Patients and their doctors face a confusing array of prescription hypnotic drugs, with complex choices about which to select. An important limitation of our study of CPSII data is that it did not determine which of the hypnotic drugs have the most risk. Possibly some of these drugs (perhaps the barbiturates) produce the main mortality risk, and the other compounds might possibly be safer. Diazepam seems to be safe in terms of mortality--and different from at least some of the other drugs which are used as sleeping pills. Clearly, the public needs to know if the particular sleeping pills they are given are safe, but this will not be known until new long-term studies are done.

Since the 1979 Institute of Medicine report , most experts have agreed that the risks of barbiturates are greater than that of benzodiazepines and the effectiveness less, if anything.  Tolerance (loss of effectiveness) is particularly prompt and well-documented with barbiturates, and the risk of physical addiction is familiar to the physicians who used these drugs. Barbiturates suppress rapid eye movement sleep, producing a rebound increase after withdrawal, which may cause nightmares to the patient withdrawing from barbiturates. Another problem is that barbiturates induce special liver enzymes which may severely alter the metabolism of other drugs, producing unpredictable drug interactions. Considering all these aspects, most experts would never choose a barbiturate for a sleeping pill. Drugs such as pentobarbital (Nembutal), secobarbital (Seconal), amobarbital (Amytal), and phenobarbital are considered obsolete as sleeping pills.

Tolerance (loss of effectiveness) is particularly prompt and well-documented with barbiturates, and the risk of physical addiction is familiar to the physicians who used these drugs. Barbiturates suppress rapid eye movement sleep, producing a rebound increase after withdrawal, which may cause nightmares to the patient withdrawing from barbiturates. Another problem is that barbiturates induce special liver enzymes which may severely alter the metabolism of other drugs, producing unpredictable drug interactions. Considering all these aspects, most experts would never choose a barbiturate for a sleeping pill. Drugs such as pentobarbital (Nembutal), secobarbital (Seconal), amobarbital (Amytal), and phenobarbital are considered obsolete as sleeping pills.

The benzodiazepine drugs which came into use in the 1960's and 1970's were regarded as a marked improvement. Also, they are at least as effective as other hypnotics. Their tendency to produce tolerance, addiction, and withdrawal syndromes is usually not severe, and they suppress REM sleep only a little. Benzodiazepines are responsible for few metabolic drug interactions in the liver. There are situations today when a benzodiazepine may be the best available choice.

 

SUMMARY OF SLEEPING PILLS

DRUG	Brand Name	My Usual Preference	Possible Indications	I NEVER Recommend
zolpidem	Ambien	under 4 weeks (if at all)
ramelteon	Rozerem		maybe for trouble falling asleep
eszopiclone	Lunesta			Never
zaleplon	Sonata			Never
diazepam	Valium		under 4 weeks
flurazepam	Dalmane		under 4 weeks
quazepam	Doral		under 4 weeks
estazolam	ProSom		under 4 weeks
temazepam	Restoril		under 4 weeks
pentobarbital	Nembutal			Never
secobarbital	Seconal			Never
amobarbital	Amytal			Never
methyprylon	Noludar			Never
methaqualone	Qualude			Never
chloral hydrate	Noctec			Never
glutethimide	Doriden			Never
ethchlorvynol	Placidyl			Never
triazolam	Halcion			Never
melatonin			maybe for delayed sleep phase syndrome

 

Two benzodiazepines, flurazepam (Dalmane) and quazepam (Doral) are rapidly metabolized by the body to desmethylflurazepam, which is an active sleep-inducing compound. The half-life (time to be half-eliminated) for desmethylflurazepam in young adults is 3-4 days. In aging people, the half-life of desmethylflurazepam may be even a week or longer. Therefore, with dosage night after night, the blood concentrations of desmethylflurazepam increase day by day to concentrations as much as 5 times or more the concentration on the initial night of use. As a result, people who take flurazepam or quazepam sleep somewhat better on the first night, but they may actually have somewhat more hypnotic effect on the second night, as the metabolite accumulates. Likewise, they are measurably sedated during the first day, and the daytime sedation may increase with nightly use. Fortunately, there seems to be tolerance to the daytime effects, so that as desmethylflurazepam concentrations increase, the daytime sedation may not be severe. However, repeated use of flurazepam and quazepam may produce insidious personality changes with nightly use, especially in elderly patients. In aging patients, the drug may accumulate for several weeks, sometimes leading to confusion or loss of memory, and it may be several weeks after the drug is withdrawn that the personality recovers. These long-acting drugs may also cause the worst problems with daytime weakness, falls, and automobile accidents. On the other hand, because they are self-tapering, these drugs have minimal withdrawal symptoms.

