The Mystery of Sleep: Why a Good Night's Rest Is Vital to a Better, Healthier Life

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Medications That Treat Sleep Disorders

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THE MYSTERY. Many medications affect sleep. Some have a side effect of insomnia; some help people with insomnia get to sleep. These medications can have unwanted effects.

The Case of the Truck Driver with Insomnia

Doctors always remember the cases that were easily solved simply because they asked the right questions. One such case involved a woman in her mid-thirties who had had severe insomnia for several years before she came to see me. She was concerned because she drove a truck for a living, delivering soft drinks for a major bottling company, and she was having trouble staying alert in the daytime. She told me that it took her several hours to fall asleep and that she frequently woke up at night and had trouble falling asleep again. Though she estimated that she probably slept only two to four hours each night, she did not want to take sleeping pills or any other medications. She was at her wit’s end.

We went through her medical history, but I could not find anything obviously wrong. She neither smoked nor drank alcohol or coffee. She had never had any medical problems and did not use any medications. I was stumped. However, the solution to her problem became clear when I asked her how the sleepiness was affecting her job. She told me that she was very sleepy during the day, but she perked up when she drank the soda she delivered—and she drank about ten quarts a day.

Drugs People Take to Fall Asleep

Many people depend on medications to help them fall asleep. Nothing else has worked for them, and they feel that their lives and health are better when they are on medication than when they are off it. There are hundreds of products being marketed to help people sleep. Several are effective and safe, and medications with few side effects have been introduced.

The products available to help people sleep can be categorized into four types.

Prescription drugs (hypnotics). Hypnotics are drugs that have been scientifically tested and released for use specifically to treat insomnia, and have been approved in the United States by government regulatory agencies.

Prescription medications used off-label. Medications that have been scientifically tested and approved by the Food and Drug Administration for treating a specific disease (not insomnia), but have sleepiness as a side effect, are sometimes prescribed as medication to help people sleep. The most common medications prescribed for this purpose are the antidepressants.

Over-the-counter products. Hundreds of nonprescription sleeping pills are available in retail outlets such as drug stores, and some can be effective in some cases.

“Natural” products. Drug or health food stores sell a variety of herbal and other naturally occurring products that are reputed to promote sleep.

PRESCRIPTION DRUGS (HYPNOTICS)

Most people who try a sleeping pill think that all they have to do is swallow it and like magic it will put them to sleep. If only it were so simple. What actually happens is that first the pill has to dissolve in the intestinal tract, next be absorbed into the body through the bloodstream, then pass through the liver, where it might be broken down, and once more make its way into the bloodstream until it finally reaches the brain, where it attaches to receptors. And throughout this process, the body will try to rid itself of the chemical. Before taking a sleeping pill, people should be aware of the basic principles of how it works.

Different drugs have different onset periods: the length of time it takes for the drug to go from the stomach into the body and finally into the brain varies by the drug and by the individual.

A medication will not put the user to sleep until molecules of the drug have activated a certain number of sleep receptors in the brain.

The drug will continue to keep the user asleep as long as the required number of sleep receptors continue to be activated.

Drugs vary in the way they are broken down by the body and therefore have different durations of effect. Scientists measure how long the effects of a drug last by finding out how long it takes for half of the chemical to disappear from the body (its half-life).

Thus, if a drug has a half-life of two hours, its level in the blood will have dropped to one-half in two hours, to one-fourth in four hours, and to one-eighth in six hours. However, some of the drug can still be attached to receptors in the brain, or the drug might have changed the receptor in such a way that the effect continues long after the drug is gone from the body. Another complication is that when some drugs are broken down, byproducts can be present that have the same effect as the drug.

The types of chemicals used in prescription sleeping pills that affect sleep receptors changed in the 1970s. Older drugs, including medications called barbiturates, were used to affect other receptors in the brain, and sometimes an overdose could cause death. These drugs are rarely used today as sleeping pills, although I occasionally encounter a person who still uses them. Barbiturates were then replaced by benzodiazepines, a large number of which are still on the market (for example, triazolam, flurazepam, and temazepam). These medications attach more specifically to sleep receptors, but they have other effects as well. Lethal overdoses of benzodiazepine medications are rare, but they can occur in combination with other drugs or alcohol. The most recently introduced hypnotics, called nonbenzodiazepines, target more specifically the sleep receptors with little effect on the rest of the brain. Overdoses of these drugs are rarely lethal.

