Department of Veterans Affairs Pharmacy Benefits Management Service and
Medical Advisory Panel

Primary Care Outpatient Algorithm: Treatment of Acute Insomnia
(Short-term, 1-4 weeks) and

Chronic Insomnia (Long--term, \> 1 month)

Selection of therapy for individual patients is ultimately based upon
the provider's assessment of clinical circumstances and patient needs.
This algorithm is not intended to interfere with clinical judgment, but
rather to assist practitioners in clinical decision-making, to
standardize and improve the quality of patient care, and to promote
cost-effective drug prescribing. This algorithm is NOT intended to be
used for any other indication of the sedative hypnotics except for the
treatment of primary insomnia in the primary care patients. This does
not imply that other non-pharmacological treatments are not indicated.
Effective treatment for insomnia usually will consist of a dual approach
using nonpharmacologic techniques and appropriate use of hypnotic
agents. Proper attention to sleep hygiene may prevent the development of
psychophysiological insomnia. It is expected that significant, new
clinical trials as well as new pharmacological agents will be
forthcoming in this class of medications. Therefore, the following
recommendation will be revised as new data become available.

An insufficient number of controlled studies, lack of comparative
studies and inconsistent reporting of meaningful outcome measures make
the development of evidence-based guidelines for the treatment of
primary insomnia in the veteran population difficult. It is recognized
that in primary care, screening for sleep problems is often overlooked
or perhaps, not even performed. Screening entails taking an adequate
sleep history including sleep and wakefulness patterns, history from the
bed partner, family history of sleep disorders and previous treatments.
To aid the provider in the management of this condition, the patient
and/or caretaker(s) needs to be trained to appropriately use monitoring
tools such as sleep diaries.

[]{.mark}

On March 14, 2007, the U.S. Food and Drug Administration (FDA) requested
that sedative-hypnotic agents used to treat insomnia undergo revised
labeling to include stronger language concerning warnings about the
following potential risks:

-   Anaphylaxis (severe allergic reaction) and angioedema (severe facial
    swelling)

-   Complex sleep-related behaviors which may include sleep-driving
    defined as "driving while not fully awake after ingestion of a
    sedative-hypnotic product, with no memory of the event," making
    phone calls, and preparing and eating food (while asleep).

For more detail see
<http://www.fda.goc/bbs/topics/NEWS/2007/NEW01587.html>.

[]{.mark}

Therefore, the purpose of this document is two-fold. First, it is to
promote and improve screening of sleep problems in the veteran
population. The second purpose of this document is to provide guidance
to practitioners in the clinical decision-making, to standardize and
improve treatment of insomnia in veterans and to promote cost-effective
drug prescribing.

Background: The prevalence of insomnia reported in the literature is
difficult to determine due to the lack of standardized diagnostic and
screening methods, including variable assessment methods used to
evaluate its presence and clinical significance as well as an
inconsistent operational definition of insomnia used amongst the
clinical studies. In the literature, insomnia has been classified as
"short-term," "transient," "occasional or intermittent," "chronic" and
"day-time functional impairment." Nevertheless, it has been reported
that 50% of primary care patients experience insomnia, only 1/3 actually
mention the problem and 5% actually seek treatment. (Ancoli-Israel S et
al. 1999; Smith MT et al. 2002; Shochat T et al. 1999) Most experts
agree that the prevalence of insomnia is more common in women, older
adults particularly those with depression and patients with chronic
medical or psychiatric problems. The prevalence rates of insomnia in
adults aged 65 and over have been reported to be between 12 and 40%.
(Morin C. 1999). It is not well-known how to best manage insomnia in
specific sub-populations. However, it is known that there are
consequences of not treating insomnia including a higher risk of
depression, cognitive impairment, mood disturbances, decrease job
performance, increase daytime fatigue and a frequent use of medical
services contributing to increase in healthcare costs. Unfortunately,
the extent to which treatment of the underlying medical and/or
psychiatric conditions ameliorates insomnia remains unclear although
certainly an assessment/evaluation of the co-morbid conditions
associated with sleep disturbances should be performed and documented.
Drug use, withdrawal, or the attempt to adjust any
medications/substances that could interfere with sleep should also be
documented.

**ACUTE INSOMNIA:** (less than one month in duration) The management of
acute insomnia has traditionally involved pharmacotherapy, although no
ideal hypnotic agent is available. Although the choice of a drug is
primarily determined by clinical efficacy, the risk of accidents, hip
fractures and falls due to residual effects should be taken into
consideration in selecting a sedative hypnotic agent. Selection of the
safest drug and dose possible among those available is a first step
towards minimizing the risk. A second step is to adequately inform
patients about any risks and ways to minimize them by adjusting their
behavior. As a result, emphasizing nonpharmacologic approaches alone or
in combination with short-term pharmacologic treatment versus indefinite
pharmacologic treatment must be in the forethought of a provider when an
appropriate treatment plan for acute insomnia is being discussed.
Initially, if a patient has an inadequate response to simple basic-sleep
hygiene principles, additional nonpharamcologic approaches (e.g.
relaxation, cognitive/behavioral therapy) in combination with a
pharmacologic agent short-term is an appropriate approach for acute
insomnia. Thus, the goals of treatment for acute insomnia which should
be discussed with the patient is to reverse the sleep disruption and
accompanying deterioration of daytime performance, as well as to prevent
possible evolution to chronic insomnia.

**CHRONIC PRIMARY INSOMNIA:** The evidence for management of chronic
insomnia with pharmacotherapy has not been systematically evaluated. As
a result, difficulty arises in attempting to provide guidance on the
optimal duration of therapy for primary chronic insomnia let alone those
with chronic medical and psychiatric co-morbid conditions. Literature
reveals that the lack of knowledge about non-drug treatment and limited
access to other forms of professional help were the main reason for
prescribing sleeping pills. (Baillargeon L et al. 1996). Two early NIH
consensus conferences (1983, 1990) concluded that long-term use of
hypnotic medications remains controversial because of the potential risk
of tolerance and dependency. More recently, evidence suggests that
relaxation and cognitive/behavioral therapy are effective in the
management of chronic insomnia in subsets of population. (AHRQ
Publication No. 05-E021-2, June 2005)

Currently, published data of one-year in duration with the newer
sedative hypnotics exists. Again, it needs to be reinforced that no
ideal hypnotic agent is available. When pharmacologic treatment is
prescribed, patients should be adequately informed of the duration and
severity of residual effects of the hypnotic agent. Residual effects
depend on the dose administered; start with the lowest dose possible,
particularly in the elderly. Reports of daytime residual effects of
these types of drugs are more likely to be affected by older
individuals, as well as increasing the risk for falls and fractures. Do
not double the dose without consideration of the consequences of
residual effects. These agents should be avoided when next day's
activities involves skilled work and where impairment of performance
could be a danger to themselves or others. If a sedative hypnotic agent
that is likely to produce moderate or severe effects cannot be avoided,
the recommendation to prohibit driving completely at the start of
treatment should be considered. Advise patients not to drive when they
feel sleepy, dizzy or are experiencing a lack of concentration. However,
it should also be made clear to them that the absence of such feelings
does not mean their performance is normal. The use of sedative hypnotic
agents in combination with other psychoactive drugs largely increases
the risk of residual effects, and should be avoided if all possible.

**Annotated Bibliography:\***

**General Overview:**

Ancoli-Israel S, Roth T. Characteristics of insomnia in the United
Status: results of the 1991 National Sleep Foundation Survey. Sleep
1999; 22 (suppl 2):S347-53.

Ancoli-Israel S, Liat A. Diagnosis and treatment of sleep disorders in
older adults. Am J Geriatr Psychiatry 2006; 14: 95-103.

Baillargeon L, Demers M, Gregoire JP, et al. Study on insomnia treatment
by family physicians. Can Fam Physician. 1996; 42: 426-32.

Buscemi N, Vandermeer B, Friesen C, et al. Manifestations and management
of chronic insomnia in adults. Evidence Report/Technology Assessment No.
125. June 2005.

Casola PG, Goldsmith RJ, Daiter J. Assessment and Treatment of sleep
problems. Psychiatr Ann 2006; 36: 862-68.

Drugs and Insomnia: The Use of Medications to Promote Sleep. NIH Consens
Statement 1983 Nov 5-17; 4(10): 1-19.

DoD Drug Class Review - Newer Sedative Hypnotics. Prepared by DoD
Pharmacoeconomic Center for the Feb 07 meeting of the DoD Pharmacy &
Therapeutics Committee.

Krahn L. Psychiatric disorders associated with disturbed sleep. Sleep in
neurological practice. Semin Neurol 2005; 25: 90-6.

Kupfer DJ and Reynolds CF. Management of insomnia. N Engl J Med
336:341-336.

Morin CM, Hauri PG, Espie CA, et al. Nonpharmacologic treatment of
chronic insomnia. Sleep 1999;22:1134-56.

Montgomery P and Dennis J. Cognitive behavioural interventions for sleep
problems in adults aged 60+ (Review). Cochrane Database of Systematic
Reviews 2003, Issue 1. Art. No.: CD003161. DOI:
10.1002/14651858.CD003161.

NIH State-of-the-Science Conference Statement on Manifestations and
Management of Chronic Insomnia in Adults. NIH Consens Sci Statements.
2005. Jun 13-15, 22 (2) 1-30.

NIH State-of-the Science Conference Statement on Manifestations and
Management of Chronic Insomnia in Adults, June 13-15, 2005. Sleep 28(9):
1049-57.

NIH State-of-the-Science Conference Statement on Manifestations and
Management of Chronic Insomnia in Adults. June 13-15, 2005. J Clin Sleep
Med 2005; 1: 412-21.

Petit L, Azad N, Byszewski A, et al. Non-pharmacological management of
primary and secondary insomnia among older people: review of assessment
tools and treatments. Age Ageing 2003;32:19-25.

Shochat T, Umphress J, Israel AG, et al. Insomnia in primary care
patients. Sleep 1999; 22(Suppl 2):S359-65.

Smith MT, Perlis M, Park A, et al. Comparative meta-analysis of
pharmacotherapy and behavior therapy for persistent insomnia. Am J
Psychiatry 2002;159:5-11.

Saskia et al. Pharmacotherapy for disordered sleep in post-traumatic
stress disorder; a systematic review. Int Clin Psychopharmacol 2006; 21:
192-202.

The Treatment of Sleep Disorders of Older People. NIH Consens Statement
1990 Mar 26-28; 8(3): 1-22.

Van Liempt S, Vermetten E, Geuze E, et al. Pharmacotherapy for
disordered sleep in post-traumatic stress disorder: a systematic review.
Int Clin Psychopharmacol 2006;21:193-202.

Wolkove N, Elkholy O, Baltzan M, et al. Sleep and aging: 2. Management
of sleep disorders in older people. CMAJ 2007;176:1449-54.

**Antidepressants: Trazodone/Doxepin**

Trazodone has been prescribed for chronic insomnia despite the lack of
good evidence. A two week trial, rated fair-quality by the Oregon
Evidence-based Practice Center assessed the use of short term zolpidem,
trazodone and placebo in patients with primary insomnia. Sleep latency
was shorter with zolpidem after 1 week (assessed by questionnaire),
compared to trazodone but the difference was not significant at week 2.
Sleep duration, number of awakenings, sleep quality, and patients'
global impressions of treatment were similar for the drugs at weeks 1
and 2. More patients reported daytime somnolence with trazodone.
Withdrawals due to adverse events and overall adverse events were
similar between the drugs.

