In dose escalation studies using up to 60 mg, symptoms appear at

approximately 30 minutes after dosing, peak at 1 to 2 hours, and are no longer

evident after 4 hours. It can be taken in the middle of the night as long as the

individual has 4 hours left in bed. Zaleplon is metabolized primarily via aldehyde

oxidase, CYP3A4 is a secondary route of metabolism, and there are no active

metabolites; it has less potential for drug or food interactions compared with

zolpidem or eszopiclone.

41

Eszopiclone maintains efficacy with no evidence of tolerance after 6 months of

continuous use, resulting in FDA approval for long-term use.

59–62 Hypnotic efficacy

has been demonstrated for up to 6 months in younger patients taking 2 to 3 mg nightly,

and in elderly patients taking 1 to 2 mg nightly, although only the higher range of

doses significantly improved sleep maintenance. As with zolpidem and zaleplon,

eszopiclone has a rapid onset of effect, but differs in that it has a longer duration of

effect (Table 84-3). Time to maximal concentration (Tmax

) is delayed up to 1 hour

when eszopiclone is administered after a high-fat meal, potentially delaying the onset

of sleep.

59,60

Eszopiclone has less receptor selectivity than either zaleplon or zolpidem,

potentially resulting in some anxiolytic, amnestic, and anticonvulsant activity.

61

Among the three Z-hypnotic drugs, eszopiclone has a dose-related unpleasant bitter

taste noted by 16% to 34% of patients.

59,60 Headache and dizziness were reported

more commonly with eszopiclone than placebo, and at higher doses, next-day

confusion and memory impairment were reported in up to 3% of patients.

38,60

Eszopiclone is primarily metabolized by CYP3A4, so drugs that induce or inhibit this

isoenzyme can have an impact on metabolism and a clinical effect.

60

P.B. needs a medication that will hasten sleep onset, but does not need continued

drug effect later in the night. Both zolpidem and zaleplon are useful alternatives for

P.B. because of their efficacy for his sleep onset difficulty. However, zaleplon may

be preferred due to quick onset and short half-life to mitigate the risk of next-day

hangover. Among the NBRAs, eszopiclone has the longest half-life and the greatest

risk for next-day impairment.

CASE 84-1, QUESTION 9: Zolpidem 5 mg is prescribed because of its rapid onset, low cost, and lower risk

for next-day impairment. P.B. expresses concern about possible adverse effects owing to its labeling as a

Schedule IV controlled substance and the FDA warning of complex sleep behaviors such as night eating and

night driving. How should P.B.’s concerns be addressed?

Patient counseling is most effective when it is interactive with both patient and

practitioner actively listening to each other while exchanging information. It is best to

begin by emphasizing the benefits of zaleplon to improve his sleep and daytime

functioning. Next, P.B. should be reassured that zaleplon is generally well tolerated

and he will be prescribed the lowest dose to minimize the likelihood of adverse

effects. Counseling should include a discussion of common and potentially serious

adverse effects along with management strategies. Common possible adverse effects

include headache (30%), abdominal pain (6%), asthenia (5%), somnolence (5%),

and dizziness (7%).

38,58 Anaphylactoid reactions and nightmares have been reported

in postmarketing studies. Additionally, P.B. should be encouraged to report both

effectiveness and all adverse effects to his clinician. Alcohol should not be

consumed together with zaleplon or any NBRA because it can cause excessive side

effects and interfere with P.B.’s sleep.

To address P.B.’s concern regarding complex sleep behaviors, a reasonable

response would be “rarely, individuals taking sleeping medication have been

reported to be making phone calls, eating, having sex, or driving while half asleep.

The risk for these potentially dangerous effects increases if consumers take a higher

than the recommended dose, or drink alcohol or mix hypnotics with other sedating

medications.”

14 Another rare allergic reaction is facial swelling (angioedema). All

manufacturers of hypnotic medication are required to include this information in their

package inserts.

14

Although the abuse potential of NBRAs is less than benzodiazepines, they are

problematic in active substance abuse disorders. NBRAs are Schedule IV controlled

substances with more potential for abuse than ramelteon or sedating antidepressants,

like trazodone.

48 Tolerance and withdrawal associated with NBRAs is unlikely but

reported with abrupt discontinuation and patients should be counseled of this

possibility, particularly at high doses.

CASE 84-1, QUESTION 10: P.B. asks about a new sleep medication, suvorexant, and whether he could use

this to help him sleep. What information can you provide P.B. regarding the safety and efficacy of suvorexant

for insomnia?

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Suvorexant is an orexin receptor antagonist FDA-approved in 2014 for treatment

of insomnia characterized by difficulty falling asleep and/or maintaining sleep. The

orexin signaling pathway promotes wakefulness and arousal; antagonism of orexin

receptors can promote sleep. Studies show that suvorexant can decrease latency to

onset of sleep and wake after sleep onset without disrupting the sleep architecture.

