1. Sleep Disorders in the Elderly Module 3
Brenda K. Keller, MD
Assistant Professor
Geriatrics & Gerontology
University of Nebraska Medical Center
Hello. This is Brenda Keller from the Section of Geriatrics and Gerontology at the University of Nebraska Medical Center. In this module, we will review the pharmacological treatment of insomnia. Our process will be for you to complete the third in a series of three modules and questions on Sleep disorders in the elderly. If you have not completed the first two modules, please do so at this time and then return to this module.
These modules will utilize Power Point with voice overlay. Each module will be followed by case-based questions with answers that will explain the right and wrong responses. To receive credit for all three sleep disorder modules you must also complete the evaluation that is accessed on the same page as the questions. Always, the learner is recommended to complete a module before disengaging. When the module and questions are completed, click on “Mark Reviewed” on the main page of the Minifellowship to indicate your completion.

2. Module 3 Pharmacological Treatments
Choose carefully due to risk of side effects
FDA Approved
Benzodiazepines
Non-Benzo hypnotics- Type I Gaba receptor agents
Eszopiclone
Rozerem
Non-FDA Approved
Herbal therapies
Hormones/naturopathic
Sedating antidepressants
OTC antihistamines
Pharmacological treatment for primary insomnia is generally reserved for those who fail non-pharmacologic therapy. For individuals with secondary insomnia, treatment is focused on the underlying disease process. Treatment of depression with antidepressants, analgesic use for pain, and dopaminergic medications for restless leg syndrome and periodic limb movement of sleep are all effective in the management of secondary insomnia. Only those items on the left part of the screen have FDA approval for insomnia. Those items on the right column should be used with caution as their effectiveness and safety for the treatment of insomnia have not been established.

3. General precautions Start low, go slow Avoid q hs dosing
Use only 2-3 weeks
Several general precautions are given for the pharmacological treatment of insomnia. First, start with low doses and go slow with titration. Second, as needed dosing of medications is recommended as opposed to a scheduled dose of hypnotic. Thirdly, the majority of hypnotics are recommended for short term use only. Medications should be used in concert with the non-pharmacological methods discussed in module 2.

4. Pharmacological Treatments
Benzodiazepines
Short acting
Lorazepam
Temazepam
Long acting
Benzodiazepines are effective in inducing, maintaining and consolidating sleep but are associated with significant side effects in the elderly. Side effects include increased risk of falls, confusion, slowed reaction time, anterograde amnesia and possible diminished effectiveness over time. As a general rule, only short acting benzodiazepines should be prescribed for the elderly patient. Courses of treatment should be less than 4 weeks in duration, and “as needed” dosing is recommended. Lorazepam is indicated for the treatment of anxiety, insomnia, and status epilepticus. The initial dose in the elderly should be 0.5 to 1mg. This is much lower than the 2-4 mg recommended for younger people with insomnia. Temazepam is indicated for insomnia only. Long acting benzodiazepines are not recommended.

5. Pharmacological Treatments
Non-Benzo hypnotics-
Type I Gaba receptor agents
Zaleplon (Sonata)
Zolpidem (Ambien)
Systemic: Both Zaleplon and Zolpidem interact with the gamma-aminobutyric acid type A-benzodiazepine (GABA-BZ) receptor complex. Modulation of the GABA-BZ receptor chloride channel macromolecular complex appears to be responsible for the pharmacological properties of the benzodiazepines including sedative, anxiolytic, muscle relaxant, and anticonvulsant effects. Zaleplon binds selectively to the brain alpha subunit of the GABA-A omega-1 receptor. The preferential binding to the BZ1 receptor may explain the relative absence of myorelaxant and anticonvulsant effects as well as the preservation of deep sleep (stages 3 and 4) at hypnotic doses. The starting dose for both Zaleplon and Zolpidem is 5 mg. Although much shorter acting than the benzodiazepines, side effects include confusion and slowed reaction time.

