CONTINUING EDUCATION

Published through an educational grant from WYETH-AYERST LABORATORIES
TRENDS IN PHARMACY AND PHARMACEUTICAL CARE

An ongoing CE program of The University of Mississippi School of Pharmacy and DRUG TOPICS

The University of Mississippi School of Pharmacy is approved by the American Council on Pharmaceutical Education as a provider of continuing pharmaceutical education. Accredited in every state requiring CE. ACPE # 032-999-02-020-H01

This lesson is no longer valid for CE credit after 10/31/04.

CREDIT:

This lesson provides two hours of CE credit and requires a passing grade of 70%.

OBJECTIVES:

Upon completion of this article, the pharmacist should be able to:

• Recognize various lifestyles, disease states, or conditions that may contribute to insomnia
• Discuss the pharmacologic basis for drug therapy of insomnia and identify potential drug interactions and adverse reactions associated with those drugs
• Recognize and counsel patients on nonpharmacologic therapies, including their goals, means of accomplishing those goals, and the potential benefit of their use in the treatment of insomnia
• Formulate an appropriate insomnia treatment regimen based on individual patients and their lifestyle, type of insomnia, and medical history

GOAL:

To review the pathophysiology, etiology, incidence, pharmacologic and nonpharmacologic treatments, and potential consequences of insomnia

Review of prescription therapy for insomnia

By Scott F. Long, R.Ph., Ph.D., Assistant Professor of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, School of Pharmacy, Southwestern Oklahoma State University

Through the suburbs sleepless people stagger, as though delivered from a shipwreck of blood.

Frederico García Lorca,
"The Dawn" (1940)
Poet in New York

Epidemiology

The most recent epidemiological surveys indicate that approximately one-third of the population suffers from occasional difficulty in sleeping. Moreover, it is estimated that some 35 million Americans suffer from chronic insomnia. Insomnia tends to be worse in women, and sleep difficulties increase with age in both genders. However, these generalizations must be qualified, since patient perception of sleep is often skewed. Typically, patients overestimate the time that is required for onset of sleep and underestimate the number of nighttime awakenings, as compared with polysomnographic assessment of sleep behavior.

Patients often perceive their problems with sleeping as falling into one of three classes: (1) trouble falling asleep, (2) frequent awakenings after falling asleep, or (3) early awakening with an inability to resume sleep. These subjective perceptions are important in choosing appropriate therapy. The more clinical definitions of insomnia must also be considered in choosing the most appropriate therapy. Sleep-study units across the nation typically define three types of insomnia. Transient insomnia is the inability to sleep well over a relatively short period (i.e., less than one week). This is most often attributed to external factors, such as personal confrontations, anticipation of a trip or event, or inappropriate nighttime exercising or meals, and is often due to stress or excitement. Short-term insomnia, resulting from prolonged periods of stress, may last for two to three weeks. As is the case with transient insomnia, once the stressful situation has passed, sleep generally returns to that patient's normal pattern.

Chronic insomnia is more dangerous to the patient since it may last for months, and the subsequent sleep deprivation and lack of restorative sleep may lead to other health consequences. Chronic insomnia may result from other chronic diseases or prolonged stress, or it may arise from some unknown factor.

Additionally, some sleep experts classify insomnia as either acute or chronic and as either primary or secondary. Either acute or chronic insomnia may be secondary to some other causative situation. Acute or transient insomnia often results from sudden changes in daily routine or a sudden stress in the life of the patient. Examples of these may include sudden shifts in time zone (i.e., jet lag); personal conflicts (such as spousal/marital difficulties, financial worries, a death in the family); and abnormal eating, drinking, or exercise behaviors.

Chronic insomnia may be secondary to a diagnosable psychiatric disease, such as depression or psychosis, or to substance abuse and addiction (including both alcohol and nicotine). Additionally, certain habits such as large evening meals (especially within two to four hours of bedtime), evening exercise within the same time frame, or excessive television watching or reading in bed immediately prior to sleep may cause sleep difficulties. Either transient or chronic insomnia may also be secondary to a preexisting medical condition, such as arthritis, peptic ulcer disease, cardiovascular disease, any of the chronic obstructive pulmonary diseases, numerous psychiatric conditions (e.g., OCD, depression, anxiety and panic disorders), and sleep apnea.

