A Good Night's Rest—Helping the Patient with Insomnia

Behavioral Objectives

After completing this continuing education article, the pharmacist should be able to:

• Review the primary causes of insomnia.
• Identify the different types of insomnia (eg, trouble withsleep onset, early awakenings).
• Review the medications currently available for the treatmentof insomnia and understand relevant patient informationthat the medical professional should solicit toguide treatment, including the primary cause of theinsomnia, the presence of concurrent medications, andparameters such as latency to persistent sleep, totalsleep time, sleep architecture, and sleep efficiency.
• Discuss dosing considerations for insomnia medicationsand appropriate initiation and titration of therapy.
• Identify special patient population concerns.
• Discuss the safety profiles of commonly prescribedinsomnia medications.
• Identify nonpharmacologic sleep hygiene measuresinsomnia patients should employ.

Sleep problems are common complaintsof individuals worldwide.In a global survey across 10 countriesand 4 continents, almost a third ofsubjects were currently experiencinginsomnia, according to self-assessmentmeasures.¹ A recent US study found an11% prevalence rate for insomnia in 13-to 16-year-olds with a median age atonset of 11 years.² Insomnia is not only aburden to the individual, producingextreme daytime fatigue,^1,3,4 functionaldisability,^5,6 restricted activity,⁵ and cognitiveimpairment,^3,4,6 but it has broaderrepercussions as well. Use of health careresources is increased,⁷ accident ratesare higher,^8,9 and work productivity^8,9 isdecreased in insomniac patients. Thecosts associated with lost productivityare substantial and considerably higherthan those reported for workers withbipolar disorder.¹⁰

Despite the high prevalence, impact,and cost of insomnia, it remains substantiallyunderreported and undertreated.^4,7Even among severe insomniacs, only 55%ever discussed sleep complaints with adoctor, and only 27% reported use of asedative or hypnotic medication.⁷ Giventhe range of efficacious medications andnonpharmacologic interventions that areavailable, increased diagnosis and treatmentof insomnia could significantlyreduce both the personal and societalburden of the condition. All patients withinsomnia are not alike, however, nor arethe treatments. The source, severity, andsymptoms of the insomnia must beunderstood in order to determine appropriatetreatment. Additionally, a patient'scomorbid medical disorders and concurrentmedications should be considered inorder to avoid adverse events and druginteractions with insomnia medications.

As a part of the health care team, pharmacistsneed to be aware of optimalpractices in the management of insomniato improve treatment of this pervasive,burdensome, and complex disorder.

Understanding the Patient withInsomnia

Pinpointing the Source

According to DSM-IV-TR criteria,¹¹ primary insomnia is defined as a sleep disordercharacterized by difficulty fallingasleep or maintaining sleep, or feelingunrestored by sleep. Additionally, it mustcause the patient significant distress orfunctional impairment to meet criteria. Inpatients with primary insomnia, a clinicalcause is not identifiable.¹² Although theprecise pathogenesis of primary insomniais unknown, research suggests thatpatients may experience a constantstate of hyperarousability.¹³ Conversely,secondary insomnia may arise from severalrecognizable sources:¹³

• Poor sleep habits
• Medical conditions that interferewith sleep such as pain, cough, d i f f icultybreathing, or restless legs syndrome
• Substance use (ie, caffeine, alcohol,nicotine, or drugs)
• Psychosocial stressors
• Psychiatric disorders such as anxietyor depression

Most insomnia is secondary in origin,¹³and stress, anxiety, and depression areprominent underlying factors.^14-17 Stressorsknown to promote insomnia includebereavement, change in sleep scheduleor environment, loneliness, and work-orfamily-related stress.^14,15 Anxiety disordersare the most common psychiatric disordersassociated with insomnia, with 24%to 36% of insomniacs reporting them.^18,19The prevalence of depression is also highand is reported in 14% to 31% of thosewith insomnia.^18,19 Although insomnia istypically viewed as a symptom of anxietyor depression, longitudinal studies showthat it often predates the emergence ofthese disorders, suggesting that insomniatreatment could possibly prevent psychiatricmorbidity.^18,19

Insomnia may also occur as a sideeffect of a medication for any numberof acute or chronic medical disorders.Clinicians should be careful to elicitinformation from patients on currentdrugs they are taking to determine ifany of them may be interfering withsleep (Table 1).