In a double-blind, randomized, placebo-controlled trial, doxepin 25-50mg
was studied objectively in 47 drug-free patients with primary insomnia
over a 4 week period followed by 2 weeks of placebo withdrawal. Doxepin
significantly increased sleep efficiency compared with patients whom
received placebo. Latency to sleep onset was not affected; however the
patients had normal baseline sleep latencies. Patients perceived that
doxepin caused significantly better global improvement at the first day
of treatment. Patients rated sleep quality and working ability to be
significantly improved with doxepin during the whole treatment period.
Patients with severe rebound insomnia occurred more frequently in the
doxepin group compared to placebo.

Buscemi N, Vandermeer B, Friesen C, et al. Manifestations and management
of chronic insomnia in adults. Evidence Report/Technology Assessment No.
125. June 2005.

Carson S, Yen-P-Y, McDonagh MS. Drug class review on newer drugs for
insomnia. 2006.
<http://www.ohsu.edu/drugeffectiveness/reports/final.cfm>.

Hajak G, Rodenbeck A, Voderhozer U, et al. Doxepin in the treatment of
primary insomnia; a placebo-controlled, double-blind, polysomnographic
study. J Clin Psychiatry 2001; 62: 453-63.

James SP, Mendelson WB. The use of trazodone as a hypnotic: a critical
review. J Clin Psychiatry. 2004; 65:752-5.

Mendelson WB. A review of the evidence for the efficacy and safety of
trazodone in insomnia. J Clin Psychiatry 2005; 66: 469-76.

Wilson S. and Argyropoulos S. Antidepressants and sleep: A qualitative
review of the literature. Drugs 2005; 65:927-47.

Walsh JK, Erman M, Erwin CE, et al. Subjective hypnotic efficacy of
trazodone in DSM3-R primary insomnia. Hum Psycholpharmacol 1998;
13:191-8.

**Antihistamine: Diphenhydramine**

Diphenhydramine for the treatment of insomnia is not supported by
rigorous data. In a double-blind, randomized, cross-over trial in 15
healthy men, aged 18-50, diphenhydramine 50 mg twice a day demonstrated
significant impairment of performance. Tolerance was noted within 3 days
of administration. In 144 psychiatric patients with insomnia, the
hypnotic effect of diphenhydramine 12.5-50 mg for 2 weeks was
significantly greater in those patients who had not been treated
previously with the medication. In another double-blind, randomized,
placebo-controlled, cross-over study with diphenhydramine 50-75mg,
temazepam (15 and 30mg) and valerian in 14 healthy elderly volunteers
(mean age, 71.6); temazepam 30mg and both doses of diphenhydramine
elicited significantly greater sedation than placebo, p\<0.5, all). No
difference in sedation scores were noted between 50 and 75 mg
diphenhydramine. No psychomotor impairment was detected with
diphenhydramine 50 mg. However, in another study using a driving
simulator, diphenhydramine 50 mg did impair the driving performance to a
greater extent than alcohol.

Glass, JR, Sproule BA, Herrmann N, et al. Acute pharmacological effects
of temazepam, diphenhydramine, and valerian in healthy elderly subjects.
J Clin Psychopharmacol 2003;23:260-68.

Kudo Y and Kurihara M. Clinical evaluation of diphenhydramine
hydrochloride for the treatment of insomnia in psychiatric patients; a
double-blind study. J Clin Pharmacol 1990;30:1041-8.

Silber MH. Chronic Insomnia. NEJM 2005; 353: 803-10.

Richardson GS, Roehrs TA, Rosenthal L, et al. Tolerance to daytime
sedative effects of H1 antihistamines. J Clin Psychopharmacol 2002;
22:511-15.

Weiler J, Bloomfield JR, Woodworth GG, et al. Effects of fexofenadine,
diphenhydramine, and alcohol on driving performance: A randomized,
placebo-controlled trial in the Iowa Driving Simulator. Ann Intern Med
2000; 132:354-64.

**Benzodiazepines:**

Buscemi N, Vandermeer B, Friesen C, et al. Manifestations and management
of chronic insomnia in adults. Evidence Report/Technology Assessment No.
125. June 2005.

Hirst A, and Sloan R. Benzodiazepines and related drugs for insomnia in
palliative care. Cochrane Database of Systematic Reviews 2001, Issue 4.
Adt. No.: CD003346. DOI: 10.1002/14651858.CD003346.

Holbrook AM, Crowther R, Lotter A, et al. Meta-analysis of
benzodiazepine use in the treatment of insomnia. CMAJ 2000; 225-33.

Nowell PD, Mazumar S, Buysee D, et al. Benzodiazepines and zolpidem for
chronic insomnia: A meta-analysis of treatment efficacy. JAMA 1997;
278:2170-77.

**Newer Sedative Hypnotics:**

Buscemi N, Vandermeer B, Friesen C, et al. Manifestations and management
of chronic insomnia in adults. Evidence Report/Technology Assessment No.
125. June 2005.

Carson S, Yen-P-Y, McDonagh MS. Drug class review on newer drugs for
insomnia. 2006.
<http://www.ohsu.edu/drugeffectiveness/reports/final.cfm>

DoD Drug Class Review - Newer Sedative Hypnotics. Prepared by DoD
Pharmacoeconomic Center for the Feb 07 meeting of the DoD Pharmacy &
Therapeutics Committee.

Eszopiclone Monograph:
[http://vaww.national.cmop.va.gov/PBM/Clinical%20Guidance/Drug%20Monographs/Eszopiclone.pdf](http://vaww.national.cmop.va.gov/PBM/Clinical Guidance/Drug Monographs/Eszopiclone.pdf),
April 2005, updated June 2005, November 2005, and October 2006.

Eszopiclone Criteria for Non-formulary Use:
[http://vaww.national.cmop.va.gov/PBM/Clinical%20Guidance/Criteria%20For%20Use/Eszopiclone,%20Criteria%20for%20Non-Formulary%20Use.pdf](http://vaww.national.cmop.va.gov/PBM/Clinical Guidance/Criteria For Use/Eszopiclone, Criteria for Non-Formulary Use.pdf)
February 2006

Holm K, and Goa KL. Zolpidem: An Update of its Pharmacology, Therapeutic
Efficacy and tolerability in the treatment of insomnia. Drugs 2000; 59:
865-889l

Ramelteon Monograph:
[http://vaww.national.cmop.va.gov/PBM/Clinical%20Guidance/Drug%20Monographs/Ramelteon.pdf](http://vaww.national.cmop.va.gov/PBM/Clinical Guidance/Drug Monographs/Ramelteon.pdf),
December 2005.

**Miscellaneous Agents**

**Atypical Antidepressants/Quetiapine:**

Fifteen subjects with refractory post-traumatic stress disorder (PTSD)
(combat and noncombat trauma) were enrolled in an 8-week open-label
trial for PTSD in which quetiapine was added to a selective serotonin
reuptake inhibitor (SSRI). The mean dose prescribed in the study was
216mg per day. The addition of quetiapine proved significant relief from
PTSD symptoms with a 42% overall improvement in PTSD symptoms based on
the Clinician-Administered PTSD Scale (CAPS). Sleep measures as a
secondary measure was evaluated using the Pittsburgh Sleep Quality Index
(PSQI). The score from the PSQI improved by approximately 42% compared
to baseline scores, (p=0.004).

In an 8-week, multicenter, randomized, double-blind, parallel-group,
placebo-controlled study, quetiapine monotherapy (300 or 600mg/day) in
comparison with placebo on overall quality-of-life (QOL) and quality of
sleep in adults with bipolar I or II depression was evaluated. Patients
were adult outpatients, aged 18-65 years and were in a current episode
of depression with a duration of greater than 4 weeks but less than 1
year. Quetiapine was initiated at 50mg/day and administered to achieve a
target daily dose of 300mg/day by day 4, or 600mg/day by week 1.
Zolpidem (5-10mg/day at bedtime for insomnia) and lorazepam (1-3mg/day
for severe anxiety) during the first 3 weeks of treatment were
permitted. Both doses of quetiapine significantly improved QOL over
baseline values in comparison with placebo. As a secondary outcome,
quetiapine therapy also caused a significant improvement in quality of
sleep compared with placebo measured using the Pittsburgh Sleep Quality
Index (PSQI).

Ahearn EP, Mussey M, Johnson C, et al. Quetiapine as an adjunctive
treatment for post-traumatic stress disorder: an 8-seek open-label
study. Int Clin Psychopharmacol 2005; 21:29-33.

Endicott, J Rajagopalan R, Minkwitz M, et al. A randomized,
double-blind, placebo-controlled study of quetiapine in the treatment of
bipolar I and II depression: improvements in quality of life. Int Clin
Psychopharmacol 2007; 22: 29-37.

**Prazosin:**

Raskind MA, Peskind ER, Kanter ED, et al. Reduction of nightmares and
other PTSD symptoms in combat veterans by prazosin: a placebo-controlled
study. Am J Psychiatry 2003; 160: 371-73.

Taylor F, and Raskind MA. The alpha1-adrenergic antagonist prazosin
improves sleep and nightmares in civilian trauma posttraumatic stress
disorder. J Clin Psychopharmacol 2002; 22: 82-5.

**Zolpidem-Intermittent Dosing:**

Cluydts R, Peeters K, DeBouyalisky I, et al. Comparison of continuous
vs. Intermittent administration of zolpidem in chronic insomniacs: a
double-blind, randomized, pilot study. J Int Med Res. 1998; 26:13-24.

Hajak G, Cluydts R, Declerck A, et al. Continuous versus non-nightly use
of zolpidem in chronic insomnia: results of a large-scale, double-blind,
randomized, outpatient study. Int Clin Psychopharmacol 2002; 17: 9-17.
Erratum in: Int Clin Psychopharmacol 2002: 17: 206.

Perlis ML, McCall WV, Krystal AD, et al. Long-term, non-nightly
administration of zolpidem in the treatment of patients with primary
insomnia. J Clin Psychiatry 2004; 65: 1128-37.

Walsh JK, Roth T, Randazzo A, et al. Eight weeks of non-nightly use of
zolpidem for primary insomnia. Sleep 2000; 23:1087-96.

\* Applicable agents currently available on the VA National Formulary as
of 5-2007

**Appendix: Additional Information/Resources Regarding Management of
Insomnia**

**Table 1:** **Sleep History Interview [\[Click here to return to
algorithm\]](#Textbox2)**

***Questions To Ask Patients/Caregivers When Obtaining a Basic Sleep
History (involving the usual sleep period)***

1.  What time do you go to bed?

2.  What time do you wake up in the morning?

3.  Would you say you get \_\_\_ hours (based on answers from questions
    1 and 2) of sleep every night?

4.  When you do go to bed, how long does it take for you to get to
    asleep?

    -   What keeps you awake?

5.  Do you sleep through the night?

    -   If not, how many times do you wake up, and why?

    -   When you do fall back to sleep, how long does it take you to get
        back to sleep?

6.  What time do you get out of bed for the day?

7.  How do you feel when you wake up in the morning?

8.  How long does it take you to "get going" in the morning?

9.  Do you believe your ability to perform daytime activities has been
    affected by your trouble sleeping?

10. Do you try to sleep longer on weekends or days off? If so, how much?

11. Do you smoke?

    -   If so, how much?

    -   Do you smoke in the evening?

12. Do you drink alcohol in the evening?

    -   Do you drink alcohol to help you fall asleep?

> []{.mark}

***Questions to Ask Patients/Caregivers about behaviors that affect
sleep: (rule-out other sleep disorders)***

1.  Do you nap during the day, when, and for how long? (hypersomnia)

2.  Do you snore? Does the bed partner observe episodes of where you
    stop breathing? (obstructive sleep apnea)

3.  When you are in bed, do you have an irresistible urge to move your
    legs? (restless leg syndrome)

-   Does your bed partner report that you kick or jerk your legs
    frequently during the night?

4.  Do you eat at night?

5.  Do you take any medications or over-the-counter preparations, herbal
    remedies, or psychoactive substances to assist with sleep?

