I Review Article
Pharmacologic Management of Chronic Insomnia
James R. Taylor, PharmD, Cristina M. Vazquez, PharmD, MPH, and Kendall M. Campbell, MD
Abstract: Chrotiic insomnia is a common disorder that is under
recognized, under diagnosed and under treated. Initial assessment
should focus on identifying and treating, if present, any secondary
causes of insomnia. Primary insomnia can be treated with behavioral
and/or pharmacological therapy. A thorough sleep history can iden-
tify the type of insomnia present, its severity, and can consequently
guide therapy. Behavioral therapy has been shown to be equivalent
to or superior to pharmacologic therapy, at least in some patients. It
is a reasonable initial approach, although there are barriers to its use.
There are several pharmacologic agents available, some of which are
more effective at reducing time to fall asleep and others for main-
taining sleep. There is some evidence to indicate that combining the
approaches may impair outcomes. There is little data on the long-
term use of pharmacologic agents.
Key Words: insomnia, hypnotics
C hronic insomnia affects about 10 to 15% of the US adult
population.'''^ Despite the common occurrence of insom-
nia, it is under recognized, under diagnosed, and as a result,
under treated.^ Roughly two thirds of patients who have symp-
toms of insomnia do not communicate this information to
their physician and physicians may not always inquire about
sleep patterns."*
The American Psychiatric Association's Diagnostic and
Statistical Manual of Mental Disorders (DSM-IV) defines
insomnia as difficulty initiating or maintaining sleep or non-
restorative sleep that causes clinically significant distress or
impairment in social, occupational, or other important areas
of functioning.^ Insomnia lasting between one night and a
few weeks is referred to as acute insomnia, while insomnia
occurring at least three nights per week for one month or
more is referred to as chronic insomnia.'' Insomnia can be
classified as primary or secondary.^ Primary insomnia has no
known pathogenesis, but evidence suggests a state of hyper-
arousal. Secondary insomnia is due to other causes, such as
From the Department of Pharmacy Practice, University of Florida College of
Pharmacy, and the Department of Community Health and Family Med-
icine, University of Florida College of Medicine, Gainesville, FL.
Reprint requests to James R. Taylor, PharmD, University of Florida College of
Pharmacy, PO Box 100486, Gainesville, FL 32610-0486. Email: jtaylor®
cop.ufl.edu
Accepted July 13, 2006.
Copyright © 2006 by The Southem Medical Association
0038-4348/0-2000/9900-1373
Southern Medical Journal • Volume 99, Number 12, December 2006
psychosocial stressors, poor sleep hygiene, medical condi-
tions, and medication or substance use. This article will focus
on the pharmacologic management of chronic primary insom-
nia. However, it should be noted that behavioral modification
plays a significant role in the management of insomnia.
Pharmacological Therapy
Treatment of insomnia should address all components of
insomnia, including sleep onset, sleep maintenance, sleep
quality and next-day functioning. Identifying previous treat-
ments and their outcomes would also prove useful. Polysom-
nograms may be useful for those who fail to respond to ap-
propriate treatment. There are several medications for the
treatment of insomnia (Table). The choice of medication is
infiuenced by whether the patient is experiencing primarily
sleep-onset insomnia or sleep maintenance insomnia.
Benzodiazepines
Currently in the United States, there are five benzodiaz-
epines approved for the short-term treatment of insomnia: flu-
razepam (Dalmane), estazolam (ProSom), quazepam (Doral),
temazepam (Restoril), and triazolam (Halcion). Long-term stud-
Key Points
• Physicians should routinely inquire about patients'
sleep habits as patients may not report these on their
own.
• Any secondary causes of insomnia should be investi-
gated and treated before a diagnosis of primary in-
somnia is made.
• Behavioral therapy has been shown to be equivalent
to, or superior to pharmacologic therapy, at least in
some patients, and is a reasonable initial approach,
although there are barriers to its use.
• Zolpidem, zaleplon or ramelteon should be consid-
ered for patients primarily suffering from sleep-onset
insomnia.
• Eszopiclone or an intermediate-acting benzodiazepine
(eg, estazolam, temazepam) would be appropriate for
insomnia that is predominantly associated with sleep
maintenance. Zaleplon can also be used for those suf-
fering from sleep maintenance insomnia when taken
in the middle of the night.