Drug therapy may also be a major cause of secondary insomnia, with many drug classes possessing the ability to interfere with sleep. This list includes, but is certainly not limited to, any central nervous system stimulant (including over-the-counter decongestants and caffeine), diuretics (by increased need to void during the night), corticosteroids, antihypertensives, and antidepressants. Both selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants may disturb normal sleep patterns. Many of the drugs that alter sleep may do so while possessing sedation as a major side effect (e.g., antihistaminics and anticholinergics). This is often attributed to their ability to interfere with the sleep cycle, reducing stage 3 and 4 sleep and, therefore, causing a loss of "restful" or restorative sleep.

Primary insomnia is reportedly less common than secondary cases of sleep disorders. The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), classifies primary insomnia as difficulty falling or maintaining sleep or unrestful sleep that persists for at least one month and is not attributable to any exogenous factors, as described above. Primary insomnia may be due to individual variations in circadian rhythm, and/or associated with deviations from normal serotonergic, GABAergic, cholinergic, adrenergic, histaminergic, and dopaminergic activity. This reflects the still poorly understood role that light/dark cycles, the optic nerve, and endogenous chemicals such as the neurotransmitters noted above, as well as melatonin and neurosteroids, play in determining sleep and wakefulness.

Patients suffering from insomnia will often report feeling sleepy in the morning with continued sleepiness during the day. They also complain of fatigue throughout the day and a consistent feeling of grogginess in the morning. Additionally, they often demonstrate high levels of anxiety in the evening with accompanying autonomic discharge that may manifest as tachycardia, tachypnea, increased muscle tone, and hypertension. This may worsen as bedtime approaches. Most sleep experts agree that this is a learned behavior, with patients becoming more anxious as they approach the time when they feel they will be unable to fall asleep.

Numerous studies correlate the lack of sleep with poor general health. In addition to the general feeling of not being rested, insomnia may provoke adverse health effects. The literature has long indicated a strong link between insomnia and heart disease. Some studies indicate that chronic sleep loss actually increases mortality rate on a par with smoking and cardiovascular disease. There are also strong correlations between chronic insomnia and the development of psychiatric disorders, including depression, various psychoses, and increased abuse of addictive substances (particularly ethanol). Additionally, chronic fatigue associated with insomnia decreases worker productivity; increases accident rates within the workplace and on the highways; and, therefore, has major societal and economic consequences. Thus, the proper treatment that will achieve the best results for both transient or chronic secondary or primary insomnia is vital not only for the health of the patient but for numerous other beneficial outcomes as well.

The best treatment may depend upon the initial source of the sleeping disturbance. In many cases, treatment of the underlying physical or mental condition may alleviate the sleep disorder. In other cases, lifestyle changes through behavior modification or reconditioning may be more beneficial. (For a more complete discussion of nonpharmacologic therapy of insomnia, the reader is referred to the continuing education article featured in the July 3, 2000, issue of Drug Topics.) Finally, for those cases of primary insomnia, short-term pharmacologic therapy may be the most appropriate choice.

Pharmacologic therapy

There have been many drugs and drug classes used through the years as soporific agents (or drugs used to induce sleep), including ethanol and the older bromide salts. The practice of using a drug compound as both a sleep aid and a mild anxiolytic has been and continues to be common. Introduction of chloral hydrate, paraldehyde, the barbituric acid derivatives, ethchlorvynol, glutethimide, methyprylon, and methaqualone comprised the first major step in the pharmacologic approach to insomnia therapy. Drugs from this group were used as both anxiolytics and sedative-hypnotics, with indications that included the treatment of insomnia.

The benzodiazepines were the second major drug class to be used extensively in the treatment of insomnia. The knowledge acquired through investigations of their pharmacologic actions has led to the newer nonbenzodiazepine sedatives that are currently available.

Additionally, other drug classes, including the OTC antihistaminics, are sometimes used as sleep aids. It should be noted here that clinicians who practice in the area of sleep disorders recommend that most drug therapies be used as short-term treatment options only. The benefit of most of the currently available sedative-hypnotics is seen early in therapy. Continued use may have the paradoxical effect of further interfering with restorative sleep, probably by altering sleep cycles as noted below.