6.  Where do you sleep, and what surrounds you in your place of sleep,
    e.g. computer, television, paperwork, room lighting, and outside
    noise?

7.  Do you drink coffee, tea, chocolate and caffeinated colas? How much?

8.  How has your mood been recently? Are you still able to enjoy
    social/family activities? (depression)

9.  Have you been told that you act strangely during your sleep?
    (parasomnias)

Adapted from Wilson S. and Nutt D. Prescriber 2005; 19:29-41. Wolkove N.
et al. CMAJ 2007; 176:1449-454.

There is a variety of co-morbid conditions associated with insomnia.
Table 2 indicates some medical, psychiatric, and environmental disorders
known to interfere with sleep. A work-up for insomnia would include the
assessment and evaluation of these conditions.

**Table 2:** **Co-morbid conditions that interfere with sleep\* [\[click
here to return to algorithm\]](#Textbox1)**

  ----------------------- ------------------ ---------------- ----------------- --------------- ----------------
  ***Medical***                                                                                 

  Angina                  CHF                                 Hyperthyroidism                   PUD

  Arthritis               Crohn's disease                     Hypoglycemia                      Periodic limb
                                                                                                movements

  Asthma                  Cushing's disease                   Malignancy                        Renal
                                                                                                insufficiency

  Bronchitis              Cystic fibrosis                     Migraine                          Restless legs
                                                                                                syndrome

  Carpal tunnel syndrome  Emphysema                           Nocturia                          Rheumatoid
                                                                                                Arthritis

  Chronic bladder         Epilepsy                            Obstructive                       Sleep apnea
  infection                                                   uropathy                          

  COPD                    Fibromyalgia                        Paresthesias                      Stroke

  Chronic painful         Gastroesophageal                    Parkinson's                       
  physical conditions     reflux                              disease                           
  (CPPC)                                                                                        

  ***Psychiatric and/or                                                                         
  Psychological***                                                                              

  Acute stress disorder                      Dementia                           Posttraumatic   
                                                                                stress disorder 

  Alcohol or substance                       Dysthymic                          Separation      
  abuse                                      disorder                           anxiety         
                                                                                disorder        

  Anxiety disorders                          Major depressive                   Somatoform      
                                             episode                            disorders       

  Bipolar disorder                                                                              

  ***Environmental***                                                                           

  Shift work                                                                                    
  ----------------------- ------------------ ---------------- ----------------- --------------- ----------------

\*Please note: Extent to which treatment for these conditions
ameliorates insomnia remains unclear. Often, treatment of insomnia in
addition to treating the co-morbid

condition may need to occur concurrently

Table 3 list medications/substances which could interfere with sleep or
associated with daytime somnolence. Documentation of drug use,
withdrawal, or the attempt to adjust any medication/substances that
could interfere with sleep should be documented.

**Table 3:** **Medications/Substances which could interfere with sleep
or daytime somnolence [\[click here to return to
algorithm\]](#Textbox1)**

  --------------------------- ---------------------- --------------------
  Alcohol                     Beta-2 Agonist         Statins

  Anticonvulsants             Caffeine               Nicotine
                              (over-the-counter      
                              products)              

  Analgesics (e.g.,           Clonidine              Methyldopa
  narcotics)\*                                       

  Anticholinesterase          CNS Stimulants         Opioids Resperine
  inhibitors (e.g.,                                  
  donepezil)                                         

  Antidepressants (e.g.       Decongestants (e.g.    Quinidine
  MAOIs, occasionally SSRIs)  pseudoephedrine)       

  Antidepressants (e.g,       Diet pills             Selective serotonin
  imipramine, trazodone)\*                           reuptake inhibitors

  Antihistamines\*            Diuretics              Steroids

  Antihypertensives (e.g.,    Herbal preparations    Stimulants
  clonidine)\*                containing M Huang     

  Antineoplastics             Histamine 2-Blockers   Theophylline
                              (e.g., cimetidine)     

  Beta-blockers (propranolol, Hormones               
  atenolol, pindolol)                                
  --------------------------- ---------------------- --------------------

\*associated with daytime sleepiness

**Table 4:** **Insomnia Educational Tools and Resources [\[click here to
return to algorithm\]](#Textbox2)**

**Table 5: Definitions of Insomnia-Related Effectiveness Outcomes**

  -------------------- --------------------------------------------------
  Sleep Effectiveness  Definitions
  Outcomes             

  Sleep latency        Time period that it takes for a person to fall
                       asleep

  Sleep duration       Time period a person remains asleep

  \# awakenings        Number of times patient wakes up

  WASO-(wake time      Total time that a person is awake between sleep
  after sleep onset)   onset and final wake-up

  Sleep quality        Usually measure by patient questionnaire (Likert
                       or visual analogues)

  Daytime alertness    Measured by patient self-report

  Rebound insomnia     Worsening of insomnia from baseline (prior to
                       pharmacotherapy) upon treatment discontinuation
  -------------------- --------------------------------------------------

**Table 6: Sleep Hygiene Education\* [\[click here to return to
algorithm\]](#Textbox3)**

Sleep hygiene education is useful for all patients regardless of
diagnosis. It ensures that patient's behaviors and lifestyle are
optimized to improve sleep efficiency

by educating patients about the interaction between lifestyle,
environment, and sleep physiology.

-   Avoid or limit caffeinated containing products, nicotine, and
    alcohol especially later in the day.

-   Avoid drinking excess liquids after supper to avoid having to get up
    during the night to go to the bathroom.

-   Avoid or limit daytime naps to 30 minutes in the early afternoon
    before 3:00 pm.

-   Go to bed only when sleepy. Sleep only as much as needed to feel
    refreshed. Staying in bed longer can result in fragmented/shallow
    sleep on following nights.

-   Create a dark, quiet, temperature-controlled bedroom. (e.g., change
    the number of blankets you use; use earplugs; close the door if
    noisy)

-   Avoid heavy meals within 2 hours of bedtime; a light snack might
    help if hungry.

-   Maintain a regular daily schedule of activities including bedtime
    and awakening times, 7 days/week. Use an alarm clock if needed.

    -   

-   Exercise regularly during the daytime. Avoid active exercise in the
    late evening when it is close to bed time.

-   Use the bed and bedroom only for sleeping or sexual activity. Do not
    eat, work or watch television while in bed.

    -   If you can not sleep, if possible, get out of bed and go to
        another room if you have not fallen asleep within 15-20 minutes.

> Go to another room, read or engage in other quiet activities; or do
> other relaxation activities before attempting to sleep again. Return
> to bed only when sleepy. Repeat if necessary. Do not watch the clock;
> turn the clock around or cover it up.

-   Solve problems before retiring. If not possible, write down your
    worries, plans and strategies during the early evening and not at
    bedtime.

-   Correct extrinsic factors such as environmental disruption (e.g.,
    pets or snoring partner)

-   Establish a "wind-down" routine going to bed and develop and
    maintain bedtime "rituals" that make going to sleep a familiar
    routine; for example:

    -   Setting time to relax before bed with 20-30 minutes of
        relaxation (e.g. soft music, medication, breathing exercises

    -   Take a warm bath

    -   Have a light snack, which could include: warm milk, foods high
        in tryptophan, such as bananas, carbohydrates, which can help
        induce sleep

Adapted from Petit L, et al. Age Ageing 2003; 32: 22. Wilson S. and Nutt
D. Prescriber 2005; 19: 29-41 Wolkove N, et al. CMAJ 2007; 176: 1449-54.

Cognitive and behavioral treatments for sleep difficulties aim to
improve sleep by changing poor sleep habits and challenging negative
thoughts attitudes and beliefs about sleep. (Montgomery P. et al.,
2003). Several cognitive-behavioral interventions exist encompassing a
broad range of treatments, from basic educational information to actual
behavioral strategies. Table 7 lists various types of cognitive
behavioral therapy interventions. It is very likely that combining
several interventions may be required to produce and sustain positive
outcomes.

