DOUGLAS KIRSCH, MD CLINICAL INSTRUCTOR, HARVARD MEDICAL SCHOOL REGIONAL MEDICAL DIRECTOR, SLEEP HEALTHCENTERS Hypnotics and OSA: Rumors and Facts.

DOUGLAS KIRSCH, MDCLINICAL INSTRUCTOR, HARVARD

MEDICAL SCHOOLREGIONAL MEDICAL DIRECTOR,

SLEEP HEALTHCENTERS

Hypnotics and OSA:Rumors and Facts

Purpose of This Talk

To examine the question of whether hypnotics are dangerous in patients who have untreated sleep-disordered breathing

To review information about whether some hypnotics may be beneficial in the treatment of OSA

To Cover:

A CaseWhat are Hypnotics Used For?What are Hypnotics?Do Hypnotics Affect the Airway?Can Hypnotics be of Benefit in OSA

Treatment?Close

A Case

An Early Case (1981)

A 38-year-old man with a long-standing history of insomnia and daytime sleepiness was evaluated.

He was found to have 7-18 primarily obstructive apneas per night on four baseline recordings.

On the first two nights on which he received 30 mg of the benzodiazepine hypnotic flurazepam, there were 22 and 100 apneas, and during the daytime he became extremely sleepy.

Mendelson WB, Garnett D, Gillin JC. J Nerv Ment Dis. 1981 Apr;169(4):261-4

An Early Case, Part II

Upon cessation of medication, his clinical condition improved, and the number of apneas decreased to 11 and 6 on withdrawal nights 4 and 6.

Although respiratory depression is neither invariable nor unique to flurazepam, this case suggests that it may be a clinically significant problem with recommended oral doses in some individuals

Mendelson WB, Garnett D, Gillin JC. J Nerv Ment Dis. 1981 Apr;169(4):261-4

Why Use a Hypnotic?

What is Insomnia?

Insomnia is a symptom:

Difficulty in sleep initiation “ I can’t fall asleep”

Difficulty in sleep maintenance “I keep waking up all night”

Complaint of non-restorative sleep “I just don’t feel rested in the morning”

Epidemiology of Insomnia

NSF Poll 200554% reported that, within the past year, they have

experienced at least one symptom of insomnia at least a few nights a week

33% said they have experienced at least one symptom every night or almost every night.

Symptoms (at least a few times per week) Waking up feeling unrefreshed (38%) Waking up a lot during the night (32%) Difficulty falling asleep (21%) Waking up too early and not able to get back to sleep

(21%)

Hypnotics

Benzodiazepines Lorazepam, Diazepam, Clonazepam, etc.

Non-Benzodiazepine Receptor Agonists Zolpidem, Eszopiclone, Zaleplon

Others: Alcohol Antidepressants: trazadone Anti-histamines: diphenhydramine Anti-psychotics: quietapine Sodium Oxybate

http://belaray.com/blog/wp-content/uploads/2008/06/medication.jpg

Insomnia Medications

Wilson and Nutt, Clin Med 2005

Sleeping Medications: General Rules

Treatment with medications should: begin with the lowest possible effective

dose be short-term, if used nightly be intermittent, if used long-term be used only in combination with good

sleep practices and/or behavioral approaches

Practice Parameters, AASM

Hypnotics: A Survey of 130 Patients

Lu et al. JCSM 2007

Prescription Sedatives in OSA Pts.

Sleep specialists tend to prescribe sedatives at a lower rate for patients with OSA than non-sleep specialists

Lu et al. JCSM 2007

Benzodiazepines

The “older” class of sleeping aids

They are considered “CNS depressants” Enhancement of the effect of the

neurotransmitter GABA

Also used to treat anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal

100 million scripts written in 1999 (DEA)

http://en.wikipedia.org/wiki/Benzodiazepinehttp://library.thinkquest.org/C0115926/drugs/sedative2.htm

Changes in Sleep with Benzos: Meta-analysis

Nowell et al.,JAMA, 278:24, 1997

Another Benefit of Hypnotics?

Sedatives and Falls In 34,163 nursing home residents

(76% women, mean age 84 +/- 8 y) Evaluated Hypnotic use

Hypnotics as defined by CMS included aprobarbital, flurazepam, quazepam, triazolam, pentobarbital, ethchlorvynol, estazolam, temazepam and secobarbital; others such as NBZRAs (e.g., zolpidem) were also included

Hypnotic use did not predict falls (adjusted odds ratio (AOR) 1.13, 95% confidence interval (CI)

0.98, 1.30). In contrast, insomnia did predict future falls

(AOR 1.52, 95% CI 1.38, 1.66).

