Methylphenidate and other amphetamine-based agents are mainstays in treating attention-deficit/hyperactivity disorder (ADHD). Although these stimulants are considered safe, their potentially addictive properties have concerned clinicians, adult patients, and parents of children and adolescents with ADHD.

Table

Atomoxetine: fast facts

Atomoxetine—a nonaddictive, nonstimulant medication—has demonstrated efficacy in placebo-controlled trials.

HOW IT WORKS

Atomoxetine enhances synaptic concentrations of norepinephrine via the presynaptic transporter. The agent has a strong affinity with norepinephrine transporters, modest affinity with serotonin transporters, and no affinity with dopamine transporters.¹

When applied directly to the prefrontal cortex, however, atomoxetine has been shown to increase both extracellular norepinephrine and dopamine. Sustained levels of norepinephrine and dopamine in the prefrontal cortex may explain why atomoxetine works well beyond its 5.3-hour biologic half-life.¹

In contrast, methylphenidate has shown high affinity with dopamine transporters. It produces intense, brief prefrontal increases in norepinephrine and dopamine and sustained dopamine increases in the nucleus accumbens and striatum.² This might explain methylphenidate’s rewarding properties and its association with stereotypic motor activity and tics. By comparison, atomoxetine has a lower abuse potential and does not affect basal ganglia motor output.³

Atomoxetine’s pharmacokinetics have been evaluated in more than 400 children and adolescents. Its half-life, clearance (0.35 L/hr/kg), and volume of distribution are similar across age groups, and the dose-plasma concentration relationship is linear, suggesting that dosing can be reliably adjusted according to weight. Atomoxetine is rapidly absorbed, food does not appreciably affect absorption, and peak plasma concentrations are achieved within 1 to 2 hours. The drug is distributed mostly in total body water and is highly protein bound.

Atomoxetine is metabolized primarily through the cytochrome P (CYP)-450 2D6 pathway. The major metabolite is 4-hydroxyatomoxetine, which is equipotent to atomoxetine as a norepinephrine transporter inhibitor.

WHAT RESEARCHERS SAY

In an 8-week study, 297 patients ages 8 to 18 received a divided fixed dosage of atomoxetine (0.5, 1.2 or 1.8 mg/kg/d) or placebo. The 1.2 and 1.8 mg/kg/d dosages were more effective than placebo and were equally effective against hyperactivity/impulsivity and inattention symptoms. The 0.5 mg/kg/d dosage was not much more effective than placebo.⁴

In a 6-week, placebo-controlled study, 85 subjects ages 6 to 16 who received a single dose of atomoxetine each morning (mean dosage 1.3 mg/kg/d) achieved favorable outcomes based on investigator, parent, and teacher ratings and on an ADHD Rating Scale (ADHD-RS) primary outcome measure. The treatment effect size (0.71) was similar to that found in the twice-daily dosing studies, suggesting that single-daily dosing is effective.⁵

Box

Two controlled, comparison studies involving 291 subjects ages 7 to 13 with ADHD found that atomoxetine (mean final dosage 1.6 mg/kg/d) compares favorably to methylphenidate with similar effect sizes across ADHD symptom domains (unpublished data). Limited published data indicate that randomized, open-label atomoxetine and methylphenidate are similarly effective across ADHD symptom domains in children.⁶

Atomoxetine also was shown to improve ADHD symptoms in two placebo-controlled trials involving a total of 536 adults (mean daily divided dose 95 mg).⁷ Inattention, hyperactivity, and impulsivity—as measured with the Conners Adult ADHD Rating Scale—were reduced among both treatment groups.

DOSING AND ADMINISTRATION

No age- or gender-related differences in response to atomoxetine have been reported, although dosing varies with age and weight (Box).

The agent should be used cautiously in patients with cardiovascular or cerebrovascular disease, as side effects include slight elevation of pulse and blood pressure. Atomoxetine also may exacerbate urinary retention or hesitation in some adults. The drug may impair sexual function; at least 7% of men in placebo-controlled trials experienced erectile disturbance, and 3% experienced impotence.⁷

In children and adolescents, gastrointestinal discomfort, asthenia, fatigue, mild appetite decreases, and slight weight loss were reported adverse effects.⁵ Nausea and vomiting were the most troublesome acute side effects in children, with most episodes lasting 1 to 2 days.⁵

CLINICAL IMPLICATIONS

Atomoxetine may help patients with ADHD who respond inadequately or do not respond to stimulants. Its lack of abuse potential suggests it may be useful in adults with comorbid substance use disorders. Atomoxetine also does not appear to exacerbate insomnia—a potential benefit for ADHD patients with poor sleep quality.

Given its pharmacologic profile, the agent will reduce the impact of comorbidities (such as anxiety and depression) common to adults with ADHD. Research is needed to determine its role in treating more complicated pathologies, such as ADHD with comorbid bipolar disorder.

Whereas some stimulants require multiple daily dosing, atomoxetine is administered once daily. This could save clinicians time by reducing the need for refills, out-of-visit prescribing, and monthly patient visits (our pediatric practice writes 20 to 40 stimulant refills per day)and enhance convenience for patients.

Related resources

• Spencer T, Biederman J, Wilens T, et al. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 1998;155:693-5.

Drug Brand Names

• Methylphenidate • Concerta, Ritalin

Disclosure

The author receives research/grant support from and is a consultant to and speaker for Eli Lilly and Co. He also receives research/grant support from Shire Pharmaceuticals and Johnson & Johnson, and is a consultant to Abbott Laboratories, Merck and Co., Pfizer Inc., and Organon.

Methylphenidate and other amphetamine-based agents are mainstays in treating attention-deficit/hyperactivity disorder (ADHD). Although these stimulants are considered safe, their potentially addictive properties have concerned clinicians, adult patients, and parents of children and adolescents with ADHD.

Table

Atomoxetine: fast facts

Atomoxetine—a nonaddictive, nonstimulant medication—has demonstrated efficacy in placebo-controlled trials.

HOW IT WORKS

Atomoxetine enhances synaptic concentrations of norepinephrine via the presynaptic transporter. The agent has a strong affinity with norepinephrine transporters, modest affinity with serotonin transporters, and no affinity with dopamine transporters.¹

When applied directly to the prefrontal cortex, however, atomoxetine has been shown to increase both extracellular norepinephrine and dopamine. Sustained levels of norepinephrine and dopamine in the prefrontal cortex may explain why atomoxetine works well beyond its 5.3-hour biologic half-life.¹

In contrast, methylphenidate has shown high affinity with dopamine transporters. It produces intense, brief prefrontal increases in norepinephrine and dopamine and sustained dopamine increases in the nucleus accumbens and striatum.² This might explain methylphenidate’s rewarding properties and its association with stereotypic motor activity and tics. By comparison, atomoxetine has a lower abuse potential and does not affect basal ganglia motor output.³

Atomoxetine’s pharmacokinetics have been evaluated in more than 400 children and adolescents. Its half-life, clearance (0.35 L/hr/kg), and volume of distribution are similar across age groups, and the dose-plasma concentration relationship is linear, suggesting that dosing can be reliably adjusted according to weight. Atomoxetine is rapidly absorbed, food does not appreciably affect absorption, and peak plasma concentrations are achieved within 1 to 2 hours. The drug is distributed mostly in total body water and is highly protein bound.