The initial recommended daily dose is 10 mg within 30 minutes of bedtime and with

at least 7 hours of sleep time available. Suvorexant should be taken on an empty

stomach as time to sleep onset may be delayed by 1.5 hours if taken with or soon

after a meal. If needed, the dose can be increased in 5 mg increments to the maximum

recommended daily dose of 20 mg at bedtime. Suvorexant is a CYP3A substrate and

a dose reduction of 5 mg daily is recommended when administered concurrently with

a moderate CYP3A inhibitor; concurrent administration with a strong CYP3A

inhibitor is not recommended.

63 No rebound insomnia or withdrawal symptoms have

been observed following abrupt discontinuation.

64 When compared to zolpidem,

suvorexant is associated with less abuse potential and like benzodiazepine receptor

agonist hypnotics is a Schedule IV medication.

63 The most commonly reported

adverse effect in clinical trials evaluating suvorexant was daytime somnolence.

Complex sleep behaviors, a dose-dependent increase in suicidal ideation, sleep

paralysis, hallucinations, and cataplexy-like symptoms have been reported with

suvorexant. Suvorexant is contraindicated in patients with narcolepsy. Studies

comparing suvorexant to other hypnotic agents, such as the Z-hypnotics, are lacking.

The role of suvorexant in the treatment of sleep disorders has yet to be established.

INSOMNIA IN A MEDICALLY ILL PATIENT

Insomnia and Effect on Sleep Stages

CASE 84-2

QUESTION 1: A.T., a 42-year-old woman with a 5-year history of hypothyroidism and a 2-year history of

hypertension and chronic lower back pain, was just transferred from the intensive care unit (ICU) into a

medical unit. Her cardiac status is considered “stable” 2 days after a myocardial infarction (MI). She is 5 feet 9

inches tall and weighs 72 kg. She is receiving aspirin 81 mg (enteric-coated), levothyroxine 112 mcg, and

felodipine 10 mg all taken by mouth 1 hour before breakfast every day. Her main complaint is insomnia,

including difficulty falling asleep, difficulty maintaining sleep, and early morning awakenings. A.T. reports

insomnia for 6 weeks before admission, which worsened during the hospitalization. What type of insomnia does

A.T. have, and how might the insomnia affect her health?

A.T.’s insomnia is considered chronic because she experienced it for 6 weeks

before hospital admission. It is severe because it involves difficulty falling asleep,

maintaining sleep, and early morning awakening. Careful monitoring and effective

treatment of A.T.’s sleep disturbance is crucial; studies show disrupted sleep can

increase the risk of another adverse cardiac event owing to worsening autonomic

instability and poor perfusion to the myocardium.

65

Because normal sleep moves through all the stages of NREM and REM in a

continuous cycle, a patient deprived of continuous sleep may not receive sufficient

time in each sleep stage. When stage 2 is diminished, muscles have insufficient

opportunity to rest and rejuvenate. If NREM stages 3 and 4 are eliminated, immune

function and the healing process can be disrupted. If REM sleep is deprived or

excessive, neurotransmitter function may be altered and physiologic homeostatic

processes can be disrupted.

15,16,28

Drug or Disease Etiologies

CASE 84-2, QUESTION 2: What individual drug or disease state factors should be assessed in A.T. before

developing a treatment plan?

The Insomnia Treatment Algorithm in Figure 84-2 is useful in systematically

addressing A.T.’s sleep complaint. It calls for thoroughly evaluating all concomitant

conditions and the type of insomnia in each patient. Numerous medical disorders and

primary sleep disorders are associated with difficulty falling asleep and maintaining

sleep (Tables 84-4 and 84-5).

5,28,65 First, A.T. should be assessed for sleep apnea

because untreated sleep apnea is a known etiology of cardiac disease and hypnotics

can be dangerous in untreated sleep apnea (see Case 84-8, in the Sleep Apnea

section). Second, A.T.’s pain management should be assessed for optimal efficacy.

Acute post-MI pain adds to A.T.’s chronic lower back pain. Of patients with lower

back pain, 50% experience chronic poor sleep patterns.

28,65 Third, A.T. was just

transferred out of the ICU. Sleep deprivation in an ICU is common and is attributed to

the continuous lighting, noise, and constant interventions. Sleep deprivation may

prolong or worsen a disease process through diminished natural killer cell activity

and decreased stages 3 and 4 of NREM sleep (when healing occurs).

41,66,67

Medications also may be contributing to A.T.’s insomnia ( Table 84-4).

Levothyroxine can overstimulate the CNS if given in excessive doses. A.T.’s thyroid

status should be re-evaluated to ensure appropriateness of the thyroid dose,

especially considering her post-MI status.

68 Calcium-channel blockers have been

associated with occasional sleep disturbances; therefore, felodipine should be

evaluated as a potential contributing factor.