J Am Geriatr Soc 53:955–962, 2005

A Hypnotic Risk: MVAs in OSA

Lu et al. JCSM 2007

Early Studies with Benzodiazepines and Sleep

http://thebrain.mcgill.ca/flash/i/i_04/i_04_m/i_04_m_peu/i_04_m_peu.html

COPD

Chronic Obstructive Pulmonary Disease Chronic obstructive bronchitis and

emphysema a pair of two commonly co-existing diseases of

the lungs in which the airways become narrowed

Associated with symptoms such as dyspnea, cough and sputum production.

COPD is caused by noxious particles or gas, most commonly from tobacco smoking, which triggers an abnormal inflammatory response in the lung

http://en.wikipedia.org/wiki/COPD

COPD and Benzodiazepines

In 1972, Gaddie et al Nitrazepam 10mg may cause hypoventilation

in 6 pts. with COPD Ex: 1 Pt: PaO2 fell from 48 to 35 mm Hg while

the PaCO2 tension rose from 59.5 to 68 mm Hg

Clark et al (1971) and Model (1973) Reported serious benzodiazepine-induced

respiratory depression in patients with COPD

March 2, 1990 The American Journal of Medicine Volume 88 (suppl 3A)

What is Hypoventilation?

Hypoventilation is too shallow or too slow breathing, which does not meet the needs of the body. It may also refer to reduced lung function.

If a person hypoventilates, the body's carbon dioxide level rises, which results in too little oxygen in the blood.

Shea SA, White DP. Disorders of ventilatory control. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Philadelphia, Pa: Saunders; 2007:chap 86http://www.nlm.nih.gov/medlineplus/ency/article/002377.htmhttp://www.southdartmoor.devon.sch.uk/pe/1127505986415.internal_lungs260.gif

CO2 O2

What is Hypoventilation (PSG)?

http://img.medscape.com/fullsize/migrated/491/438/sin491438.fig2.gif

CO2 >44 & O2 < 88

Why Does Hypoventilation Occur?

Benzodiazepines may depress the arousal response to hypoxia and hypercapnia during sleep and reduce genioglossal muscle tone

So what does that mean for an OSA patient?

Hedemark LL, Kronenberg RS. Flurazepam attenuates the arousal response to co2 during sleep in normal subjects. Am Rev Respir Dis 1983;128:980-3.

Normal System for an OSA patient

↓ Oxygen levels↑ Carbon Dioxide

Levels

Airway Collapse

Arousal

System with Benzodiazepines

↓ Oxygen levels↑ Carbon Dioxide

Levels

AirwayCollapse

Arousal

Benzos

+

-

Hypnotics and The Airway

http://content.revolutionhealth.com/contentimages/n1573.jpg

Diazepam Injection in a Cat

Sanders MH. In: Principles and Practice of Sleep Medicine. Philadelphia: W.B. Saunders Company, 1994.

Pea

k In

teg

rate

d a

ctiv

ity

(% c

on

tro

l)

Minutes after injection

Diazepam Injection

Hypoglossal Nerve Output

Phrenic Nerve Output

0 5 15 3060

150

100

50

0

Benzos and the Airway

Benzos may reduce genioglossal muscle tone

http://www.pwsdots.org/uploads/osa.jpg

Summary: Pathophysiology of OSA

Awake: Small airway + neuromuscular Awake: Small airway + neuromuscular compensationcompensation

Loss of Loss of neuromuscular neuromuscular compensationcompensation

Sleep Sleep OnsetOnset

HyperventilatHyperventilate: connect e: connect hypoxia & hypoxia &

hypercapniahypercapniaDecreased Decreased pharyngeal pharyngeal

muscle activitymuscle activityAirway opensAirway opens

Airway Airway collapsescollapses Pharyngeal Pharyngeal

muscle muscle activity activity restoredrestored

ApneaApnea

Arousal from Arousal from sleepsleepHypoxia & Hypoxia &

HypercapnHypercapniaia

Increased Increased ventilatory ventilatory

efforteffort

++

Benzos

Alcohol, Apnea, and the Airway

Alcohol as a Sleep Aid?

• Alcohol is also used as a sleep aid• 28% of insomniacs indicated that they had used

alcohol to help them fall asleep• Occasional insomniacs used alcohol for an average of

3.6 nights/month• Chronic insomniacs used alcohol for an average of 6.8

nights/month. • An equal number of occasional insomniacs and chronic

insomniacs (67%) described alcohol as an effective or very effective method to induce sleep.

