Curr Psychiatry Rep (2012) 14:494–502
`DOI 10.1007/s11920-012-0302-y
`
`SLEEP DISORDERS (MJ SATEIA, SECTION EDITOR)
`
`What Is the Role of Sedating Antidepressants,
`Antipsychotics, and Anticonvulsants in the Management
`of Insomnia?
`
`Catherine McCall & W. Vaughn McCall
`
`Published online: 17 August 2012
`# Springer Science+Business Media, LLC 2012
`
`Abstract Psychiatric medications such as antidepressants,
`antipsychotics, and anticonvulsants are commonly pre-
`scribed by physicians for the off-label use of improving
`sleep. Reasons for preferential prescription of these medi-
`cations over FDA-approved insomnia drugs may include a
`desire to treat concurrent sleep problems and psychiatric
`illness with a single medication, and/or an attempt to avoid
`hypnotic drugs due to their publicized side effects. Howev-
`er, there have been few large studies demonstrating the
`efficacy and safety of most off-label medications prescribed
`to treat insomnia. In addition, many of these medications
`have significant known side effect profiles themselves. Here
`we review the pertinent research studies published in recent
`years on antidepressant, antipsychotic, and anticonvulsant
`medications frequently prescribed for sleep difficulties. Al-
`though there have been few large-scale studies for most of
`these medications, some may be appropriate in the treatment
`of sleep issues in specific well-defined populations.
`
`Keywords Sleep disorders . Insomnia . Comorbid
`insomnia . Slow wave sleep . SWS . Off-label .
`Antidepressants . Antipsychotics . Anticonvulsants .
`Hypnotics . Psychiatry
`
`W. V. McCall (*)
`The Department of Psychiatry,
`Georgia Health Sciences University,
`The Stoney (EG Building), 997 St. Sebastian Way,
`Augusta, GA 30912, USA
`e-mail: wmccall@georgiahealth.edu
`
`C. McCall (*)
`Wake Forest University School of Medicine,
`Medical Center Blvd., #2644,
`Winston-Salem, NC 27157, USA
`e-mail: cmccall@wakehealth.edu
`
`Introduction
`
`The off-label prescription of antidepressants, antipsy-
`chotics, and anticonvulsants for the treatment of sleep
`problems is a common practice among physicians. In
`fact, analyses in the past decades have found that cer-
`tain off-label medications have been prescribed more
`commonly than FDA-approved medications for insomnia
`[1, 2]. One analysis of data from a national service
`tracking physician prescription activity in 2002 found
`that
`the number of prescriptions of antidepressants for
`insomnia had passed the use of FDA-approved hyp-
`notics for insomnia, with 5.28 million prescriptions for
`antidepressants and 3.4 million prescriptions for insom-
`nia medications that year. The most commonly pre-
`scribed medication of all was trazodone, which was
`prescribed 32 % more than the most widely prescribed
`insomnia drug [2].
`A survey of 1273 members of the American Acade-
`my of Child and Adolescent Psychiatry in 2003–2004
`found that trazodone was also the most commonly pre-
`scribed medication for the treatment of insomnia in
`children with concurrent mood and anxiety disorders,
`with other antidepressants, atypical antipsychotics, anti-
`convulsants, and short-acting hypnotics also being com-
`monly prescribed for sleep complaints in children with
`mood disorders [3].
`Some reasons for prescribing off-label medications over
`FDA-approved medications for insomnia include: (1) the
`benefit of using a single medication with sedating properties
`to manage both a psychiatric or medical disorder and con-
`current insomnia; (2) using a medication with sedating
`properties to offset sleep difficulties caused by another
`medication; and (3) avoiding the use of hypnotics due to
`concerns about dependence and side effects. In children, the
`American Academy of Pediatrics and the National Sleep
`Foundation have stated that there are inadequate data to
`
`ARGENTUM Exhibit 1153
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
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`495
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`guide pharmacologic treatment of insomnia in children [4].
