceutical industry. Lynn is a former president of the American Academy of Pain Medicine, author of the award-winning book “The Painful Truth” and co-producer of the documentary “It Hurts Until You Die.”

You can find him on Twitter: @LynnRWebsterMD.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

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.

"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.

FDA: Opioid Cold Meds Too Risky for Kids

By Pat Anson, Editor

The Food and Drug Administration has ordered stronger warning labels for cough and cold medications containing opioids and said they should no longer be prescribed to patients younger than 18. The agency also signaled it that it could enact new limits on the dose and duration of other types of opioid prescriptions.

“Given the epidemic of opioid addiction, we’re concerned about unnecessary exposure to opioids, especially in young children. We know that any exposure to opioid drugs can lead to future addiction,” said FDA Commissioner Scott Gottlieb, MD. “It’s become clear that the use of prescription, opioid-containing medicines to treat cough and cold in children comes with serious risks that don’t justify their use in this vulnerable population.”

The FDA action involves nine different types of cough and cold medicines, four of which contain codeine and five that have hydrocodone. The brand names include Tuxarin ER, Tuzistra XR, Triacin C, FlowTuss and Zutripro. Several of the medications also come in generic form.

The FDA said it conducted an extensive review of the products and convened a panel of pediatric experts, who said the risk of misuse, abuse and addiction outweighed the benefits in patients younger than 18.

“These products will no longer be indicated for use in children, and their use in this age group is not recommended.  Health care professionals should reassure parents that cough due to a cold or upper respiratory infection is self-limited and generally does not need to be treated.  For those children in whom cough treatment is necessary, alternative medicines are available,” the FDA said in a statement.

The agency also ordered stronger “Black Box” warning labels on opioid cough and cold medicines to make them more consistent with safety warnings that come with opioid pain medications.

‘Too Many People Prescribed Opioids’

The FDA this week also released its 2018 Strategic Policy Roadmap, which outlines four priority areas in the year ahead.

The agency's first goal is to reduce the abuse of opioid medication. The FDA said opioid addiction and overdoses were claiming lives at a “staggering rate” of 91 deaths every day – although it failed to point out that most of those deaths involve illegal opioids such as heroin and illicit fentanyl, not prescription pain medication. Also unmentioned in the “roadmap” is that opioid prescriptions have been declining since 2010.

“Too many people are being inappropriately prescribed opioid drugs. When these prescriptions are written, they are often for long durations of use that create too much opportunity for addiction to develop,” the FDA said.

“We need to take steps to reduce exposure to opioid drugs by helping to make sure that patients are prescribed these drugs only when properly indicated, and that when prescriptions are written, they are for dosages and durations of use that comport closely with the purpose of the prescription.” 

Several states have already enacted limits on opioid prescriptions for acute, short term pain. Minnesota, for example, recently adopted strict new guidelines that limit the initial supply of opioids for acute pain to just three days. 

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.

“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.

FDA Bans Use of Codeine and Tramadol in Children

By Pat Anson, Editor

The U.S. Food and Drug Administration is tightening restrictions on the use of codeine and tramadol in young children.

The agency says the opioid medications carry "serious risks" for children under the age of 12, including slowed or difficult breathing and possibly even death. The FDA is also recommending against the use of codeine and tramadol by breastfeeding mothers due to possible harm to their infants.

Codeine is approved to treat mild pain and cough, while tramadol is used to treat moderate pain. Codeine is usually combined with other medicines, such as acetaminophen, in prescription pain medication, as well as in some over-the-counter (OTC) cough and cold remedies. The FDA action only applies to prescription codeine.

"We know that some children who received codeine or tramadol have experienced life-threatening respiratory depression and death because they metabolize these medicines much faster than usual, casing dangerously high levels of active drug in their bodies," said Doug Throckmorton, MD, deputy director for regulatory programs, at the FDA Center for Drug Evaluation and Research.

"This is especially concerning in children under 12 years of age and adolescents who are obese or have conditions that may increase the risk of breathing problems, like obstructive sleep apnea or lung disease. Respiratory depression can also occur in nursing babies, when mothers who are ultra-rapid metabolizers take these types of medicines and pass it along to their children through their breast milk."

In a review of adverse event reports from 1969 to 2015, the FDA said it identified 64 cases of serious breathing problems, including 24 deaths, with codeine-containing medicines in children younger than 18. The agency also identified nine cases of serious breathing problems, including three deaths, with the use of tramadol by children.

The majority of serious side effects with both codeine and tramadol occurred in children younger than 12, and some cases occurred after a single dose.

The FDA is requiring drug makers to add a tougher warning to the labels of codeine and tramadol products, alerting healthcare providers and parents that codeine should not be used to treat pain or cough and tramadol should not be used to treat pain in children younger than 12.

The new labeling also cautions against their use in adolescents between 12 and 18 who are obese or have conditions such as obstructive sleep apnea or severe lung disease. Breastfeeding mothers will also be warned not to use the medications.

The FDA said it is considering additional regulatory action for the OTC codeine products that are available in some states. It is also considering an FDA Advisory Committee meeting to discuss the role of prescription opioid cough-and-cold medicines, including codeine, to treat cough in children.

The agency did not recommend or suggest any alternatives to codeine and tramadol to treat childrens' cough or pain. OTC medicines such as acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) also have risks and side effects.

"We understand that there are limited options when it comes to treating pain or cough in children, and that these changes may raise some questions for health care providers and parents. However, please know that our decision today was made based on the latest evidence and with this goal in mind: keeping our kids safe," said Throckmorton.

In 2015, the FDA approved the use of OxyContin in children ages 11 to 16  who are in severe pain, a move widely panned by addiction treatment activists who claimed kids would get easily hooked on the painkiller.