68

Another clue to a possible cause of A.T.’s sleep problem is her description of

early morning awakening, which could be related to hospital activity during these

hours or to the presence of a major depressive disorder. A.T. requires psychiatric

evaluation to rule out depression, which occurs in about one-third of patients after an

MI.

69

In general, patients with chronic illnesses are at increased risk of experiencing

major depression, which typically presents with insomnia or hypersomnia.

Interestingly, medical outcome studies of other chronic illnesses (cardiovascular,

pulmonary, renal, neurologic disease) show a high prevalence of sleep disturbance

even in those not suffering from depression.

28,65 Chronic insomnia related to multiple

causes can be resistant to treatment; however, treatment of underlying causes

increases the likelihood of insomnia resolution.

Comparing Available Hypnotics

CASE 84-2, QUESTION 3: A.T.’s pain is now under control, her levothyroxine dose is appropriate, and

felodipine-induced sleep disturbance, sleep-disordered breathing, RLS, and PLMS have all been ruled out. A

psychiatric evaluation finds that A.T. does not have major depression, but she is anxious about “life after a heart

attack.” She meets criteria for primary insomnia and adjustment disorder with anxiety. She continues to have

trouble falling asleep and staying asleep. She will be discharged in 2 days. The psychiatric consultation suggests

an adjunctive medication with anxiolytic properties that may also help with sleep. Which hypnotic is best for

A.T., considering her individual clinical characteristics?

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Figure 84-2 Algorithm for treatment of insomnia. DFA, difficulty falling asleep; DMS, difficulty maintaining sleep;

EMA, early morning awakening.

Table 84-4

Potential Causes and Contributing Factors for Each Chronic Sleep

Complaint

5,28,65

Difficulty Falling Asleep (DFA)

Learned or conditioned activation (primary insomnia): restless legs syndrome (RLS)

Medications: methylphenidate, modafinil, fluoxetine, bupropion, steroid, β-blocker

Substances: caffeine, guarana, alcohol

Psychiatric disorders:schizophrenia, depression, anxiety disorder, bipolar disorder

Medical disorder: chronic pain, neuropathy, gastrointestinal disorder, cardiopulmonary disorders (particularly if in

recumbent position)

Difficulty Maintaining Sleep (DMA)

Excessive time in bed

Psychiatric disorder: major depression, anxiety or bipolar disorder, substance abuse

Sleep-disordered breathing:sleep apnea, acute respiratory distress syndrome

Cardiac disease: atrial fibrillation, heart failure, angina

Neurologic disorder: dementia, Parkinson disease, multiple sclerosis

Early Morning Awakening (EMA)

Major depression

Advanced sleep phase syndrome: learned or conditioned activation (primary insomnia)

Forced to get up because of family or work obligations

Excessive Daytime Sleepiness

Medications: clonidine, antihistamines, antipsychotic, antidepressant, benzodiazepine, chloral hydrate, opioid,

anticonvulsant, α1

-adrenergic blockers

Obstructive sleep apnea, centralsleep apnea, narcolepsy

Chronic sleep deprivation

The ideal hypnotic for A.T. should act quickly and continue working throughout the

night to provide her with uninterrupted sleep. A hypnotic that is not metabolized in

the liver would have a lower potential for drug interactions and lessen the

opportunity for systemic accumulation. If daytime drug concentrations are needed to

calm anxiety, however, a hypnotic with slowly eliminated active metabolites may be

desirable. The comparable doses of the hypnotic medications are listed in Table 84-

3. When considering available hypnotic medications, differences in

pharmacodynamic and pharmacokinetic properties should be considered (Table 84-

3). Onset of effect is related to lipophilicity, receptor binding affinity, and Tmax

.

39,41

Benzodiazepine Dependence and Tolerance

CASE 84-2, QUESTION 4: In further discussion with A.T., who prefers to try cognitive-behavioral

interventions for anxiety reduction and sleep induction, temazepam 15 mg at bedtime is prescribed on an asneeded basis. A.T. will be monitored regularly as an outpatient for efficacy and tolerability. As A.T. is

preparing to leave the hospital, her daughter expresses concerns about the potential for physical dependence on

temazepam and the risk of A.T. becoming an addict. How would you respond to her concerns?

A benzodiazepine hypnotic that is nonselective is preferable in A.T. because of the

need for anxiolytic properties in addition to hypnotic efficacy. NBRAs are not

effective anxiolytic agents. The pharmacodynamic and pharmacokinetic properties of

triazolam have already been presented. Its rapid onset is an advantage for A.T.;

however, the duration of action would not be sufficient to help A.T. stay asleep. In

addition, it should not be used for longer than 7 to 10 days because of the greater

potential for adverse effects with prolonged use and the possibility of significant

rebound insomnia on withdrawal.