FDA-Approved Medications to Treat Insomnia

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The table above lists the more commonly used and more recently approved medications that act on the sleep receptors. (All prescription medications have two names, a chemical name and a brand name.) The longer the half-life of a medication (the longer the drug takes to be eliminated from the body), the more likely the user is to have residual sleepiness or drowsiness the following morning, which can impair his or her ability to perform certain activities such as driving. (Intermezzo, taken under the tongue, starts working quickly and is effective for middle-of-the-night insomnia as long as it is taken when more than four hours of bedtime remain.) Notice that two of the drugs have a half-life of more than twenty-four hours. After repeated use, such drugs will probably accumulate in the body and cause daytime sleepiness or grogginess. Patients may not even realize that they are impaired if they have been using such medications for long periods of time.

Some of the drugs can cause disturbing, bizarre behaviors during sleep such as sleep eating and sleepwalking; some users have even gone outside or driven a motor vehicle. These occurrences should be reported immediately to the doctor.

Research suggests that among the benzodiazepines, the shorter the half-life, the more likely it is that there will be side effects (such as temporary worsening of insomnia) when the person stops using the medication. Generally, both the benzodiazepines and nonbenzodiazepines are considered fairly safe because they do not depress breathing if taken in the normal doses (those suggested on the label). Patients with a breathing problem or a serious medical problem should make sure the doctor is aware of it before using any sleeping medication.

PRESCRIPTION MEDICATIONS USED OFF-LABEL

Some readers of this book may have noticed that their sleeping medication is not listed in the table. This is because the doctor might have chosen to treat their insomnia with medications that are normally used for other conditions but have sleepiness as a side effect. In the United States, such medications have not been approved as treatments for insomnia by the FDA, and this practice is called off-label prescribing. This practice is perfectly legal, but insurance carriers may not cover these medicines. Some antidepressants, for example, have sleepiness as a side effect and have frequently been used to treat sleep problems in certain patients, especially those who also have symptoms of depression. This dual efficacy may help explain why so many women, who are considered more prone to depression, are on antidepressants for insomnia. The most widely used antidepressants are trazodone (Desyrel) and some of the older medications such as amitriptyline, imipramine, and doxepin. A very low dose of doxepin has been approved as a hypnotic by the FDA under the brand name Silenor.

OVER-THE-COUNTER PRODUCTS

Most of the sleep aids or medications found on drugstore or grocery store shelves to treat insomnia have an antihistamine as their main ingredient. Many of these products were originally introduced to treat allergy problems, and their main side effect was sedation. The newer antihistamines do not have this side effect, so people who buy one of the new antihistamines to help them sleep will be disappointed unless their problem sleeping is that allergies are giving them a stuffy nose and an itchy throat. For these sufferers, getting relief from these symptoms will help them sleep.

The over-the-counter sleep products that contain the older antihistamines have not been extensively or rigorously tested for their effect as sleep aids, but they are probably safe for short-term or occasional use. Their main side effect is also their main effect: sedation. People often feel dopey or groggy the next day. This is because the medication might not have completely cleared from the body, or it might not have given the best type of sleep. Use of these medications for weeks, months, or longer is not advised because they affect the histamine system in the body, which can cause unwanted effects, including restless legs syndrome, nervousness, nausea, and more. People using these drugs should read the fine print on the package. As a general rule, I do not recommend sleep remedies that are manufactured for other therapeutic purposes. My caution is based on the fact that most of these drugs have not been adequately tested for any but their stated purpose.

Some products that promise to help sleep might contain a mixture of compounds including antihistamines, melatonin, and other ingredients. These products have not been proven to be effective.

Some people self-medicate with over-the-counter sleeping pills so they can sleep through their bed partner’s snoring. For better ways to deal with a snoring bed partner, see Chapter 12.

“NATURAL” PRODUCTS

Several products that are sometimes used to treat sleeplessness are available in health food and other retail outlets. These include cannabis, melatonin, kava, and valerian root. Some also swear by chamomile tea. These products were not tested as rigorously as the hypnotic medications that have been approved by government agencies and are prescribed by a doctor. The long-term effect of these products and the ways they interact with other medications are generally not known. People considering these natural products should be aware that much less scientific information is available about these products than about prescription sleep medications. As I noted in Chapter 5, the fact that a product is “natural” does not mean it is safe, nor does it mean that the product is what it is labeled to be. Using DNA testing, a recent study found that products from only two of twelve manufacturers contained the ingredients that were listed on the labels. Products of the other ten companies had ingredient substitutions, contamination with other plants, or fillers that could pose serious health risks. Buyer beware!

