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Many insomnia drugs in therapeutic pipeline.

DENVER -- The pharmaceutical industry envisions the insomnia market as a field of dreams, judging by the sizable array of agents moving through the developmental pipeline.

And these aren't "me-too" drugs, either. They involve a wealth of new therapeutic targets and novel mechanisms of action.

"I think we're really going to have some better options for our patients in the near future," Daniel Jr Buysse, M.D., said at a satellite symposium held with the annual meeting of the Associated Professional Sleep Societies.

Many drugs are commonly used off-label for insomnia, but the benzodiazepine receptor agonists and the newly approved melatonin receptor agonist ramelteon (Rozerem) are the only medications with Food and Drug Administration approval for this indication. Of the FDA-approved drugs, only two--the benzodiazepine receptor agonist eszopiclone (Lunesta) and ramelteon--were approved based on studies that lasted more than 30 days.

Little evidence of efficacy exists for off label use of agents for insomnia. Many patients with chronic insomnia self-medicate with alcohol, which is obviously problematic, and with diphenhydramine, which causes cognitive and anticholinergic adverse effects, particularly in the elderly, added Dr. Buysse, professor of psychiatry at the University of Pittsburgh.

Here are highlights of emerging pharmacologic developments:

* GABA receptor agents. Gaboxadol is a nonselective [gamma]-aminobutyric acid-A agonist. (See story on p. 35.) Unlike all of the other [gamma]-aminobutyric acid (GABA) receptor agents, which are directed at synaptic receptors, gaboxadol interacts primarily with extrasynaptic GABA receptors. It appears to have an additive rather than synergistic effect with benzodiazepine receptor agonists. No cross-tolerance has been observed. Tiagabine (Gabitril), a selective GABA reuptake inhibitor already on the market for the treatment of partial seizures, is under evaluation for insomnia.

* New benzodiazepine receptor agonists. Indiplon is well along in clinical trials. It is a nonbenzodiazepine benzodiazepine receptor agonist selective for receptors having the alpha-1 subunit. Both immediate-release and modified-release formulations are being developed. Also under investigation is a new formulation of zolpidem (Ambien). It consists of 5 mg of immediate-release drug and 7.5 mg of prolonged-release drug, for a total of 12.5 mg of zolpidem.

* Alpha-2 delta ligands. Gabapentin (Neurontin) and pregabalin inhibit release of excitatory neurotransmitters such as substance P and glutamate. Although gabapentin is marketed for postherpetic neuralgia and epilepsy, these drugs are under study for insomnia, anxiety, chronic pain, and neuropathic pain.

* Melatonin receptor agents. The recently approved ramelteon is a highly selective agonist for the melatonin ML-1 receptor, which is thought to play a more important role in sleep than the ML-2 receptor. It is approved at the dose of 8 mg for long-term use in adults. It is the only approved insomnia drug without a schedule IV classification.

* Serotonin 5HT2 antagonists. Serotonin antagonists seem to increase slow-wave sleep and enhance sleep continuity while having little impact on sleep latency. Drugs with a strong 5HT2 antagonist effect include trazodone (Desyrel), doxepin, mirtazapine, and amitriptyline. Dr. Buysse said he doesn't prescribe mirtazapine often because weight gain is a prominent side effect. But he does use trazodone and doxepin.

Dr. Buysse's first-line pharmacotherapy, used in combination with behavioral measures, is a short-acting benzodiazepine receptor agonist. If the patient still wakes up too early, he'll switch to one with a longer half-life. His second-line therapy is low-dose trazodone, doxepin, or amitriptyline. Third-line therapy, reserved for desperate cases, is gabapentin or tiagabine.

One of the few situations where he doesn't use a benzodiazepine receptor agonist as first-line therapy is in patients with a history of substance abuse. "If I know that a person has a history of, say, alcohol abuse, I'll start with something else," said Dr. Buysse, a consultant to Sepracor Inc., sponsor of the satellite session, as well as to many other pharmaceutical firms.

BY BRUCE JANCIN

Denver Bureau
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Title Annotation:Psychiatry
Author:Jancin, Bruce
Publication:Internal Medicine News
Geographic Code:1USA
Date:Nov 1, 2005
Words:621
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