Atomoxetine is metabolized primarily through the cytochrome P (CYP)-450 2D6 pathway. The major metabolite is 4-hydroxyatomoxetine, which is equipotent to atomoxetine as a norepinephrine transporter inhibitor.

WHAT RESEARCHERS SAY

In an 8-week study, 297 patients ages 8 to 18 received a divided fixed dosage of atomoxetine (0.5, 1.2 or 1.8 mg/kg/d) or placebo. The 1.2 and 1.8 mg/kg/d dosages were more effective than placebo and were equally effective against hyperactivity/impulsivity and inattention symptoms. The 0.5 mg/kg/d dosage was not much more effective than placebo.⁴

In a 6-week, placebo-controlled study, 85 subjects ages 6 to 16 who received a single dose of atomoxetine each morning (mean dosage 1.3 mg/kg/d) achieved favorable outcomes based on investigator, parent, and teacher ratings and on an ADHD Rating Scale (ADHD-RS) primary outcome measure. The treatment effect size (0.71) was similar to that found in the twice-daily dosing studies, suggesting that single-daily dosing is effective.⁵

Box

Two controlled, comparison studies involving 291 subjects ages 7 to 13 with ADHD found that atomoxetine (mean final dosage 1.6 mg/kg/d) compares favorably to methylphenidate with similar effect sizes across ADHD symptom domains (unpublished data). Limited published data indicate that randomized, open-label atomoxetine and methylphenidate are similarly effective across ADHD symptom domains in children.⁶

Atomoxetine also was shown to improve ADHD symptoms in two placebo-controlled trials involving a total of 536 adults (mean daily divided dose 95 mg).⁷ Inattention, hyperactivity, and impulsivity—as measured with the Conners Adult ADHD Rating Scale—were reduced among both treatment groups.

DOSING AND ADMINISTRATION

No age- or gender-related differences in response to atomoxetine have been reported, although dosing varies with age and weight (Box).

The agent should be used cautiously in patients with cardiovascular or cerebrovascular disease, as side effects include slight elevation of pulse and blood pressure. Atomoxetine also may exacerbate urinary retention or hesitation in some adults. The drug may impair sexual function; at least 7% of men in placebo-controlled trials experienced erectile disturbance, and 3% experienced impotence.⁷

In children and adolescents, gastrointestinal discomfort, asthenia, fatigue, mild appetite decreases, and slight weight loss were reported adverse effects.⁵ Nausea and vomiting were the most troublesome acute side effects in children, with most episodes lasting 1 to 2 days.⁵

CLINICAL IMPLICATIONS

Atomoxetine may help patients with ADHD who respond inadequately or do not respond to stimulants. Its lack of abuse potential suggests it may be useful in adults with comorbid substance use disorders. Atomoxetine also does not appear to exacerbate insomnia—a potential benefit for ADHD patients with poor sleep quality.

Given its pharmacologic profile, the agent will reduce the impact of comorbidities (such as anxiety and depression) common to adults with ADHD. Research is needed to determine its role in treating more complicated pathologies, such as ADHD with comorbid bipolar disorder.

Whereas some stimulants require multiple daily dosing, atomoxetine is administered once daily. This could save clinicians time by reducing the need for refills, out-of-visit prescribing, and monthly patient visits (our pediatric practice writes 20 to 40 stimulant refills per day)and enhance convenience for patients.

Related resources

• Spencer T, Biederman J, Wilens T, et al. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 1998;155:693-5.

Drug Brand Names

• Methylphenidate • Concerta, Ritalin

Disclosure

The author receives research/grant support from and is a consultant to and speaker for Eli Lilly and Co. He also receives research/grant support from Shire Pharmaceuticals and Johnson & Johnson, and is a consultant to Abbott Laboratories, Merck and Co., Pfizer Inc., and Organon.

Methylphenidate and other amphetamine-based agents are mainstays in treating attention-deficit/hyperactivity disorder (ADHD). Although these stimulants are considered safe, their potentially addictive properties have concerned clinicians, adult patients, and parents of children and adolescents with ADHD.

Table

Atomoxetine: fast facts

Atomoxetine—a nonaddictive, nonstimulant medication—has demonstrated efficacy in placebo-controlled trials.

HOW IT WORKS

Atomoxetine enhances synaptic concentrations of norepinephrine via the presynaptic transporter. The agent has a strong affinity with norepinephrine transporters, modest affinity with serotonin transporters, and no affinity with dopamine transporters.¹

When applied directly to the prefrontal cortex, however, atomoxetine has been shown to increase both extracellular norepinephrine and dopamine. Sustained levels of norepinephrine and dopamine in the prefrontal cortex may explain why atomoxetine works well beyond its 5.3-hour biologic half-life.¹

In contrast, methylphenidate has shown high affinity with dopamine transporters. It produces intense, brief prefrontal increases in norepinephrine and dopamine and sustained dopamine increases in the nucleus accumbens and striatum.² This might explain methylphenidate’s rewarding properties and its association with stereotypic motor activity and tics. By comparison, atomoxetine has a lower abuse potential and does not affect basal ganglia motor output.³

Atomoxetine’s pharmacokinetics have been evaluated in more than 400 children and adolescents. Its half-life, clearance (0.35 L/hr/kg), and volume of distribution are similar across age groups, and the dose-plasma concentration relationship is linear, suggesting that dosing can be reliably adjusted according to weight. Atomoxetine is rapidly absorbed, food does not appreciably affect absorption, and peak plasma concentrations are achieved within 1 to 2 hours. The drug is distributed mostly in total body water and is highly protein bound.

Atomoxetine is metabolized primarily through the cytochrome P (CYP)-450 2D6 pathway. The major metabolite is 4-hydroxyatomoxetine, which is equipotent to atomoxetine as a norepinephrine transporter inhibitor.

WHAT RESEARCHERS SAY

In an 8-week study, 297 patients ages 8 to 18 received a divided fixed dosage of atomoxetine (0.5, 1.2 or 1.8 mg/kg/d) or placebo. The 1.2 and 1.8 mg/kg/d dosages were more effective than placebo and were equally effective against hyperactivity/impulsivity and inattention symptoms. The 0.5 mg/kg/d dosage was not much more effective than placebo.⁴

In a 6-week, placebo-controlled study, 85 subjects ages 6 to 16 who received a single dose of atomoxetine each morning (mean dosage 1.3 mg/kg/d) achieved favorable outcomes based on investigator, parent, and teacher ratings and on an ADHD Rating Scale (ADHD-RS) primary outcome measure. The treatment effect size (0.71) was similar to that found in the twice-daily dosing studies, suggesting that single-daily dosing is effective.⁵

Box

Two controlled, comparison studies involving 291 subjects ages 7 to 13 with ADHD found that atomoxetine (mean final dosage 1.6 mg/kg/d) compares favorably to methylphenidate with similar effect sizes across ADHD symptom domains (unpublished data). Limited published data indicate that randomized, open-label atomoxetine and methylphenidate are similarly effective across ADHD symptom domains in children.⁶

Atomoxetine also was shown to improve ADHD symptoms in two placebo-controlled trials involving a total of 536 adults (mean daily divided dose 95 mg).⁷ Inattention, hyperactivity, and impulsivity—as measured with the Conners Adult ADHD Rating Scale—were reduced among both treatment groups.