Even when we know that the ingredients are pure and as listed, we do not know whether taking such products over extended periods is safe or effective. Many people complain that natural remedies do not work for them, although many others who take these products find them satisfactory. The most important issue I want to emphasize here and throughout this book is that anyone who has a serious problem falling or staying asleep that lasts more than a few weeks needs to see a medical practitioner to make sure that the insomnia is not a symptom of another disorder. Sleeping pills do not cure a single medical condition. People should be very careful about using any medication to treat insomnia, particularly if they find themselves using it every night for more than a few months.

Cannabis. For people in severe pain that is interfering with sleep, cannabis has been reported to reduce pain and improve sleep. In some jurisdictions doctors may prescribe marijuana for medical use. When patients stop using the marijuana, however, it can result in disturbed sleep. In a few U.S. states recreational use has been decriminalized. There is more than one species of marijuana plant (sativa, indica), and different species have different concentrations of ingredients; additionally, plants have been genetically modified to vary the amounts of these chemicals. Users appear to favor some preparations more than others to treat pain or insomnia. In the absence of another reason to prescribe marijuana (pain), I do not recommend its use as a sleep aid.

Melatonin. Melatonin is a hormone produced by the human brain in the pineal gland. It has been called the hormone of darkness because sunlight brings a drop in the level of this hormone. Most people who take melatonin to fall asleep have either insomnia or a problem with their body clock (see Chapter 8), usually as a result of jet lag or crossing time zones. In many countries it is widely available in health food stores, drugstores, and other retail outlets. In some countries a pharmaceutical formulation is available that requires a doctor’s prescription.

Melatonin is one of only two hormones available without a prescription in the United States. (The other is DHEA, a product with male hormone properties that is frequently used by athletes to bulk up their muscles.) Although people argue that melatonin is natural because it is a chemical that the brain naturally produces, the dosage usually taken is many times greater than that produced by even the most high-functioning pineal gland.

Whereas most prescription drugs undergo rigorous testing to make sure they are effective and safe, melatonin has not been studied to find out whether it is safe when used over the long term by the general population. Additionally, no rigorous studies have been performed to determine whether melatonin is effective in the treatment of insomnia or what the optimal dose should be. We do not know what an effective dose would be for most people. Furthermore, people buying it over the counter should be aware that the packaging usually does not list information about side effects—and they might actually feel dopey and tired the day after using it.

Though there have been some studies as to melatonin’s effectiveness in alleviating both jet lag and delayed sleep phase, the studies have not involved a large number of subjects. The fact that it is a natural substance does not mean that it is safe to use. Both insulin and thyroid hormone are natural substances, but they will never be approved in the United States for widespread use without a prescription because we know that taking too much of these hormones can cause severe medical problems. Also, unlike the companies that produce prescription drugs, manufacturers and importers of melatonin are not closely regulated by the FDA to ensure that the manufacturing process is safe and that the ingredients are accurately stated on the label or product insert. Melatonin is not classified as a drug in the United States; it is marketed as a dietary supplement along with vitamins and similar products. Melatonin is available because of a technicality in the U.S. drug laws, and I believe that it needs to undergo the same rigorous study that we would give to any other drug.

Two drugs, ramelteon (Rozerem) and tasimelteon (Hetlioz), that stimulate some of the same receptors as melatonin have been approved by the FDA. These medications are very safe, but they are not as effective as other approved prescription hypnotics. Tasimelteon has been approved in the treatment of people with circadian rhythm problems, in particular people who are blind and as a result cannot synchronize their circadian clock.

Kava and valerian. Two other products available over the counter, especially in health food stores, are derived from the plants kava (a plant that grows in the South Seas) and valerian (a flowering plant).

Few medical studies have been published about the effectiveness of kava for treating insomnia. What is known, however, is that kava can, in rare cases, cause liver failure. This product has been removed from the market in Canada because it was not shown to be effective and could pose a dangerous health risk. In the United States, the FDA has issued an alert warning the public about this serious side effect.

