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.

Migraine Drugs No More Effective Than Placebo for Kids

By Pat Anson, Editor

Two medications commonly prescribed to prevent migraines in adults are no more effective than a placebo when given to children and teenagers, according to a new study published in The New England Journal of Medicine.

Researchers affiliated with the Childhood and Adolescent Migraine Prevention (CHAMP) study randomly assigned 328 children and adolescents into three groups. One group received a daily dose of amitriptyline (Elavil), the second group received topiramate (Topamax), and the third group was given an ordinary sugar pill.

After 24 weeks, 52 percent of those taking amitriptyline and 55 percent of those taking topiramate had a 50 percent or more reduction in the number of headache days.

But the sugar pill was more effective, with 61% of the placebo group reporting their number of headache days reduced by 50 percent or more.

Researchers say the expectation of responding to a medication may have surpassed the pharmacological effects of taking a drug.

"The study was intended to demonstrate which of the commonly used preventive medications in migraine was the most effective. What we found is that we could prevent these headaches with either a medication or a placebo," says Andrew Hershey, MD, co-director of the Cincinnati Children's Headache Center and senior author of the study. "This study suggests that a multi-disciplinary approach and the expectation of response is the most important, not necessarily the prescription provided."

The children taking amitriptyline or topiramate had a significantly higher rate of side effects, including fatigue, dry mouth and, in three cases, mood alteration. About a third of those taking topiramate had paresthesia, a "pins and needles" tingling sensation in their hands, arms, legs or feet.

"The interpretation of these results is very challenging. In most situations, trials that fail to show benefit of an intervention do so because study participants do not improve. That was not the situation here. A majority of all study participants improved, regardless of their assigned treatment group," says Chris Coffey, PhD, a professor of biostatistics in the University of Iowa's College of Public Health, who was lead statistician for the study.

Researchers say further studies are needed identify the best ways to treat pediatric migraines. Simply prescribing sugar pill would be unethical without the patient’s knowledge.

"Our national team was hoping to develop evidence to drive the choice by medical providers of the first line prevention medication for helping youth with migraine, but the data showed otherwise, says Scott Powers, PhD, a pediatric psychologist and co-director of the headache center at Cincinnati Children's.

"We see this as an important opportunity for health care providers, scientists, children, and families because our findings suggest a paradigm shift. First line prevention treatment will involve a multidisciplinary team approach and focus on non-pharmacological aspects of care."

One of the non-pharmacological therapies being used is cognitive behavior therapy (CBT). While CBT has not been directly compared to a placebo for pediatric migraines, neurologists and psychologists say it can be a helpful component in pain care.

As many as one out of five teens suffers from migraines, but treatment options are limited compared to adults.  Last year the Food and Drug Administration approved two new treatments for pediatric migraine. Zonig is a nasal spray that provides pain relief in as little as 15 minutes, while Treximet is a medication that contains sumatriptan and naproxen, a non-steroidal anti-inflammatory drug (NSAID). Both Zonig and Treximet have been available for years to treat adult migraine.

Migraine is thought to affect a billion people worldwide and about 31 million Americans adults. In addition to headache pain and nausea, migraine can also cause vomiting, blurriness or visual disturbances, and sensitivity to light and sound. About half of people living with migraine are undiagnosed.