DOSING AND ADMINISTRATION

No age- or gender-related differences in response to atomoxetine have been reported, although dosing varies with age and weight (Box).

The agent should be used cautiously in patients with cardiovascular or cerebrovascular disease, as side effects include slight elevation of pulse and blood pressure. Atomoxetine also may exacerbate urinary retention or hesitation in some adults. The drug may impair sexual function; at least 7% of men in placebo-controlled trials experienced erectile disturbance, and 3% experienced impotence.⁷

In children and adolescents, gastrointestinal discomfort, asthenia, fatigue, mild appetite decreases, and slight weight loss were reported adverse effects.⁵ Nausea and vomiting were the most troublesome acute side effects in children, with most episodes lasting 1 to 2 days.⁵

CLINICAL IMPLICATIONS

Atomoxetine may help patients with ADHD who respond inadequately or do not respond to stimulants. Its lack of abuse potential suggests it may be useful in adults with comorbid substance use disorders. Atomoxetine also does not appear to exacerbate insomnia—a potential benefit for ADHD patients with poor sleep quality.

Given its pharmacologic profile, the agent will reduce the impact of comorbidities (such as anxiety and depression) common to adults with ADHD. Research is needed to determine its role in treating more complicated pathologies, such as ADHD with comorbid bipolar disorder.

Whereas some stimulants require multiple daily dosing, atomoxetine is administered once daily. This could save clinicians time by reducing the need for refills, out-of-visit prescribing, and monthly patient visits (our pediatric practice writes 20 to 40 stimulant refills per day)and enhance convenience for patients.

Related resources

• Spencer T, Biederman J, Wilens T, et al. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 1998;155:693-5.

Drug Brand Names

• Methylphenidate • Concerta, Ritalin

Disclosure

The author receives research/grant support from and is a consultant to and speaker for Eli Lilly and Co. He also receives research/grant support from Shire Pharmaceuticals and Johnson & Johnson, and is a consultant to Abbott Laboratories, Merck and Co., Pfizer Inc., and Organon.

Careful investigation can often reveal insomnia’s cause¹—whether a psychiatric or medical condition or poor sleep habits. Understanding why patients can’t sleep is key to effective therapy.

Acute and chronic sleep deprivation is associated with measurable declines in daytime performance (Box). Some data even suggest that long-term sleeplessness increases the risk of new psychiatric disorders—most notably major depression.³

PSYCHIATRIC DISORDERS AND INSOMNIA

Depression. Many depressed persons—up to 80%—experience insomnia, although no one sleep pattern seems typical.² Depression may be associated with:

• difficulties in falling asleep
• interrupted nocturnal sleep
• and early morning awakening.

Anxiety disorders. Generalized anxiety disorder (GAD), social phobia, panic attacks, and posttraumatic stress disorder (PTSD) are all associated with disrupted sleep. Patients with GAD experience prolonged sleep latency (time needed to fall asleep after lights out) and fragmented sleep, similar to those with primary insomnia.

Box

Subjective sleep quality may be impaired in patients with social phobia. Some patients experience panic symptoms while sleeping, possibly in association with mild hypercapnia. Patients with sleep panic attacks tend to have earlier onset of panic disorder and a higher likelihood of comorbid mood and other anxiety disorders.⁴

In patients with PTSD, disturbed sleep continuity and increased REM phasic activity—such as eye movements—are directly correlated with severity of PTSD symptoms. Nightmares and disturbed REM sleep are hypothesized hallmarks of PTSD.⁵

Schizophrenia. Patients with schizophrenia often have disrupted sleep patterns. These include prolonged sleep latency, fragmented sleep with frequent arousals, decreased slow-wave sleep, variable REM latency, and decreased REM rebound after sleep deprivation. Despite investigations going back to the 1950s, no specific link between REM sleep and psychosis has been found.⁶ Interestingly, increases in REM sleep time and REM activity have been associated with an increased risk of suicide in patients with schizophrenia.⁷

Adjustment sleep disorder. Acute emotional stressors—such as bereavement, job loss, or hospitalization—often cause adjustment sleep disorder. Symptoms typically remit soon after the stressors abate, so this transient insomnia usually lasts a few days to a few weeks. Treatment with behavioral therapies and hypnotics⁸ is warranted if:

• sleepiness and fatigue interfere with daytime functioning
• a pattern of recurring episodes develops.⁹

Psychophysiologic insomnia. Once initiated—regardless of cause—insomnia may persist well after its precipitating factors resolve. Thus, short-term insomnia may develop into long-term, chronic difficulty with recurring episodes or a constant, daily pattern of insomnia. Sufferers often spend hours in bed awake focused upon—and brooding over—their sleeplessness. which in turn further aggravates their insomnia.

Adjustment sleep disorder and psychophysiologic insomnia are included within DSM-IV’s term “primary insomnia.”

OTHER CAUSES OF INSOMNIA

Medications that may affect sleep quality include antidepressants (Table 1),^10,11 antihypertensives, antineoplastic agents, bronchodilators, stimulants, corticosteroids, decongestants, diuretics, histamine-2 receptor blockers, and smoking cessation aids.

Recreational drugs, such as cocaine, often cause insomnia. Hypnotics and anxiolytics can cause insomnia following long-term use and during withdrawal.

Other disorders known to disturb sleep include periodic limb movement disorder (PLMD), restless legs syndrome (RLS), sleep apnea syndrome, disrupted circadian rhythms (as with travel or shift work), cardiopulmonary disorders, chronic pain, diabetes, hyperthyroidism, hot flashes associated with menopause, seizures, dementia, and Parkinson’s disease, to name a few.

WORKUP OF SLEEP COMPLAINTS

Acute. Most short-term insomnias—lasting a few weeks or less—are caused by situational stressors, circadian rhythm alterations, and sleep hygiene violations. A logical initial approach, therefore, is to combine sleep hygiene measures with supportive psychotherapy. Hypnotic agents may be considered for apparent daytime consequences—such as sleepiness and occupational impairment—or if the insomnia seems to be escalating.

Chronic. For longer-term insomnias—lasting more than a few weeks—consider a more thorough evaluation, including medical and psychiatric history, physical examination, and mental status examination. Inquire about cardinal symptoms of disorders associated with insomnia, including:

• snoring or breathing pauses during sleep (sleep apnea syndrome)
• restlessness or twitching in the lower extremities (PLMS/RLS).

Question the bed partner, who may be more aware of such symptoms than the patient. Carefully review sleep patterns on weekdays and weekends, bedtime habits, sleep hygiene habits, and substance and medication use.

Table 1

Antidepressants’ effects on sleep and wakefulness

Sleep clinic referrals. Consider an evaluation by a sleep disorders center when:

• the diagnosis remains unclear
• or treatment of the presumed conditions fails after a reasonable time

BEHAVIORAL TREATMENTS

Behavioral treatments—with or without hypnotics—are appropriate for a wide variety of insomnia complaints, including adjustment sleep disorder, psychophysiologic insomnia, and depression. Behavioral measures may take longer to implement than drug therapy, but their effects have been shown to last longer in patients with primary insomnia. In many cases, it may be useful to start with both hypnotic and behavioral treatments and withdraw the hypnotic after behavioral measures take effect.