`Thus, the physician who wishes to prescribe pharmacother-
`apy for insomnia in the child or adolescent must choose a
`medication without an approved indication or adequate re-
`search on the effects of these medications in this population.
`In adults, the frequent prescription of sedating anti-
`depressants, antipsychotics, and anticonvulsants for in-
`somnia implies
`that prescribers believe these
`medications are more effective, or safer, or less prone
`to dependence or side effects when compared with
`hypnotic medications. It
`is true that until recently the
`FDA included a warning with Schedule-IV hypnotics
`that
`these medications not be taken for more than 2
`consecutive weeks without reevaluation. Patients and
`physicians may also be concerned about using hypnotics
`such as zolpidem after much-publicized reports of sleep
`driving and other complex behaviors occurring with its
`use [5]. However,
`there also remains a paucity of re-
`search establishing the safety and efficacy of most anti-
`depressants, antipsychotics, and anticonvulsants for the
`purpose of treating insomnia. Furthermore, many of
`these medications may be both expensive and associated
`with a significant known side effect profile. In the case
`of antidepressants, side effects may include sleep dis-
`turbances such as increased wakefulness after sleep on-
`set (WASO), exacerbation of restless leg syndrome and
`increased periodic limb movements [6, 7].
`FDA approval of new medications for insomnia requires
`at least 2 randomized, placebo-controlled trials in insomnia
`patients that show more effective induction and/or mainte-
`nance of sleep compared with placebo. Approval also
`requires evidence of this effectiveness using both objective
`measurement of sleep and subjective patient report. To a
`large extent, trials of this magnitude have not been con-
`ducted for many off-label prescriptions of these medications
`for insomnia. One notable exception is doxepin, a tricyclic
`antidepressant, which was approved by the FDA in 2010 for
`the treatment of insomnia after 3 large phase III trials dem-
`onstrated improved WASO, total sleep time (TST), and
`sleep efficiency (SE) compared with placebo [8]. The FDA
`does not prohibit the use of approved medications for off-
`label purposes; however, the decision to use a medication
`for a purpose other than its approved indication warrants
`discussion with the patient concerning the clinical rationale
`for choosing the medication, as well as documentation of the
`discussion in the patient’s medical record [9, 10].
`The off-label prescription of medications for insomnia
`has been described extensively in the past [11(cid:129)(cid:129)]. For the
`purposes of this article, we will briefly summarize previous
`research on the sleep effects of specific sedating antidepres-
`sants, antipsychotics, and anticonvulsants commonly pre-
`scribed for insomnia, with subsequent focus on more
`recent studies performed in the last 2 years.
`
`Antidepressants
`
`Trazodone
`
`Background
`
`Trazodone is a triazolopyridine antidepressant that blocks
`post-synaptic serotonin receptors 5-HT1A, 5-HT1C, and 5-
`HT2, as well as post-synaptic α1-adreneregic receptors. It is
`a relatively weak SSRI with an elimination half-life of 5–
`9 hours. Typical doses for depression are >150 mg daily.
`Since its introduction in the United States in 1983, few
`studies have investigated the beneficial effects of trazodone
`on sleep in people with primary insomnia; however, it is one
`of the most prescribed off-label medications for sleep diffi-
`culties in both adults and children [2, 3, 12]. In small studies
`with primary insomniacs and normal sleepers, trazodone
`50–200 mg has been found to increase slow wave sleep
`(SWS) over short periods of time, compared with placebo
`[13–15]. It may be noted that although the clinical signifi-
`cance of increased SWS is not entirely clear, it is often
`assumed to be a sign of improved sleep. Many more small
`studies examining the use of trazodone for sleep have been
`conducted in depressed patients, and in patients whose
`insomnia is depression-associated or antidepressant-
`induced. These studies also report increases in SWS and
`improvements in sleep quality; however, there is no clear
`trend of benefits in sleep continuity [16–18].
