Insomnia: Therapeutic Approach.

ABSTRACT: Insomnia is a common complaint. Transient and short-term insomnias usually result from stress or the use of certain pharmaceuticals or drugs and may be managed by reduced caffeine use, behavioral means, and/or pharmacologic treatment. Long-term insomnia is often a symptom of a medical or psychiatric condition or a primary sleep disorder. A diagnostic workup is expected; treatment should focus on the causative condition, as well as addressing the sleep problem itself. Established medications for the symptomatic treatment of insomnia include benzodiazepines, zolpidem, zaleplon, and certain antidepressant or occasionally antihistaminic drugs.

INSOMNIA is characterized by difficulty in initiating or maintaining sleep and by finding sleep nonrestorative. [1] Insomnia periodically affects 50% of adults, [2] and more than 90% of the population have trouble with sleep at some point during their lives. [3] Insomnia becomes a problem when excessive daytime sleepiness impairs feeling well and performing functions that require alertness. Inadequate sleep can result in adverse personal, medical, or psychiatric sequela and increased risk for accidents. Many people with a sleep problem seek help from their doctor. [4] Difficulties with sleep are divided into transient, short-term insomnias and more chronic versions (Table 1).

Transient and short-term insomnias lasting from days to weeks, are common during emotional distress. [5] Bereavement or other personal crises often disturb sleep. Such difficulty is observed also initially with the initiation, use, or discontinuance of certain pharmaceuticals or drugs and ethanol. [6] This includes stimulants, such as theophylline, cocaine, and caffeine. The emergence of some physical illnesses, such as peptic ulcer disease, with awakenings due to dyspepsia, also can present in such a way. The same can occur with environmental disturbances and job shift changes or travel-initiated jet lag. [6]

Chronic insomnias last over several weeks [7] and are usually related to specific medical or psychiatric conditions [8,9]; the nocturia of prostatic hypertrophy is an example. Depression and anxiety-related disorders are common causes of poor sleep and characterize the bulk of psychiatric causes. [1] Psychophysiologic insomnia can emerge once one becomes worried about insomnia, thus actually perpetuating conditioned inability to sleep. There are also a number of primary sleep disorders.

Medical evaluation of insomnia should define a causative diagnosis with an etiologyspecific treatment plan. Insomnias may call also for the use of "sleeping pills." combining time-linked drug treatments with nonpharmacologic therapies gives the best results. [10]

DIAGNOSIS OF PROBABLE CAUSES

Evaluation

In assessing possible causes of a patient's insomnia, the physician should obtain a complete history and perform the appropriate physical examination or laboratory studies. Knowing the duration and type of sleep complaint is critical. [8] Medical problems that can cause insomnia include a wide range of endocrine, cardiovascular, pulmonary, gastrointestinal, and other disorders. [11] A patient-recorded sleep diary may be diagnostically helpful. Psychiatric symptoms might reveal mental illness, especially depression, or emotional factors, such as grief. Questionnaires on well-being and sleep habits can provide information. [12] Symptomatology may suggest a primary sleep disorder. [13]

Substance Use History

Determine whether pharmacologic agents are the cause of insomnia. Stimulants, bronchodilators, xanthines, decongestants, diuretics, histamine antagonists, antihypertensives, and steroids are drugs that may cause sleep difficulty. [14-17] Some activating antidepressant medicines (eg, fluoxetine) can induce insomnia. The same applies to illegal stimulants (eg, cocaine). Nicotine, alcohol, and caffeine frequently cause or exacerbate sleep disturbances and should be avoided at night. [15,17] Alcohol does overcome sleep latencies but often results in less restorative sleep with nocturnal awakenings. The negative implications of caffeine and/or ethanol consumption on sleep is common, yet underappreciated. Check for substance abuses and recent discontinuance of ethanol or sedatives to explain insomnia.

Other Factors

Check for stress factors such as the loss of a loved one, divorce, a job problem, or family or health concerns. [1,14,18] Always consider depression, anxiety, and stress-related disorders. [5,14,18,19] Pain can be a factor. Patients sometimes may be unaware of their sleep problem, and in such cases, interview a bed partner familiar with the person's habits, complaints, moods, movements, or breathing and snoring. [20] Sleep phase disorders with an aberrant circadian cycle can result in sleep deficiency with alertness difficulties. [7,14,18,19] Table 2 reviews these altered patterns of sleep timing, with suggested phototherapy.