 

Among aging people, sleeping pills such as flurazepam and quazepam can produce gradually-developing weakness, confusion, and memory loss. Diazepam also has this danger.

 

Diazepam (Valium) is marketed as a tranquilizer and anticonvulsant, but many physicians prescribe diazepam as a sleeping pill. Diazepam is a relatively short-acting drug on the first night, because its metabolite desmethyldiazepam rapidly enters fat stores. After several days of usage, however, the concentrations of desmethyldiazepam may accumulate, producing accumulating daytime sedation and hangover. Thus, diazepam functions as a moderately-long-acting hypnotic with repeated use. When taken by elderly people, diazepam may accumulate for weeks and produce progressive confusion, memory loss, and weakness. Diazepam is one of the few benzodiazepines where controlled studies have demonstrated long-term effectiveness, albeit as an anti-anxiety agent and not as a hypnotic. In our CPSII analysis, people who said they took "Valium" 30 times or more per month had no increase in mortality risk, unlike those reporting regular "sleeping pill" use. This would be one argument for choosing diazepam.

Temazepam and estazolam have intermediate half-lives, which result in continuing effectiveness throughout the night and diminishing sedation during the day. They do not accumulate significantly with nightly use, at least, until aging increases the half-life. A problem with temazepam in formulations which have been sold in the U.S. is rather slow absorption, so that it is ineffective for decreasing time-to-fall-asleep unless it is taken 30-45 minutes before bedtime. Lorazepam (Ativan) and oxazepam (Serax) have many of the same disadvantages and advantages of temazepam, although they are not marketed specifically as sleeping pills.

Triazolam (Halcion), as mentioned, has a particularly short half-life, so it causes relatively little daytime hang-over. Triazolam is quite effective for helping people fall asleep, but as mentioned, for some patients it produces early awakening. Triazolam may also increase daytime anxiety, tension, and panic. Triazolam produces particularly brisk withdrawal symptoms. Triazolam might be particularly prone to produce behavioral and memory abnormalities. Because of these side effects, many physicians have largely abandoned triazolam. I cannot imagine a patient for whom I would recommend triazolam.

I would never recommend zaleplon (Sonata), since it does not significantly increase sleep.

Incidentally, most experts would not recommend over-the-counter sleeping pills, although less is known about their effects. The suspicion is that the over-the-counter pills might be safer (at least in terms of addiction) but also even less effective. Most of the comments in this booklet refer to the prescription sleeping pills.

6.A.  Zolpidem.  The most popular option in the U.S. in 2000 - 2005 has been zolpidem (Ambien), which rapidly captured the majority of the U.S. market. Although zolpidem is not a benzodiazepine, it binds with benzodiazepine receptors and apparently acts like a benzodiazepine. However, zolpidem binds more specifically to some of the several kinds of benzodiazepine receptors, and for this reason, it possibly causes less anti-anxiety effect, less muscle weakness and less anti-epileptic effect than most benzodiazepines. It has been claimed that zolpidem distorts EEG sleep patterns less than other hypnotics and that it produces less withdrawal symptomatology. Because of its short half-life, zolpidem produces relatively little hangover but lacks effectiveness for treating early awakening. Zolpidem might increase daytime anxiety in some patients. It appears that zolpidem has little tendency to produce addiction, but addiction with zolpidem does occasionally occur. Ambien brand is extremely expensive compared to most hypnotics, and it is not recommended for long-term use, but inexpensive generic zolpidem may be available soon. Ambien CR is approved for long-term use. There is little evidence available as I write in May, 2006, but I believe Ambien CR (zolpidem tartrate extended release) will have more side effects than Ambien, though it will cause less early awakening. Weighing all factors, many physicians have concluded that zolpidem is the best available choice as a hypnotic for short-term use when early awakening and cost are not problems. I am inclined to agree.