1373
 Taylor, Vazquez, and Campbell • Pharmacologic Management of Chronic Insomnia

Table. Pharmacologic agents for the treatment of insomnia

Drug Indication Comments
Benzodiazepines
Flurazepam (Dalmane) Sleep maintenance insomnia Improves total sleep time and number of awakenings but has long half-life.
Anxiolytic effects may be useful in patients with anxiety disorder. More daytime
residual effects.
Quazepam (Doral) Sleep maintenance insomnia Improves total sleep time and number of awakenings but has very long half-life.
Anxiolytic effects may be useful in patients with anxiety disorder. More daytime
residual effects.
Estazolam (ProSom) Sleep maintenance insomnia Improves total sleep time and number of awakenings. Anxiolytic effects may be
usefiil in patients with anxiety disorder. May cause daytime residual effects.
Temazepam (Restoril) Sleep maintenance insomnia Improves total sleep time and number of awakenings. Anxiolytic effects may be
useful in patients with anxiety disorder. May cause daytime residual effects.
Triazolam (Halcion) Sleep-onset insomnia Improves total sleep time with greater benefit on sleep latency. Anxiolytic effects
may be useful in patients with anxiety disorder. Associated with rebound
insomnia.
Nonbenzodiazepines
Zolpidem (Ambien or Sleep-onset insomnia Improves sleep latency with less of an effect on total sleep time. May improve sleep
Ambien CR) efficiency and number of awakenings. Less daytime residual effects and rebound
insomnia.
Zaleplon (Sonata) Sleep-onset or sleep maintenance Improves sleep latency but lacks data on improving sleep maintenance. Less
insomnia daytime residual effects and rebound insomnia.
Eszopiclone (Lunesta) Sleep maintenance insomnia Improves sleep latency, total sleep time and number of awakenings. Less tolerance.
Ramelteon (Rozerem) Sleep-onset insomnia Improves sleep latency, total sleep time and sleep efficiency. No abuse potential.
Trazodone (Desyrel) Limited data for insomnia. May improve sleep latency and quality of sleep. May be
useful in patients with depression. Low risk of abuse.
Over-the-counter agents Modest, short-term improvements in total sleep latency, number of awakenings, total
(antihistamines) sleep time, quality of sleep.

ies beyond 6 months have not been reported. Benzodiazepines
bind to the gamma subunit of the GABA^ receptor, also known
as the benzodiazepine or omega receptor. These agents are dif-
ferentiated by their pharmacokinetic properties. Flurazepam and
quazepam have long half-lives due to their metabolites (48-120
h), estazolam and temazepam have intermediate half-lives
(10-24 and 8-15 h, respectively), and triazolam has the
shorter half-life (2-5 h). These agents are metabolized in the
liver. Concomitant administration with alcohol or other CNS
depressants can potentiate the CNS effects.
Benzodiazepines are associated with next day sedation,
psychomotor impairment, and cognitive impairment.^ All of
these are of concern when these agents are used in the elderly,
especially those with a longer half-life. Long-acting agents
have also been associated with increased risk of falls resulting
in hip fractures in the elderly as a result of residual sedation
and impaired motor coordination and currently have a limited
role in the management of insomnia.^ Short-acting agents are
associated with rebound insomnia and anterograde amnesia.^
In addition, all benzodiazepines have the risk of patients de-
veloping tolerance, abuse, and dependence.''^ Benzodiaz-
epines are pregnancy category X and thus are contraindicated
in these patients. They are also not recommended in children
for treating insomnia. They should be used with caution in
patients with seizure disorders, respiratory depression, severe
hepatic disease, or renal impairment. Starting doses for the
short and intermediate agents are: estazolam 1 to 2 mg at
bedtime, temazepam 15 mg 30 minutes before bed, and tria-
zolam 0.25 mg at bedtime. Doses should be reduced by 50%
in the elderly or those with hepatic impairment.
Trial data demonstrates that benzodiazepines produce sig-
nificant subjective improvements in total sleep time, niunber of
awakenings, and sleep quality as compared with placebo.'""'