Antihistaminics: The antihistaminic class of drugs, many of which are available OTC, have also been used for the treatment of insomnia. The pharmacologic basis for their ability to induce sleep is related to the role that histamine apparently plays in CNS stimulation and providing wakefulness. Blockade of the H₁ receptor by any agent that can cross the blood brain barrier would, theoretically, block this action, with sedation and sleepiness as the result. Of the class, the two most commonly used agents in the treatment of insomnia are the OTC drugs diphenhydramine and doxylamine. The typical hypnotic doses for diphenhydramine and doxylamine are 50 mg and 25 mg, respectively.

These agents have relatively high levels of anticholinergic action, which may also produce sedation. Therefore, the exact mechanistic action that produces sedation in these compounds is poorly understood. Indeed, the general recommendation is that those antihistaminics with a high degree of cholinergic blockade provide the best sedative effect for the short-term treatment of insomnia.

Side effects associated with the antihistamines include the expected anticholinergic effects of dry mouth, constipation, and dysuria, especially in older men. Decreased mental alertness, sluggishness, and a hangover effect are typical when these agents are used in doses that promote sedation. Additionally, these agents may alter the sleep cycle, decreasing the time spent in stages 3 and 4, thus causing a deficit of restful sleep. This disruption in restorative sleep may contribute, at least in part, to the complaints of sluggishness and daytime sedation observed with the antihistaminics. CNS depression also contributes to the major drug interaction, namely additive effects with other CNS depressants. Pharmacists should be aware and, consequently, warn their patients that doxylamine should not be taken by pregnant or lactating women, due to the risk of teratogenesis and neonatal effects via excretion in breast milk, respectively.

The older prescription drugs: Older drugs that are approved for the treatment of insomnia include acetylcarbromal, ethchlorvynol, glutethimide, chloral hydrate, and paraldehyde. These are seldom used today owing to abuse potential, toxicities, and/or the advent of more efficacious compounds. These agents all act in a manner similar to the barbiturates (see below for a full description of this mechanism). Table 1 provides the normal dosage and pharmacokinetic parameters of these older agents.

Acetylcarbromal is an older drug still available for use but largely replaced by newer, more effective, and safer drugs. It is metabolized by dehalogenation that liberates free bromide ions, which contribute to its toxicity. Signs and symptoms of toxicity include respiratory depression, memory disturbances, conjunctivitis, dermatitis, gastrointestinal upset, and constipation. Since the mechanism of bromism is related to displacement of chloride ions by bromide, treatment generally is limited to normal saline infusion, which will correct the problems associated with hypochloremia. Although not labeled as such, chronic use of acetylcarbromal has been demonstrated to be habit-forming.

Ethchlorvynol is a controlled substance that was formerly widely used as a hypnotic, anticonvulsant, and sedative. It is similar to the barbiturates in its mechanism and scope of action, with acute intoxication resembling that induced by ethanol. It, too, induces hepatic metabolizing systems, thus contributing to numerous drug interactions and potential porphyria. It will also cause an aftereffect or hangover effect on days following use (refer to the barbiturate section for a more detailed discussion of these effects). Additional toxicities associated with ethchlorvynol include pancytopenia that has been fatal in at least one case.

Glutethimide is yet another older drug that is still available. It is virtually indistinguishable from the barbiturates in action, hepatic effects, and toxicity. The primary difference between this drug and the barbiturates is the relatively high degree of anticholinergic activity of glutethimide. This contributes to the additional side effects of dry mouth, constipation, mydriasis, and other typical anticholinergic effects observed with this drug.

Chloral hydrate is metabolized to trichloroethanol by hepatic alcohol dehydrogenase. This active metabolite exerts the same mechanism of action at GABA_A receptors as do the barbiturates described below. It may also cause a hangover effect, although the incidence is less than that seen with the barbiturates. It is irritating and potentially corrosive to mucosal tissues, contributing to the higher incidence of gastric upset that is observed with oral administration. Idiosyncratic reactions, including paranoia, have been observed in some patients taking chloral hydrate. It, too, induces hepatic enzymes. Toxicities associated with chloral hydrate overdose include hepatotoxicity characterized by jaundice, nephrotoxicity, and arrhythmias.

