Video 5 – Insomnia_ Sleeping Pills

We talked in the last edition of behavioral therapy for insomnia. We went over relaxation technique, sleep restriction therapy, cognitive therapy, and cognitive-behavioral therapy. What we’re gonna talk about next is the part that everybody thinks about when we talk about insomnia. That’s sleeping pills, medications. There are four different classes of medications. They are the benzodiazepines, non benzodiazepines sedatives, melatonin agonists, and finally the antidepressants.


Medications, in general, do usually improve daytime function. People have better quality of life. There are a few comorbidities, but you’ve got to consider that in general, especially the benzodiazepines, that there are side effects of addiction with time, long-term use. The longer you use a sleeping, the less likely it is to do the job that you intended it to do in the first place. You have more tolerance to these medications.


What type of patients with these risks goes up? Well, in pregnancy, you have an increased risk of fetal malformations. Also if there’s alcohol consumption going on at the same time, kidney, liver or lung disease certainly. If the patient has sleep apnea, giving them a sleeping pill could make the sleep apnea worse. You really want to be careful in nighttime decision-makers, for example, the people who are on the job, people who are watching alarms, and things of that nature. Finally, the elderly people who are 75 years plus.


So this is a busy slide, but let’s go through this methodically. So we’ve got medications. There are four different classes of medications, and let’s talk about the first two classes: benzodiazepines and nonbenzodiazepines. So these nonbenzodiazepines are very similar to benzodiazepines, but they have a different chemical structure.


The benzodiazepines in general, and we’re talking about like triazolam and some of these drugs like Prosom, Antivan, Restoril, Dalmane,  and Doral. These all bind to the gaba-a receptors, and there are long-acting. They decrease sleep latency, which is the amount of time it takes to fall asleep. So they do their job. But they also increase that second type of sleep (N2), not REM, not stage 3 sleep, but stage 2 sleep. They also increase total sleep time. So that is intuitive.


They decrease REM; that’s a very interesting characteristic because in patients with REM Behavior Sleep Disorder, where REM sleep seems to be the problem, these benzos actually help. Now, these benzos can cause amnesia, so you have to be aware that they do impair memory. They decrease anxiety. They have also been used as anticonvulsants. As you know, Ativan is a great anticonvulsant.


Some of the side effects include daytime sleepiness, motor and cognitive problems with dependence, and complex sleep-related behaviors such as sleep sex, sleep eating, and sleepwalking. There have been many lawsuits associated with people with automatic nocturnal behavior related to benzodiazepines.


When we look over at the cousins of the benzodiazepines, which are the nonbenzodiazepines, and I’ve got some of their structures down here. So this is the benzodiazepine structure generally speaking, and these are a couple of the other ones. This is zolpidem, which is a nonbenzodiazepine. This is zaleplon, and then finally eszopiclone, which is the same as Lunesta.


These three are different in structure to the benzodiazepine. That’s why they’re called the nonbenzodiazepines. But these are probably the ones that you’re familiar with. There are Ambien, Sonata, and Lunesta. So these also target the gaba-A receptors, but they’re born specific; they are cleaner. They do decrease sleep latency. They do increase stage 2 sleep just like their benzodiazepine counterparts; they also increase total sleep time, reduce RAM sleep, and impair memory.


However, they seem to cause less decrease in anxiety, and they’re less of an anticonvulsant because of their specificity in terms of side effects. We see less of the side effects that we do with the regular benzos such as less daytime sleepiness, fewer problems with the motor, fewer problems with cognitive-behavioral problems, less dependence, and less complex sleep-related behaviors.


The other important thing is looking at the half-life, which I have listed here. The half-life is important because if you take long-acting sleep medication, and you wake up eight hours later, you could still have this medication hanging around. So it’s important to know the half-life of these medications.


So Ambient’s got a half-life of two hours, Ambien-CR also two hours. Sonata is pretty short. In fact, it’s the shortest; it’s about one hour. Sonata maybe lasts a little bit longer, and then finally Lunesta is very slow, which is longer-acting and I just think of a slow-moving butterfly if you will. So those are the characteristics of both the benzos and the non-benzos. What I would remember there is that they are both potential causes of dependence, so be aware of that, but the non-benzos are probably cleaner in terms of sleep medication.


Now recently (this came out in 2013 and you should probably know about this,) the FDA, which has approved the use of Ambien, Ambien CR, Edluar and Zolpimist for sleep, but they were looking at new data, and blood levels in some patients may be high enough the morning after, which could impair activities. So again, they’re sensitive to these long-acting drugs that can cause high levels of sleep medication in the patient’s blood when they’re supposed to be getting up. As a result of that, they recommended lowering the dose specifically in elderly patients.

现在最近(这是在2013年问世的,您可能应该知道这一点),FDA已批准使用Ambien,Ambien CR,Edluar和Zolpimist进行睡眠,但他们正在研究新的数据以及某些患者的血液水平患者可能在第二天早晨足够高,这可能会损害活动。同样,他们对这些长效药物很敏感,这些药物在应该起床时会在患者血液中引起大量的睡眠药物。因此,他们建议降低老年患者的剂量。

Specifically, the FDA warns (in January of 2013) that for Zolpidem: recommended the use of a lower dose in women than previously recommended and also considering this in men as well. Of course, the Ambien CR recommendation was a lower dose and the quote was here that patients should not drive five or engage in other activities that require complete mental alertness the day after taking Zolpidem because Zolpidem levels can remain high enough the next day to impair these activities. So if this is something you want to take on a daily basis, if you read their recommendation, you pretty much shouldn’t be driving. So you’ve got to be aware of these FDA warnings.

