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Geriatric patients: choose wisely: age-related physiologic changes, risk of adverse effects guide your prescribing.

Mr. R, age 75, is having difficulty sleeping. When he goes to bed, he lies there for what seems like forever, unable to fall asleep. He feels "so tired" and ends up taking naps during the day, but he cannot break this cycle. He has tried using over-the-counter products with little relief.

Mr. R's primary care physician prescribes zaleplon, 10 mg/d, and asks him to call the clinic in 2 weeks to discuss his progress. He takes zaleplon as directed for several nights and begins to feel "sluggish" during the day, both mentally and physically, despite reporting an increase in the overall amount of sleep at night.

Sedative-hypnotic drugs are among the most commonly used medications in the United States. Use of these drugs, as well as anxiolytics, has increased from 2.8% between 1988 and 1994 to 4.7% between 2007 and 2010, according to the Department of Health and Human Services. (1) In 2011, drugs categorized as sedative-hypnotics or antipsychotics were involved in 6.1% of all human exposures identified in the American Association of Poison Control Centers' National Poison Data System. (2) Therefore, an understanding of clinical and pharmacological variables related to safe and effective use is important for clinicians prescribing and monitoring therapy with these agents.

Neuropsychiatric disorders are prevalent among geriatric patients and are associated with age-related physiologic changes in the CNS. (3) Such changes involve:

* neuroanatomy (brain atrophy, decreased neuronal density, increased plaque formation)

* neurotransmitters (reduced cholinergic transmission, decreased synthesis of dopamine and catecholamines), and

* neurophysiology (reduced cerebral blood flow).

These physiologic processes manifest as alterations in mental status, reflexes, sensation, gait, balance, and sleep. Examples of sleep changes among geriatric patients include decreased sleep efficiency, more frequent awakenings, and more variable sleep duration. (3), (4) Sleep disorders also may be related to mental disorders and other medical conditions. (5) For example, the prevalence of sleep-related respiratory disorders, such as obstructive sleep apnea and central sleep apnea, increases with age. (6)

Sleep disorders are common among geriatric patients. In a large epidemiologic study of sleep complaints in patients age [greater than or equal to]65, more than one-half of patients had at least 1 sleep complaint (ie, difficulty falling asleep, trouble waking up, early awakening, need for naps, and feeling ill-rested). (7) As many as 34% of patients reported symptoms of insomnia. In an analysis of National Ambulatory Medical Survey Data over 6 years, 24.8% to 27.9% of sleep-related medical office visits were attributed to patients age [greater than or equal to]65. (8)

Pharmacology in aging

Prescribing sedative-hypnotic drugs is not routinely recommended for older patients with a sleep disorder. Geriatric patients, compared with younger patients, are at higher risk of iatrogenic complications because of polypharmacy, comorbidities, relative renal and hepatic insufficiency, and other physiologic changes leading to alterations in drug exposure and metabolism (Table 1).(9-12)

Aging is associated with changes in body composition, including an increase in total body fat and decrease in lean body mass and total body water. These changes, as well as a prolonged GI transit time, decrease in active gut transporters, decreased blood perfusion, and decrease in plasma proteins such as albumin (because of 'educed liver function or malnutrition), may lead to alteration in drug absorption patterns and may increase the volume of distribution for lipophilic drugs. Additionally, the elimination half-life of some drugs may increase with age because of larger volumes of distribution and reduction in hepatic or renal clearance.

The clinical significance of these changes is not well established. Although the process of drug absorption can change with age, the amount of drug absorbed might not be significantly affected. An increase in the volume of distribution and reduction in drug metabolism and dearance might lead to increasing amounts of circulating drug and duration of drug exposure, putting geriatric patients at an increased risk for adverse effects and drug toxicity. (9)

Among these mechanisms, Dolder et all (11) hypothesized that drug metabolism catalyzed by cytochrome P450 (CYP) enzymes and renal excretion may be of greatest concern. Although in vitro studies suggest that concentration of CYP enzymes does not decline with age, in vivo studies have demonstrated reduced CYP activity in geriatric patients. (11), (12) Theoretically, a reduction in CYP activity would increase the bioavailability of drugs, especially those that are subject to extensive first-pass (ie, hepatic) metabolism, and may lead to a reduction in systemic clearance.

