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TCPR Dec 07 Insomnia

TCPR Dec 07 Insomnia

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Published by dcarlat
TCPR December 2007 Issue
TCPR December 2007 Issue

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Published by: dcarlat on Jul 19, 2008
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leep Drugs Found Only Mildly Effective, but Wildly Popular”proclaimed the headline of arecent
 New York Times
article (S. Saul,October 23, 2007).
The Times
analyzedthe results of a newly published meta-analysis of chronic insomnia treatmentsand concluded that, on average, sleepingpills reduce the time to go to sleep(sleep latency) by only 12.8 minutesbeyond placebo, and increase total sleeptime by only 11.4 minutes.These apparently unimpressive num-bers were derived from an NIH-fundedstudy available for free on the web(Buscemi N et al., AHRQ Report, accessedat http://www.ahrq.gov/downloads/pub/ evidence/pdf/insomnia/insomnia.pdf),andit’s well worth scanning, although at 135pages (not including the 154-pageappendix), it’s not suitable for between-appointment reading. The bottom lineof the report is that when you hook patients up to dozens of wires and putthem in a sleep lab bed, you
can still 
demonstrate that sleeping pills beatplacebo, but the numbers won’t blow  your socks off. In the real world, notonly do patients snooze wirelessly intheir own Serta Perfect Sleeper, but they benefit from both the drug effect andthe placebo effect. Combining placeboand drug effects leads to roughly a half hour of improved sleep latency over takingno pill any kind.Clearly, sleeping pills work; the morerelevant issue is whether there are any significant differences among them, and whether we should pony up 3 dollarsper pill for the Maserati medications or just3 cents per pill for perfectly adequate Civics.
 Benadryl (Diphenhydramine)
To begin our review with the Civics,Benadryl is an antihistamine with anti-cholinergic properties, and is probably being taken by more patients than yourealize. Why? Because it’s a popular ingredient in over-the-counter cold andpain remedies, including Tylenol PM(500 mg acetominophen and 25 mgdiphenhydramine) and the newer AdvilPM (200 mg ibuprofen and 38 mgdiphenhydramine). Benadryl definitely makes people drowsy and is an effectivesleep aid, but anecdotally, patients aresaid to quickly develop tolerance and tohave nasty cognitive side effects. Is thereany actual data to guide us? The only large study to look at side effects was of 426 hospitalized elderly patients (meanage, 80), 114 of whom had been givenBenadryl vs. 312 who had not. Patientsgiven Benadryl had about double therate of subtle symptoms of delirium,including inattention, disorganizedspeech, and altered consciousness(Agostini JV et al.,
 Arch Int Med 
2001;161(17):2091-2097). But this study is unlikely to be generalizable to mostphysically healthy outpatients in psychiatricpractices. Studies of young healthy patientsgiven Benadryl 50 mg BID (a dosing reg-imen for allergic rhinitis) have shown thatany daytime sedation or cognitiveimpair-ment wears off quickly, within a coupleof days (Richardson GS et al.,
 J Clin Psychopharm
2002;22:511-515). Butthere are no published studies support-ing the anecdotal impression thatpatients quickly develop tolerance toBenadryl when it is used at bedtime as asleeping pill. The bottom line onBenadryl is that you should avoid it inthe elderly, especially those who aremedically ill, but that it is likely safe andeffective for most other patients, at leastfor short term use.
Desyrel (Trazodone)
First, I’ll lay out my own bias: I think trazodone is a great sleeping pill, I’veused it with hundreds of patients andhave never seen any dangerous sideeffects, priapism included. Nonetheless,trazodone has been the target of numerous
•Sleeping Pills, New and Old2007 IndexPractice Tips: Four Questionsto Evaluate InsomniaExpert Q & A:
Michael Breus, Ph.D.Practical Sleep Hygiene Tips
 Focus of the Month:
The Treatment of Insomnia
December 2007
Continued on Page 2
Sleeping Pills, New and Old
Learning objectives for this issue:
1. Evaluate the advantages and disadvantages of commonly used hypnotics. 2. Describe potential side effects of hypnotics. 3. Develop a practical approach to discussing sleep hygiene with your patients.This CME/CE activity is intended for psychiatrists, psychiatric nurses, psychologists and other health care professionals with an interest in the diagnosisand treatment of psychiatric disorders.