Results on sleep latency have been conflicting. Those agents
with intermediate and long half-lives have been shown to
reduce wake time after sleep onset and number of awaken-
ings, which results in improved sleep maintenance.^ Triazo-
lam has a greater effect on sleep latency.^
Nonbenzodiazepines
Zolpidem. Zolpidem (Ambien) acts on the GABA^ re-
ceptor benzodiazepine site. It has an onset of action of 30
minutes, a half-life of 2.5 hours and its effects will last for up
to eight hours." Zolpidem controlled release (Ambien CR)
immediately releases 80% of the dose with the remainder
being released 3 hours later. Zolpidem undergoes hepatic
metabolism to inactive metabolites. Antiretroviral protease
inhibitors may inhibit the metabolism of zolpidem resulting
in excessive sedation. Likewise, alcohol and other CNS de-

1374 © 2006 Southern Medical Association


pressant drugs may have additive effects on psychomotor
performance when used with zolpidem. Side effects are dose
related and include drowsiness, amnesia, dizziness, headache,
and gastrointestinal complaints."
Zolpidem has not been evaluated for use in patients un-
der the age of 18. Zolpidem controlled release is classified as
pregnancy category C, while the regular release is category B.
There are no adequate, well-controlled studies in pregnant
women. Although there are no absolute contraindications, it
should be used cautiously in patients with hepatic impair-
ment, chronic obstructive pulmonary disease or depression.
The recommended doses are 10 mg at bedtime in healthy
adults and 5 mg in older patients, those with hepatic dysfunc-
tion or patients on another drug which causes CNS depres-
sion. For the extended release product, 12.5 mg or 6.25 mg
should be used, respectively.
Zolpidem has been shown to produce similar effects on
sleep latency and total sleep time with fewer next-day resid-
ual effects as compared with benzodiazepines.'''^"''* It may
also improve sleep efficiency (ratio of time asleep to time in
bed), but it has not consistently shown improvement over
placebo in reducing wake time after sleep onset or number of
awakenings. Zolpidem's benefit in sleep seems to be a result
of its effect on sleep onset rather than sleep maintenance.
Zolpidem has been studied for up to 5 weeks of continuous
use and for 12 weeks of intermittent use.'''^"'"* Short-term
tolerance has not been noted in these studies. In addition,
after discontinuation of zolpidem, rebound insomnia is rare
with short-term use.
Zaleplon. Zaleplon (Sonata), like zolpidem, binds to the
G A B A A receptor benzodiazepine site but with less affinity. It
has an onset of action of 20 minutes, a half-life of 0.5 to 1
hour, and its effects will last about 4 hours.'^ It is primarily
metabolized by the liver to inactive metabolites. Drugs that
have CNS depressant effects (eg, alcohol, anxiolytics, barbi-
turates) may potentiate the CNS effects of zaleplon. Zaleplon
contains tartrazine dye and thus should not be used in patients
with an allergy to this dye.'^ Its safety has not been estab-
lished in children. It is pregnancy category C with no studies
in pregnant women. Zaleplon should be used cautiously in
patients with depression or respiratory insufficiency and is
not recommended for those with severe hepatic disease. The
most cotnmon side effects include headache, drowsiness, diz-
ziness, nausea, and dyspepsia. The recommended dose is 10
mg at bedtime, although 5 mg is recommended for the el-
derly, those with mild to moderate hepatic impairment or in
patients taking another CNS depressant medication.
Zaleplon has been shown to be effective in reducing
sleep latency as compared with placebo, but lacks data sup-
porting it effects in maintenance of sleep when administered
at sleep onset.'*'" Zaleplon is useful for patients who have
frequent nocturnal awakening because it can be taken in the
middle of the night without causing next-day impairment, as
long as it is taken 4 hours before time needed to awaken.'^
Southern Medical Journal • Volume 99, Number 12, December 2006
Review Article
Eszopiclone. Eszopiclone (Lunesta) is believed to inter-
act with the GABA-receptor complex at binding domains
close to the benzodiazepine receptor. Its pharmacologic prop-
erties are similar to those of benzodiazepines, including an-
xiolytic, hypnotic, and sedative activity. Eszopiclone has a
half-life of 5 to 7 hours and a duration of about 8 hours."