Geriatrics 

Elderly people exhibit insomnia more often than youthful ones and have greater problems when taking pharmaceuticals. Their sleep is characterized by low stress tolerance, with frequent awakenings. They are more prone to troubled sleep from medical, psychiatric, and/or sleep disorders. [8,21,22] Comorbidity increases risk for polypharmacy drug interactions. [23] Aged patients are more susceptible to drug side effects, such as sedation or orthostasis, which results in a higher risk for injury from falling. [5,24] Readily predictable insomnias also occur more frequently (eg, before hospitalizations or during a painful illness) [15,20]

Sleep Center Referral

Insomnia is subjective, [17,25] yet doctor-patient communication can provide clues to diagnosing a primary sleep disorder (eg, apneic spells associated with loud snoring). Referral to a sleep disorder center is considered when a causative factor for long-tern insomnia cannot be identified, when therapy is not effective, or' when primary sleep disorders are suspected. [20] Such centers evaluate people in a controlled environment using such methods as polysomnography. [26]

MANAGEMENT OF INSOMNIA

Insomnia should be addressed to avoid functional impairment. Persistent insomnia might be a precursor to depressive illnesses [27-29] and to psychophysiologic insomnia. [9] Diagnosing sleep disorders has important treatment implications. Hypnotic medications may worsen conditions such as sleep apneas, and symptomatic therapies without management of the actual cause of an insomnia may be countertherapeutic.

Short-term insomnia due to stress can be interrupted by a short course of hypnotics. [30] Such agents might be helpful in brief exposures, during bereavements, hospitalizations, and other acutely disturbing events. [20] In more chronic cases, sparingly prescribe symptomatic medicines after treatment of the specific cause of the insomnia. Life-style adjustment in conjunction with drug treatment is advised. Monitor patients, especially for dependence, and do not provide prolonged, multiple refills without clinical observation; provide careful follow-up to assess the pattern of use, efficacy, and possible abuse. [26] There are also people under medical supervision who take sleeping pills for prolonged periods without complications or misuse.

NONPHARMACOLOGIC THERAPIES

Table 3 lists some sleep-enhancing behavioral techniques, exercises, life-style adjustments, and environmental recommendations. [10,31,32] These entail changing personal habits, such as setting a regular sleep schedule and avoiding nocturnal caffeine or alcohol. Such measures can effectively improve sleep. Pharmaceuticals alone may not resolve the problem and thus may enhance the development of tolerance and dependence on sleep medication. [5,7]

GUIDELINES FOR SEDATION

Prescribing

When a medicinal strategy is chosen, consider potential side effects, interactions, underlying conditions, and drug dependency risk factors. Sedative prescribing includes precautions for decreased alertness or impaired psychomotor function. Although food in the stomach generally slows drug absorption times, most of these medicines are not significantly affected by taking them with meals. Short-term use of the lowest effective dose should be used to minimize side effects, rebound insomnia, tolerance, and habituation. [9,26] Rebound insomnia refers to problems with sleep induced by abrupt discontinuance of long-term sedative administrations; intermittent use and dosage tapering minimize discontinuance difficulties. [1] A trial period without medication is advised periodically for anyone taking them for long periods.

Selection

Choosing from among the wide array of available medicines depends on the pharmacokinetic properties of the agent and the specific needs of the patient (eg, life-style or interacting drugs). Co-prescribing medications with sedative properties or concurrent use of alcohol will result in additive, synergistic effects; however, in practical clinical use, there are few other drug-to-drug interactions of significance, with the exception of aiprazolam and triazolam, which are increased in concentration by cytochrome P-450 3A 3/4 enzyme inhibitors (eg, erythromycin or ketoconazole). Sedatives should be avoided in people prone to substance abuse, because of a risk for addiction. [5,7] Use of such agents in this population may be more acceptable during hospitalization for an acute illness than in outpatient applications. Patients with respiratory disorders, such as chronic obstructive pulmonary disease (COPD), should not receive medicinals that cause respiratory depression [25,30,33,34] Firemen, ambulance workers, and others who must be rapidly awakened and alert early or unpredictably should not use sleep-enhancing drugs:

Dosage

Consider age when choosing among pharmaceuticals. [29] In older patients, only half the usual adult dose is initially prescribed. [20,26] More care must be taken when prescribing to persons with renal or hepatic insufficiency. Decreased clearance of drugs and their metabolites may lead to accumulation, sedation, and/or cognitive impairment. [30,34] Appropriate dosing diminishes unwanted effects.

