A second sleep medication has failed as an effective treatment for sleep problems in children with comorbid ADHD.
A large, randomized, controlled 12-week trial of eszopiclone (Lunesta, Sunovion Pharmaceuticals Inc) in children and adolescents with ADHD and insomnia was no better than placebo in treating the sleep disorder. This study comes on the heels of an earlier trial of zolpidem (multiple brands) that showed similar results.
The current multisite, randomized controlled trial (RCT) of 486 children and adolescents clinically diagnosed with ADHD and complaining of insomnia showed that those who received high- or low-dose eszopiclone for 12 weeks did not differ significantly from those who received placebo in sleep measures assessed by polysomnography.
"We were somewhat surprised because medicines like eszopiclone that work on the benzodiazepine receptor complex in the brain help with poor sleep in adults, at least for a short duration of time," lead author R. Bart Sangal, MD, director of the Sleep and Attention Disorders Institute in Sterling Heights, Michigan, and professor at Oakland Beaumont School of Medicine in Rochester Hills, told Medscape Medical News.
"On the other hand, a previous study showed that zolpidem didn't work in children. So perhaps our results are not so surprising," he added.
Dr Sangal noted that the take-away message for clinicians is to not automatically treat children who have insomnia with the same medications typically prescribed for adults.
The study was published online September 29 in Pediatrics.
The prevalence of pediatric insomnia in the general population ranges from 1% to 6%. However, as many as 50% to 60% of children and adolescents with ADHD are plagued by sleep difficulties ― a phenomenon that cannot entirely be attributed to stimulant medications.
Although some medications have been shown to be effective in treating adult insomnia, none are indicated for use in pediatric populations.
"Thus, a wide range of over-the-counter and prescription products are used to treat insomnia and other sleep difficulties in children and adolescents, with little evidence of efficacy," the authors write.
The study included 486 participants from 63 US sites who were recruited between April 2009 and July 2011. Of these, 163 were randomly assigned to receive low-dose eszopiclone for 12 weeks (1 mg for children between the ages of 6 and 11 years, 2 mg for adolescents between the ages of 12 and 17 years), 162 received high-dose eszopiclone (2 mg for the children, 3 mg for the adolescents), and 161 received matching placebo.
All participants were instructed to take their assigned medication orally at bedtime.
The study's primary outcome measure was "change in latency to persistent sleep from baseline to week 12, based on polysomnography."
Secondary measures included wake time after sleep onset, which was also assessed via polysomnography, and scores on the Clinical Global Impression Parent/Caregiver and Child scales and the Conners' ADHD rating scale.
A second long-term, open-label study assessed 55 participants who completed the first double-blind study and 249 new adolescent participants who had no history of eszopiclone use.
Results from the first study showed no significant differences in reduced latency to persistent sleep between any of the randomized groups. There were also no significant between-group differences in any of the secondary outcomes.
Treatment-related adverse events (AEs) were reported by 61% of the participants who received high-dose eszopiclone, 59.5% of those receiving the low-dose version of the medication, and 46% of those receiving placebo.
The most frequent AEs reported by the participants receiving eszopiclone were headache (13.8% of the high-dose group, 11.7% of the low-dose group, 11.8% of the placebo group), a distorted sense of taste (13.8%, 14.9%, and 1.2%, respectively), and dizziness (8.2%, 3.7%, and 1.9%, respectively). In addition, 5, 4, and 3 patients, respectively, dropped out of the study because of treatment-emergent AEs.
"As with zolpidem, eszopiclone failed to demonstrate efficacy in children and adolescents with ADHD-related insomnia," the investigators write.
They note that the medication was generally well tolerated over the long term.
Results of the second study showed that 70% of the participants experienced at least 1 treatment-related AE. But only 11.2% of the total group discontinued open-label use of eszopiclone because of an AE. Unsettlingly, though, was the finding that 3% of the participants reported hallucinations and that suicidal ideation was noted by 1% to 2%.
Overall, the researchers note that it is unclear whether the reason why these sleep medications are not effective is because of the pediatric population, because the participants had ADHD, or because of something else entirely. "Studies of these agents in children without ADHD and in adults with ADHD may be informative," they write.
They add that the benzodiazepine binding site on the GABA receptor "may be the wrong pharmacologic target for this population."
Dr Sangral noted that insomnia in children with ADHD is not always related to stimulant use. Instead, it could be that insomnia is caused by their hyperactivity or by circadian rhythm changes. "But we just don't know."
Ineffective Medication Class
"I think the most important take-away point for me is that it doesn't seem like this particular class of medication is very effective in this particular patient population," Judith Owens, MD, director of sleep medicine at Children's National Medical Center in Washington, DC, and professor of pediatrics at George Washington School of Medicine and Health Sciences, told Medscape Medical News.
"It doesn't necessarily mean that these drugs don't have some utility in a non-ADHD population. And in fact, that was one of my concerns with the study design: that it was strictly limited to kids with ADHD," she said.
Dr Owens, who was not involved with this research, also noted a concern that more than 50% of the trial participants were taking some type of stimulant medication to treat their ADHD.
"We know that these stimulant medications can affect sleep. So that sort of muddies the water in terms of really having a clean assessment of efficacy and of adverse events."
She added that she understands that the investigators might have worried that taking the children off their daytime ADHD medication during these studies was potentially unethical, especially in the 1-year open-label trial.
"But I think it also raises some issues about the validity of the results," she said.
"Still, I would say that this class of drugs is probably not very effective in the ADHD population, especially as opposed to a number of trials now that have used melatonin and shown that it seems to be quite effective and well tolerated," said Dr Owens.
She added that it was also interesting to see a pharmaceutical company–funded study with negative results published.
"I would applaud the editorial decision of Pediatrics to publish this, and the authors really deserve credit. I just hope that it doesn't discourage further research," she said.
"There are children who need medications for insomnia, although they should always be in combination with behavioral treatment. If these particular drugs don't work, then we need good efficacy and safety data on others."
The study was funded by Sunovian Pharmaceuticals, and two of the study authors are full-time employees there. Dr Sangal and one of the other study authors have disclosed several relevant financial relationships and potential conflicts of interest, which are fully listed in the original article. The other study author and Dr Owens have reported no relevant financial relationships.
Pediatrics. Published online September 29, 2014. Abstract
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Cite this: Second Med Fails to Treat ADHD Kids' Sleep Problems - Medscape - Oct 02, 2014.