Drugs for Insomnia Table Treatment Guidelines Published by The Medical Letter, Inc.. RECOMMENDATIONS: Benzodiazepine receptor agonists, benzodiazepines, the melatonin agonist ramelteon a
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Drugs for Insomnia
Table
Treatment Guidelines
Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication Volume 10 (Issue 119) July 2012
www.medicalletter.org
Pharmacological treatment of insomnia includes
pre-scription drugs, non-prepre-scription medications and
“natural” remedies Behavioral changes are often
needed as well.1
BENZODIAZEPINE RECEPTOR AGONISTS —
Zolpidem (Ambien, and others) is the most widely
prescribed hypnotic in the US It is available in
immedi-ate-release, extended-release, sublingual and oral spray
formulations A low-dose sublingual formulation of
zolpidem (Intermezzo) is the only hypnotic approved by
the FDA for middle-of-the-night awakening.2 Zolpidem,
zaleplon (Sonata, and others), and eszopiclone (Lunesta)
are not structural benzodiazepines, but bind to
benzodi-azepine receptors They are believed to act through an
agonist effect on GABA A receptor complexes located
close to or coupled with benzodiazepine receptors All
act rapidly to decrease sleep latency and do not affect
deep sleep; the primary differences between them are in
their duration of action (see Table 1)
Adverse Effects – These agents may impair
performance in the morning, including driving
Anterograde amnesia can occur Complex
sleep-relat-ed behaviors may occur without conscious awareness
Eszopiclone leaves some patients with an unpleasant
taste Hallucinations have been reported Like the
ben-zodiazepines, benzodiazepine receptor agonists are
schedule IV controlled substances Withdrawal, dependence and abuse can occur Some reports have associated use of hypnotics, particularly zolpidem, with excess mortality and an increased risk of cancer.3
Drug Interactions – Zolpidem, zaleplon and
eszopi-clone are metabolized to some extent by CYP3A4 Concurrent administration with a CYP3A4 inhibitor,
such as clarithromycin (Biaxin, and others),
theoreti-cally could increase the risk of toxicity, but at least with zolpidem and zaleplon, the effect appears to be clinically insignificant Potent inducers of CYP3A4,
such as rifampin (Rifadin, and others), could decrease
the effectiveness of these drugs Concurrent use of alcohol or other CNS depressants increases the risk of CNS depression
BENZODIAZEPINES — Benzodiazepines shorten
the time to onset of sleep and prolong the first two stages of sleep They slightly reduce the relative amount of deep non-rapid-eye-movement and REM sleep The primary differences between the benzodi-azepines are in their duration of action (see Table 1)
Adverse Effects – Benzodiazepines may impair
next-day performance, including driving.4 In addition, complex sleep-related behaviors and anterograde amnesia, particularly with triazolam, may occur Aggressive behavior has also been reported.5
In elderly patients, benzodiazepines can cause weak-ness, impair coordination and cause an increased incidence of falls and hip fractures.6
Lethal overdose with oral benzodiazepines taken alone occurs rarely; fatalities almost always involve concurrent use of alcohol or other CNS depressants All benzodiazepines are schedule IV controlled sub-stances Dependence, tolerance, abuse and rebound insomnia can occur
RECOMMENDATIONS: Benzodiazepine receptor
agonists, benzodiazepines, the melatonin agonist
ramelteon and low doses of the antidepressant
dox-epin are effective and generally safe for treatment of
insomnia The antidepressant trazodone is widely
used for this indication, but convincing evidence of its
efficacy in patients who are not depressed is lacking
Over-the-counter antihistamines marketed as
“sleep-aids” are not recommended; they can cause next-day
sedation, impairment of performance skills such as
driving, and troublesome anticholinergic effects
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Trang 3Drugs for Insomnia
Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 119) • July 2012
Drug Interactions – Most benzodiazepines (except
lorazepam, oxazepam and temazepam) are
metabo-lized to some extent by CYP3A4 Inhibitors of
CYP3A4, such as clarithromycin, can increase the risk
of benzodiazepine toxicity, and inducers, such as
rifampin, can decrease their effectiveness.7The proton
pump inhibitors (PPIs) omeprazole (Prilosec, and
oth-ers) and esomeprazole (Nexium) can increase serum
concentrations of diazepam Alcohol and other CNS
