Review Article

Journal of Pharmacy Practice

2023, Vol. 36(1) 126–138
ª The Author(s) 2021
Evaluation of Medications Used for Article reuse guidelines:
sagepub.com/journals-permissions
Hospitalized Patients With Sleep DOI: 10.1177/08971900211017857
journals.sagepub.com/home/jpp
Disturbances: A Frequency Analysis and
Literature Review

Brittany White, PharmD, BCPS, CACP1,2,

Heather S. Snyder, PharmD, BCPS3,
and Megan Van Berkel Patel, PharmD, BCCCP1

Abstract
Purpose: Poor sleep during hospitalization is common and implicated in worse patient outcomes. Despite implementation of
non-pharmacologic techniques, medications are still frequently required. The study objective is to assess the frequency of new
medications administered for sleep in hospitalized patients and to review literature evaluating these drug therapies in the inpatient
setting. Methods: This retrospective study included adult inpatients if they received a new medication for sleep during a 5-day
period. Patients were excluded if the medication was continued from home or if sleep was not the documented indication. For the
literature review, a MEDLINE search was conducted to identify studies pertaining to pharmacotherapy for sleep in hospitalized
patients. Results: Of 1,968 patient-days reviewed, a medication for sleep was given for 166 patient-days (8.4%) in 78 patients.
Melatonin was most commonly received (70.5%), followed by benzodiazepines (9.6%). A review of antihistamines, benzodiaze-
pines, melatonin, quetiapine, trazodone, and Z-drugs (non-benzodiazepine hypnotics) was conducted and 23 studies were
included. Conclusions: Despite widespread use of pharmacotherapy for sleep, there is a paucity of data evaluating use in the
inpatient setting. Although there is significant heterogeneity among studies, melatonin has the strongest evidence for use and is an
attractive option given its lack of adverse reactions and drug interactions. Benzodiazepines and Z-drugs were also frequently
utilized; however, their reduced clearance in the elderly and potential for compounded sedative effects should be weighed heavily
against potential sleep benefits. Antipsychotic agents cannot be recommended for routine use due to limited data and the
potential for significant adverse effects.

Keywords
insomnia, sleep, inpatient, antihistamine, benzodiazepine, melatonin, zolpidem, quetiapine

Introduction in Table 1. The most objective measurements of sleep quality

Sleep disturbance is common in hospitalized patients and can
be attributed to increased noise levels, interruptions for phle-
botomy and physical assessments, anxiety, discomfort, pain,
and restricted movement.1-3 Such factors may be additive to
chronic illnesses that negatively impact sleep such as obstruc-
tive sleep apnea, gastroesophageal reflux disease, and neuro-
pathy. The inability to achieve adequate sleep can impair
illness recovery. In fact, sleep disruptions in the hospital have
been implicated in delirium, prolonged mechanical ventilation,
hypertension, poor neurologic sequelae, and even increased
mortality.1,3,4
Each sleep cycle is divided into 2 stages including rapid eye
movement (REM) and 3 phases of non-REM sleep. Subjective
sleep quality may depend on several aspects including sleep
disturbance, effectiveness, and supplementation.5 Definitions
of these components and assessment tools are described
include polysomnography or actigraphy evaluation, however
routine use of these tools is not recommended.6 Although it
is not common to formally evaluate and chart sleep in daily
clinical practice, published reports in hospitalized patients
reveal disruptions in both quality and quantity of sleep.6
Implementation of non-pharmacologic strategies is an
instrumental first step to improving sleep quality. Simple
1
Department of Pharmacy, Erlanger Health–System, Chattanooga, TN, USA
2
Department of Internal Medicine, The University of Tennessee Health Sci-
ence Center College of Medicine–Chattanooga, TN, USA
3
Department of Pharmacy, Emory University Hospital, Atlanta, GA, USA
Corresponding Author:
Megan Van Berkel Patel, Department of Pharmacy, Erlanger Health–System,
975 E Third. St, Chattanoooga, TN 37415, USA.
Email: megan.patel@erlanger.org
White et al 127

Table 1. Common Sleep Terminology and Sleep Assessments.

Sleep terminology
Sleep disturbance Sleep fragmentation, movement during sleep, soundness of sleep, quality of disturbance, sleep latency, and quality
of latency
Sleep effectiveness Sleep sufficiency evaluation, subjective quality of sleep, total sleep time and rest upon awakening
Sleep fragmentation Interruptions of the sleep wake cycle
Sleep latency Time it takes to transition from being fully awake to asleep
Sleep maintenance Ability to stay asleep throughout the night and fall back asleep after nighttime awakenings
Sleep supplementation Remaining awake after the final arousal and need for additional daytime sleep in the morning, afternoon, or
evening
Total sleep time Time from falling asleep to final awakening
Sleep assessments
Richards Campbell sleep Validated survey of 5 items and nighttime noise that is measured on a 100 mm analog scale
questionnaire (RCSQ)
Pittsburgh sleep quality index score A self-rated questionnaire of 19 items, with total score of 0 (no difficulty) to 21 (severe difficulty)
(PSQI)
Verran and Snyder-Halpern (VSH) A survey characterizing 15 different items into 3 domains of sleep (disturbance, effectiveness, and
sleep scale supplementation)
Bispectral index (BIS) monitoring A continuous electroencephalogram (EEG) historically used by anesthesia to monitor intraoperative sedation;
range of 0-100 with 100 indicating an awake state and 0 indicating an isoelectric EEG
Wrist actigraphy Data collected by movements to determine sleep patterns and quality
Polysomnography Gold standard sleep study test, typically includes data from an EEG, electrooculogram, electromyogram,
and electrocardiogram