41 A.T. may require a hypnotic for more than 7 to 10

days, which is the maximal duration for triazolam use.

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p. 1772

Table 84-5

Potential Causes of Chronic Sleep Disorders

5,28,65,68

Psychiatric Disorders

Anxiety disorders Depressive disorders

Bipolar disorder Psychotic disorders

Personality disorders Somatoform disorders

Organic mental disorders Substance abuse

Medical and Neurologic Disorders

Angina pectoris Dementia

Bronchitis Peptic ulcer disease

Chronic fatigue Hyperthyroidism and hypothyroidism

Cystic fibrosis Asthma

Huntington disease COPD

Parkinson disease Epilepsy

Hypertension Gastroesophageal reflux

Arthritis Renal insufficiency

Cardiac disease Connective tissue disease

Chronic pain

Cancer

Sleep Disorders

RLS Sleep apnea (obstructive or central)

PLMS (nocturnal myoclonus) Primary snoring

Circadian rhythm sleep disorder (jet lag, shift work,

delayed sleep phase)

Narcolepsy

Drugs Associated With Sleep Disturbance

Insomnia Hypersomnia

Alcohol Alcohol

Bupropion Benzodiazepines

Fluoxetine Antihypertensives

Sertraline Clonidine

MAO inhibitors α-Adrenergic blockers

TCA ACE inhibitors

Thyroid supplements β-Blockers

Calcium-channel blockers Anticonvulsants

Decongestants Analgesics

Appetite suppressants Chloral hydrate

Theophylline Antipsychotics

Corticosteroids Antihistamines

Dopamine agonists Opioids

ACE, angiotensin-converting enzyme; COPD, chronic obstructive pulmonary disease; MAO, monoamine oxidase;

PLMS, periodic limb movements during sleep; RLS, restless legs syndrome; TCA, tricyclic antidepressants.

Flurazepam induces sleep within 15 to 45 minutes during chronic dosing. On the

first night of use, however, flurazepam does not induce sleep as well as triazolam. It

has intermediate fat solubility but depends on the plasma concentrations of its

metabolite, N-desalkylflurazepam, for most of its activity.

41 N-desalkylflurazepam

concentrations take approximately 24 hours to accumulate and induce sleep. Studies

show flurazepam maintains efficacy in sleep induction for at least 30 days; Ndesalkylflurazepam has weak receptor binding affinity and a long half-life, resulting

in gradual elimination and little chance for rebound insomnia.

41 Ndesalkylflurazepam can accumulate during chronic dosing and affect daytime

cognition in some patients or compete for hepatic metabolism, resulting in altered

levels of other hepatically metabolized medications.

41,68 A.T. has difficulty moving

around during the day because of her chronic lower back pain, and oversedation from

accumulation may impair her daytime functioning. Flurazepam is infrequently used

because of the risk of next-day impairment; it is useful to explore other options.

Similarly, quazepam having an extended half-life and potential for drug accumulation

would not be an optimal agent for A.T.

Temazepam takes 1 to 2 hours to induce sleep. It has moderate fat solubility,

similar to N-desalkylflurazepam, but it has a longer dissolution time. Temazepam

takes 1.5 to 2 hours to reach peak plasma concentrations. Temazepam’s longer

dissolution time is caused by its large drug particle size in a gelatin capsule. A

potential advantage for using temazepam in A.T.’s case is its lack of hepatic

oxidative metabolism and intermediate duration of action of 8 to 12 hours. It does not

interfere with the metabolism of other hepatically metabolized drugs and it does not

accumulate, minimizing the potential for daytime impairment relative to

flurazepam.

41,70 The long onset of action may be of concern, although A.T. could take

the drug an hour before bedtime to optimize timing for sleep.

For A.T., the most appropriate choice is temazepam. Of the five approved

benzodiazepine agents approved for insomnia (see Table 84-3), temazepam’s

advantages are intermediate duration of activity that would keep her asleep

throughout the night, anxiolytic benefit, and low risk of daytime impairment owing to

no known active metabolites.

41,70

Fear of dependence and addiction to medications is a concern among the general

public. Television station “medical experts” and popular magazine “health sections,”

while providing information, may increase the potential for confusion, erroneous

impressions, and misinformation. For healthcare practitioners, it becomes even more

crucial to provide sound drug information in common, easy-to-understand terms.

An example of the practitioner’s response may be, “I’m glad you have expressed a

concern; it gives us a chance to discuss temazepam therapy before your mother leaves

the hospital.” Temazepam has been prescribed for a medical reason, to improve your

mother’s sleep and to aid in her healing process. One therapeutic benefit of

temazepam is an 8-hour duration of effect. Your mother will be able to sleep

throughout the night so that she is well rested during the day. It also may decrease her

anxiety over not sleeping, and that puts less stress on her heart.

“The possible side effects of temazepam include sedation, unsteadiness, and

dizziness. She should let her doctor know if she experiences any adverse effects.

