{

Kyle P. Edmonds, MD
Fellow, Institute for Palliative Medicine
San Diego Hospice
Absence of distress
 Circadian timing (time of the day)
 Sleep drive (time since last slept)
 Physical comfort
 Enviro...
Age
0-2 Mos
3-11 Mos
1-3 Yrs
3-5 Yrs
5-10 Yrs
10-17 Yrs
Adults (inc seniors)

Sleep Needs (Hours)
12-18 hours
14-15 hours
...
Biological recovery
 Enhanced immune function
 Regulation of circadian hormones
 Memory consolidation


Hanks et al. (...
Diagnostic Category
Representative Diagnoses
Insomnia
Primary, Secondary
Sleep-related breathing d/o OSA, CSA
Hypersomnole...
General population1

9-12%

Healthy seniors1

12-25%

Hospital population2

23%

Chronic lung disease3

50%

Cancer2

70%
...
Activated
HPA axis

Increased
metabolic
rate

Increased
autonomic
nervous
system

Psychophysiologic
Hyperarousal

Increase...
Situation
Sitting and reading
Watching TV
Sitting inactive in a public place (e.g. theater or a
meeting)
As a passenger in...
Hygiene
 Chronology
 Environment
 Physical Symptoms
 Medical Conditions
 Spiritual Concerns


Miller & Arnold (2011)...
Persistent

Medical, neurologic
or psychiatric

Difficulty
staying asleep

Nightmares, OSA

Frequent
awakening

Medication...
Hugel et al. (2004).
Hugel et al. (2004).
38%

What do
you
think
would
help you
sleep?

• Symptom control

21%

• Address worry

19%

• Combination of measures

13%...
Disease
Mgmt
Loss, gri
ef

End-oflife/death
mgmt

Physical
issues

Patient/Family
Characteristics

Practical
issues

Psych...
Relaxation therapies
 Sleep restriction therapy
 Stimulus control therapy
 Cognitive behavioral therapy
 BiPAP
 Palat...
Hanks et al. (2010).
“Patients may be able to avoid
[spiritual] concerns during the day
through the distraction of daily
activities but have di...
Consider stopping:



Steroids
 Stimulant antidepressants
 Bronchodilators
 Diuretics

Sanna & Brurera (2002).
Increase stage 2 (N2)
 Decrease stages 3 and 4 (N3)
 Interfere with slow-wave sleep


Bastien et al. (2003).
Medication Dosage Half-life Tmax Metabolites

Comments

Other benzodiazepine receptor agonists
Zolpidem

5

1.5-4

1-1.5

...
Studied only in depressed
insomniacs
 25-100mg may improve sleep*
 Biphasic half-life (3-6h, 5-9h)

Proven phase-shifting capability
 Mixed evidence for benefit in
elderly
 Poorly-regulated formulations



Sedative-hypnotics
Falls
 Hip fracture
 Cognitive impairment




Preferred
Zolpidem (Ambien)
 Eszopiclone (Lunesta...
Great source of oracles to human kind,
when stealing soft, and whispering to the
mind,
through sleep’s sweet silence, and ...
Sleep and it’s disturbance are
physiologically complex
 Begin with a thorough history and
sleep hygiene counseling
 Phar...



Bastien CH et al. (2003). Sleep EEG power spectra, insomnia and chronic
use of benzodiazepines. Sleep. 26(3): 313-317...
Want Of Sleep
Want Of Sleep
Want Of Sleep
Want Of Sleep
Want Of Sleep
Want Of Sleep
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Want Of Sleep

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Evidence-based management of insomnia for the primary palliative management of patients.

