Irene S. Hong, PharmD, BCPS

Mr. R, 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 ≥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 ≥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 reduced 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 clearance 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 al¹¹ 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.9 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).^13,14Table 2^14-29 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).

FDA-approved agents for treating insomnia include amobarbital, butabarbi­tal, pentobarbital, phenobarbital, secobar­bital, chloral hydrate, diphenhydramine, doxylamine, doxepin, estazolam, fluraz­epam, lorazepam, quazepam, temazepam, triazolam, eszopiclone, 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.^14-29 These BZDs have different onsets of effect as evidenced by time to achieve maximum plasma con­centration (T_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.

Benzodiazepine-receptor agonists. There is substantial variation in the phar­macokinetic characteristics of BzRAs.^15,16,22-28 There also are differences among the zolpi­dem 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 eszopiclone (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 orexin-receptor antagonist, suvorexant represents a novel pharmaco­logic class. 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 BZDs (lower initial and maximum dosages for most agents) and BzRAs.^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, diphenhy-dramine, doxylamine) and herbal therapies (eg, melatonin, valerian), are used for their sedative-hypnotic properties. There is a lack of evidence supporting using diphenhydra-mine 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 patients³²; 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.^13,33 In con­junction, the American Medical Directors Association (AMDA) recommends address­ ing underlying causes and exacerbating fac­tors (eg, medical condition or medication).³³ The AMDA recommends avoiding long-term pharmacotherapy and advises caution with BZD-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 ramelteon for initial pharmaco­logic management of primary insomnias and insomnias comorbid with other condi­tions. The AASM also recommends specific dosages of BzRAs and BZDs for geriatric patients, which coincide with manufacturer-recommended dosages (Table 2).^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’s³⁴ 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 ≥65 because of the risk of sedation, confusion, and anti­cholinergic side effects. STOPP recognizes that any use of BZDs, 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 alertness36; 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 con­sidered.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]).

CASE CONTINUED
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.

Related Resources
• Institute for Safe Medication Practices. www.ismp.org.
• MedWatch: The FDA Safety Information and Adverse Event Reporting Program. www.fda.gov/Safety/MedWatch/default.htm.

Drug Brand Names
Amitriptyline • Elavil                                   Mirtazapine • Remeron
Amobarbital • Amytal                                  Olanzapine • Zyprexa
Butabarbital • Butisol                                  Pentobarbital • Nembutal
Chloral hydrate • Somnote                          Phenobarbital • Luminal
Diazepam • Valium                                     Quazepam • Doral
Diphenhydramine • Benadryl, others            Quetiapine • Seroquel
Doxepin • Silenor                                       Ramelteon • Rozerem
Doxylamine • Unisom, others                      Secobarbital • Seconal
Estazolam • ProSom                                   Suvorexant • Belsomra
Eszopiclone • Lunesta                                 Temazepam • Restoril
Flurazepam • Dalmane                               Tiagabine • Gabitril
Gabapentin • Neurontin,                             Trazodone • Desyrel
Gralise, Horizant                                        Zaleplon • Sonata
Lorazepam • Ativan                                   Zolpidem • Ambien, Edluar,
Meprobamate • Equanil                                 Intermezzo, Zolpimist

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

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. R, 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 ≥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 ≥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 reduced 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 clearance 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 al¹¹ 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.9 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).^13,14Table 2^14-29 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).

FDA-approved agents for treating insomnia include amobarbital, butabarbi­tal, pentobarbital, phenobarbital, secobar­bital, chloral hydrate, diphenhydramine, doxylamine, doxepin, estazolam, fluraz­epam, lorazepam, quazepam, temazepam, triazolam, eszopiclone, 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.^14-29 These BZDs have different onsets of effect as evidenced by time to achieve maximum plasma con­centration (T_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.

Benzodiazepine-receptor agonists. There is substantial variation in the phar­macokinetic characteristics of BzRAs.^15,16,22-28 There also are differences among the zolpi­dem 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 eszopiclone (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 orexin-receptor antagonist, suvorexant represents a novel pharmaco­logic class. 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 BZDs (lower initial and maximum dosages for most agents) and BzRAs.^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, diphenhy-dramine, doxylamine) and herbal therapies (eg, melatonin, valerian), are used for their sedative-hypnotic properties. There is a lack of evidence supporting using diphenhydra-mine 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 patients³²; 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.^13,33 In con­junction, the American Medical Directors Association (AMDA) recommends address­ ing underlying causes and exacerbating fac­tors (eg, medical condition or medication).³³ The AMDA recommends avoiding long-term pharmacotherapy and advises caution with BZD-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 ramelteon for initial pharmaco­logic management of primary insomnias and insomnias comorbid with other condi­tions. The AASM also recommends specific dosages of BzRAs and BZDs for geriatric patients, which coincide with manufacturer-recommended dosages (Table 2).^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’s³⁴ 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 ≥65 because of the risk of sedation, confusion, and anti­cholinergic side effects. STOPP recognizes that any use of BZDs, 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 alertness36; 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 con­sidered.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]).

