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Dr. Knudsen is an assistant professor of pharmacy practice at Midwestern University College of Pharmacy—Glendale, Glendale, Arizona.

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In 2004, Surgeon General Richard H. Carmona estimated that sleep disorders cost the United States $15 billion in health care expenses and $50 billion in productivity losses each year.¹ Productivity losses usually stem from excessive daytime sleepiness, which is a symptom associated with all sleep disorders.

Although insomnia is the most well-known sleep disorder and has the most pharmacotherapy options, the sleep-disorder category actually contains 4 disorders— including narcolepsy (daytime sleep attacks), sleep apnea (breathing interruptions during sleep), restless legs syndrome (RLS; a tingling or prickly sensation in the legs), and insomnia (difficulty falling or staying asleep).²

Insomnia

Of the 4 sleep disorders, insomnia affects the largest number of patients—an estimated 10% to 20% of the US population—and 47% of elderly patients experience chronic insomnia.³ In 2007, insomnia patients incur annual costs between $92.5 billion and $107.5 billion.⁴ Although these numbers are staggering, so is the plethora of treatment options.

Medication classes available for insomnia treatment include: benzodiazepine (BZD) hypnotics, non-BZD hypnotics, a melatonin receptor agonist, and OTC antihistamines. Pharmacotherapy should include "use of the lowest effective dose, use of intermittent dosing (2-4 times weekly), short-term medication prescribing (regular use for not more than 3-4 weeks), and gradual medication discontinuation to reduce rebound insomnia."⁵

BZDs improve insomnia by "reducing REM sleep, decreasing sleep latency, and decreasing nocturnal awakenings."⁶ They are initially very effective in inducing and prolonging sleep and are relatively inexpensive; however, many problems are associated with them.

BZDs are associated with rebound insomnia that can occur within 1 or 2 weeks of use, hangover effects, tolerance (which can develop rapidly on repeated administration), and addiction potential.⁶ Whereas short-acting BZDs are preferred, both short-acting (eg, temazepam) and long-acting (eg, diazepam) agents have the potential to cause these problems.

Non-BZD hypnotics, like zolpidem (Ambien), zaleplon (Sonata), eszopiclone (Lunesta), changed the landscape of insomnia treatments. Ancoli-Israel and colleagues described the benefits of zaleplon in older adults during short- and long-term treatment as having "no pharmacologic tolerance developed during treatment and no rebound insomnia or withdrawal symptoms after medication discontinuation."⁷

As much as these agents have positive aspects, adverse effects became apparent during postmarketing monitoring.

In December 2006, the FDA asked manufacturers of products approved for the treatment of sleep disorders to revise their product labeling to include warnings about potential adverse events such as "anaphylaxis (severe allergic reaction) and angioedema (severe facial swelling), which can occur as early as the first time the product is taken," as well as "complex sleep-related behaviors, which may include sleep driving, making phone calls, and preparing and eating food (while asleep)."⁸ Complex sleep-related behaviors have received a great deal of press.⁹ At this time, the exact mechanism is not clear, nor is the commonality of these types of events in patients treated with these agents.

Ramelteon (Rozerem), a melatonin receptor agonist, was included in the label revisions. Griffiths and colleagues reported that, compared with 19 other agents including non-BZDs, BZDs, and diphenhydramine, ramelteon produced no detectable subjective effects that affect likelihood of abuse at up to 20 times the recommended therapeutic dose.¹⁰

Sleep Apnea

Sleep apnea causes repetitive episodes of upper airway occlusion during sleep. Although the mechanism of action of this condition does not seem to fall into the category of sleep disorder, it is the result of excessive daytime sleepiness that allows its inclusion. These repetitive episodes cause oxygen desaturation and sleep disruption.

