Question

The woman who liked late-night TV.

• List three questions you might ask the patient if he or she were in your office. Provide a rationale for why you might ask these questions.
• Identify people in the patient’s life you would need to speak to or get feedback from to further assess the patient’s situation. Include specific questions you might ask these people and why.
• Explain what physical exams and diagnostic tests would be appropriate for the patient and how the results would be used.
• List three differential diagnoses for the patient. Identify the one that you think is most likely and explain why.
• List two pharmacologic agents and their dosing that would be appropriate for the patient’s sleep/wake therapy based on pharmacokinetics and pharmacodynamics. From a mechanism of action perspective, provide a rationale for why you might choose one agent over the other.
• If your assigned case includes “check points” (i.e., follow-up data at week 4, 8, 12, etc.), indicate any therapeutic changes that you might make based on the data provided.
• Explain “lessons learned” from this case study, including how you might apply this case to your own practice when providing care to patients with similar clinical presentations.

Answer 1

The woman who liked late-night TV.

List three questions you might ask the patient if he or she were in your office. Provide a rationale for why you might ask these questions

Question 1. Why you should not watch TV before bed?

REASONS YOU SHOULDN’T WATCH TV BEFORE BED

• Watching TV before bed disrupts your hormones. : Our bodies aren’t used to this. A hundred years ago, nobody was gazing at screens for any amount of time during the day. The second half of the 20th century saw artificial light sources quadruple as our sleep quality dipped. The reason might be hormonal: sitting ourselves in front of screens appears to trick the body into believing it’s still daytime, as the light impairs the secretion of the hormone melatonin, which is really important for quality sleep. One study even showed a 22 percent decrease in melatonin among people engaged with screens in the hours before bed, and the effect is especially pronounced in younger people

• Watching TV makes you go to sleep later. : Let’s say you get six hours of sleep. If you needed eight hours of sleep per night (and you almost certainly do), then you have a “sleep debt” of two hours. A lot of people unfortunately never balance their sleep debt, because they get less than seven hours of sleep per night, but a 2009 study of 21,475 Americans in the journal Sleep suggested that cutting pre-bedtime TV is the number one way to reduce our sleep debt. That is to say, we keep ourselves awake to watch television. If we swore off that final hour of channel surfing, it’s likely we would simply go to sleep instead of filling that time with something else—which is exactly what we should be doing.

• Watching TV makes it harder to go to sleep. : It’s a matter of cognitive stimulation: flashing colors, other people’s voices, engaging storylines, breaking news, all of this and more is what you encounter with a flickering TV set—and it’s the total opposite of what you need as your day is winding down.

  Despite how easy it can be to fall asleep right there on the couch, television is still one of the most stimulating activities you can undertake without actually moving, and the firing of neurons and electrical activity taking place in the brain can wind up the nervous system. Instead, seek out activities that help you wind down. Read fiction or meditate before you go to sleep, and kill all electronics at least half an hour before lights out. In the day’s final hour, let calmness call the shots.

Question 2: Did you know sleeping late is bad for your health?

Many effects of a lack of sleep, such as feeling grumpy and not working at your best, are well known. One in 3 of us suffers from poor sleep, with stress, computers and taking work home often blamed. However, the cost of all those sleepless nights is more than just bad moods and a lack of focus.

Regular poor sleep puts you at risk of serious medical conditions, including obesity, heart disease and diabetes – and it shortens your life expectancy.

Question 3: What to do when you can't sleep?

Don't try to force yourself to sleep. Tossing and turning only amps up the anxiety. Get up, leave the bedroom, and do something relaxing, such as reading, drinking a cup of herbal tea, or taking a bath. When you're sleepy, go back to bed.

Identify people in the patient’s life you would need to speak to or get feedback from to further assess the patient’s situation. Include specific questions you might ask these people and why.

Question 1: Tell me the family history of sleep disorders.