Characterizing the Insomnia

The profile of insomnia differs frompatient to patient and may even changeover time within a given patient.¹⁰ It isimportant to carefully characterize theparticular sleep difficulties so that treatmentcan be individualized. Sleep diariesmay be kept for a period of weeks to collectinformation on bedtime and time ofarising, duration and quality of sleep, timingand quantity of meals and exercise,and ingestion of alcohol, drugs, caffeine,etc.²⁰ Several characteristics should beconsidered for optimal management:

• Type of insomnia (primary or secondary)If secondary, underlying cause(s)are identified
• Duration of insomnia (transient,short-term, or chronic)
• Symptoms of insomnia Difficulty falling asleepFrequent nocturnal awakeningsEarly morning awakening withinability to return to sleepPoor quality of sleep (easilyawakened, excessive dreaming,feeling unrestored after sleep)

Primary insomnia is a diagnosis ofexclusion after all secondary sources ofinsomnia are ruled out.¹³ If the insomniaappears to be secondary, then inmost situations, the secondary causesshould be treated first, keeping in mindthat there may be more than onecause.²⁰ If this treatment is unsuccessful,then the insomnia should be treatedas primary.¹³

Most insomnia is transient or short-termin duration. In a large US survey, 75%of respondents with insomnia reportedthat it was occasional, lasting only about5 days (on average) for a single bout ofinsomnia. These individuals had beenexperiencing episodes of short-terminsomnia for a mean duration of 9.3years, however.¹⁴ Chronic insomnia wasreported by 9% overall (25% of insomniacs),although the incidence was muchgreater in the elderly (>65 years old), with20% reporting chronic insomnia.¹⁴

Review of medical and psychiatrichistory, sleep history, and sleep diaryinformation will facilitate characterizationof insomnia and determination ofthe source of difficulties. Difficulties inmaintaining sleep are very common andhave been reported by >66% of insomniacs,whereas sleep initiation problemsare reported by a somewhat lower proportionoverall (~60%).^4,14 The type andduration of sleep complaints have beenassociated with demographic variables.Chronic insomnia is more common inthe elderly¹⁴ and patients with psychiatric¹⁹or medical disorders.²¹ Sleepmaintenance difficulties (versus sleepinitiation difficulties) predominate inanxious,²² depressed, and elderlypatients.¹⁰

Management of Insomnia:Nonpharmacologic Interventions

Nonpharmacologic therapies for insomniaare usually cognitive-behavioralin nature, and they have proven effectivein clinical trials when delivered by well-trainedtherapists. Table 2 describes thenonpharmacologic therapies that metthe American Psychological Association( APA) criteria for efficacious treatments,based on a thorough review of clinical trialsdata.²³ Additionally, although sleephygiene education has not proven effectivewhen used alone, it is often employedin combination with other therapiesand may be useful as an adjunct.²³The basic rules of sleep hygiene recommendthe following:¹²

• Maintain a consistent bedtime andawakening time every day
• Exercise regularly, but no vigorousexercise within 2 to 4 hours ofbedtime
• Avoid caffeine and nicotine at least 6hours before bedtime; moderate useof alcohol is acceptable but nonewithin 4 hours of bedtime
• Keep bedroom quiet and temperaturemoderate
• Avoid naps during the day
• Relax before bedtime, and do notwatch the clock during the night

The use of nondrug therapies is attractivefrom a side-effect perspective butcan be impractical. Sessions are time-consumingand require trained personnelto administer.¹⁰ Insurance may notcover the cost, and patients may not beadequately motivated to follow throughwithout close supervision.¹² Moreover,these interventions are not well-testedin a primary care setting or in patientswith insomnia secondary to comorbiddisorders. More research is needed todevelop a nondrug therapy that is applicableto primary care and effective ininsomnia associated with medical andpsychiatric illness.²³

Pharmacologic Managementof Insomnia

Benzodiazepine-receptor agonists(BZRAs) are considered drugs of choicefor pharmacologic management ofinsomnia. They are recommended fortreatment of primary insomnia andtransient or short-term insomnia dueto acute illness, stress, and travel (eg, jetlag). Ideally, treatment of secondarychronic insomnia should be directed atthe underlying cause (eg, depression,anxiety, arthritis pain). Resolution ofthese disorders takes time, however,and concurrent treatment of insomniamay be desirable. Furthermore, treatmentof an underlying disorder doesnot always lead to remission of insomnia.²⁴ Historically, BZRAs have beenrecommended for short-term use.Recently, however, sleep specialistshave begun to question the need tolimit therapy duration, given the positiveefficacy and safety profiles of availableBZRAs.²⁵ Although most of thehypnotics are indicated for short-termuse, the 2 newest entries into the market—eszopiclone (a BZRA) andramelteon (a melatonin receptor agonist)—are not restricted to short-termuse in the package labeling.

