The International Classification of Sleep Disorders1 lists more than 88 disorders. These may be either chronic or temporary and can be caused by a variety of environmental, physical, psychiatric, or medical conditions. The treatments for these disorders are almost as numerous. They vary from improved sleep hygiene, positive airway-pressure therapy, and surgical interventions to sleep medications. Sleep medications have been receiving considerably more attention recently, with manufacturers not only increasing marketing efforts, but also devoting considerable resources to research. While many drugs do not reach the market, there are scores of treatments that do, and there will certainly be more to come. By following clinical trials, physicians can get an early understanding of pharmaceuticals in development and can know what types of treatments may soon be available to patients with one or more sleep disorders.
Although there are many medications, in various phases of research, currently being investigated for all types of sleep disorders, insomnia appears to be the focus of a high percentage of sleep-medication research. Recent studies2 have indicated that as many as 20 million people in the United States experience chronic insomnia, and an additional 20 to 30 million people experience intermittent sleep disturbances. Statistics3 also show that the use of off-label medications in the treatment of insomnia increased during the 1990s. A high proportion of individuals with complaints of insomnia respond well to, and sometimes request, a pharmaceutical form of treatment. This, plus the fact that prescription-drug expenditures are the fastest-growing sector of health care spending, provides the pharmaceutical companies with strong incentives to become involved in research and development for new and/or improved medications.4 Wolters Kluwer Health5 estimated the US insomnia-drug market at about $4.6 billion of annual sales for 2006, up from $1.3 billion in 2001. This is a growth rate of 29%.
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The American Academy of Sleep Medicine has recommend that people who experience insomnia see a sleep medicine specialist or primary care physician for proper diagnosis, and to discuss treatment options, before undertaking drug therapy.6 Understanding the neuropathophysiological underpinnings of insomnia better is of critical importance in sleep disorders research and medicine. Gaining such knowledge will help validate, repudiate, or refine current (and often competing) models of etiology and pathophysiology. The ultimate outcome of further research will be to provide insights into the relationship between insomnia and common comorbid conditions, as well as to improve both behavioral and pharmacological treatment strategies.7 Attempts to improve treatment strategies can be best understood by examining developmental drugs based on how they work.
Agonists work by activating or enhancing cellular activity once they bond to the receptor. The binding of the agonist creates a chemical series that changes the function of the cellular activity. This change, depending on which cells the agonist binds with, has an impact on sleep by either promoting somnolence or decreasing alertness. Antagonists have the ability to bind to the receptor, but do not initiate a change in cellular function. By binding to the receptor, they can block the binding and action of agonists. Thus, they are commonly referred to as blockers.
Melatonin is a neurotransmitter-like compound produced by the pineal gland. Its role in circadian-rhythm disorders has been established. The sleep-promoting effects of melatonin are due to interactions with the subtypes of human melatonin receptors MT1 and MT2. Decreases in melatonin production are highly correlated with insomnia. Melatonin receptor agonists work on sections in the brain that may be involved in maintaining a normal sleep-wake cycle by bonding to MT1 and MT2, promoting increased sleepiness.
Phase 2 Discovery is researching a melatonin receptor agonist (PD-6735) acquired from Eli Lilly. PD-6735 is in phase-II development and has produced statistically significant improvement in both objective and subjective sleep measures. It is believed to be nonaddictive.8 Vanda Pharmaceuticals’ melatonin agonist, VEC-162, has undergone a clinical trial studying healthy adults in a model of insomnia and moved into phase-III trials to study adult patients with primary insomnia. VEC-162 appears to be safe, with no significant side effects or effects on next-day performance. It is unlikely to be scheduled as a controlled substance by the US Drug Enforcement Administration because it has a mechanism of action similar to that of ramelteon9 (Rozerem™, Takeda). Ramelteon is a melatonin receptor agonist that was approved for insomnia in July 2005 and is now under evaluation for treatment of circadian rhythm disorders.10
Arena’s APD125 for treatment of insomnia recently underwent a phase-II clinical trial. This 5-hydroxytryptamine (serotonin) receptor 2A (5-HT2A) inverse agonist selectively targets the 5-HT2A serotonin receptor, blocking a stimulatory pathway of the central nervous system. Phase-I trials indicated excellent tolerability and significantly improved sleep maintenance without adverse effects on rapid–eye-movement (REM) sleep. A selective 5-HT2A inverse agonist is predicted to lack the ability to produce hangover effects and the potential for abuse.11 Another 5-HT2A antagonist for insomnia is being developed by Sanofi-Aventis. The treatment, volinanserin, is in phase-III research.12 With this drug, there appear to be no detrimental effects on daytime function.
Orexins are neuropeptides produced by a very small number of dedicated neurons located in the hypothalamus. They play an important role in maintaining wakefulness. Actelion’s ACT-078573 is the first oral orexin receptor antagonist that penetrates the blood-brain barrier and is capable of inducing a transient and reversible blockade of two receptors, OX1 and OX2. Actelion is advancing the compound to final development stages with the RESTORA program, which it expected to initiate by the end of 2007. Studies of the drug are not only looking at its sleep-inducing properties, but also trying to demonstrate that antagonizing the orexin receptor could result in different sleep and side-effects profiles than those of current sleep medications affecting the g-aminobutyric acid A (GABAA) receptor. Improvements are being sought in the areas of addictive properties, memory loss, muscle weakness, and impaired next-day cognitive performance. ACT-078573 differs from the GABAA receptor modulator zolpidem in its impact on REM sleep. Zolpidem has been shown to decrease REM sleep, but ACT-078573 administration was associated with an increase in REM sleep in animal models. In future clinical studies of ACT-078573, special protocols are planned to determine the relationship between increased REM sleep and memory.13
GABAA modulators have not been dismissed in the current research. Indiplon, currently being studied by Neurocrine, is a non-narcotic, nonbenzodiazepine agent that acts on a specific site on the GABAA receptor. It has been shown to bind selectively to the specific subtype of GABAA receptor within the brain believed to be responsible for promoting sleep. Clinical trials14 have shown that patients taking indiplon do not exhibit tolerance or loss of efficacy with continuing use. The rapid-onset drug is suggested for sleep initiation, sleep maintenance, middle-of-the-night dosing, and long-term treatment of sleep disorders.