Independent of metabolic changes, geriatric patients are at risk of reduced renal clearance because of age-related changes in glomerular filtration rate. Pharmacodynamic changes might be observed in older patients and could be a concern even in the setting of unaltered pharmacokinetic factors.' These changes usually require administering smaller drug dosages.

Sedative-hypnotic medications

Sedative-hypnotic agents include several barbiturates, benzodiazepines (BZDs), non-BZD benzodiazepine-receptor agonists (BzRAs), a melatonin-receptor agonist (ie, ramelteon), and an orexin-receptor antagonist (ie, suvorexant). (13), (14) Table 2 (page 46) (14-29) summarizes selected sedative-hypnotic drugs. Additional drug classes used to treat insomnia include:

* sedating antidepressants (trazodone, amitriptyline, doxepin, mirtazapine)

* antiepileptic drugs (gabapentin, tiagabine)

* atypical antipsychotics (quetiapine, olanzapine).
Table 1
Effects of age-associated physiologic changes on pharmacokinetic

Physiologic          Pharmacokinetic parameters       Clinical
changes                                              implications

[down arrow] Total  Absorption                      May observe slight
body fat [down      * Unaffected for IV drugs       decrease in
arrow] Lean body    * E[down arrow]tent of          absorption;
mass [down arrow]   absorption may be complete,     literature
Total body water    but [T.sub.max] may be longer,  suggests that this
[down arrow] Gl     [C.sub.max] may be lower        rarely is
motility [down      * Reduced for drugs requiring   clinically
arrow] Plasma       lower pH environment            significant

                    Distribution                    May require dosage
                    * Reduced for water-soluble     reduction of
                    drugs and drugs bound to        hydrophilic drugs
                    muscle                          May observe
                    * Increased for lipid-soluble   prolonged time to
                    drugs                           elimination of
                                                    lipophilic drugs
                                                    Note: reduction in
                                                    protein binding
                                                    alone does not
                                                    usually result in
                                                    significant change
                                                    in volume of

[down arrow]        Metabolism                      Potential increase
Hepatic mass [down  * Reduced first-pass            in bioavailability
arrow] Hepatic      metabolism                      of drugs subject
blood flow          * Reduced Phase I metabolism    to e[down
                                                    hepatic metabolism
                                                    and increased drug

[down arrow]        Elimination                     Increased plasma
Cardiac output      * Reduced renal elimination     concentration of
[down arrow]        * Increased elimination         drug or
Blood flow to       half-life                       metabolites and
kidneys and liver                                   duration of drug
[down arrow]                                        action
Renal mass [down
arrow] Renal or
hepatic clearance

[C.sub.max]: maximum plasma concentration; [T.sub.max]: time to
maximum plasma concentration Source: References 9-12

FDA-approved agents for treating insomnia include amobarbital, butabarbital, pentobarbital, phenobarbital, secobarbital, chloral hydrate, diphenhydramine, doxylamine, doxepin, estazolam, flurazepam, lorazepam, quazepam, temazepam, triazolam, eszopidone, zaleplon, zolpidem, ramelteon, and suvorexant. Not all of these drugs are recommended for use in geriatric patients. Barbiturates, for example, should be avoided. (30)

Pharmacokinetic characteristics vary among drugs and drug classes. Choice of pharmacotherapy should account for patient and drug characteristics and the specific sleep complaint. Sleep disorders may be variously characterized as difficulty with sleep initiation, duration, consolidation, or quality. (13) Therefore, onset and duration of effect are important drug-related considerations. Sedative-hypnotic drugs with a short time-to-onset may be ideal for patients with sleep-onset insomnia.