`The most common side effects of small doses at bedtime
`are residual morning sedation and orthostatic hypotension
`from peripheral adrenergic blockade. Priapism, though often
`cited as a concerning side effect, is a relatively rare occur-
`rence [19–22].
`
`Recent Studies
`
`There are still few studies on the efficacy and safety of
`trazodone for primary insomnia, despite its popularity
`among providers. One within-subjects, randomized,
`double-blind, placebo-controlled study administered 50 mg
`to 16 insomniacs 30 minutes before bedtime for 7 days, and
`found that trazodone produced small but significant impair-
`ments of short-term memory, verbal learning, equilibrium,
`and arm muscle endurance across time-points. Relative to
`placebo across test days, trazodone was associated with
`fewer night-time awakenings, minutes of Stage 1 sleep and
`self-reports of difficulty sleeping. On day 7 only, slow wave
`sleep was greater and objective measures of daytime sleep-
`iness lower with trazodone than with placebo [23(cid:129)].
`Two recent studies have demonstrated improvement of
`both depression and insomnia with trazodone. Fourteen
`patients with primary insomnia and high Beck Depression
`Inventory (BDI) scores (>10), and 15 sex- and age-matched
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`patients with primary insomnia and low BDI scores (≤10)
`were treated with trazodone CR 25–150 mg/d for 3 months
`and followed for 1 month after discontinuation of the med-
`ication. Significant improvements in subjective sleep time
`and several sleep rating scales occurred in both high and low
`BDI groups. No significant differences were found with
`actigraphic measurements of sleep [24]. In another double-
`blind study, 412 patients with major depressive disorder
`were randomized 1:1 to receive either Trazodone Contra-
`mid® OAD (150–375 mg) or placebo for 8 weeks. There
`was a statistically significant difference between trazodone
`and placebo on the mean 17-item Hamilton Depression
`Rating Scale score; secondary findings included improve-
`ments in quality of sleep as measured by self-report. This
`study did not include objective measures of sleep [25].
`Trazodone has also been extensively studied in the treat-
`ment of fibromyalgia. One study with 66 fibromyalgia
`patients treated with flexibly dosed trazodone (50-300 mg/
`day) over 12 weeks found that trazodone significantly im-
`proved global fibromyalgia severity, sleep quality, and de-
`pression, as well as pain interference with daily activities
`although without showing a direct effect on bodily pain
`[26]. In another study, a flexible dose of trazodone (50–
`300 mg/day), was administered to 66 fibromyalgia patients
`for 12 weeks. The primary outcome measure was the Pitts-
`burgh Sleep Quality Index (PSQI). Trazodone markedly
`improved sleep quality, with large effect sizes in total PSQI
`score as well on sleep quality, sleep duration and SE. Sig-
`nificant improvements, although with moderate effect sizes,
`were also observed in standardized fibromyalgia, anxiety,
`and depression rating scores, as well as pain interference
`with daily activities [27].
`A retrospective study on sleep effects of trazodone in
`patients with dementia found that trazodone was among
`the antidepressants used with good tolerability in this sam-
`ple, showing effectiveness in resolving sleep complaints and
`caregiver distress in 2/3 of patients. “Effectiveness” was
`defined as improvement of the sleep complaint and reduc-
`tion in distress of the caregiver as rated on the Neuropsy-
`chiatric Inventory Scale (Nighttime Behavior items). One
`third terminated treatment with trazodone due to a lack of
`effectiveness but not due to adverse effects [28].
`A study on 137 people receiving methadone who
`reported a Pittsburgh Sleep Quality Index (PSQI) score of
`6 or higher found that trazodone did not improve subjective
`or objective sleep in this sample [29].