Surgery, dental appliances, and continuous positive airway pressure are the preferred treatments. Antidepressants, protriptyline, or fluoxetine may be used in combination with nonpharmacotherapy treatments to decrease excessive daytime sleepiness because of their suppression of rapid eye movement (REM) sleep.¹¹

RLS

RLS has a complicated history and has only recently received FDA-approved treatments. The condition occurs most frequently in middle-aged and older adults, is worsened by stress, and its cause remains unidentified.¹² It can be difficult for patients and physicians to communicate symptoms and come to a positive diagnosis. RLS is described in very patient-specific, subjective terms, which can include "burning," "creeping," "crawling," "aching," "tingling," and/or "tugging." Many people with RLS have difficulty explaining the odd sensations they feel, even when talking to their doctors.¹³

RLS has 2 FDA-approved treatment options: pramipexole (Mirapex) and ropinirole (Requip). Other agents, such as sedatives (eg, diazepam, temazepam) and narcotics (eg, hydrocodone, propoxyphene), have been used in the past, but these have adverse effects that may outweigh the possible benefits they provide.

The pathophysiology of RLS is for the most part unknown; neuropharmacologic evidence proposes primary dopaminergic system involvement. Although the precise mechanisms of action of pramipexole and ropinirole for RLS are unknown, both agents are dopamine agonists,⁵,¹⁴ so their effectiveness in RLS is understandable. Both agents also are used for Parkinson's disease because of their dopamine agonist properties, but the doses used for RLS are much lower than those used for Parkinson's disease. These agents should be administered 1 to 2 hours before symptoms occur.

Pramipexole's adverse events seem to be dose-related (>3 mg/day): postural hypotension, nausea, constipation, somnolence, and amnesia. The incidence of somnolence reported with pramipexole at a dose of 1.5 mg/day is comparable with placebo, which is higher than the maximum dose recommended of 0.5 mg for RLS.

Ropinirole's prescribing information includes a warning that "patients treated have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on ropinirole, some perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event."¹⁵ The prescribing information further states that "some of these events have been reported as late as 1 year after initiation of treatment." These events seem to occur at higher doses than are used for RLS, however.

Narcolepsy

Narcolepsy affects only a very small percentage of the population—about 1 in every 2000 Americans, totaling about 135,000 individuals.¹⁶ It affects men and women equally.¹⁶ Few treatment options exist for narcolepsy, and no cure exists.

Pharmacotherapy for narcolepsy can be split into 2 categories: nonamphetamines and amphetamines. The nonamphetamine medication includes modafinil (Provigil). Amphetamine medications include methylphenidate (Ritalin) and dextroamphetamine.

Modafinil is the medication of choice for initial treatment. Compared with other medication options, modafinil has less rebound hypersomnia, tolerance is limited, and it does not affect blood pressure. The main side effect of modafinil is headache.¹⁷

Although nonamphetamine treatments are preferred for first-line treatment, do not carry controlled-substance status, and have decreased risk of abuse, the amphetamine medication class is still an option. If tolerance develops during amphetamine treatment, switching drugs is more appropriate, compared with increasing the dose of current treatment. LexiComp reports that little cross-tolerance exists in this treatment category.

Auxiliary symptoms, such as cataplexy, hypnagogic hallucinations, and sleep paralysis also have treatment options, which may include antidepressants because of their suppression of REM sleep.¹⁵

With all 4 sleep disorders, the main goals of therapy are to balance the need to prevent excessive daytime sleepiness, improve the quantity and quality of patient sleep, and avoid adverse effects of pharmacotherapy.

References

1. Traynor K. Insomnia sufferers need better care, experts say. Am J Health-Syst Pharm. 2005;62:1534.
2. Sleep Disorders. Medline Plus Web site. www.nlm.nih.gov/medlineplus/sleepdisorders.html. Accessed December 6, 2007.
3. Navarro R, Mitrzyk BM, Bramley TJ. Chronic insomnia treatment and Medicare Part D: Implications for Managed Care Organizations. Am J Manag Care. 2007;13:S121-S124.
4. Reeder CE, Franklin M, Bramley TJ. Current Landscape of Insomnia in Managed Care. Am J Manag Care. 2007;13:S112-S116.
5. Mirapex [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2007. bidocs.boehringer-ingelheim.com. Accessed 6 December 2007.
6. Kamel NS, Gammack JK. Insomnia in the Elderly: Cause, Approach, and Treatment. Am J Med. 2006;119(6):463-469.
7. Ancoli-Israel S, Richardson GS, Mangano RM. Long-term use of sedative hypnotics in older patients with insomnia. Sleep Med. 2005;6:107-113.