www.DarkSideOfSleepingPills.com

Daniel F. Kripke, M.D.

The Cancer Prevention Study Ishowed that cigarettes cause cancer and heart disease

The Cancer Prevention Study IIshowed that filter cigarettes cause cancer and heart disease

The Cancer Prevention Study I showed that hypnotics are associated with increased mortality

The Cancer Prevention Study IIshowed that benzodiazepine hypnotics are associated with increased mortality

(1.12-1.38)

1.24

(1.14-1.38)1.2530/mo

(1.03-1.17)

1.10

(1.08-1.22)1.151-29/mo

WOMENMENUsage

MORTALITY HAZARD MORTALITY HAZARD RATIOS RATIOS FOR USE OF FOR USE OF HYPNOTICSHYPNOTICS FROM CPSII

Kripke, et al. Arch. Gen. Psychiatry. 2002;59:131-136

Molecular mechanisms by which cigarettes cause cancer and heart disease are still a bit uncertain.

Molecular mechanisms by which hypnoticscause death, e.g., through apnea, arewell understood.

Kripke et al 1979 Allgulander et al 1987Allgulander et al 1990Rumble and Morgan 1992Thorogood et al 1992Merlo et al 1996Sundquist et al 1996Kojima et al 2000Kripke et al 2002Mallon et al 2002Ahmad et al 2005

ElevenEleven STUDIES SHOW INCREASED MORTALITY ASSOCIATED WITH HYPNOTICS USE

OTHER RISKS

OF HYPNOTICS

The preponderance of studies show that hypnotics IMPAIR next day performance or produce no improvement.

This is true for zolpidem, zaleplon, and eszopiclone as well as for the older compounds.

Epidemiological studies show that chronic use of hypnotics is associated with increased insomnia.

Drug withdrawal studies indicate that it is possible that chronic hypnotic use causes insomnia.

“Use of sedative medication more than doubled the odds for incident insomnia and increased the odds for retaining

symptoms by approximately 80%.”

--Foley et al., Sleep, 1999; 22:S366-S372.

Use of sleep medication prospectively predicted

WORSE: Physical functioningBodily painVitalitySocial functioningGeneral mental health

on SF-36 after 3-year follow-up, after control for baseline sleep difficulty and medication use, comorbidity, age, and life events. -- Byles et al., Age and Aging 2003; 32:154-163

HYPNOTICS CAUSE

FALLS

&

ACCIDENTS

ODD BEHAVIORSODD BEHAVIORS

HallucinationsAmnesiaNocturnal binge eatingViolent behavior

UNCOMMON ADVERSE EFFECTS

OF “Z” DRUGS

• Hallucinations• Somnambulistic night eating• Zombie driving• Confusion

? BENEFITS OF

LONGTERM

HYPNOTICS ?

The 4th and 5th week of treatment with flurazepam and triazolam produced no significant advantage vs. placebo. However, triazolam patients were WORSE upon drug withdrawal.

--Johnson, Mitler, & Dement, 1984

After 2 weeks treatment in chronic hypnotic users, flurazepam and midazolam had no significant advantage over placebo. --Kripke et al., 1990

After 8 weeks of treatment, polysomnography showed no significant advantage of temazepam over placebo. --Morin et al., 1999

Zolpidem (in recommended dosage) not significantly better than placebo in the 5th week of use. --Scharf, et al., 1994

Intermittent zolpidem produced no significant increase in total sleep in weeks 5-8 of intermittent use, because of worse sleep on withdrawal nights. --Walsh et al., 2000

Zaleplon “…has not been shown to increase total sleep time or decrease the number of awakenings.”

--Sonata prescribing information, Wyeth, 2002

SLEEP TIME

0 20 40 60 80 100 120 140

HOURS after first dose ( taken each bedtime )

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50

100

150

200

250

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350

400R

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IVE

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HALF LIVES OF HYPNOTICS~ 8 HOURS ~ 2 HOURS ~ 48 HOURS +

TRIAZOLAMZOLPIDEMZALEPLON

TEMAZEPAMLORAZEPAMOXAZEPAM

DIAZEPAMFLURAZEPAMQUAZEPAM

HALF-LIFE EFFECTS ON PLASMA LEVELS

EXAMPLES:

HIGH EARLYLOW BEFOREWAKE

HIGH AFTERWAKE

ACCUMULATESNIGHT & DAY

TIME IN BED HOURS AFTER BEDTIME

DRUG METABOLISM: TOO SHORT: EARLY AWAKENING. TOO LONG: HANGOVER.SOMETIME BOTH!

DAYTIME IMPAIRMENT

• Preponderance of evidence that all hypnotics result in daytime impairment, NOT improved function.

• Daytime impairment is much worse from hypnotics with half-life >>4 hours.

• Risks include increased automobile accidents, falls, memory loss, and confusion.

“Adverse events . . . that suggest a dose-response relationship in adults include viral infection, dry mouth, dizziness, hallucinations, infection, rash, and unpleasant taste, with this relationship clearest for unpleasant taste.” [ The rate of unpleasant taste for LUNESTA 3 mg was 34%. ]

---Lunesta Approved Labeling Text, December 15, 2004

LUNESTA (Eszopiclone)

ESZOPICLONE• FDA permitted an indication for long-

term use, 2005

• Based on one study with only self-report evidence of effectiveness*

• The study did suggest improved daytime function compared to placebo.

• However, severe adverse effects were 3 times as common with eszopiclone as with placebo.

* Krystal AD, Walsh JK, Laska E et al. Sleep 2003;26(7):793-9.

