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Two common treatments for insomnia flopped for patients undergoing hemodialysis, according to the trial.

After 6 weeks of treatment, people who underwent cognitive behavioral therapy for insomnia (CBT-I) or took trazodone had no difference in (ISI; 0=none and 4=very severe) score compared with placebo at week 7, stated Rajnish Mehrotra, MD, MS, of the University of Washington School of Medicine in Seattle, and colleagues. Specifically, they reported:

• CBT-I: -3.7 ISI score change (95% CI -5.5 to -1.9)
• Trazodone: -4.2 (95% CI -5.9 to -2.4)
• Placebo: -3.1 (95% CI -4.9 to -1.3)

The pattern was consistent when measuring differences in ISI from baseline out to 25 weeks: -4.8 for CBT-I, -4.0 for trazodone, and -4.3 for placebo, they wrote in .

"The lack of efficacy of CBT-I and of trazodone [in the trial] was surprising," Mehrotra told MedPage Today. "CBT-I has been tested widely in many populations for treating insomnia, and so we expected to confirm its efficacy in patients undergoing hemodialysis. Trazodone is one of the most widely used drugs to treat insomnia, albeit off-label."

Ronald Postuma, MD, MSc, of McGill University in Quebec, also said the findings were a surprise. In an , he called the lack of CBT-I effectiveness "remarkable," given its strong history of utility in primary insomnia.

"This discrepancy may suggest that the typical psychophysiological drivers of insomnia in the general population are simply less pertinent in hemodialysis patients," Postuma wrote. "In other words, insomnia in hemodialysis is more 'biological,' and so it may be resistant to CBT-I." The take-home message is that not all insomnia is the same, he noted.

The lack of efficacy shown in this study "underscores the importance of testing treatments for common conditions specifically in this population, rather than extrapolating them from experiences in other populations," Mehrotra observed.

That being said, these long-term dialysis patients still need symptom relief -- as nearly 50% of this patient population suffers from insomnia -- and can't wait until new options have been researched, Mehrotra said. "As such, [clinicians] should undertake careful assessment of potential risks and benefits of treatment and engage in shared decision-making with patients to make treatment decisions."

A total of 126 patients undergoing long-term, in-center hemodialysis from 26 dialysis units in Albuquerque, New Mexico, and Seattle, were randomized in the trial. This included 43 assigned to CBT-I, 42 to trazodone, and 41 to placebo. All patients had an ISI score of 10 or greater, with sleep disturbances on 3 or more nights per week for 3 or more months.

During the 1-week run-in period, all patients maintained a daily sleep diary for baseline data. After that, they were randomized to undergo 6 weeks in one of the arms. CBT-I included six 30-minute virtual sessions with therapists. Patients on trazodone started on a 50-mg nightly dose with an option to increase to 100 mg in the second or third week. "The dose achieved by the end of the third week was maintained for the remaining 3 weeks," the authors explained.

All patients in any arm were allowed to use over-the-counter or prescription sleeping aids other than trazodone during the entire study period. After the 6-week treatment phase, any participant could request a trazodone prescription regardless of study assignment.

While effectiveness of the three arms didn't differ, rates of serious adverse events (SAE) did, especially serious cardiovascular events. These were more frequent with trazodone (annualized cardiovascular SAE incidence rate 0.64, 95% CI 0.34-1.1), than with CBT-I (0.05, 95% CI 0-0.29) and placebo (0.21, 95% CI 0.06-0.53). Of the 42 patients on trazodone, eight developed a serious cardiovascular event compared with five of 84 in the other two arms (19% vs 6%).

This could be due to a few reasons, Postuma suggested. First, trazodone can prolong QT interval in a dose-dependent manner. Also, trazodone is partially renally excreted and patients taking over 100 mg daily may have had "higher than anticipated" side effects.

"Our finding of a higher cardiovascular risk with trazodone is relevant not just for patients undergoing long-term hemodialysis but in other populations with multimorbidity and higher cardiovascular risk," said Mehrotra. "As such, clinicians should exercise caution and make a careful assessment of risk-benefit of treatment before prescribing trazodone for insomnia."

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