PHARMACOTHERAPY 

Benzodiazepines

The most common therapy for insomnias has been the benzodiazepines, especially those of short to intermediate half-life. Binding of these drugs to [gamma]-aminobutyric acid (GABA) receptors in the brain results in stimulatory effects on GABAergic transmission and hyperpolarization of neuronal membranes. [14,33] Benzodiazepines have sedative, anxiolytic, myorelaxant, and anticonvulsant properties. [33] Extensively prescribed since their introduction in the 1960s, they have a good efficacy record, have few side effects, and are safe even upon overdose. [34] There is risk for habituation, tolerance, addiction, and withdrawal. [17,33] Benzodiazepines enhance sleep duration and reduce arousals. [35] Exposure increases stage 2 sleep while decreasing REM and stages 3 and 4 sleep. [33,35,36]

Side effects are dose-dependent and vary according to the pharmacokinetics of each benzodiazepine. [5] They are usually recommended for short-term use only; this standard of care minimizes dependency. Many clinicians, however, have vast experience with reliable patients who responsibly use these drugs for years without abuses, while maintaining efficacy. Clinical discretion is required; monitoring should continue during all prescribing. The various benzodiazepines are similar in action but differ according to onset and duration. Table 4 outlines these parameters. The following are examples of commonly used compounds from each class.

Short Half-Life. Triazolam is the most rapidly acting and cleared of the oral benzodiazepines. [37] It is best indicated for sleep onset problems, common during high anxiety states, and for insomnias in younger individuals. [38] Shorter-acting benzodiazepines are well suited to active persons and the elderly, since they are readily eliminated and have minimal next-day sedation. [9,23,24] Major side effects of short-acting benzodiazepines include rebound insomnia, amnesia, and intoxication, which can occur even after brief exposure. [5] Triazolam is best used only for short durations because tolerance and addiction can easily develop with prolonged use. [5,35]

Intermediate Half-Life. Temazepam is a frequently prescribed benzodiazepine with a duration of action in the intermediate range and a slower rate of absorption than triazolam. Temazepam is less effective for inducing sleep and more indicated for sleep maintenance and decreasing nocturnal awakenings. [22] It is well tolerated by most geriatric patients, [20,22] but rebound insomnia and significant next-day sedation may follow temazepam administration. [39] With appropriate dosing and when taken only at 24-hour intervals, these effects and the risk of addiction can be minimized. [40]

Long Half-Life. Flurazepam exemplifies long-acting benzodiazepines and has a duration of several days. It is best indicated for people with insomnia plus concomitant daytime anxiety. [25,41] Flurazepam and its metabolites require days for elimination. Accumulation of active metabolites is most problematic in elderly patients or in those with impaired liver function. [15] Next-day sedative effects is a major concern, especially in older people and anyone who needs full daytime alertness. [7,34,41] Rebound insomnia is minimal, but it can occur after prolonged periods at high doses. [35] It is less highly associated with risk for addiction.

Zolpidem

Zolpidem is a safe new drug with a short half-life (Table 5). [37] It exhibits hypnotic effects with less significant myorelaxant, anticonvulsant, and anxiolytic properties than benzodiazepines. [25,30,42] This selective sedative action is thought to be mediated by its affinity for the GABA benzodiazepine-1 receptor. [25,33,43] Abuse remains, nevertheless, a theoretical concern.

The safety and efficacy of zolpidem for insomnia have been proven similar to those of short-acting benzodiazepines, [44.48] with less daytime sedation. [36] It is effective for reducing sleep latency and nocturnal awakenings and increasing total sleep time. [44,47,49] Rebound effects upon withdrawal and tolerance, even with prolonged use, are minimal. [36,45,49,50] As with other sedative medications, treatment optimally should not exceed 4 weeks, to minimize the risk of habituation. [34] Patient selection and monitoring by the physician are important safety factors, but again some physician experiences indicate longer usages without problems. Zolpidem is less disruptive of sleep stages than benzodiazepines. [14,49.51] The incidence of adverse events is low when adhering to recommended dosing. [50] The most commonly encountered side effects include drowsiness, dizziness, and headache.

Zaleplon

Zaleplon recently was approved for the treatment of short-term insomnia. It also interacts with the GABA-receptor complex, with selective binding. [52] Zaleplon has a rapid onset of action and ultra brief duration, with a short elimination half-life. [52-53] It is effective for decreasing time to sleep onset but not for reducing nighttime awakenings or increasing total sleep time. [52-56] With this profile, zaleplon may be used as a sleep aid for middle-of-the night awakenings, if there still are a few hours of bedtime remaining.