Valerian has been studied a bit more, but again the sampling of people studied using modern methods has in most cases been quite small (fifteen to thirty people), and the results are inconsistent. Some studies showed sleep-promoting benefits, while others showed little or modest improvement. The largest scientific review of all the articles about valerian (and other herbal products) found that the results were inconclusive.

Medicine has learned the hard way that side effects of drugs, even when rare, can be dangerous. These risks should not be ignored or dismissed. How can a conscientious doctor recommend a treatment when a study has examined only a small number of subjects?

Drugs People Use to Stay Awake

Feeling sleepy during the daytime is a common consequence of our lifestyle, the distractions in the world we live in, and a number of sleep disorders. Many sleep-deprived people cannot function without their morning coffee, and at the office, the coffeemaker has become as ubiquitous as the computer. Caffeine and other stimulants increase the function of several organ systems, including the brain and the cardiovascular system. At low doses only one organ—for example, the brain—might be stimulated and cause the user to be more alert. At higher doses several systems might be stimulated, resulting in unwanted side effects.

CAFFEINE

Caffeine is probably the most commonly used stimulant drug in the world. It has been estimated that at least 80 percent of North Americans take some form of caffeine during the course of a day. Caffeine is found in soft drinks, some foods, and of course coffee and tea, as well as some medications. (The website Caffeineinformer.com gives the caffeine content of a number of products.) Many people drink a cup of coffee or tea to become more alert first thing in the morning, and they might have two or three more cups during the day. But although caffeine can help them start the day, it carries risks.

After someone drinks coffee (it doesn’t really matter how much), it takes the liver three to four hours to reduce the caffeine blood level by half. Thus it could take nine to twelve hours for the caffeine to completely clear the system. Birth control pills can slow down the body’s elimination of caffeine even further.

People who drink more than 200 milligrams of caffeine a day, especially in the afternoon or evening, are likely to have insomnia. As we saw in Chapter 1, while we are awake we accumulate a chemical called adenosine in the brain that makes us sleepy. Caffeine antagonizes the effect of adenosine. Few people should take more than 400 milligrams of caffeine a day. The amount of caffeine in dark roasts varies, but two cups of most of them have more than 400 milligrams. Even many “decaf” coffees have some caffeine, as reported in Consumer Reports in 2014. (As regards coffee, the news is not all bad: coffee—even decaf—has been reported to have many beneficial effects, including protecting the liver from scarring; it might also have anti-cancer properties and help counter Parkinson’s disease and dementia.)

“Energy drinks” and related products might also contain a great deal of caffeine. I have had patients who drank energy drinks or other products that promised hours of energy all day long and then developed symptoms of caffeine toxicity. Such products can even result in death if overused.

Menopausal women should be aware that medical studies suggest that more than 300 milligrams of caffeine a day (eighteen ounces of brewed coffee) speeds up bone loss and can increase the risk of osteoporosis.

In excess amounts, caffeine also contributes to symptoms of anxiety.

Parents might be amazed (and dismayed) to discover how much caffeine their children imbibe without their realizing it, particularly in soft drinks. Some of the most popular soft drinks contain high levels of caffeine. A study published in 2003 reported that caffeine intake was significant in seventh-, eighth-, and ninth-graders; 70 percent of them drank caffeine daily, and almost 20 percent were drinking more than 100 milligrams a day. One eighth-grader took 380 milligrams a day! The 2004 National Sleep Foundation Poll reported that 26 percent of children over three years old have at least one caffeinated drink daily. Children drinking caffeinated beverages sleep less than those who do not, averaging 9.1 versus 9.7 hours per night, and thus losing about 3.5 hours a week.

During pregnancy the body breaks caffeine down more slowly. Pregnant women have many reasons to feel sleepy (see Chapter 4) and might believe that they could combat the sleepiness by drinking coffee. Research from Sweden published in 2000 showed that women who consumed 300 to 499 milligrams of caffeine per day increased their risk of miscarriage by 40 percent, while those who consumed 500 milligrams or more per day increased their risk by 120 percent. Another study, from Denmark, in 2003 reported a 120-percent risk of miscarriage when caffeine use exceeded 375 milligrams per day. How much coffee is safe in pregnancy? Probably about one cup per day.

Over the years I have seen many patients, including children, with insomnia caused by excessive caffeine. Some people even become addicted to caffeine, drinking fifteen to thirty cups a day. Cutting back is difficult for them and they might develop symptoms such as headaches and nervousness when trying to reduce their intake. The best way for caffeine addicts to reduce their dependence is slowly, over one or two weeks.