Right now, it is unclear how long your mother will be taking temazepam. Duration of

therapy needs to be assessed on an ongoing basis. If your mother takes temazepam

every night for more than 4 weeks, two things could happen: (a) she may develop a

tolerance and it may not help her sleep anymore, or (b) her system may develop a

dependence in which she may have worse insomnia if she does not take it. The

primary concern is not addiction but the possible dependence. This means your

mother should not change her dose or stop on her own. Any changes in dose or

stopping must be done slowly and with her doctor’s involvement. These two

scenarios do not always occur and are not likely because your mother will be taking

it on an as-needed basis. If one or the other does happen, some other intervention may

be tried to help with her sleep, or the temazepam dose can be gradually decreased to

prevent

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withdrawal problems. It is important to advise your mother to avoid alcohol, and

report any decrease in effectiveness or any adverse effects to her healthcare

practitioner.”

Patients taking benzodiazepines for longer than 1 year tend to be older, medically

ill, and chronically dysphoric and have panic disorder or chronic insomnia. Most

chronic use appears to be medically appropriate and does not lead to dose escalation

or abuse. Among chronic dysphoric patients, the indications are less clear, and dose

escalation is noted sometimes without notable therapeutic benefit. Benzodiazepine

hypnotics rarely are taken alone for pleasure and generally are not likely to be

abused. Among substance abusers, however, they frequently are taken as part of a

polysubstance abuse pattern by alcoholics and narcotic, methadone, and cocaine

users. In these groups, abuse is highly prevalent. Benzodiazepines are used to

augment euphoria (narcotics and methadone users), to decrease anxiety and

withdrawal symptoms (alcoholics), and to ease the “crash” from stimulant-induced

euphoria (cocaine users).

71,72

Physiologic dependence on benzodiazepines, resulting in a withdrawal and

abstinence syndrome, develops usually after 2 to 4 months of daily use of the longer

half-life benzodiazepines. Shorter half-life benzodiazepine use can result in

physiologic dependence earlier (days to weeks) and may be associated with more

withdrawal problems.

41,44 See Table 84-3 for a comparison of pharmacokinetic

properties of hypnotics.

INSOMNIA AND PSYCHIATRIC DISORDERS

Stepwise Approach to Selecting a Hypnotic

CASE 84-3

QUESTION 1: M.B., a 33-year-old woman, is hospitalized after a suicide attempt in which she tried to

overdose on sertraline, ibuprofen, and diphenhydramine. Before the suicide attempt, M. B. had been sober for 3

years. She is diagnosed with major depression and alcohol substance use disorder. After completing an

interview with M.B., you learn she stopped taking fluoxetine 5 months ago due to insomnia. She reports doing

well until 3 months ago where depression symptoms worsened during her divorce. Two weeks before

admission, her outpatient primary-care doctor prescribed sertraline for depression and omeprazole for acid

reflux. She went on a drinking binge 5 days ago that ended with the suicide attempt. Her target symptoms

include early morning awakening, trouble falling asleep, 15-pound weight loss, apathy, social withdrawal,

depressed mood, hopelessness, and anhedonia. Medications continued in the hospital include sertraline 100 mg

daily and omeprazole 20 mg daily. M.B. currently reports feeling restless and sleeping only 3 to 4 hours a night.

Use Tables 84-3 and Figure 84-2 to compare the clinically significant differences between available hypnotics

and to demonstrate how such information can be used to develop a patient-specific treatment plan. What is the

best approach to solving M.B.’s sleep problem?

The Insomnia Treatment Algorithm outlined in Figure 84-2 serves as a useful guide

for the assessment and management of M.B.’s sleep complaint. Concomitant

conditions and the type of insomnia (difficulty falling asleep, difficulty maintaining

sleep, early morning awakening) are assessed simultaneously. Possible causes or

contributing factors are identified and treated. The type of insomnia can aid in

treatment selection. Cognitive-behavioral interventions can be implemented if M.B.

is willing and able to participate.

Factors to consider in the drug selection process include substance abuse history,

the need for rapid onset and duration of effect. For example, agents with long-acting

metabolites (e.g., flurazepam) may accumulate or cause daytime hangover. If the

hypnotic has no hepatic metabolism, it will not be subject to drug interactions with

other agents that are hepatically metabolized. Also, if insomnia is chronic and

resistant to hypnotic treatment, or if a low abuse potential agent is desired (e.g., for a

person with an existing substance use disorder like M.B.), trazodone or another

sedating antidepressant may be selected.

Sleep Disturbance of Depression

CASE 84-3, QUESTION 2: What type of insomnia does M.B. have, and how is it different from other types

of insomnia?