Ancoli-Israel S, Roth T. Sleep. 1999;22(suppl 2):S347-S353.

Risk Factor: Alcohol

Bonara M et al. Am Rev Respir Dis 1984;130 © American Lung Association.

Before Alcohol

Blood Alcohol = 83 mg/dl

Blood Alcohol = 134 mg/dl

Phrenic

Hypoglossal

Phrenic

Hypoglossal

Phrenic

Hypoglossal

A Fun Study? (i.e., 1982 Studies)

Evaluating the effect of alcohol on sleep-disordered breathing.

On the night after the control study, (6.00-9.00 pm) the subject drank wine or beer under supervision, to an amount equivalent to the maximum he would drink on social occasions.

http://www.brainandspinalcord.org/blog/wp-content/uploads/2009/10/alcohol.jpg

Issa and Sullivan, JNNP 1982

OSA Patient, Control Night; ex: Hour 1

Issa and Sullivan, JNNP 1982

Diaphragmatic EMG

OSA Patient, Alcohol night; ex. Hr 1

Issa and Sullivan, JNNP 1982

Prolonged Apneas and worse Oxygen Desaturations with Alcohol

OSA Patient

A) OSA patient, Control night B) Same patient, Alcohol night

Issa and Sullivan, JNNP 1982

A

B

What about non-OSA?: A Snoring Patient

A) Snoring patient, Control nightB) Same patient, Alcohol night

Issa and Sullivan, JNNP 1982

A

B

Results of this Alcohol Study

In all 7 pts. studied, alcohol exacerbated the sleep-induced breathing abnormalities, and variably caused worsening of SaO2 in sleep.

The effects of alcohol were: Dose related Occurred during the first 1-2 hr of sleep following alcohol

intake.

The finding was that alcohol intake can induce OSA in subjects with “benign chronic snoring”.

1) Alcohol clearly increased the duration of apneic episodes2) It promotes upper airway occlusion during sleep

Issa and Sullivan, JNNP 1982

Does Alcohol Cause Other Problems?

Healthy Elderly Subjects0.6mg/kg ethyl alcohol (whiskey) 1h before

bed

In case of alcohol: Those patients with initial AHI of 5-10 -> increased

apneas 1 patient had increased PVCs with apneas

Guilleminault et al, Journal of Gerontology 1984 39(6):655-661

Alcohol and CPAP

Ten obese male subjects undergoing CPAP 1st night – CPAP titration 2nd night – Control night at correct PAP pressure 3rd night - subjects ingested either 1.5 (A) or 2 (B) ml/kg of

50 percent ethanol (100 proof vodka) over one half-hour starting 1 h before bedtime.

Chest 1991: 99:339-43)

If using CPAP No Change with Alcohol

Review: Effects of Alcohol

The genioglossus and geniohyoid muscles undergo a decrease in tone during REM sleep

Alcohol, which depresses the CNS, significantly decreases the activity of the genioglossus muscle during sleep and may be a factor in snoring (partial obstruction of the upper airway) or OSA (complete upper airway obstruction).

However, alcohol with PAP in place does not have as much of an effect on AHI

Guilleminault, The American Journal of Medicine Volume 88 (suppl 3A); March 2, 1990

So, What Happens with Benzos and OSA?

http://www.americasleeps.com/_borders/Snoring1.jpg

Effect of 30 mg of Flurazepam, 1982

Double-blind, placebo-controlled, randomized study20 patient, 17 men and 3 womenIn controls, SDB minimally worse with 30 mg Flurazepam

FLURAZEPAM AND NOCTURNAL OXYGEN DESATURATION-DOLLY AND BLOCK, AJM 1982

Flurazepam in Controls

In these patients, flurazepam had the same effect as alcohol, i.e., a complete airway obstruction was noted compared with baseline.

http://www.21stcenturydental.com/smith/sleepapena_tapappliance.htm

Berry, 1995: Triazolam and OSA

Assessment of the effect of triazolam (0.25 mg) on apnea duration and the arousal response to airway occlusion during sleep in patients with severe OSA.

12 male subjects were studied on two nights Mean age of 46.6 +/- 14.1 yr Mean weight of 260.8 +/- 55.9 lb

They ingested triazolam (0.25 mg) or placebo 0.5h before bedtime in a randomized double-blind crossover manner.

Berry RB, Kouchi K, Bower J, Prosise G, Light RW Am J Respir Crit Care Med. 1995 Feb;151(2 Pt 1):450-4.