**Table 7: Other types of Cognitive Behavioral Therapy**~~^\*^~~
[**\[click here to return to algorithm\]**](#Textbox4)

+----+-----+-----+---------+------------------------+----------------+
| ** | *   | *   | **Po    | **Process**            | **Comments**   |
| In | *Pr | *Ra | tential |                        |                |
| te | inc | tio | Candi   |                        |                |
| rv | ipl | nal | dates** |                        |                |
| en | e(s | e(s |         |                        |                |
| ti | )** | )** |         |                        |                |
| on |     |     |         |                        |                |
| ** |     |     |         |                        |                |
+----+-----+-----+---------+------------------------+----------------+
| St | He  | D   | P       | Explain to the patient | For sleep      |
| im | lps | isr | atients | the rationale of each  | onset and      |
| ul | the | upt | that    | principle (see below)  | sleep          |
| us | p   | sle | as      | so the significance of | maintenance    |
| C  | ati | ep- | sociate | each component of the  | insomnia.      |
| on | ent | inc | bedroom | overall treatment is   | Effective for  |
| tr | ass | omp | with    | understood. Instruct   | primary,       |
| ol | oci | ati | other   | the patient on each    | chronic        |
|    | ate | ble | act     | item. Subsequent       | insomnia, and  |
|    | ra  | a   | ivities | sessions are used to   | co-morbid      |
|    | pid | cti | besides | encourage the patient  | insomnia.      |
|    | sl  | vit | s       | to comply with the     | Sleep onset    |
|    | eep | ies | leeping | instructions and to    | latency and    |
|    | on  | by  | (r      | address any new        | wake after     |
|    | set | tr  | eading, | concerns or            | sleep onset    |
|    | w   | ain | w       | difficulties.          | are reduced.   |
|    | ith | ing | atching |                        | Total amount   |
|    | the | the | TV      | 1\. Go to bed only     | sleep is       |
|    | bed | i   | etc.).  | when you feel tired;   | increased.     |
|    | and | ndi | P       |                        | Additional     |
|    | be  | vid | atients | 2\. Use the bed only   | improvements   |
|    | dro | ual | will    | for sleeping and sex.  | can be seen    |
|    | om. | to  | need to | Do not read books,     | when combined  |
|    |     | re  | be      | magazines, watch TV,   | with other     |
|    |     | ass | highly  | or eat while in bed;   | interventions. |
|    |     | oci | mo      |                        | The patient    |
|    |     | ate | tivated | 3\. Leave the bed/room | can be         |
|    |     | the | and     | if you have not fallen | instructed on  |
|    |     | b   | com     | to sleep within 15-20  | this           |
|    |     | ed, | pliant. | minutes and return     | intervention   |
|    |     | b   |         | only when feeling      | by general     |
|    |     | edt |         | sleepy again. Repeat   | practitioner   |
|    |     | ime |         | as often as necessary  | or other       |
|    |     | and |         | through the night;     | trained health |
|    |     | b   |         |                        | care           |
|    |     | edt |         | 4\. Get up at the same | professionals. |
|    |     | ime |         | time each morning      |                |
|    |     | s   |         | regardless of the      |                |
|    |     | tim |         | amount of sleep        |                |
|    |     | uli |         | achieved in the        |                |
|    |     | w   |         | previous night. (use   |                |
|    |     | ith |         | an alarm clock if      |                |
|    |     | sl  |         | necessary);            |                |
|    |     | eep |         |                        |                |
|    |     | rat |         | 5\. Don't sleep during |                |
|    |     | her |         | the day. Avoid napping |                |
|    |     | t   |         |                        |                |
|    |     | han |         | 6\. Correct            |                |
|    |     | w   |         | environmental factors  |                |
|    |     | ith |         | affecting sleep (pets  |                |
|    |     | the |         | or snoring bed         |                |
|    |     | fr  |         | partner); bedroom      |                |
|    |     | ust |         | temperature; alcohol   |                |
|    |     | rat |         | usage; watching the    |                |
|    |     | ion |         | clock.                 |                |
|    |     | or  |         |                        |                |
|    |     | a   |         |                        |                |
|    |     | nxi |         |                        |                |
|    |     | ety |         |                        |                |
|    |     | res |         |                        |                |
|    |     | ult |         |                        |                |
|    |     | ing |         |                        |                |
|    |     | f   |         |                        |                |
|    |     | rom |         |                        |                |
|    |     | ly  |         |                        |                |
|    |     | ing |         |                        |                |
|    |     | in  |         |                        |                |
|    |     | bed |         |                        |                |
|    |     | try |         |                        |                |
|    |     | ing |         |                        |                |
|    |     | to  |         |                        |                |
|    |     | sle |         |                        |                |
|    |     | ep. |         |                        |                |
+----+-----+-----+---------+------------------------+----------------+
| Re | Te  | Re  | P       | Two components have    | Implementation |
| la | ach | duc | atients | been suggested.        | requires       |
| xa | pa  | ing | who     |                        | minimal        |
| ti | tie | le  | develop | 1.  Physical           | provider's     |
| on | nts | vel | a high  |     component:         | time compared  |
| T  | how | of  | level   |     Progressive muscle | to other       |
| he | to  | str | of      |     relaxation:        | interventions. |
| ra | rec | ess | somatic |     Instruct the       | Most           |
| py | ogn | and | arousal |     patient to tense   | relaxation     |
|    | ize | t   | at      |     and relax groups   | therapy can be |
|    | and | ens | night.  |     of muscles, first  | administered   |
|    | dis | ion |         |     separately, then   | by the patient |
|    | sip | w   |         |     with the aim of    | through        |
|    | ate | ill |         |     relaxing the whole | listening      |
|    | str | i   |         |     body at once.      | treatment      |
|    | ess | mpr |         |     Biofeedback can    | verbatim or    |
|    | and | ove |         |     also be included.  | music/sounds   |
|    | te  | sl  |         |                        | on tape. Not   |
|    | nsi | eep |         | 2.  Mental component:  | all relaxation |
|    | on. | d   |         |     Imagery training,  | therapy is     |
|    |     | iff |         |     mediation,         | well supported |
|    |     | icu |         |     hypnosis can also  | in the         |
|    |     | lti |         |     be added.          | literature.    |
|    |     | es. |         |                        |                |
+----+-----+-----+---------+------------------------+----------------+
| C  | Ass | Ide | P       | Therapists must        | Intervention   |
| og | ist | nti | atients | explain the purpose of | is probably    |
| ni | pa  | fyi | with    | cognitive therapy to   | more important |
| ti | tie | ng, | dysfun  | the patient. Faulty    | for older      |
| ve | nts | ch  | ctional | beliefs are identified | insomniacs.    |
| T  | to  | all | beliefs | using tools related to | This           |
| he | id  | eng | and     | beliefs about sleep.   | intervention   |
| ra | ent | ing | em      | Maladaptive beliefs    | usually        |
| py | ify | and | otional | and attitudes are      | requires       |
|    | and | ch  | d       | replaced. Education to | significant    |
|    | cha | ang | istress | change faulty beliefs  | professional   |
|    | lle | ing | that    | and attitudes about    | involvement.   |
|    | nge | a   | results | sleep should take      | It is possible |
|    | t   | set | in      | place (e.g. provision  | that cognitive |
|    | hem | of  | sleep   | the patient with a     | therapy may    |
|    | to  | d   | distur  | fact sheet listing     | need to be     |
|    | cha | ysf | bances. | what is normal and     | m              |
|    | nge | unc | Ex      | abnormal sleep)        | ulti-component |
|    | or  | tio | amples: | Reappraisal and        | therapy for    |
|    | eli | nal | "I have | attention shifting are | best outcomes. |
|    | min | bel | to have | involved.              |                |
|    | ate | ief | 10      |                        |                |
|    | fau | and | hours   |                        |                |
|    | lty | att | of      |                        |                |
|    | b   | itu | sleep   |                        |                |
|    | eli | des | in      |                        |                |
|    | efs | ab  | order   |                        |                |
|    | and | out | to      |                        |                |
|    | att | sl  | fu      |                        |                |
|    | itu | eep | nction" |                        |                |
|    | des | and | and "if |                        |                |
|    | ab  | how | I try   |                        |                |
|    | out | it  | harder  |                        |                |
|    | sle | i   | I will  |                        |                |
|    | ep. | mpa | eve     |                        |                |
|    |     | cts | ntually |                        |                |
|    |     | d   | fall    |                        |                |
|    |     | ay- | a       |                        |                |
|    |     | to- | sleep." |                        |                |
|    |     | day | P       |                        |                |
|    |     | li  | atients |                        |                |
|    |     | fe. | have    |                        |                |
|    |     |     | often   |                        |                |
|    |     |     | been    |                        |                |
|    |     |     | di      |                        |                |
|    |     |     | agnosed |                        |                |
|    |     |     | with    |                        |                |
|    |     |     | ps      |                        |                |
|    |     |     | ychophy |                        |                |
|    |     |     | siology |                        |                |
|    |     |     | i       |                        |                |
|    |     |     | nsomnia |                        |                |
|    |     |     | and     |                        |                |
|    |     |     | their   |                        |                |
|    |     |     | po      |                        |                |
|    |     |     | lysomno |                        |                |
|    |     |     | graphys |                        |                |
|    |     |     | are     |                        |                |
|    |     |     | normal. |                        |                |
+----+-----+-----+---------+------------------------+----------------+
| S  | It  | Li  | P       | Progressive            | Sleep          |
| le | is  | mit | atients | lengthening of sleep   | restriction    |
| ep | be  | the | with    | time after first       | requires less  |
| -R | lie | t   | fra     | improving sleep        | time to        |
| es | ved | ime | gmented | efficiency.            | implement than |
| tr | t   | sp  | (f      |                        | other          |
| ic | hat | ent | requent | 1\. Determine the      | non-p          |
| ti | exc | in  | a       | required average       | harmacological |
| on | ess | bed | rousal) | estimated amount of    | insomnia       |
| T  | ive | at  | sleep   | total sleep based on   | treatments.    |
| he | t   | ni  | p       | patient's diary for    | There is a     |
| ra | ime | ght | atterns | the previous 2 weeks.  | tendency for   |
| py | in  | and | or      |                        | the treatment  |
|    | bed | re  | dif     | 2\. Restrict the time  | results to be  |
|    | cau | str | ficulty | in bed to the average  | long term and  |
|    | ses | ict | falling | estimated total sleep  | there is a     |
|    | f   | sl  | asleep. | time.                  | potential for  |
|    | rag | eep | Older   |                        | excessive      |
|    | men | dur | people, | Example: If a patient  | day-time       |
|    | ted | ing | many of | is in bed for 8 hours  | sleepiness in  |
|    | sl  | the | whom    | but only actually      | older people   |
|    | eep | day | may     | sleeps 6 of them,      | undertaking    |
|    | wh  | t   | have    | their allowed time in  | this therapy.  |
|    | ich | her | tried   | bed would be six       | However, this  |
|    | t   | eby | to      | hours.                 | type of        |
|    | hen | i   | com     |                        | treatment is   |
|    | co  | ncr | pensate | 3\. Each week,         | thought to be  |
|    | ntr | eas | their   | determine the weekly   | effective in   |
|    | ibu | ing | poor    | sleep efficiency from  | older people,  |
|    | tes | the | sleep   | the patient's sleep    | many whom have |
|    | in  | ho  | by      | diary (total           | tried to       |
|    | per | meo | s       | sleep/time in bed x    | compensate for |
|    | pet | sta | pending | 100).                  | poor sleep by  |
|    | uat | tic | more    |                        | spending more  |
|    | ing | dr  | time in | 4\. When sleep         | time in bed.   |
|    | ins | ive | bed.    | efficiency exceeds     |                |
|    | omn | for | P       | 90%, increase the time |                |
|    | ia. | sl  | atients | allowed in bed by      |                |
|    | So, | eep | that    | 15-20 minutes.         |                |
|    | re  | The | wake up | Decrease it by 15-20   |                |
|    | str | t   | fre     | minutes when sleep     |                |
|    | ict | ime | quently | efficiency is below    |                |
|    | ing | sp  | or have | 80%.                   |                |
|    | t   | ent | dif     |                        |                |
|    | ime | in  | ficulty | 5\. Adjust the total   |                |
|    | in  | bed | falling | time in bed weekly     |                |
|    | bed | is  | asleep. | until the expected     |                |
|    | can | l   |         | optimal amount of      |                |
|    | cre | imi |         | sleep time is reached  |                |
|    | ate | ted |         | (i.e. sleep efficiency |                |
|    | a   | to  |         | is between 80-90%).    |                |
|    | m   | the |         |                        |                |
|    | ild | act |         | 6\. Do not reduce time |                |
|    | sl  | ual |         | in bed to below 5      |                |
|    | eep | t   |         | hours.                 |                |
|    | de  | ime |         |                        |                |
|    | pri | sle |         | 7\. Brief midday naps  |                |
|    | vat | epi |         | are permissible,       |                |
|    | ion | ng. |         | especially in the      |                |
|    | and |     |         | early phase of         |                |
|    | p   |     |         | treatment.             |                |
|    | rov |     |         |                        |                |
|    | ide |     |         | 8\. When applying this |                |
|    | a   |     |         | to the elderly, some   |                |
|    | m   |     |         | recommend reducing the |                |
|    | ore |     |         | time in bed only when  |                |
|    | so  |     |         | sleep efficiency is    |                |
|    | lid |     |         | below 75%.             |                |
|    | sle |     |         |                        |                |
|    | ep. |     |         |                        |                |
+----+-----+-----+---------+------------------------+----------------+

Impaired motor and or cognitive performance attributable to the
accumulation of benzodiazepines and their active metabolites following
several days of repeated use at their recommended doses is a concern in
certain vulnerable patients. Benzodiazepines (see Table 8) should be
administered with caution in patient exhibiting signs or symptoms of
depression. The least amount of drug that is feasible should be
prescribed for the patients any one time. Withdrawal symptoms are more
commonly noted after the discontinuation of higher than therapeutic
doses of benzodiazepines. Gradual withdrawal is the preferred course for
any patient taking benzodiazepines for a prolonged period. Patients with
a history of seizures, regardless of their concomitant antiseizure drug
therapy, should not be withdrawn abruptly from benzodiazepines.
Individuals with a history of addiction to or abuse of drugs or alcohol
should be under careful surveillance when receiving benzodiazepines
because of the risk of habituation and dependence to such patients.
Benzodiazepines should be given caution if given concomitantly with
other drugs acting on the central nervous system.

