Sleep Disorder Medications

A sleep disorder (insomnia), a disorder in which there is difficulty sleeping, occurs occasionally in most people but usually lasts only a few days. The body then "corrects" itself naturally, and people return to a normal pattern of sleep. Insomnia may be short-term (less than three weeks) or chronic, lasting longer than three weeks. Contributing factors include, but are not limited to,

• poor sleeping habits,
• stress,
• jet lag,
• medications,
• disease, and
• depression.

Chronic insomnia may warrant the use of sedative/hypnotic medications; however, it is important that the treating physician perform a complete diagnostic evaluation as well as take medication and substance abuse histories, to determine if it is secondary insomnia due to other conditions that may require treatment. Studies have shown that the best treatment strategies for insomnia include behavioral modifications.

Hypnotic and sedative medications (henceforth referred to as hypnotics) work, in general, by increasing the activity of gamma-aminobutyric acid (GABA), a neurotransmitter in the brain. Neurotransmitters are chemicals made and released by nerves that attach to receptors on other nerves and serve as a means of communication between nerves.

• Increases in GABA activity in the brain produce drowsiness and facilitate or maintain sleep.

Hypnotics are used for the treatment of insomnia which is characterized by difficulties with falling asleep or maintaining sleep.

• Specific hypnotics such as Intermezzo (zolpidem tartrate) can be used for insomnia involving middle-of-the-night waking followed by difficulty returning to sleep.

There are a variety of hypnotics that are used for treating insomnia. The main difference among the various hypnotics is their half-life, that is, how long the drug is active in the body.

• The half-life determines the type and duration of hypnotic effects and the unwanted side effects.
• When hypnotic drugs have long half-lives, the drug itself or the chemicals that the body makes from the drug tend to accumulate with nightly use, and the accumulation can cause impairment of normal day-time functions involving thought and motor skills.

There also is a larger risk of interactions with other drugs due to a carry-over effect of the hypnotic drug. In contrast, when hypnotic drugs with short half-lives are taken, the drugs are cleared from the body before the next dose is ingested or other drugs are taken, hence the carry-over effects are minimal or absent and do not affect thought and motor skills.

Side effects of hypnotics include:

• Headache
• Nervousness
• Nausea
• Talkativeness
• Apprehension
• Irritability
• Confusion
• Euphoria
• Relaxed feeling
• Weakness
• Tremor
• Lack of concentration
• Disorders of coordination
• Depression
• Dreaming/nightmares
• Insomnia
• Palpitations
• Chest pains
• Rapid heart rate
• Abnormal behaviors during sleep including sleepwalking and other sleep-related activities

Side effects involving the stomach and intestines include:

• Heartburn
• Nausea
• Vomiting
• Diarrhea
• Constipation
• Abdominal pain
• Loss of appetite
• Alterations in taste
• Dry mouth
• Excessive salivation (rare)

If any of these side effects persist or worsen, a physician should be notified promptly.

If a patient has a history of depression, or liver, kidney, and respiratory disease, it is advisable to communicate this to the treating physician in order to be certain that commencing treatment with hypnotics is safe.

• Benzodiazepines, when taken with alcohol and other types of depressants of brain and body function such as prescription pain medicines and some over-the-counter cold and allergy medications, can have additive depressant effects (additional slowing of brain and body function) that can lead to slow heart rate and reduced respiration and even death.
• Oral contraceptives, Tagamet (cimetidine), Antabuse (disulfiram), or Nydrazid (isoniazid), may reduce the elimination of benzodiazepines by the liver, which, in turn, increases the blood levels of benzodiazepines. This causes an increase in the depressant effects of benzodiazepines.
• When selective serotonin reuptake inhibitors (SSRIs) are taken with Valium (diazepam), they may increase diazepam blood levels and the depressant effects of diazepam.
• Serzone (nefazodone) taken with Xanax (alprazolam) may increase alprazolam blood levels and its depressant effects.
• Smoking could increase the elimination of benzodiazepines from the body. This may reduce the effects of benzodiazepines.
• Benzodiazepines will increase blood levels of Digitek, Lanoxin (digoxin), and digoxin toxicity may occur.
• Antifungals, for example, Diflucan (fluconazole), Sporanox (itraconazole), and Nizoral, Xolegel (ketoconazole), may increase the blood levels and effects of zolpidem by reducing the activity of the enzymes that break down zolpidem in the liver. Therefore, it is important to monitor and adjust zolpidem doses as needed when antifungals are taken. Conversely, Rifadin (rifampin) may reduce the concentration of zolpidem by increasing the activity of the enzymes that break down zolpidem.
• Opiates (such as codeine) can impair the thinking and physical abilities required for driving or operating machinery. Alcohol and other sedatives such as alprazolam can produce further brain impairment and even confusion when combined with codeine. Therefore, alcohol and other sedatives should be limited when taking codeine.
• Anticonvulsants such as Carbatrol, Epitol, Equetro, Tegretol, Tegretol XR (carbamazepine) can increase the breakdown of the hormones in birth control pills and can reduce the effectiveness of birth control pills. Unexpected pregnancies have occurred in patients taking both carbamazepine and birth control pills. It is important to use the second form of birth control when taking carbamazepine.
• Anti-narcoleptics (drugs that prevent drowsiness) such as Provigil (modafinil) should be carefully monitored if taken with certain drugs such as Gengraf, Neoral, Sandimmune (cyclosporine), Elixophyllin, Theo-24, TheoCap, Theochron, Theo-Time, Uniphyl (theophylline), and hormonal contraception as modafinil may reduce their effectiveness. Use of anti-Parkinson drugs such as carbidopa-levodopa with monoamine oxidase inhibitors (MAOI's) antidepressants, for example, Marplan (isocarboxazid), Nardil (phenelzine), can result in severe and dangerous elevations in blood pressure. MAOI's should be stopped 2-4 weeks before starting carbidopa-levodopa therapy.