Eszopiclone is hepatically metabolized to two metabolites,
one with minimal potency and one which is inactive. Use of
eszopiclone with alcohol or other CNS depressants may have
additive effects. The most common side effects include bitter
taste, dry mouth, drowsiness, and dizziness." Its safety in
children has not been established. Eszopiclone is pregnancy
category C. There are no published reports on its use in
pregnant women. It should be used with caution in patients
with pre-existing respiratory depression or those with depres-
sion." The starting dose is typically 2 mg at bedtime, al-
though the dose can be titrated to 3 mg as needed. Elderly
patients or those with severe hepatic impairment should begin
with 1 mg. No dosage adjustment is necessary in mild to
moderate hepatic impairment.
Eszopiclone has demonstrated a significant reduction in
sleep latency and improved measures of sleep maintenance,
such as wake time after sleep onset and number of awaken-
ings as compared with placebo.^""^'* In addition, eszopiclone
showed no evidence of clinically significant tolerance after 6
months of treatment and it has been studied for up to 12
months in an open-label extension trial.^'''•^'' This is the first
sedative hypnotic with data to support its continuous use for
up to 12 months.
Ramelteon. Ramelteon (Rozerem) is a highly selective
agonist for the melatonin MT1/MT2 receptors and the newest
FDA-approved agent for insomnia. Melatonin is believed to
mediate the circadian rhythm in mammals. It is also the first
hypnotic agent that is not classified as a controlled substance.
Ramelteon has an onset of action of 30 minutes and a half-life
of 1 to 2 hours.^^ It is metabolized by the liver to several
metabolites with varying degrees of activity, although they
are much less potent than the parent compound. Concurrent
administration with the SSRI fluvoxamine significantly in-
creases the serum concentrations of ramelteon, and thus these
medications should not be used together. Other medications
that could itihibit the metabolism of ramelteon include agents
such as ciprofloxacin, norfloxacin, and mexiletine. Without
any data, the concomitant use of over-the-counter melatonin
is not recommended. Alcohol does not directly affect ramel-
teon, but it may still result in additive effects on psychomotor
performance. Potential adverse effects include somnolence,
dizziness, nausea, fatigue and headache.^^ Serum prolactin
increased in 32% of patients in one study.^^ Assessment of
prolactin and testosterone concentrations should be consid-
ered in patients with unexplained amenorrhea, galactorrhea,
decreased libido, or problems with fertility. Its use is contra-
indicated in children, nursing mothers, and those with severe
hepatic disease. It is pregnancy category C with no well-
1375
Taylor, Vazquez, and Campbell • Pharmacologic Management of Chronic Insomnia
controlled human studies. Ramelteon should be used cau-
tiously in those with pre-existing neurologic disease, mild to
moderate hepatic disease, endocrine disease, seizure disorder,
or the elderly.^^ The recommended dose is 8 mg taken within
30 minutes of going to bed.
Ramelteon has been shown to be significantly more ef-
fective than placebo in reducing sleep latency, increasing
total sleep time and sleep efficiency in studies for up to 5
weeks in duration.^*"^' Ramelteon had no effect on any be-
havioral and cognitive performance tests, and showed no po-
tential for abuse.
Trazodone. Trazodone (Desyrel), an antidepressant with
sedating properties, is commonly prescribed for the treatment
of insotnnia, although it lacks FDA approval for this use. It
inhibits the reuptake of serotonin, a-adrenergic blocking ac-
tion and modest histamine blockade. It is metabolized in the
liver to inactive metabolites. It can interact with numerous
medications, including other medications affecting serotonin
(eg, selective serotonin reuptake inhibitors), other CNS de-
pressants (eg, alcohol), ketoconazole, and itraconazole. The
most common side effects include drowsiness, dry mouth,
nausea, vomiting, constipation, headache and blurred vision.
Trazodone is not approved for use in children and it is preg-
nancy category C. It should be used with caution in patients
with hepatic or renal impairment. The recommended dose for
treatment of insomnia is 50 mg at bedtime. If it is also being
used for depression, higher doses will be used.