**Table 8: Comparison of Select Oral VA Benzodiazepine Formulary Agents
(graded area) to other Non-VA Formulary Oral Benzodiazepine Agents**

**More Commonly Prescribed to Treat Insomnia in U.S. [\[Click here to
return to algorithm\]](#Textbox2)**

+----+----+---+---+---+--------+--------------------------------------+
| ** | ** | * | * | * | **M    | **Comments**                         |
| Ag | Ti | * | * | * | etabol |                                      |
| en | me | P | E | P | ism/** |                                      |
| ts | u  | e | l | r |        |                                      |
| ** | nt | a | i | o | **     |                                      |
|    | il | k | m | t | Active |                                      |
|    | O  | T | i | e | M      |                                      |
|    | ns | i | n | i | etabol |                                      |
|    | et | m | a | n | ites** |                                      |
|    | of | e | t | * |        |                                      |
|    | A  | , | i | * |        |                                      |
|    | ct | ( | o |   |        |                                      |
|    | io | h | n | * |        |                                      |
|    | n, | ) | T | * |        |                                      |
|    | (  | * | 1 | B |        |                                      |
|    | mi | * | / | i |        |                                      |
|    | n) |   | 2 | n |        |                                      |
|    | ** |   | * | d |        |                                      |
|    |    |   | * | i |        |                                      |
|    |    |   |   | n |        |                                      |
|    |    |   | * | g |        |                                      |
|    |    |   | * | ( |        |                                      |
|    |    |   | ( | % |        |                                      |
|    |    |   | r | ) |        |                                      |
|    |    |   | a | * |        |                                      |
|    |    |   | n | * |        |                                      |
|    |    |   | g |   |        |                                      |
|    |    |   | e |   |        |                                      |
|    |    |   | , |   |        |                                      |
|    |    |   | h |   |        |                                      |
|    |    |   | ) |   |        |                                      |
|    |    |   | * |   |        |                                      |
|    |    |   | * |   |        |                                      |
+----+----+---+---+---+--------+--------------------------------------+
| *  |    |   |   |   |        |                                      |
| ** |    |   |   |   |        |                                      |
| Sh |    |   |   |   |        |                                      |
| or |    |   |   |   |        |                                      |
| t- |    |   |   |   |        |                                      |
| Ac |    |   |   |   |        |                                      |
| ti |    |   |   |   |        |                                      |
| ng |    |   |   |   |        |                                      |
| (h |    |   |   |   |        |                                      |
| al |    |   |   |   |        |                                      |
| f- |    |   |   |   |        |                                      |
| li |    |   |   |   |        |                                      |
| fe |    |   |   |   |        |                                      |
| \< |    |   |   |   |        |                                      |
| 10 |    |   |   |   |        |                                      |
| h  |    |   |   |   |        |                                      |
| )* |    |   |   |   |        |                                      |
| ** |    |   |   |   |        |                                      |
+----+----+---+---+---+--------+--------------------------------------+
| o  | 30 | 2 | 5 | 8 | CYP450 | -   15mg capsule contains FD&C       |
| xa | -6 | - | . | 0 | (sub   |     Yellow 5 (tartrazine) which may  |
| ze | 0^ | 4 | 7 | ^ | strate |     cause allergic-type reaction in  |
| pa | a^ | ^ | - | d | unkno  |     certain susceptible individuals. |
| m† |    | b | 1 | ^ | wn)/No |                                      |
|    |    | , | 0 | - |        | -   Caution in patients in whom a    |
|    |    | e | ^ | 8 |        |     drop in blood pressure might     |
|    |    | ^ | b | 7 |        |     lead to cardiac complications.   |
|    |    |   | , | ^ |        |                                      |
|    |    |   | f | b |        | -   Increase in elimination          |
|    |    |   | ^ | ^ |        |     half-life in the very elderly    |
|    |    |   |   |   |        |     (\>80 years of age) compared to  |
|    |    |   | 2 |   |        |     younger subjects has been        |
|    |    |   | . |   |        |     reported, due to a 30% increase  |
|    |    |   | 8 |   |        |     in volume of distribution, as    |
|    |    |   | - |   |        |     well as a 50% reduction in       |
|    |    |   | 5 |   |        |     unbound clearance.               |
|    |    |   | . |   |        |                                      |
|    |    |   | 7 |   |        |                                      |
|    |    |   | ^ |   |        |                                      |
|    |    |   | a |   |        |                                      |
|    |    |   | ^ |   |        |                                      |
|    |    |   |   |   |        |                                      |
|    |    |   | 5 |   |        |                                      |
|    |    |   | - |   |        |                                      |
|    |    |   | 2 |   |        |                                      |
|    |    |   | 0 |   |        |                                      |
|    |    |   | ^ |   |        |                                      |
|    |    |   | b |   |        |                                      |
|    |    |   | , |   |        |                                      |
|    |    |   | d |   |        |                                      |
|    |    |   | ^ |   |        |                                      |
+----+----+---+---+---+--------+--------------------------------------+
| t  | 45 | 1 | 3 | 9 | Not    | -   Indicated for the short-term     |
| em | -6 | . | - | 6 | subj   |     treatment of insomnia (generally |
| az | 0^ | 2 | 2 | ^ | ective |     7-10 days). For patients in whom |
| ep | a^ | ^ | 5 | 2 | to     |     the drug is used for more than 2 |
| am |    | e | ^ | ^ | met    |     to 3 weeks, periodic             |
| \* |    | ^ | a |   | abolic |     reevaluation is recommended to   |
|    |    | - | ^ |   | inhi   |     determine whether there is a     |
|    |    | 1 |   |   | bition |     continuing need.^b^              |
|    |    | . | 3 |   | by CYP |                                      |
|    |    | 6 | . |   | enzyme | -   Dose should be individualized.   |
|    |    | ^ | 5 |   | inhi   |     For adults: Give 15-30mg before  |
|    |    | b | - |   | bitors |     bedtime; 7.5mg may be sufficient |
|    |    | ^ | 1 |   | or     |     for some. For elderly or         |
|    |    |   | 8 |   | induc  |     debilitated patients: Initiate   |
|    |    |   | . |   | ers/No |     with 7.5mg-15mg until individual |
|    |    |   | 4 |   |        |     response is determined.          |
|    |    |   | ^ |   |        |                                      |
|    |    |   | b |   |        | -   The usual precaution should be   |
|    |    |   | ^ |   |        |     observed in patients with        |
|    |    |   |   |   |        |     impaired renal or hepatic        |
|    |    |   |   |   |        |     function. Use caution in         |
|    |    |   |   |   |        |     severely depressed patients or   |
|    |    |   |   |   |        |     those in whom there is any       |
|    |    |   |   |   |        |     evidence of latent depression    |
+----+----+---+---+---+--------+--------------------------------------+
| t  | 15 | 1 | 1 | 8 | CYP    | -   Indicated for the short-term     |
| ri | -3 | . | . | 9 | 3A4/No |     treatment of insomnia (generally |
| az | 0^ | 3 | 5 | ^ |        |     7-10days). Use for more than 2-3 |
| ol | a^ | ^ | - | g |        |     weeks requires complete          |
| am |    | e | 5 | ^ |        |     reevaluation of the patients.    |
| \* |    | ^ | ^ |   |        |                                      |
|    |    |   | g | 7 |        | -   Use caution in elderly patients  |
|    |    | 1 | , | 8 |        |     and patients with renal or       |
|    |    | - | h | - |        |     hepatic impairment, depression   |
|    |    | 2 | ^ | 8 |        |     or suicidal tendencies, drug     |
|    |    | ^ |   | 9 |        |     abuse and dependence, chronic    |
|    |    | b |   | ^ |        |     pulmonary insufficiency or       |
|    |    | ^ |   | d |        |     apnea, seizure disorder.         |
|    |    |   |   | , |        |                                      |
|    |    | 2 |   | , |        |                                      |
|    |    | - |   | b |        |                                      |
|    |    | 3 |   | ^ |        |                                      |
|    |    | ^ |   |   |        |                                      |
|    |    | c |   |   |        |                                      |
|    |    | ^ |   |   |        |                                      |
+----+----+---+---+---+--------+--------------------------------------+
| ** |    |   |   |   |        |                                      |
| *I |    |   |   |   |        |                                      |
| nt |    |   |   |   |        |                                      |
| er |    |   |   |   |        |                                      |
| me |    |   |   |   |        |                                      |
| di |    |   |   |   |        |                                      |
| at |    |   |   |   |        |                                      |
| e- |    |   |   |   |        |                                      |
| ac |    |   |   |   |        |                                      |
| ti |    |   |   |   |        |                                      |
| ng |    |   |   |   |        |                                      |
| (h |    |   |   |   |        |                                      |
| al |    |   |   |   |        |                                      |
| f- |    |   |   |   |        |                                      |
| li |    |   |   |   |        |                                      |
| fe |    |   |   |   |        |                                      |
| 1  |    |   |   |   |        |                                      |
| 0- |    |   |   |   |        |                                      |
| 20 |    |   |   |   |        |                                      |
| h  |    |   |   |   |        |                                      |
| )* |    |   |   |   |        |                                      |
| ** |    |   |   |   |        |                                      |
+----+----+---+---+---+--------+--------------------------------------+
| a  | N  | 1 | 6 | 7 | CYP3A4 | -   Contraindicated in patients with |
| lp | /A | - | . | 0 | and    |     acute narrow angle glaucoma.     |
| ra |    | 2 | 3 | ^ | 3A5a/  |                                      |
| zo |    | ^ | - | a | Yes    | -   Abrupt discontinuation should be |
| la |    | b | 2 | ^ |        |     avoided. Dosage should be        |
| m† |    | , | 6 | - | (al    |     limited to the smallest          |
|    |    | d | . | 8 | though |     effective dose in the elderly or |
|    |    | ^ | 9 | 0 | not    |     debilitated patients.            |
|    |    |   | ^ | ^ | suffic |                                      |
|    |    |   | b | b | iently | ```{=html}                           |
|    |    |   | ^ | , | high   | <!-- -->                             |
|    |    |   |   | d | co     | ```                                  |
|    |    |   | 1 | ^ | ncentr | -   An increased plasma half-life    |
|    |    |   | 2 |   | ations |     has been observed in both        |
|    |    |   | - |   | to be  |     alcoholic liver disease patients |
|    |    |   | 1 |   | of     |     and obese patients.              |
|    |    |   | 5 |   | cl     |                                      |
|    |    |   | ^ |   | inical | -   Concentrations may be reduced by |
|    |    |   | d |   | impor  |     up to 50% in smokers compared to |
|    |    |   | ^ |   | tance) |     non-smokers                      |
|    |    |   |   |   | ^g^    |                                      |
+----+----+---+---+---+--------+--------------------------------------+
| e  | 15 | 2 | 8 | 9 | CYP3A4 | -   Indicated for the short-term     |
| st | -3 | ^ | - | 3 | /Yes   |     management of insomnia           |
| az | 0^ | b | 2 | ^ |        |     characterized by difficulty in   |
| ol | a^ | ^ | 4 | b | (al    |     falling asleep, frequent         |
| am |    | - | ^ | ^ | though |     nocturnal awakenings, and/or     |
| \* |    | - | a |   | no     |     early morning awakenings.        |
|    |    | 3 | ^ |   | signi  |                                      |
|    |    | ^ |   |   | ficant | -   Recommended initial dose for     |
|    |    | e | 8 |   | contri |     adults is 1 mg at bedtime. In    |
|    |    | ^ | - |   | bution |     small or debilitated older       |
|    |    |   | 2 |   | to the |     patients, a starting dose of     |
|    |    |   | 8 |   | hy     |     0.5mg-1mg^b^ should be           |
|    |    |   | ^ |   | pnotic |     considered.                      |
|    |    |   | b |   | effect |                                      |
|    |    |   | ^ |   | is     | -   Closely related in structure to  |
|    |    |   |   |   | not    |     alprazolam and triazolam         |
|    |    |   |   |   | ed)^g^ |                                      |
+----+----+---+---+---+--------+--------------------------------------+
| lo | 30 | 2 | 1 | 8 | CYP450 | -   Not recommended for use in       |
| ra | -6 | ^ | 0 | 5 | (sub   |     patients with a primary          |
| ze | 0^ | e | - | ^ | strate |     depressive disorder or           |
| pa | a^ | ^ | 2 | b | unkno  |     psychosis.                       |
| m† |    | - | 0 | , | wn)/No |                                      |
|    |    | 4 | ^ | d |        | -   Observe the usual precaution for |
|    |    | ^ | b | ^ |        |     treating patients with impaired  |
|    |    | b | , |   |        |     renal or hepatic function. Used  |
|    |    | , | d |   |        |     in caution in patients with      |
|    |    | d | ^ |   |        |     compromised respiratory function |
|    |    | ^ |   |   |        |     (e.g. COPD, sleep apnea          |
|    |    |   |   |   |        |     syndrome)                        |
+----+----+---+---+---+--------+--------------------------------------+
| ** |    |   |   |   |        |                                      |
| *L |    |   |   |   |        |                                      |
| on |    |   |   |   |        |                                      |
| g- |    |   |   |   |        |                                      |
| ac |    |   |   |   |        |                                      |
| ti |    |   |   |   |        |                                      |
| ng |    |   |   |   |        |                                      |
| (h |    |   |   |   |        |                                      |
| al |    |   |   |   |        |                                      |
| f- |    |   |   |   |        |                                      |
| li |    |   |   |   |        |                                      |
| fe |    |   |   |   |        |                                      |
| \> |    |   |   |   |        |                                      |
| 20 |    |   |   |   |        |                                      |
| h  |    |   |   |   |        |                                      |
| )* |    |   |   |   |        |                                      |
| ** |    |   |   |   |        |                                      |
+----+----+---+---+---+--------+--------------------------------------+
| qu | 20 | 2 | 3 | 9 | CYP3A4 | -   Selectively binds to BZ1         |
| az | -4 | ^ | 6 | 5 | and    |     receptor                         |
| ep | 5^ | b | ^ | ^ | C      |                                      |
| am | a^ | ^ | g | b | YP2C9/ | -   Indicated for the treatment of   |
| \* |    |   | ^ | ^ | Yes    |     insomnia characterized by        |
|    |    | 2 |   |   |        |     difficulty in falling asleep,    |
|    |    | . | 3 |   |        |     frequent nocturnal awakenings,   |
|    |    | 5 | 9 |   |        |     or early morning awakenings.     |
|    |    | ^ | ^ |   |        |                                      |
|    |    | e | b |   |        | -   Initiate therapy at 15mg until   |
|    |    | ^ | ^ |   |        |     individual responses are         |
|    |    |   |   |   |        |     determined. In some patients,    |
|    |    |   |   |   |        |     the dose may then be reduced to  |
|    |    |   |   |   |        |     7.5mg. Initiate therapy in       |
|    |    |   |   |   |        |     geriatric patients at 7.5mg; if  |
|    |    |   |   |   |        |     not effective after 1 to 2       |
|    |    |   |   |   |        |     nights, dosage may be increased  |
|    |    |   |   |   |        |     to 15mg.                         |
+----+----+---+---+---+--------+--------------------------------------+