Drugs that are FDA-approved forinsomnia include the BZRAs (benzodiazepinesand nonbenzodiazepines) andthe recently approved melatonin agonistramelteon. Table 3 lists the individualdrugs by class along with their marketeddosage strengths, dose range,half-life, and the receptors believed tobe responsible for their therapeuticaction. The obvious pharmacologic differencesamong these hypnotics aretheir half-lives and receptor pharmacology.Benzodiazepines differ fromnonbenzodiazepines in receptor selectivity.The nonbenzodiazepines, zolpidemand zaleplon, are selective forGABA^A receptors containing the α¹subunit, whereas benzodiazepines arenonselective with comparable affinityfor GABA^A receptors containing eitherα¹, α², α³, or α⁵ subunits.²⁶ The precisebinding site of eszopiclone (the S-isomerof racemic zopiclone) on theGABA^A receptor complex is unknown.²⁷Ramelteon is a melatonin agonist withselectivity for the melatonin MT¹ andMT² receptors.²⁸

Several products aimed at improvingsleep are available without a prescription.Herbal products said to improveinsomnia include valerian root andkava kava.^29,30 Valerian may work bestfor mild insomnia when taken continuouslyrather than as an acute sleepaid.³¹ Kava kava is no longer recommendedfor use by the FDA as it maycause severe liver toxicity.³⁰ Melatonin,a naturally occurring hormone, is alsomarketed as a sleep aid, but its performancein treating insomnia appearsinconsistent.^32-34 A few antihistamines,including diphenhydramine and doxylamine,are also used as sleep aids dueto their sedating properties. Anticholinergicside effects and excessivenext-day sedation limit their chronicuse, however.

Individualizing Therapy Based onEfficacy Parameters

Differences in receptor pharmacologyamong hypnotics can potentially beexploited when tailoring therapy topatients' needs. GABA^A receptors containingα¹ subunits are believed tomediate the sedative, anticonvulsant,and amnestic effects of BZRAs, whereasthose containing α² subunits mediateanxiolytic action. (GABA^A receptorscontaining α³ and α⁵ subunits constitutea small minority of GABA^A receptors,and their functions have not yetbeen defined.²⁶) Theoretically, patientswith an underlying anxiety disorder orwhose insomnia is definitely stress-inducedmay garner additional efficacybenefits from a benzodiazepine hypnotic.Unfortunately there are no head-to-head comparator studies evaluatingnonbenzodiazepine BZRAs (α¹ selective)versus benzodiazepines in anxiety-induced insomnia to properly testthis hypothesis. Additionally, it shouldbe noted that triazolam, a short-actingbenzodiazepine, has been associatedwith rebound daytime anxiety and maytherefore be less appropriate in anxiety-induced insomnia.³⁵

Ramelteon is the only FDA-approvedhypnotic that does not exert its effectsvia benzodiazepine receptors. Instead,ramelteon is a selective agonist atmelatonin MT¹ and MT² receptors,receptors believed to participate inregulation of the circadian rhythm thatunderlies the sleep-wake cycle.²⁸Patients suffering from insomnia relatedto dysregulation of circadian rhythmcould potentially receive additionalbenefit from this agent. This theory hasnot been specifically tested, however.Interestingly, studies of melatonin as ahypnotic have shown inconsistent efficacyacross a variety of experimentalparadigms,³⁶ but efficacy in patientswith disturbances of sleep-wake cyclehas been more promising.³⁷ Thesepatients include shift workers, travelerswith jet lag, blind patients, andpatients with delayed sleep phase syndrome.Elderly individuals are alsomore likely to suffer from insomnia asa result of an underlying circadian dysregulation.³⁸

Sedating antidepressants such astrazodone, nefazodone, and mirtazapineare not indicated for insomnia butare frequently employed in thisregard.²⁵ Inhibition of serotonin (5HT²)receptors by these agents may mediatehypnotic effects, at least in part.³⁹Despite their popularity, their evidenceof effectiveness in nondepressedpatients with insomnia is scant, andthey are associated with next-daysedative effects and other tolerabilityproblems.^13,24 For depressed patientswith insomnia, however, sedating antidepressantsmay be a reasonablealternative because they have shownbetter efficacy results in this populationand have the benefit of also treatingthe underlying depression.³⁹