6.B.  A word about melatonin.  Melatonin was first discovered because it blanches the skin of frogs.  .  Next it was learned that in small animals, melatonin can make the gonads atrophy .  Indeed, there is evidence that melatonin interferes with gonadal functions in humans, so it is probably risky for sex and fertility.  In some mammals, melatonin whitens the fur or promotes obesity .  Considerable evidence indicates that melatonin might cause depression.  Melatonin causes headache and nightmares.  In animals, melatonin constricts brain blood vessels and affects the arteries of the heart.  In humans, melatonin affects blood pressure.  Melatonin is a hormone of darkness.  I sometimes imagine that melatonin is recommended by the same sorcerers of darkness who mix owl eyes, newt ears, and wormwood to make magical concoctions.  You might wonder why people think melatonin is such a great idea.  So do I.

It has been claimed that melatonin is low among people with insomnia.  Don’t believe it.  In our studies, there appears to be little or no relationship.

It has been claimed that melatonin is useful for treatment of insomnia. In most studies, the sleep benefit is very weak or completely absent. Some meta-analyses have concluded that melatonin is ineffective as a sleeping pill. Melatonin is not primarily a sedative drug. For example, in rats, melatonin is highest when the animals are most alert. For the person whose sleep problem is awakening during the night or awakening too early in the morning, there is evidence that melatonin would do more harm than good. For common insomnia, I do not recommend melatonin.

Melatonin does have some effects on the body clock. There are some studies which suggest that melatonin helps with jet lag or night shift problems, and other studies which show no value in these situations. There has been insufficient testing. The only application where benefits of melatonin seem quite likely to outweigh risks is for the completely blind person who may have lost his or her eyeballs.

There is evidence that melatonin may be of some help for people with delayed sleep phase syndrome. I am not sure if it is of substantial use in the long run. When being used to make the body clock earlier (helping people fall asleep earlier and awaken earlier), melatonin should be taken about 6 hours before bedtime and in a very low dose, perhaps 0.1 to 0.5 mg only.

6.C.  Ramelteon.  Ramelteon (Rozerem) is a drug which is thought to work much like melatonin. It is not a benzodiazepine agonist. It stays in the blood much longer than melatonin and has some metabolites about which not much is known. As mentioned, by EEG, ramelteon helps insomniacs fall asleep only 7-16 minutes faster, and is virtually useless the rest of the night. Many patients experience no subjective benefit with ramelteon.

Although ramelteon has less risk of hangover and addiction than other sleeping pills, it is not without reported side effects. In part I.B., I have explained that ramelteon is one of the new hypnotics which (as a group) appear to cause cancer. All in all, I am skeptical that it is worth the risk, but ramelteon is so new that we need to learn more about it.

6.D.  Eszopiclone.  Eszopiclone (Lunesta) is the S-isomer of zopiclone. That is, zopiclone contains both eszopiclone and its mirror image. I don't know of any evidence that eszopiclone is more effective than zolpidem, certainly not as compared to Ambien CR, the extended release form of zolpidem. On the other hand, there is European evidence that zopiclone may cause more automobile accidents than zolpidem. There seems to be more evidence of cancer risk for zopiclone and eszopiclone than for zolpidem. Zopiclone and eszopiclone cause more hangover (daytime impairment) than zolpidem, though the comparison with the extended release form of zolpidem (Ambien CR) is unknown to me. Eszopiclone seems to cause viral infections and bitter taste in the mouth, side effects which do not seem common with zolpidem. All in all, I do not see any situation in which the benefits/risks ratio of eszopiclone would be as good as that of zolpidem. Therefore, eszopiclone is not a drug which I choose.

6.E.  Quetiapine (Seroquel).  Quetiapine is a powerful atypical antipsychotic drug which is indicated for treatment of schizophrenia and bipolar mania. It is not indicated for treatment of insomnia, though some physicians have been prescribing it as a sleeping pill. Quetiapine is a dangerous drug which frequently kills people when given to elderly patients with dementia. It has other serious side effects such as neuroleptic malignant syndrome, tardive dyskinesia (permanent problems with movement), and diabetes. I would not ever advise quetiapine use simply as a sleeping pill.

 

Continued in Chapter 7