No next-day sedation or rebound insomnia is documented with zaleplon at recommended doses. [52,54,55] There is concern about dependence, but insufficient data; however, development of tolerance does not appear to be significant. [53,57] Use over a few weeks at a time is discouraged; drug dependency risk is a theoretical possibility. This medication is well tolerated, but adverse effects include headache, dizziness, somnolence, and nausea. [55] There are two drug interactions of note: zaleplon plasma levels are increased when combined with cimetidine and are decreased with rifampin. [57] With limited time since its introduction, the true safety and benefits of zaleplon are yet to be determined.

Gabapen tin

Gabapentin is a relatively new anticonvulsant and mood stabilizer drug that can be safely and successfully used in pain management and to treat insomnia. Although structurally related to the neurotransmitter GABA, this pharmaceutical does not interact with GABA receptors. The mechanism of its action is unknown.

Gabapentin is eliminated unchanged from systemic circulation by renal excretion. The half-life at 5 to 7 hours is almost unaltered by dose or multiple administrations. Because gabapentin is not metabolized in the liver, it is safe even in patients with hepatic impairment. There is little indication for drug-to-drug interactions. This medicine is well tolerated and has few side effects. The most commonly observed adversities include mild degrees of somnolence, dizziness, ataxia, fatigue, and nystagmus. Abuse or dependence on gabapentin has not been reported; this factor is an important advantage, especially when treating insomnia in people with substance misuse histories.

Antidepressant Drugs

Antidepressant agents are the primary pharmacotherapy for depression; they also are prescribed for pain, and sedating versions are advised for treating insomnia in patients with substance abuse risk factors. Using these drugs for sleeplessness without depression is common but not well studied. [7,34] Sedating antidepressants are not habituating and thus may be especially advantageous for extended treatment durations or for use in former alcoholics and other substance abusers. [7,35]

Tricyclic Antidepressants (TCAs). Sedating tricyclics such as amitriptyline, doxepin, and nortriptyline are effective, for inducing sleep and improving sleep continuity. [58,59] Daytime sedation can be significant. [7] Side effects include anticholinergic activity, adrenergic blockade, and cardiac conduction prolongations--all potentially problematic in geriatric patients and in overdose toxicities. [15,60] The TCAs can alter sleep architecture by reducing REM sleep. [59] Not all TCAs offer prominent sedation; desipramine causes little somnolence.

Trazodone. This drug is strongly sedating and improves sleep continuity. [58,59] Addiction or tolerance is not a problem. [20] Trazodone is popular for insomnia management, especially in persons prone to substance abuse. Side effects of trazodone include oversedation and [alpha]adrenergic blockade. Anti-adrenergic effects with orthostatic hypotension can occur in young people but are more dangerous in elderly patients who are susceptible to injury from falling. [20,60] Postural blood pressure drop is the main risk of this pharmaceutical; priapism is an unlikely possibility.

New Generation Antidepressants. Some selective serotonin reuptake inhibitors (especially paroxetine) are prominently soporific, while others are not and may even cause insomnia (eg, fluoxetine, sertraline, etc). The same applies to other new generation antidepressants; certain ones are sedating (eg, mirtazapine) while others are alerting (eg, bupropion). Sedating versions may be effective even in nondepressed patients, and they are recommended for depression with sleep problems. The presence or degree of sedating or alerting effects from antidepressant drugs varies widely in individual expression. Without dependency problems, these drugs are useful' in substance abuse cases. They are safe medications, even in overdoses, and are among the most frequently prescribed pharmaceuticals.

Antihistamines 

Antihistamines are included in many over-the-counter sleep products. They exhibit sedating properties and are effective for mild insomnia. [5,7,14] They are generally safe and popular, especially in lay usage. Psychomotor impairment with sedation and anticholinergic manifestations are common adverse effects. [7,15,61] Next-day sedation may be a problem, especially in older people. Tolerance may develop with repeated diphenhydramine use. [61,62] Physician prescribing of antihistamines is becoming less frequent with the entry of new, shorter action drugs.

Others

Melatonin is not well studied, yet it may have utility in circadian rhythm-based sleep disorders. Barbiturates are not recommended because of their low therapeutic index, enzyme-induction, and addiction risks.

SUMMARY

Insomnia is common. Recognizing the specific etiology is important. [63] Transient and short-term insomnias are generally the result of stress and are evident in the history. These insomnias may resolve on their own or with life-style changes; however, when rapid relief is indicated, or if the sleep disturbance persists and is recurrent, a medication may help to restore normal sleep. Treatment is brief and dosage conservative (Table 6).