`
`Summary
`
`Trazodone may be effective in improving night-time awak-
`enings, subjective sleep difficulties, and objective daytime
`sleepiness in patients with primary insomnia, but there is
`evidence that it may also produce significant cognitive and
`
`motor impairment. Research on the efficacy of trazodone for
`sleep difficulties in the last several years has focused on
`patients with depression and those with fibromyalgia. In
`these patient groups, significant improvements have been
`observed in both sleep and comorbid disorder, though with-
`out improvements in objective sleep parameters.
`
`Amitriptyline
`
`Background
`
`Amitriptyline is a tricyclic antidepressant (TCA) that inhib-
`its reuptake of serotonin and norepinephrine, with choliner-
`gic, histaminergic, and α1-adreneregic receptor blockade. It
`has an elimination half-life of 20–30 hours. Typical antide-
`pressant dosages are >75 mg.
`Before the introduction of fluoxetine in the US in
`1987,
`tricyclic antidepressants were first-line treatment
`for depression, and were commonly prescribed to im-
`prove sleep in that patient population. However,
`there
`have been no data on the effects of amitriptyline on
`sleep in patients with primary insomnia and little data
`on sleep effects in patients with depression. There is
`limited evidence that in depressed patients, amitriptyline
`may improve PSG sleep measures of TST, sleep latency
`(SL), early morning awakening, and total REM time;
`however,
`this research was performed without placebo
`comparison or patient self-report [30].
`
`Recent Studies
`
`We found no studies on the effects of amitriptyline on sleep
`in primary insomniacs in the last 3 years. One study with
`healthy male subjects investigated the impact of evening
`doses of 75 mg amitriptyline over 2 nights on PSG-
`recorded nocturnal sleep and day-time sleepiness measured
`by the multiple sleep latency test, in comparison to 10 mg
`escitalopram and placebo. While amitriptyline did reduce
`PSG-determined WASO, compared with placebo, it also
`was associated with greater rates of periodic limb move-
`ments (PLM) and a higher PLM-arousal index. In turn,
`amitriptyline was associated with increased daytime sleepi-
`ness compared with placebo, as reflected in shorter mean
`sleep latencies [31].
`Amitriptyline has also been studied in sleep disturbance
`associated with fibromyalgia. A randomized, double-blind,
`active-control, equivalency crossover trial compared nabi-
`lone (0.5–1.0 mg before bedtime) to amitriptyline (10–
`20 mg before bedtime) in patients with fibromyalgia with
`chronic insomnia. Although sleep was improved by both
`amitriptyline and nabilone, nabilone was superior to ami-
`triptyline as rated on the Insomnia Severity Index. No ob-
`jective measure was reported [32].
`
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`Summary
`
`There remains little data on the benefits of amitriptyline for
`the treatment of sleep difficulties, whether in insomnia or
`fibromyalgia. Large research efforts in recent years have
`focused on other TCAs such as doxepin, which has shown
`promise in the treatment of insomnia at low dosages with
`minimal side effects.
`
`Doxepin
`
`Background
`
`Like amitriptyline, doxepin is a TCA that inhibits reuptake
`of serotonin and norepinephrine, with cholinergic, histamin-
`ergic, and α1-adreneregic receptor blockade. Typical antide-
`pressant dosage is >75 mg daily. However, it is likely that at
`low doses under 10 mg, doxepin’s main pharmacologic
`effect is histaminergic blockade, with little effect on seroto-
`nergic or adrenergic receptors [8].
`There has been a dramatic increase in research on the
`sleep effects of doxepin that has led to recent FDA approval
`in 2010 of doxepin as Silenor® (Somaxon Pharmaceuticals,
`San Diego, CA) in 3 mg and 6 mg doses for the treatment of
`insomnia characterized by difficulty with sleep mainte-
`nance. Although doxepin is thus no longer considered an
`off-label prescription for insomnia, we will include it here to
`illustrate the large research efforts that led to FDA approval
`of this medication.