techniques such as restoration of the circadian rhythm and
attenuating nighttime noise is linked to enhancing sleep and
reducing daytime fatigue.7 This can include increasing daytime
light exposure, minimizing daytime napping, and reducing
lights at night. Assistance with eye masks and ear plugs for
light and sound mitigation has also been implicated in improv-
ing both the quality and quantity of sleep.1,8,9 Discontinuation
of unnecessary overnight phlebotomy can also reduce sleep
disruptions. Finally, implementing physical therapy has also
been proven to have a beneficial effect on sleep.10 Unfortu-
nately, these non-pharmacologic approaches may be unsuc-
cessful or impractical causing patients and providers to rely
on pharmacologic therapy for assistance.
Despite widespread use of medication therapy to improve
sleep, there is minimal literature assessing safety and efficacy
within the hospital setting where patients are at increased risk
of drug interactions and oversedation. The aim of this study is
to determine the frequency and type of pharmacologic therapy
used to treat acute sleep disturbance at a single medical center
over a 5-day period, and to review the available literature
reporting on safety and efficacy of pharmacotherapy for sleep
in hospitalized patients.
Methods
Adult inpatients at a 545-bed academic, level 1 trauma center
were included if they received a new medication designated for
sleep during the 5-day study period. Based on our hospital
formulary, the following medications were assessed: loraze-
pam, oxazepam, temazepam, triazolam, alprazolam, trazodone,
mirtazapine, quetiapine, doxylamine, diphenhydramine, zolpi-
dem, melatonin, ramelteon, amitriptyline, or doxepin. Patients
were excluded if the medication was documented as a home
medication, or if the indication of sleep was not clearly docu-
mented in the order or chart notes. Additionally, patients were
not included if the medication was ordered pro re nata (PRN; as
needed) for sleep but not administered during the study period.
The hospital inpatient daily census was also collected. The
primary outcome was the frequency of medication administra-
tion for sleep, defined as number of patient-days. Secondary
outcomes assessed the drug regimens utilized including type
of medication, dose, and directions (PRN or scheduled).
A descriptive analysis was performed. The study was approved
by the institutional review board.
For the literature review, a search of MEDLINE database
from 1980 through November 2020 was completed using the
following search terms: insomnia, sleep, hospital, inpatient,
antihistamine, benzodiazepine, melatonin, mirtazapine, tricyc-
lic antidepressant, quetiapine, ramelteon, trazodone, z-drugs.
Medication names within drug classes were also used as search
terms (i.e. zolpidem). All abstracts and titles were screened to
identify studies pertaining to the efficacy or safety of pharma-
cotherapy for sleep in hospitalized patients. Case reports were
excluded but all other study formats were included for review.
Reference lists were reviewed to identify additional relevant
publications. Non-human studies and non-English language
publications were excluded. Identified articles were reviewed
and summarized by the authors.
Results
Over a 5-day period, the average daily inpatient census was 393
patients for a combined analysis of 1,968 patient-days. After
identifying qualifying medications, 146 patient-days were
excluded due to continuation of a home medication. A phar-
macologic sleep agent was prescribed for 166 patient-days
128 Journal of Pharmacy Practice 36(1)

Table 2. Frequency of New Medications Prescribed for Sleep. excluded tricyclic antidepressants, ramelteon, and mirtazapine
from this review given the dearth of literature combined with
Number of Number of Number of
Medication and patients, patient-days, PRN orders,
the absence of use in our study.
strength ny, n ¼ 78 n (%), n ¼ 166 n (%)z