Long-term insomnias may be a symptom of a medical, psychiatric, or primary sleep disorder. The evaluation focuses on causation. In considering therapeutic options, the priority should be treating the cause of the underlying condition that disturbs sleep rather than prescribing symptomatic pharmacotherapy; apply the appropriate, specific intervention for prostatic hypertrophy or congestive heart failure rather than just "sleeping pills." Antidepressant drugs are prescribed for depression. Sleep habit changes are recommended. Intermittent pharmacotherapy is an option for the patient with long-term insomnia, once other conditions are addressed. Long-term use is discouraged but may be acceptable and is widely practiced under physician observation. Elderly patients require lower dosages. The drugs of choice for symptomatic treatment of insomnia are shorter acting benzodiazepines, zolpidem, zaleplon, gabapentin, and sedating antidepressant medicines. Treatment of patients at risk for substance abuse focuses primari ly on antidepressants, gabapentin, and possibly antihistamines.

From the Department of Psychiatry and Behavioral Medicine, University of Louisville School of Medicine, Louisville, Ky.

References

(1.) Gillin JC: Relief from situational insomnia: pharmacologic and other options. Postgrad Med 1992; 92:157-160

(2.) The Gallup Organization: Sleep in America: A National Survey of U.S. Adults. washington, DC National Sleep Foundation, 1995

(3.) Hajak G, Bandelow B: Safety and tolerance of zolpidem in the treatment of disturbed sleep: a post-marketing surveillance of 16,944 cases. Int Clin Psychopharmacol 1998; 13:157-167

(4.) Radecki SE, Brunton SA: Management of insomnia in office-based practice: national prevalence and therapeutic patterns. Arch Earn Med 1993; 2:1129-1134

(5.) Gillin JC, Byerley WF: The diagnosis and management of insomnia. N Engl J Med 1990; 322:239-248

(6.) Roehrs T, Zorick F, Roth T: Transient and short-term insomnia. Principles and Practice of Sleep Medicine. Kryger MH, Roth T, Dement WC (eds). Philadelphia, WB Saunders Co, 2nd Ed, 1994, pp 486-493

(7.) Hauri PJ: Insomnia. Clin Chest Med 1998; 19:157-168

(8.) Drugs and insomnia: the use of medications to promote sleep. JAMA 1984; 251:2410-2414

(9.) Walsh JK, Fillingim JM: Role of hypnotic drugs in general practice. Am J Med 1990; 88:345-385

(10.) Bootzin RR, Perlis ML: Nonpharmacologic treatments of insomnia. J Clin Psychiatry 1992; 53:37-41

(11.) Buysse DJ, Reynolds CF III: Insomnia. Handlook of Sleep Disorders. Thorpy MJ (ed). New York, Marcel Dekker Inc, 1990, pp 375-432

(12.) Dinner DS, Erman MK, Roth T: Help for geriatric sleep problems. Patient Care 1992; 26:166-187

(13.) Cooper R: The classification of sleep disorders. Sleep. Cooper R (ed). London, Chapman and Hall, 1994, p 269

(14.) Hartmann PM: Drug treatment of insomnia: indications and newer agents. Am Fam Physician 1995; 51:191-194

(15.) Becker PM, Jamieson AO, Brown WD: Insomnia: use of a 'decision tree' to assess and treat. Postgrad Med 1993; 93:66-85

(16.) Ancoli-Israel S: All I Want Is a Good Night's Sleep. St. Louis, Mosby-Year Book Inc., 1996, p 116

(17.) Brunton SA: when your patient can't sleep. Fam Prac Recertif 1992; 14:149-170

(18.) Rakel RE: Insomnia: concerns of the family physician. J Fam Pract 1993; 36:551-558

(19.) Ball EM: Sleep disorders in primary care. Comp Ther 1997; 23:25-30

(20.) Pary R, Tobias CR, Webb WK, et al: Treatment of insomnia: getting to the root of sleeping problems. Postgrad Med 1996; 100:195-210

(21.) Mosier WA, Nelson AS, walgren KD: wanted: a good night's sleep. Adv Nurse Pract 1998; 6:30-35

(22.) Nakra BRS, Grossberg GT, Peck B: Insomnia in the elderly. Am Fam Physician 1991; 43:477-483

(23.) Regestein QR: Treatment of insomnia in the elderly. Clinical Geriatric Psychopharmacology. Salzman C (ed). New York, McGraw Hill, 1984, pp 149-170