CASE CONTINUED
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.

Related Resources
• Institute for Safe Medication Practices. www.ismp.org.
• MedWatch: The FDA Safety Information and Adverse Event Reporting Program. www.fda.gov/Safety/MedWatch/default.htm.

Drug Brand Names
Amitriptyline • Elavil                                   Mirtazapine • Remeron
Amobarbital • Amytal                                  Olanzapine • Zyprexa
Butabarbital • Butisol                                  Pentobarbital • Nembutal
Chloral hydrate • Somnote                          Phenobarbital • Luminal
Diazepam • Valium                                     Quazepam • Doral
Diphenhydramine • Benadryl, others            Quetiapine • Seroquel
Doxepin • Silenor                                       Ramelteon • Rozerem
Doxylamine • Unisom, others                      Secobarbital • Seconal
Estazolam • ProSom                                   Suvorexant • Belsomra
Eszopiclone • Lunesta                                 Temazepam • Restoril
Flurazepam • Dalmane                               Tiagabine • Gabitril
Gabapentin • Neurontin,                             Trazodone • Desyrel
Gralise, Horizant                                        Zaleplon • Sonata
Lorazepam • Ativan                                   Zolpidem • Ambien, Edluar,
Meprobamate • Equanil                                 Intermezzo, Zolpimist

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

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. R, 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 ≥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 ≥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 reduced 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 clearance 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 al¹¹ 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.9 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).^13,14Table 2^14-29 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).

FDA-approved agents for treating insomnia include amobarbital, butabarbi­tal, pentobarbital, phenobarbital, secobar­bital, chloral hydrate, diphenhydramine, doxylamine, doxepin, estazolam, fluraz­epam, lorazepam, quazepam, temazepam, triazolam, eszopiclone, 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.^14-29 These BZDs have different onsets of effect as evidenced by time to achieve maximum plasma con­centration (T_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.

Benzodiazepine-receptor agonists. There is substantial variation in the phar­macokinetic characteristics of BzRAs.^15,16,22-28 There also are differences among the zolpi­dem 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 eszopiclone (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 orexin-receptor antagonist, suvorexant represents a novel pharmaco­logic class. 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 BZDs (lower initial and maximum dosages for most agents) and BzRAs.^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, diphenhy-dramine, doxylamine) and herbal therapies (eg, melatonin, valerian), are used for their sedative-hypnotic properties. There is a lack of evidence supporting using diphenhydra-mine 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 patients³²; 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.^13,33 In con­junction, the American Medical Directors Association (AMDA) recommends address­ ing underlying causes and exacerbating fac­tors (eg, medical condition or medication).³³ The AMDA recommends avoiding long-term pharmacotherapy and advises caution with BZD-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 ramelteon for initial pharmaco­logic management of primary insomnias and insomnias comorbid with other condi­tions. The AASM also recommends specific dosages of BzRAs and BZDs for geriatric patients, which coincide with manufacturer-recommended dosages (Table 2).^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’s³⁴ 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 ≥65 because of the risk of sedation, confusion, and anti­cholinergic side effects. STOPP recognizes that any use of BZDs, 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 alertness36; 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 con­sidered.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]).

CASE CONTINUED
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.

Related Resources
• Institute for Safe Medication Practices. www.ismp.org.
• MedWatch: The FDA Safety Information and Adverse Event Reporting Program. www.fda.gov/Safety/MedWatch/default.htm.

Drug Brand Names
Amitriptyline • Elavil                                   Mirtazapine • Remeron
Amobarbital • Amytal                                  Olanzapine • Zyprexa
Butabarbital • Butisol                                  Pentobarbital • Nembutal
Chloral hydrate • Somnote                          Phenobarbital • Luminal
Diazepam • Valium                                     Quazepam • Doral
Diphenhydramine • Benadryl, others            Quetiapine • Seroquel
Doxepin • Silenor                                       Ramelteon • Rozerem
Doxylamine • Unisom, others                      Secobarbital • Seconal
Estazolam • ProSom                                   Suvorexant • Belsomra
Eszopiclone • Lunesta                                 Temazepam • Restoril
Flurazepam • Dalmane                               Tiagabine • Gabitril
Gabapentin • Neurontin,                             Trazodone • Desyrel
Gralise, Horizant                                        Zaleplon • Sonata
Lorazepam • Ativan                                   Zolpidem • Ambien, Edluar,
Meprobamate • Equanil                                 Intermezzo, Zolpimist

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

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.