Melatonin 58 117 (70.5) 31 (26.5) Discussion

1.5 mg 3 12 In this retrospective evaluation of hospitalized adult patients
3 mg 31 70
over a 5-day period, we found that a new medication for sleep
5 mg 21 32
10 mg 3 3 was prescribed in 8.4% of patient-days, with melatonin being
Zolpidem 8 14 (8.4) 14 (100) the most common. A previous retrospective analysis over a
5 mg 5 8 2-month period by Gillis et al found that 26.2% of patients
10 mg 3 6 received a medication for sleep, with 68.5% of patients not
Trazodone 5 10 (6) 2 (20) having a prior diagnosis of insomnia or medication use prior
25 mg 2 4 to hospitalization.12 Their broader inclusion criteria of medica-
50 mg 3 6
tions continued from a home regimen and any sedative medi-
Diphenhydramine 7 7 (4.2) 7 (100)
12.5 mg 2 2 cations administered between 6 pm and 6 am the following day
25 mg 5 5 without a specific indication may have contributed to the
Lorazepam 3 6 (3.6) 4 (66.7) higher frequency of medication use compared to the present
0.5 mg 2 4 study. The authors also included haloperidol (incidence of
1 mg 1 2 10.7%), which we did not assess. Another study by Frighetto
Temazepam 4 6 (3.6) 2 (33.3) et al prospectively evaluated 100 hospitalized patients over a
7.5 mg 2 3
70-day study period and found a 29% incidence of new phar-
15 mg 1 2
30 mg 1 1 0 (0) macologic agents prescribed for sleep.13 Home medications
Alprazolam 3 4 (2.4) 4 (100) continued on admission were included and patients unable to
0.25 mg 1 1 complete a sleep assessment questionnaire were excluded.
0.5 mg 2 3 Both of the aforementioned studies only included ward
Quetiapine 1 2 (1.2) (0) patients, whereas we included ICU patients and patients with
12.5 mg 1 2 altered mentation. These patient populations may be less likely
y
Total is greater than 78 because 5 patients received 2 different medications to vocalize sleep complaints, thus decreasing our observed
for sleep and 2 patients received 3 different medications for sleep. frequency of medication use.
z
Percent calculated as number of PRN orders divided by number of patient Comparable to previous studies, we found a wide variation
days for each medication.
of pharmacologic agents selected for insomnia treatment. The
most frequent medication utilized was melatonin followed by
benzodiazepines. In the study by Gillis et al, the most com-
(frequency 8.4%) in78 unique patients. The median patient age monly prescribed medications included trazodone, lorazepam,
was 59.5 years (25-75% interquartile range 42.2-71.5) and and zolpidem; melatonin was not available at their institu-
36 (46%) were male. Nine patients (11.5%) were in the inten- tion.12 Frighetto et al found that lorazepam was most widely
sive care unit (ICU) and the remainder were on a medical or used, followed by zopiclone and oxazepam.13 In our study, the
surgical ward. Our secondary outcomes of medication fre- majority of medications were scheduled rather than prescribed
quency, dose, and directions are listed in Table 2. Seven PRN, which is consistent with the Gillis et al study which found
patients received multiple medications simultaneously for 18.6% of medications were for PRN use. They also reported a
sleep during the study period. Melatonin and benzodiazepines variety of doses used including higher doses than what is typically
were the most commonly prescribed agents, accounting for prescribed for the sole indication of sleep; for example, the
70.5% and 9.6% of patient-days, respectively. Medications authors reported use of trazodone doses up to 450 mg. Medication
prescribed with a PRN frequency occurred for 38.5% of orders. doses and frequency were not reported by Frighetto et al.
An extensive literature search yielded 24 studies that were This analysis is not without limitations inherent to the nature
specific to inpatients; 19 randomized trials, 2 prospective of a retrospective review. Additional agents may have been
observational studies, 2 cross sectional cohorts, and 1 retro- given during the study period with the intent for sleep; how-
spective review. We did not identify any studies evaluating ever, lack of clear documentation in the medication order or
tricyclic antidepressants or ramelteon for sleep in hospitalized progress note caused these administrations to be excluded from
patients. One small, open-label study evaluating mirtazapine our analysis. For example, a 1-time order of diphenhydramine
for sleep as a secondary outcome was identified; however, all at night was not included without instructions for sleep, even if
study subjects were inpatient due to treatment for amphetamine no other indication was documented. Medications with multi-
withdrawal and the comparator was modafanil.11 The trial ple purposes (such as sedating antipsychotics) were not
design severely limits the applicability of this study to the included unless sleep was documented as the specific reason
general population, and therefore was not included. We for initiation. The intent of this study was a frequency analysis,
White et al
therefore it was beyond its scope to assess the efficacy and
safety of the medications given. We did not assess for factors
affecting medication selection including comorbidities such as
concomitant psychiatric illnesses. Hospital formulary also may
have affected prescribing habits. Finally, in contrast to the
studies by Frighetto et al and Gillis et al we reported our fre-
quency as patient-days instead of number of patients; therefore,
the frequencies cannot be directly compared.
Despite the widespread use of pharmacologic sleep agents
initiated during hospitalization with varying dosing regimens,
there is little evidence regarding the safety and efficacy of these
drug therapies within the inpatient setting. The available liter-
ature for commonly used agents is further discussed.
Antihistamines
Diphenhydramine and doxylamine are nonselective, competi-
tive histamine1 receptor (H1) antagonists that exert their sedat-
ing effects through centrally mediated anticholinergic activity.
The sedating properties of this class are limited to first-
generation agents which cross the blood brain barrier. Daily
use is not recommended as tolerance develops quickly, and is
not overcome by dose escalation.14 Widespread accepted use of
these agents is likely due to their nonprescription status, lack of
abuse potential, and perception of safety by patients and pro-
viders alike. However, randomized controlled studies reporting
on objective measures of sleep efficacy with antihistamine use
are generally limited to healthy, ambulatory patients receiving
diphenhydramine.15,16
Randomized controlled trials in the ambulatory setting
found modest beneficial effects on patient-reported measures
of sleep maintenance rather than sleep latency with single and
repeated nightly dosing of diphenhydramine 50 mg. However,
improved sleep components have not been consistently demon-
strated with objective measures such as polysomnography and
sleep scoring tools.15-17 Evaluation in the hospital setting is
limited to a single randomized, placebo-controlled trial con-
ducted in 2,931 postoperative patients.18 Patients without a
history of sleep disturbances received doxylamine 25 mg, a
combination of doxylamine with acetaminophen 1000 mg, or
placebo. Patients receiving doxylamine, either as monotherapy
or in combination with acetaminophen, were more likely to
report improved sleep, sleep maintenance, and duration of
sleep; although the effects were greater with combined analge-
sic therapy. The study results suggest a potential synergistic
effect of acetaminophen and doxylamine on improved sleep,
including a subset of patients who reported an absence of pain.
Interestingly, patients receiving doxylamine monotherapy were
more likely to request additional medications for sleep than the