(24.) Roth T, Roehrs TA: A review of the safety profiles of benzodiazepine hypnotics. J Clin Psychiatry 1991; 52(suppl 9):38-41

(25.) Wagner J, Wagner ML, Hening W: Beyond benzodiazepines: alternative pharmacological agents for the treatment of insomnia. Ann Pharmacother 1998; 32:680-691

(26.) Gillin JC, Ancoli-Israel S, Erman M: Sleep and sleep-wake disorders. Psychiatry. Tasman A, Kay J, Lieberman JA (eds). Philadelphia, WB Saunders Co, 2nd Ed, 1996, pp 1217-1248

(27.) Ford DE, Kamerow DB: Epidemiologic study of sleep disturbances and psychiatric disorders: an opportunity for prevention? JAMA 1989; 262:1479-1484

(28.) Eaton WE, Badawi M, Melton B: Prodromes and precursors: epidemiologic data for primary prevention of disorders with slow onset. Am J Psychiatry 1995; 152:967-972

(29.) Keck PE: Insomnia in anxiety and depression: differential diagnosis and treatment options. Modern Med 1992; 60:79-86

(30.) Lahmeyer HW: Insomnia: how to help patients get a good night's sleep. Consultant 1995, pp 108-111

(31.) Czeisler CA, Johnson MP, Duffy JF, et al: Exposure to bright light and darkness to treat physiologic maladaption to night work. N Engl J Med 1990; 322:1253-1259

(32.) Guilleminault C, Clerk A, Black J, et al: Nondrug treatment trials in psychophysiologic insomnia. Arch Intern Med 1995; 55:838-844

(33.) Dingemanse J: Pharmacotherapy of insomnia: practice and prospects. Pharm World Sci 1995; 17:67-75

(34.) Kupfer DJ, Reynolds CF III: Management of insomnia. N Engl J Med 1997; 336:341-346

(35.) Tsoi WF: Insomnia: drug treatment. Ann Acad Med 1991; 20:269-272

(36.) Parrino L, Terzano MG: Polysomnographic effects of hypnotic drugs: a review. Psychopharmacol 1996; 126:1-16

(37.) Physicians' Desk Reference. Montvale, NJ, Medical Economics Co, 1999

(38.) Hoehns JD, Perry PJ: Zolpidem: a nonbenzodiazepine hypnotic for treatment of insomnia. Clin Pharm 1993; 12:814-828

(39.) Heel RC, Brogden RN, Speight TM, et al: Temazepam: a review of its pharmacological properties and therapeutic efficacy as a hypnotic. Drugs 1981; 21:321-340

(40.) Wheatley D: Prescribing short-acting hypnosedatives: current recommendations from a safety perspective. Drug Safety 1992; 7:106-115

(41.) Morin CM, Kwentus JA: Behavioral and pharmacological treatments for insomnia. Ann Behav Med 1988; 10:91-100

(42.) Mendelson WB, Jam B: An assessment of short-acting hypnotics. Drug Safety 1995; 13:257-270

(43.) Zolpidem--a hypnotic with a difference? Drug Ther Bull 1995; 33:37-39

(44.) Dockhorn RJ, Dockhorn DW: Zolpidem in the treatment of short-term insomnia: a randomized, double-blind, placebo-controlled clinical trial. Clin Neuropharmacol 1996; 19:333-340

(45.) Monti JM, Attali P, Monti D, et al: Zolpidem and rebound Insomnia--a double blind, controlled, polysomnographic study in chronic insomniac patients. Pharmacopsychiatry 1994; 27:166-175

(46.) Monti JM, Monti D, Estevez F, et al: Sleep in patients with chronic primary insomnia during long-term zolpidem administration and after its withdrawal. Int Clin Psychopharmacol 1996; 11:255-263

(47.) Roth T, Roehrs T, Vogel C: Zolpidem in the treatment of transient insomnia: a double-blind, randomized comparison with placebo. Sleep 1995; 18:246-251

(48.) Maarrek L, Cramer P, Attali P, et al: The safety and efficacy of zolpidem in insomniac patients: a long-term study in general practice. J Int Med Res 1992; 20:162-170

(49.) Scharf MB, Roth T, Vogel GW, et al: A multicenter, placebocontrolled study evaluating zolpidem in the treatment of chronic insomnia. J Clin Psychiatry 1994; 55:192-199

(50.) Allain H, Monti J: General safety profile of zolpidem: safety in elderly, overdose and rebound effects. Eur Psychiatry 1997; 12(suppl 1):21S-29S