Individualizing drug therapy topatient needs is a complex process andshould involve consideration of othermedication factors in addition to receptorpharmacology. The pharmacokineticprofile, particularly half-life, alsoimpacts efficacy and safety and differentiateshypnotics where receptorpharmacology may not. In the contextof efficacy, pharmacokinetic profile maydictate whether an agent is effectivefor sleep-onset problems, sleep maintenanceproblems, or both. Table 4 listsFDA-approved hypnotics and the typeof sleep symptom for which they haveproven efficacy. Not surprisingly, agentswith shorter half-lives tend to be lesseffective for sleep maintenance-relateddifficulties. Neither zaleplon norramelteon has proven efficacy for sleepmaintenance (when taken before retiring),and they are indicated for patientswith sleep-onset difficulties only.^28,40 Inclinical practice, zaleplon is often usedin the early morning hours for patientswho wake up too early and have difficultyfalling back to sleep.²⁴ Estazolamhas shown inconsistent efficacy inimproving sleep-onset time^41,42 andmay therefore be less suitable for sleepinduction than the other hypnotics listedin Table 4. This may be a result ofslower absorption and/or lowerlipophilicity as compared with most ofthe other hypnotics listed.^42,43

Insomnia in elderly populations is characterizedby complaints of both poorquality and reduced quantity of sleep.Early morning awakening is one of themost common specific complaints in thisage group.⁴⁴ Hypnotics with sustainedefficacy throughout the night would bemost appropriate in patients with thisproblem. Although the efficacy of hypnoticshas not been well-tested for thisparameter, several studies objectivelyevaluated wake time at the end of thenight using polysomnography. Triazolam(0.25 mg),⁴⁵ zolpidem (10 mg),⁴⁶ and zaleplon(5 or 10 mg),⁴⁷ the agents with theshortest half-lives, were no more effectivethan placebo in reducing wake timein the latter portion of the night (last thirdor quarter). Temazepam (an intermediate-acting hypnotic) significantly reducedwake time in the last third of the nightduring short-term use in elderly insomniacs,however (7.5-mg dose).⁴⁸ Studies ofestazolam, eszopiclone, or ramelteonthat measured polysomnographic sleepparameters related to early morningawakening could not be identified.

Poor sleep quality is also a frequentcomplaint, particularly among elderlyinsomniacs.⁴⁴ Both benzodiazepines andnonbenzodiazepine hypnotics have beenshown to improve subjective measures ofsleep quality (ie, patients report sleepingmore deeply or feeling more refreshedafter sleep). However, sleep architecture isan objective parameter that may reflectsleep quality and has been differentiallyaffected by hypnotic treatment. Sleeparchitecture is determined by the proportionof time spent in each of the sleepstages using polysomnography. A patientwho spends more time in the lighterstages of sleep or in REM (rapid eye movementstage of sleep associated withdreaming) may feel less refreshed bysleep in the morning. Stages 3 and 4 arecalled slow wave sleep and are the deepestlevels of sleep.⁴⁹ Slow wave sleep maybe reduced by benzodiazepines but tendsto be preserved by nonbenzodiazepines.^49,50 Effects of hypnotics on slowwave sleep appear dose-dependent aswell. Suppression of slow wave sleep hasbeen reported with high doses oftemazepam (30 mg)^51,52 and zolpidem⁴⁹but not with lower doses.

Tolerance to Long-term Use ofHypnotic Therapy

The efficacy of hypnotics has sometimesbeen reported to decrease afterrepeated use, particularly with benzodiazepines.A meta-analysis of short-actingagents found that triazolam was associatedwith the most severe tolerance, buttolerance was mild with zolpidem.⁵³Temazepam,⁵¹ estazolam,⁵⁴ zaleplon,⁵⁵zolpidem,⁵⁶ and ramelteon²⁸ have showncontinued efficacy over a period of severalweeks with nightly use. Intermittentuse of zolpidem over a period of 8 weekswas also effective.⁵⁷ Eszopiclone hasshown the most sustained efficacy withsleep improvements demonstrated forup to 6 months.⁵⁸

Safety and Tolerability IssuesAffecting Drug Selection

Safety and tolerability issues associatedwith hypnotic use vary widely.Table 5 lists some of the prominentissues and summarizes information oneach of these for various hypnotics.These issues as well as the issues specificto special patient populationsmust be taken into account for optimalmanagement of insomnia.