The drugs' duration of effect (eg, presence of active metabolites, long elimination half-life) also must be reviewed. A long elimination half-life may lead to increased drug exposure and unwanted side effects such as residual daytime drowsiness. Despite this, sedative-hypnotic drugs with a longer duration of effect (eg, intermediate- or long-acting drugs) may be best for patients with insomnia defined by difficulty maintaining sleep.

Benzodiazepines vary in their time to onset of effect, rate of elimination, and metabolism. (15-21) BZDs that are FDA-approved for use as sedative-hypnotics are listed in Table 2 (page 46). (14-29) These BLDs have different onsets of effect as evidenced by time to achieve maximum plasma concentration ([T.sub.max]), ranging from 0.5 hours (flurazepam) to 2 hours (estazolam, quazepam, triazolam). The elimination half-life varies widely among these medications, from 1.5 hours (triazolam) to >100 hours (flurazepam). Flurazepam's long half-life is attributable to its active major metabolite. Although most BZDs are metabolized hepatically, temazepam is subject to minimal hepatic metabolism.
Table 2
Characteristics of select oral sedative-hypnotic agents and
recommended dosing in geriatric patients

                       Pharmacokinetic characteristics

Drug           Dosage       Absorption     Distribution
                form         (onset of      (protein
                               effect,     binding, Vd)
                            [T.sub.max])       (b)


Estazolam    1,2 mg       [T.sub.max]:   High protein
             tablets      2 hours        binding Vd: large

Flurazepam   15, 30 mg    Onset of       High protein
(e)          capsules     effect: 15 to  binding Vd: large
                          20 minutes
                          0.5 to 1
                          of major
                          10.6 hours

Quazepam     15 mg        [T.sub.max]:   High protein
(e)          tablets      2 hours        binding Vd: large

Temazepam    7.5,15,      [T.sub.max]:   High protein
             22.5, 30 mg  1.2 to 1.6     binding Vd: medium
             capsules     hour

Triazolam    0.125, 0.25  Onset of       High protein
             mg tablets   effect: 0.25   binding Vd: medium
                          to 0.5 hour
                          2 hours

Benzodiazepine-receptor agonists

Eszopiclone  1,2,3 mg     [T.sub.max]:   Moderate
             tablets      1 hour         protein
                                         binding Vd: medium

Zaleplon     5,10 mg      [T.sub.max]:   Moderate
             capsules     1 hour         protein
                                         binding Vd: medium

Zolpidem     5,10 mg      Onset of       High protein
             tablets      effect: 0.5    binding Vd: small
                          1.6 hour

             6.25,12.5    [T.sub.max]:
             mg ER        1.5 hour

             5,10 mg      [T.sub.max]:
             sublingual   0.5 to 3
             tablets      hour

             1.75, 3.5    [T.sub.max]:
             mg           0.5 to 1.25
             sublingual   hours

             5 mg spray   [T.sub.max]:
             solution     0.9 hour

Melatonin-receptor agonist

Ramelteon    8 mg         Onset of       Moderate
             tablets      effect: 0.5    protein
                          hour           binding Vd: medium
                          0.75 hour

Orexin-receptor antagonist

Suvorexant   5,10,15,20   [T.sub.max]:   High protein
             mg tablets   2 hour         binding Vd: small

                 Pharmacokinetic characteristics

Drug          Metabolism     Elimination   Recommended
                  (c)           (d)        adult dosing

Estazolam    Hepatic;       [T.sub.1/2]:  Hypnotic: 1
             extent high    10 to 24      or 2 mg at
             Enzyme: CYP    hours         bedtime
             3A4                          Geriatric:
                                          0.5 mg
                                          for small or
                                          patients; 1
                                          mg if

Flurazepam   Hepatic;       [T.sub.1/2]:  Hypnotic: 30
(e)          extent high    2.3 hours     mg at
             Enzyme: CYP    [T.sub.1/2]   bedtime
             3A4            of major      Geriatric:
                            metabolite:   15 mg
                            47 to 100
                            hours; mean
                            126 to 158
                            hours in

