What is Insomnia?
Insomnia is an important public health problem that requires accurate diagnosis and effective treatment. Insomnia symptoms occur in approximately 33% to 50% of the adult population and general insomnia disorder in 10% to 15%. Risk factors for insomnia include increasing age, female sex, comorbid conditions, shift work, and possibly unemployment and lower economic status. Insomnia can cause distress because of the fear of not being able to fall asleep at bedtime and lack of sleep affects the ability to complete daily normal activity. This can impair work-related productivity because of daytime drowsiness or fatigue.
Complaints of insomnia consist of one or more of the following:
- Difficulty initiating or maintaining sleep
- Poor Quality Sleep
- Early Awakening
- Difficult Sleep despite adequate conditions
Insomnia can be chronic (ongoing) or acute (short-term) problem. Chronic insomnia means having symptoms at least 3 nights a week for more than a month. Acute insomnia can range from one to two times for up to 2 weeks.
Medications that can interfere with sleep include allergy and cold medicines (e.g., Zyrtec, Allegra), beta-blockers (e.g., atenolol, carvedilol, metoprolol), sterioids (e.g., cortisone, methylprednisolone, triamcinolone), and asthma medications (e.g., theophylline).
Despite the relative prevalence of insomnia only 5% of individuals seek medical attention for management of their insomnia. Approximately 10% to 20% of people that report insomnia use either nonprescription drugs or alcohol to self-treat.
Prescription Drugs for Treatment of Insomnia
Primary treatment goals are:
- Improve sleep quality and quantity
- Improve insomnia related daytime impairments
Different Treatment Approaches
The different treatment approaches to insomnia are based on the relationship between the neurophysiological mechanisms that promote wakefulness versus sleep. The sleep versus wake cycle is determined by coordinated activity between the sleep-promoting system and the wake-promoting system of the brain. Each system has chemical messengers (neurotransmitters). The sleep-promoting neurotransmitters include gamma amino-butyric acid (GABA) and galanin. The wake-promoting neurotransmitters are histamine, orexin, norepinephrine, and serotonin. Both groups of neurotransmitters influence the sleep state and dysfunction in either system can contribute to insomnia.
Benzodiazepine Hypnotic Agents
The most commonly used treatments for insomnia are the benzodiazepine receptor agonists. These medications affect the sleep-promoting system, by enhancing activity of GABA, the inhibitory neurotransmitter in the body. Binding to GABA to receptors inhibits neurons in the brain that maintain wakefulness.
This group of medications consists of traditional benzodiazepines and nonbenzodiazepine agonists. Traditional benzodiazepines have sedative, anti-anxiety, muscle relaxant, and anticonvulsant properties. Nonbenzodiazepine agonists have only sedative properties. Benzodiazepines relieve insomnia by reducing sleep latency and increasing total sleep time.
The benzodiazepine agents that are used for insomnia are temazepam (Restoril) 7.5 mg to 30 mg and Estazolam (Prosom) 1 to 2 mg. Both agents are taken before bedtime. Factors including symptom pattern, sleep history, cost, and preference can help select a specific medication.
Adverse Side effects:
- Daytime somnolence
- Early morning Insomnia
- Daytime anxiety & confusion
- Ataxia and falls in elderly
Nonbenzodiazepine Hypnotic Agents
Short-acting nonbenzodiazepine hypnotic agents help people fall sleep. These drugs are zolpidem (Ambien) 5 mg, 10 mg and zaleplon (Sonata) 5 mg, 10 mg. Zaleplon is helpful in patients that present with early night awakening. The safety and efficacy of Zolpidem is similar to the benzodiazepines. Adverse side effects of Zolpidem are dose related and include drowsiness, amnesia, dizziness, headache, and stomach upset. Side effects related to Zaleplon consist of dizziness, headache, and drowsiness. Zolpidem is less expensive than other brand name medications. It cost $12 to $14 7 tablets.
Longer-acting formulations of nonbenzodiazepine agents are used to help with better sleep maintenance. Drugs such as Zolpidem CR (Ambien CR) 6.25 mg and 12.5 mg can help with initiation and maintenance of sleep.The FDA urged to decrease the doses of zolpidem being prescribed to women. Women eliminate the drug more slowly from their bodies than men. Lower doses of zolpidem will result in lower blood levels in the morning. FDA has informed the manufacturers that the recommended dose of zolpidem for women should be lowered from 10 mg to 5 mg for immediate-release products (Ambien, Edluar, and Zolpimist) and from 12.5 mg to 6.25 mg for extended-release products (Ambien CR). FDA also informed the manufacturers that, for men, the labeling should recommend that health care professionals consider prescribing the lower doses of 5 mg for immediate-release products and 6.25 mg for extended-release products
A relatively newer drug, called Intermezzo, a lower dose zolpidem product approved for middle-of-the-night awakenings also have a recommended lower dose. At the time of Intermezzo’s approval in November 2011, the label already recommended a lower dosage for women than for men.
Eszopiclone (Lunesta) 1 mg, 2 mg, 3 mg is a longer-acting nonbenzodiazepine. This drug should not be taken with or right after a meal because it has a half-life of 6 hours. The starting dose of Lunesta taken at bedtime was decreased to 1 mg for both men and women because higher doses are likely to result in next-day impairment of activities that require full alertness. Lower doses results in less drug remaining in the body in the morning. Average wholesale package price is $389.16 for a bottle of 30 tablets. Overall, the patient at whole and how effective these medications are should be taken into account and carefully monitored by prescribing physicians.
