sleep aides and insomnia

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Evaluation of Insomnia and Treatment Strategies

Insomnia may result from many different and sometimes simultaneous causes.

In chronic insomnia, major influences causing sleep disturbance may change

over time.[2] For example, work conflicts or physical discomfort from a

medical problem may initiate an insomnia episode. Insomnia may be

perpetuated by factors such as daytime napping, alcohol use, psychologic

conditioning, and major depression. Effective treatment may require a

combination of therapies; therefore, in reviewing insomnia treatment

approaches, it is useful to consider both specific and general strategies.

Specific insomnia treatment strategies address primarily any identified

underlying medical or other disorders. Major depression may be treated with

an antidepressant; sleep apnea with continuous positive airway pressure; and

pain with analgesics. Clearly, the management of these contributing

conditions must be optimized to improve the sleep disturbance.

The simultaneous use of 1 or more general treatment strategies may be

beneficial in a broad spectrum of patients suffering from insomnia. These

approaches include behavioral, schedule, and environmental changes conducive

to improved sleep. Valuable recommendations are based on well-established

principles regarding the regulation of the sleep-wake cycle.

Psychotherapeutic approaches and most formalized behavioral sleep medicine

therapies, which often are combined in a cognitive-behavioral approach, also

have broad applicability with insomnia patients. The use of hypnotic

medications can be seen as a general approach with value in the treatment of

patients with insomnia from varied causes.

Evidence-based guidelines for the pharmacologic treatment of insomnia are

rather limited, in part because insomnia is not a specific disease but

rather a diffuse condition with a wide range of severity and duration.

However, short-term pharmacologic studies and extensive long-term clinical

experience have demonstrated that certain medications show safety,

tolerability, and efficacy in the treatment of insomnia in both acute and

chronic cases.

The ideal medication intended primarily for insomnia will have a rapid

sedating effect that does not persist into the desired waking time; will not

promote the development of tolerance and dependence; will have specific

pharmacodynamic activity that avoids adverse effects from undesired receptor

activity; and will have low toxicity if an excessive dose is ingested. In

improving the duration and quality of nighttime sleep, the use of the

insomnia medication should result in improved daytime symptoms, such as

greater alertness and concentration.

Many factors influence the choice of medications and other substances taken

for insomnia. Patients may view OTC, herbal, and dietary supplement

preparations as safer and more " natural, " whereas some may worry about

dependence on " sleeping pills. " Others desire a medication to put them to

sleep. Recommendations made by health care providers are determined by their

own sleep medicine knowledge and their attitudes about treating insomnia.

The result may be an appropriate treatment plan, but in the community as

well as in clinical practice, remedies used for insomnia are sometimes much

less rationally determined.

The comprehensive evaluation of an insomnia patient should first focus on

any specific underlying processes and disorders that can be directly

addressed.[3] General pharmacologic and behavioral approaches can then be

considered. Any patient history should review what the patient has done to

improve sleep and daytime functioning. In addition to past treatment trials

(successes and failures), the history should include all current OTC and

prescription medications to assess the potential for pharmacokinetic and

pharmacodynamic interactions.

The pharmacologic management of insomnia, especially with chronic insomnia

patients, should be in the context of a strong therapeutic relationship.

Education about sleep and patient support during the treatment process are

important components. The use of medication for sleep should be integrated

with good sleep hygiene and other appropriate behavioral changes. Although

the pharmacologic approach to insomnia is beneficial for many patients, it

is rarely the sole solution. In fact, a medication that might otherwise help

some patients fall asleep more quickly could be undermined by their intense

anxiety and fear that they will never again sleep well and function

normally. Ultimately, the resolution of insomnia lies at the nexus of

psychologic and physiologic processes.

Insomnia and Major Depression

Insomnia is one of the most common symptoms of a major depressive

episode.[4,5] About 90% of depressed patients will report difficulty

initiating or maintaining sleep. Often insomnia is the first symptom

heralding a relapse.[6] Several pharmacologic treatment strategies are

available. One choice is a sedating antidepressant, which may improve sleep

while treating the depression. The single medication approach is appealing

and may benefit compliance; however, this strategy limits the range of

antidepressant selections and exposes the patient to a medication that may

cause undesired daytime sedation. An alternative treatment plan would be to

combine an antidepressant with a hypnotic, which allows for a broader range

of antidepressant choices and offers greater reliability in helping with

nighttime sleep while minimizing daytime sedation. This combined approach

may be particularly advantageous with selective serotonin reuptake inhibitor

(SSRI) antidepressants as the hypnotic can offer immediate relief from the

insomnia and also help minimize the sleep disturbance that could result from

the antidepressant. A placebo-controlled study performed with zolpidem in

combination with several different SSRI antidepressants demonstrated

hypnotic efficacy, improvement in daytime functioning, and no worsening of

depression scores.[7] Studies of zolpidem combined with fluoxetine or

sertraline found no clinically significant pharmacokinetic and

pharmacodynamic interactions in healthy individuals.[8,9]