Sleep hygiene. Many individuals unknowingly engage in habitual behaviors that impair sleep. Those with insomnia, for example, often try to compensate for lost sleep by staying in bed later in the morning or by napping, which further fragment nocturnal sleep. Advise these patients to adhere to a regular awakening time—regardless of how long they slept the night before—and to avoid naps. Other tips for getting a good night’s sleep are outlined in Table 2.¹²

Caffeine has a plasma half-life of 3 to 7 hours, although individual sensitivity varies widely and caffeine’s erratic absorption can prolong its effects. Advise patients with insomnia to avoid caffeine-containing beverages—including coffee, tea, and soft drinks—after noon.

Relaxation training. Muscle tension can be reduced through electromyography (EMG) biofeedback, abdominal breathing exercises, or progressive muscle relaxation techniques, among others. Relaxation training is usually effective within a few weeks.

Psychotherapy. Cognitive-behavioral therapy can help identify and dispel tension-producing thoughts that are disrupting sleep, such as preoccupation with unpleasant work experiences or school examinations. Reassurance may help patients overcome fears about sleeplessness; suggest that patients deal with anxiety-producing thoughts during therapy sessions and at times other than bedtime.

Insight-oriented psychotherapy may enhance patients’ awareness of psychological conflicts from their past that may be producing anxiety and contributing to sleeplessness.

PRESCRIBING HYPNOTICS

Sedative-hypnotics are indicated primarily for short-term management of insomnia. Most are used prophylactically at bedtime until insomnia dissipates or the physician advises the patient to take a break.

Treatment principles. Because many insomnias are recurrent, prolonged hypnotic treatment given in short bouts is often optimal. Longer treatment—months to years—is not recommended by standard textbooks but is clearly needed by a small number of patients with chronic insomnia. In these cases, carefully monitor for tolerance, as manifested by dosage escalation. Long-term hypnotic treatment is not suitable for patients with drug abuse or dependence histories.

Table 2

How to get a good night’s sleep

Although chloral hydrate and barbiturates are effective hypnotics, adverse effects limit their safety and usefulness. Benzodiazepines and more recently introduced agents have milder side effect profiles (Table 3). Choose agents based on the patient’s situation, preferences, and effects of prior trials with similar agents. Guidelines for hypnotics discourage chronic use to minimize abuse, misuse, and habituation (Table 4).

Elimination half-life is the primary pharmacokinetic property that differentiates the hypnotics from each other:¹³

• longer half-life: flurazepam, quazepam
• intermediate half-life: estazolam, temazepam
• short half-life: triazolam, zolpidem, zaleplon (Table 3).

Table 3

Actions and available doses of common hypnotics

Whereas benzodiazepines bind to benzodiazepine receptor types 1 and 2, zolpidem and zaleplon (and possibly quazepam) bind selectively to type 1. This selectivity may explain why zolpidem and zaleplon are more easily tolerated.

Hypnotic agents with relatively longer half-lives tend to be associated with greater potential for residual daytime effects such as sedation, motor incoordination, amnesia, and slowed reflexes. These effects may impair performance and increase the risk of auto accidents and injuries, especially hip fractures in the elderly.

Nonbenzodiazepines. Because of its ultra-short half-life, zaleplon is least likely to cause residual daytime effects when administered at bedtime. At 10-mg doses, its side effects seem to last no more than 4 hours following administration. Zaleplon can be safely taken after nocturnal awakenings if the patient remains in bed 4 hours or longer after taking it.¹⁴

Some patients feel that taking zaleplon only when needed allows them to use hypnotics more sparingly. On the other hand, zaleplon’s ultrashort half-life makes it less useful for patients who have frequent episodes of sleep-interruption insomnia every night. For them, a longer elimination half-life agent such as zolpidem may be more predictably effective for the entire night.¹⁵ Short half-life hypnotics have many advantages, but they do not offer anxiolysis for patients with daytime anxiety, as the longer half-life agents do.

Tolerance and rebound. Tolerance can develop following repeated dosing with benzodiazepines—primarily triazolam—and rebound insomnia can follow abrupt discontinuation. Despite widespread concerns, neither tolerance nor rebound insomnia has been well documented. Nevertheless, both can be minimized by using benzodiazepines at the lowest effective dosages and for brief periods. Gradual tapering when discontinuing the drug can help control rebound.

Tolerance and rebound seem to be less of a concern with the newer hypnotics than with benzodiazepines. In preliminary uncontrolled trials, zolpidem and zaleplon did not show evidence of these problems in 1 year of continued use.

NONHYPNOTIC SLEEP AIDS

Sedating antidepressants. Physicians often prescribe low doses of sedating antidepressants to control insomnia, a practice supported by some controlled clinical trials. For example, polysomnography showed that patients who took doxepin, 25 to 50 mg at bedtime, had enhanced sleep efficiency (ratio of time slept to time spent in bed) yet no change in sleep latency. Liver abnormalities, leukopenia, and thrombopenia developed in a few patients.¹⁶ Controlled studies have also shown subjective efficacy of trazodone¹⁷ and trimipramine¹⁸ in treating insomnia.

Some physicians advocate using the more sedating antidepressants—at dosages needed to treat depression—to control insomnia in depressed patients. Evening dosing can minimize daytime sedation. If you choose an activating antidepressant, the potential side effect of insomnia can be managed by judicious use of hypnotic agents. Little is known about antidepressants’ effects on sleep quality after the first 6 to 8 weeks of treatment.¹⁹

Although possibly helpful as sleep aids, antidepressants are also associated with side effects. Trazodone, for example, may cause daytime sedation, orthostatic hypotension, and priapism. As a class, the tricyclics are associated with anticholinergic effects such as dry mouth, urinary flow difficulties, and cardiac dysrhythmias.

Table 4

Guidelines for safe use of hypnotics

Alcohol. Patients with insomnia often self-medicate with agents that are not specifically indicated to induce sleep. Alcohol is widely used at bedtime because it enhances sleepiness and induces a more rapid sleep onset.²⁰ Drinking a “nightcap” is a poor choice, however, because alcohol—especially after prolonged use—can impair sleep quality, resulting in daytime somnolence. Alcohol is also associated with rapid development of tolerance.

Patients who use alcohol report unrefreshing and disturbed sleep, with frequent nocturnal awakenings even after prolonged abstinence. Alcohol also can further impair sleep-related respiration in patients with obstructive sleep apnea syndrome.

Antihistamines and over-the-counter products whose main active ingredients are antihistamines—such as doxylamine and diphenhydramine—can cause unpredictable efficacy and side effects such as daytime sedation, confusion, and systemic anticholinergic effects.²¹

Melatonin is a dietary supplement used in dosages of 0.5 to 3,000 mg. Anecdotal reports indicate it may be efficacious in certain subtypes of insomnia—such as shift work, jetlag, blindness, delayed sleep phase syndrome—and in the elderly. However, melatonin’s efficacy has not been established conclusively and is in doubt. Concerns have been expressed regarding the purity of available preparations and possible coronary artery tissue stimulation, as observed in animal studies of melatonin.