Nonbenzodiazepines are associated with less withdrawal, tolerance, and rebound insomnia compared to the benzodiazepine hypnotics.
Sedating Low-dose Antidepressants
Antidepressants are prescription medications that can be used to treat insomnia. Antidepressants are indicated for insomnia with co-morbidity such as major depression or hyperactivity history. Antidepressants are for patients who have trouble with non-restorative sleep who should not receive benzodiazepines. Adverse side effects when taking antidepressants to treat insomnia can result in anticholinergic affects such as dry mouth, constipation, morning hangover feeling, drowsiness, headache, urinary retention or difficulty.
Antidepressants that are used for treating insomnia:
- Doxepin (Adapin, Sinequan, Silenor) 3 mg and 6 mg tablets
- Amitriptyline (Elavil) 25 mg-100 mg at bedtime
- Trazodone (Desyrl) 50-150 mg at bedtime
- Mirtazipine (Remeron) 15-45mg daily
Factors such as treatment history, coexisting conditions, side-effects and cost can be used select a specific medication. Trazodone affects chemical messengers (neurotransmitters) in the brain that nerves use to communicate. Trazodone affects serotonin by inhibiting the uptake of serotonin in nerves. Trazodone is cheaper than other medications. It is around $3 for a week supply compared to $45 and $34 for Lunesta and Rozerem. Trazodone has been used with patients prone to substance abuse since dependence is not a problem. It is indicated as an “off-label” usage for insomnia and is not a controlled substance so doctors can prescribe with less constraint. It can be used for patients on medications that affect sleep. For example, selective serotonin reuptake inhibitor (SSRI) and bupropion-induced insomnia. Doxepin blocks histamine (H1) and also increases levels of serotonin and norepinephrine. It has little to no anticholinergic activity. Mirtazapine is associated with daytime sedation and weight gain.
Combination of Benzodiazepines and Antidepressants
The combination of medications from two different classes may improve efficacy by targeting different sleep and wake mechanisms. This can also prevent toxicity that could occur with higher doses of single medications. Side effects include daytime sedation which can be minimized by lower doses of antidepressants.
Antihistamines Used for Insomnia
Antihistamines are effective in the treatment of mild insomnia and are generally safe. Antihistamines treat insomnia by affecting the wake-promoting system by blocking histamine. This reduces histamine activity, which promotes sleep. Antihistamines are used for insomnia because of their sedative side effect. Benadryl (diphenhydramine) and Unisom (doxylamine) are more sedating than Pyrlex (pyrilamine). Antihistamines are less effective than benzodiazepines and they cause anticholinergic side effects (for example, dry mouth, constipation). They are not recommended for the elderly.
- Diphenhydramine (Benadryl) 25 mg to 50 mg at bedtime
- Doxylamine (Unisom) 12.5 mg to 25 mg at bedtime
- Hydroxyzine (Vistaril) 25 mg to 100 mg at bedtime
Also Read: Over-the-Counter (OTC) Medications for Sleep
Antipsychotics or Anti-epilepsy Medications
Sedation is a common effect of antipsychotics and anti-epilepsy medications. When other medications fail to work antipsychotics are an option. These agents block histamine receptors, causing sedation. Quetiapine (Seroquel) is often prescribed for sleep.
Dependence, Tolerance, and Withdrawal
Dependence, tolerance, and abuse of insomnia medications can be an issue. Scheduled non-nightly dosing helps prevent tolerance, dependence, and abuse. However, these problems are less likely with medications such as non-benzodiazepine agents. Also, the use of “as needed” medications is a way to prevent tolerance and dependence. The duration of prescription treatment is a period of 2-4 weeks, followed by re-evaluation.
Discontinuing medications can lead to rebound insomnia and withdrawal symptoms. Rebound insomnia and withdrawal can be minimized by gradually tapering the dose and frequency of administration. Successful tapering could take weeks or months.
From the Journal of Clinical Sleep Medicine the recommended medication trials are:
- Short-intermediate acting benzodiazepine receptor agonists or nonbenzodiazepine agonists
- Alternate short-intermediate benzodiazepine or nonbenzodiazepine if the initial agent was unsuccessful
- Sedating antidepressants, useful in conjunction with treating comorbid depression/anxiety
- Combination of benzodiazepine and sedating antidepressant
- Other sedating agents, such as atypical antipsychotics or anti-epilepsy medications
Pharmacologic treatment should be used in conjunction with patient education regarding goals, safety concerns, potential side effects, drug interactions, cognitive and behavioral treatments, dosage escalation, and rebound insomnia.
Sleep disturbances can affect one third of the population. Lack of sleep can take a toll on a person’s well-being and ability to perform daily activities which can affect health and relationships. It is important to seek help to prevent worsening of insomnia and to improve quality of life. There are several types of medications approved for treating insomnia.
Dopp JM, Phillips BG. Sleep Disorders. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill; 2011: 1241-1251
Schutte-Rodin S; Broch L; Buysse D; Dorsey C; Sateia M. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med 2008;4(5):487-504.
Kirkwood CK. Management of insomnia. J Am Pharm Association 1999; 39:688-96. Acessed May 29, 2014.
Sleep and Sleep Disorders. Centers for Disease Control and Prevention; July 2013. Accessed June 19, 2014.
U.S. Food and Drug Administration. (2013, January 1). Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist). Accessed June 20, 2014.
U.S. Food and Drug Administration. (2014, May 15). FDA requiring lower starting dose for sleep drug Lunesta. Accessed May 29, 2014.