`Previously, studies on doxepin at lower doses than typi-
`cally used for antidepressant effect (1, 3, and 6 mg) were
`found to improve sleep as measured by PSG and patient
`self-report. Side effects of low-dose doxepin in primary
`insomniacs are similar to placebo [33].
`
`Recent Studies
`
`FDA approval of Silenor occurred after 3 large phase III
`clinical trials in adult and elderly patients with chronic
`primary insomnia demonstrated that low-dose doxepin
`3 mg or 6 mg once daily improved PSG-determined WASO,
`TST, and SE compared with placebo. Five weeks of nightly
`administration of DXP 3 mg and 6 mg to adults with chronic
`primary insomnia resulted in significant and sustained
`improvements in sleep maintenance and early morning
`awakenings. These sleep improvements were not accompa-
`nied by next-day residual effects or followed by rebound
`insomnia or withdrawal effects upon discontinuation [34(cid:129)(cid:129)].
`Two randomized, double-blind, placebo-controlled trials
`studied low-dose doxepin in elderly patients with primary
`insomnia. Elderly adults with primary insomnia were ran-
`domized to 4 weeks of nightly treatment with either doxepin
`6 mg or placebo. Doxepin 6 mg produced significant
`
`497
`
`improvements in patient-reported WASO, TST, and sleep
`quality endpoints that were sustained throughout the trial
`[35(cid:129)(cid:129)]. Doxepin 1 mg and 3 mg administered nightly to
`elderly chronic insomnia patients for 12 weeks resulted in
`significant and sustained improvements in PSG-measured
`WASO, TST, SE, and WASO compared with placebo; they
`also noted improvement in patient-reported SOL, TST, and
`sleep quality. These improvements were not accompanied
`by evidence of next-day residual sedation or other signifi-
`cant adverse effects [36(cid:129)(cid:129)].
`
`Summary
`
`The approval of doxepin for the management of insomnia
`characterized by difficulty in sleep maintenance introduces a
`medication that has a well-established mechanism of action
`and few side effects. Perhaps more importantly, it has been
`studied in geriatric patients, a population with common
`sleep complaints of early morning awakenings and frag-
`mented sleep. The low anticholinergic effect of this dosage
`also makes it appropriate for the elderly population.
`
`Mirtazapine
`
`Background
`
`Mirtazapine is a tetracyclic piperazino azepine with potent
`inhibition of 5-HT2, 5-HT3 and central α2-adrenergic recep-
`tors, with minimal monoamine uptake. It has a half-life of
`22–40 hours, and typical antidepressant dosage is >15 mg
`daily.
`There have been no placebo-controlled randomized clin-
`ical trials of mirtazapine in primary insomniacs. Mirtazapine
`has been shown to reduce PSG-measured SL and increase
`slow wave sleep and SE in normal sleepers [37, 38]. In
`depressed insomniacs, 8 weeks of treatment produced great-
`er reductions in PSG SL and increased TST as compared
`with fluoxetine, with no patient report described. Antide-
`pressants such as mirtazepine have also shown efficacy in
`treating disturbed sleep associated with hot flashes in peri-
`menopausal women [39].
`Side effects of bedtime mirtazapine 30 mg have been
`observed, include prolonged next-day motor reaction and
`impaired driving performance when compared with placebo,
`for acute but not chronic dosing [40]. Mirtazapine may also
`cause significant weight gain.
`
`Recent Studies
`
`No recent studies were performed in normal sleepers or
`primary insomniacs. Two studies tested the effects of mirta-
`zapine in patients with depression. In one of the studies, 16
`depressed patients experienced significant improvement of
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`sleepiness and fatigue measures on subjective scales as well
`as the Multiple Sleep Latency Test (MSLT); there was no
`placebo comparison [41].
`Previously noted side effects of motor impairment were
`revisited in another study in which 14 depressed patients took
`mirtazapine 30 mg at bedtime for 30 days. A computerized
`driving simulator test (DST) and the Maintenance of Wake-
`fulness Test (MWT) were conducted at baseline and on days
`2, 9, 16, and 30 after commencement of antidepressant use.
