Karl Doghramji, MD: A number of pharmacologic agents are available for insomnia. I think the use of these agents is appropriate in older individuals. Generally speaking, they’re appropriate if the treatments of the comorbid condition have really not been successful in eliminating insomnia or if direct treatment of the insomnia with cognitive behavioral techniques has not been affected. The agents that are used fall into 2 general classes. No. 1, those who are indicated specifically for insomnia. And No. 2, those that are not indicated for insomnia but used for insomnia off-label.
In the second category we have many agents such as antipsychotic agents, antidepressants, at low doses. Even antiepileptic agents that have sedating qualities that are used for the treatment of insomnia. The reason they’re used that way is that many of these are cheap and readily available, and there’s a perception that their adverse-effect profile is more desirable. What we do find, though, unfortunately, is that in many of these agents—for example, trazodone, regular-dose doxepin, mirtazapine, and so on—although they do have a sedating quality, the effects hence seem to be inconsistent for insomnia. And because of the long-acting effects, long half-lives, they may have negative effects on daytime cognitive and other measures producing daytime sleepiness, possible impairment in memory, judgment, and even confusion and delirium.
The American Geriatric Society has recommended that these antidepressants not be utilized for the treatment of insomnia. It has also recommended that any psychotics not be utilized for the treatment of insomnia in this fashion, because of the problems I just talked about as well as the metabolic burden associated with some of these. For example, agents like quetiapine.
Now let’s go on to the prescribed agents, or rather the agents indicated for insomnia that are prescribed. They fall into a few categories. No. 1, there are those who are GABA receptor agonists, and No. 3, there are those that are agonists, or antagonists, at other neurotransmitter systems. So to backtrack for a second, the process of sleep and wakefulness is controlled by 2 general systems. No. 1, the GABAergic system, which is the system which promotes sleep. And No. 2, the ascending reticular-activating system, which is the system that controls arousal and wakefulness. And that is innervated by histamine, dopamine, norepinephrine, epinephrine, and acetylcholine.
There’s another neurotransmitter and the wakefulness system that’s called the orexin system. It’s also called the hypocretin system, and that system is an interesting one in that it promotes wakefulness to some extent, but it also seems to regulate the transition between sleep and wakefulness, in a very interesting fashion, so that it regulates sleep to make sure that people who are asleep stay asleep, and it regulates wakefulness to make sure that people who are awake stay awake. When that system is disrupted there is a syndrome called narcolepsy, which is characterized by too much sleep during the day and not enough sleep at night. So disruptive sleep at night.
To summarize there are 2 large systems controlling why we sleep and how we sleep: the sleep-promoting system, which is GABAergic, and the arousing system, which comprises a number of neurotransmitters, and these 2 systems are in balance with each other. The sleeping pills that are available act on 1 of these systems. So the benzodiazepines act at the GABAergic system. They’re the GABA receptor agonists essentially. By promoting the activity of GABA, they promote sleep. And they work very well. A number of studies have shown that they’re effective for the treatment of insomnia.
The issues that exist with these agents are 2-fold. No. 1, some of them have long half-lives and produce daytime sedation. The older benzodiazepines—for example, quazepam, flurazepam, and so on, temazepam—these are longer or intermediate acting agents, which can produce daytime sedation, especially in older individuals who metabolize these drugs more slowly and have a greater degree of end-organ sensitivity to the effect of these agents. It’s for this reason that the American Geriatric Society has recommended that these long-acting and intermediate, even short-acting, benzodiazepines not be utilized for the treatment of insomnia in older individuals because of their recognition that they seem to have a greater array of systemic side effects.
The other set of benzodiazepine receptor agonists are the so-called selective benzodiazepine receptor agonists. And those are the so-called Z drugs: zaleplon, zolpidem, and zopiclone. Zolpidem is also available in extended-release version. And these agents may be a bit more desirable than the older benzodiazepines in that they produce fewer adverse effects possibly. But they also are shorter-acting and, in general, are limited in their effect to the nighttime for the most part. They either promote the entry into sleep by helping sleep-latency problems, or they help people sleep for the entire night, or both. The way we select them is based on whether the patient has a problem with falling asleep or staying asleep, depending on the medication’s profile.
Fortunately, the American Geriatric Society has recommended they also not be used for older individuals because of, again, the recognition that they may also be responsible for daytime sleepiness problems, falls possibly, motor impairment, falling asleep while driving, and so on and so forth.
Interestingly, these drugs have also been associated with something we describe as amnestic behavior, in which individuals can get up out of bed and enact, or rather engage in, activity—sleepwalking for example, even sleep driving—and hurt themselves. Those types of behaviors have been rare over the past 20 years or so. But because they can cause catastrophic consequences with these drugs, it seems there’s a degree of caution there, and the FDA now has recommended that these drugs not be used in individuals who have parasomnias of this nature. I think it’s important to educate patients on the use of the benzos [benzodiazepines]. One of the most important points is that they should take them right at bedtime and go to sleep, as opposed to taking them a little before bedtime and be walking around.
Many older patients begin to have motor imbalance without being aware of the cognitive effects that the drug may be having on them and the motor effects. Take the drug at bedtime, go right to bed, and don’t mix with alcohol, which seems to reinforce amnestic behavior, and the respiratory compromise. And do not mix with other sedating compounds as well as much as possible. Third, warn older individuals, and anybody who takes these medications, that if they do develop parasomnia behavior—getting out of bed, walking out of bed—to discontinue the drug right away and call the physician. Fourth, they should tell the physician at all times if they develop new medical conditions that may impact the patient negatively if mixed with the drug. And of course, they should tell the doctor anytime they have a new prescription for another medication.