Quazepam     Hepatic;       [T.sub.1/2]:  Hypnotic:
(e)          extent high    39 hours      7.5 mg
             Enzyme: CYP    [T.sub.1/2]   initially
             3A4            of major      Geriatric:
                            metabolite:   NS
                            73 hours

Temazepam    Hepatic;       [T.sub.1/2]:  Hypnotic: 15
             extent low     3.5 to 18.4   mg at
             Enzyme: CYP    hours, mean   bedtime
             2B6,2C19,2C9,  8.8 hours     Geriatric:
             3A4 (all                     7.5 mg
             minor)                       initially

Triazolam    Hepatic;       [T.sub.1/2]:  Hypnotic:
             extent         1.5 to 5.5    0.25 mg at
             moderate       hours         bedtime;
             Enzyme: CYP                  0.125 mg for
             3A4                          patients
                                          with low
                                          body weight
                                          0.125 mg
                                          0.25 mg

Eszopiclone  Hepatic;       [T.sub.1/2]:  Hypnotic: 2
             extent high    6 hours       mg at
             Enzyme: CYP                  bedtime
             3A4, 2E1                     Geriatric: 1
                                          initially, 2
                                          mg maximum

Zaleplon     Hepatic;       [T.sub.1/2]:  Hypnotic: 10
             extent high    1 hour        mg at
             Enzyme: CYP                  bedtime
             3A4                          Geriatric: 5
                                          10 mg

Zolpidem     Hepatic;       [T.sub.1/2]:  Hypnotic: 5
             extent high    2.5 to 2.6    or 10 mg at
             Enzyme:        hours         bedtime
             primarily CYP                Geriatric: 5
             3A4, minor                   mg

             1A2, 2C19,     [T.sub.1/2]:  Hypnotic:
             2C9, and 2D6   2.8 hours     6.25 or 12
                                          mg at
                                          6.25 mg

                            [T.sub.1/2]:  Hypnotic: 5
                            2.65 to 2.85  or 10 mg at
                            hours         bedtime

                            2.5 hours

                            [T.sub.1/2]:  Hypnotic: 5
                            3.0 hours     or 10 mg at
                                          Geriatric: 5

Ramelteon    Hepatic;       [T.sub.1/2]:  Hypnotic: 8
             extent high    1 to 2.6      mg at
             Enzyme:        hours         bedtime
             primarily CYP                Geriatric:
             1A2, minor 2C                NS
             and 3A4

Suvorexant   Hepatic;       [T.sub.1/2]:  Hypnotic: 10
             extent high    12 hours      mg at
             Enzyme:                      bedtime, 20
             primarily CYP                mg maximum
             3A, minor                    Geriatric:
             2C19                         NS

(a.) Time to maximum plasma concentration and/or onset of effect
specified if available

(b.) Extent of protein binding: high: >90%; moderate: <90% and >50%;
low: <50%; Vd specified if available: large: >2 L/kg; medium: [less
than or equal to]2 and 21 L/kg; small: <1 L/kg

(c.) Extent of metabolism: high: <10% excreted unchanged; moderate:
[less than or equal to]50% and >10% excreted unchanged; low: >50%
excreted unchanged

(d.) For half-lives reported as a range, a mean is specified if

(e.) Flurazepam and quazepam are not recommended in geriatric
patients because of safety concerns

CR: controlled-release; CYP: cytochrome P450; ER: extended-release;
NS: not specified; [T.sub.1/2]: elimination half-life; [T.sub.max]:
maximum plasma concentration; Vd: volume of distribution

Source: References 14-29

Benzodiazepine-receptor agonists.

There is substantial variation in the pharmacokinetic characteristics of BzRAs. (15), (16), (22-28) There also are differences among the zapi-dem dosage forms; sublingual formulations have the shortest onset of effect. Eszopiclone and zaleplon have low protein binding compared with zolpidem. Elimination half-lives vary among drugs with the shortest attributed to zaleplon (1 hour) and longest to eszopidone (6 hours). All BzRAs are subject to extensive hepatic metabolism.