† off-label use; \*FDA-approved as sedative hypnotics; CYP450 =
Cytochrome P450; NA = Not available. a. N Engl J Med 1997; 336:341-46.
b. Facts and Comparison 4.0; 2007. \[Accessed October 24, 2007\]. c.
Drug Intell Clin Pharm 1982; 16:650-6. d. J Clin Pharmacol 1994;
34:801-811.

e\. J Clin Psychiatry 2005; 66 Suppl 9: 31-41.f. Available at
[www.rxlist.com/cgi/generic/oxazepam_cp.htm](http://www.rxlist.com/cgi/generic/oxazepam_cp.htm)
(Accessed October 24, 2007). g. Psychopharmacology Bulletin 2003;
37:10-29.

**Table 9: Comparison of VA Formulary Agent Zolpidem (graded area) to
other Non-VA Formulary Newer Sedative-Hypnotic Agents [\[Click here to
return to algorithm\]](#Textbox2)**

+-------+-----------+-------------+-----------+------------+----------+
|       | Zolpidem  | Zolpidem    | Zaleplon\ | Es         | Rame     |
|       | IR\       | ER\         | (Sonata)  | zopiclone\ | lteon\*\ |
|       | (Ambien)  | (Ambien CR) |           | (Lunesta)  | (        |
|       |           |             |           |            | Rozerem) |
+-------+-----------+-------------+-----------+------------+----------+
| **S   | 5, 10 mg  | 6.25, 12.5  | 5, 10 mg  | 1, 2, 3 mg | 8 mg     |
| treng |           | mg          |           |            |          |
| ths** |           |             |           |            |          |
+-------+-----------+-------------+-----------+------------+----------+
| **In  | 10 mg     | 12.5 mg     | 10 mg     | 2 mg       | 8 mg     |
| itial | im        | immediately | im        | i          | within   |
| Dose\ | mediately | before      | mediately | mmediately | 30       |
| (non- | before    | bedtime; do | before    | before     | minutes  |
| elder | bedtime   | not crush,  | bedtime   | bedtime;   | of       |
| ly)** |           | divide or   | OR after  | must be    | bedtime  |
|       |           | chew        | patient   | able to    |          |
|       |           |             | has had   | get 8 or   |          |
|       |           |             | d         | more hours |          |
|       |           |             | ifficulty | of sleep   |          |
|       |           |             | falling   |            |          |
|       |           |             | asleep    |            |          |
+-------+-----------+-------------+-----------+------------+----------+
| **Ma  | 10 mg     | 12.5 mg     | May       | Can        | 8 mg     |
| ximum |           |             | titrate   | titrate to |          |
| D     |           |             | to max of | max dose   |          |
| ose** |           |             | 20 mg if  | of 3 mg    |          |
|       |           |             | no        |            |          |
|       |           |             | benefit   |            |          |
|       |           |             | from      |            |          |
|       |           |             | lower     |            |          |
|       |           |             | dose      |            |          |
+-------+-----------+-------------+-----------+------------+----------+
| *     | For       | For faster  | Effects   | Effects on | Do not   |
| *Food | faster    | onset do    | may be    | sleep      | take     |
| C     | onset, do | not give    | reduced   | latency    | with or  |
| onsid | not give  | with or     | if taken  | may be     | imm      |
| erati | with or   | immediately | with or   | reduced if | ediately |
| ons** | im        | after a     | im        | taken      | after a  |
|       | mediately | meal.       | mediately | i          | high-fat |
|       | after a   |             | after a   | mmediately | meal     |
|       | meal      |             | heavy     | after/with |          |
|       |           |             | /high-fat | a          |          |
|       |           |             | meal      | heav       |          |
|       |           |             |           | y/high-fat |          |
|       |           |             |           | meal       |          |
+-------+-----------+-------------+-----------+------------+----------+
| *     | Elderly,  | Elderly,    | Reduce    | 1 mg       | No dose  |
| *Dose | de        | debilitated | dose to 5 | starting   | ad       |
| a     | bilitated | or patients | mg in     | dose in    | justment |
| djust | or        | with        | mild to   | severe     | for      |
| ments | patients  | hepatic     | moderate  | hepatic    | elderly; |
| in    | with      | impairment  | hepatic   | i          | do not   |
| sp    | hepatic   | should      | im        | mpairment. | use in   |
| ecial | i         | start with  | pairment, | In         | severe   |
| pop   | mpairment | 6.25 mg,    | do not    | patients   | hepatic  |
| ulati | should    | may titrate | use in    | taking     | imp      |
| ons** | start     | to 12.5 mg  | severe    | potent     | airment; |
|       | with 5    |             | hepatic   | CYP3A4     | use with |
|       | mg, may   |             | im        | i          | caution  |
|       | titrate   |             | pairment. | nhibitors, | in       |
|       | to        |             | Start     | start with | moderate |
|       |           |             | elderly / | 1 mg; do   | hepatic  |
|       | 10 mg     |             | de        | not exceed | im       |
|       |           |             | bilitated | 2 mg.      | pairment |
|       |           |             | patients  |            |          |
|       |           |             | at 5 mg;  |            |          |
|       |           |             | doses \>  |            |          |
|       |           |             | 10 mg not |            |          |
|       |           |             | rec       |            |          |
|       |           |             | ommended; |            |          |
|       |           |             | start at  |            |          |
|       |           |             | 5 mg when |            |          |
|       |           |             | given     |            |          |
|       |           |             | with      |            |          |
|       |           |             | c         |            |          |
|       |           |             | imetidine |            |          |
+-------+-----------+-------------+-----------+------------+----------+

\* hypnotic only. DoD Drug Class Review - Newer Sedative Hypnotics.
Prepared by DoD Pharmacoeconomic Center for the Feb 07 meeting of the
DoD Pharmacy & Therapeutics Committee.

**Table 10: Pharmacokinetics of VA Formulary Agent Zolpidem IR (graded
area) to other Non-VA Formulary Newer Sedative-Hypnotic Agents**

[**\[Click here to return to algorithm\]**](#Textbox2)

  ------------- ----------------- ------ --------- ----------------- ------------------- --------------------------
  Drug          Estimated         Tmax   Plasma    Bioavailability   Metabolism /        Comments
                half-life (hr)\*  (hr)   protein                     Elimination         
                                         binding                                         

  Zolpidem IR   2.5               1.6    92.5%     70%               Primarily renal     No active metabolites.
                                                                     excretion           Olubudon et al (2003)†
                                                                                         reported substantial
                                                                                         decreases in clearance in
                                                                                         the elderly, particularly
                                                                                         elderly men; possible
                                                                                         relation to levels of free
                                                                                         testosterone, which is
                                                                                         known to affect the CYP450
                                                                                         system

  Zolpidem ER   2.8               1.5    92.5%                       Primarily renal     No active metabolites
                                                                     excretion           

  Zaleplon      1                 1      \~60%     30% (due to rapid Primarily           Significant first pass
                                                   first pass        metabolized by      hepatic metabolism; no
                                                   metabolism)       aldehyde oxidase,   active metabolites
                                                                     to a lesser extent  
                                                                     by P450 3A4; mostly 
                                                                     renal excretion     
                                                                     (71%) as            
                                                                     metabolites; 17% in 
                                                                     feces as metabolite 

  Eszopiclone   6 (non-elderly);\ 1      52-59%    80%               Hepatic metabolism  No active metabolites;
                9 (elderly                                           (P450 3A4 and 2E1); does not appear to
                                                                     primarily renal     interconvert to (R)
                                                                     excretion as        zopiclone; AUC increases
                                                                     metabolites         by 41% in elderly (≥ 65
                                                                                         years)

  Ramelteon\*   1 - 2.6\          45 min 82%,      1.8% (due to      Metabolism          Significant first pass
                (M-II metabolite         mostly to rapid first pass  primarily via       metabolism; high
                2-5)                     albumin   metabolism)       oxidation; major    intersubject variability;
                                                                     hepatic isoenzyme   major metabolite (M-II) is
                                                                     1A2, also 2C, 3A4;  active but has
                                                                     primarily renal     substantially less
                                                                     excretion; the      affinity for MT~1~ and
                                                                     major metabolite    MT~2~; M-II has weak
                                                                     (M-II) is rapidly   affinity for serotonin
                                                                     produced, with a    5-HT~2B~, but no other
                                                                     systemic exposure   receptor types.
                                                                     20-40-fold higher   
                                                                     than parent drug.   
  ------------- ----------------- ------ --------- ----------------- ------------------- --------------------------

\* hypnotic only. DoD Drug Class Review - Newer Sedative Hypnotics.
Prepared by DoD Pharmacoeconomic Center for the Feb 07 meeting of the
DoD Pharmacy & Therapeutics Committee.

† Olubudon JO, Ochs HR, von Moltke LL, et al. Pharmacokinetic properties
of zolpidem in elderly and young adults: possible modulation by
testosterone in men. Br J Clin Pharmacol 2003; 56:297-304.