The final older treatment, paraldehyde, is also a gastric irritant. It produces a nonspecific, generalized, CNS depressant effect. Special considerations for paraldehyde (apart from the CNS depression and addiction liability) include its contraindication in bronchopulmonary disease—since a route of elimination for the drug is the lungs—and its drug interaction with disulfiram, which inhibits the metabolism of paraldehyde by inhibiting the enzyme aldehyde dehydrogenase. Overdoses of paraldehyde may cause severe acidosis in addition to acute gastritis, pulmonary hemorrhage, and profound CNS depression. Death has occurred following ingestion of as little as 25 ml of paraldehyde.

Barbiturates and other drugs: Mechanistically, the barbiturates enhance GABAergic neurotransmission to decrease neuronal activity within the CNS. Additionally, these drugs have been demonstrated to reduce excitatory neurotransmission by inhibiting glutamate-mediated stimulation of the CNS. Specifically, the barbiturates enhance the actions of the GABA_A receptor.

The inhibitory amino acid neurotransmitter aminobutyric acid (GABA) contributes to numerous functions of the CNS. It is generally accepted that it predominantly acts to diminish the neurotransmission of other neuronal pathways. The inhibitory action of GABA is most likely due to a GABA receptor-associated chloride channel that, upon activation of the receptor by GABA, enhances chloride influx, thus hyperpolarizing the postsynaptic neuron to diminish neuronal activity. At least two GABA receptors—GABA_A and GABA_B—have been identified.

The barbiturates enhance GABAergic activity by binding to the receptor and increasing the duration of chloride channel activation or opening (as compared with the benzodiazepines that increase the frequency or chloride channel opening). Additionally, at subanesthetic doses, the barbiturates inhibit the firing of AMPA-type (also known as kainate type) glutamate receptors. These receptors are normally excitatory within the CNS. Therefore, their inhibition by a barbiturate would also lead to CNS depression. This dual mechanism is now considered to be the primary explanation of the CNS effects of the barbiturates.

The following four barbiturates have approved indications for the treatment of insomnia: phenobarbital, butabarbital, secobarbital, and pentobarbital. Their pharmacokinetic differences are summarized in Table 2. These pharmacokinetic differences provide the basis for choosing one barbiturate over another, since mechanistically they all work in the same manner. For example, a longer-acting drug such as phenobarbital is desirable if the patient is waking early (to provide effects throughout the night), while a shorter-acting agent such as secobarbital or pentobarbital is preferred if the patient is having trouble falling asleep (to aid in achieving sleep while minimizing aftereffects the next day).

The clinical use of the barbiturates for insomnia is limited by the rapid development of tolerance to their hypnotic effects. In the best-case scenario, the beneficial effects of the barbiturates are evident for about two weeks. Following this period, tolerance develops to the hypnotic actions of the drug, requiring successively higher doses that may produce greater and greater side effects and the potential for barbiturate toxicity. Additionally, the barbiturates, while decreasing sleep latency and number of awakenings, also decrease the time spent in REM and slow-wave sleep. Therefore, although the patient may be sleeping, it is not the restorative sleep that is most beneficial to the patient, thus contributing to further sleep deprivation over time.

The barbiturates are relatively nonselective in their actions and may produce generalized, as well as CNS, depression. Blockade of the paravertebral ganglia may account for the hypotensive effects and decreased intestinal motility observed in some patients. They have the potential to cause profound respiratory and general CNS depression. The therapeutic indices of the barbiturates are relatively narrow, compared with the benzodiazepines and other newer agents. Therefore the potential for life-threatening respiratory depression is greater with these agents than with the newer drugs.

The primary side effect associated with the barbiturates is drowsiness and sedation (in this instance, not a side effect, but the desired therapeutic outcome). True side effects of which patients should be warned or the pharmacist should be aware include the aforementioned effects on blood pressure and the gastrointestinal tract. Other adverse drug reactions include the aftereffects mentioned previously. These may present as slight alterations in mood, poor judgment, and loss of fine motor control. Vertigo, nausea, and even diarrhea have also been reported. Some patients may experience an ethanol-like intoxication accompanied by feelings of euphoria and increased energy. Paradoxical excitation may occur in a few individuals with the barbiturates. This effect, observed more frequently in elderly patients, typically presents again as a mild state of inebriation. Although the barbiturates are often prescribed as adjuncts in pain therapy, they may actually accentuate pain and also cause restlessness, excitation, and delirium in patients experiencing pain. Hyperalgesia is notably evident in psychiatric patients who are prescribed barbiturates specifically for the treatment of insomnia.