Ramelteon. Singular in its class, ramelteon is a treatment option for insomnia. (29) This drug has a short onset of effect, moderate protein binding, and extensive hepatic metabolism. Ramelteon is primarily excreted in the urine as its metabolites, and the drug half-life is relatively short.

Suvorexant is the latest addition to the sedative-hypnotic armamentarium, approved by the FDA in August 2014 for difficulty with sleep onset and/or sleep maintenance. (14) As an mexin-receptor antagonist, suvorexant represents a novel pharmacologic dass. Suvorexant exhibits moderately rapid absorption with time to peak concentration ranging from 30 minutes to 6 hours in fasting conditions; absorption is delayed when taken with or soon after a meal. The drug is highly protein bound and extensively metabolized, primarily through CYP3A. The manufacturer recommends dose reduction (5 mg at bedtime) in patients taking moderate CYP3A inhibitors and avoiding suvorexant in patients taking strong CYP3A inhibitors. Suvorexant is primarily excreted through feces and the mean half-life is relatively long.

Considering these characteristics and age-related physiologic changes, the practitioner should be concerned about drugs that undergo extensive hepatic metabolism. Age-related reductions in CYP activity may lead to an increase in drug bioavailability and a decrease in the systemic clearance, (11) which might be associated with an increase in elimination half-life and duration of action. Dosage adjustments are recommended for several BLDs (lower initial and maximum dosages for most agents) and BzIZAs. (17-28) No dosage adjustments for ramelteon or suvorexant in geriatric patients have been specified (14), (29); the manufacturers for both products assert that no differences in safety and efficacy have been observed between older and younger adult patients.

Alternative and complementary medications

Several non-prescription products, including over-the-counter drugs (eg, diphenhydramine, doxylamine) and herbal therapies (eg, melatonin, valerian), are used for their sedative-hypnotic properties. There is a lack of evidence supporting using diphenhydramine in patients with chronic insomnia, and tolerance to its hypnotic effect has been reported with repeated use. (31) Concerns about anticholinergic toxicity and CNS depression limit its use in geriatric patients. Among herbal therapies, melatonin may have the strongest evidence for its ability to alleviate sleep disorders in geriatric patients (32); however, meta-analyses have demonstrated small effects of melatonin on sleep latency and minimal differences in wake time after sleep onset and total sleep time. (13)

Clinical practice guidelines

Non-pharmacotherapeutic interventions, such as behavioral (eg, sleep hygiene measures) and psychological therapy, are recommended for initial management of sleep disorders in geriatric patients.1133 In conjunction, the American Medical Directors Association (AMDA) recommends addressing underlying causes and exacerbating factors (eg, medical condition or medication). (33) The AMDA recommends avoiding longterm pharmacotherapy and advises caution with BLD-hypnotic drugs, tricyclic antidepressants, and antihistamines. The American Academy of Sleep Medicine (AASM) recommends an initial treatment period of 2 to 4 weeks, followed by re-evaluation of continued need for treatment. (13) The AASM recommends short- or intermediate-acting BzRAs or ra-melteon for initial pharmacologic management of primary insomnias and insomnias comorbid with other conditions. The AASM also recommends specific dosages of BzRAs and BZUs for geriatric patients, which coincide with manufacturer-recommended dosages (Table 2, page 46). (14-29)

Barbiturates, chloral hydrate, and non-barbiturate, non-BZD drugs such as meprobamate are not recommended because of potential significant adverse effects and tolerance/dependence, and low therapeutic index. The AASM advises caution when using prescription drugs off-label for insomnia (eg, antidepressants, antiepileptics, antipsychotics) and recommends avoiding them, if possible, because of limited evidence supporting their use. (13)

Safety concerns

Two commonly used references contain recommendations for sedative-hypnotic medication use in geriatric patients. (30), (34) According to Gallagher et al's (34) Screening Tool of Older Person's Prescriptions (STOPP), long-term (>1 month) use of long-acting BZDs (eg, flurazepam, diazepam) and prolonged use (>1 week) of first-generation antihistamines (eg, diphenhydramine, doxylamine) should be avoided in patients age [greater than or equal to]65 because of the risk of sedation, confusion, and anticholinergic side effects. STOPP recognizes that any use of BZUs, neuroleptics, or first-generation antihistamines may contribute to postural imbalance; therefore these agents are not recommended in older patients at risk for falls.