depressants can increase the risk of
benzodiazepine-induced CNS depression
58
A MELATONIN RECEPTOR AGONIST —
Ramelteon (Rozerem), a melatonin agonist, is
FDA-approved for sleep-onset insomnia.8 Clinical studies have shown a statistically significant reduction in sleep latency (by 7.5-15.7 minutes), but not in sleep maintenance.9 Comparative studies with other hyp-notics are lacking
Adverse Effects – The most common adverse effects
reported with ramelteon have been dizziness, nausea, fatigue and headache Increased serum prolactin and
Some Oral Hypnotic Dose in Pregnancy Drug Onset of Action Duration Formulations Dose Elderly Category* Cost 1
Benzodiazepine Receptor Agonists
Zaleplon – generic rapid (15-30 min) ultra-short 5, 10 mg caps 10-20 mg 5 mg C $ 5.50
Zolpidem –
immediate-release rapid (<30 min) short 5, 10 mg tabs 10 mg 5 mg C
extended-release rapid (<30 min) intermediate 6.25, 12.5 mg 12.5 mg 6.25 mg C
sublingual
Intermezzo rapid (20 min) ultra-short 1.75, 3.5 mg 1.75, 3.5 mg 2 1.75 mg C 64.50
oral spray
(Nova Del)
Eszopiclone – rapid (15-30 min) intermediate 1, 2, 3 mg tabs 2-3 mg 1-2 mg C
Benzodiazepines
Triazolam – generic rapid (15-30 min) short 0.125, 0.25 0.125- 0.125 mg X 2.20
Estazolam – generic rapid-intermediate intermediate 1, 2 mg tabs 1-2 mg 0.5-1 mg X 3.90
(15-60 min) Temazepam – generic intermediate-slow intermediate 7.5, 15, 22.5, 15-30 mg 7.5-15 mg X 1.00
Diazepam 5 – generic rapid (15-30 min) long 2, 5, 10 mg 5-10 mg 2.5-5 mg D 0.48
Melatonin Receptor Agonist
Tricyclic Antidepressant
* FDA pregnancy categories: A = controlled studies show no risk; B = no evidence of risk in humans; C = risk cannot be ruled out; D = positive evidence
of risk; X = contraindicated in pregnancy.
1 Cost of 10 days’ treatment with the lowest hypnotic dose Source: PricePointRx™ Reprinted with permission by FDB All rights reserved ©2012 http://www.firstdatabank.com/support/drug-pricing-policy.aspx Accessed June 11, 2012 Actual retail prices may be higher.
2 The dose is 1.75 mg for women and 3.5 mg for men.
3 Cost of a 7.7-mL bottle that contains 60 (5-mg) sprays after 5 initial priming sprays.
4 Cost based on 0.25-mg tablets.
5 Insomnia is not an FDA-approved indication.
Table 1 Some Hypnotics
Trang 4decreased serum testosterone concentrations have also
been reported Unlike the benzodiazepine receptor
agonists and benzodiazepines, ramelteon has no
poten-tial for abuse and is not a controlled substance
Drug Interactions – Ramelteon is metabolized by
CYP1A2 and to a lesser extent by CYP2C9 and
CYP3A4 Concurrent administration of the selective
serotonin reuptake inhibitor (SSRI) fluvoxamine
(Luvox, and others), which is a strong 1A2 inhibitor,
markedly increases serum concentrations of ramelteon;
they should not be used together Other 1A2 inhibitors,
such as ciprofloxacin (Cipro, and others), could have a
similar effect Drugs that inhibit CYP3A4 or CYP2C9
could also increase ramelteon serum concentrations and
increase the risk of toxicity Rifampin, a potent inducer
of various CYP isozymes, decreases ramelteon serum
concentrations by 80% and presumably would decrease
its hypnotic effect
LOW-DOSE DOXEPIN — The tricyclic
antidepres-sant doxepin (Silenor) is the only antidepresantidepres-sant
approved by the FDA for the treatment of insomnia.10In
doses much lower than those used to treat depression
(3-6 mg vs 150-300 mg), it is claimed to have a hypnotic
effect without the typical tricyclic anticholinergic and
other adverse effects Its affinity for H1-receptors is
thought to be largely responsible for its sedating effect
Some clinical studies have demonstrated efficacy in
both healthy volunteers (51 minutes more total sleep
time) and in elderly patients with chronic insomnia.11,12
Adverse Effects – Residual next-day somnolence has
been reported with the 6-mg dose Low-dose doxepin
is not classified as a controlled substance
Drug Interactions – Coadministration with cimetidine
(Tagamet, and others), an inhibitor of CYP2C19, 2D6,
and 1A2, can double doxepin serum concentrations; a
maximum dose of 3 mg of doxepin is recommended for
patients taking cimetidine Doxepin is contraindicated
for use with a monoamine oxidase inhibitor or within
two weeks of discontinuing one
OTHER PSYCHIATRIC DRUGS — A wide
vari-ety of other medications, although not FDA-approved
for this indication, are commonly prescribed for
insomnia The most common are antidepressants
such as trazodone (Desyrel, and others), mirtazapine
(Remeron) or amitriptyline (Elavil, and others).
