November/December 2018

Medication Monitor: Hypnotic Risks in Older Adults
By Mark D. Coggins, PharmD, BCGP, FASCP
Today's Geriatric Medicine
Vol. 11 No. 6 P. 9

The use of hypnotic medications in older adults is not recommended due to a lack of strong evidence supporting their long-term use, especially in light of the risk for numerous drug side effects, including increased mortality.1

Hypnotics include medications from a number of different classes, including benzodiazepines (BZDs), nonbenzodiazepines, antidepressants, antihistamines, antipsychotics, melatonin, anticonvulsants, and others with sedative properties.

This article focuses on risk associated with different classes of hypnotics and the need for great caution before prescribing these medications to older adults.

Mortality Risk
BZDs, nonbenzodiazepines or Z-drugs, and antihistamines (diphenhydramine) increase mortality risk across age groups, with older adults having the greatest risk of death.1 A number of causal pathways by which hypnotics might lead to mortality have been demonstrated, including the following1:

• overdose deaths (especially with alcohol and opioids);

• increased suicide risk;

• increased incident of depression;

• impaired motor and cognitive function leading to accidents;

• falls from hangover sedation;

• increased sleep apnea, prolonged apnea, or suppression of respiratory drive;

• sleep apnea leading to motor vehicle accidents, hypertension, heart failure, arrhythmias, cardiovascular diseases, and death;

• night eating syndromes leading to poor diet and obesity;

• increased gastroesophageal regurgitation and peptic ulcer disease; and

• possible chromosomal damage leading to increased cancer risks.

BZDs
BZDs approved by the FDA for the short-term treatment of insomnia include triazolam, estazolam, temazepam, flurazepam, and quazepam.2 Lorazepam and other BZDs are also frequently used off-label for the treatment of insomnia.

The 2014 "Clinical Guideline for the Treatment of Primary Insomnia in Middle-Aged and Older Adults" published by the Agency for Healthcare Research and Quality (AHRQ) recommends against the use of BZDs to treat primary insomnia.3 In 2015, the American Geriatrics Society (AGS) published an Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults (Beers Criteria), which strongly recommends avoiding the use of BZDs in geriatric patients due to increased risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents.4

The 2016 American College of Physicians (ACP) guidelines discuss observational studies linking BZDs to daytime drowsiness, dizziness or lightheadedness, dementia, increased falls, hip fractures, mobility problems, and an increased incidence of cancer.5

The potential for developing physical dependence is a major concern, even with short-term BZD use (less than two weeks). For patients taking BZDs routinely for more than several weeks, abrupt discontinuation may result in withdrawal symptoms,2 including agitation, anxiety, dysphoria, rebound insomnia, tachycardia, diarrhea, increased awareness of sensory stimuli, perceptual disturbances, depersonalization, confusion, delirium, and seizures.2

Gradual dose tapering, as opposed to abrupt discontinuation, is safer and less likely to lead to withdrawal symptoms.2 The benzodiazepine dosage should be tapered gradually by 5% to 10% every one to two weeks to discontinue.2

Nonbenzodiazepines (Z-Drugs)
Z-drugs, which include zolpidem, zopiclone, eszopiclone, and zaleplon, are the most commonly prescribed hypnotics worldwide.2 They have less potential to cause rebound insomnia and may result in less dependence compared with BZDs. However, nonbenzodiazepines have serious adverse effects, including dementia, delirium, sleepwalking, serious injury, fractures, anterograde amnesia, hallucinations, and increased cancer risk.1,2 Z-drug use is associated with increased hospitalizations and motor vehicle accidents.1

The AHRQ and ACP guidelines recommend all adult patients receive cognitive behavioral therapy (CBT) as the initial treatment for chronic insomnia.3,5 ACP cautiously recommends adding pharmacologic therapy when CBT is unsuccessful and recommends short-term use of only four to five weeks.5 The Beers Criteria strongly recommend avoiding Z-drugs in older adult patients without consideration for duration of use due to their minimal efficacy in treating insomnia and significant risk for possible adverse effects.4

Antihistamines
Over-the-counter medications contain sedating antihistamines such as diphenhydramine. Within one to two weeks of chronic use, tolerance develops, rendering them ineffective for longer-term therapy.2

Common adverse effects of diphenhydramine include anticholinergic side effects such as dry mouth, blurred vision, urinary retention, constipation, orthostatic hypotension, and tachycardia.4 Diphenhydramine use is associated with next-day drowsiness, confusion, and memory loss.2 Hospitalized patients receiving diphenhydramine have been noted to be at increased risk of delirium, altered consciousness, and increased length of hospital stay.2

Sedating Antidepressants
Low-dose sedating antidepressants are often used in the treatment of insomnia for patients with comorbid depression or when other courses of treatment fail.2

Amitriptyline is a tricyclic antidepressant that was used commonly for insomnia in the past. The AGS Beers Criteria strongly discourage the use of amitriptyline in the older adult population due to its anticholinergic effects, including dry mouth, urinary retention, constipation, and drowsiness, in addition to impaired cognition and increased risk of delirium.4

Mirtazapine is a sedating antidepressant approved for the treatment of depression. It promotes sleep through its high affinity for histamine H1 receptors and its inhibition of 5-HT2 receptors with enhancement of noradrenergic neurotransmission, increasing the synthesis of melatonin.2 Mirtazapine generally is well tolerated, with its most common adverse effects being drowsiness, excessive sedation, increased appetite, weight gain, and dry mouth. Interestingly, lower doses cause more sedation.2