The contribution of genes, environment and gene-environment interactions to sleep disorders is increasingly recognized. Well-documented familial and twin sleep disorder studies suggest an important influence of genetic factors. However, only few sleep disorders have an established genetic basis including four rare diseases that may result from a single gene mutation: fatal familial insomnia, familial advanced sleep-phase syndrome, chronic primary insomnia, and narcolepsy with cataplexy. However, most sleep disorders are complex in terms of their genetic susceptibility together with the variable expressivity of the phenotype even within a same family. Recent linkage, genome-wide and candidate gene association studies resulted in the identification of gene mutations, gene localizations, or evidence for susceptibility genes and/or loci in several sleep disorders.

Question 2: Did you know patient have stress?

Stress has long been known to be linked with sleep problems. Most people have experienced this connection at some point in their life when difficult circumstances may have made it hard to get to sleep or fall back asleep after waking up in the night.

Anxiety, stress, and depression are some of the most common causes of chronic insomnia. Having difficulty sleeping can also make anxiety, stress, and depression symptoms worse. Other common emotional and psychological causes include anger, worry, grief, bipolar disorder, and trauma. Treating these underlying problems is essential to resolving your insomnia.

Question 3: Is there a good sleep environment?

Create an environment that establishes the right conditions that you need for sleep. Make it cool, quiet, dark, comfortable, and free of interruptions. Check for and remove distractions — light, heat, noise, or other things that may cause stress. Consider adding ear plugs, blackout curtains, or white noise to your bedroom.

Explain what physical exams and diagnostic tests would be appropriate for the patient and how the results would be used.

History taking
Diagnosis of insomnia is primarily based on the account given by the patient (and/or family member or carer) about their sleep.

• a detailed history should be carried out to
  • assess sleep and waking function
  • identify precipitating factors
  • detect any comorbid medical or psychiatric illness

When obtaining history, inquire about:

• sleep itself
  • time the patient goes to bed
  • time the patient falls asleep
  • awakening - number, duration, cause, presence of associated symptoms e.g. - heartburns, shortness of breath, anxiety, full bladder
  • time out of bed in the morning
  • usual duration of sleep
  • is the routine same during weekends and holidays

• pre sleep conditions
  • bedroom, environment
  • any vigorous activity late in the evening
• impact of any sleep problems
  • on awakening does the patient feel unrefreshed or still sleepy
  • presence of symptoms such as headache and dry mouth
  • daytime sleepiness

• Physical exam. If the cause of sleep less is unknown, your doctor may do a physical exam to look for signs of medical problems that may be related to insomnia. Occasionally, a blood test may be done to check for thyroid problems or other conditions that may be associated with poor sleep.

• Sleep habits review. In addition to asking you sleep-related questions, your doctor may have you complete a questionnaire to determine your sleep-wake pattern and your level of daytime sleepiness. You may also be asked to keep a sleep diary for a couple of weeks.
• Sleep study. If the cause of your insomnia isn't clear, or you have signs of another sleep disorder, such as sleep apnea or restless legs syndrome, you may need to spend a night at a sleep center. Tests are done to monitor and record a variety of body activities while you sleep, including brain waves, breathing, heartbeat, eye movements and body movements.

List two pharmacologic agents and their dosing that would be appropriate for the patient’s sleep/wake therapy based on pharmacokinetics and pharmacodynamics.

1. Eszopiclone (Lunesta)

2. Zaleplon (Sonata)

1. Eszopiclone (Lunesta)

INDICATION

Eszopiclone is indicated for the treatment of insomnia in patients ≥18 years of age. Unlike other nonbenzodiazepine agents, there is no restriction on its duration of use .

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PHARMACOLOGY

The precise mechanism of action of eszopiclone as a hypnotic is unknown, but its effect is believed to result from its interaction with GABA receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors. Eszopiclone is a nonbenzodiazepine hypnotic that is structurally unrelated to pyrazolopyrimidines, imidazopyridines, benzodiazepines, barbiturates, or other drugs with known hypnotic properties .

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PHARMACOKINETICS

Onset of action

In a study conducted by Zammit et al in adults with chronic insomnia, the average onset of sleep (measured by sleep latency) was 10.4 minutes faster in the eszopiclone 2 mg group than in the placebo group.