Trazodone especially is widely used for this
indica-tion There is little evidence that these agents are
effective in treating insomnia not associated with
depression.13,14 Second-generation antipsychotics
such as quetiapine (Seroquel), ziprasidone (Geodon)
and olanzapine (Zyprexa, and others) have also been
prescribed for insomnia but their serious adverse
effects would be difficult to justify for treatment of insomnia alone
GABAPENTIN — The antiepileptic/neuropathic
analgesic gabapentin (Neurontin, and others), which is
FDA-approved for multiple indications, but not for insomnia, has been claimed to have a beneficial effect
on sleep Convincing studies are lacking.15
OLDER HYPNOTICS — Chloral hydrate is an
effective hypnotic when used for a few nights to treat transient insomnia Within 2 weeks, however, its effec-tiveness can wane, and continued use often leads to physical dependence Withdrawal of the drug can cause disrupted sleep and intense nightmares Chloral hydrate is a schedule IV controlled substance The usual hypnotic dose is 0.5-1 gram; fatalities have occurred following ingestion of as little as 4 grams
Barbiturates, once widely used for insomnia, have
the disadvantages of a narrow therapeutic index, lethality in overdosage, rapid development of toler-ance, high potential for physical dependence and abuse, and many drug interactions They are schedule
II controlled substances
NON-PRESCRIPTION DRUGS — Antihistamines –
Two first-generation antihistamines – diphenhydramine
(Nytol, Benadryl and others) and doxylamine (Unisom,
and others) – are currently approved by the FDA as
“sleep-aids” for sale without a prescription They are also heavily marketed as hypnotics in combination
products such as Tylenol PM (acetaminophen plus
diphenhydramine) These drugs are sedating, but there is little acceptable evidence that they improve the quality
or quantity of sleep Tolerance to the sedative effects of antihistamines may develop rapidly They can cause next-day sedation, impairment of performance skills such as driving, and troublesome anticholinergic effects such as dry mouth and urinary retention, which have been associated with cognitive impairment and increased mortality in elderly patients.16
Doxylamine and diphenhydramine are probably safe
for short-term use during pregnancy Doxylamine
combined with pyridoxine was available for many
years as Bendectin for treatment of nausea and
vomit-ing durvomit-ing pregnancy; it was taken off the market in the US in 1983 because of a poorly documented asso-ciation with congenital limb defects A similar product
is still available for this indication in Canada
Alcohol – Although widely used as a hypnotic, alcohol
is a poor choice It causes initial CNS depression fol-lowed by rebound excitation, which disrupts sleep Moreover, self-medication with alcohol to relieve insomnia has led to the development of alcoholism
Trang 5Drugs for Insomnia
20 S Bent et al Valerian for sleep: a systematic review and meta-analy-sis Am J Med 2006; 119:1005.
21 DM Taibi et al A systematic review of valerian as a sleep aid: safe but not effective Sleep Med Rev 2007; 11:209.
22 J Sarris and GJ Byrne A systematic review of insomnia and comple-mentary medicine Sleep Med Rev 2011; 15:99.
Melatonin – Taken 3-5 hours before the desired time
of sleep onset, melatonin has been reported to be
effective in some patients with insomnia.17,18 It does
not appear to be effective when taken at bedtime A
sustained-release formulation of melatonin (Circadin)
has been approved for use in Europe; one study found
it more effective than placebo for use 2 hours before
bedtime in patients >65 years old.19 The hypnotic dose
and purity of melatonin “dietary supplements” have
not been established
Herbal Products – Valerian root is claimed to be a
mild hypnotic that may improve the quality of sleep,
but some studies have found it ineffective.20,21As with
other herbal products, optimal dosage is unclear and
purity is a concern Similarly, there is no convincing
evidence that any of the other “natural” remedies used
for insomnia, such as kava, L-tryptophan (5-HT),
chamomile tea, passion flower, coenzyme Q10,
hops, lemon balm, lavender, or skull cap, are
effec-tive for this purpose.22No objective data support the
subjective claim of sleep improvement attributed to
cannabis or its various extracts The purity of all of
these products is suspect, and there is little, if any,
information on their safety during pregnancy
1 CM Morin and R Benca Chronic insomnia Lancet 2012; 379:1129.
2 Low-dose sublingual zolpidem (Intermezzo) for insomnia due to
mid-dle-of-the-night awakening Med Lett Drugs Ther 2012; 54:25.
3 DF Kripke et al Hypnotics’ association with mortality or cancer: a
matched cohort study BMJ Open 2012; 2:e000850.
4 MJ Rapoport et al Benzodiazepine use and driving: a meta-analysis.
J Clin Psychiatry 2009; 70:663.
5 T Saias and T Garlarda Paradoxical aggressive reactions to
benzodi-azepine use: a review Encephale 2008; 34:330.