FDA特别警告(2013年1月),对于唑吡坦:建议女性使用比先前推荐剂量低的剂量,男性也应考虑使用这种剂量。当然,Ambien CR建议的剂量要低一些,在此引用的意思是患者服用Zolpidem后的第二天不应开车五次或进行其他需要完全精神警觉的活动,因为第二天Zolpidem的水平可能会保持足够高的水平,从而损害这些能力。活动。因此,如果您每天都想这样做,并且阅读了他们的建议,则几乎不应该开车。因此,您必须了解这些FDA警告。

Let’s move on to Melatonin agonists. There’s only one in that category and that’s ramelton, Rozerem. And this is a melatonin agonist, and it binds to M receptors tighter than melatonin does, and it is actually pretty short-acting and because melatonin is used in sleep onset. This medication Rozerem is actually good for sleep-onset insomnia, so if the patient has trouble getting to sleep but has no trouble staying asleep, this might be a good medication for them.

让我们继续研究褪黑激素激动剂。该类别中只有一个,那就是拉梅尔顿,罗泽雷姆(Rozerem)。这是一种褪黑激素激动剂,与褪黑激素相比,与M受体的结合更紧密,而且实际上作用很短,因为褪黑激素帮助进入睡眠。 Rozerem的这种药物实际上对入睡困难型失眠有好处,因此,如果患者难以入睡,但在保持睡眠方面没有任何困难,这对他们来说可能是一个很好的药物。

There are fewer side effects than there are with benzos or nonbenzos, and there are no hypnotic problems symptoms the next day. Now, this is the key point. It’s not habit-forming, so it is not a dependent medication. So if you’re concerned about a patient becoming addicted to sleep medication, this might be the medication for them.  It can increase prolactin and decrease testosterone levels; however, the FDA does not at this point see the need to monitor, so this is another medication that may be beneficial.


Again, antidepressants are the last category. We look at things like doxepine, amitriptyline and trazodone, and this is what I would say if you’ve got a patient who’s depressed and they’re also having problems with sleep, fine, go ahead and pick an antidepressant that also treats insomnia, but I wouldn’t go to an antidepressant as a first-line agent if the patient does not have a psychiatric illness.


So Doxepin is FDA approved, but things like amitriptyline and trazodone are probably not the first-line drugs. I would go to unless the patient also was depressed. So if you look at some of these studies here,  “trazodone versus zolpidem,”  there was really no difference. So why don’t we go with the one that’s actually FDA approved for insomnia?


Basically, the sleep societies don’t recommend the use of sedating antidepressants if the patient doesn’t have a psychiatric illness already. So generally speaking, I would stay away from antidepressants unless there’s another reason to choose them.


Some of the things that are commonly used are not recommended in terms of the state of the science conference that was done. Benadryl of this is particularly not good in the elderly as it causes a decrease in alertness, cognitive function and increases dry mouth. Antipsychotics: there have only a few trials looking at this and many side effects. Barbiturates: again few trials many side effects.

根据已完成的科学会议的状态,不建议使用某些常用的东西。 Benadryl在老年人中尤其不好,因为它会导致机敏性,认知功能下降和口干增加。抗精神病药:目前只有很少的试验可以观察到这种现象以及许多副作用。巴比妥类药物:再次很少尝试许多副作用。

Some of the things that are done over the counter like valerian, melatonin and alcohol. We’ve already talked about alcohol. It can actually promote sleep disturbance later in the night because of its short-acting nature. Melatonin is not FDA approved. In fact, it’s not even regulated. It’s a nutritional supplement so it can be used in sleep phase delay syndromes, and usually it’s a lower dose that’s going to help, but again reserve my thinking that the medication probably would work better. Valerian does decrease latency by less than a minute. No regulation once again, so you don’t know how much Valerian you’re actually buying when you think you’re buying Valerian, which is not regulated. So again, the sleep societies do not recommend it.

柜台上做的一些事情,如Valeria,Melatonin和酒精。我们已经谈论过酒精。由于它的短效性质,它实际上可以在晚上晚些时候促进睡眠障碍. Melatonin未经FDA批准, 实际上,它甚至没有受到监管。它是一种营养补品,因此可以用于睡眠阶段延迟综合症,通常使用较低剂量的药物会有所帮助,但再次保留我的想法,认为这种药物可能会更好。Valerian确实减少了不到一分钟的等待时间。再次没有监管,因此,当您认为自己购买的未受监管的Valerian,您不知道实际购买了多少Valerian。同样,睡眠协会不建议这样做。

A couple of issues about side effects for older adults. We talked about increasing sleep quality, increase in total sleep time, and decrease frequent awakening. However, there is about a 2-5x time adverse cognitive or psychomotor event. So we got falls; we got fractures, and that goes up.


Interestingly, a study not too long ago showed that mortality went up. This was an observational study rather than a randomized, placebo-controlled trial, so the evidence is not as strong, but it is very concerning that observational studies connected sedative-hypnotics and all-cause mortality to as high as an odds ratio of 4.5. This still needs prospective study data to look at it to see if there’s actually causation as opposed to just association.


So what do we talked about patients with insomnia? They come into the office. We look for diseases that are easy to rule out. We do hygiene and stimulus therapy and if that still doesn’t work, then we go down the road to behavioral therapy and select medication. Which one do we do first in terms of behavioral therapy and medication? Do we do them at the same time? Do we do one and then the other? What does the data say? Join us for the next lecture where we get into that.



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