Sedative-hypnotics for sleepless geriatric patients

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