PRESCRIBED STIMULANT MEDICATIONS

Some stimulant medications are prescribed to treat sleepiness in patients with sleep disorders such as narcolepsy (see Chapter 13); they are also used to treat attention deficit hyperactivity disorder in adults and children. These medications have been used for decades. Stimulant medications work by affecting cells in the central nervous system. Some stimulant medications—which include amphetamine, dextroamphetamine, methamphetamine, cocaine, and methylphenidate—have also become street drugs. They affect the sympathetic nervous system, so they can cause changes in heart rate and rhythm and might increase blood pressure and cause jitteriness. They can increase the levels of the chemical dopamine in the brain and elsewhere, which can excite nerve cells, including those controlling heart rate and blood pressure.

Methylphenidate and related drugs (Ritalin, Concerta, Vyvanse) are widely used to treat children with ADHD. They are also sometimes used to treat narcolepsy. But though these can be effective in combating sleepiness in narcolepsy, they seem to have the opposite effect on ADHD. Other drugs used to treat ADHD include guanfacine (Estulic, Tenex, and the extended-release Intuniv), which is also used to treat high blood pressure, and atomoxetine (Strattera).

The amphetamine drugs include amphetamine, dextroamphetamine (Dexedrine, DextroStat), and methamphetamine (Desoxyn). Adderall and Biphetamine are combination drugs that contain both amphetamine and dextroamphetamine. Years ago, doctors prescribed amphetamines as appetite suppressants; many women, in particular, took them to lose weight. One doctor told me that her mother had taken amphetamine around 1950 to lose weight while she was pregnant with her. The long-acting versions of these drugs are sometimes used to treat ADHD. Stimulants are more difficult to prescribe than other types of drugs because of the rigid controls on medications that have abuse potential. Pemoline (Cylert) is a stimulant medication that is no longer available in the United States or Canada because of concerns about side effects, especially liver problems. Mazindol (Mazanor and Sanorex), which is used to decrease appetite, is also sometimes prescribed as a stimulant.

Many students who do not have sleep disorders are somehow obtaining prescription stimulant medications and using them to try to improve their school grades.

Ironically, the main effect of and reason why a stimulant is used, alertness, is also its major negative side effect. The user’s alertness might continue long into the night, making it very difficult for him or her to fall and stay asleep.

ALERTNESS-PROMOTING DRUGS

Modafinil (Alertec in Canada, Provigil in the United States and the United Kingdom) was introduced in North America to treat sleepiness in patients suffering from narcolepsy. A modified longer-acting version of this compound called armodafinil (Nuvigil) has also been approved. Modafinil works differently from the stimulants mentioned earlier because it does not stimulate several organ systems but instead seems to act on the centers of the brain that are involved in keeping the person awake. It is beginning to be used for many conditions in which the patient might be sleepy or tired, including multiple sclerosis, depression, Parkinson’s disease, and cancer. It has been approved in the United States for use in treating people with sleepiness caused by shift-work disorders and in treating sleep apnea patients who are using CPAP but have residual sleepiness. This is a medication that seems to wake people up without the sympathetic nervous system activation that is observed in those who take amphetamines. Provigil is often best taken twice a day, the first dose first thing in the morning, and the second dose at lunchtime. If patients take the medication later in the day, they might have trouble sleeping that night. Nuvigil is taken once a day, in the morning. These new compounds so far have not been shown to be addictive and have few side effects.

Sodium oxybate (a form of gamma hydroxybutyrate), by enhancing sleep for narcolepsy patients, improves alertness in these patients. It is not approved to be used for any other condition at this time.

Back to the Truck Driver with Insomnia

The truck driver was drinking about ten quarts a day of a cola containing caffeine. Her insomnia was caused by the huge amounts of caffeine she was unknowingly taking into her body. Although she got the soft drinks free, she had paid a big price over several years. She had never realized that the soft drinks had so much caffeine. After she weaned herself from her dependence on the cola and limited her intake of caffeine to a reasonable amount, her problem was solved.

Medications used to treat sleep problems can improve symptoms, but they can have unwanted effects. Medications can be used safely only when the doctor and the patient know what the problem is and have discussed treatment options. For insomnia patients who find CBT ineffective or difficult, medication taken in consultation with a doctor can be the most acceptable option.