placebo group.
Although these agents are generally considered safe at rec-
ommended doses, adverse effects are common. The American
Academy of Sleep Medicine advises against use of diphenhy-
dramine for inducing sleep or achieving sleep maintenance
citing conflicting evidence of sleep quality improvement com-
pared to placebo and evidence of harm.19 Safety concerns with
129
first-generation antihistamines are attributed to their unfavor-
able anticholinergic side effects. Of particular concerns are the
risks of significant cognitive impairment, urinary retention,
residual next-day sedation, and dizziness with the potential to
precipitate falls in susceptible populations such as older
patients and those receiving concomitant hypnotics or addi-
tional agents with anticholinergic properties. A thorough
assessment for drug interactions should be conducted with a
focus on limiting or avoiding use in patients already receiving
agents with anticholinergic properties.20
It is important for practitioners to recognize that although
studies of antihistamines indicate small improvements in sub-
jective sleep measures in healthy ambulatory patients, these
effects may not translate to improvements in sleep for acutely
ill hospitalized patients. Clinicians should avoid H1 antagonists
in older patients as recommended by the American Geriatric
Society Beers Criteria.21 Reduced metabolism and clearance of
first-generation antihistamines is problematic in the elderly,
and may result in exaggerated anticholinergic effects persisting
beyond the reported serum half-life.22 One systematic review
examined randomized controlled studies reporting on efficacy
and safety outcomes with diphenhydramine use for occasional
or transient insomnia.23 The authors concluded that strong evi-
dence to support antihistamines use in healthy patients with
sleep disturbances is lacking and their use increased the risk
of next-day performance impairment and rebound insomnia.
Additionally, tolerance to the sedative effects of diphenhydra-
mine may develop with repeated daily dosing, thereby limiting
its efficacy.
Benzodiazepines
Benzodiazepines (BZD) act by potentiating the nonspecific
inhibitory action of gamma-aminobutyric acid (GABA), but
other neurotransmitters affected include serotonin, norepi-
nephrine, and dopamine.24 The effect of BZDs on total sleep
time and fragmentation of sleep vary depending on the indi-
vidual agent’s duration of action and metabolism (Table 3).
The primary metabolic pathways for BZDs include hepatic
oxidation and glucuronide conjugation.25 Populations with
reduced capacity for drug metabolism including elderly and
those with hepatic insufficiency, are more likely to experience
prolonged sedative effects due to drug accumulation, especially
when given agents with active metabolites.24 Agents under-
going oxidative metabolism or with a long duration of action
should be avoided or require a dose reduction if used in older
adults.
Studies investigating the effects of BZDs on sleep in the
hospital setting are limited and reported outcomes have been
primarily assessed by subjective patient reports of sleep latency
and efficiency. Recent comparative studies of BZD use in the
hospital setting confirm that these agents shorten sleep latency;
however, meaningful effects on other sleep parameters, such as
total sleep duration and sleep fragmentation, are not consis-
tently demonstrated. BZDs may even reduce meaningful sleep
phases such as REM sleep.26 Additionally, there is a paucity of
130
Table 3. Pharmacokinetics of Selected Benzodiazepine Agents.
Generic name Usual dose range Peak plasma levely (h) Elimination half-life, parent (h)
Alprazolam 0.25-1 mg 1-2
Clonazepam 0.25-0.5 mg 1-4
Estazolamz 1-2 mg 0.5-1.5
Flurazepamz 15-30 mg 3-6
Lorazepam 0.5-2 mg 2-4
Oxazepam 10-15 mg 2-4
Quazepamz 7.5-15 mg 1.5
Temazepamz 7.5-30 mg 1-2
Triazolamz 0.125-0.25 mg 2 1.5-6
y
After oral administration.
z
Food and Drug Administration-approved for insomnia.
data describing optimal dosing of BZDs for sleep induction and
maintenance in this setting. All studies reviewed were limited
by small sample size and subjective assessments of sleep
measures.
A review of historic randomized controlled studies high-
lights the apparent efficacy of BZDs with greater lipophilic
properties for the treatment of insomnia. In 1 randomized con-
trolled study of 50 hospitalized adult patients, investigators
evaluated the effects of orally administered midazolam
15 mg, oxazepam 15 mg, and placebo on sleep latency and
total sleep time as reported by nursing staff.27 Included patients
were generally less than 35 years old without history of a sleep
disorder. Sleep latency was significantly shorter in patients
receiving midazolam compared to oxazepam, and both inter-
vention groups experienced more improvements than placebo.
However, there was no difference in total sleep time. Rebound
insomnia and residual next-day sedation were not observed
after BZD administration. Notably, patients receiving oxaze-
pam reported reduced satisfaction with sleep effects after
repeated consecutive nightly dosing. In a separate randomized
controlled trial, increasing the nighttime dose of oxazepam to
50 mg did not improve its performance when compared to
midazolam.28 In this study, 59 patients without significant
comorbidities were included. Both drugs were associated with
increased total sleep time compared to placebo, however oxa-
zepam did not shorten sleep latency, nor was there any mean-
ingful difference in duration of sleep between groups. The
results of these studies suggest that oxazepam is not well-
suited for use as a hypnotic in hospitalized patients compared
to more lipophilic BZD agents and higher doses do not corre-
late with improved sleep effects. Midazolam administered
orally at bedtime results in rapid onset of sleep without residual
sedation in hospitalized adults without a previous history of
sleep disorders.
Although lorazepam is not approved for treatment of insom-
nia, its rapid onset and familiarity among providers results in
frequent inpatient use. Only 1 study evaluated lorazepam for
insomnia in the hospital setting.29 This randomized, prospec-
tive study compared lorazepam 0.5-1 mg and zopiclone 3.75-
7.5 mg administered at bedtime over 7 days in 15 patients. The
majority of patients in the lorazepam group received the 1 mg
Journal of Pharmacy Practice 36(1)
Metabolic pathway Active metabolite
12-15 Oxidation No
30-40 Nitroreduction No
10-24 Oxidation No
47-100 Oxidation Yes
10-20 Glucuronidation No
5-20 Glucuronidation No
25-114 Oxidation, N-dealklylation Yes
4-18 Glucuronidation No
Oxidation No
dose (78%) and 71% of patients in the zopiclone dose received
the 7.5 mg dose. Twenty-two percent of patients reported use of
a psychotropic antidepressant at baseline. Both agents were
equally effective in measures of total sleep time, as reported
by nursing staff, without observed differences in cognition
assessed by a validated objective assessment tool.
Studies of triazolam in the perioperative hospital setting
have shown favorable effects on sleep without significant
safety concerns. In a placebo-controlled evaluation of 357
patients undergoing elective surgery, both triazolam 0.25 mg
and zolpidem 10 mg shortened sleep latency when adminis-
tered the evening prior to surgery.30 Nighttime sleep interrup-
tion was reported less frequently in the triazolam group, but
there was no difference between groups in requests for addi-
tional sleep medications. Residual next-day sleepiness was not
reported in either study group. Jacobson et al also randomized
47 patients to triazolam 0.125 mg or placebo for 3 consecutive
evenings in the perioperative setting.31 Patients in the BZD
group experienced less nighttime awakenings and reported
improvements in overall sleep quality. Interestingly, there was