In the 2012 American Geriatrics Society (AGS) Beers Criteria, the AGS recommends avoiding barbiturates in older adults because of the high rate of physical dependence, tolerance to sleep effects, and overdose risk at low dosages. (30) The AGS also recommends avoiding BZDs, stating that older adults have increased sensitivity to these agents and are at an increased risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents when taking these drugs. Non-BZD BzRAs also should not be prescribed to patients with a history of falls or fractures, unless safer alternatives are not available.

The FDA has issued several advisory reports regarding sedative-hypnotic drugs. In 2007, all manufacturers of sedative-hypnotic drugs were required to modify their product labeling to include stronger language about potential risks. (35) Among these changes, warnings for anaphylaxis and complex sleep-related behaviors were added. Also, the FDA requested that manufacturers of sedative-hypnotic drugs develop and provide patient medication guides, advising consumers on the potential risks and precautions associated with these drugs. More recently, the FDA announced changes to dosing recommendations for zolpidem-containing products because of the risk of impaired mental a1ertness (36); manufacturers were required to lower the recommended dosages for each product.

Manufacturers of FDA-approved sedative-hypnotic drugs urge caution when prescribing these medications for geriatric patients, citing the potential for increased sensitivity, manifesting as marked excitement, depression, or confusion (eg, barbiturates), and greater risk for dosage-related adverse effects (eg, oversedation, dizziness, confusion, impaired psychomotor performance, ataxia). (17-29)

Use in clinical practice

Several variables should be considered when evaluating appropriateness of pharmacotherapy, including characteristics of the drug and the patient. Geriatric patients may be prone to comorbidities resulting from age-related physiologic changes. These diseases may be confounding (ie, contributing to sleep disorders); examples include medical illnesses, such as hyperthyroidism and arthritis, and psychiatric illnesses, such as depression and anxiety.37 Other conditions, such as renal and hepatic dysfunction, may lead to alteration in drug exposure. These conditions should be assessed through routine renal function tests (eg, serum creatinine and glomerular filtration rate) and liver function tests (eg, serum albumin and liver transaminases).

Multiple comorbidities suggest a higher likelihood of polypharmacy, leading to other drug-related issues (eg, drug-drug interactions). Although these issues may guide therapy by restricting medication options, their potential contribution to the underlying sleep complaints should be con-sidered. (37) Several drugs commonly used by geriatric patients may affect wakefulness (eg, analgesics, antidepressants, and antihypertensives [sedating], and thyroid hormones, corticosteroids, and CNS stimulants [alerting]). In Mr. R's case, zaleplon was initiated at 10 mg/d. Because of his age and the nature of his sleep disorder, the choice of sedative-hypnotic was suitable; however, the prescribed dosage was inappropriate. The sluggishness Mr. R experienced likely was a manifestation of increased exposure to the drug. According to manufacturer and AASM recommendations, a more appropriate dosage is 5 mg/d. (13), (23) Mr. R's medical history and current medications, and his hepatic and renal function, should be assessed. If Mr. R continues to have issues with sleep initiation, zaleplon, 5 mg at bedtime, should be considered.

(8.) Morlock RI, Tan M, Mitchell DY. Patient characteristics and patterns of drug use for sleep complaints in the United States: analysis of National Ambulatory Medical Survey Data, 1997-2002. Clin Ther. 2006; 28(7): 1044-1053.

(9.) Diasio RB. Principles of drug therapy. In: Goldman L, Schafer Al, eds. Goldman's Cecil medicine. 24th ed. Philadelphia, PA: Elsevier Saunders; 2011: 124-132.