Rebound Insomnia. Rebound insomnia(a worsening of sleep difficulties ascompared with baseline) after abruptwithdrawal of therapy has been reportedfor both benzodiazepines and nonbenzodiazepines.This phenomenon isrelated to the dose and half-life of BZRAhypnotics—a shorter half-life and higherdose increase the risk for reboundinsomnia.⁵⁹ It tends to be mild and of shortduration (1 night) for the nonbenzodiazepines^27,40,60and has not beenreported for ramelteon²⁸ or temazepam7.5 mg.^48,61 A study directly comparingzolpidem 10 mg with temazepam 20 mg(~equivalent doses) detected nodifferences in incidence of reboundinsomnia.⁶² In head-to-head comparisonsof zolpidem and zaleplon, zolpidem 10 mgbut not zaleplon (5-20 mg) produced ahigher rate of rebound insomnia(subjectively reported) as compared withplacebo on the first withdrawal night.^55,63Rebound insomnia is most severe withtriazolam, the shortest-acting benzodiazepine.^53,64 Tapering of hypnoticmedications rather than abrupt withdrawalhas been shown to amelioraterebound insomnia.⁶⁵ Additionally, usingthe lowest effective dose of a hypnoticmay prevent rebound, as studies haveshown that rebound insomnia is dose-specific—ie, it appears at dose levels thatshow no additional efficacy as comparedwith a lower dose.⁶⁶

Residual Effects. Residual effectsreported the day after hypnotic use (orlater) consist primarily of sedation,psychomotor impairment, and cognitiveproblems. They can affect next-dayperformance and are quite common withlong-acting benzodiazepines that accumulatein the circulation after repeatedadministration.²⁴ Residual effects such asataxia and impaired coordination havebeen particularly concerning in elderlypatients, because they raise the risk forfalls and hip fracture.⁶⁷ In adult patients ofall ages, the risk for car accidents isincreased, particularly with high-dose orlong-half-life benzodiazepines.⁶⁷ Short-half-life nonbenzodiazepine hypnotics canalso cause problems. A recent report inThe New York Times indicates thatzolpidem is one of the top 10 drugsdetected in impaired drivers in 10 of 24states that routinely test for it.⁶⁸

Although flurazepam and quazepamcarry indications for insomnia, they arenot generally recommended becausenext-day residual effects are commonwith these agents.¹³ These benzodiazepineshave long half-lives and produceactive metabolites during biotransformation.The accumulation oftheir final metabolite is believed tounderlie the next-day sedative effects.The final metabolite of both flurazepamand quazepam is desalkylflurazepamand has an elimination half-life of 48 to120 hours.⁴³

The residual effects of shorter-actingbenzodiazepines and the nonbenzodiazepinesare much less severe and, atlower doses, may be undetectable within8 hours of administration. Comparingamong these agents is difficult, however,because of the paucity of head-to-headtrials that evaluated residual effects. Arecent comprehensive review of hypnoticresidual effects was based on expertratings, meta-analyses, and results froma standardized driving test and comparedfindings for zolpidem, zaleplon,temazepam, and triazolam, among otheragents.⁶⁷ The probability of residualeffects (sleepiness, psychomotor or cognitiveimpairment) 8 to 12 hours afterhypnotic administration was consideredunlikely for temazepam (20 mg), triazolam(0.125 mg), zaleplon (10-20 mg), andzolpidem (10 mg). The risk increased butwas still considered "minor" for triazolam0.25, and temazepam 30 mg; the riskwith triazolam 0.5 mg was moderate.(Note that the hypnotics included in thereview may have been reformulated incurrently marketed drugs, and effects ofcurrent formulations could be different.)

Lower doses of zolpidem (5 mg) andtemazepam (7.5 or 15 mg) and any doseof estazolam were not included in thereview, nor were the 2 newest hypnotics—eszopiclone and ramelteon, likelybecause data were minimal or nonexistentat the time of the review (publishedin 2004). Because residual effectsare clearly dose-related, it can beassumed that the lowest doses of zolpidemand temazepam would be even lesslikely to produce residual effects than thehigher doses. Little evidence is availablefor estazolam, but a double-blindcrossover study designed to evaluatenext-day effects found significant deficitsin psychomotor and cognitive performanceat 10 hours after dosing as comparedwith placebo.⁶⁹ Considering thesefindings, the side-effect profile (dominatedby sedation-related events),⁷⁰ and thelonger half-life of estazolam, it seemslikely that next-day residual effectswould be more probable for this agent ascompared with others listed in Table 5.

Based on data available for eszopiclone(residual effects as reported inpackage labeling and 1 comparatortrial⁷¹), residual effects 8 hours or moreafter administration would be unlikely,similar to the other nonbenzodiazepinesand the shorter-half-life benzodiazepines.In the only comparator trialavailable, no differences were detectedbetween eszopiclone 1 mg to 3 mg andzolpidem 10 mg on subjective measuresof morning sleepiness, daytime alertness,or daytime function.⁷¹ Data onramelteon are even more lacking butsuggest next-day effects would beunlikely with this hypnotic as well.²⁸Additional direct comparator studiesbetween hypnotics are needed to sortout any potential differences among low-dosetemazepam, low-dose triazolam,ramelteon, and the nonbenzodiazepineBZRAs. Zaleplon appears to have someadvantage among hypnotics included inthe comprehensive review, because itwas the only hypnotic rated as unlikely tohave residual effects as early as 4 to 8hours after dosing,⁶⁷ thus reflecting itsultrashort half-life.