no significant difference between groups in sleep latency. Sub-
jective patient assessments of next-day hang-over effects
revealed no difference between groups. Collectively, these
studies in the perioperative setting provide evidence of safety
and reasonable efficacy with triazolam. However, providers
should interpret these results with caution as sample size was
limited, results were subjectively reported, and patients at
increased risk of BZD adverse effects were not well-
represented.
Elderly patients are more likely to experience insomnia and
sleep disturbances. Although long-term use of BZDs is discour-
aged in the geriatric population, there is a lack of objective
research on short-term BZD use in the hospital. One prospec-
tive observational study examined hospital prescribing patterns
and the effects of BZDs in 54 older patients on an acute care
ward.32 Patients experienced shorter sleep latency and fewer
awakenings compared to home sleep patterns after receiving
temazepam 10-20 mg (mean dose 11 mg), but had no differ-
ence in duration of sleep.32 Patients with a history of BZD use
prior to hospitalization experienced less benefit on sleep
latency. A majority of study patients receiving a BZD
White et al
experienced rebound insomnia, but no residual next-day
sedation was observed. Results of this study indicate that
temazepam may be an effective and relatively safe option for
hospital use.
While BZDs may produce desirable effects on sleep latency
for transient and situational etiologies of insomnia, use of these
agents is not without significant risks.21 Benzodiazepine-
induced cognitive impairment, confusion, or decreased alert-
ness may limit patient assessments or the patient’s ability to
participate in physical therapy. Loss of balance and dizziness
may predispose patients to falls and injury. Few studies of
limited quality indicate triazolam and temazepam are the most
commonly employed BZDs for the treatment of insomnia in the
hospital. However, beneficial effects are likely limited to
reducing sleep latency and increasing patient perception of
improved overall sleep quality rather than increasing the dura-
tion of sleep. Studies evaluating the effects of BZDs on objec-
tive measures of sleep and cognition, such as polysomnography
and validated scoring tools, are needed to better characterize
their effects on the sleep cycle. In regard to the safety of lipo-
philic, short-acting agents, available evidence suggests mini-
mal risk of next-day sedation and cognitive impairment.
Elderly patients and those with hepatic impairment are more
likely to experience increased sedation with agents that
undergo oxidative hepatic metabolism, therefore dose reduc-
tions should be considered. BZDs with prolonged durations of
action should be avoided in the hospital setting. When selecting
a pharmacologic agent for the treatment of insomnia, a thor-
ough review of the patient’s medications should be conducted
to avoid concomitant administration of BZDs with other drugs
that may cause central nervous system (CNS) depression.
Melatonin
Melatonin is an endogenous hormone secreted by the pineal
gland to promote sleep and maintenance of the circadian
rhythm. Literature describing the utility of melatonin for the
treatment of sleep disorders is abundant. Its nonprescription
status, low cost, and lack of major adverse effects make it an
attractive therapy option.33 Physiologic effects of melatonin
are observed at doses of 0.1-0.5 mg with peak serum concen-
trations approximately 1 hour after administration. Older adults
experience higher serum levels with typical nonprescription
doses compared to younger adults.34 A review of available
literature revealed studies evaluating the use of melatonin for
sleep in patients with varying acuities of illness and measured
sleep outcomes.
A total of 7 randomized placebo-controlled studies and 1
prospective cohort study were identified evaluating melatonin
in hospitalized patients (Table 4).35-42 Four studies describe its
use in the ICU setting, 3 in a general ward, and 1 prior to an
elective procedure. Overall, 4 studies indicated an overall ben-
eficial effect with melatonin use.35,37,38,41 Although the hetero-
geneity of the trials impedes the comparison of outcomes, there
are several unique noteworthy findings that warrant further
discussion. In the trial by Andrade et al, the increase in
131
melatonin dose after study day 5 suggests the possibility of a
tolerance phenomenon, which has not been previously
described.35 The results presented by Bourne et al should be
interpreted with caution based on several study limitations:
small sample size with imbalanced patient groups, a wide con-
fidence interval for reported bispectral index area under the
curve findings, and an incongruence between objective and
subjective assessments of sleep efficiency.37 This study also
noted a lack of association between mean peak plasma mela-
tonin concentrations and objective measurements of nocturnal
sleep. In the trial by Jaiswal et al, delirium was observed in
15% of study subjects, which may limit applicability of the
results to a broader inpatient population.40 There were signif-
icant differences in baseline characteristics between groups in
the study by Stoianovici et al.42 Patients who received melato-
nin were older and with a higher mean Charlson-Deyo comor-
bidity index, whereas more patients in the zolpidem group used
a hypnotic agent for sleep at home. However, to address these
differences, a post-hoc analysis was performed and found no
difference between groups in sleep quality among patients
older than 65 years or those who took a sleep aid at home.
Finally, the trial by Gandolfi et al is unique with reporting of
serum melatonin levels. 41 After melatonin was given for
7 nights, peak serum melatonin concentrations varied from
1.5 to 27 times that of physiologic values. The differences in
serum concentrations were attributed to variations in nutri-
tional intake because administration with food reduces drug
absorption. No differences were observed between groups in
analgesic or sedative requirements, suggesting that melatonin
does not have a sedative-sparing effect. Interestingly, the
observed benefits of melatonin on increasing depth of sleep
in this study were not apparent after patients transferred to a
general ward. The reason for this loss of effect is unclear, but
the decreased utilization of analgesics and/or sedatives outside
of the ICU may have impacted perceptions of sedation and
quality of sleep. Although this study did not find positive objec-
tive results on sleep outcomes, it was the first to report on the
impact of melatonin on depth of sleep. This is an important
finding as other hypnotic agents such as benzodiazepines are
known to negatively impact both slow wave and REM sleep.
Melatonin is generally well-tolerated. Andrade et al found
that a melatonin dose of 3-5 mg had the potential to cause mild,
transient, residual morning effects, including headache and
heaviness in the head.35 Headache and residual next-day som-
nolence have been consistently reported across a broad range of
study populations, particularly with doses of 10 mg or
more.37,43 Advanced age and higher melatonin doses (>10
mg) may increase the risk of adverse CNS effects; therefore,
elderly patients may benefit from lower doses.34 Dependence
has not been reported with melatonin use and serious side
effects were not observed in 1 large systematic review.43 The
optimal dose providing the greatest therapeutic effect while
minimizing adverse effects is still unknown. Factors such as
age and concomitant use of sedative medications should be
considered when recommending or prescribing melatonin.
Despite several studies reporting minimal side effect, next-
 132