Insomnia and Bipolar Disorder

It is often said that when bipolar disorder patients are experiencing manic

or hypomanic episodes, they do not complain of insomnia but simply need less

sleep and keep themselves busy with other activities. Although this does

seem true for some patients, many suffer considerably with insomnia during

these episodes. In fact, sleep loss from any cause can precipitate or

exacerbate a manic or hypomanic episode.[10] Therefore, it is important for

bipolar disorder patients to avoid situations leading to sleep loss.

Education about the need for adequate sleep is crucial, and sedating

medications, including hypnotics, may play a pivotal role in preventing or

minimizing exacerbations.

Alcohol

Alcohol deserves special attention because of the popular notion that it can

be used medicinally to enable sleep. Prior to seeking professional help for

insomnia, some people will try drinking wine or experiment with some other

kind of alcoholic " nightcap. " Those who do not drink alcoholic beverages

regularly may attempt this remedy out of desperation. Alcohol may be

sedating initially, but over a period of a few hours as the blood alcohol

level decreases, there may be a hyperarousal effect that causes more sleep

disruption and awakenings.[11] For some patients, the effective treatment of

their insomnia will require the avoidance of alcohol, particularly within a

few hours before bedtime.

Dietary Supplements and Herbal and Homeopathic Preparations

A confusing collection of compounds marketed as sleep aids can be found on

pharmacy and supermarket shelves. Many do not have active ingredients with

sedating properties or any other actions related to sleep-wake cycle

regulation. Few studies have evaluated the safety and efficacy of these

products as many are not subject to Food and Drug Administration (FDA)

control.[12] In some cases there may be a placebo benefit. In others, such

as valerian preparations, there may be a degree of sedating action, but

questions remain about the duration of action, appropriate dosage, potential

interactions, and preparation purity. In recent years kava preparations have

been banned in some countries because of reports of liver failure associated

with its use. In the United States, the FDA has issued a warning regarding

this potential problem. Evidence is equivocal regarding the use of

melatonin* as a sleep-inducing agent-most studies have not demonstrated

subjective or objective improvement in sleep, but there is some evidence

that it may be useful for selected patients in modulating the intrinsic

circadian system. A major problem with these OTC sleep aids is that in

experimenting with them, persons may delay seeking medical attention and

receiving effective treatment for their insomnia.

Antihistamines

A major class of the OTC products marketed as sleep aids contains

antihistamines (primarily diphenhydramine), although these medications may

be available by prescription at higher doses for various indications,

including allergic reactions. These H1 antihistamines may be mildly to

moderately sedating for some individuals. The elimination half-life tends to

be relatively long (about 8 hours); therefore, residual next-morning

" hangover " effects may be present after bedtime use. Some degree of

tolerance to the sedating effects of these medications also may occur. In

addition to the postsynaptic H1 antagonism, muscarinic antagonism must also

be considered. Accordingly, attention should be paid to the potential

anticholinergic effects of antihistamines, especially in elderly patients or

patients taking concomitant medications with anticholinergic effects, such

as antidepressants, antipsychotics, and bladder control agents. Excessive

anticholinergic activity may lead to blurred vision, constipation, urinary

retention, confusion, and delirium, all of which have been associated with

diphenhydramine alone or in combination with other medications.[13] It

should be noted that diphenhydramine may inhibit CYP2D6-mediated hepatic

metabolism.

Another concern about OTC antihistamine use is the popular combination with

analgesics, especially acetaminophen. While this may be a useful combination

in certain circumstances, such as when pain interrupts sleep, often these

preparations are taken in the absence of any pain symptoms. Chronic use and

high doses of analgesics unnecessarily expose patients to the risks

associated with analgesics, especially hepatic and renal effects.

Antidepressants

Antidepressants play a vital role in treating major depression and other

psychiatric disorders. Some sedating antidepressants may have an immediate

effect in improving sleep; however, the role of antidepressants employed as

sleep-inducing agents in the absence of depression remains debatable. In the

past, amitriptyline commonly had been prescribed, and in recent years

trazodone has been used in this manner. The potential adverse effects of the

tricyclic antidepressants are well known, and they also have various

possible pharmacokinetic and pharmacodynamic drug interactions. A common

undesired consequence of using tricyclic antidepressants primarily for

insomnia is the residual daytime sedation resulting from the relatively long

elimination half-lives of these agents. These daytime symptoms also may

result from some nontricyclic antidepressants, such as mirtazapine and

trazodone.