(51.) Besset A, Tafti M, Villemin E, et al: Effects of zolpidem on the architecture and cyclical structure of sleep in poor sleepers. Drugs Exp Clin Res 1995; 21:161-169

(52.) Beer B, leni J, Wu WH, et al: A placebo-controlled evaluation of single, escalating doses of CL 284,846, a non-benzodiazepine hypnotic. J Clin Pharmacol 1994; 34:335-344

(53.) Sakamoto T, Uchimura N, Mukai M, et al: Efficacy of L-846 in patients with insomnia: evaluation by polysomnography. Psychiatr Clin Neurosci 1998; 52:156-157

(54.) Elie R, Ruther E, Farr I, et al: Sleep latency is shortened during 4 weeks of treatment with zaleplon, a novel nonbenzodiazepine hypnotic. J Clin Psychiatry 1999; 60:536-544

(55.) Walsh JK, Fry J, Erwin CW, et al: Efficacy and tolerability of 14-day administration of zaleplon 5 mg and 10 mg for the treatment of primary insomnia. Clin Drug Invest 1998; 16:347-354

(56.) Roth T, Roehrs TA, Fortier J, et al: Dose response effects of a new hypnotic in insomniacs, Sleep Res 1995; 24:53

(57.) Sonata (zaleplon) prescribing information. Wyeth-Ayerst Laboratories, 1999

(58.) Sharpley AL, Gowen PJ: Effect of pharmacological treatments on the sleep of depressed patients. Biol Psychiatry 1995; 37:85-98

(59.) Winokur A, Reynolds CF: The effects of antidepressants on sleep physiology. Prim Psychiatry 1994; 1:22-27

(60.) McElroy SL, Keck PE, Friedman LM: Minimizing and managing antidepressant side effects. J Clin Psychiatry 1995; 56:49-55

(61.) McEvoy GK (ed). Antihistamine drugs. AHFS Drug Information 95. Bethesda, American Society of Hospital Pharmacists, 1995

(62.) Crismon ML, Jermain DM: Sleep aid and stimulant products. Handbook of Non-prescription Drugs. 10th Ed, 1996, pp 135-146

(63.) Chessor A: Practice parameters for the evaluation of chronic insomnias. Sleep 2000; 22:237-241

TABLE 1

Types of Insomnia


Pattern        Duration     Causative Groupings

Transient      A few days   Acute illness or social stress,
                            jet lag, work shift changes
Short-term     A few weeks  Grief, stress, substance or
                            medicinal exposures
Chronic        Long-term    Medical illnesses (eg, COPD)
                            Psychiatric conditions (eg,
                            depression)
                            Psychophysiologic insomnia
                            Chronic stress, bereavement
                            Behavioral reasons (eg, caffeine)
Primary sleep  Long-term    Sleep apneas (central or
disorders                   obstructive) [*]
                            Periodic limb movement
                            disorder [+]
                            Restless legs syndrome [**]
                            Narcolepsy [++]



(*)Sleep apnea: Transient periods of breathing cessation during sleep.
Two primary types exist: Central sleep apnea results from failure of
stimulation by the respiratory centers in the medulla. Obstructive sleep
apnea is caused by collapse or obstruction of the airway due to the
inhibition of muscle tone during REM sleep.

(+)Periodic limb movement disorder: Repetitive leg-jerking movements
during sleep, 2 to 3 times per minute, with awakening periods.

(**)Restless leg syndrome: An uncomfortable sensation in the leg
musculature causing changes of position during sleep, with recurrent
arousals.

(++)Narcolepsy: Recurrent, irresistible brief episodes of sleep, often
associated with hypnogogic or hypnopompic hallucinations, and cataplexy.
TABLE 2

Sleep Phase Disorders [6]


  Condition              Clinical Features

Delayed phase [+]   Common in younger people
                    Going to sleep early in the morning
                    Awakening late in the day

Advanced Phase [+]  Common in older people
                    Going to sleep early in the evening
                    Awakening early in the day




  Condition            Bright Light Therapy [*]

Delayed phase [+]   Early morning light exposures
                    7,000-12,000 lux
                    30 minutes daily

Advanced Phase [+]  Late evening light exposures
                    7,000-12,000 lux
                    30 minutes daily



(*)Aim: Correct chronobiologic rhythm to more normal patterns.

(+)May be related to jet lag, shift changes, or endogenous patterns.