Drug Interactions. All the FDA-approvedhypnotics, with the exception oftemazepam, are metabolized via CYP3A4enzymes to a degree capable of allowingtheir involvement in clinically significantpharmacokinetic interactions with someCYP3A4 inhibitors or inducers. Estazolamand triazolam are contraindicated withpotent inhibitors of CYP3A4 such asketoconazole and itraconazole. Triazolamis also contraindicated with nefazodone.Cautious use with possible dosagereduction of the benzodiazepine is recommendedwith less potent CYP3A4inhibitors (eg, fluvoxamine, cimetidine,diltiazem, isoniazid, and some macrolideantibiotics).^42,72

The nonbenzodiazepines have shownclinically significant interactions withstrong CYP3A4 inhibitors (eg, ketoconazole,erythromycin) and inducers (eg,rifampicin).^27,40,60,73 Efficacy of the nonbenzodiazepinesmay be reduced by CYP3A4inducers. Cautious use with stronginhibitors of CYP3A4 may be necessary,although dosage reductions are notspecifically recommended in packagelabeling. Zaleplon is also metabolized viaaldehyde oxidase, and dosage reductionto 5 mg is recommended when it is coadministeredwith cimetidine (a CYP3A4 andaldehyde oxidase inhibitor).⁴⁰

Ramelteon is metabolized primarilythrough CYP1A2, but CYP3A4 and theCYP2C subfamily also participate. Ramelteonshould not be administered withthe strong CYP1A2 inhibitor, fluvoxamine,which raises the area under the curve forramelteon ~190-fold. Ramelteon shouldbe administered with caution in patientstaking less potent CYP1A2 inhibitors,strong CYP3A4 inhibitors (ketoconazole),or strong CYP2C9 inhibitors (fluconazole).The efficacy of ramelteon may be reducedif used in combination with strong CYPinducers (rifampin).²⁸

All hypnotics have the potential forpharmacodynamic interactions whenadministered with other drugs capable ofproducing CNS depression such as psychotropics,anticonvulsants, antihistamines,narcotic analgesics, and alcohol.Dosage adjustment of the hypnotic maybe necessary to reduce additive CNS-depressanteffects.

Abuse Liability

All the benzodiazepine and nonbenzodiazepineBZRAs are Schedule IVcontrolled substances. Ramelteon isnot a controlled substance andshowed no potential for abuse atdoses up to 20 times the recommendedtherapeutic dose.²⁸

The relative abuse potential of 19sedative-hypnotics has been rankedbased on 3 sources of information:(1) data from studies of reinforcingeffects in human and animal models ofdrug self-administration; (2) data fromstudies of human drug liking; (3) actualabuse rates estimated from epidemiologystudies and case reports.⁷⁴ Interestingly,abuse potential did not appearto be linked with GABA^A receptor selectivity.Among the FDA-approved hypnotics,temazepam, triazolam, zaleplon, andeszopiclone were ranked similarly andreceived moderate abuse liability scores(about halfway between the hypnoticsmost and least likely to be abused). Therelative abuse potential of zolpidem andestazolam was estimated to be somewhatlower (at the top of the bottomthird). Rankings were not differentiated bydose, however, and the authors recommendthat when prescribing hypnotics inpotentially vulnerable patients theyshould be restricted to the lowest effectivedose and limited quantities.⁷⁴

Special Issue with Ramelteon

Data with ramelteon are limited givenits recent entry into the hypnotic market,but thus far its safety profile appears relativelybenign based on package insertcontent and results from 1 publishedstudy.⁷⁵ A potential concern exists, however,that is specific to this hypnotic andthat involves its effects on prolactin levels.A 6-month study with a daily 16-mgdose (twice the recommended dose)found a 34% increase in mean prolactinlevels for ramelteon-treated women ascompared with a 4% decrease in placebo-treated women. For both men andwomen, the incidence of elevated prolactinlevels among ramelteon-treatedpatients was increased (32% versus 19%for placebo).²⁸ A 4-week study did notdetect clinically significant changes inprolactin levels, however.²⁸ Increases inprolactin level have been associated withsexual dysfunction and reproductiveabnormalities in both men and women.⁷⁶Whether long-term, daily, or intermittentuse of ramelteon 8 mg would affect prolactinor produce hyperprolactinemiainducedadverse events remains to bedetermined.