M.B. has trouble falling asleep and early morning awakening, and sleep time has

decreased to 3 or 4 hours a night. She is diagnosed with major depression, and sleep

difficulty is part of the disorder. Generally, initial insomnia and early morning

awakening are associated with depression, although difficulty maintaining sleep and

next-day fatigue are common as well. M.B. is most bothered by trouble falling

asleep, early morning awakening, and next-day fatigue. Up to 65% of outpatients with

major depression report one or more symptoms of sleep disturbance, whereas 90%

of inpatients with depression like M.B. report insomnia.

73

The insomnia of depression is likely related to a dysregulation of

neurotransmitters, such as serotonin, norepinephrine, and dopamine, in addition to

dysregulation of the hypothalamic–pituitary axis. All are involved in regulating mood

and the sleep–wake cycle.

16,66 Neurotransmitter activity is modified by the effects of

antidepressants on REM sleep. Most pro-serotonergic antidepressants suppress

REM, causing increased REM latency and decreased total REM time.

73,74

Indeed,

REM sleep deprivation can elevate mood.

73,75 Depressed patients deliberately

deprived of REM sleep have had a reduction in depressive symptoms. In addition to

effects on REM, antidepressants redistribute slow-wave sleep to more

physiologically natural patterns, with increased intensity in the first half of the night.

75

Sedating antidepressants with serotonin 2 (5-HT2

) antagonist properties, such as

trazodone and mirtazapine, alleviate insomnia and improve sleep architecture.

73

CASE 84-3, QUESTION 3: M.B. and the treatment team ask you what factors other than depression (i.e.,

medications, alcohol) may contribute to M.B.’s insomnia. How can her sleep problem be solved?

Treatment

The treatment for M.B.’s insomnia should begin with patient education. She should

be informed that more than 90% of depressed patients have some sleep disturbance,

either too little or too much, and her sleep should improve as depressive symptoms

improve (in 2–8 weeks). Counseling on cognitive-behavioral interventions to

improve sleep may be appropriate when M.B.’s depression begins to clear and she is

more motivated to improve her sleep hygiene. In the meantime, the potential

contribution of sertraline causing restlessness or insomnia should be assessed by

confirming the drug is dosed in the early morning to minimize this effect.

70 A sedating

antidepressant such as mirtazapine may be preferred unless M.B.’s history includes a

positive response with sertraline that would justify ongoing treatment. M.B. also was

using alcohol before admission. Alcohol disrupts sleep and can increase arousal

when its sedative effects wear off, leading to more fragmented sleep.

37 All patients

should be counseled to have their last alcoholic drink at least 3 hours before sleep.

M.B. should avoid

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alcohol altogether given her history of abuse. Drug and alcohol withdrawal and the

lingering “abstinence syndromes” often are associated with insomnia, although

sometimes hypersomnia is the predominant symptom.

37,76

HYPNOTICS

CASE 84-3, QUESTION 4: What is the evidence for trazodone’s use in managing insomnia? What other

antidepressants are used in the treatment of insomnia? Discuss the advantages and disadvantages of using

sedating antidepressants for the treatment of insomnia in M.B.

Prescribing a hypnotic short-term or a sedating antidepressant is recommended for

depressed patients with insomnia because a good night’s sleep can improve treatment

adherence and daytime functioning until antidepressant effects become apparent.

65,66

All antidepressants, including selective serotonin reuptake inhibitors (SSRIs), such

as sertraline, can improve sleep as the depression lifts; however, most

antidepressants like SSRIs, serotonin norepinephrine reuptake inhibitors (e.g.,

venlafaxine, desvenlafaxine, duloxetine), bupropion, and monoamine oxidase

inhibitors can all cause insomnia as well.

68,73 Analysis of residual symptoms in

partially treated depressed patients taking SSRIs shows continuing insomnia is

present in 44%, requiring additional interventions such as trazodone or mirtazapine.

Hypnotics that act at benzodiazepine receptors are not recommended for M.B. due

to her drug use history and recent alcohol abuse. Older nonselective benzodiazepines

like temazepam can have a euphoric effect, are cross-tolerant with alcohol, and are

likely to be abused by patients with alcohol and substance abuse problems.

41 Abuse,

dependence, and withdrawal reactions have been reported with newer GABAA

receptor α1

-subunit selective NBRAs (zolpidem, zaleplon, eszopiclone); therefore,

neither class of drugs is appropriate for M.B.

38,58

If the clinician determines that sertraline treatment is preferred, then trazodone may

be added to alleviate insomnia.

77 The addition of trazodone to fluoxetine, bupropion,

or monoamine oxidase inhibitors decreased time to sleep and increased duration of

sleep but caused intolerable sedation in a few patients who received fluoxetine.

Tolerance did not develop to the sedative effects of trazodone in short-term studies

(<6 weeks) used adjunctively for depression; however, decreased benefit with time

has been reported.