(10.) Hilrner SN, Ford GA. General principles of pharmacology. In: Halter JB, Ouslander JG, Tmetti ME, et al, eds. Hazzard's geriatric medicine and gerontology 6th ed. New York, NY: McGraw-Hill; 2009: 103-122.

(11.) Dolder C, Nelson M, McKinseyt Use of non-benzodiazepine hypnotics in the elderly: are all agents the same? CNS Drugs. 2007; 21(5): 389-405.

(12.) Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev. 2009; 41(2): 67-76.

(13.) Schutte-Rodin 5, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2(X)8; 4(5): 487-504.

(14.) Belsomra [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2014.

(15.) Micromedex Healthcare Series. Greenwood Village, CO: Thomson Efealthc.are. Accessed August 22,2014.

(16.) Lexicomp. St. Louis, MO: Wolters Kluwer Health. Accessed August 22,2014. 17. Estazolam [package insert]. Corona, CA: Watson Pharma, Mc; 2008.

(32.) Insomnia. In: Natural Standard. Somerville, MA: Natural Standari https://naturalmedicines.therapeuticreseardtcom/databases/medica-condtions/i/insomnia.aspx. Accessed August 22, 2014.

(33.) American Medical Directors Association. Clinical practice guideline: sleep disorders. Columbia, MD: American Medical Directors Association; 2006.

(34.) Gallagher P, Ryan C, Byrne S. et al. STOPP (Screening Tool of Older Person's Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment). Consensus validation. Int J Clin Phannacol Then 2008; 46(2): 72-83.

35. Food and Drug Administration. FDA requests label change for all sleep disorder drug products. Published Mardi 14, 2007. Accessed August 22,2014.

(36.) Food and Drug Administration. FDA drug safety communication: risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist). Published January 10, 2013. Accessed August 22, 2014.

37. Cohen-Zion M, Ancoli-Israel S. Sleep disorders. In: Hazzard's geriatric medicine and gerontology 6th ed. New York, NY: McGraw-Hill; 2009: 671-682.

Clinical Point

Although the process of drug absorption can change with age, the amount of drug absorbed might not be significantly affected

Clinical Point

Prescribing sedative-hypnotic drugs is not routinely recommended for older patients with a sleep disorder

Clinical Point

Geriatric patients are at risk of reduced renal clearance because of age-related changes in glomerular filtration rate

Clinical Point

Sedative-hypnotic drugs with a longer duration of effect may be best for patients who have difficulty maintaining sleep

Clinical Point

No dosage adjustments for ramelteon or suvorexant in geriatric patients have been specified

Clinical Point

Non-drug interventions are recommended for initial management of sleep disorders in geriatric patients

Clinical Point

Recently, FDA changed dosing recommendations for zolpidem-containing products because of the risk of impaired mental alertness

Clinical Point

Geriatric patients may be prone to comorbidities resulting from age-related physiologic changes that may be confounding

RELATED ARTICLE: Practice points

* Review the patient's medical history for conditions that may be related to sleep disorders.

* Initiate non-pharmacotherapeutic management, such as sleep hygiene measures.

* If a sleep disorder persists, determine the need for an agent with a short onset of effect or long duration, or both.

* Assess renal and hepatic function.

* Evaluate the metabolic profile for drugs subject to extensive hepatic metabolism and identify those with active metabolites; such drugs may be associated with increased exposure/effect.

* Once an agent is selected, start with a low dosage and monitor for improvement within 2 weeks.

* Use the lowest effective dosage and limit the treatment period, if possible.

* Watch for drug-related adverse effects, such as residual drowsiness and confusion, and address the risk of falls.

* Monitor for changes in drug therapy; recognize and avoid potentially inappropriate medications.

(18.) Flurazepam [package insert]. Eatontown, NJ: West-Ward Pharmaceutical Corp; 2010.

(19.) Doral [package insert]. Las Vegas, NV: Num Pharma, Inc; 2013.