`Several driving safety measures improved with mirtazepine
`over time, and several were also superior compared with
`untreated patients. The authors observed greatest improve-
`ment in morning performance, and suggested this may related
`to the circadian pattern often observed in untreated depression,
`in which mood is lower in the morning [42].
`A case series of 11 perimenopausal women with insom-
`nia without depression found that treatment with mirtaza-
`pine 15 mg followed by prolonged-release melatonin add-on
`therapy significantly improved sleep quality as measured by
`PSQI scores [43].
`
`Summary
`
`Mirtazapine, as with other sedating antidepressants, may be
`effective for sleep difficulties in depressed patients, particu-
`larly those with a need for weight gain. These studies
`suggest that it may also improve next-day sleepiness and
`fatigue, possibly due to its antidepressant effect. Mirtaza-
`pine may also be effective in treating insomnia associated
`with hot flashes in perimenopausal women.
`
`Antipsychotics
`
`Quetiapine
`
`Background
`
`Quetiapine is an atypical antipsychotic with high affinity for
`5-HT2A receptors and weak affinity for dopamine, musca-
`rinic, and adrenergic receptors. It has a half-life of 2–3 hours,
`and a typical antipsychotic dose is 150–800 mg daily.
`In small studies of patients with primary insomnia or
`dementia, quetiapine was previously found to increase
`PSG or actigraphic TST at doses starting at 25 mg
`[44–46]. Side effects of quetiapine include weight gain with
`potential glucose intolerance [47].
`
`Recent Studies
`
`use of quetiapine for sleep in demented patients between
`January 2007 and December 2009, authors found that 43 of
`the 101 patients included in the study were prescribed
`quetiapine, "probably for sleep" [48].
`We found only 1 study evaluating the effect of quetiapine
`in primary insomnia in a randomized controlled trial. Quetia-
`pine 25 mg at night led to nonsignificant improvement of self-
`reported TST and SOL in patients with primary insomnia [49].
`In adolescents with autistic spectrum disorder and ag-
`gressive behavior, treatment with 25 mg twice a day
`(50 mg/d) for the first 4 days of treatment, titrated to a
`maximum of 150 mg/day based on physician judgment,
`significantly improved subjective sleep disturbances; a pos-
`itive correlation was found between the improvements in
`aggression and sleep [50].
`Quetiapine has also been recently studied in regards to
`generalized anxiety disorder (GAD). One prospectively
`planned pooled analysis of 3 10-week, randomized,
`double-blind, placebo-controlled studies evaluated the effi-
`cacy and tolerability of acute extended release quetiapine
`fumarate (quetiapine XR) monotherapy in GAD. Significant
`improvements vs placebo at Week 8 included Pittsburgh
`Sleep Quality Index global scores for all quetiapine XR
`doses (50, 150, and 300 mg/day) [51].
`Two studies evaluated adjunctive quetiapine XR in
`patients with major depressive disorder (MDD) who dem-
`onstrated inadequate response to antidepressant treatment.
`Among the individual Montgomery–Åsberg Depression
`Rating Scale items, the greatest magnitude of improvement
`at Weeks 1 and 6 was observed in Item 4 (reduced sleep).
`Quetiapine XR was also associated with significant im-
`provement in PSQI global score and HAM-D sleep distur-
`bance factor scores at Week 6 [52].
`
`Summary
`
`Quetiapine has been most studied for the treatment of in-
`somnia in disorders characterized by psychosis, frequently
`with symptoms of agitation. In recent years, a number of
`studies have suggested it may be useful for treating sleep
`difficulties in patients with a variety of disorders, including
`autism with aggressive behavior, GAD, and depression.