77 The 5-HT2 antagonist properties of trazodone at low dosages, in

addition to its antagonism at histamine-1 and α1 adrenergic receptors, provide the

rationale for its efficacy as a sedating agent.

78

Trazodone is not thought to be a highly effective antidepressant medication

because most people cannot tolerate an effective dose (300–600 mg/day). Because of

its sedating properties, low-dose trazodone (50–200 mg/day at bedtime) has become

a commonly prescribed adjunctive medication to induce sleep while awaiting the

onset of another primary antidepressant’s effect.

77 Trazodone has a half-life of

approximately 6.4 hours in younger adults and 11.6 hours in the elderly. It undergoes

hepatic metabolism via CYP2D6 and CYP3A4; thus, inhibitors of these isoenzymes

can increase blood levels and worsen side effects. The most common side effects of

trazodone include drowsiness (29.1%), dizziness (21.9%), and dry mouth (17.7%).

Cardiac arrhythmias are possible at doses greater than 200 mg/day, as is priapism, a

painful prolonged erection that occurs in 1 of 1,000 to 10,000 men. Although

priapism is considered rare, it can lead to impotence if untreated; therefore, men

should be counseled about priapism at any dose of trazodone.

77

In the only placebo-controlled trial of trazodone conducted in primary insomnia,

investigators compared the hypnotic efficacy of trazodone and zolpidem with placebo

in 306 adults (21–65 years of age). Subjects were randomly assigned to receive

trazodone 50 mg, zolpidem 10 mg, or placebo nightly for 2 weeks. Sleep parameters

were assessed using a subjective sleep questionnaire, which patients completed each

morning and at weekly office visits. Trazodone was found to be as effective as

zolpidem for the first week of treatment, but during the second week, only zolpidem

was more effective than placebo.

77 Tricyclic antidepressants (TCAs; e.g.,

amitriptyline, doxepin) were used to treat primary insomnia for years based on case

reports describing efficacy in doses of 10 to 75 mg/night.

41,73 TCAs, however,

increase the risk of cardiovascular problems and anticholinergic side effects in a

dose-related manner (see Chapter 86 Depression).

Ultra-low-dose doxepin 3 and 6 mg tablets are now available (Silenor) for the

treatment of insomnia characterized by difficulties with sleep maintenance. Doxepin

is not a controlled substance, so it may be of value in patients with a history of

substance abuse. Four clinical trials conducted in slightly more than 1,000 patients

demonstrated ultra-low-dose doxepin’s efficacy and safety in both younger adults and

the elderly.

79 Doxepin demonstrated improved sleep efficiency during the final third

of the night and in the seventh and eighth hours of sleep. Doxepin was well tolerated,

with residual sedation and anticholinergic effects no different than placebo. There

were no significant effects on next-day alertness, memory, or psychomotor function.

Hypnotic efficacy with doxepin was demonstrated for up to 3 months. The primary

disadvantage of this brand formulation is its cost. It remains to be seen whether these

low-dose studies will prompt increased use of generic doxepin 10 mg, and whether

any advantages can be demonstrated in using the branded formulation.

For M.B, a TCA raises additional safety concerns. M.B. has a history of substance

abuse and prior suicide attempts. Both are risk factors for future suicide attempts.

TCAs are more toxic in overdose when compared with trazodone, and there are

multiple reports of TCA plasma levels increasing to toxic levels when administered

in combination with CYP450 2D6 inhibitors (see Chapter 86, Depression).

Switching to mirtazapine as an antidepressant that offers more sedation is a

reasonable consideration for M.B. If M.B. has a partial but significant response to

sertraline at maximal tolerated doses and good tolerability except for insomnia at 4

weeks, mirtazapine can be added to facilitate remission. Mirtazapine has 5-HT2

antagonist and antihistamine effects, which impart sedation, and it is safer than TCAs

in overdose.

73 Mirtazapine is not associated with priapism, but it can cause weight

gain.

INSOMNIA IN THE ELDERLY

CASE 84-4

QUESTION 1: S.D., a 77-year-old man, is seen for his initial geriatrics primary-care clinic visit. Vital signs

include temperature, 98.8°F; heart rate, 58 beats/minute; respiratory rate, 18 breaths/minute; BP, 166/69 mm

Hg; height, 5 feet 3 inches; and weight, 109 pounds. He was referred from an emergency department (ED) visit

4 days earlier with complaints of palpitations and anxiety. Before his ED visit, his medications included atenolol

50 mg daily, lorazepam 1 mg at bedtime, and saw palmetto 320 mg daily. At his ED visit, he stated he had taken

lorazepam for sleep for more than 1 year, but did not take it the prior 2 nights and started feeling palpitations

and anxiety. His electrocardiogram showed normal sinus rhythm at 67 beats/minute, and S.D.’s head computed

tomography scan was negative for any hemorrhage. S.D. was told not to restart the lorazepam, but instead to

take diphenhydramine 50 mg at bedtime. He took only one dose, felt “terrible” and fatigued for the next 2 days.