Berry, 1995: Triazolam and OSA

In non-rapid-eye-movement (NREM) sleep Mean duration of event was slightly increased with drug:

Seconds: 26.8 vs 23.8, p < 0.02 Mean nadir in SaO2 lower on drug nights

% Saturation: 80.1 vs 84.2, p < 0.001 In NREM sleep, the deflections in esophageal pressure

prior to apnea termination were higher on triazolam nights Pes: 53.3 vs 44.5 cm H2O, p < 0.001

Triazolam increases the arousal threshold to airway occlusion This results in only modest prolongation of event duration

and increased desaturation at a dose of 0.25 mg in a group of OSA pts.

Berry RB, Kouchi K, Bower J, Prosise G, Light RW Am J Respir Crit Care Med. 1995 Feb;151(2 Pt 1):450-4.

Nitrazepam in OSA patients

14 consecutive patients (12 males and 2 females), found to have mild to moderate OSA (60–180 apneas/6 h of self-reported sleep time)

The principal finding of this study was that NIT had no consistent effect on the severity of sleep-disordered breathing in patients with mild to moderate SA.

Eur Respir J, 1994,

Berry, 1992: Triazolam and Arousals

6 men, mean age 28.1 +/- 7.1 yr , had their arousal response tested by occluding a mask covering the nose with the mouth sealed.

They ingested triazolam (0.25 mg) or placebo one-half hour before bedtime in a randomized double-blind crossover manner.

Mask occlusion was performed 1-4 h after triazolam/placebo ingestion while the subjects breathed air /O2 mix -> SaO2 of 98%.

Results The time to arousal was significantly longer on

triazolam nights (32.0 +/- 5.2 s versus 22.6 +/- 3.2 s, p < 0.01).

Conclusion: triazolam prolongs the time to arousal following airway occlusion by increasing the arousal threshold.

Berry RB, McCasland CR, Light RW. Am Rev Respir Dis. 1992 Nov;146(5 Pt 1):1256-60.

Newer Hypnotics: Are They Better?

http://www.nytimes.com/2004/11/14/business/yourmoney/14drug.html?_r=1

Kryger, 2007: Ramelteon and OSA

Ramelteon is a selective MT(1)/MT(2)-receptor agonist indicated for insomnia Double-blind, randomized, crossover study

26 adults with mild to moderate OSA received ramelteon 16 mg and placebo for one night each, administered 30 min before habitual bedtime.

AHI was similar: 11.4 vs 11.1, P = 0.812 Ramelteon – no effect on # of central, obstructive, or mixed

apneas.

No significant differences were observed in SaO(2) for the entire night (95.1 vs 94.7%); P = 0.070

Ramelteon did not statistically affect sleep when evaluated by polysomnography and post-sleep questionnaire.

Kryger M, Wang-Weigand S, Roth T. Sleep Breath. 2007 Sep;11(3):159-64..

Rosenberg, 2007: Eszopiclone and OSA

This double-blind, randomized crossover study Patients (35–64 yrs) with mild-to-moderate OSAS [AHI 10-40]. Patients received eszopiclone 3 mg or placebo for two

consecutive nights

Results Mean total AHI, was similar to placebo - 16.5 (plac) and 16.7

(esz)

No significant differences in respiratory arousals, duration of respiratory episodes, or oxygen saturation were noted.

Significant differences in: Sleep efficiency (85.1% and 88.4%) Wake time after sleep onset (61.8 and 48.1 min) Wake time during sleep (55.9 and 43.2 min).

Rosenberg R, Roach JM, Scharf M, Amato DA. Sleep Med. 2007 Aug;8(5):464-70. 2007

Zaleplon and OSA on PAP

Placebo controlled cross-over design: 15 mild to moderate OSA patients for the presence of worsening apnea with home-monitoring

Administering zaleplon (10 mg) or Placebo over a period of five consecutive nights then cross over

Results: No statistically significant treatment differences between zaleplon and placebo were observed AHI (ZN=7.2 vs PL=7.5; p=0.602) Mean SpO2 (ZN=94.6 vs PL=94.7; p=0.859). Small difference: ZN (79.2±1.3) and PL (82.1±0.9) for nadir

SpO2 (p=0.008).

These data support the hypothesis that short-acting, non-benzodiazepines may be used safely in middle-aged patients with mild to moderate OSA while receiving CPAP therapy in the home environment.

Coyle et al. JCSM 2005

Effect of Zolpidem vs. Flurazepam

In this 1988 study, Zolpidem was associated with slightly higher AHI and lower oxygen saturations than Flurazepam or placebo.