“critical reviews” over the last few years,all funded by the makers of brandedhypnotics that lose market share totrazodone (see for example, Mendelson WB,
 J Clin Psychiatry
2005;66:469-476,and James SP et al.,
 J Clin Psychiatry
2004;65:752-755). The gist of thesereviews is that trazodone has not under-gone the same kinds of rigorous clinicaltrials for non-depressed primary insom-nia as the newer agents, so we simply don’t know how well it really  works. This is true, becausetrazodone is generic and thereare no big-money sponsors willingto pay for fancy studies to show it works. Nonetheless, severalstudies over the years have shownlow dose trazodone (50-100 mgHS) to be effective for insomniain depressed patients (e.g.,Saletu-Zyhlarz GM et al.,
 Prog  Neuropsychopharmacol Biol  Psychiatry
2002;26:249-260).One study, however, funded by  Ambien’s original manufacturer,did compare Ambien and tra-zodone head-to-head, and foundthat both drugs were better thanplacebo for primary insomnia(Walsh JK et al.,
 Human Psychopharm
1998;13:191-198).The sponsor has spun the resultsof the study to argue that Ambien was superior to tra-zodone, but a close read of thestudy does not support this con-clusion. bottom line: For a very cheap, long-half-life sleeping pill,it’s hard to beat trazodone,but be sure toassess your patients for next-day sedation,orthostatic hypotension,and priapism, allof which are possible side effects.
Ambien (Zolpidem) and Ambien CR
 We’ll start with the potential dark side of Ambien, simply because this hasbeen on patients’ minds ever since an Ambien-addled Patrick Kennedy crashedhis car enroute to a 2 AM “vote” onCapitol Hill (the last vote had occurredat 9 PM). Since then, the FDA has issuedalerts regarding possible “sleep-driving”and “sleep-eating” on all sleeping pills.Is Ambien (and by extension, theother nonbenzodiazepines) “abusable?”Undoubtedly. But is it less abusable thenbenzodiazepines? Almost certainly. Therehave been numerous case reports of zolpidem abuse (for example, seeCubala WJ et al., Br 
 J Clin Pharm
2007;online early article). Typically, Ambien abusers take an awful lot of thestuff to get high (these authors reporteda range from 160 mg/day to 2000 mg/day –  yes, 2000 mg), and in rare cases zolpi-dem withdrawal seizures have occurred.But one study provided strong evidencethat Ambien abuse is much rarer thanbenzodiazepine abuse. Researchers inGermany looked at the reported rates of ambien and zopiclone (mother of Lunesta) abuse from 1992 to 1997. They found an average of 4.5 cases of nonben-zo abuse per 10,000 doses, vs. a rate of benzo abuse of 106.7 per 10,000 doses(Hajak G et al.,
2003;98:1371-1378). This implies that benzos areabout 20 times more likely to be abusedthan the non-benzos.Sleep-driving, -eating, and -walkingare not really abuse issues, but possibleside effects. While not common, they occur frequently enough that most psy-chiatrists have seen cases in their practices. They can usually (butnot always) be prevented by reminding patients to get into bedright after taking their sleepingpill.On the positive side, Ambienis an effective, FDA-approvedsleeping pill. Now that it is avail-ablegenerically, its manufactur-er, Sanofi, has been pushing usto switch patients from Ambiento Ambien CR. Well, should we?Theoretically, Ambien CR hasthe ideal pharmacokinetic pro-file. After ingestion, 60% of thedose is released immediately,and the remainder is releasedgradually throughout the night.This meansthat it should pro- vide enough GABA agonism toget patients to sleep and keepthem asleep. Indeed, while Ambien is approvedfor sleepinitiation only, Ambien CR pro- videdsufficient evidence to winan additional FDA approvalfor “sleep maintenance.”Nonetheless, it is troubling to many that Sanofi has never funded a head-to-head trial comparing Ambien with Ambien CR. Are they afraid that IR will endup outshining CR? Instead of an appro-priate comparative trial, we see researchdesigned to guarantee a favorableimpres-sion of Ambien CR, such as one recentstudy of elderly patients comparing Ambien CR with Dalmane 30 mg, which
December 2007
Sleeping Pills, New and Old
Continued from Page 1Continued on Page 3
Practice Tips: Four Questions to EvaluateInsomnia
Stephen C. Ellen, a psychiatrist and sleep medicineexpert who is the medical director of The CounselingCenter of Nashua, New Hampshire, recommends thefollowing four questions for a quick initial evaluation of insomnia.1)How long does it usually take you to fall asleep?(Normal sleep latency is about 10 minutes; while we focuson long latencies for diagnosing initial onset insomnia,patients who report very 
latencies, such as 2 minutes,may be suffering sleep deprivation and should be counseledto increase sleep time.)2)How many times a night do you wake up? (Asthis of the patient’s sleep partner as well.)3)After each awakening, how long does it take to fallback asleep? (This, combined with the answer to question#2, gives you an accurate measure of exactly how muchsleep is being lost.)4)Do you feel refreshed upon awakening in themorning? (This is really the most important question for assessing the need for clinical intervention.)
 Note: These practice tips are not a part of this month’s formal ACCME-accredited continuing medical educationmaterial.
is double the recommended dose for older patients. Dalmane, with a half-lifeof between 50-100 hours, is not exactly afirst-line sleeping pill for the elderly,and, not surprisingly, it caused morenext-day cognitive impairment than Ambien CR.Bottom line: In the absence of therelevant comparative data, we’re left to our own anecdotal sense of whether AmbienCR actually poses clinical advantages.