Another treatment, Neurogen’s adipiplon, is currently in phase-IIb studies and has produced sleep induction and sleep maintenance with no next-day residual effects. It differs from other GABA insomnia drugs in that it has a novel selectivity profile. It is a partial GABA agonist preferentially affecting the α3 subtype receptor, which is associated with the reduction of anxiety (as well as hypnotic effects). Adipiplon has been shown to be safe and well tolerated.2
Intermezzo™ (zolpidem tartrate lozenge), also in development, is currently in phase-III clinical trials and being studied for treatment of middle-of-the-night insomnia.15 Transcept is developing Intermezzo as a low-dose, fast-acting prescription sleep aid for insomnia patients who awaken in the middle of the night and have difficulty returning to sleep. Intermezzo employs the company’s proprietary Bimucoral™ technology in a mint-flavored, sublingual lozenge formulated to dissolve under the tongue in approximately 2 minutes.
Other drugs, such as Organon’s ORG 50081 are being developed for multiple indications. ORG 50081 is in phase-III development for two major indications: insomnia and menopausal symptoms (hot flashes). Trials of the drug as a treatment for menopausal symptoms have been completed, and Organon reports that clinical trials to investigate safety and effectiveness for the treatment of insomnia were expected to reach completion in 2007. The serotonin-2 blockade of ORG 50081 acts on the serotonergic and histaminergic systems. It may improve both sleep initiation and sleep maintenance, and it is not likely to cause dependence.16
Continuing research is critically important, whether to investigate new medications prior to marketing or to evaluate a current medication for dosing and side effects. There have been significant advances in pharmaceutical treatments over the past few decades, and the investigations currently under way suggest great promise for the future. People with chronic sleep and wakefulness disorders are at higher risk for a range of health effects, from diabetes to depression to stroke.11 The increasing prevalence of sleep-related complaints with age, coupled with the fact that the Baby Boomers are growing older, suggests that sleep research will continue to be a significant part of pharmaceutical research.
Michael Garrison, RPSGT, is codirector of education for somniSchool, an affiliate of somniTech Inc, Overland Park, Kan.
- American Academy of Sleep Medicine. International Classification of Sleep Disorders. Diagnostic and Coding Manual. 2nd ed. Westchester, Ill: American Academy of Sleep Medicine; 2005
- GABA: Adipiplon (formerly NG2-73). Available at: www.neurogen.com/products/gaba%20ng273index.htm. Accessed December 11, 2007.
- McCall WV. Use of off-label medications in the treatment of chronic insomnia. J Clin Sleep Med. 2005;1(4):e494-e495.
- Balkrishnan R, Joish V, Bhosle M, Rasu R, Nahata M. Prior authorization of newer insomnia medications in managed care: is it cost saving? J Clin Sleep Med. 2007;3;4:393-398
- Piskora B. Sleep drugs rouse big pharma. Available at: www.businessweek.com/investor/content/oct2007/pi2007105_564105.htm?ca. Accessed December 11, 2007.
- AASM statement on use of sleep medications. Available at: www.aasmnet.org/Articles.aspx?id=196. Accessed December 11, 2007.
- Drummond S. Searching for the brain bases of insomnia. J Clin Sleep Med. 2006;2:323-324.
- New pharmaceuticals for brain disorders: product pipeline. Available at: findarticles.com/p/articles/mi_m0EIN/is_2004-May_26/ai_n6044196. Accessed December 11, 2007.
- Development pipeline: VEC-162. Available at: [removed]www.vandapharma.com/development-vec162.html[/removed]. Accessed December 11, 2007.
- Rozerem. Lincolnshire, Ill: Takeda Pharmaceuticals; 2005.
- APD125 for insomnia. Available at: www.arenapharm.com/wt/page/apd125.html. Accessed December 11, 2007.
- Clinical trial: efficiency and safety of volinanserin on sleep maintenance insomnia—polysomnographic study. Available at: trials.counsellingresource.com/clinical-trials/trials/NCT00464243.html. Accessed December 11, 2007.
- Almorexant in clinical development. Available at: www.actelion.com/uninet/www/www_main_p.nsf/Content/Development+Orexin+ Accessed December 11, 2007.
- Insomnia: indiplon capsules and tablets. Available at: 18.104.22.168/html/clin_insomnia.html. Accessed December 11, 2007.
- Intermezzo. Available at: [removed]www.transcept.com/index.php?option=com_content&task=blogsection&id=10&Itemid=33[/removed]. Accessed December 11, 2007.
- Insomnia compound (Org 50081) shows promise as it moves into Phase III clinical trials. Available at: www.organon.com/media/press_releases/insomnia_compound_shows_promise.as. Accessed December 11, 2007.