`
`Anticonvulsants
`
`Gabapentin
`
`Background
`
`The prescription of quetiapine for sleep difficulties in
`patients with psychiatric illness and dementia is commonly
`employed [2]. In 1 retrospective cross-sectional study on the
`
`Gabapentin is a GABA analogue that interferes with the influx
`of calcium into nerve terminals. It is excreted via the kidneys
`as an unchanged drug, and has a half-life of 5–7 hours. Initial
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`499
`
`dosing for epilepsy is >900 mg daily. For neuropathic pain,
`dosing upwards of 2400–3600 mg per day is typical.
`Gabapentin has been shown to increase SWS in normal
`sleepers [53]. Much of the research on gabapentin sleep
`effects has been conducted in alcoholics, in whom FDA-
`approved hypnotics treatment for insomnia may not be
`recommended. Gabapentin has not been found to have sig-
`nificant abuse potential and does not affect hepatic function.
`It has been studied extensively in treating insomnia during
`alcohol abstinence, with findings that gabapentin may re-
`duce insomnia as well as alcohol use and cravings [54, 55].
`Gabapentin may also reduce sleep disturbance in pain-
`related disorders such as fibromyalgia, peripheral neuropa-
`thy, and traumatic nerve injury [56–60].
`
`Pregabalin
`
`Background
`
`Pregabalin is closely related to gabapentin, with a similar
`mechanism of action. Its half-life is 5–6 hours and it is
`excreted by the kidneys. Pregabalin is FDA-approved for
`the treatment of fibromyalgia, epilepsy, neuropathic pain,
`and post-herpetic neuralgia. Dosing for pain syndromes is
`150–600 mg per day.
`Pregabalin has been shown to increase SWS in normal
`sleepers [64]. Many studies have been performed showing
`that treatment with pregabalin in pain-related syndromes
`reduces sleep disturbance [65–68].
`
`Recent Studies
`
`Recent Studies
`
`One small, uncontrolled study with 18 primary insom-
`niacs receiving gabapentin treatment for at least 4 weeks
`showed improved PSQI score, as well as increased
`PSG-measured SE and slow-wave sleep, decreased
`WASO, and spontaneous arousal index after gabapentin
`treatment [61].
`A secondary analysis of data from a cohort of menopausal
`women participating in a randomized, double-blind, placebo-
`controlled trial of gabapentin 300 mg, 3 times daily (TID) for
`hot flashes saw gabapentin-associated improvement in the
`global PSQI score and SE factor score at 4 weeks [62].
`Research also continues on the sleep effects of gabapen-
`tin in alcoholics. One hundred individuals seeking outpa-
`tient treatment of alcohol withdrawal with Clinical Institute
`Withdrawal Assessment for Alcohol-Revised (CIWA-Ar)
`ratings ≥10 were randomized to double-blind treatment with
`2 doses of gabapentin (900 mg tapering to 600 mg or 1200
`tapering to 800 mg) or lorazepam (6 mg tapering to 4 mg)
`for 4 days. The Epworth Sleepiness scale was significantly
`lower in the high dose gabapentin vs lorazepam group
`during the randomized treatment, but not during follow-up.
`The authors note that symptoms of impaired sleep, mood
`instability, and anxiety play a role in alcohol relapse; how-
`ever, they do not speculate on whether lower Epworth
`Sleepiness scale scores were due to improved sleep or
`decreased daytime sedation with gabapentin compared with
`lorazepam [63].
`
`Summary
`
`Gabapentin has been extensively studied in the treatment of
`sleep disturbance associated with pain disorders. In addi-
`tion, it may improve insomnia associated with menopause
`and alcohol withdrawal. Additional placebo-controlled re-
`search in primary insomniacs may be helpful in establishing
`its effect in that population.