6. Pharmacological Treatments
Eszopiclone (Lunesta)
Single isomer, nonbenzodiazepine cyclopyrrolone
Affects both onset and maintenance of sleep
Although the exact mechanism of action of eszopiclone is unknown, It is believed that eszopiclone binds to or interacts allosterically at the GABA-receptor complex domain . The lowest dose of 1 mg is suggested for patients having a difficult time falling asleep, whereas the 2 mg tablet should be prescribed for those with difficulty staying asleep. Neurologic side effects include: Confusion, Dizziness, Headache, Migraine, Somnolence, whereas
Psychiatric symptoms can include: Anxiety, Depression, Hallucinations, Nervousness

7. Pharmacological Treatments
Ramelteon (Rozerem)
Selective melatonin type 1 and type 2 receptor agonist
Targets receptors in the suprachiasmatic nucleus
Ramelteon is one of the newer agents available for the treatment of insomnia. Ramelteon is a melatonin receptor agonist with higher selective affinity for melatonin MT1 and MT2 receptors verses the MT3 receptor. This contributes to sleep-promotion and maintenance of the circadian rhythm underlying the normal sleep-wake cycle.
The initial dose for insomnia is 8 mg at bedtime. Potential side effects include nausea, dizziness, fatigue, and somnolence.

8. Pharmacological Treatments
Herbal therapies
Valerian
Hormones/naturopathic
Melatonin
While many small studies have shown that valerian extract possesses mild sedative and tranquilizing characteristics, the mechanism of action for this effect has not been clarified. Some constituents may influence the brain gamma-aminobutyric acid (GABA) metabolism and the properties of the cortical membrane receptors. Valerian dosage for mild to moderate sleeping disorders is 400 to 900 milligrams before bed.
Melatonin effects are described in the previous slide for Ramelteon. Natural melatonin, however, is not selective and attaches to M1, M2, and M3 receptors with equal affinity. Melatonin dosage for INSOMNIA in the elderly population is 1 to 2 milligrams taken 2 hours before bedtime
The dosing of dietary supplements is highly dependent on a variety of factors such as quality of raw materials, manufacturing process, and packaging. Since no official standards have been established to date to regulate the production of dietary supplements in the United States, dosage ranges must be employed as guidelines only.

9. Pharmacological Treatments
Sedating antidepressants
Trazodone
Tricyclic antidepressant
Mirtazapine
Sedating antidepressants have been used “off label” for the treatment of insomnia due to their anticholinergic side effects. The doses of trazodone (25 mg) and tricyclic antidepressants (less than 50 mg) used to induce sleep are much lower than those used for depression, however constipation, hypotension, dry mouth and confusion limit their usefulness in the geriatric population. Mirtazapine is better tolerated, but it is important to know that the desired sedation effects are most pronounced at the lower doses of 7.5 to 15 mg. In general, I would reserve these medications for those with underlying depression.

10. Pharmacological Treatments
OTC antihistamines
diphenhydramine
Over the counter antihistamines such as diphenhydramine are marketed as sleep aids. In the elderly population this medication should be used with caution due to potential anticholinergic side effects of confusion, dry mouth, and constipation. It is important to take a careful medication history to identify both prescription and non-prescription medications as some older people may not think of over the counter preparations as “Medicine.”

11. Summary
In summary, we have discussed many different treatment options for insomnia, emphasizing the potential side effects in the older population. To receive credit of this module, please close out and return to the sleep disorder main page, advance to the question and review the answer. Also to receive credit you must complete the evaluation list on the main page as the questions. When you have completed all of this, please return to the main page to mark reviewed on the Minifellowship to designate your completion. Thank you for your attention.

12. Critiques from the Geriatric Review Syllabus. AGS 2002 New York, NY.
Post-test question 1
A 78-year-old woman presents with conjugal bereavement and a chief complaint of insomnia and daytime fatigue. She describes morbid dreams that have progressively worsened over the past 6 months following the death of her spouse. Her Mini–Mental State Examination score is 24/30. Sleep laboratory (polysomnographic) studies show shortened period of rapid-eye movement (REM) sleep onset latency, increased REM density, and reduced total sleep time. Which of the following medications would be the best treatment in this case?
A.Zolpidem
B.Clonazepam
C.Mirtazapine
D.Donepezil
E.Thioridazine
Used with permission from: Murphy JB, et. Al. Case Based Geriatrics Review: 500 Questions and
Critiques from the Geriatric Review Syllabus. AGS 2002 New York, NY.

13. Correct Answer: C. Mirtazapine
This case represents a common clinical presentation, that of spousal bereavement and sleep complaints. Both the disturbing dreams reported by the patient and her mild cognitive impairment add further complexity to the case. Comorbid psychiatric disorders often contribute to the development of insomnia, as will any condition, such as grief, that results in psychologic arousal. Spousal bereavement is associated with a high prevalence of depression and associated sleep disturbance. Disorders of cognitive impairment, including dementia and delirium, also contribute to insomnia and disturbances of the sleep-wake cycle, including nighttime wandering and delirium (ie, sundowning). In this case, efforts were made using sleep electroencephalography to distinguish major depression from other psychopathologic states. The primary well-documented changes in sleep architecture include shortened period of rapid-eye movement (REM) sleep onset latency, increased REM density, reduced total sleep time, reduced sleep efficiency, increased awakenings, increased slow-wave sleep, and a shift of slow-wave sleep from the first non-REM cycle to the second. The causes of these alterations are the subject of much speculation.