Table 4. Description of Studies Evaluating Melatonin.

Author Trial design Patient population Intervention Sleep measures Efficacy outcomes

Andrade Double-blind, n ¼ 33 Melatonin 3 mg nightly over a total Patient-reported mean sleep latency, Sleep latency: 1.1 hr reduction in
et al35 randomized, placebo- Medical, non-ICU study period of 16 nights. Patients mean total nighttime sleep melatonin group vs 0.8 hr,
controlled Exclusions: none permitted to request dose increase. duration, nighttime awakenings, p < 0.05
Mean melatonin dose increased to non-validated patient assessed Total nighttime sleep duration: 2.2 hr
5.4 mg after study day 5. sleep questionnaire increase in melatonin group vs
1.2 hr, p ¼ 0.08
Nighttime awakenings: no difference
Sleep questionnaire: positive patient
perception of melatonin effect on
overall daytime freshness and
functioning that was not observed
in the placebo group (p ¼ 0.03)
Shilo et al36 Pilot, double-blind, n ¼ 14 Controlled-release melatonin 3 mg Actigraphy-measured sleep quality Change in nighttime sleep from
placebo-controlled Intervention: pulmonary ICU nightly  3 days baseline: descriptive data only; no
Placebo: general ward difference between groups
Exclusions: receipt of narcotics or
BZDs, hemodynamic instability
Bourne Double-blind, placebo- n ¼ 24 Melatonin 10 mg nightly at 9 p.m.  Actigraphy-measured Sleep Nocturnal sleep duration: no
et al37 controlled General ICU patients requiring 4 days Efficiency Index (SEI), Bispectral difference
mechanical ventilation and Index (BIS) Area Under the Curve Actigraphy-measured SEI: no
tracheostomy (AUC), nurse-reported sleep difference
quality, patient-reported sleep BIS AUC: reduction in melatonin
quality group, indicating improved sleep
(-54.23, 95% CI 104.47 to
3.98, p ¼ 0.04)
Nurse-reported sleep measures: no
difference
Patient-reported sleep measures: no
difference
Borazan Double-blind, randomized, n ¼ 52 Melatonin 6 mg on evening prior to Patient-reported comparison of Comparison of study sleep quality to
et al38 placebo-controlledy Surgical patients undergoing elective surgery, plus 6 mg 1 hour before study sleep quality to “usual” sleep “usual” sleep: melatonin group
prostatectomy surgery using visual analog scale more likely to report “good” or
Exclusions: significant organ “excellent” study sleep (p < 0.05)
dysfunction, analgesics prior to
surgery
Mistraletti Double-blind, randomized, n ¼ 82 Melatonin 3 mg at 8 p.m. followed by Nursing-reported total sleep time Total sleep time: no difference
et al39 placebo-controlledy Medical-Surgical ICU patients additional 3 mg at 11 p.m. nightly per shift
intubated receiving sedation from ICU day 3 until discharge
(continued)
Journal of Pharmacy Practice 36(1)
Table 4. (continued)
Author Trial design Patient population
Jaiswal Double-blind, randomized, n ¼ 87
et al40 placebo-controlledy Elderly, medical, non-ICU
Exclusions: length of stay <48 hr,
altered mental status
Gandolfi Double-blind, randomized, n ¼ 203
et al41 placebo-controlled Medical-Surgical ICU
Exclusions: significant organ
impairment, inability to answer
questionnaires, neurologic illness,
psychiatric illness
Stoianovici Prospective, observational, n ¼ 100
et al42 cross-sectional cohort Medical-Surgical ward (n ¼ 96)
ICU (n ¼ 4)
Exclusions: additional medications
for sleep or sedation in previous
24 hr, moderate-severe liver
disease, psychiatric admission,
history of alcohol or substance
abuse, sleeping disorder
Abbreviations: RCSQ, Richard Campbell Sleep Questionnaire; BZD, benzodiazepine.
y
Sleep assessed as secondary outcome.
Intervention
Melatonin 3 mg nightly  14
consecutive nights (mean length
of stay: 3 days)
Melatonin 10 mg nightly at 8 p.m.  Nurse-reported sleep time, RCSQ
7 days
Melatonin 3-5 mg vs Zolpidem 5 mg Patient completed Verran and
 1 night (2 patients in each group Snyder-Halpern sleep scale
took higher doses)
Sleep measures
Actigraphy-measured average
nighttime sleep, total sleep
duration, average sleep duration,
RCSQ scores
scores, melatonin serum
concentrations
questionnaire
White et al
Efficacy outcomes
Average nighttime sleep: 539.8 min
melatonin vs 492.3 min, p ¼ 0.28
Total sleep duration: 577 min
melatonin vs 536.5 min, p ¼ 0.41
Average sleep episode duration: no
difference, p ¼ 0.89
RCSQ scores: no difference for any
variables
Mean ICU nocturnal sleep time: 396
+ 132 min melatonin vs
384 + 120 min, p ¼ 0.477
RCSQ scores: higher score in
melatonin group (69.7 + 21.2 vs.
60.7 + 26.3, p ¼ 0.029)
RCSQ component score for sleep
depth better with melatonin in
ICU (70.9 + 33.2 vs 57.7 + 28.6,
p ¼ 0.004) and after ward transfer
(69.6 + 26.0 vs 58.0 + 27.4,
p ¼ 0.008)
RCSQ component score for ability
to return to sleep after awakening
better in melatonin (74 + 27 vs
63.5 + 34.2, p ¼ 0.053)
Melatonin serum concentrations:
Median 2 a.m. serum
concentration 150 pg/ mL (range,
125-2,125) in melatonin vs
32.5 pg/mL (18.5-35); p < 0.001
Verran and Snyder-Halpern sleep
scale: no difference for any
component
133
134
day drowsiness and hangover effect are unlikely to be observed
at low doses of 1-10 mg/day with short-term use.35,41
The heterogeneity of available studies adds complexity
when attempting to discern the clinical impact of melatonin
use. The optimal dosing strategy in hospitalized patients with
sleep disturbance is unknown, as endogenous melatonin secre-
tion varies in both amount and timing among individuals.
Reported melatonin doses range from 0.1-10 mg nightly with
doses varying between 3-10 mg in the included studies with no
obvious correlation between dose and positive outcomes. After
interpreting the results of these studies, it is apparent that mel-
atonin does provide benefit in alleviating physiologic and envi-
ronmental sleep disruptions in the critically ill patient.
However, its true clinical significance has not yet been estab-
lished. In 2018, guidelines for the Prevention and Management
of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep
Disruption in Adult Patients in the ICU reviewed available
evidence for the use of melatonin and made no recommenda-
tion for or against use.1 In the medical-critical care populations,
enterally administered melatonin 3-10 mg nightly may be an
appropriate, low-risk intervention to promote restoration of the
physiologic sleep cycle and potentially reduce overall sedation
and analgesic requirements. Unfortunately, due to the multi-
tude of etiologies for sleep interruption in the critically ill, the
results of these studies cannot be extrapolated to the treatment
of hospitalized, non-critically ill patients.
Quetiapine
Quetiapine is commonly used for hyperactive delirium and is
often given at night for the added benefit of sedation. Quetia-
pine is a second-generation antipsychotic that acts as an
antagonist at serotonin (5-HT1a and 5-HT2a), dopamine D1 and
D2, H1, and a1 and a2 adrenergic receptors. The sedating effects
of quetiapine along with its tolerability has resulted in increas-
ing use in hospitalized patients with insomnia despite a lack of
evidence in this population. For example, results from a survey
of 2,613 prescribers at a Veteran’s Health Administration med-
ical center reported 32% of respondents used quetiapine par-
tially for sleep and 12% identified sleep as the only reason for
prescribing quetiapine.44 One prospective, observational study
evaluated 125 hospitalized patients 60 years old over a
16-month period who were prescribed quetiapine and found
sleep was the sole indication for use in 64% of patients.45
Sedation associated with quetiapine use coupled with its low
abuse potential makes it an available option for the treatment of
insomnia in hospitalized patients without comorbid psychiatric