Use of Hypnotics in SpecialPopulations

The clearance of many of the FDA-approved hypnotics is reduced in elderlypatients, and initiation of therapy isrecommended at the lowest availabledose for all of them. Additionally, a halftablet (0.5 mg) is recommended withestazolam for small elderly patients.Increased dose-related adverse eventshave been reported in the elderly duringtriazolam use.⁷² Elderly patientsmay be more sensitive to the effects ofhypnotics in general, even when plasmadrug levels are not increased, andthese agents should be used with cautionin geriatric populations.⁷⁷

Exposure to eszopiclone, zaleplon,zolpidem, and ramelteon is increasedin patients with hepatic impairment.^27,28,40,60 Dosage adjustments maybe necessary with eszopiclone, zaleplon,and zolpidem. Zaleplon andramelteon should not be used inpatients with severe hepatic impairment.Renally impaired patients do notrequire dose adjustments. The packageinserts for estazolam, temazepam,and triazolam do not report problemswith hepatic or renal impairment, andno specific dosing recommendationsare given.

Benzodiazepines are labeled pregnancycategory X and are contraindicated inpregnancy. Zaleplon, eszopiclone, zolpidem,and ramelteon carry a category Crating and are not generally recommendedbut can be used if the potential benefitoutweighs the risk.

The package labeling should be consultedfor further information on the useof hypnotics in patients with concurrentmedical conditions.

Role of the Pharmacist

Pharmacists can be particularly helpfulto patients experiencing insomnia.Medication lists and refill data along withOTC purchases may provide clues aboutproblems with sleep. Consider the followingideas when supporting patientswith sleep difficulty:

• Understand the patient's type ofsleep problem. Inquire if the patienthas trouble falling asleep, sleepingthrough the entire night, waking upearlier than desired, or feeling tiredupon awakening.
• Learn if the insomnia is secondary toanother medical condition. Ensurethat the underlying cause of insomniais being properly treated, and bewatchful for undiagnosed depressionor anxiety. Report any clinical observationsto the prescribing physician.
• If an underlying condition is documented,consider if the prescribedtreatment addresses both theinsomnia and the primary condition.If not, determine if an alternativeproduct could meet both needs.
• Evaluate if the pharmacokinetic andpharmacodynamic properties of theprescribed medication match thepatient's need based on the primarysleep-related issue.
• Ensure that the prescribed medicationfor insomnia could not make anyunderlying health conditions worse.
• Get a complete list of medicationsused by the patient, including prescription,nonprescription, and herbalremedies. OTC products that caninterfere with sleep include coughand cold or pain medications thatcontain pseudoephedrine, caffeine, orother ingredients. Prescription medicationsknown to potentially causesleep problems include some diuretics,hormones including oral contraceptives,steroids, beta-agonists, dietpills, drugs used to improve attentioncontrol, and some antidepressantmedications.
• Inquire about the use of OTC orherbal products as a self-treatmentof insomnia to avoid drug duplication.In older persons, ensure thatthe physician adjusts drug doses toaccommodate potential changes inmetabolism or loss of functionalreserve. Encourage physicians tostart patients at risk for a drug-relatedproblem at the lowest possibledose. Counsel the patient onavoiding alcohol and nicotinebefore bedtime, as both chemicalscan disturb sleep.
• Gather information on the patient'slifestyle and habits. Will the prescribedagent interfere with day-todayroutines or lifestyle preferences?If so, consider recommending analternative agent to the prescribingphysician.
• Provide patients with explicit informationabout how the medicine willwork, when to take the medicine,potential side effects, and how toassess the drug's effectiveness.Reinforce that insomnia medicationsare intended for short-term use andthat the underlying cause of insomniamust be treated.
• Give patients a written list ofnonpharmacologic interventionsknown to improve sleep. Encouragethe patient to implementas many as possible in addition tothe medication.
• Review possible residual effects ofthe medication with the patient.Encourage the patient to follow upwith the physician if residualeffects occur that interfere withdaily activities.
• Discuss the potential for reboundinsomnia upon drug discontinuation,especially with long-termmedication use.

Conclusion

The recognition and management ofinsomnia need to be improved in orderto reduce its tremendous burden onpatients as well as society as a whole.Therapy should be chosen to best meetthe needs of each individual patient. Ifdrug treatment is deemed necessary,patients' specific sleep complaints andmedical history should be carefully profiledand matched to the hypnotic withthe most compatible efficacy and safetyprofile. In all cases, treatment with thelowest effective dose is key to an optimaloutcome.

Deborah L. Due, PhD, Scientific Information Specialist, Raleigh, NC& Lynn S. Fitzgerald, BSPharm, PharmD, President, Bullhorn Communications Inc, Apex, NC

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CEReview Questions

1.Which one of the following is not apotential source of secondary insomnia?