Related resources

• American Academy of Sleep Medicine. Sleep logs, patient education materials. www.aasmnet.org
• American Sleep Apnea Association. www.sleepapnea.org
• National Sleep Foundation. www.sleepfoundation.org

Drug brand names

• Amitriptyline • Elavil
• Bupropion • Wellbutrin
• Citalopram • Celexa
• Doxepin • Sinequan
• Escitalopram • Lexapro
• Estazolam • Prosom
• Flurazepam • Dalmane
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Protriptyline • Vivactil
• Quazepam • Doral
• Temazepam • Restoril
• Trazodone • Desyrel
• Triazolam • Halcion
• Trimipramine • Surmontil
• Venlafaxine • Effexor
• Zaleplon • Sonata
• Zolpidem • Ambien

Disclosure

Dr. Doghramji receives research grant support from Cephalon Inc., GlaxoSmithKline, Merck & Co., and Sanofi-Synthelabo.

Careful investigation can often reveal insomnia’s cause¹—whether a psychiatric or medical condition or poor sleep habits. Understanding why patients can’t sleep is key to effective therapy.

Acute and chronic sleep deprivation is associated with measurable declines in daytime performance (Box). Some data even suggest that long-term sleeplessness increases the risk of new psychiatric disorders—most notably major depression.³

PSYCHIATRIC DISORDERS AND INSOMNIA

Depression. Many depressed persons—up to 80%—experience insomnia, although no one sleep pattern seems typical.² Depression may be associated with:

• difficulties in falling asleep
• interrupted nocturnal sleep
• and early morning awakening.

Anxiety disorders. Generalized anxiety disorder (GAD), social phobia, panic attacks, and posttraumatic stress disorder (PTSD) are all associated with disrupted sleep. Patients with GAD experience prolonged sleep latency (time needed to fall asleep after lights out) and fragmented sleep, similar to those with primary insomnia.

Box

Subjective sleep quality may be impaired in patients with social phobia. Some patients experience panic symptoms while sleeping, possibly in association with mild hypercapnia. Patients with sleep panic attacks tend to have earlier onset of panic disorder and a higher likelihood of comorbid mood and other anxiety disorders.⁴

In patients with PTSD, disturbed sleep continuity and increased REM phasic activity—such as eye movements—are directly correlated with severity of PTSD symptoms. Nightmares and disturbed REM sleep are hypothesized hallmarks of PTSD.⁵

Schizophrenia. Patients with schizophrenia often have disrupted sleep patterns. These include prolonged sleep latency, fragmented sleep with frequent arousals, decreased slow-wave sleep, variable REM latency, and decreased REM rebound after sleep deprivation. Despite investigations going back to the 1950s, no specific link between REM sleep and psychosis has been found.⁶ Interestingly, increases in REM sleep time and REM activity have been associated with an increased risk of suicide in patients with schizophrenia.⁷

Adjustment sleep disorder. Acute emotional stressors—such as bereavement, job loss, or hospitalization—often cause adjustment sleep disorder. Symptoms typically remit soon after the stressors abate, so this transient insomnia usually lasts a few days to a few weeks. Treatment with behavioral therapies and hypnotics⁸ is warranted if:

• sleepiness and fatigue interfere with daytime functioning
• a pattern of recurring episodes develops.⁹

Psychophysiologic insomnia. Once initiated—regardless of cause—insomnia may persist well after its precipitating factors resolve. Thus, short-term insomnia may develop into long-term, chronic difficulty with recurring episodes or a constant, daily pattern of insomnia. Sufferers often spend hours in bed awake focused upon—and brooding over—their sleeplessness. which in turn further aggravates their insomnia.

Adjustment sleep disorder and psychophysiologic insomnia are included within DSM-IV’s term “primary insomnia.”

OTHER CAUSES OF INSOMNIA

Medications that may affect sleep quality include antidepressants (Table 1),^10,11 antihypertensives, antineoplastic agents, bronchodilators, stimulants, corticosteroids, decongestants, diuretics, histamine-2 receptor blockers, and smoking cessation aids.

Recreational drugs, such as cocaine, often cause insomnia. Hypnotics and anxiolytics can cause insomnia following long-term use and during withdrawal.

Other disorders known to disturb sleep include periodic limb movement disorder (PLMD), restless legs syndrome (RLS), sleep apnea syndrome, disrupted circadian rhythms (as with travel or shift work), cardiopulmonary disorders, chronic pain, diabetes, hyperthyroidism, hot flashes associated with menopause, seizures, dementia, and Parkinson’s disease, to name a few.

WORKUP OF SLEEP COMPLAINTS

Acute. Most short-term insomnias—lasting a few weeks or less—are caused by situational stressors, circadian rhythm alterations, and sleep hygiene violations. A logical initial approach, therefore, is to combine sleep hygiene measures with supportive psychotherapy. Hypnotic agents may be considered for apparent daytime consequences—such as sleepiness and occupational impairment—or if the insomnia seems to be escalating.

Chronic. For longer-term insomnias—lasting more than a few weeks—consider a more thorough evaluation, including medical and psychiatric history, physical examination, and mental status examination. Inquire about cardinal symptoms of disorders associated with insomnia, including:

• snoring or breathing pauses during sleep (sleep apnea syndrome)
• restlessness or twitching in the lower extremities (PLMS/RLS).

Question the bed partner, who may be more aware of such symptoms than the patient. Carefully review sleep patterns on weekdays and weekends, bedtime habits, sleep hygiene habits, and substance and medication use.

Table 1

Antidepressants’ effects on sleep and wakefulness

Sleep clinic referrals. Consider an evaluation by a sleep disorders center when:

• the diagnosis remains unclear
• or treatment of the presumed conditions fails after a reasonable time

BEHAVIORAL TREATMENTS

Behavioral treatments—with or without hypnotics—are appropriate for a wide variety of insomnia complaints, including adjustment sleep disorder, psychophysiologic insomnia, and depression. Behavioral measures may take longer to implement than drug therapy, but their effects have been shown to last longer in patients with primary insomnia. In many cases, it may be useful to start with both hypnotic and behavioral treatments and withdraw the hypnotic after behavioral measures take effect.

Sleep hygiene. Many individuals unknowingly engage in habitual behaviors that impair sleep. Those with insomnia, for example, often try to compensate for lost sleep by staying in bed later in the morning or by napping, which further fragment nocturnal sleep. Advise these patients to adhere to a regular awakening time—regardless of how long they slept the night before—and to avoid naps. Other tips for getting a good night’s sleep are outlined in Table 2.¹²

Caffeine has a plasma half-life of 3 to 7 hours, although individual sensitivity varies widely and caffeine’s erratic absorption can prolong its effects. Advise patients with insomnia to avoid caffeine-containing beverages—including coffee, tea, and soft drinks—after noon.

Relaxation training. Muscle tension can be reduced through electromyography (EMG) biofeedback, abdominal breathing exercises, or progressive muscle relaxation techniques, among others. Relaxation training is usually effective within a few weeks.

Psychotherapy. Cognitive-behavioral therapy can help identify and dispel tension-producing thoughts that are disrupting sleep, such as preoccupation with unpleasant work experiences or school examinations. Reassurance may help patients overcome fears about sleeplessness; suggest that patients deal with anxiety-producing thoughts during therapy sessions and at times other than bedtime.

Insight-oriented psychotherapy may enhance patients’ awareness of psychological conflicts from their past that may be producing anxiety and contributing to sleeplessness.

PRESCRIBING HYPNOTICS

Sedative-hypnotics are indicated primarily for short-term management of insomnia. Most are used prophylactically at bedtime until insomnia dissipates or the physician advises the patient to take a break.