There are seven different types of hypnotic medications:

1. Nonbarbiturates
2. Barbiturates
3. Nonprescription sleep aids
4. Anti-Parkinson drugs ( Dopamine Agonists)
5. Opiates
6. Anticonvulsants
7. Antinarcoleptics

Benzodiazepines

Benzodiazepines have a variety of uses, which include inducing sedation and sleep, relieving anxiety, agitation, and muscle spasms, and prevention of seizures. In general, they help in increasing total sleep time. With benzodiazepines, there may be issues of dependence, toxicity and abuse.

Examples of benzodiazepines:

• Prosom (estazolam)
• Dalmane (flurazepam)
• Doral (quazepam)
• Restoril (temazepam)
• Halcion (triazolam)
• Valium (diazepam)

Non-benzodiazepines

This is a newer class of drugs that is used for the short-term treatment of insomnia. They cause the onset of sleep to occur faster and allow for a longer period of sleep throughout the night. Non-benzodiazepines have a short half-life and have less chance of causing dependency, tolerance, and impairment of daytime activities due to carry-over effects.

Examples of non-benzodiazepines:

• Imidazopyridines: Ambien, Ambien CR, Intermezzo (zolpidem) (class of its own)
• Sonata (pyrazolopyrimidine) (class of its own)
• melatonin receptor stimulator: Rozerem (ramelteon)
• Notec (chloral hydrate)
• Precedex (dexmedetomidine hydrochloride)
• Lunesta (eszopiclone)

Another class of medications that helps with insomnia has become recently available. It acts by decreasing the activity in the wake system (lateral hypothalamus) of our brain, rather than increasing the activity in the sleep centers of our brain. Suvorexant (Belsomra), is an orexin antagonist which decreases activity in the wake center and therefore promoting sleep. It is thought to be generally safe and well tolerated, but some patients may have side effects.

Barbiturates are used to treat anxiety, insomnia, and seizure disorders. They are not, however, prescribed as often due to the availability of benzodiazepines and non-benzodiazepines. Barbiturates can be addictive and have strong withdrawal symptoms and rebound (exaggerated) effects on rapid eye movement (REM) sleep when they are abruptly stopped and can interfere with sleep. It is advisable, therefore, to stop barbiturates by slowly lowering their dose over a period of more than five or six days. It also is important to use the correct dose of barbiturates since a relatively small overdose may lead to coma or death.

The main differences among barbiturates are their half-lives (duration of their effects). Drugs such as secobarbital sodium and pentobarbital sodium are short-acting, while others such as amobarbital sodium and butabarbital sodium are intermediate-acting, and phenobarbital and mephobarbital are long-acting.

Examples of barbiturates:

• Nembutal (phenobarbital)
• Mebaral (mephobarbital)
• Amytal Sodium (amobarbital sodium)
• Butisol (butabarbital sodium)
• Seconal Sodium Pulvules (secobarbital sodium)

It is advisable to talk to the local pharmacist for advice on any of the various medication options purchased in a pharmacy.

Examples of non-prescription sleep aids:

• Unisom Nighttime Sleep-Aid
• Dormin
• Nytol
• Simply Sleep
• Sominex
• Extra Strength Tylenol PM
• Diphenhydramine hydrochloride
• Excedrin P.M.
• Over the counter formulations of melatonin

These drugs may be used to treat conditions that contribute to sleep disruption such as restless leg syndrome and periodic limb movement disorder (nocturnal myoclonus syndrome).

Examples of anti-Parkinson's drugs:

• Sinemet, Sinemet CR, Lodosyn (carbidopa-levodopa)
• Parlodel (bromocriptine mesylate)
• Requip, Requip XL (ropinirole Hcl)
• Permax (pergolide mesylate)
• Mirapex (pramipexole)

These drugs may be used to treat conditions that contribute to sleep disruption such as restless legs syndrome as a second line drug.

• Codeine Sulfate (codeine)
• Combunox (oxycodone HCI and ibuprofen)
• Endocet (oxycodone and acetaminophen)
• Percocet (oxycodone and acetaminophen)
• Percodan ( aspirin, oxycodone hydrochloride, oxycodone terephthalate)
• Roxicodone (oxycodone hydrochloride)
• Dolophine, Methadose (methadone)
• Dihydromorphine (not available in the U.S.)
• Darvon, Darvocet-N (propoxyphene)

These drugs may be used to treat conditions that contribute towards sleep disruption such as restless legs syndrome, nocturnal eating syndrome, periodic limb movement disorder, and insomnia related to bipolar disorder.

Examples of anticonvulsants:

• Tegretol (carbamazepine)
• Carbatrol (carbamazepine extended-release)
• Depakene (valproic acid)
• Depakote (divalproex sodium)
• Neurontin (gabapentin)

These drugs may be used to improve daytime wakefulness and to control excessive daytime sleepiness and loss of muscle control in people with narcolepsy.

Examples of antinarcoleptics:

• Provigil (modafinil)
• Nuvigil (armodafinil)
• Xyrem (sodium oxybate)

REFERENCE: FDA Prescribing Information.