SAN DIEGO— Until recently, two main groups of prescription hypnotics used for the treatment of insomnia—benzodiazepines and the newer agents that act at benzodiazepine receptors but have a nonbenzodiazepine structure—were indicated for short-term therapy only (generally seven to 10 days). Evidence from randomized clinical trial data supporting long-term use was scant. Now, the results of three studies conducted or funded by the pharmaceutical industry suggest that three new agents may be safe and effective for durations of treatment ranging from five weeks to six months.

In a five-week, randomized, double-blind study of 269 adults with chronic insomnia (based on DSM-IV-TR criteria), approximately two thirds of patients receiving 8 mg of ramelteon nightly experienced at least a 50% reduction in latency to persistent sleep. By contrast, less than 50% of patients receiving placebo reached the same threshold for this measure, a difference that met statistical significance throughout the study. Ramelteon is a novel melatonin (MT) receptor agonist that acts on the MT1/MT2 receptors. The agent was recently approved by the FDA for short-term treatment of insomnia.

Eszopiclone, a nonbenzodiazepine insomnia drug approved by the FDA, has demonstrated effectiveness over a six-month period of insomnia treatment in both a double-blind comparison with placebo and an open-label extension. However, neither study was designed to systematically examine rebound insomnia or discontinuation effects. In a new study involving more than 800 patients, adults with DSM-IV primary insomnia sleeping less than 6.5 hours and/or who experienced sleep latency greater than 30 minutes per night received 3 mg of eszopiclone or placebo nightly for six months, followed by a two-week placebo run-out. Investigators found that compared to placebo, eszopiclone significantly improved sleep latency, wake time after sleep onset, total sleep time, and sleep quality—results that were consistent with previous six-month data.

A third study evaluated the long-term efficacy of indiplon, a novel g-aminobutyric acid (GABAA) receptor potentiator for which FDA approval is pending. Investigators studied its effect in two different doses versus that of placebo in approximately 700 adult patients who met DSM-IV criteria for chronic primary insomnia of at least three months’ duration and who reported latency to sleep onset of 45 minutes or longer and total sleep time of 6.5 hours or less at least three nights per week. Both doses of indiplon (10 and 20 mg) were found to significantly improve the primary end point of latency to sleep onset, compared to placebo, as well as to result in significant improvements in total sleep time, wake time after sleep onset, sleep quality, Insomnia Severity Index (ISI) measurements, and global improvement at all assessment time points.

The investigators in all three trials reported that the study drug was well tolerated, with the two most common adverse effects overall being headache and somnolence, and they found no evidence of withdrawal or rebound insomnia.

The results, which were similar for the three different compounds, point to an expanded set of treatment options for insomnia. But they also suggest that clinicians will have to bear a greater responsibility for finding the right drug for individual patients, says Sonia Ancoli-Israel, PhD, Professor of Psychiatry at the University of California, San Diego.

"All these drugs work," she said at the 58th Annual Meeting of the American Academy of Neurology, where the results of the three trials were presented. "They all help people fall asleep faster and/or help them stay asleep longer—so what does that tell us? It tells us that we as health care professionals need to ask our patients what their complaint is and then choose the appropriate agent, because not everyone responds to every drug. It is important to have multiple options about what to prescribe to different patients, as different patients have different problems and different needs."

The first job of the clinician then, in Dr. Ancoli-Israel’s view, is to determine the specific problem patients are experiencing. "Are they having trouble falling asleep?" she asked. "Are they having trouble maintaining sleep? Or are they having trouble with both? How many hours can the patients devote to staying in bed after they take the hypnotic? Because of course, these drugs have different half-lives, and the FDA has required that the amount of time patients need to spend in bed after they take the drug be printed in the label."

A DIFFERENT WAY TO LOOK AT DRUG RESPONSE

Chronic insomnia is highly prevalent in the United States, affecting 10% to 15% of the general population. For some subgroups, such as older adults, incidence rates have been estimated to be as high as 40%, according to Louis Mini, MD, Medical Director, Neuroscience, at Takeda Pharmaceuticals North America, who presented the results of the company’s latest study of ramelteon. Several previous studies have shown that treatment with ramelteon reduces latency to persistent sleep and increases total sleep time as measured by polysomnography.