diagnoses. However, literature evaluating its efficacy and
safety in the hospital setting is limited.
Literature evaluating the use of quetiapine in the critical
care setting for treatment of agitation and delirium is abundant
but less is known about its efficacy in improving sleep in
acutely ill hospitalized patients. Sleep quality was assessed in
patients randomized to receive quetiapine compared with other
concomitant psychiatric medications for schizophrenia at an
inpatient psychiatric hospital.46 Patients received quetiapine
Journal of Pharmacy Practice 36(1)
doses ranging from 400-500 mg daily and reported improve-
ment in Pittsburgh Sleep Quality Index (PSQI) scores from
baseline, over a 4-weeks period. A prospective, observational
study by Doroudgar et al, evaluated the effects of quetiapine
and trazodone in patients with a history of psychiatric illness
and insomnia admitted to a behavioral health facility.47 Inves-
tigators assessed differences in total sleep time, sleep effi-
ciency, sleep latency, number of nighttime awakenings, and
sleep quality. Sleep outcomes in 31 patients receiving a median
quetiapine dose of 100 mg (range 12.5-1,500 mg) over 180
study nights were compared to 30 patients receiving a median
trazodone dose of 100 mg (12.5-300 mg) over 132 study nights.
Patients receiving quetiapine reported less total sleep time
compared to those receiving trazodone, which was consistent
with nursing calculated sleep time. Nurse-reported outcomes
indicated fewer nighttime awakenings in the trazodone group,
though this was not clinically significant (0.52 vs. 0.75, p ¼
0.04). No differences in other patient-reported sleep measures
were observed. These results suggest quetiapine may not pro-
vide any clinically meaningful advantages over trazodone in an
inpatient psychiatric population. However, quetiapine doses
used in this study were higher than previously reported by an
outpatient study of patients without a psychiatric history where
doses of 25-75 mg improved subjective sleep variables
assessed by PSQI.48 Based on these results, the optimal que-
tiapine dose for hospitalized patients on a general medical unit
may be lower than those required to treat a psychiatric condi-
tion. This is an important consideration given the dose-
dependent cardiac and CNS effects associated with quetiapine
such as hypotension, QT-prolongation, and somnolence.
Results of these studies must be cautiously applied to patients
without history of psychiatric disease, as it is unclear if
improvements in insomnia occurred with treatment of the pri-
mary psychiatric disorder or solely due to the sedating effects
of quetiapine.
The safety of quetiapine use in the inpatient setting was
evaluated in the Doroudgar study.47 Patients receiving quetia-
pine reported lower rates of constipation, diarrhea, and nausea
when compared to trazodone (constipation 8.0% vs. 17.7%,
p < 0.02; nausea 0.6% vs. 4.5%, p < 0.05; diarrhea (0% vs.
5.31%, p < 0.01). The study also found a non-significant trend
toward increased weight gain in the quetiapine group over an
average length of stay of 7-14 days. Though weight gain asso-
ciated with prolonged quetiapine treatment is well-described,
metabolic effects are likely negligible with short-term
(<14 day) use in the hospital setting. Patients should be eval-
uated carefully to ensure that quetiapine is not inadvertently
continued after a discharge for primary insomnia, although it
may be appropriate if the patient has a concomitant psychiatric
illness. Cardiac effects were not reported in this study. Ortho-
static hypotension, QT-prolongation, constipation, and excessive
sedation are common dose-dependent adverse effects that should
prompt close monitoring of hospitalized patients receiving que-
tiapine. Some patients may be predisposed to such effects,
including those with baseline QT-prolongation or receiving con-
comitant medications known to prolong the QTc interval, history
White et al
of cardiac disease or other significant comorbidities, older
patients who may be sensitive to the effects of sedating medica-
tions, or those receiving higher doses of quetiapine.
Trazodone
Trazodone is an antidepressant acting as a serotonin reuptake
inhibitor, antagonist at serotonin type 2 (5HT2) receptors,
H1-receptor antagonist, and a1-receptor antagonist. Because
this drug exerts its effects at the H1- and a1-receptors at lower
concentrations, doses less than 100 mg are typically effective
for the treatment of sleep disorders.49 Trazodone is hepatically
metabolized to active metabolites and undergoes renal excre-
tion; therefore this medication should be used cautiously in
patients with renal or hepatic impairment. Similar to previously
described medications, the half-life of this agent is prolonged in
elderly patients and should be prescribed at lower initial
doses.50
Sleep studies have demonstrated that trazodone prolongs
stage III and IV non-REM sleep.50 A meta-analysis of 7 ran-
domized controlled trials comparing trazodone to placebo
found no difference in sleep efficacy but did find improve-
ments in patient-perceived sleep quality and the number of
sleep awakenings.51 Unfortunately, all but 1 study was con-
ducted in outpatients. A previously described observational
study conducted in psychiatric inpatients by Doroudgar et al
compared trazodone to quetiapine and found that trazodone
reduced the number of nighttime awakenings (see quetiapine
section).47 Another randomized open label study compared
PRN trazodone 50 mg (n ¼ 9) to zaleplon (n ¼ 7) in psychiatric
inpatients.52 There was no difference found in quality of sleep
assessed via an analog scale or total sleep time assessed via a
nurse recorded sleep log. However, there was limited power to
detect a difference between groups based on the small sample
size. Additionally, the concomitant psychiatric comorbidities
may limit its applicability to a general hospital population.
Like other antidepressants, trazodone is not without the
potential for adverse effects. It can prolong the QTc interval
and is not recommended for use during the initial recovery
phase of a myocardial infarction.49 Based on its effects as an
a1-receptor antagonist, trazodone can also induce priapism and
cause orthostatic hypotension. As previously mentioned in the
Doroudgar study, patients in the trazodone group reported
increased adverse drug events including constipation, diarrhea,
and nausea when compared to quetiapine.47 In another study,
there was an increase in daytime sleepiness with trazodone and
1 patient discontinued trazodone due to orthostatic
hypotension.52
Although trazodone has a relatively mild side effect profile,
prescribers should be cautious of the potential for orthostatic
hypotension when prescribing this medication for sleep in the
inpatient setting. Unless there is a concomitant psychiatric
component to the patient’s insomnia, lower doses up to 100 mg
are preferred with additional caution in the elderly and patients
with renal or hepatic impairment.
135
Z-Drugs (Non-Benzodiazepine Hypnotics)
Non-benzodiazepine hypnotics, commonly referred to as Z
drugs, selectively bind to GABAA receptors to promote sleep
while avoiding common adverse effects associated with
BZDs.53 There are currently 3 medications available in the
United States within this class: zolpidem, zaleplon, and eszo-
piclone. Each agent has differing pharmacokinetic properties,
thus drug selection should be based on the patient’s sleep
needs. All of the Z-drugs are substrates of cytochrome P450
(CYP), therefore patient medication profiles should be
reviewed for drug interactions prior to initiation. Zolpidem