Doxepin, a tricyclic antidepressant, commonly is used in the treatment of depression. Doxepin is FDA approved for primary insomnia at doses of 3 mg and 6 mg. At low doses (3 mg to 6 mg), it has high selectivity for histamine receptors and primarily acts as a histamine antagonist that produces a sedative effect.2

The AGS Beers criteria caution against doxepin use in doses greater than 6 mg daily in the geriatric population.4 At low doses, doxepin has high selectivity for histamine receptors and little to no effect on serotonin and adrenergic receptors, thus it doesn't produce anticholinergic adverse effects associated with higher doses.2 The most commonly experienced adverse effects are headache and somnolence/sedation.2

Trazodone is indicated by the FDA for the treatment of depression.2 Side effects, which are relatively mild, include dizziness, drowsiness, fatigue, headache, xerostomia, nausea, and vomiting. The drug lacks anticholinergic activity and cardiotoxicity.2 Trazodone is considered a favorable option compared with other sleep aids such as hypnotics, BZDs, and tricyclic antidepressants, which have unfavorable side effect profiles.1,2

Melatonin Agonists
Melatonin is a hormone secreted by the pineal gland. Endogenous melatonin is released at night and binds to its receptors (MT1 and MT2). Melatonin production is controlled by light; thus, during the evening hours, melatonin levels rise, while during the day they stay low.2 Levels are decreased in geriatric patients, increasing risk of conditions related to circadian rhythms such as sleep disorders, cognitive impairment, and delirium.2

Melatonin also may be given as a dietary supplement and generally is well tolerated.6 There may be a potential for residual daytime sedation and prolonged duration of action. When choosing a melatonin supplement for use in older adults, avoid controlled-release products because they can result in prolonged melatonin levels.2

Ramelteon is a prescription melatonin agonist that helps regulate circadian rhythm. It has fewer side effects than the nonbenzodiazepines or BZDs, is not associated with next-day residual performance deficits, withdrawal, or rebound insomnia, and doesn't appear to be habit forming.2 The most common side effects are somnolence, nasopharyngitis, dizziness, nausea, fatigue, and headache.2

An evaluation of ramelteon and melatonin by European authorities concluded that the benefits/risks ratio of melatonin is probably better than that of ramelteon.1

Orexin Antagonist
FDA-approved for insomnia in 2014, suvorexant is an orexin receptor antagonist.7 The most common adverse effects are daytime somnolence, fatigue, abnormal dreams, and headache. Other potential side effects include sleepwalking, REM sleep behavior disorder, suicidal ideation, and the emergence of sleep paralysis, hypnogogic hallucinations, and mild cataplexy (as seen in narcolepsy).2

When used at approved doses, suvorexant produces some mild adverse effects, including somnolence, fatigue, headache, and dry mouth.2 Few serious adverse effects were reported but included excessive daytime sleepiness, driving impairment, sleep paralysis, falls, and complex sleep-related behaviors.2 All adverse effects were more common in women than men and appeared to be dose dependent.2

The FDA-approved dosing range of suvorexant is 5 mg to 20 mg daily.2,7 The FDA concluded that suvorexant was effective at doses ≤20 mg with minimal safety concerns. Higher doses were associated with a larger incidence and/or severity of adverse events.8

Suvorexant should be taken only if the patient can guarantee getting a minimum of seven hours of sleep.7 Caution is needed with this medication in older adults due to its adverse effect profile and its strict administration requirements.2

Recommendations
The research is clear that the risk of using BZDs, nonbenzodiazepines, and diphenhydramine almost always outweighs any potential benefits. For other agents, including trazodone, doxepin, and melatonin used for sleep, there are no adequate data to estimate whether long-term risks outweigh benefits.1,2

Guidelines recommend that clinicians use strategies to address precipitating causes of insomnia, including the treatment of underlying medical conditions that may contribute (eg, pain, depression), before prescribing sedative medications for sleep problems in older adults. Instead of sedatives for this population, the use of CBT and bright light treatment appear to be the safest and most effective treatments.2

If nonpharmacological interventions are attempted and found insufficient, the use of hypnotic medications may be considered carefully. Using the lowest possible doses for short durations is preferred. Based on current data, the use of low-dose trazodone, doxepin (3 mg to 6 mg), or melatonin agonists appears to be the safest and most effective treatment option.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in 10 states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
1. Kripke DF, Langer RD, Kline LE. Hypnotics' association with mortality or cancer: a matched cohort study. BMJ Open. 2012;2(1):e000850.

2. Schroeck JL, Ford J, Conway EL, et al. Review of safety and efficacy of sleep medicines in older adults. Clin Ther. 2016;38(11):2340-2372.

3. Agency for Healthcare Research and Quality. Clinical guideline for the treatment of primary insomnia in middle-aged and older adults. https://www.multiplechronicconditions.org/assets/
pdf/Insomnia%20Guidelines/AHRQ_2014_Clinical_guideline_for_the_treatment_of_primary_
insomnia_in_middle-aged_and_older_adults.pdf 

4. American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2015;63(11):2227-2246.

5. Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD; Clinical Guidelines Committee of the American College of Physicians. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;165(2):125-133.

6. Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. Gen Intern Med. 2005;20(12):1151.

7. Lowes R. FDA OKs new kind of sleep drug suvorexant (Belsomra). Medscape website. https://www.medscape.com/viewarticle/829893. Published August 13, 2014.

8. Vermeeren A, Sun H, Vuurman EF, et al. On-the-road driving performance the morning after bedtime use of suvorexant 20 and 40 mg: a study in non-elderly healthy volunteers. Sleep. 2015;38(11):1803-1813.