Sonata (Zaleplon)
Sonata seems to have completely dropped off everybody’s radar screen, which is too bad, because it helpspatients get to sleep and it causes nonext day grogginess, even when taken inthe middle of the night (Hindmarch I, etal.,
 Hum Psychopharmacol 
. 2001;16(2):159-167). It is not approved for sleepmaintenance.
Lunesta (Eszopiclone)
Let’s face it: aside from a memorablecommercial, Lunesta has no advantagesover its competitors and has marked dis-advantages. Its half-life is long, at 6hours, meaning that it likely causesmore next-day impairment than its com-petitors. In its promotional material,Sepracor claims no next-day residual effectsin most patients. But if you dig into theactual data behind this claim, you’ll findthat they chose a very convenienttimepoint for their assessment-9.5 hours and12 hours (Lunesta package insert) –  whereas the other nonbenzos assessedfor cognitive effects at 8 hours (see, for example, Ambien CR package insert).Like the foolish man looking for his car keys far from where he dropped them“because the light’s better here,” Sepracor opted to shed their research light far enoughaway from the time of ingestion toguarantee a good marketing line.In fact, the precursor of Lunesta,zopiclone, does cause next-day impair-ment and is associated with a risk of car accidents (Staner L et al.,
(Berlin) 2005;181(4):790-798). The nailin Lunesta’s coffin is that it causes anunpleasant taste in 20-40% of people who take it (Lunesta package insert),prompting some Sepracor reps to recom-mend that patients bite into a lemon whenthey wake up in the morning. Thanks, butI’ll order the waffles instead.If you don’t have anything compellingto say about your product, just keep fund-ing opinion leaders to write somethingabout it, no matter how irrelevant– even-tually, you’ll build up market share, if only through literature saturation alone.Thus, we have company-funded studiessuch as a recent one in which 410menopausal women with insomnia wererandomized to receive either Lunesta or placebo. And indeed, Lunesta, a sleepingpill, helped these women sleep better (Soares CN et al.,
Obset Gynecol 
2006;108:1402-1410). This is a contribu-tion to the medical literature…how?bottom line: Lunesta has the samehalf life as Restoril (temazepam), is 100times more expensive, and has resulted ina scourge of Luna moths fluttering aroundpeople’s ears while they are trying to sleep.
Rozerem (Ramelteon)
There are two good things to say about Rozerem: it has no abuse potential(really, none,
 ) and it has a differentmechanism of action from its competitors.Rather than acting by revving up GABA, itstimulates two subtypes of the melatoninreceptors in the brain’s suprachiasmaticnucleus (SCN): MT1 and MT2. Of the two,MT1 is most specific for sedation, andRozerem has a 15-fold greater affinity for MT1 than straight melatonin, a fact thatprobably accounts for why melatonin isonly mildly effective as a sleep aid (seethis meta-analysis of melatonin studies:Brzezinski A et al.,
 Sleep Med 
Rev 2005;9:41-50).For some reason, Rozerem has theanecdotal reputation of having a one totwo week “lag time” before working, butthis is not true. In fact, a recent review of the Rozerem studies, written by twopharmacists who received no paymentsfrom Takeda, concluded that it improvessleep latency on nights one and two as well as any of the competing agents(Borja NL et al.,
Clin Ther 
2006;28:1540-1555). It has not been shown todecrease a standard measure of sleep, WASO (wake time after sleep onset), soit did not win the sleep maintenanceindication. According to experts I consulted,Rozerem doesn’t deliver the obvious“knock out punch” that the benzos and
 Publisher and Editor-in-Chief:
Daniel J. Carlat, M.D.,
is assistant clinical professor of psychiatry at Tufts University School of Medicine andmaintains a private practice in Newburyport, Massachusetts. He graduated from the psychiatric residency at Massachusetts General Hospital in1995 and is founding editor of 
The Practical Guide Series in Psychiatry
, published by Lippincott Williams & Wilkins.
 Associate Editor:
Marcia L. Zuckerman, M.D.,
practices psychiatry at HRI/Arbour in Brookline, Massachusetts.
 Editorial Board:
Dan Egli, Ph.D.,
private practice, Williamsport, Pennsylvania
Ivan Goldberg, M.D.,
creator, Depression Central Web Site, psychopharmacologist in private practice, New York City 
 Alan D. Lyman, M.D.,
child and adolescent psychiatrist in private practice, New York City 
Robert L. Mick, M.D.,
medical director, DePaul Addiction Services, Rochester, New York 
Michael Posternak, M.D.,
staff psychiatrist, Massachusetts General Hospital, BostonDr. Carlat, with editorial assistance by Dr. Zuckerman, is the author (unless other authorship is specified) of all articles and interviews for 
The Carlat Psychiatry Report 
. All editorial content is peer reviewed by the editorial board. Dr. Carlat, Dr. Egli, Dr. Goldberg, Dr. Lyman, Dr. Mick,Dr. Posternak, and Dr. Zuckerman have disclosed that they have no significant relationships with or financial interests in any commercial
companies pertaining to this educational activity.
December 2007
Sleeping Pills, New and Old
Continued from Page 2Continued on Page 8

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