improves both sleep latency with its rapid onset and total sleep
time with a duration of action of 6-8 hours.53 Zaleplon has a
rapid onset of action and short half-life of 1 hour which makes
it ideal for patients requiring treatment for sleep onset insom-
nia.19,54 Based on its fast onset and offset, zaleplon should be
taken immediately at bedtime or at least 4 hours before antici-
pated wake up. Finally, eszopiclone is recommended to
improve sleep latency and sleep maintenance.19 Similar to the
other non-BZD hypnotics, this drug has a rapid onset with
effects lasting up to 6 hours.53 All 3 Z drugs are recommended
for use by the American Academy of Sleep Medicine for the
treatment of chronic insomnia.19
Despite widespread utilization of these agents, there is a
paucity of evidence surrounding their use in the inpatient set-
ting. As previously described in the melatonin section and
Table 4, Stoianovici et al found both melatonin and zolpidem
were effective in improving subjective sleep quality in hospi-
talized patients with side effects of headache and grogginess
similarly reported in a small number of patients receiving each
medication.42 Zopiclone, which is not available in the United
States, was compared to lorazepam in a previously mentioned
study and no difference was found between groups (see BZD
section).29 One randomized controlled trial evaluated 3 weeks
of zolpidem therapy compared to placebo in 119 elderly inpa-
tient psychiatric patients.55 Subjects who received zolpidem
10 mg reported improvements in total sleep time, sleep
latency, nocturnal awakenings, and total time awake. Only 1
patient experienced daytime sedation and none of the patient
reported withdrawal symptoms after discontinuation.
The utilization of zolpidem to assist with sleep in patients
undergoing elective procedures has also been evaluated. A
study comparing zolpidem to triazolam has been previously
discussed in the BZD section and found no difference in sleep
outcomes between groups.30 Gong et al studied zolpidem for
transient insomnia in 148 patients undergoing total knee arthro-
plasty.56 Study subjects were randomized to zolpidem 5 mg or
placebo with doses starting the first night after surgery and
continuing through postoperative day 14. There was a positive
correlation between sleep efficacy and active range of motion.
The zolpidem group also experienced less nocturnal pain and
required significantly less opioid analgesics. Another double-
blind, randomized controlled trial evaluated the efficacy of
zolpidem after a total hip arthroplasty.57 A total of 160 patients
were randomized to receive zolpidem 10 mg or placebo for
136
2 days preoperatively to 5 days postoperatively. Patients who
received zolpidem reported lower sleepiness scores after sur-
gery and experienced significantly better sleep quality, sleep
latency, and sleep duration at 3 weeks and 3 months postopera-
tive. Similar to the findings of Gong et al, patients treated with
zolpidem reported less pain and a significantly improved qual-
ity of life. The results of these trials suggest the short-term use
of zolpidem for transient insomnia in the perioperative period
appears to be safe and effective.
The use of zaleplon and eszopiclone have rarely been stud-
ied in the hospitalized setting. We identified 1 study involving
the use of zaleplon previously discussed in the trazodone sec-
tion.52 Eszopiclone was evaluated in a randomized controlled
trial conducted in 45 patients given either eszopiclone 3 mg or
placebo for 2 nights.58 Study participants in the eszopiclone
arm experienced significantly less nighttime awakenings,
improved quality and depth of sleep, and increased total sleep
time. The intervention group also reported less pain at all time
periods throughout the 2 days of therapy, although there was no
significant difference in total opioid use.
Adverse effects of this class are significant, with the most
common being drowsiness and dizziness. In rare cases, zolpi-
dem may cause confusion, amnesia, psychosis, and sleep eat-
ing. 19,53 One retrospective analysis of non-ICU patients
identified zolpidem as an independent risk factor for inpatient
falls; therefore zolpidem should be used cautiously in the
elderly and other high fall risk populations.19 Patients taking
long-term zolpidem in the outpatient setting may experience
rebound insomnia and withdrawal symptoms with treatment
discontinuation and should be monitored closely. A study of
119 general medicine ward patients evaluated the safety of
zolpidem 5 and 10 mg doses in patients > 50 years.59 Overall,
19.3% of study subjects experienced adverse effects including
daytime somnolence, slurred speech, mental slowing, nocturnal
confusion, delirium, amnesia, dizziness, confusion, and agita-
tion. The 10 mg group experienced more CNS-related adverse
effects and had a higher rate of patients requiring treatment
discontinuation. Functional impairment at baseline was an
independent risk factor for developing CNS-related side
effects. Similarly, a separate correlation cross-sectional study
among hospitalized patients  50 years old newly started on
zolpidem found that patients experienced worsening mental
status after medication administration.60 Therefore, healthcare
providers within the inpatient setting should monitor older
patients closely for cognitive and behavior changes when initi-
ating zolpidem. Zaleplon is generally well-tolerated with rare
reports of CNS-related adverse effects. Patients taking eszopi-
clone may experience dizziness, somnolence, and unpleasant
taste.19 Reduced doses of all 3 medications are recommended
in the elderly and those with hepatic impairment to limit
unwanted adverse effects.
Z-drugs are commonly prescribed in the ambulatory setting
for the treatment of sleep disorders. Unfortunately, there is
limited evidence available regarding the safety and efficacy
of these medications for inpatient use. Current literature sug-
gests these agents may be beneficial in patients experiencing
Journal of Pharmacy Practice 36(1)
sleep disturbances during admission; however, these medica-
tions should be carefully initiated at the appropriate doses with
close monitoring for CNS adverse effects and falls.
Conclusion
Our study found a high incidence of new sleep medications
administered to adult inpatients. Melatonin, the most fre-
quently prescribed agent for sleep, has the most robust evi-
dence available for use in the inpatient setting including
several randomized controlled trials. Although there is conflict-
ing evidence regarding the efficacy of melatonin, it is an attrac-
tive option due its lack of reported adverse reactions and drug
interactions. Benzodiazepines and Z-drugs were also fre-
quently utilized; however, their reduced clearance in the
elderly and potential for compounded sedative effects should
be weighed heavily against potential sleep benefits. Antipsy-
chotic medications have been primarily studied in populations
with underlying psychiatric conditions and cannot be recom-
mended in patients without these comorbidities due to their
prominent adverse effect profiles. The wide heterogeneity of
outcomes measured in the literature makes it difficult to com-
pare the efficacy of these agents. Implementation of non-
pharmacologic techniques is strongly encouraged and clini-
cians should evaluate patient-specific factors when choosing
drug therapies for sleep.
Acknowledgments
Cyle White, PharmD, BCPS, BCIDP; Breanna Carter, PharmD,
BCPS, BCCCP.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
Megan Van Berkel Patel, PharmD, BCCCP https://orcid.org/0000-
0003-2282-3043
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