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  • The patterns of sleep…throughout life, throughout the day.How this pattern can be disrupted.How do we assess sleep problems and what are the ways in which we can address them?Image credit: http://www.susangrahamart.com/insomnia-installation-large.gif
  • Greek mythology. (Roman=Somnus.)“Hypnos and Thánatos, Sleep and His Half-Brother Death by John William Waterhouse” (sleep in the foreground, bathed in light)We can see the beginnings of an understanding of the complexity of sleep in the description of Hypnos’s environment…“His palace was a dark cave where the sun never shines. At the entrance were a number of poppies and other hypnogogic plants. His dwelling has no door or gate so that he might not be awakened by the creaking of hinges.”According to Ovid, his sons are the Oneiroi (Morpheus, Phobetor and Phantasos) who represent the various components of dreams.Image credit: http://en.wikipedia.org/wiki/File:Waterhouse-sleep_and_his_half-brother_death-1874.jpg
  • The neuroendocrine pattern of the day: hypothalamic circadian processes regulated by adenosine, which builds up throughout the day and inhibits processes associated with wakefulness. Image credit: http://en.wikipedia.org/wiki/File:Biological_clock_human.PNG
  • Image credit: http://homepages.abdn.ac.uk/e.lindstrom.08/6a00d8341c630a53ef010536d056ba970c-800wi.jpg
  • Adolescent.According to the 2007 AASM standards, NREM consists of three stages. There is relatively little dreaming in NREM.Stage N1 refers to the transition of the brain from alpha waves to theta waves. This stage is sometimes referred to as somnolence or drowsy sleep. Sudden twitches and hypnic jerks, also known as positive myoclonus, may be associated with the onset of sleep during N1. Some people may also experience hypnagogic hallucinations during this stage. During N1, the subject loses some muscle tone and most conscious awareness of the external environment.Stage N2 is characterized by sleep spindles and K-complexes. During this stage, muscular activity as measured by EMG decreases, and conscious awareness of the external environment disappears. This stage occupies 45–55% of total sleep in adults.Stage N3 (deep or slow-wave sleep) is characterized by the presence of a minimum of 20% delta waves. This is the stage in which parasomnias such as night terrors, nocturnal enuresis, sleepwalking, and somniloquy occur.Image credit: http://adc.bmj.com/content/94/1/63/F1.large.jpg
  • In dementia: decreased nocturnal sleep, increased awakenings; increased daytime sleep
  • “…recent studies have demonstrated alterations in natural killer cell activity associated with sleep deprivation.” T-cell population characteristics. Ifn-gamma and IL-1 levels.Circadian hormones: MelatoninTSH, Cortisol, GH, ProlactinSleep before: preparation for encoding. Sleep after: consolidation of new memories.Sleep debt: poor multitasking and executive function, mood lability with increased rage, fear and depression.Knowing the value of sleep, what are the ways in which it can be disrupted…
  • Given the increased tendency toward rage, it might be nice to know how many people around us have significant sleep debt…
  • Cancer pts: 71% regularly and 29% occasionally (75% had developed their problems at or after CA Dx)So what is going wrong in these patient’s to cause insomnia…?
  • Also changes in cytokine activity and cognitive hyperactivity. Knowing these questions, what are the best ways for us to assess sleep disruption?
  • 0-no chance of dozing1-slight chance2-moderate chance3-high chance0-9 normal10-24 abnormal
  • Image credit: http://mccormackdentistry.com/wp-content/uploads/2010/10/medical-records1.jpg
  • Nightmaresspiritual suffering?
  • Questionnaire presented to 74% of patients with advanced cancer and sleep disturbance.
  • Whole patient assessment of insomnia. As we come to a better idea of what our assessment might be, it’s time to start thinking about therapies, but before we do that…