As an antidepressant, trazodone has the advantage of
treating insomnia while treating concurrent conditions like
depression or psychological disorders. In addition, trazodone
offers a low cost potential for long-term use, and a low abuse
potential. However, there is limited data from double-blind,
controlled studies on its efficacy for treating insomnia. Tra-
zodone has been shown to be effective in two small trials in
patients with concurrent depression without concurrent hyp-
notic use.''^'''^ Even though trazodone has shown subjective
improvement in ease of falling asleep and quality of sleep, it
has also been associated with negative effects on ease of
awakening and feelings at or after wakening. Studies have
also shown a decline in efficacy after one to two weeks of
treatment, suggesting the potential for development of toler-
ance.^^'^"^ Side effects of trazodone include orthostatic hypo-
tension and blurred vision which can lead to falls, especially
in the elderly. Other side effects include nausea, dry mouth,
constipation, drowsiness, and headache. Trazodone has also
been associated with rebound insomnia after withdrawal.
Over-the-counter agents Sedating antihistamines such
as diphenhydramine are marketed as sleep aids to induce
sleep. They are readily available and relatively inexpensive
and thus are often used by patients. However, data on the use
of these agents is sparse and of short duration and poor qual-
ity.^^'^^ In addition, they are also associated with next-day
sedation, anticholinergic side effects, psychomotor impair-
ment and the development of tolerance.^^'^^
1376
Melatonin and valerian are alternative therapies which
are also readily available. Melatonin has been shown to in-
duce sleep in healthy volunteers, elderly patients and those
with insomnia.^'"''^ Its effects on sleep maintenance are less
impressive with conflicting results."*"'"' The studies have in-
volved small numbers of subjects treated for short durations.
It appears to be well tolerated, at least for short-term use.
Valerian has been shown to reduce sleep latency, and im-
prove sleep maintenance, although large, well-designed trials
are lacking.'*'' It may take 2 to 4 weeks before significant
effects are seen. Side effects may include next-day sedation,
headache, uneasiness and excitability. Without more data on
its efficacy and safety, it is not recommended at this time.
Summary and Recommendations
Before the diagnosis of primary insomnia is made, any
secondary causes should be identified and treated. A reason-
able approach is to first begin with behavioral therapy. Cli-
nicians may provide this therapy themselves or refer patients
to a sleep specialist. Realizing when referral is needed is very
important for the primary care physician. Referral is appro-
priate for chronic, resistant and/or unexplained insomnia. Rec-
ognize that not all patients will adequately respond to behav-
ioral therapy as it may not be effective in all subsets of
patients.
Despite the fact that long-term data is lacking, patients
who do not respond to behavioral therapy may proceed to
pharmacolgical therapy. Efficacy, tolerance and side effects
will need to be closely monitored. The two approaches should
generally not be combined since this may reduce the long-
term benefit of behavioral therapy, although this recommen-
dation is based on somewhat limited data. However, pharma-
cologic therapy may be considered for short-term use when
initiating behavioral therapy, especially in those who would
benefit from the more rapid results. Combination therapy
could be considered in patients who are willing to comply
with the behavioral therapies. Zolpidem, zaleplon or ramelt-
eon should be considered for patients primarily suffering from
sleep onset insomnia. Ramelteon is the least likely of these
agents to cause cognitive or behavioral impairment with short-
term use, but long-term differences are unknown. Eszopi-
clone or an intermediate-acting benzodiazepine (eg, estazo-
lam, temazepam) would be appropriate for insomnia that is
predominantly associated with sleep maintenance. Zaleplon
can also be used for those suffering fi-om sleep maintenance
insomnia when taken in the middle of the night. Long-term
use of hypnotic agents is largely unsupported at this time.
Further research is needed on the long-term effects of
pharmacologic therapy, comparing pharmacologic agents to
one another, to determine which patients benefit most from
behavioral therapy, and to clarify the role of combining be-
havioral and pharmacological therapy. Strategies to improve
the availability of behavioral therapy and primary care clini-
cian training are also encouraged.
© 2006 Southern Medical Association

References
1. Costa e Silva JA, Chase M, Sartorius M, et al. Special report from a
symposium held by the World Health Organization and World Federa-
tion of Sleep Research Societies: an overview of insomnias and related
disorders: recognition, epidemiology, and rational management. Sleep
1996;I9:412^16.