6 A Pariente et al Benzodiazepines and injurious falls in community
dwelling elders Drugs Aging 2008; 25:61.
7 CYP3A and drug interactions Med Lett Drugs Ther 2005; 47:54.
8 Ramelteon (Rozerem) for insomnia Med Lett Drugs Ther 2005; 47:89.
9 M Erman et al An efficacy, safety, and dose-response study of Ramelteon
in patients with chronic primary insomnia Sleep Med 2006; 7:17.
10 Low-dose doxepin (Silenor) for insomnia Med Lett Drugs Ther
2010; 52:79.
11 T Roth et al Efficacy and safety of doxepin 6 mg in a model of
tran-sient insomnia Sleep Med 2010; 11:843.
12 AD Krystal et al Efficacy and safety of doxepin 3 and 6 mg in a
35-day sleep laboratory trial in adults with chronic primary insomnia.
Sleep 2011; 34:1433.
13 MH Wiegand Antidepressants for the treatment of insomnia: a
suit-able approach? Drugs 2008; 68:2411.
14 WB Mendelson A review of the evidence for the efficacy and safety
of trazodone in insomnia J Clin Psychiatry 2005; 66:469.
15 HS Lo et al Treatment effects of gabapentin for primary insomnia.
Clin Neuropharmacol 2010; 33:84.
16 C Fox et al Anticholinergic medication use and cognitive impairment
in the older population: the medical research council cognitive
func-tion and ageing study J Am Geriatr Soc 2011; 59:1477.
17 LC Lack and HR Wright Clinical management of delayed sleep phase
disorder Behav Sleep Med 2007; 5:57.
18 JJ Baskett et al Does melatonin improve sleep in older people? A
ran-domised crossover trial Age Ageing 2003; 32:164.
19 AG Wade et al Nightly treatment of primary insomnia with prolonged
release melatonin for 6 months: a randomized placebo controlled trial
on age and endogenous melatonin as predictors of efficacy and safety.
BMC Medicine 2010; 8:51.
Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 119) • July 2012
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Trang 7Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 119) • July 2012
1 The most widely prescribed hypnotic in the US is:
a diphenhydramine
b zolpidem
c chamomile
d cannabis
Issue 119
2 What do zolpidem, zaleplon and eszoplicone have in common?
a they are all benzodiazepines
b they are all schedule II controlled substances
c they are all metabolized by CYP3A4
d none of the above
Issue 119
3 Benzodiazepine receptor agonists have been reported to cause:
a hallucinations
b anterograde amnesia
c impaired driving performance
d all of the above
Issue 119
4 A 41-year-old woman who is taking fluoxetine and trazodone for
depression complains of difficulty sleeping She says that since
she has been taking trazodone in addition to fluoxetine, she has
no difficulty falling asleep, but she awakens in the middle of the
night and then cannot get back to sleep The only drug approved
by the FDA specifically for this indication is:
a triazolam
b ramelteon
c a sublingual formulation of zolpidem
d none of the above
Issue 119
5 Lethal overdose with oral benzodiazepines is:
a rare when they are taken alone
b the most common cause of death in adolescent girls
c used as a means of legal execution in Arkansas
d none of the above
Issue 119
6 Drugs that might increase serum concentrations of diazepam
include:
a rifampin
b omeprazole
c alcohol
d all of the above
Issue 119
7 The reduction in sleep latency reported in clinical trials of ramelteon was about:
a 7-15 minutes
b 10-20 minutes
c 15-22 minutes
d >20 minutes
Issue 119
8 A 64-year-old man with a long history of insomnia resistant to most FDA-approved hypnotics has started taking ramelteon He says that he is sleeping better, but his libido has decreased and
he wonders if there could be any connection with the drug You could tell him that:
a the drug is probably making him too sleepy to think about sex
b all the drugs he took in the past are taking their toll
c there could be a connection; ramelteon has been reported to lower serum testosterone levels
d now you understand why he always had so much difficulty falling asleep
9 The only antidepressant approved by the FDA for treatment of insomnia is:
a trazodone
b fluoxetine
c doxepin
d olanzapine
Issue 119
10 Antihistamines like diphenhydramine:
a are approved by the FDA for sale over the counter as sleep-aids
b can cause anticholinergic effects
c can cause next-day impairment of driving
d all of the above
Issue 119
11 Alcohol:
a has been shown to improve the quality of sleep
b disrupts sleep by causing rebound excitation
c use as a hypnotic does not lead to alcoholism
d all of the above
Issue 119
12 Natural remedies for insomnia:
a can do no harm
b are approved by the FDA as over-the-counter sleep-aids
c have clearly been shown to be effective
d none of the above
Issue 119
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Issue 119 Questions
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