Absorption and distribution

Eszopiclone is rapidly absorbed following oral administration. Peak plasma concentrations are achieved within 1 hour after oral administration. It is weakly bound to plasma proteins (52%–59%) .

Metabolism

Following oral administration, eszopiclone is extensively metabolized in the liver by oxidation and demethylation. The primary plasma metabolites have little to no binding potency to GABA receptors. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone .

Elimination

The mean elimination half-life (t1/2) of eszopiclone is approximately 6 hours. Less than 10% of an oral dose is excreted in the urine as parent drug .

Effect of food

In healthy adults, administration of a 3-mg dose of eszopiclone after a high-fat meal resulted in no change in area under the curve (AUC), a 21% reduction in peak concentration (Cmax), and a 1-hour delayed time to reach peak concentration (tmax). The t1/2 remained unchanged .

Efficacy and safety of eszopiclone over 2 weeks in elderly patients

A randomized, double-blind, multicenter, placebo-controlled trial of eszopiclone was conducted in elderly patients, aged 65 to 85 years . A total of 231 patients were assigned to one of three treatment groups: placebo (n = 80), eszopiclone 1 mg (n = 72), or eszopiclone 2 mg (n = 79) nightly for 2 weeks. Patients reported results from a questionnaire each morning and evening through an interactive voice response system. Participants also returned to the clinic for weekly follow-up. The primary endpoint was sleep latency averaged over the double-blind period, and the primary analysis was the comparison between the eszopiclone 2 mg and placebo groups. Secondary endpoints included wake time after sleep onset, number of awakenings, sleep quality, sleep depth, total sleep time averaged over the double-blind period, and daytime function variables.

Efficacy and safety of eszopiclone over 6 weeks

A randomized, double-blind, multicenter, placebo-controlled, parallel group trial conducted in adults aged 21 to 64 years assigned a total of 308 patients to one of three treatment groups: placebo (n = 99), eszopiclone 2 mg (n = 104), or eszopiclone 3 mg (n = 105) nightly for 44 consecutive days . This was followed by 2 nights of placebo to assess the occurrence of rebound insomnia. Patients reported results nightly via an interactive voice response system and had overnight stays in the sleep laboratory for polysomnography recording. The primary endpoint was poly-somnography-determined latency to persistent sleep. Secondary endpoints were mean sleep efficiency and wake time after sleep onset.

Efficacy and safety of eszopiclone over 6 months

A randomized, double-blind, multicenter, placebo-controlled trial was conducted in patients aged 21 to 69 years and assigned a total of 788 patients to receive either eszopiclone 3 mg (n = 593) or placebo (n = 195) nightly for 6 months . Patients reported results weekly via an interactive voice response system.

Compared with placebo, eszopiclone produced a statistically significant improvement (P < 0.05)in all of the aforementioned endpoints. These differences were evident at the first measured time point (week 1), as well as the subsequent 6 time points. At week 1, patients taking eszopiclone fell asleep a mean of 37.2 minutes faster, had 0.6 fewer nightly awakenings, experienced 0.9 fewer nights awake per week, and slept 50.2 minutes longer than patients in the placebo group. At 6 months, patients treated with eszopiclone fell asleep 16.1 minutes faster, had 0.7 fewer nightly awakenings, experienced 0.8 fewer nights awake per week, and slept 39 minutes longer.

2. Zaleplon (Sonata)

Zaleplon, sold under the brand names Sonata among others, is a sedative-hypnotic, used to treat insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class.

Interactions

Cimetidine, rifampicin, and thioridazine cause interactions with zaleplon.

Cimetidine and grapefruit are known to increase blood plasma concentrations of benzodiazepines metabolized by the P450 CYP3A4 liver enzyme by extending the time by which the drug leaves the body, effectively extending the half-life and enhancing effects to potentially toxic levels. Thus, given the similarities between zaleplon and benzodiazepines, particularly in effect, and not just chemical structure, it is reasonable to take precautions before one consumes cimetidine while also taking zaleplon.