**Table 11: Special Considerations for the Use of Newer Sedative
Hypnotic Agents [\[Click here to return to algorithm\]](#Textbox2)**

  ------------------------------------------------------------------------------------------------------------------
                          Zolpidem IR†\    Zolpidem ER\       Zaleplon\           Eszopiclone\    Ramelteon\*\
                          (Ambien)         (Ambien CR)        (Sonata)            (Lunesta)       (Rozerem)
  ----------------------- ---------------- ------------------ ------------------- --------------- ------------------
  **Contraindications**   None known       Hypersensitivity   Hypersensitivity    None known      Hypersensitivity

  **Pediatric patients**  Safety &         Safety & efficacy  Safety & efficacy   Safety &        Not studied;
                          efficacy not     not established    not established     efficacy not    associated with
                          established                                             established     decreases in
                                                                                                  testosterone
                                                                                                  levels and
                                                                                                  increases in
                                                                                                  prolactin levels
                                                                                                  in adults; effect
                                                                                                  on reproductive
                                                                                                  axis in children &
                                                                                                  adolescents
                                                                                                  unknown

  **Elderly patients**    Cmax, half-life, Data limited;      PK similar to       Total exposure  Total exposure and
                          total exposure   reduce dose        non-elderly, reduce increased &     Cmax higher in
                          significantly                       dose because appear half-life       elderly patients;
                          increased;                          more sensitive to   prolonged in    no dose adjustment
                          reduce dose.                        effects; adverse    elderly, adjust recommended; no
                          Reports of                          effects similar to  dose; pattern   overall
                          falls, confusion                    placebo in          of adverse      differences in
                          among patients ≥                    short-term trials   effects in      safety or efficacy
                          70 years,                           (14 nights)         2-week studies  noted in clinical
                          primarily with                                          at 2-mg dose    trials
                          doses \>10 mg                                           not different   
                                                                                  from            
                                                                                  non-elderly pts 

  **Race / gender**       No differences   No differences     Cmax and AUC        No differences  No gender
                          noted based on   noted based on     increased in Asian  noted based on  differences noted
                          race or gender   race or gender     populations         race or gender  

  **Pregnancy &           Pregnancy        Pregnancy Category Pregnancy Category  Pregnancy       Pregnancy Category
  Lactation**             Category C;      C; small amounts   C; small amounts in Category C; not C; not known if
                          small amounts in in breast milk;    breast milk         known if        excreted in breast
                          breast milk;     inhibited breast   (unlikely to be     excreted in     milk; not
                          inhibited breast milk production in clinically          breast milk;    recommended while
                          milk production  rat study; not     important \[Darwish not recommended breastfeeding
                          in rat study;    recommended while  1999^126^\]); not   while           
                          not recommended  breastfeeding      recommended while   breastfeeding   
                          while                               breastfeeding                       
                          breastfeeding                                                           

  **Renal impairment**    PK not altered;  ER formulation not PK not altered; no  PK not altered  PK not altered; no
                          no dose          studied; should be dose adjustment;    in mild, mod,   dose adjustment
                          adjustment       similar to IR      not studied in      severe renal    needed even in
                                                              severe renal        impairment; no  dialysis patients
                                                              impairment          dose adjustment 
                                                                                  needed          

  **Hepatic impairment**  Cmax 2-fold      ER formulation not Clearance reduced   Use with        Exposure increased
                          higher; total    studied; should be in compensated &    caution; total  almost 4-fold with
                          exposure 5-fold  similar to IR      non-compensated     exposure        mild hepatic
                          higher in                           cirrhotic pts;      doubled in      impairment; more
                          hepatic                             reduce dose in mild severe hepatic  with moderate. Use
                          impairment; mean                    to moderate hepatic impairment;     with caution in
                          half-life of 9.9                    impairment; do not  reduce dose; no moderate hepatic
                          hours in                            use in severe       dose adjustment impairment; do not
                          cirrhotic pts;                                          in mild to      use in severe
                          adjust dose                                             moderate        

  **Psychiatric           Use with caution Use with caution   Use with caution in Use with        
  patients**              in depressed     in depressed       depressed patients, caution in      
                          patients,        patients,          intentional         depressed       
                          intentional      intentional        overdose more       patients,       
                          overdose more    overdose more      common              intentional     
                          common           common                                 overdose more   
                                                                                  common          

  **Other**               No respiratory   Data in patients   Contains FD&C                       1-night trial in
                          depressant       with comorbid      Yellow No 5                         COPD patients
                          effects in with  illnesses limited; (tartrazine), which                 showed no
                          mild to moderate precautions        is rarely                           respiratory
                          COPD; however,   similar to IR      associated with                     depressant effect;
                          reduction in                        allergic type                       1-night trial in
                          Total Arousal                       reactions (more                     sleep apnea showed
                          Index and oxygen                    common in patients                  no exacerbation in
                          saturation in                       who also have                       mild to moderate
                          patients with                       aspirin                             sleep apnea. Not
                          mild to moderate                    hypersensitivity)                   studied and
                          sleep apnea;                                                            therefore not
                          precautions with                                                        recommended in
                          compromised                                                             severe sleep apnea
                          respiratory                                                             or severe COPD
                          function;                                                               
                          post-marketing                                                          
                          reports of                                                              
                          respiratory                                                             
                          insufficiency                                                           
  ------------------------------------------------------------------------------------------------------------------

†zolpidem-only agent listed on this table that resides on VA National
Formulary \* hypnotic only. DoD Drug Class Review - Newer Sedative
Hypnotics. Prepared by DoD Pharmacoeconomic Center for the Feb 07
meeting of the DoD Pharmacy & Therapeutics Committee

Table 12: Drug Interactions of Newer Sedative Hypnotic\* Agents
(primarily based on labeling)

[\[Click here to return to algorithm\]](#Textbox2)

+----------------+-------+---+------------------------------------------+
| **Drug Causing | *     |   | **Description**                          |
| Effect**       | *Drug |   |                                          |
|                | Affec |   |                                          |
|                | ted** |   |                                          |
+================+=======+===+==========================================+
| Ketoconazole   | Es    | * | *Eszopiclone* - Ketoconazole, a potent   |
| (& other       | zopic | * | 3A4 inhibitor, increased systemic        |
| potent 3A4     | lone, | ↑ | bioavailability of eszopiclone by 2.2    |
| inhibitors:    | zale  | * | fold                                     |
| itraconazole,  | plon, | * |                                          |
| c              | ramel |   | *Zaleplon* - Erythromycin, a potent 3A4  |
| larithromycin, | teon, |   | inhibitor, increased maximum             |
| t              | zol   |   | concentrations of zaleplon by 34%, AUC   |
| roleandomycin, | pidem |   | by 20%; 3A4 is a minor pathway for       |
| nefazodone,    |       |   | zaleplon metabolism; routine dose        |
| ritonavir,     |       |   | adjustment not considered necessary      |
| nelfinavir)    |       |   |                                          |
|                |       |   | *Ramelteon* -- Ketoconazole increased    |
|                |       |   | total exposure of ramelteon by 84% and   |
|                |       |   | Cmax by 36%; use with caution            |
|                |       |   |                                          |
|                |       |   | *Zolpidem* -- Itraconazole increased     |
|                |       |   | total exposure of zolpidem by 34%; no    |
|                |       |   | effect on drowsiness, postural sway,     |
|                |       |   | psychomotor performance                  |
+----------------+-------+---+------------------------------------------+
| Rifampin (&    | Es    | * | *Eszopiclone* - Rifampicin, a potent     |
| other potent   | zopic | * | inducer of CYP450 3A4, decreased         |
| 3A4 and        | lone, | ↓ | exposure to racemic zopiclone by 80%;    |
| general CYP    | zale  | * | may also occur with eszopiclone          |
| P450 inducers: | plon, | * |                                          |
| phenytoin,     | ramel |   | *Zaleplon* - Rifampin decreased exposure |
| carbamazepine, | teon, |   | to zaleplon by about 80%; however, 3A4   |
| phenobarbital) | zol   |   | is a minor pathway for zaleplon          |
|                | pidem |   | metabolism                               |
|                |       |   |                                          |
|                |       |   | *Ramelteon* -- Rifampin decreased total  |
|                |       |   | exposure to ramelteon by about 80% after |
|                |       |   | a 32 mg dose                             |
|                |       |   |                                          |
|                |       |   | Zolpidem -- Rifampin decreased total     |
|                |       |   | exposure 73%, Cmax 58%, half-life (36%)  |
|                |       |   | and decreased pharmacodynamic effects    |
+----------------+-------+---+------------------------------------------+
| Alcohol        | Es    |   | No PK interaction; additive but not      |
|                | zopic |   | synergistic effect on psychomotor        |
|                | lone, |   | performance                              |
|                | zale  |   |                                          |
|                | plon, |   |                                          |
|                | ramel |   |                                          |
|                | teon, |   |                                          |
|                | zol   |   |                                          |
|                | pidem |   |                                          |
+----------------+-------+---+------------------------------------------+
| Olanzapine     | E     |   | Impairment of psychomotor performance    |
|                | szopi |   | upon coadministration                    |
|                | clone |   |                                          |
+----------------+-------+---+------------------------------------------+
| Thioridazine   | Zal   |   | Impairment of psychomotor performance    |
|                | eplon |   | upon coadministration^a^                 |
+----------------+-------+---+------------------------------------------+
| Promethazine   | Zal   | * | Decreased maximum concentrations of      |
|                | eplon | * | zaleplon by 15%; no information on       |
|                |       | ↓ | pharmacodynamic effects, use caution     |
|                |       | * |                                          |
|                |       | * |                                          |
+----------------+-------+---+------------------------------------------+
| Drugs          | Zal   |   | No PK interaction after single dose;     |
| inhibiting     | eplon |   | pharmacodynamic effect possible          |
| aldehyde       |       |   |                                          |
| oxidase        |       |   |                                          |
| (di            |       |   |                                          |
| phenhydramine) |       |   |                                          |
+----------------+-------+---+------------------------------------------+
| Drugs          | Zal   | * | Inhibits both metabolic pathways,        |
| inhibiting     | eplon | * | increases mean concentrations by about   |
| aldehyde       |       | ↑ | 85%, reduce initial dose                 |
| oxidase and    |       | * |                                          |
| 3A4            |       | * |                                          |
| (cimetidine)   |       |   |                                          |
+----------------+-------+---+------------------------------------------+
| Drugs          | Rame  | * | Fluvoxamine 100 mg BID for 3 days prior  |
| inhibiting 1A2 | lteon | * | to a single 16 mg dose of ramelteon      |
| (fluvoxamine)  |       | ↑ | increased AUC by 190-fold and Cmax by    |
|                |       | * | 70-fold. Do not give with fluvoxamine.   |
|                |       | * |                                          |
+----------------+-------+---+------------------------------------------+
| 1A2 inducers   | Rame  | * | Smoking induces 1A2 and may decrease     |
| (e.g.,         | lteon | * | efficacy of ramelteon                    |
| smoking)       |       | ↓ |                                          |
|                |       | * |                                          |
|                |       | * |                                          |
+----------------+-------+---+------------------------------------------+
| Imipramine     | Zol   |   | Decreased alertness                      |
|                | pidem |   |                                          |
+----------------+-------+---+------------------------------------------+
| Chlorpromazine | Zol   |   | Decreased alertness and psychomotor      |
|                | pidem |   | performance                              |
+----------------+-------+---+------------------------------------------+
| Sertraline     | Zol   | * | Increased zolpidem Cmax by 43% and       |
|                | pidem | * | decreased Tmax by 53%^b^                 |
|                |       | ↑ |                                          |
|                |       | * |                                          |
|                |       | * |                                          |
+----------------+-------+---+------------------------------------------+

Ramelteon-hypnotic only. DoD Drug Class Review - Newer Sedative
Hypnotics. Prepared by DoD Pharmacoeconomic Center for the Feb 07
meeting of the DoD Pharmacy & Therapeutics Committee.

^a^Hetta J, Broman JE, Darwich M, et al. Psychomotor effects of zaleplon
and thioridazine coadministration. Eur J Clin Pharmacol 2000; 56:211-17.