• Anxiety or depression
• Being in a state of hyperarousability
• Poor sleep habits
• Alcohol use

2.Which of the following statements aboutchronic insomnia is false?

• It is more common than short-terminsomnia.
• It may have more than one cause.
• It occurs more frequently in the elderly.
• It may be caused by diuretic use.

3. In the treatment of secondary insomnia,it is always important to:

• Determine the underlying cause, ifpossible.
• Treat the underlying cause until it iscompletely resolved, before treatingthe insomnia.
• Treat the underlying cause with amedication that has sedative properties.
• Use a nonpharmacologic therapy forinsomnia.

4. The rules of sleep hygiene suggest thatinsomnia will be improved by:

• Keeping the bedroom very warm.
• Relaxing during the day.
• Sleeping in late when possible (eg,on weekends).
• Regular exercise (performed at least4 hours before bedtime).

5. According to American PsychologicalAssociation criteria, which of the followingnonpharmacologic techniques has (have)well-established efficacy for treatinginsomnia?

• Stimulus control
• Good sleep hygiene
• Biofeedback
• All of the above

6. The primary goal of one of the nonpharmacologicinterventions for insomnia is todecrease the patient's worries about notbeing able to fall asleep. This therapy iscalled:

• Stimulus control.
• Paradoxical intention.
• Progressive muscle relaxation.
• Sleep restriction.

7. Benzodiazepines are distinguished fromBZRAs based on:

• Drug half-life.
• Lipophilicity.
• Receptor selectivity.
• All of the above

8.Which of the following is true oframelteon?

• It is a melatonin antagonist.
• It acts at melatonin MT¹ and MT²receptors.
• It is indicated for sleep maintenanceinsomnia.
• It is indicated for short-term useonly.

9.Which of the following statements istrue for all the FDA-approved hypnotics?

• They improve sleep maintenance.
• They are controlled substances.
• They are FDA-approved for short-termuse only.
• None of the above

10. Poor sleep quality:

• May be improved by BZRAs.
• Is commonly reported in elderlyinsomniacs.
• May appear as a decrease in slowwave sleep during polysomnographyrecordings.
• All of the above

11.Which of the hypnotics has (have)demonstrated efficacy in a long-term( 6-month) controlled trial?

• Ramelteon
• Eszopiclone
• All the nonbenzodiazepine BZRAs
• Triazolam

12. Rebound insomnia may be less likelyto occur:

• When using a hypnotic with a shorthalf-life.
• If the hypnotic medication is taperedrather than discontinued abruptly.
• When a higher dose of a hypnotic isused.
• All of the above

13. Factors that may increase the risk ofresidual or next-day sedative effectsinclude:

• Using a sedating antidepressant as ahypnotic.
• Using a BZRA in combination with anopioid analgesic.
• Using a hypnotic with active metabolites.
• All of the above

14. Residual effects of hypnotics:

• May increase the risk of car accidents.
• Are unlikely with quazepam and flurazepam.
• May be increased in the elderly.
• A and C

15.Which hypnotic(s) is (are) metabolizedvia CYP3A4 enzymes and may participatein clinically significant drug interactionswith CYP3A4 inhibitors?

• Estazolam, triazolam, zaleplon,eszopiclone, and ramelteon
• Ramelteon only
• All FDA-approved hypnotics
• Estazolam, triazolam, andtemazepam

16. The following combinations of medicationsare contraindicated or not recommended:

• Ramelteon with fluvoxamine
• Triazolam with nefazodone
• Estazolam or triazolam with itraconazole
• All of the above

17. Pharmacodynamic drug interactionsmay occur between:

• Benzodiazepines and alcohol.
• Benzodiazepines and nonbenzodiazepineBZRAs.
• Zaleplon and cimetidine.
• A and B

18.Which of the following statements is(are) true?

• Abuse liability is lowest with nonbenzodiazepineBZRAs.
• Ramelteon has a high abuse potential.
• Limited quantities of hypnoticsshould be prescribed in patientsprone to drug abuse.
• A and C

19. The use of hypnotics in elderlypatients:

• Should be initiated at the lowestavailable dose.
• May be associated with an increasedincidence of adverse events.
• Should be limited to patients inwhom nonpharmacologic interventionsare impractical or unsuccessful.
• All of the above

20. Hepatically impaired patients:

• Should not use nonbenzodiazepineBZRAs.
• Should not use ramelteon or zaleplonif their impairment is severe.
• Should use only the lowest availabledose of eszopiclone or zolpidem.
• Should not use benzodiazepines.