The barbiturates are also potent inducers of the hepatic microsomal system. This leads to numerous drug interactions by enhancing the hepatic metabolism of any drug whose primary metabolic pathway is the liver (thus effectively reducing the efficacy of any such drug). This action also increases the synthesis of porphyrins. Therefore, barbiturates are contraindicated in patients with porphyria. Additionally, the barbiturates are classified as pregnancy category D drugs, with known teratogenicity occurring. They also may cause CNS depression in infants through excretion in breast milk. Therefore, extreme caution should be taken with pregnant or lactating women.

Signs and symptoms of acute barbiturate overdose and toxicity include slurred speech, ataxia, and nystagmus. Behavioral changes including poor judgment, confusion, and irritability are also common. Death is most often due to respiratory depression. Moreover, the practitioner will recall that the lethal dose is fixed, despite increases in the dose as tolerance develops.

Additionally, the abuse potential of the barbiturates is relatively greater than that of newer drug classes. This potential, due in part to the tolerance alluded to previously, is likely in patients taking the drugs for prolonged periods of time. Signs and symptoms of barbiturate dependence are similar to those of ethanol and include a desire on the part of the patient to continue taking the drug, increase drug dose, and increase dosing frequency. Withdrawal signs and symptoms initially appear as anxiety, fine motor tremors, weakness, visual disturbances, GI upset, insomnia, and hypotension and may proceed to convulsions and delirium in severe dependence.

This combination of increased toxicity, numerous drug interactions, and high abuse potential has led to the barbiturates being recommended rarely, if at all, in the current treatment regimens.

Benzodiazepines: Five of the drugs that belong to the benzodiazepine class are indicated for use as hypnotics. These are estazolam, flurazepam, quazepam, temazepam, and triazolam. Mechanistically, all are assumed to be acting in a similar manner, although there are slight differences in the pharmacodynamic effects produced by each.

The GABA_A receptor is the specific ligand for the benzodiazepine receptors. It, in turn, has at least two subtypes. One of these subtypes—identified variously as the benzodiazepine-1 (BZ₁) or omega-1 receptor—is believed to play a role in sleep onset and the sleep cycle. The second subtype, BZ₂, may affect learning, memory, sensory, and motor function.

The omega-1 receptor is currently thought to be a pentameric receptor composed of two a, two b, and one g subunits. These are arranged such that they form a channel or pore, which, upon activation by GABA, opens, allowing chloride influx into the neuronal cell. GABA will bind specifically at the junction of the a and b subunits. The modulating site at which the benzodiazepines bind is the junction of a and g subunits. Binding of the receptor with a benzodiazepine appears to enhance GABA binding to its site and, thus, increase chloride influx.

This action modifies the sleep cycle, decreasing the time required to fall asleep as well as altering the time spent in individual sleep cycles. The specific effects may arise from either the decrease in excitatory neurotransmitter activity (possibly noradrenergic) or it could result from some modulation of the cycle itself. The exact sequence of neurochemical events that occur during sleep cycles is not well understood. The specific pharmacodynamic effects of the benzodiazepines on the sleep cycle are known, however. In general, all benzodiazepines will decrease the time required to fall asleep, the number of awakenings after sleep has begun, and the time spent awake.

Some of the class (flurazepam, quazepam, and temazepam) will decrease the period identified as descending drowsiness (stage 1 = that time when the patient begins to feel sleepy but is not yet asleep). While all benzodiazepines will increase stage 2 sleep (initial sleep = the time immediately following loss of consciousness), they will shorten the length of stages 3 and 4 sleep (so-called slow-wave sleep, the deep, restorative sleep that most authorities agree is required for full rest). Additionally, the benzodiazepines will shorten the time spent in REM (rapid eye movement sleep = the time during which vivid dreaming usually occurs, a component that most experts agree is also required since chronic REM deprivation may cause psychiatric symptoms). Finally, all benzodiazepines may increase the total time spent in sleep.

There are some differences in the actions of the various benzodiazepines. Quazepam appears to be slightly more selective in its binding to the omega-1 receptor, while others of the class may bind to either the omega-1 or the BZ₂ receptor. This may be significant not only when considering modulation of GABA but also with potential side effects. The newer, nonbenzodiazepines appear to be even more selective in their action, and this will be discussed more in depth below.