In addition, there has been no evidence of withdrawal dependence or rebound insomnia across multiple trials, Dr. Mini reported. "There’s [also] been no evidence of abuse potential in clinical trials, which makes this the first prescription insomnia treatment that is not classified as a controlled substance," he said.

The primary objective of this new study was to examine the long-term effectiveness of ramelteon in adults ages 18 to 64 who were experiencing chronic insomnia. The study was actually a post hoc analysis of a larger trial, the results of which were submitted to the FDA for registration of ramelteon, Dr. Mini explained.

"What we decided to do in this post hoc analysis was to try to give clinicians a different understanding and perhaps a more useful way to look at drug effect in this trial," he said. "As you’ve probably seen in the insomnia trials with various standards, the data are almost always reported in terms of absolute minutes from baseline versus placebo. That was done in the initial reporting of the ramelteon data at the American Psychiatric Association meeting last year. What we wanted to do was look at these data in a different, perhaps more clinically relevant, context.

"What we hear a lot from practicing physicians is, ‘OK, so the compound helps people fall asleep 15, 18, 20 minutes faster than placebo, but what does that mean to us?’ So we looked at another measure using the same data, and the measure we looked at is a 50% improvement. What percentage of the patients had their latency persistence cut in half or better versus placebo?"

For this post hoc analysis, Dr. Mini and his colleagues considered only the 8-mg dose, because that is the recommended dose in the drug’s labeling information. They did not look at the 16-mg dose that was used in the original trial.

The researchers found that a significantly greater percentage of patients receiving ramelteon had at least a 50% reduction in latency to persistent sleep compared to those receiving placebo, and this difference held from week 1 through week 5. Adverse events occurred at a low frequency: Headache, somnolence, and fatigue were the only side effects to occur in at least 5% of the patients.

Dr. Mini emphasized the absence of rebound insomnia or withdrawal. "Similar measures were used in this study that are used in all insomnia trials, and there was no difference [in withdrawal]," he concluded. "There was no evidence of clinically meaningful next-day residual effects in this post hoc analysis."

REPLICABLE SYMPTOMS

The study of eszopiclone demonstrated that nightly use of the drug resulted in consistent and sustained improvements across all sleep and daytime parameters measured. In presenting the results of the Sepracor-funded study, James K. Walsh, PhD, Executive Director and Senior Scientist, the Sleep Medicine and Research Center at St. Luke’s Hospital in St. Louis, emphasized that this was the second six-month trial of eszopiclone and that the results were virtually identical.

"We were able to replicate not only our nighttime symptoms but our daytime symptoms as well," he said. "The result of the ISI was more likely to improve on eszopiclone than with placebo. We got 50% of the eszopiclone group into the no-clinically-significant-insomnia group at the end of six months. The full radius of daytime function and fatigue improved with eszopiclone more than if they were on placebo."

In the trial of indiplon, which was funded by Neurocrine Biosciences, Inc, and Pfizer Inc, investigators found the mean latency-to-sleep-onset time at month 1 to be 34.0 minutes for the 10-mg group, 33.0 minutes for the 20-mg group, and 48.7 minutes for the placebo group. Efficacy was sustained through month 3 and represented a roughly 50% reduction in latency-to-sleep-onset compared to baseline, observed Robert Farber, PhD, of Neurocrine.

"The improvement in these symptoms was associated with an improvement not only in the sleep quality of these patients but also in the investigator ratings of improvement in insomnia severity," he said, concluding his presentation of the results. "Indiplon was well tolerated in this study, particularly at the 10-mg dose, and there were no withdrawal symptoms observed as measured by the BWSQ [Benzodiazepine Withdrawal Symptom Questionnaire]."

INDIVIDUAL INSOMNIA

In summarizing the prescription hypnotics currently on the market, Dr. Ancoli-Israel observed that all of the drugs help initiate sleep, while only some of them help maintain sleep or can be used when there is a limited opportunity for the individual to sleep. Most of them have been shown to require anywhere from four to eight hours in bed following administration.

"We need to use the combination of all these pieces of information when we decide which hypnotic is the right hypnotic for any given patient," she emphasized. "And I think it’s wonderful that we have so many different options now to treat the millions and millions of patients who do have insomnia."

—Fred Balzac

Suggested Reading
Ancoli-Israel S, Ayalon L. Diagnosis and treatment of sleep disorders in older adults. Am J Geriatr Psychiatry. 2006;14:95-103.

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