The SSRI antidepressants warrant particular attention because they are

widely prescribed for several different indications. Some practitioners will

recommend these medications for insomnia, although in the absence of a

depressive disorder, they tend not to be beneficial for sleep. In fact,

SSRIs may result in excessive stimulation and insomnia as side effects. Most

classes of antidepressants, including the SSRIs and tricyclics, may be

associated with the development or exacerbation of periodic limb movements

during sleep, which can result in awakenings or a decrease in sleep quality.

Trazodone is often prescribed for insomnia. Trazodone is typically

prescribed in doses of 50 to 150 mg. It may be mildly to moderately sedating

and beneficial for selected patients; however, there has been little

research regarding either its efficacy or safety when used for insomnia at

these doses and there is no body of data supporting its safety or efficacy

at lower doses. There are several concerns regarding its use. The most

frequent problem encountered is residual morning sedation or difficulty in

concentrating following bedtime use. The elimination half-life is ~8 hours.

Although some patients may feel that they fall asleep better, they do not

necessarily wake up better. The postsynaptic alpha antagonism may promote

orthostatic hypotension, which may be clinically significant in elderly

patients or patients taking antihypertensives. Priapism and painful clitoral

engorgement are rare adverse reactions. More important is the development of

the serotonin syndrome, which has been reported with trazodone

coadministered with other serotonergic medications (eg, fluoxetine,

paroxetine, monoamine oxidase inhibitor antidepressants). Symptoms and

consequences of the serotonin syndrome may include agitation, restlessness,

confusion, hyperreflexia, autonomic instability, fever, coma, and death.[14]

In addition trazodone is a substrate of CYP3A4, and it is metabolized to

meta-chlorophenylpiperazine (mCPP), which also is pharmacologically active;

therefore, drug interactions are possible with other 3A4 substrates, in

hibitors, and inducers. For instance, fluoxetine, a 3A4 inhibitor, may

increase the concentration of trazodone and mCPP.

Hypnotics

Bromides, barbiturates, paraldehyde, and metha qualone are among the

medications that have been employed as hypnotics. While they have marked

sedating properties, they also have significant toxicity and no current role

in the treatment of insomnia.[12] The use of chloral hydrate for insomnia is

limited by toxicity and tolerance. Current medications available in the

United States that are indicated for use in treating insomnia include 5

traditional benzodiazepines and 2 newer nonbenzodiazepine medications

(zaleplon and zolpidem) that also function as benzodiazepine receptor

agonists (BZRAs) (Table). BZRAs enhance the normal inhibitory activity of

the GABA(A) receptor complex. The traditional and newer-generation BZRAs can

be differentiated by their specificity for the benzodiaze-pine receptor

subtypes, of which at least 5 have now been identified.[15] Generally, the

traditional benzodiazepine hypnotics are agonists for all of the identified

subtypes, whereas the newer-generation BZRAs preferentially bind to the

type-1 receptor. It is speculated that this pharmacologic property explains

some of the clinical advantages of the newer hypnotics. For example,

zaleplon and zolpidem generally are not associated with tolerance,

withdrawal, and dependence difficulties and therefore have minimal abuse

potential.

Traditional benzodiazepines have been available for use as hypnotics since

the 1960s. Aside from the 5 traditional benzodiazepine hypnotics, several

other benzodiazepines (eg, alprazolam, lorazepam, clonazepam) are prescribed

for insomnia. The traditional benzodiazepines vary widely in their

elimination half-lives and subsequent durations of action, which is a

concern regarding adverse effects. The half-lives range from a few hours

(eg, triazolam) to a few days (eg, flurazepam). The longer half-life

hypnotics may be associated with residual daytime effects after a single

dose. Repeated nightly doses may lead to a blood-concentration accumulation

and a steady-state level with an increased potential for daytime impairment,

and may be associated with a greater risk of falls, accidents, and cognitive

effects. Only rarely are daytime effects from a bedtime hypnotic desirable;

therefore, shorter-acting medications almost always are recommended.

The pharmacologic specificity noted earlier and the short elimination

half-lives contribute to the benefits of the newer nonbenzodiazepine BZRAs

zaleplon and zolpidem. Zolpidem first became available in 1988 in Europe and

was marketed in the United States in 1993. Zaleplon became available in

1999. These 2 medications function similarly in helping people fall asleep.

The onset of action may be rapid, so patients should take the medication

just before they get into bed and not earlier in anticipation of falling

asleep instantly when they go to bed. The duration of action is influenced

by the elimination half-life, which for zolpidem is about 2.5 hours and for

zaleplon about 1 hour; therefore, there is little risk of morning sedation

or other cognitive impairment following bedtime use. When taken at bedtime,

zolpidem is more likely to promote improved sleep throughout the night. The

ultrashort zaleplon half-life should minimize any residual effects 4 hours

after its use; therefore, it could be taken (1 dose only) during the

night.[16] Zaleplon and zolpidem typically are well tolerated. There are no

contraindications to their use, although they are not recommended during

pregnancy. Both medications are available in 5-mg and 10-mg strengths; 10 mg

is the standard recommended dose for adults and 5 mg is suggested for

initial use in the elderly and for patients with hepatic or renal

impairment. Serious adverse reactions are infrequent; however, based on

controlled clinical trials, the more common reactions are headache,

dizziness, drowsiness, and nausea.