`
`Much of the recent efforts on studying sleep effects of pre-
`gabalin have focused on treating sleep disturbance in fibro-
`myalgia. One study published analyses of 2 randomized,
`double-blind, placebo-controlled trials of pregabalin (300,
`450, and 600 mg daily) in adult fibromyalgia patients. Prega-
`balin significantly improved quality of sleep as measured by
`daily sleep diary and the Medical Outcomes Study Sleep Scale
`items for sleep disturbance, quantity of sleep, and sleep prob-
`lems, relative to placebo. Mediation models indicated that
`43 %–80 % of the benefits on sleep (vs placebo) were direct
`effects of pregabalin, with the remainder resulting from an
`indirect effect of treatment via pain relief [69].
`Another international, multicenter, double-blind, placebo-
`controlled trial randomly assigned 747 patients with fibromy-
`algia to placebo or 300, 450, or 600 mg/day pregabalin twice
`daily for 14 weeks. All pregabalin doses demonstrated supe-
`riority to placebo on the Medical Outcomes Study-Sleep Scale
`Sleep Disturbance subscale and the Sleep Quality diary [70(cid:129)].
`Sleep effects of pregabalin were also studied in generalized
`anxiety patients. Data were analyzed from 6 double-blind,
`placebo-controlled, 4- to 6-week trials of outpatients with
`GAD with a minimum Hamilton Rating Scale for Anxiety
`(HAM-A) score018. Response was evaluated for 3 fixed-
`dose pregabalin groups (150, 300–450, 600 mg/day), and for
`a benzodiazepine group (alprazolam or lorazepam). In the
`“high-insomnia” subgroup (defined by a baseline HAM for
`Depression (HAM-D) insomnia factor score greater than “3”,
`treatment with the 2 higher doses of pregabalin (300–450 and
`600 mg), and with alprazolam/lorazepam, was associated with
`significant endpoint improvement on the 3-item HAM-D in-
`somnia factor score [71(cid:129)].
`
`Summary
`
`Pregabalin, like gabapentin, is well-established in its subjective
`improvement of insomnia associated with pain disorders such
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`Curr Psychiatry Rep (2012) 14:494–502
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`as fibromyalgia. In addition, a number of studies have sug-
`gested it may improve sleep difficulties associated with GAD.
`
`Conclusion
`
`Off-label prescriptions for antidepressants, antipsychotics,
`and anticonvulsants continue to rival that of FDA-approved
`medications for the treatment of insomnia. The last several
`years have seen the approval of doxepin following placebo-
`controlled, randomized clinical trials demonstrating its effica-
`cy and safety in adult and elderly patients with primary
`insomnia. Other medications are increasingly studied in the
`treatment of comorbid insomnia in special populations such as
`patients with fibromyalgia and generalized anxiety. Still other
`medications that were (and possibly still are) frequently pre-
`scribed for insomnia, such as amitriptyline, nortriptyline, val-
`proic acid, and tiagabine, have had very little published
`research in recent years investigating their effects on sleep.
`Although few of the studied medications have reached
`the level of research required for FDA approval, many of
`them do show sleep improvement within well-defined pop-
`ulations. For physicians treating these disorders, the ability
`to prescribe one medication for the patient’s underlying
`disorder and treat concurrent insomnia is an attractive qual-
`ity. Many of these medications also enhance SWS, a charac-
`teristic not seen in most FDA-approved hypnotics [72, 73].
`While off-label use of these medications may or may not be
`appropriate for primary insomnia, they may be useful in the
`special populations for whom the medications have been
`studied heavily, even without specific FDA approval. For
`many of these drugs, it is unclear whether the drug is directly
`treating the insomnia itself, or merely easing sleep difficulties
`secondary to an underlying psychiatric condition.
`
`Disclosure C. McCall: none; W. V. McCall: consultant for Sunovion.
`
`References
`
`Papers of particular interest, published recently, have been
`highlighted as:
`(cid:129) Of importance
`(cid:129)(cid:129) Of major importance
`
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`4. Mindell J, Emslie G, Blumer L, et al. Pharmacologic management
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