However, the n was 12 patients

Pharmacol Biochem Behav. 1988

Zolpidem and OSA on PAP

Obese adult patients who had been undergoing treatment of severe OSA (AHI > 30/hour) with CPAP therapy for least 6 months. All patients were compliant with their CPAP therapy

14 men and 2 women

3 nights: Titration, and then the patient slept in the lab with PAP and one night of placebo and one night of zolpidem 10 mg in a randomized order

Berry, Sleep 2006

Berry, Sleep 2006: Respiration

There was no significant effect of zolpidem on any respiratory variable

Berry, Sleep 2006: AHI

The AHI overall, AHI during REM sleep, and the AHI during supine sleep did not differ between placebo and zolpidem nights.In summary, in a study of 16 patients with severe OSA, there was no significant worsening in the AHI or in any index of arterial oxygen desaturation during CPAP treatment with the acute use of zolpidem, 10 mg.

Patients Often Feel Trapped By PAP

http://uashome.alaska.edu/~jndfg20/website/youngfrankenstein.gif

Can Hypnotics Help This process?

Benefits to Sedatives in Sleep Apnea?

Tolerance to CPAP can be problematic for patients

Ranges of 50-70% of continued use over timeThe only consistently reliable predictor of long-

term adherence has been the use of CPAP during the initial treatment period

Long term adherence patterns may be determined within the first few days of therapy.

Therefore, strategies aimed at improving adherence with therapy should focus on the initial experience with CPAP

Methods to Improve CPAP tolerance

Adjustment through continued use

For those experiencing difficulty: Early Education Alterations in mask Changing pressures / type of pressure

delivery Humidification Sedatives?

Can Hypnotics Help with PAP?

So, CPAP is hard to use, particularly if poorly tolerated early.

Can the addition of a hypnotic medication help improve PAP tolerance?

Bradshaw, Chest 2006

Evaluation of Zolpidem 10mg vs. Placebo during initiation of PAP

Will it help improve PAP use over 28 days?

Bradshaw, Chest 2006: Study Flow

CHEST 2006; 130:1369–1376

Bradshaw, Chest 2006: Results in CPAP

CHEST 2006; 130:1369–1376

Use of Eszopiclone in Polysomnography

Prospective, double-blinded, randomized, placebo-controlled trial assessing the effect of eszopiclone 3 mg on the quality of polysomnography

3 study arms: diagnostic polysomnography, split-night polysomnography, and CPAP titration polysomnography 79 diagnostic studies, 67 split-night studies, and 80 CPAP

titration studies

Enrolled 226 subjects: 113 received eszopiclone and 113 received placebo

Letteri, Sleep 2008

Letteri, Sleep 2008

Non-usable polysomnograms were defined as studies with less than 120 min of total sleep time (does not meet criteria for a diagnostic study) or complete CPAP intolerance.

Poor quality polysomnograms were defined as studies with less than 120 min of TST, sleep efficiency less than or equal to 70%, or an incomplete CPAP titration.

Defined incomplete CPAP titrations as those with a residual AHI ≥ 5 on the highest level of CPAP achieved, or complete CPAP intolerance.

CPAP intolerance was defined as the patient’s complete inability to sleep on CPAP or their request to end the study prematurely due to CPAP discomfort.

Letteri, Sleep 2008

Individuals were not studied both with and without this agent. Therefore, the study does not directly address the question of whether or not eszopiclone has these effects in individual patients.

Letteri, Sleep 2008

Letteri, Annals Int Med 2009

Evaluation of Eszopiclone to improve CPAP use for 14 days with open label afterward

Letteri, Annals Int Med 2009: AEs

Letteri, Annals Int Med 2009: Effect on PAP

Finally, One Last Point

We’ve reviewed that data that hypnotics may help with PAP use, but…

Can “hypnotic” medications actually treat OSA?

Sodium Oxybate and OSA

OSAS pts. (n=48) off treatment received 2-week SXB or placebo (PBO) treatment with PSG at baseline and day 14.

SXB led to a reduction in mean AHI with SXB and significantly increased slow wave sleep duration (5.2± 25.0 min vs. 29.4±37.0 min; p=0.0038).

George et al., Sleep Breathing Jan 2010

Summary

Data is MIXED

Data suggests that alcohol and benzodiazepines may worsen sleep disordered breathing in patients who already are at risk for it

Some studies demonstrate that use of NBZRAs may be useful in CPAP titration and early home PAP use