^b^Allard S, Sainati SM, Roth-Schechter BF. Coadministration of
short-term zolpidem with sertraline in healthy women. J Clin Pharmacol
1999; 39:184-191.

**Recommendation for Use: Zolpidem Immediate Release (IR)**

**VHA Pharmacy Benefits Management Service and Medical Advisory Panel**

*The following recommendations are based on current medical evidence.
The content of the document is dynamic and will be revised as new
clinical data become available. The purpose of this document is to
assist practitioners in clinical decision making, to standardize and
improve the quality of patient care, and to promote cost-effective drug
prescribing. The clinician, however, must make the ultimate judgment
regarding the propriety of any course of treatment in light of
individual patient situations.*

+-----------------------------------------------------------------------+
| **EXCLUSION RECOMMENDATIONS**                                         |
+-----------------------------------------------------------------------+
| -   Patients with alcohol abuse or dependence or active use of        |
|     illicit drugs                                                     |
|                                                                       |
| -   No attempts or consideration has been made and documented of      |
|     contributing co-morbid conditions or medications known to         |
|     interfere with sleep.                                             |
+-----------------------------------------------------------------------+
| **INCLUSION RECOMMENDATIONS**                                         |
+-----------------------------------------------------------------------+
| ***For Short-Term Therapy for Insomnia***                             |
|                                                                       |
| -   Patient with acute (short-term) insomnia defined as periods of    |
|     sleep difficulty lasting less than one month and basic sleep      |
|     interventions (e.g., sleep hygiene, relaxation training) have     |
|     failed to improve sleep difficulties                              |
|                                                                       |
| ```{=html}                                                            |
| <!-- -->                                                              |
| ```                                                                   |
| -   Patient with acute (short-term) insomnia until treatment          |
|     associated with any underlying psychiatric and/or medical         |
|     illnesses takes effect (e.g., depression)                         |
|                                                                       |
| ***For Long-Term Therapy for Insomnia***                              |
|                                                                       |
| -   Patient with DSM-IV criteria for chronic primary insomnia (≤ 6.5  |
|     hours of sleep/night and requires \> 30 min to fall asleep each   |
|     night for at least 1 month) **AND** basic sleep interventions     |
|     (e.g., sleep hygiene, relaxation training) failed to improve      |
|     sleep difficulties.                                               |
|                                                                       |
| > *Note: Treatment such as cognitive behavioral therapy (e.g.,        |
| > stimulus control, sleep restriction, cognitive therapy, and sleep   |
| > education), IF AVAILABLE and FEASIBLE, must be considered prior to  |
| > or in combination with zolpidem IR.*                                |
|                                                                       |
| -   Patient with chronic insomnia associated with comorbid medical or |
|     psychiatric conditions that exacerbate or contribute to both the  |
|     nighttime complaints and or daytime impairment that has lasted    |
|     for more than three weeks and is persistent without treatment AND |
|     basic sleep interventions (e.g., sleep hygiene, relaxation        |
|     training) failed to improve sleep difficulties.                   |
|                                                                       |
| > *Note: Treatment such as cognitive behavioral therapy (e.g.,        |
| > stimulus control, sleep restriction, cognitive therapy, and sleep   |
| > education), IF AVAILABLE and FEASIBLE, must be considered prior to  |
| > or in combination with zolpidem IR.*                                |
+-----------------------------------------------------------------------+
| **Dosage and Administration**                                         |
+-----------------------------------------------------------------------+
| ***For Short-Term Therapy for Insomnia***                             |
|                                                                       |
| -   Short trial of Zolpidem IR 5-10mg orally immediately before       |
|     bedtime x 7-10 days with no refills.                              |
|                                                                       |
| ***For Long-Term Therapy for Insomnia***                              |
|                                                                       |
| -   Zolpidem IR 5-10 mg orally immediately before bedtime x 2         |
|     refills.                                                          |
|                                                                       |
|     -   For selected patients, consider minimizing the frequency      |
|         e.g., take no fewer than 3 and no more than 5 tablets per     |
|         week (3-5x/week - QTY 20/month x 2 refills)                   |
+-----------------------------------------------------------------------+
| **Recommended Monitoring**                                            |
+-----------------------------------------------------------------------+
| -   It is strongly recommended that patients be evaluated within 2-3  |
|     weeks of the initial Rx to document any improvement in the        |
|     symptoms related to insomnia. Patients should be re-evaluated     |
|     regularly and adjunctive behavioral modification therapy be       |
|     continued. If not done, reconsideration should be made whether Rx |
|     for zolpidem IR should be continued.                              |
|                                                                       |
| -   The failure of symptoms of insomnia to improve after 7-10 days of |
|     treatment for short-term therapy may indicate the presence of an  |
|     underlying condition that needs to be evaluated.                  |
|                                                                       |
| -   Consultation with a sleep disorder specialist (e.g.,              |
|     neurologists, pulmonologists, psychiatrists, medical              |
|     practitioners board certified in sleep medicine) or a behavioral  |
|     therapist that are experienced in sleep intervention techniques   |
|     is recommended if the standard behavioral treatments are not      |
|     effective and patient is not a candidate for pharmacologic        |
|     treatment or pharmacologic agent is not continued.                |
+-----------------------------------------------------------------------+
| **Issues For Consideration**                                          |
+-----------------------------------------------------------------------+
| -   The evaluation of insomnia should include assessment of other     |
|     drugs or conditions (e.g. chemical dependence, sleep apnea) that  |
|     may be interfering with sleep. There are no studies showing       |
|     benefit in the combination of benzodiazepines and zolpidem IR in  |
|     the treatment of insomnia.                                        |
|                                                                       |
| -   Prior to using medications to treat insomnia, clinicians should   |
|     ask the patient about use of caffeine and other stimulants  which |
|     can exacerbate insomnia; these include over the counter products  |
|     (e.g., ephedrine or pseudoephedrine) and beverages such as coffee |
|     (drip or brew), tea, ice tea and various sodas (e.g., colas,      |
|     citrus drinks) and sports/energy drinks (e.g., super-caffeinated  |
|     drinks)                                                           |
|                                                                       |
| ```{=html}                                                            |
| <!-- -->                                                              |
| ```                                                                   |
| -   An adequate sleep history should be obtained. Provide patient     |
|     with a sleep diary with instructions. Document the type of        |
|     insomnia disorder at each visit. Instruct patient on the basic    |
|     sleep-hygiene interventions.                                      |
|                                                                       |
| -   Inform patients about any risks of taking zolpidem IR and the     |
|     prescribed duration of therapy.                                   |
|                                                                       |
| -   No studies are available using zolpidem IR in combination with    |
|     benzodiazepines for the treatment of insomnia.                    |
|                                                                       |
| -   If the patients' activities the day after the use of zolpidem IR  |
|     (or any other sedative hypnotic) require optimal alertness or     |
|     involves skilled work and where impairment of performance could   |
|     be a danger to themselves or others, zolpidem should be avoided.  |
|     Advise patients not to drive when they feel sleepy, dizzy or are  |
|     experiencing a lack of concentration. However, it should also be  |
|     made clear to them that the absence of such feelings does not     |
|     mean their performance is normal.                                 |
|                                                                       |
| -   Residual effects depend on the dose administered; start with the  |
|     lowest dose possible, particularly in the elderly. Do not double  |
|     the dose without consideration of the consequences of residual    |
|     effects. For patients whom are still working or active, consider  |
|     initiating therapy on a weekend or before a day off. Use of       |
|     hypnotics in combination with other psychoactive drugs largely    |
|     increases the risk of residual effects; use of multiple drugs     |
|     should be avoided.                                                |
|                                                                       |
| -   There are no adequate and well-controlled studies in pregnant     |
|     women. Zolpidem IR should be used during pregnancy only if the    |
|     potential benefit justifies the potential risk to the fetus. Use  |
|     of zolpidem in nursing mothers is not recommended.                |
|                                                                       |
| -   ***Patient Resources for Basic Hygiene Education:                 |
|     <http://www.womenshealth.gov/faq/insomnia.htm#5>***               |
|                                                                       |
| ***<http://www.aasmnet.org/FactSheet.aspx> and                        |
| <http://www.sleepfoundation.org/>***                                  |
|                                                                       |
| -   ***Example of a sleep diary:                                      |
|     <http://www.nhlbi.nih.gov/health/prof/sleep/insom_pc.pdf>***      |
|                                                                       |
| -   ***Professional Education: <http://www.sleepfoundation.org/> and  |
|     <http://www.ahrq.gov/clinic/epcsums/insomnsum.htm>***             |
+-----------------------------------------------------------------------+

References:

Ambien package insert. Sanofi-aventis US. LLC Bridgewater, NJ. March,
2007.

Allain H, Arbus L, Schuck S, et al. Efficacy and safety of zolpidem
administered 'as needed" in primary insomnia: Results of a double-blind,
placebo-controlled study. Clin Drug Invest 2001; 21:391-400.

Buscemi N, Vandermeer B, Friesen C, et al. Manifestations and management
of chronic insomnia in adults. Evidence report/technology assessment No.
125. AHRQ Publication No. 05-E021-2. Rockville, MD: Agency for
Healthcare Research and Quality. June 2005.

Carson S, Yen P-Y, McDonagh MS. Drug class review on newer drugs for
insomnia. 2006.
<http://www.ohsu.edu/drugeffectiveness/reports/final.cfm>

Cluydts R, Peeters K, DeBouyalisky I, et al. Comparison of continuous
vs. intermittent administration of zolpidem in chronic insomniacs: a
double-blind, randomized, pilot study. J Int Med Res 1998; 26:13-24.

Darcourt G, Pringuey D, Sallière D, et al. The safety and tolerability
of zolpidem-an update. Psychopharmacology 1999; 13:81-93.

Lahmeyer H, Wilcox CS, Kann J, et al. Subjective efficacy of zolpidem in
outpatients with chronic insomnia. Clin Drug Invest 1997; 13:134-44.

Dundar Y, Boland A, Strobl J, et al. Newer hypnotic drugs for the
short-term management of insomnia: a systematic review and economic
evaluation. Health Technol Assess 2004; 8:140.

DoD Drug Class Review - Newer Sedative Hypnotics. Prepared by DoD
Pharmacoeconomic Center for the Feb 07 meeting of the DoD Pharmacy &
Therapeutics Committee

Hajak G, Cluydts R, Declerck A, et al. Continuous versus non-nightly use
of zolpidem in chronic insomnia: results of a large-scale, double-blind,
randomized, outpatient study Int Clin Psychopharmacol 2002: 17: 9-17.

Perlis ML, McCall WV, Krystal AD, et al. Long-term, non-nightly
administration of zolpidem in the treatment of patients with primary
insomnia. J Clin Psychiatry 2004; 65:255-63.

Roth T, Roehrs T, Vogel G. Zolpidem in the treatment of transient
insomnia: A double-blind, randomized comparison with placebo. Sleep
1994.18: 246-51.

Scharf MB, Roth T, Vogel GE, et al. A multicenter, placebo-controlled
study evaluating zolpidem in the treatment of chronic insomnia. J Clin
Psychiatry 1994; 55: 192-99.

Schlich D, L'Heritier C, Coquelin JP, et al. Long-term treatment of
insomnia with zolpidem: A multicentre general practitioner study of 107
patients. J Int Med Res 1991: 19: 271-79.

Verster JC, Volkerts ER, Schreuder AH, et al. Residual effects of
middle-of-the-night administration of zaleplon and zolpidem on driving
ability, memory functions, and psychomotor performance. J Clin
Psychopharmacol 2002; 22:576-583.

Walsh JK, Roth T, Randazzo A, et al. Eight weeks of non-nightly use of
zolpidem for primary insomnia. Sleep 2000; 23:1087-96.