Other differences among the benzodiazepines are primarily pharmacokinetic in nature and are summarized in Table 3. These differences may determine the most appropriate choice for specific patients. For example, in a patient whose primary complaint is difficulty falling asleep, a drug with a rapid onset of action could be the most appropriate choice. For a patient who needs to awaken with minimal hangover effects, a short-acting drug could be preferred. Finally, for a patient whose chief complaint is numerous awakenings or an early awakening with an inability to go back to sleep, a longer-acting drug could be more appropriate.

Numerous side effects have been associated with use of the benzodiazepines. Those occurring in more than 3% of patients include asthenia, hypokinesia, and hangover. The hangover effect is the most common complaint, especially of the longer-acting benzodiazepines. Patients experiencing this will typically report headache, a decreased mental alertness, and a feeling of slowness upon awakening. Continued use of the benzodiazepines has the potential to cause physical dependence. Patients suffering from depression accompanied by insomnia who are treated with a benzodiazepine may experience a worsening of their depression. Patients who have preexisting pulmonary disease or sleep apnea may also experience a worsening of symptoms.

Additional side effects that are of special interest are those that result from the nonspecific binding of most benzodiazepines to both subtypes of the GABA_A receptor. As noted previously, the BZ₂ receptor is thought to play a role in numerous CNS functions. Side effects arising from the inhibition of this receptor may cause movement, sensory, and learning/memory impairment. Amnesia has been noted in patients taking certain benzodiazepines for insomnia. Triazolam has especially been associated with the development of retrograde amnesia as well as behavioral disinhibition and violent actions.

Rapid withdrawal of the benzodiazepines, in addition to causing typical withdrawal symptoms of dysphoria, abdominal cramping, vomiting, diaphoresis, tremor, and potential seizures, may cause rebound insomnia. Therefore, these agents should be discontinued slowly. For longer-acting benzodiazepines, this may be accomplished by tapering the dose down over time. In patients who have taken a short-acting benzodiazepine for more than two weeks, substitution of a longer-acting drug and then tapering its dose (typically over the course of four weeks) may prevent withdrawal symptoms. Clinical evidence also supports the substitution of the newer nonbenzodiazepines, which may then be discontinued following one month of therapy with few withdrawal effects.

The benzodiazepines can increase the toxicity of digoxin, increase or decrease the actions of neuromuscular blocking agents, and increase the toxicity of phenytoin. Other drug interactions include an increase in benzodiazepine activity caused by other CNS depressants, cimetidine, oral contraceptives, disulfiram, isoniazid, and probenecid. The efficacy of the benzodiazepines may be reduced by rifampin, theophylline, and smoking.

Zaleplon and zolpidem: Zaleplon and zolpidem are nonbenzodiazepine hypnotics that act in a manner similar to the benzodiazepines. However, they are more selective for the omega-1 subtype of the GABA_A receptor. This relative selectivity may account for the differences in pharmacodynamic effect observed with either drug. Both agents will increase the amount of time spent in stages 3 and 4 sleep, as compared with the benzodiazepines. Therefore, they will theoretically provide more restful sleep for the patient. Both drugs are also less likely to produce a hangover effect in patients, relative to the benzodiazepines. However this probably arises from the relatively short half-life of both drugs. The major difference between the two drugs appears to be a longer sleep time provided by zolpidem and less rebound insomnia upon withdrawal and fewer memory/psychomotor impairments observed with zaleplon.

The relative selectivity of these drugs also accounts for some of their differences in side effects relative to the benzodiazepines.

Neither drug is as likely to cause memory impairment as the benzodiazepines. Of the two, zaleplon is reported to cause significantly fewer cases of memory impairment. Frequent (greater than 3%) side effects associated with zaleplon include dizziness, nausea, eye pain, abdominal pain, asthenia, headache, and myalgia. Adverse reactions associated with zolpidem include headache, dizziness, GI upset, myalgia, and allergy.

Both drugs may be potentially addictive. However, relative to the benzodiazepines, the abuse potential of zaleplon and zolpidem appears to be less, and discontinuation of therapy produces fewer withdrawal effects. Zaleplon appears to be especially effective in elderly patients, and tolerance does not appear to develop when the drug is administered over time. Additionally, it is indicated for use when patients experience awakenings in mid-sleep.