Treatment principles. Because many insomnias are recurrent, prolonged hypnotic treatment given in short bouts is often optimal. Longer treatment—months to years—is not recommended by standard textbooks but is clearly needed by a small number of patients with chronic insomnia. In these cases, carefully monitor for tolerance, as manifested by dosage escalation. Long-term hypnotic treatment is not suitable for patients with drug abuse or dependence histories.

Table 2

How to get a good night’s sleep

Although chloral hydrate and barbiturates are effective hypnotics, adverse effects limit their safety and usefulness. Benzodiazepines and more recently introduced agents have milder side effect profiles (Table 3). Choose agents based on the patient’s situation, preferences, and effects of prior trials with similar agents. Guidelines for hypnotics discourage chronic use to minimize abuse, misuse, and habituation (Table 4).

Elimination half-life is the primary pharmacokinetic property that differentiates the hypnotics from each other:¹³

• longer half-life: flurazepam, quazepam
• intermediate half-life: estazolam, temazepam
• short half-life: triazolam, zolpidem, zaleplon (Table 3).

Table 3

Actions and available doses of common hypnotics

Whereas benzodiazepines bind to benzodiazepine receptor types 1 and 2, zolpidem and zaleplon (and possibly quazepam) bind selectively to type 1. This selectivity may explain why zolpidem and zaleplon are more easily tolerated.

Hypnotic agents with relatively longer half-lives tend to be associated with greater potential for residual daytime effects such as sedation, motor incoordination, amnesia, and slowed reflexes. These effects may impair performance and increase the risk of auto accidents and injuries, especially hip fractures in the elderly.

Nonbenzodiazepines. Because of its ultra-short half-life, zaleplon is least likely to cause residual daytime effects when administered at bedtime. At 10-mg doses, its side effects seem to last no more than 4 hours following administration. Zaleplon can be safely taken after nocturnal awakenings if the patient remains in bed 4 hours or longer after taking it.¹⁴

Some patients feel that taking zaleplon only when needed allows them to use hypnotics more sparingly. On the other hand, zaleplon’s ultrashort half-life makes it less useful for patients who have frequent episodes of sleep-interruption insomnia every night. For them, a longer elimination half-life agent such as zolpidem may be more predictably effective for the entire night.¹⁵ Short half-life hypnotics have many advantages, but they do not offer anxiolysis for patients with daytime anxiety, as the longer half-life agents do.

Tolerance and rebound. Tolerance can develop following repeated dosing with benzodiazepines—primarily triazolam—and rebound insomnia can follow abrupt discontinuation. Despite widespread concerns, neither tolerance nor rebound insomnia has been well documented. Nevertheless, both can be minimized by using benzodiazepines at the lowest effective dosages and for brief periods. Gradual tapering when discontinuing the drug can help control rebound.

Tolerance and rebound seem to be less of a concern with the newer hypnotics than with benzodiazepines. In preliminary uncontrolled trials, zolpidem and zaleplon did not show evidence of these problems in 1 year of continued use.

NONHYPNOTIC SLEEP AIDS

Sedating antidepressants. Physicians often prescribe low doses of sedating antidepressants to control insomnia, a practice supported by some controlled clinical trials. For example, polysomnography showed that patients who took doxepin, 25 to 50 mg at bedtime, had enhanced sleep efficiency (ratio of time slept to time spent in bed) yet no change in sleep latency. Liver abnormalities, leukopenia, and thrombopenia developed in a few patients.¹⁶ Controlled studies have also shown subjective efficacy of trazodone¹⁷ and trimipramine¹⁸ in treating insomnia.

Some physicians advocate using the more sedating antidepressants—at dosages needed to treat depression—to control insomnia in depressed patients. Evening dosing can minimize daytime sedation. If you choose an activating antidepressant, the potential side effect of insomnia can be managed by judicious use of hypnotic agents. Little is known about antidepressants’ effects on sleep quality after the first 6 to 8 weeks of treatment.¹⁹

Although possibly helpful as sleep aids, antidepressants are also associated with side effects. Trazodone, for example, may cause daytime sedation, orthostatic hypotension, and priapism. As a class, the tricyclics are associated with anticholinergic effects such as dry mouth, urinary flow difficulties, and cardiac dysrhythmias.

Table 4

Guidelines for safe use of hypnotics

Alcohol. Patients with insomnia often self-medicate with agents that are not specifically indicated to induce sleep. Alcohol is widely used at bedtime because it enhances sleepiness and induces a more rapid sleep onset.²⁰ Drinking a “nightcap” is a poor choice, however, because alcohol—especially after prolonged use—can impair sleep quality, resulting in daytime somnolence. Alcohol is also associated with rapid development of tolerance.

Patients who use alcohol report unrefreshing and disturbed sleep, with frequent nocturnal awakenings even after prolonged abstinence. Alcohol also can further impair sleep-related respiration in patients with obstructive sleep apnea syndrome.

Antihistamines and over-the-counter products whose main active ingredients are antihistamines—such as doxylamine and diphenhydramine—can cause unpredictable efficacy and side effects such as daytime sedation, confusion, and systemic anticholinergic effects.²¹

Melatonin is a dietary supplement used in dosages of 0.5 to 3,000 mg. Anecdotal reports indicate it may be efficacious in certain subtypes of insomnia—such as shift work, jetlag, blindness, delayed sleep phase syndrome—and in the elderly. However, melatonin’s efficacy has not been established conclusively and is in doubt. Concerns have been expressed regarding the purity of available preparations and possible coronary artery tissue stimulation, as observed in animal studies of melatonin.

Related resources

• American Academy of Sleep Medicine. Sleep logs, patient education materials. www.aasmnet.org
• American Sleep Apnea Association. www.sleepapnea.org
• National Sleep Foundation. www.sleepfoundation.org

Drug brand names

• Amitriptyline • Elavil
• Bupropion • Wellbutrin
• Citalopram • Celexa
• Doxepin • Sinequan
• Escitalopram • Lexapro
• Estazolam • Prosom
• Flurazepam • Dalmane
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Protriptyline • Vivactil
• Quazepam • Doral
• Temazepam • Restoril
• Trazodone • Desyrel
• Triazolam • Halcion
• Trimipramine • Surmontil
• Venlafaxine • Effexor
• Zaleplon • Sonata
• Zolpidem • Ambien

Disclosure

Dr. Doghramji receives research grant support from Cephalon Inc., GlaxoSmithKline, Merck & Co., and Sanofi-Synthelabo.

Careful investigation can often reveal insomnia’s cause¹—whether a psychiatric or medical condition or poor sleep habits. Understanding why patients can’t sleep is key to effective therapy.

Acute and chronic sleep deprivation is associated with measurable declines in daytime performance (Box). Some data even suggest that long-term sleeplessness increases the risk of new psychiatric disorders—most notably major depression.³

PSYCHIATRIC DISORDERS AND INSOMNIA

Depression. Many depressed persons—up to 80%—experience insomnia, although no one sleep pattern seems typical.² Depression may be associated with:

• difficulties in falling asleep
• interrupted nocturnal sleep
• and early morning awakening.

Anxiety disorders. Generalized anxiety disorder (GAD), social phobia, panic attacks, and posttraumatic stress disorder (PTSD) are all associated with disrupted sleep. Patients with GAD experience prolonged sleep latency (time needed to fall asleep after lights out) and fragmented sleep, similar to those with primary insomnia.