2. Morin CM, Culbert JP, Schwartz SM. Nonpharmacolgical interventions
for insomnia: a meta-analysis of treatment efficacy. Am J Psychiatry
1994;151:1172-1180.
3. Roth T. New developments for treating sleep disorders. J Ctin Psychi-
atry 200\;62{Supp\ \oy.3-4.
4. Shochat T, Umphress J, Israel AG, et al. Insomnia in primary care
patients. Sleep 1999;22(Suppl 2):S359-S365.
5. American Psychiatric Association. Diagnostic and Statistical Manual of
Mental Disorders. 4th ed. Washington, DC, Ameriean Psychiatrie As-
sociation, 1994.
6. The International Classification of Sleep Disorders, Revised: Diagnostic
and Coding Manual. Rochester, Minn, American Sleep Disorders As-
sociation, 1997.
7. Roth T, Roehrs TA. A review of the safety profiles of benzodiazepine
hypnotics. J Clin Psychiatry 1991;52(Suppl):38-4l.
8. Meddelson WB. Clinical distinctions between long-acting and short-
acting benzodiazepines. J Clin Psychiatry 1992;53(Suppl):8-9.
9. Nowell PD, Mazumdar S, Buysse DJ, et al. Benzodiazepines and zol-
pidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA
1997;278:2170-2177.
10. Holbrook AM, Crowther R, Lotter A, et al. Meta-analysis of benzodi-
azepine use in the treatment of insomnia. CM^J 2000; 162:225-233.
11. Prescribing information. Ambien (zolpidem). New York, NY, Sanofi
Synthelabo, March 2004.
12. Scharf MB, Roth T, Vogel GW, et al. A multicenter, placebo-controlled
study evaluating zolpidem in the treatment of chronic insomnia. J Clin
Psychiatry 1994;55:192-199.
13. Walsh JK, Roth T, Randazzo A, et al. Eight weeks of non-nightly use of
zolpidem for primary insomnia. Sleep 2000;23:1087-1096.
14. Perlis ML, McCall WV, (Crystal AD, et al. Long-term, non-nightly ad-
ministration of zolpidem in the treatment of patients with primary in-
somnia. J Clin Psychiatry 2004;65:l 128-1137.
15. Prescribing information. Sonata (zaleplon). Philadelphia, Pa, Wyeth
Pharmaceuticals, March 2006.
16. Elie R, Ruther E, Farr 1, et al. Sleep latency is shortened during 4 weeks
of treatment with zaleplon, a novel nonbenzodiazepine hypnotic: Zale-
plon Clinical Study Group. J Clin Psychiatry 1999;60:536-544.
17. Walsh JK, Vogel GW, Seharf M, et al. A five week, polysomnographic
assessment of zaleplon lOmg for the treatment of primary insomnia.
Sleep Med 2000;l:4l-49.
18. Walsh JK, Pollak CP, Scharf MB, et al. Lack of residual sedation fol-
lowing middle-of-the-night zaleplon administration in sleep maintenance
insomnia. Clin Neuropharmacol 2000;23:17-21.
19. Prescribing information. Lunesta (eszopiclone). Marlborough, Mass,
Sepracor, February 2005.
20. Krystal AD, Walsh JK, Laska E, et al. Sustained efficacy of eszopiclone
over 6 months of nightly treatment: results of a randomized, double-
blind, placebo-controlled study of adults with chronic insomnia. Sleep
2003;26:793-799.
21. Zammit GK, McNabb LJ, Caron J, et al. Efficacy and safety of eszopi-
clone across 6-weeks of treatment for primary insomnia. Curr Med Res
Opin2004;20:1979-1991.
22. Scharf M, McCall WV, Erman M, et al. Patient-reported efficacy of
eszopiclone (ESZ) in elderly patients with chronic insotnnia (abstract).
JAm Geriatr Soc 2004;52:S14.
Southern Medical Journal • Volume 99, Number 12, December 2006
Review Article
23. Erman M, Rosenburg R, Caron J. Polysomnographic and patient-re-
ported evaluation of the efficacy and safety of eszopiclone in elderly
subjects with chronic insomnia (abstract). Steep 2004;27(Suppl):A257.