14. Both major depression and aging result in increased awakenings, reduced slow-wave sleep, and reduced REM sleep latency. Older persons with depression have more difficulty maintaining sleep than younger persons or nondepressed older persons, and relatively reduced slow-wave sleep appears to be a strong characteristic of depression in all age groups. Unlike in a younger person with depression, the occurrence of REM sleep in less than 10 minutes after sleep onset seems to be most characteristic of the depressed elderly patient. Indeed, it appears that aging coupled with depression tends to cause a precipitous reduction in REM sleep latency. The degree of sleep disturbance may be somewhat related to the severity of depression. Associated cognitive difficulties are also related to the degree of sleep fragmentation caused by depression. Consideration of these findings suggests that the most useful medication in treating the patient in this case is mirtazapine.

15. Mirtazapine is an effective antidepressant that tends to be sedating at low doses (15 mg). If this sedation is a problem, increasing the dose (eg, to 30 or 45 mg) is beneficial since at higher doses, more noradrenergic stimulation occurs. Zolpidem, although a useful sedative in elderly patients, is not the best choice for the patient in question, since she has an underlying depression. Similarly, clonazepam may be useful in the treatment of disordered sleep movement but is also not effective for depression. Donepezil is useful in the treatment of cognitive symptoms, and in this case further evaluation for dementia is indicated following the resolution of the depressive symptoms. It is quite possible that the cognitive impairment will reverse with antidepressant therapy, in which case pseudodementia may be diagnosed in retrospect. Thioridazine is not a useful drug for this patient. Antipsychotic agents are primarily useful in treating patients with psychosis and severe nonpsychotic agitation. Thioridazine is a low-potency agent with potential for anticholinergic side effects, daytime drowsiness, and the development of orthostatic symptoms, all significant concerns in the elderly age group.

16. Post-test question 2
An 83-year-old woman who has hypertension and osteoarthritis has a 3-week history of difficulty falling asleep and several awakenings throughout the night. Her symptoms are attributed to acute psychosocial stressors. You determine that a short course of a hypnotic agent is indicated. Which of the following drugs is most appropriate?
A. Amitriptyline
B. Diphenhydramine
C. Melatonin
D. Triazolam
E. Zolpidem tartrate

17. Correct Answer: E. Zolpidem tartrate
Zolpidem is a nonbenzodiazepine hypnotic that has a desirable pharmacologic profile for older patients with medical illnesses. It is effective both in inducing and maintaining sleep. Onset of effect is 30 minutes to 1 hour; it has no active metabolites and is eliminated rapidly (half-life of 2.5 hours). The sedative advantages over short-acting benzodiazepines may not be significant in short-term use. However, lack of tolerance and withdrawal phenomenon are advantageous, particularly for long-term administration. Zolpidem is not associated with memory effects, daytime sleepiness, or drug-drug interactions (except with alcohol). Generally, this patient could be expected to have a better outcome if pharmacotherapy is combined with behavioral therapy. Tricyclic antidepressants often are used for insomnia in older patients.

18. Amitriptyline is the most sedating and most frequently prescribed, although it is associated with anticholinergic and other adverse effects, such as orthostatic hypertension. The disadvantages of using tricyclic antidepressants usually outweigh any therapeutic advantage. Diphenhydramine and other antihistamines may improve acute insomnia, but even low doses sometimes are associated with impaired daytime functioning. Diphenhydramine also has anticholinergic effects and may be associated with delirium, especially when administered with other medications that act on the central nervous system. Melatonin has received much attention as an over-the-counter sleep aid. Although age-related changes in its secretion cycle may contribute to insomnia in healthy older adults, supplementation is of unknown therapeutic value in patients such as this. Moreover, studies suggest that it is not useful as a hypnotic agent. Triazolam is an ultra–short-acting benzodiazepine hypnotic. Its advantages are rapid onset and minimal adverse effects, including little hangover. However, it may be associated with early morning rebound insomnia and anxiety. Of greater concern is the risk of tolerance and dependence and some risk of anterograde amnesia. Less common adverse effects include disinhibition and delirium or withdrawal, especially at higher dosages. End