Box

Subjective sleep quality may be impaired in patients with social phobia. Some patients experience panic symptoms while sleeping, possibly in association with mild hypercapnia. Patients with sleep panic attacks tend to have earlier onset of panic disorder and a higher likelihood of comorbid mood and other anxiety disorders.⁴

In patients with PTSD, disturbed sleep continuity and increased REM phasic activity—such as eye movements—are directly correlated with severity of PTSD symptoms. Nightmares and disturbed REM sleep are hypothesized hallmarks of PTSD.⁵

Schizophrenia. Patients with schizophrenia often have disrupted sleep patterns. These include prolonged sleep latency, fragmented sleep with frequent arousals, decreased slow-wave sleep, variable REM latency, and decreased REM rebound after sleep deprivation. Despite investigations going back to the 1950s, no specific link between REM sleep and psychosis has been found.⁶ Interestingly, increases in REM sleep time and REM activity have been associated with an increased risk of suicide in patients with schizophrenia.⁷

Adjustment sleep disorder. Acute emotional stressors—such as bereavement, job loss, or hospitalization—often cause adjustment sleep disorder. Symptoms typically remit soon after the stressors abate, so this transient insomnia usually lasts a few days to a few weeks. Treatment with behavioral therapies and hypnotics⁸ is warranted if:

• sleepiness and fatigue interfere with daytime functioning
• a pattern of recurring episodes develops.⁹

Psychophysiologic insomnia. Once initiated—regardless of cause—insomnia may persist well after its precipitating factors resolve. Thus, short-term insomnia may develop into long-term, chronic difficulty with recurring episodes or a constant, daily pattern of insomnia. Sufferers often spend hours in bed awake focused upon—and brooding over—their sleeplessness. which in turn further aggravates their insomnia.

Adjustment sleep disorder and psychophysiologic insomnia are included within DSM-IV’s term “primary insomnia.”

OTHER CAUSES OF INSOMNIA

Medications that may affect sleep quality include antidepressants (Table 1),^10,11 antihypertensives, antineoplastic agents, bronchodilators, stimulants, corticosteroids, decongestants, diuretics, histamine-2 receptor blockers, and smoking cessation aids.

Recreational drugs, such as cocaine, often cause insomnia. Hypnotics and anxiolytics can cause insomnia following long-term use and during withdrawal.

Other disorders known to disturb sleep include periodic limb movement disorder (PLMD), restless legs syndrome (RLS), sleep apnea syndrome, disrupted circadian rhythms (as with travel or shift work), cardiopulmonary disorders, chronic pain, diabetes, hyperthyroidism, hot flashes associated with menopause, seizures, dementia, and Parkinson’s disease, to name a few.

WORKUP OF SLEEP COMPLAINTS

Acute. Most short-term insomnias—lasting a few weeks or less—are caused by situational stressors, circadian rhythm alterations, and sleep hygiene violations. A logical initial approach, therefore, is to combine sleep hygiene measures with supportive psychotherapy. Hypnotic agents may be considered for apparent daytime consequences—such as sleepiness and occupational impairment—or if the insomnia seems to be escalating.

Chronic. For longer-term insomnias—lasting more than a few weeks—consider a more thorough evaluation, including medical and psychiatric history, physical examination, and mental status examination. Inquire about cardinal symptoms of disorders associated with insomnia, including:

• snoring or breathing pauses during sleep (sleep apnea syndrome)
• restlessness or twitching in the lower extremities (PLMS/RLS).

Question the bed partner, who may be more aware of such symptoms than the patient. Carefully review sleep patterns on weekdays and weekends, bedtime habits, sleep hygiene habits, and substance and medication use.

Table 1

Antidepressants’ effects on sleep and wakefulness

Sleep clinic referrals. Consider an evaluation by a sleep disorders center when:

• the diagnosis remains unclear
• or treatment of the presumed conditions fails after a reasonable time

BEHAVIORAL TREATMENTS

Behavioral treatments—with or without hypnotics—are appropriate for a wide variety of insomnia complaints, including adjustment sleep disorder, psychophysiologic insomnia, and depression. Behavioral measures may take longer to implement than drug therapy, but their effects have been shown to last longer in patients with primary insomnia. In many cases, it may be useful to start with both hypnotic and behavioral treatments and withdraw the hypnotic after behavioral measures take effect.

Sleep hygiene. Many individuals unknowingly engage in habitual behaviors that impair sleep. Those with insomnia, for example, often try to compensate for lost sleep by staying in bed later in the morning or by napping, which further fragment nocturnal sleep. Advise these patients to adhere to a regular awakening time—regardless of how long they slept the night before—and to avoid naps. Other tips for getting a good night’s sleep are outlined in Table 2.¹²

Caffeine has a plasma half-life of 3 to 7 hours, although individual sensitivity varies widely and caffeine’s erratic absorption can prolong its effects. Advise patients with insomnia to avoid caffeine-containing beverages—including coffee, tea, and soft drinks—after noon.

Relaxation training. Muscle tension can be reduced through electromyography (EMG) biofeedback, abdominal breathing exercises, or progressive muscle relaxation techniques, among others. Relaxation training is usually effective within a few weeks.

Psychotherapy. Cognitive-behavioral therapy can help identify and dispel tension-producing thoughts that are disrupting sleep, such as preoccupation with unpleasant work experiences or school examinations. Reassurance may help patients overcome fears about sleeplessness; suggest that patients deal with anxiety-producing thoughts during therapy sessions and at times other than bedtime.

Insight-oriented psychotherapy may enhance patients’ awareness of psychological conflicts from their past that may be producing anxiety and contributing to sleeplessness.

PRESCRIBING HYPNOTICS

Sedative-hypnotics are indicated primarily for short-term management of insomnia. Most are used prophylactically at bedtime until insomnia dissipates or the physician advises the patient to take a break.

Treatment principles. Because many insomnias are recurrent, prolonged hypnotic treatment given in short bouts is often optimal. Longer treatment—months to years—is not recommended by standard textbooks but is clearly needed by a small number of patients with chronic insomnia. In these cases, carefully monitor for tolerance, as manifested by dosage escalation. Long-term hypnotic treatment is not suitable for patients with drug abuse or dependence histories.

Table 2

How to get a good night’s sleep

Although chloral hydrate and barbiturates are effective hypnotics, adverse effects limit their safety and usefulness. Benzodiazepines and more recently introduced agents have milder side effect profiles (Table 3). Choose agents based on the patient’s situation, preferences, and effects of prior trials with similar agents. Guidelines for hypnotics discourage chronic use to minimize abuse, misuse, and habituation (Table 4).

Elimination half-life is the primary pharmacokinetic property that differentiates the hypnotics from each other:¹³

• longer half-life: flurazepam, quazepam
• intermediate half-life: estazolam, temazepam
• short half-life: triazolam, zolpidem, zaleplon (Table 3).

Table 3

Actions and available doses of common hypnotics

Whereas benzodiazepines bind to benzodiazepine receptor types 1 and 2, zolpidem and zaleplon (and possibly quazepam) bind selectively to type 1. This selectivity may explain why zolpidem and zaleplon are more easily tolerated.

Hypnotic agents with relatively longer half-lives tend to be associated with greater potential for residual daytime effects such as sedation, motor incoordination, amnesia, and slowed reflexes. These effects may impair performance and increase the risk of auto accidents and injuries, especially hip fractures in the elderly.