24. Roth T, Krystal A, Walsh J, et al. Twelve months of nightly eszopiclone
treatment in patients with chronic insomnia: assessment of long-term
efficacy and safety (abstract). Sleep 2004;27(Suppl):A260.
25. Prescribing information. Rozerem (ramelteon). Lincolshire, III, Takeda,
August 2005.
26. Roth T, Seiden D, Weigand S, et al. Phase III study to determine the
efficacy of ramelteon in elderly patients with chronic insomnia (ab-
stract). 45th Annual Meeting of the New Clinical Drug Evaluation Unit
(NCDEU); June 6-9, 2005, Boca Raton, Fla.
27. Zammit G, Roth T, Erman M, et al. Polysomnogaraphy and outpatient
study to determine the efficacy of ramelteon in adults with chronic
insomnia (abstract). 158th Annual Meeting of the American Psychiatric
Association: New Research Abstracts; May 21-26, 2005, Atlanta, p227.
28. Roth T, Seiden D, Zee P, et al. Phase III outpatient trial of ramelteon for
the treatment of chronic insorrmia in elderly patients (abstract). J Am
Geriatr Soc 2005;53(Suppl 4):S25.
29. Zammit G, Roth T, Erman M, et al. Double-blind, placebo-controlled
polysomnography and outpatient trial to evaluate the efficacy and safety
of ramelteon in adult patients with chronic insomnia (abstract). Sleep
2005;28:A228-A229.
30. Seiden D, Zee P, Weigand S, et al. Double-blind, placebo-controlled
outpatient clinical trial of ramelteon for the treatment of chronic insom-
nia in an elderly population (abstract). Sleep 2005;28:A228.
31. Erman M, Seiden D, Zammit G, et al. An efficacy, safety, and dose-
response study of ramelteon in patients with chronic primary insomnia.
Sleep Med 2006;7.\l-24.
32. Nierenberg AA, Adler LA, Peselow E, et al. Trazodone for antidepres-
sant-associated insomnia. Am J Psychiatry 1994; 151:1069-1072.
33. Walsh JK, Erman M, Erwin CW, et al. Subjective hypnotic efficacy of
trazodone and zolpidem in DSM-III-R primary insomnia. Hum Psycho-
pharmacol I998;13:191-198.
34. Montgomery 1, Oswald I, Morgan K, et al. Trazodone enhances sleep in
subjective quality but not in objective duration. Br J Clin Pharmacol
1983;16:139-144.
35. Rickels K, Morris RJ, Newman H, et al. Diphenhydramine in insomniac
family practice patients: a double-blind study. J Clin Pharmacol 1983;
23:234-242.
36. Kudo Y, Kurihara M. Clinical evaluation of diphenhydramine hydro-
chloride for the treatment of insomnia in psychiatric patients: a double-
blind study. J Clin Pharmacol 1990;30:1041-1048.
37. Richardson GS, Roehrs TA, Rosenthal L, et al. Tolerance to daytime
sedative effects of HI antihistamines. J C//« Psychopharmacol 2002;22:
511-515.
38. Roth T, Roehrs T, Koshorek G, et al. Sedative effects of antihistamines.
J Allergy Clin Immunol 1987;80:94-98.
39. Mishima K, Satoh K, Shimizu T, et al. Hypnotic and hypothermic action
of daytime-administered melatonin. Psychopharmacology (Berl) 1997;
133:168-171.
40. Haimov I, Lavie P, Laudon M, et al. Melatonin replacement therapy of
elderly insomniacs. Sleep 1995;18:598-603.
41. Hughes RJ, Sack RL, Lewy AJ. The role of melatonin and circadian
phase in age-related sleep-maintenance insomnia: assessment in a clin-
ical trial of melatonin replacement. Sleep 1998;21:52-68.
42. Andrade C, Srihari BS, Reddy KP, et al. Melatonin in medically ill
patients with insomnia: a double-blind, placebo-controlled study. J Clin
Psychiatry 2001 ;62:41-45.
43. Wagner J, Wagner ML, Hening WA. Beyond benzodiazepines: alterna-
tive pharmacologic agents for the treatment of insomnia. Ann Pharma-
cother 1998;32:680-691.
1377