TABLE 3. Behavioral Sleep Enhancement Tips. [10,31,32]

* Regular bedtime

* Regular time for arousal

* Avoid naps

* Exercise several times each week (best not at bedtime)

* Participate in relaxing activities (eg, yoga, hobbies, etc)

* No caffeine (coffee, tea, cola) after noon

* No late evening alcohol

* Make bedroom comfortable, quiet, and dark

* Do calm activities before bedtime

* Mask background noise, if needed

* Sleep mask or earplugs, if needed

* Use bed only for sleeping, reading, or sex

* Limit challenging activities in the evening

* Avoid unpleasant tasks in the evening

* Consciously relax your muscles when going to bed

* Read or think about pleasant matters when trying to sleep

* Listening to music or watching television in bed is helpful for some people

* If unable to sleep after 30 minutes, get out of bed and do something calmative.

TABLE 4

Oral Benzodiazepine Comparison [20]


                                 Half-life [*]

Drug                                 Hours            Days

Faster Onset

  Triazolam (Halcion)                 1-5              -
  Clorazepate (Tranxene)               -              1-3
  Diazepam (Valium, Valrelease,        -              1-3
    Zetram)
  Quazepam (Doral)                     -              2-3
  Flurazepam (Dalmane)                 -        2-5 (with active
                                                  metabolites)

Slower Onset

  Oxazepam (Serax)                    3-12             -
  Temazepam (Restoril)                3-20             -
  Alprazolam (Xanax)                  6-20             -
  Lorazepam (Ativan)                 10-20             -
  Estazolam (ProSom)                   -             1/2-1
  Clonazepam (Klonopin)                -             3/4-2
  Chlordiazepoxide (Librium,           -              1-3
    Mitran)
  Halazepam (Paxipam)                  -               3+
  Prazepam (Centrax)                   -               3+



(*)The time involved for one half of an administered drug to be lost via
metabolism and/or excretion.
TABLE 5

Other Sleep-Inducing Medications


                                 Half-life [*]

Drug                                 Hours       Days

Zolpidem (Ambien)                    2 - 3        -
Zaleplon (Sonata)                      1          -
Gabapentin (Neurontin)               5 - 7        -
Sedating version tricyclic
antidepressants [*]                    -        1/3 -2
Trazodone (also an
antidepressant) (Desyrel)            5 - 9        -
Sedating version new generation                 1 - 10
antidepressants [+]                    -          -
Diphenhydramine (Benadryl)          3 - 12        -
Hydroxyzine (Atarax, Vistaril)         3          -
Doxylamine (Unisom)                   10          -



(*)Half-lives highly variable between specific drugs in this class: eg,
doxepine (Sinequam) = 8 hours; amitriptyline (Elavil, Endep) = 1 day;
nortirptyline, (Aventyl, Pamelor) = 1 day.

(+)Half-lives extremely variable between specific drugs in this class:
eg, paroxetine (Paxil) = 1 day; mirtazapine (Remeron) = 1-2 days.
TABLE 6

Dosage for Commonly Prescribed Sleep Medications


Drug                                Hypnotic Use Only

Benzodiazepines

  Triazolam (Halcion)                  0.125-0.5 mg
  Oxazepam (Serax)                        10-30 mg
  Temazepam (Restoril)                   7.5-30 mg
  Alprazolam (Xanax)                    0.25-2 mg
  Lorazepam (Ativan)                     0.5-2 mg

Antidepressants

  Amitriptyline (Elavil, Endep)           25-100 mg
  Nortriptyline (Aventyl, Damelor)        25-50 mg
  Paroxetin (Paxil)                         20 mg
  Mirtazapine (Remeron)                     15 mg
  Trazodone (Desyrel)                     50-300 mg

Other

  Zolpidem (Ambien)                        5-10 mg
  Zaleplon (Sonata)                        5-10 mg
  Gabapentin (Neurontin)                 300-800 mg
  Diphenhydramine (Benadryl)              25-100 mg
  Hydroxyzine (Atarax, Vistaril)          25-100 mg

KEY POINTS

Insomnias are common and have specific causes:

* Seek to diagnose the exact cause of problems with sleep (eg, congestive heart failure, depression, sleep apnea, etc).

* Avoiding alcohol and caffeine at night is helpful.

* Treat all conditions that might impair sleep.

* Use symptomatic pharmacotherapy for insomnia sparingly, after addressing the previous factors, and individualize medicinal choice to patient characteristics.

* Avoid prescribing sedatives in patients prone to substance abuse; rather, select sedating antidepressants, gabapentin, and possibly antihistamines.