HighMediumRECEPTOR SPECIFICITY

2.6 hours(? 3 hours in elderly)

6 hours(9 hours in elderly)

HALF LIFE

AMBIENzolpidem

LUNESTAeszopiclone

MELATONIN

A night hormone which makes

animal gonads atrophy

and can turn fur white

MELATONIN RISKS• Long-term safety in humans not

established:

– Probably causes gonadal suppression in young men and women and may cause infertility

– Suspected risks of seizure, myocardial infarction, or stroke

– Purity and potency of over-the-counter preparations is variable

– Might cause or protect against cancer

MELATONIN for INSOMNIA

• Effectiveness and safety not demonstrated for chronic insomnia

• Limited evidence of minor short-term benefits

• Some meta-analyses not favorable

RAMELTEON

• FDA approved long-term use indication, 2005

• Melatonin agonist

• Does not bind to benzodiazepine-GABA receptor: no cross-tolerance

• Complex metabolism, active metabolites

RAMELTEON• Little benefit:

7-16 min. shorter time to fall asleep

• Little risk apart from cancer concern

RAMELTEON• Likely to have no risk of

dependency and less other risks than benzodiazepine agonists

• Possible affects on reproductive endocrinology, e.g., prolactin, testosterone

INSOMNIA: 1) Sleep Difficulty

• Complaints of disturbed sleep in the presence of adequate opportunity and circumstance for sleep

– (1) difficulty in initiating sleep

– (2) difficulty in maintaining sleep or

– (3) waking up too early

– ? nonrestorative or poor-quality sleep

• NIH conference on chronic insomnia http://consensus.nih.gov/2005/2005InsomniaSOS026html.htm

• Most insomnia is comorbid with other

disorders, especially depression,

substance abuse and anxiety.

• In comorbid insomnia, it is unclear

when treatment focus should be on

comorbidities.

• Primary insomnia is insomnia without

comorbidities.

INSOMNIA TREATMENT

• Most hypnotics are only FDA-approved and indicated for short-term use, e.g., < 1 month.

• Most hypnotics are not recommended for chronic treatment.

• However, acute treatment of chronic insomnia often leads to long-term use.

NIH conference on chronic insomnia found better evidence for cognitive-behavioral treatments than for long-term pharmacologic agents.

http://consensus.nih.gov/2005/2005InsomniaSOS026html.htm

COGNITIVE-BEHAVIORALTREATMENT OF INSOMNIA

• Cognitive treatment: why “Don’t worry!”

• Sleep hygiene (education and counseling)

• Relaxation therapies (e.g., deep breathing, meditation, muscle relaxation)

• Sleep restriction therapy (limitation of time spent in bed)

COGNITIVE: ideas

• The healthiest people sleep 6.5 – 7.5 hours

• The average adult in the U.S. sleeps 6.5 hours: you don’t need 8 hours

• Do not spend longer in bed than you need to feel rested

• Spend more time in bed if you are sleepy in the day – IF more time in bed gives more sleep

3 4 5 6 7 8 9 >10

HOURS of SLEEP

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10

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30

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PE

RC

EN

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0.91

1.11.21.31.41.5

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RD

It is safe not tosleep 8 hours, as long as patientis not too sleepy:

Kripke et al., Arch. Gen. Psychiatry2002;59:131-136

8 HOURS SLEEPHIGHER MORTALTY

NOT MUCH RISK TOSLEEPING 5-6 HOURS

Good Sleep Hygiene• Sleep hygiene

– consistent bedtime and wake time

– Do not spend extra hours in bed to make up for poor sleep

– No long daytime naps (e.g. <90 min)

– Can try 15 - 40 min naps and closely follow sleep logs to decide if naps are OK

– Don’t go to bed unless sleepy

• Avoid caffeine from mid afternoon on• Limit alcohol in the evening• Use bedroom only for sleeping and sex

– No work

– No TV, etc.

Avoid alerting in bed

• If patient needs to spend time worrying, do it outside of bed.

• No scary mystery books or TV in bed

• Avoid alerting activities in bed.

SLEEP RESTRICTION• Reducing time-in-bed has powerful

and lasting benefits for insomnia

• e.g., person who says she only sleeps 5 hours should reduce time-in-bed to 5 hours

• Corrects negative conditioning to bedtime experience

SLEEP RESTRICTION• If person is sleeping 85% of time in

bed, may increase time in bed by 15 min. per week

• If person reports sleeping <85% of time in bed, then time in bed should be reduced

• Maintain regular get-up time

SLEEP APNEA

The most common cause of

complaints of excessive

sleepiness (falling asleep in

the day)

Circadian Rhythm Sleep Disorders

• Delayed Sleep Phase Type

• Advanced Sleep Phase

Type

• Jet Lag Type

• Shift Work Type

Symptoms of Delayed Sleep Phase

• Can’t get to sleep at night• Can’t get up in the morning• Tired most of the day• More alert in the evening

NOON 6PM MN 6AM NOON

MELATONIN

TEMPERATURE

---SLEEPY---

Preferred Sleep

NOON 6PM MN 6AM NOON

MELATONIN

TEMPERATURE

---SLEEPY---

Preferred Sleep

Delayed Sleep Phase

Treatment of Delayed Sleep Phase

• Bright light in the morning: as soon after arising as possible

• Vitamin B12: 1-3mg orally daily– Some evidence that it phase advances– Might augment light treatment

• Melatonin 0.02-0.10 mg. ~10 hours after arising

Ohta et al. 1992

DELAY

ADVANCE REGION:MORNING LIGHTSHIFTS SLEEPINESSEARLIER

DELAY REGION:EVENING LIGHTSHIFTS SLEEPINESSLATER

PHASE RESPONSE CURVE D

EL

AY

AD

VA

NC

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SLEEPINESS

ADVANCE