Pharmacology

Mechanism of action

Zaleplon is a high-affinity ligand of positive modulator sites of GABAA receptors, which enhances GABAergic inhibition of neurotransmission in the central nervous system. The ultrashort half-life gives zaleplon a unique advantage over other hypnotics because of its lack of next-day residual effects on driving and other performance-related skills.[15][16] Unlike nonselective benzodiazepine drugs and zopiclone, which distort the sleep pattern, zaleplon appears to induce sleep without disrupting the natural sleep architecture.

A meta-analysis of randomized, controlled clinical trials which compared benzodiazepines against zaleplon or other Z-drugs such as zolpidem, zopiclone, and eszopiclone has found few clear and consistent differences between zaleplon and the benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.

Zaleplon has a pharmacological profile similar to benzodiazepines, characterized by an increase in slow wave deep sleep (SWDS) with rapid onset of hypnotic action. Zaleplon is a full agonist for the benzodiazepine α1 receptor located on the GABAA receptor complex in the body, with lower affinity for the α2 and α3 subsites. It selectively enhances the action of GABA similar to, but more selectively than benzodiazepines. Zaleplon, although not a benzodiazepine, maintains a very similar pharmacological profile nonetheless, known for inducing hypnotic effects by α1 subreceptor sites, anxiolytic and muscle relaxant effects via α2 and α3 subsites, with negligible anticonvulsant properties (via α5 subsite), as zaleplon action is modulated at benzodiazepine receptor sites. The elimination half-life of zaleplon is about 1–1.5 hours. The absorption rate of zaleplon is rapid and the onset of therapeutic effects is typically breached within 5–15 minutes following ingestion.

Zaleplon should be understood as an ultrashort-acting sedative-hypnotic drug for the treatment of insomnia. Zaleplon increases EEG power density in the δ-frequency band and a decrease in the energy of the θ-frequency band

Pharmacokinetics

Zaleplon is primarily metabolised by aldehyde oxidase, and its half-life can be affected by substances which inhibit or induce aldehyde oxidase. Taken orally, zaleplon reaches full concentration in about one hour. It is extensively metabolised into 5-oxozaleplon and 5-oxodesethylzaleplon (the latter via desethylzaleplon), with less than 1% of it excreted intact in urine.

Transient Insomnia

Normal adults experiencing transient insomnia during the first night in a sleep laboratory were evaluated in a double-blind, parallel-group trial comparing the effects of two doses of Sonata (5 mg and 10 mg) with placebo. Sonata 10 mg, but not 5 mg, was superior to placebo in decreasing latency to persistent sleep (LPS), a polysomnographic measure of time to onset of sleep.

Explain “lessons learned” from this case study, including how you might apply this case to your own practice when providing care to patients with similar clinical presentation

Tips for a Better Night's Sleep

RELATED CONDITIONS

Insomnia

Patients with sleep problems can follow some simple guidelines for a better night's sleep.

DO:

• Maintain a regular time to go to bed and wake up every day. Sleep for a consistent number of hours, but not more. Excessively long periods of sleep often result in fragmented and shallow sleep.
• Create a comfortable, quiet, clean and dark place for sleeping. Your bed and the temperature of your bedroom should be comfortable.
• Establish a regular pattern of relaxing behaviors, such as reading, for 10 minutes to an hour before bedtime.
• Use the bed for sleeping or relaxing only. For example, don't bring your laptop to bed to finish a pressing assignment before trying to fall asleep.
• Exercise on a regular basis but not immediately before bedtime.

DON'T:

• Don't nap during the day or evening.
• Don't eat heavy meals or drink large amounts of liquid before bedtime. If you are hungry, a light snack or glass of milk may help you sleep.
• Don't drink caffeine in the evening.
• Don't smoke. Chronic tobacco use disturbs sleep.
• Don't dwell on intense thoughts or feelings before bedtime.
• Don't lie awake in bed for long periods. If you're not asleep within 20 to 30 minutes, get up and read or watch TV until you feel sleepy
• Don't rely on sleeping pills for extended periods. Long-term use is ineffective for most insomniacs.
• Don't use alcohol to help you fall asleep. Alcohol may cause a fragmented night's sleep, causing you to wake up during the nigh