Nonbenzodiazepines. Because of its ultra-short half-life, zaleplon is least likely to cause residual daytime effects when administered at bedtime. At 10-mg doses, its side effects seem to last no more than 4 hours following administration. Zaleplon can be safely taken after nocturnal awakenings if the patient remains in bed 4 hours or longer after taking it.¹⁴

Some patients feel that taking zaleplon only when needed allows them to use hypnotics more sparingly. On the other hand, zaleplon’s ultrashort half-life makes it less useful for patients who have frequent episodes of sleep-interruption insomnia every night. For them, a longer elimination half-life agent such as zolpidem may be more predictably effective for the entire night.¹⁵ Short half-life hypnotics have many advantages, but they do not offer anxiolysis for patients with daytime anxiety, as the longer half-life agents do.

Tolerance and rebound. Tolerance can develop following repeated dosing with benzodiazepines—primarily triazolam—and rebound insomnia can follow abrupt discontinuation. Despite widespread concerns, neither tolerance nor rebound insomnia has been well documented. Nevertheless, both can be minimized by using benzodiazepines at the lowest effective dosages and for brief periods. Gradual tapering when discontinuing the drug can help control rebound.

Tolerance and rebound seem to be less of a concern with the newer hypnotics than with benzodiazepines. In preliminary uncontrolled trials, zolpidem and zaleplon did not show evidence of these problems in 1 year of continued use.

NONHYPNOTIC SLEEP AIDS

Sedating antidepressants. Physicians often prescribe low doses of sedating antidepressants to control insomnia, a practice supported by some controlled clinical trials. For example, polysomnography showed that patients who took doxepin, 25 to 50 mg at bedtime, had enhanced sleep efficiency (ratio of time slept to time spent in bed) yet no change in sleep latency. Liver abnormalities, leukopenia, and thrombopenia developed in a few patients.¹⁶ Controlled studies have also shown subjective efficacy of trazodone¹⁷ and trimipramine¹⁸ in treating insomnia.

Some physicians advocate using the more sedating antidepressants—at dosages needed to treat depression—to control insomnia in depressed patients. Evening dosing can minimize daytime sedation. If you choose an activating antidepressant, the potential side effect of insomnia can be managed by judicious use of hypnotic agents. Little is known about antidepressants’ effects on sleep quality after the first 6 to 8 weeks of treatment.¹⁹

Although possibly helpful as sleep aids, antidepressants are also associated with side effects. Trazodone, for example, may cause daytime sedation, orthostatic hypotension, and priapism. As a class, the tricyclics are associated with anticholinergic effects such as dry mouth, urinary flow difficulties, and cardiac dysrhythmias.

Table 4

Guidelines for safe use of hypnotics

Alcohol. Patients with insomnia often self-medicate with agents that are not specifically indicated to induce sleep. Alcohol is widely used at bedtime because it enhances sleepiness and induces a more rapid sleep onset.²⁰ Drinking a “nightcap” is a poor choice, however, because alcohol—especially after prolonged use—can impair sleep quality, resulting in daytime somnolence. Alcohol is also associated with rapid development of tolerance.

Patients who use alcohol report unrefreshing and disturbed sleep, with frequent nocturnal awakenings even after prolonged abstinence. Alcohol also can further impair sleep-related respiration in patients with obstructive sleep apnea syndrome.

Antihistamines and over-the-counter products whose main active ingredients are antihistamines—such as doxylamine and diphenhydramine—can cause unpredictable efficacy and side effects such as daytime sedation, confusion, and systemic anticholinergic effects.²¹

Melatonin is a dietary supplement used in dosages of 0.5 to 3,000 mg. Anecdotal reports indicate it may be efficacious in certain subtypes of insomnia—such as shift work, jetlag, blindness, delayed sleep phase syndrome—and in the elderly. However, melatonin’s efficacy has not been established conclusively and is in doubt. Concerns have been expressed regarding the purity of available preparations and possible coronary artery tissue stimulation, as observed in animal studies of melatonin.

Related resources

• American Academy of Sleep Medicine. Sleep logs, patient education materials. www.aasmnet.org
• American Sleep Apnea Association. www.sleepapnea.org
• National Sleep Foundation. www.sleepfoundation.org

Drug brand names

• Amitriptyline • Elavil
• Bupropion • Wellbutrin
• Citalopram • Celexa
• Doxepin • Sinequan
• Escitalopram • Lexapro
• Estazolam • Prosom
• Flurazepam • Dalmane
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Protriptyline • Vivactil
• Quazepam • Doral
• Temazepam • Restoril
• Trazodone • Desyrel
• Triazolam • Halcion
• Trimipramine • Surmontil
• Venlafaxine • Effexor
• Zaleplon • Sonata
• Zolpidem • Ambien

Disclosure

Dr. Doghramji receives research grant support from Cephalon Inc., GlaxoSmithKline, Merck & Co., and Sanofi-Synthelabo.

Supplement Editor:
Alejandro C. Arroliga, MD

Contents

Primary pulmonary hypertension: An overview of epidemiology and pathogenesis
Z.W. Ghamra, MD, and R.A. Dweik, MD

Diagnosis and evaluation of pulmonary hypertension
M.M. Budev, DO, MPH; A.C. Arroliga, MD; and C.A. Jennings, MD

Treatments and strategies to optimize the comprehensive management of patients with pulmonary arterial hypertension
T.R. Gildea, MD; A.C. Arroliga, MD; and O.A. Minai, MD

Implementing a shared-care approach to improve the management of patients with pulmonary arterial hypertension
M.M. Mughal, MD; B. Mandell, MD, PhD; K. James, MD; K. Stelmach, RN; and O.A. Minai, MD

Supplement Editor:
Alejandro C. Arroliga, MD

Contents

Primary pulmonary hypertension: An overview of epidemiology and pathogenesis
Z.W. Ghamra, MD, and R.A. Dweik, MD

Diagnosis and evaluation of pulmonary hypertension
M.M. Budev, DO, MPH; A.C. Arroliga, MD; and C.A. Jennings, MD

Treatments and strategies to optimize the comprehensive management of patients with pulmonary arterial hypertension
T.R. Gildea, MD; A.C. Arroliga, MD; and O.A. Minai, MD

Implementing a shared-care approach to improve the management of patients with pulmonary arterial hypertension
M.M. Mughal, MD; B. Mandell, MD, PhD; K. James, MD; K. Stelmach, RN; and O.A. Minai, MD

Supplement Editor:
Alejandro C. Arroliga, MD

Contents

Primary pulmonary hypertension: An overview of epidemiology and pathogenesis
Z.W. Ghamra, MD, and R.A. Dweik, MD

Diagnosis and evaluation of pulmonary hypertension
M.M. Budev, DO, MPH; A.C. Arroliga, MD; and C.A. Jennings, MD

Treatments and strategies to optimize the comprehensive management of patients with pulmonary arterial hypertension
T.R. Gildea, MD; A.C. Arroliga, MD; and O.A. Minai, MD

Implementing a shared-care approach to improve the management of patients with pulmonary arterial hypertension
M.M. Mughal, MD; B. Mandell, MD, PhD; K. James, MD; K. Stelmach, RN; and O.A. Minai, MD