The primary drug interactions that occur with both zaleplon and zolpidem are additive CNS depression and any drug that may induce (rifampin) or inhibit (cimetidine) the CYP3A4 metabolizing system since this is a major route of metabolism for zolpidem and a minor pathway for zaleplon.

Other drug therapies: The use of low-dose tricyclic antidepressants and mild anxiolytics for the treatment of insomnia in patients who have not been diagnosed with either depression or anxiety has increased in recent years. This approach assumes that the insomnia may be caused by either disease state or that the sedative effect observed with low doses will be enough to provide some relief. The obvious disadvantages of this approach include unneeded drug therapy and unwanted side effects and/or toxicities while not treating the true underlying condition.

Current recommendations for the pharmacologic treatment of various insomnias support the short-term use of the agents discussed above. Although the newer agents may exhibit less tolerance or abuse potential and fewer side effects, they, too, are currently indicated only for short-term treatment. Typically, most clinicians recommend therapy of no longer than seven to 10 days for the treatment of either chronic or transient insomnia. This conservative approach is taken to minimize the potential for physical dependence and the further disturbance of sleep cycles.

Nonpharmacologic therapy

A number of behavioral, educational, and lifestyle approaches have been used successfully in the treatment of insomnia. These may be effective in all types of insomnia and are generally considered to be the treatment of choice in primary chronic insomnia. The potential value of these approaches would be increased sleep not influenced by drugs that may develop tolerance, cause physical dependence, produce unwanted or dangerous side effects and drug interactions, and alter normal sleep cycles.

Different approaches to nonpharmacologic control of insomnia include:

• Stimulus control therapy: associating the bed with sleep or intercourse, but not with reading, watching TV, or other activities, and going to bed only when sleepy, developing a routine sleep and waking pattern, and avoiding daytime naps

• Relaxation therapy and biofeedback: reducing the wakefulness of the patient and causing him or her to feel more relaxed through muscle relaxation, meditation, rhythmic breathing, etc.

• Paradoxical intention: staying awake even longer to eliminate the performance anxiety associated with an inability to fall asleep

• Sleep restriction: an approach that uses the actual amount of time a patient is sleeping and accepting that as the norm for initial therapy

• Cognitive therapy: dispelling misconceptions of sleep requirements

• Sleep hygiene: limited intake of caffeine four to six hours prior to bedtime; limited intake of alcohol during a similar time frame; avoidance of large meals four to six hours prior to bed, although a light snack within the hour before retiring may be beneficial; avoidance of heavy exercise three to four hours prior to sleep, although light exercise earlier than this may improve sleep; minimizing the light and noise levels in the bedroom. These nonpharmacologic therapies have proven beneficial in many patients and may be used in combination to produce a nonpharmacologic synergistic effect. The reader is referred to previous issues of this journal (Drug Topics, July 3, 2000) for a more in-depth discussion of these nonpharmacologic therapies.

The current approach to the treatment of insomnia is to (1) determine the etiology of the disorder if possible, (2) treat any underlying syndromes that may be causing the insomnia (i.e., antidepressant therapy for depression-associated insomnia), (3) make initial use of nonpharmacologic therapies if feasible, and (4) make use of short-term drug therapy if the insomnia is not improving with other approaches.

The 1996 International Consensus Conference on Insomnia recommended that (1) defined diagnostic criteria needed to be established to detect insomnia, (2) survey instruments be developed to assess both patient and caregiver understanding of the insomnia and that these individuals need to be educated, (3) sleep hygiene techniques, an understanding of the prevalence of insomnia, and the social and economic consequences that transcend social and cultural barriers need to be identified, and (4) studies need to be conducted to gain further understanding of insomnia. If these goals are incorporated along with the general treatment strategies into the therapy of insomnia, then pharmacists, nurses, and physicians will be better able to provide valuable treatment options for patients suffering from insomnia.

Conclusion

Prevention and treatment of insomnia presents an area in which pharmacists may integrate their skills in patient assessment, education, and professional interaction. Using the nonpharmacologic approaches presented above, patients may be counseled on lifestyle changes that could improve their sleep patterns and/or prevent insomnia. When drug therapy is required, the pharmacist may make recommendations to patients or other healthcare providers based upon the pharmacist's knowledge of the common agents used as sedative-hypnotics and the patient's drug and medical history.

