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New directions for pharmacologic treatment of insomnia

Monday, June 16 2008 | Comments
Evidence Grade 0 What's This?
By David N. Neubauer, M.D.
Associate Director, Johns Hopkins Sleep Disorders Center

The abstracts, oral presentations, and symposia presented at the APSS 2008 meeting in Baltimore provided evidence of the wide diversity of compounds currently being investigated as possible insomnia treatment medications. In addition to new research regarding therapeutic applications of currently available medications, such as eszopiclone, ramelteon, and zolpidem extended-release, safety and efficacy data were presented for substances with entirely new mechanisms of action; among these were APD125, EVT 201, Neu-P11, adipiplon, almorexant, and eplivanserin. Further, there were reports on new formulations of currently available compounds.

All of the current insomnia medications are available only in standard pill formulations, so the onset of action is affected by the time required for stomach absorption. However, studies have been reported with the use hypnotics employing alternate delivery approaches, such as oral and nasal sprays, sublingual tablets, and a pulmonary inhaled formulation. The APSS presentations included studies on Intermezzo, a sublingual zolpidem formulation, with data suggesting that rapid-onset approaches with relatively short half-life hypnotics may be ideal for middle-of-the-night dosing.

The insomnia treatment pipeline also includes variations on the benzodiazepine receptor agonist (BZRA) mechanism of action. The BZRA hypnotics all are positive allosteric modulators of benzodiazepine responses at the GABAA receptor complex, which is made up of 5 transmembrane subunits. The hypnotics with a benzodiazepine structure have limited selectivity among the subunit subtypes, while the nonbenzodiazepine hypnotics (eszopiclone, zaleplon, and both zolpidem formulations) have somewhat greater affinity for GABAA complexes containing alpha-1 subunits. Some investigational drugs are more selective for alpha-3 subunits. One pipeline BZRA-related insomnia medication presented at the APSS meeting was EVT 201, which is described as a GABAA partial agonist.

Ramelteon remains the only available melatonin receptor agonist. However, other related compounds--such as the melatonin receptor agonist Neu-P11--also are being investigated. Some melatonin receptor agonist compounds interact with other receptors, possibly promoting additional therapeutic effects.

Another older, approved medication being investigated at new doses for a new indication is the antidepressant doxepin. Research has focused on the safety and efficacy of ultra-low doses--1 mg, 3 mg, and 6 mg--as a treatment for insomnia. Studies have been especially positive for sleep maintenance and early morning awakening symptoms. It appears that highly selective antihistamine activity provides the sleep-enhancing effects and protects against other undesired receptor effects at these low doses.

Many compounds with 5-HT2A receptor antagonist activity are also being investigated as insomnia treatments. There is special interest in these agents due to their ability to enhance slow wave sleep. Data on eplivanserin and APD125 (described as a 5-HT2A inverse agonist) were presented. Some of these new insomnia treatments may challenge the assumptions associated with sleep-promoting medicines in that they may have recommendations for morning dosing and delays in therapeutic effects, as seen with antidepressants.

Another entirely new approach in the treatment of insomnia is the use of an antagonist of the excitatory hypothalamic peptide orexin. The activity of orexin is deficient in people with narcolepsy, so it has been hypothesized that people with insomnia might sleep better with reduced orexin activity. The APSS meeting included updates on the orexin antagonist almorexant.

Many of the new directions being explored for the treatment of insomnia are focused on pharmacologic targets identified by new discoveries about the regulation of the sleep-wake cycle. All of the currently available insomnia medications are beneficial for a broad spectrum of patients with insomnia; however, in the future, it may be possible to identify patients with certain abnormalities or deficiencies that would suggest the use of a very specific insomnia medication. While many of our current insomnia treatments may remain helpful for patients, it is likely that the diversity of medications available for the treatment of sleep disturbances will expand significantly.

This information concerns uses that have not been approved by the Food and Drug Administration.

Disclosure Statement: Dr. Neubauer reports having served as a consultant and/or as a member of a speakers' bureau for Sanofi-Aventis Group, Takeda Pharmaceuticals North America, Inc., and VerusMed.

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