(20.) Restoril [package insert]. Hazelwood, MO: Mallinc.krodt Inc; 2010.

(21.) Halcion [package insert]. New York, NY: Pharmacia & Upjohn Co; 2013. 22. Lunesta [package insert]. Marlborough, MA: Sunovion Pharmaceuticals Inc; 2012.

(23.) Sonata [package insert]. New York, NY: Pfizer Inc; 2013.

(24.) Ambien [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2013.

(25.) Ambien CR [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2013.

(26.) Edluar [package insert].Somerset, N]: Meda Pharmaceuticals mc; 2009.

(27.) Intermezzo [package insert]. Point Richmond, CA: Transcept Pharmaceuticals, Inc; 2011.

(28.) Zolpirnist [package insert]. Richmond, VA: ECR Pharmaceuticals; 2013.

(29.) Rozerem [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2010.

(30.) The American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. j Am Geriatr Soc. 2012; 60(4): 616-631.

(31.) Kirkwood CK, Melton ST. Insomnia, drowsiness, and fatigue. In: Krinsky DL, Berardi RR, Ferreri SP, et al, eds. Handbook of nonprescription drugs: an interactive approach to self-care. 17th ed. Washington, DC: American Pharmacists Association; 2012: 867-884.

RELATED ARTICLE: Related resources

* Institute for Safe Medication Practices.

* Med Watch: The FDA Safety Information and Adverse Event Reporting Program.

Drug Brand Names

Amitriptyline * Elavil

Amobarbital * Amytal

Butabarbital * Butisol

Chloral hydrate * Somnote

Diazepam * Valium

Diphenhydramine * Benadryl, others

Doxepin * Silenor

Doxylamine * Unisom, others

Estazolam * ProSom

Eszopiclone * Lunesta

Flurazepam * Dalmane

Gabapentin * Neurontin, Gralise, Horizant

Lorazepam * Ativan

Meprobamate * Equanil

Mirtazapine * Remeron

Olanzapine * Zyprexa

Pentobarbital * Nembutal

Phenobarbital * Luminal

Quazepam * Doral

Quetiapine * Seroquel

Ramelteon * Rozerem

Secobarbital * Seconal

Suvorexant * Belsomra

Temazepam * Restoril

Tiagabine * Gabitril

Trazodone * Desyrel

Triazolam * Halcion

Zaleplon * Sonata

Zolpidem * Ambien, Edluar, Intermezzo, Zolpimist


Vicki L. Ellingrod, PharmD, FCCP, is the series editor of Savvy Psychopharmacology.


(1.) National Center for Health Statistics. Health, United States, 2012, with special feature on emergency care. Published May 2013. Accessed August 22, 2014.

(2.) Bronstein AC, Spyker DA, Cantilena LR Jr, et al. 2011 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 29th annual report. Clin Toxicol (Phila). 2012; 50(10): 911-1164.

(3.) Inouye SK. Neuropsychiatric aspects of aging. In: Goldman L, Schafer Al, eds. Goldman's cedl medicine. 24th ed. Philadelphia, PA: Elsevier Saunders; 2011: 114-116.

(4.) Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association; 1994.

(5.) American Psychiatric Association. Highlights of changes from DSM-IV-TR to DSM-5. 2013. Accessed August 22, 2014.

(6.) Edwards BA, O'Driscoll DM, Ali A, et al. Aging and sleep: physiology and pathophysiology. Semin Respir Crit Care Med. 201031(5): 618-633.

(7.) Foley DJ, Monjan AA, Brown SL, et at. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep. 1995;18(6): 425-432.

Irene S. Hong, PharmD, BCPS

Clinical Assistant Professor School of Pharmacy and Pharmaceutical


State University of New York at Buffalo Buffalo, New York

Jeffrey R. Bishop, PharmD, MS, BCPP

Associate Professor

University of Minnesota College of Pharmacy Minneapolis, Minnesota


The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
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Author:Hong, Irene S.; Bishop, Jeffrey R.
Publication:Current Psychiatry
Date:Oct 1, 2014
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