Acknowledgments – The author would like to thank Ms. Patricia Zbikowski, data analyst/database coordinator for the Sleep and Chronobiology Center, University of Pittsburgh Medical Center, for her assistance in the areas of epidemiology and nonpharmacologic therapies of insomnia.

References are available upon request.

TEST QUESTIONS

Write your answers on the answer form below (photocopies of the answer form are acceptable) or on a separate sheet of paper. Mark the most appropriate answer.

1. The incidence of insomnia is higher in:

a. Men
b. Adolescents
c. The elderly
d. All of the above

2. Chronic insomnia may precipitate:

a. Daytime drowsiness
b. Increased mortality
c. Fatigue
d. All of the above

3. Mechanistically, the benzodiazepines act to enhance neuronal activity mediated by:

a. Noradrenaline
b. GABA
c. Serotonin
d. Histamine

4. Activation of the receptor by the ligand noted in question 3 may cause hyperpolarization of the neurone by:

a. Decreasing sodium influx
b. Increasing chloride influx
c. Increasing potassium efflux
d. None of the above

5. The preferred sleep cycle may be maintained and side effects minimized by drugs that specifically act at the:

a. BZ₂ receptor
b. GABA_B receptor
c. Omega-1 receptor
d. H₁ receptor

6. Based on its pharmacokinetics, which benzodiazepine is most likely to cause hangover effects?

a. Triazolam
b. Temazepam
c. Flurazepam
d. Estazolam

7. Among the benzodiazepines, the one that is especially prone to cause amnesia as a side effect is:

a. Triazolam
b. Quazepam
c. Flurazepam
d. Estazolam

8. A major advantage of zaleplon and zolpidem over the benzodiazepines is their ability to:

a. Decrease time spent in REM sleep
b. Increase time spent in stage 3 and 4 sleep
c. Increase latency time for sleep onset
d. None of the above

9. Which hepatic inducer would have the potential to decrease the efficacy of benzodiazepines as well as zaleplon and zolpidem?

a. Cimetidine
b. Rifampin
c. Digoxin
d. All of the above

10. What is the major drug interaction that may be seen with over-the-counter insomnia medications if taken with OTC antihistaminics or tricyclic antidepressants?

a. Inhibition of metabolism
b. Enhanced metabolism
c. Additive CNS depression
d. None of the above

11. Duration of pharmacologic therapy of insomnia should not exceed:

a. Two to three days
b. Seven to 10 days
c. Two to three weeks
d. Six to eight weeks

12. Bromism is a potential toxicity associated with:

a. Acetylcarbromal
b. Glutethimide
c. Ethchlorvynol
d. Chloral hydrate

13. Pancytopenia has been reported to cause the death of at least one individual taking:

a. Acetylcarbromal
b. Glutethimide
c. Ethchlorvynol
d. Chloral hydrate

14. Which of the following is corrosive to mucosal tissues?

a. Acetylcarbromal
b. Glutethimide
c. Ethchlorvynol
d. Chloral hydrate

15. Acidosis may occur with:

a. Paraldehyde
b. Glutethimide
c. Ethchlorvynol
d. Chloral hydrate

16. Which of the following drugs is most likely to cause anticholinergic-like side effects?

a. Paraldehyde
b. Glutethimide
c. Ethchlorvynol
d. Chloral hydrate

17. The barbiturates are contraindicated, or at least should be used cautiously, in:

a. Porphyria
b. Pregnancy
c. Lactation
d. All of the above

18. Which of the following nonpharmacologic approaches induces mild sleep deprivation in order to enhance sleep quality?

a. Stimulus control
b. Biofeedback
c. Sleep restriction
d. Cognitive therapy

19. Sleep hygiene may help to prevent insomnia by teaching patients:

a. To eat a small snack before retiring
b. To exercise immediately before retiring
c. To take a "night-cap" (ethanol) immediately before retiring
d. All of the above

20. Optimal treatment for insomnia may include which of the following:

a. Proper diagnosis of insomnia and its etiology
b. Nonpharmacologic therapy either alone or in combination
c. Short-term drug therapy
d. All of the above

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