The short-term safety and efficacy of these newer-generation BZRAs are well

established[17-21] although long-term, double-blind, placebo-controlled

studies of their safety and efficacy have not been performed. Nonetheless,

clinical experience does exist that supports the continued effectiveness and

safety of the BZRAs when they are prescribed for long-term nightly use,

episodic use over a period from months to years, and long-term frequent

intermittent use (a few nights per week). Dose escalation is rare. Discon

tinuation effects (eg, worsened insomnia relative to baseline sleep quality)

are minimal and transient, and usually can be prevented with a gradual de

crease in the dose.

Hypnotics and Abuse Potential

The potential abuse of hypnotic medications remains a concern for some

physicians that may lead them to avoid or limit the use of this

pharmacologic approach in treating their insomnia patients. There likely is

some residual apprehension due to the earlier generation of hypnotics that

had significant safety, dependence, and abuse problems. Some physicians are

reluctant to prescribe hypnotics, not because they fear they will be

ineffective or unsafe, but because they worry that patients will sleep much

better and be reluctant to discontinue the medication. In actuality, most

patients take hypnotics for a relatively short period (days to weeks), and

of those who do use them, only about 10% to 15% do so chronically. This

long-term use may be entirely appropriate from a clinical perspective. The

class labeling for all hypnotics specifies a class IV scheduling and an

indication for short-term use, but it does not restrict long-term use. For

some providers, it is the regulatory concerns more than any clinical issues

that influence their prescribing practices.

Abuse of the BZRA hypnotics is rare among insomnia patients. Abuse might be

indicated by excessive nonprescribed doses, recreational daytime

non-sleep-related use, and the acquisition of multiple prescriptions from

different clinicians. While insomnia patients rarely do so, substance

abusers will sometimes abuse the traditional benzodiaze pines; however, they

rarely abuse the newer-generation nonbenzodiazepine hypnotics.[22] It is

good clinical practice to monitor prescriptions and regularly assess the

patient's medication use.

An important issue in the treatment of insomnia is the management of sleep

complaints of patients with a history of substance abuse.[23] Many

clinicians restrict or limit the use of any hypnotic for this population.

One key question: Is the risk of abusing a hypnotic the same for a person

with a very recent history of substance abuse as it is for a person who last

abused substances 10 years ago? It is a concern because insomnia may in

crease the risk for substance-abuse relapse as the patient attempts

" self-medication. " Further research is necessary to determine the risks and

benefits of using low-abuse-potential hypnotics to help maintain abstinence

for these patients.

Hypnotic Prescribing Guidelines

The use of a hypnotic medication may be key in the overall treatment plan

for a patient suffering with insomnia. Whenever possible, the physician

should identify and address specific behaviors, circumstances, and

underlying disorders that might be contributing to the insomnia. General

treatment strategies can then be employed. A pharmacologic approach is most

likely to help if it is part of an integrated plan that incorporates

behavioral changes and monitors progress in alleviating insomnia symptoms.

Having the patient maintain a sleep log may aid this process. It is useful

to establish particular therapeutic goals in relation to the patient's chief

complaints, such as lengthy nighttime awakenings or poor daytime

concentration.

In selecting a medication for insomnia, the safety, tolerability, and

efficacy of the newer-generation BZRA hypnotics make them first-line

choices. They should be prescribed at the recommended doses to maximize the

therapeutic benefit, and should be taken when the patient is attempting to

fall asleep. The frequency and duration of use should be customized to each

patient's circumstances. Some patients who experience transient crises may

benefit for a few days or weeks and then discontinue the medication when no

longer necessary. Others can be supported with a pattern of intermittent use

that reflects fluctuations in their symptoms. For selected patients, the

best clinical solution may be long-term use of the hypnotic, which may

maximize nighttime sleep, daytime functioning and overall quality of life.

In some cases, patients using hypnotics on a nightly basis can transition to

an intermittent pattern.[24,25] When patients who have taken hypnotics

nightly for several weeks or longer are to stop using the medication, a

gradual decrease in the dose should minimize the potential for recurrence of

the insomnia.

*Not FDA approved for the management of insomnia.

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