On further questioning, he states that he falls asleep without difficulty, usually

p. 1774

p. 1775

awakens 2 to 3 times each night to urinate, and often has difficulty falling back to sleep. In the past, lorazepam

was helpful with his sleep difficulty. What considerations are important for the assessment and treatment of

insomnia in an elderly patient such as S.D.?

Treatment of insomnia in the elderly represents a therapeutic dilemma. Evidence

supports an increased need to treat insomnia in the elderly to reduce its potentially

serious complications, yet many drug treatment options have potential for harm that

may outweigh their benefit. In a large epidemiological study of sleep complaints in

9,282 individuals 65 years and older conducted by the National Institute on Aging,

57% of subjects indicated at least one sleep complaint occurring most of the time,

19% had difficulty falling asleep, 30% complained of awakening at night, and 19%

complained of awakening too early.

80 Despite such high frequency of sleep

complaints, these complaints are primarily thought to be more a marker of poor

physical and mental health rather than caused by aging itself.

80,81

Historically, it was accepted that age-related sleep changes begin in early

adulthood and progress steadily across the adult lifespan.

82 However, in a meta-

analysis of 65 studies of quantitative sleep parameters across the lifespan of

individuals from ages 5 to 102 without sleep complaint, most changes in sleep were

found to occur by age 60.

73 Changes in sleep latency are small and subtle, with an

overall increase between 20 and 80 years of less than 10 minutes. Increases in

percentages of stage 1 and 2 sleep, as well as decreases in total sleep time,

percentage of slow-wave and REM sleep, and REM latency, were significant with

aging up to age 60, but only minimal changes were seen after age 60. Only sleep

efficiency was found to continue to significantly decrease after age 60. Therefore,

identifying factors underlying sleep complaints in the elderly is critical and can lead

to appropriate diagnosis and treatment. Elderly patients need not be resigned merely

to getting the sleep that they do because they are “getting older.”

82

CASE 84-4, QUESTION 2: What are the more common underlying causes of sleep complaints in the

elderly?

Common precipitants of acute insomnia in the elderly include acute medical

illnesses, hospitalization, changes in the sleeping environment, medications, and

acute or recurring psychological stressors. Chronic or long-term insomnia may be

associated with a variety of underlying medical, behavioral, and environmental

conditions, as well as a variety of medications.

83

Identification of treatable

underlying causes should be the first step in management of insomnia, based on a

medical and medication history, physical and mental status examination, and

laboratory investigations including thyroid function, serum chemistry panel, and

cardiopulmonary studies if indicated.

83,84 Special attention should be directed to

chronic pain from any cause, pulmonary disease, chronic renal disease, neurologic

disorders, and polyuria from urinary, prostate, or endocrine disorders. Medical

conditions with a strong association with insomnia include heart disease,

hypertension, diabetes, stomach ulcers, arthritis, migraine, asthma COPD

neurological problems, menstrual problems, depression, and bipolar disorder.

85,86

Primary sleep disorders are RLS, sleep apnea, and circadian rhythm disorders.

65,81,86

The potential contribution of medications to the sleep complaint needs to be

evaluated, and changes in medication or timing of administration should be

considered. Many drugs with CNS effects can alter patterns of sleep and

wakefulness, both during their use and their withdrawal.

36,80,86 Both prescribed and

OTC medications must be evaluated. The more common drugs of concern include

stimulants (caffeine, nicotine, and amphetamines), alcohol, activating antidepressants

(e.g., SNRIs and bupropion), pseudoephedrine, bronchodilators, β-blockers,

calcium-channel blockers, corticosteroids, and dopamine agonists. Evening

administration of drugs like diuretics may also contribute to nighttime awakenings

and sleep complaints.

Psychological Versus Drug Treatments for Insomnia

CASE 84-4, QUESTION 3: Which nondrug therapy treatment options might be appropriate for S.D.?

CBT is an effective and safe alternative to drug therapy for insomnia and has also

been shown to be an effective augmenting treatment with drug therapy.

34,35 CBT

limitations include that it is little known, not widely available, and more timeconsuming than drug therapy. Both pharmacologic and nonpharmacologic approaches

are effective for the short-term management of insomnia in late life, and current

evidence suggests that sleep improvements are better sustained over time with

behavioral treatment.

34 A comparative meta-analysis of 21 studies of

pharmacotherapy and behavior therapy for persistent insomnia in adults found that

both treatments similarly produced moderate to large improvements in number of

awakenings, wake time after sleep onset, total sleep time, and sleep quality.

87

Behavior therapy, however, resulted in a greater reduction of sleep latency than

pharmacotherapy. CBT was compared with pharmacotherapy (zolpidem) and its

combination in 63 young and middle-aged adults with chronic sleep onset insomnia.

34