  • Heath: Valium, Xanax, Restoril, an antihistamine and two pain relieversMichael: propofol, lorazepam and midazolamMarilyn: phenobarbital and chloral hydrateAnna Nicole: chloral hydrate, valium, Serax (oxazepam), Ativan and KlonopinJudy: Secobarbital (Seconal)Elvis: Ethchlovynol (Placidyl) (and Dexedrine in the morning)
  • Stimulus control: go to bed only when sleepy, maintain a regular schedule, avoid naps, use the bed only for sleep.CBT to address thoughts such as “I can’t sleep without medication”; “If I can’t sleep I should stay in bed and try harder to fall asleep”; catastrophizing consequences of poor sleep.
  • Relate back to psychophysiological hyperarousal. Image credit: http://docakilah.files.wordpress.com/2012/06/spiritual.jpg
  • Image credit: http://www.rizzotees.com/blog/wp-content/uploads/2011/05/stop-sign.jpg
  • Dalmane (flurazepam) has a major active metabolite (n-desalkylflurazepam) with a half life of >50h. Long-acting bzd sleep aids can have carry-over daytime anxiolytic effects. In healthy adults, they have the side effects of performance decrement and daytime sedation. May predispose to nocturnal confusion and behavioral disturbance especially in those with preexisting cognitive deficits and with respiratory disturbance in seniors.
  • Same article: insomniacs who chronically use benzos report worse subjective sleep scores than unrxed insomniacs!Decrease sleep latency, increase total sleep time, decrease slow wave sleep.Image credit: http://en.wikipedia.org/w/index.php?title=File:Benzodiazepine_a.svg&page=1
  • GABA-A: Regulation of neuronal potential through the flow of Cl-.We can see that, beyond the benzos, many of the other medications that are used act on this same receptor…Image: Richards G, Schoch P, Haefely W: Benzodiazepine receptors: new vistas. Seminars in Neuroscience 1991, 3:191–203.
  • We can see that this is missing one of the medications that we reach for first here at San Diego Hospice…
  • SARI: serotonin antagonist and reuptake inhibitorComparably small numbers of study participants. *When used as an adjunct with another antidepressant.Metabolized by CYP3A4 and renally excreted.Major metabolite, mCPP(meta-Chlorophenylpiperizine) may lead to false positive MDMA on Utox. Causes headaches, anorexia. Image credit: http://en.wikipedia.org/w/index.php?title=File:Trazodone.svg&page=1
  • Produced in the Pineal Gland and regulated by light stimulus through the optic pathways. headaches, nausea, next-day grogginess, irritability, hormone fluctuations, vivid dreams, nightmares, orthostatic hypotensionImage credit: http://en.wikipedia.org/w/index.php?title=File:Melatonin2.svg
  • Best to choose drugs that are short-acting and directly inactivated (rather than processed through the liver) without anticholinergic SEs.
  • “Nyx and Winged Morpheus Johannes Schilling 1868”Image credit: http://1.bp.blogspot.com/_3CPUjl8SUn8/Sc0lTgH_JkI/AAAAAAAAAK0/KpYkprVW9q8/s1600-h/NachtJohannesSchillingNyxandMorpheus.jpg
  • In one study, 95% of cancer care givers reported severe sleep disturbance!!Image credit: http://www.photographycorner.com/images/blog/interviews/corner-member-interviews-fa1sal-insomnia.jpg
  • Transcript of "Want Of Sleep"

    1. 1. { Kyle P. Edmonds, MD Fellow, Institute for Palliative Medicine San Diego Hospice
    2. 2. Absence of distress  Circadian timing (time of the day)  Sleep drive (time since last slept)  Physical comfort  Environment  Intact CNS function  Hanks et al. (2010).
    3. 3. Age 0-2 Mos 3-11 Mos 1-3 Yrs 3-5 Yrs 5-10 Yrs 10-17 Yrs Adults (inc seniors) Sleep Needs (Hours) 12-18 hours 14-15 hours 12-14 hours 11-13 hours 10-11 hours 8-9 hours 7-9 hours Adapted from Carol (2011).
    4. 4. Biological recovery  Enhanced immune function  Regulation of circadian hormones  Memory consolidation  Hanks et al. (2010).
    5. 5. Diagnostic Category Representative Diagnoses Insomnia Primary, Secondary Sleep-related breathing d/o OSA, CSA Hypersomnolence Narcolepsy Circadian rhythm disorder Shift work Movement disorder RLS Parasomnia Isolated symptoms Night terror; REM sleep behavior Primary snoring; Sleep talking Adapted from Table 10.12.1. Hanks et al. (2010).
    6. 6. General population1 9-12% Healthy seniors1 12-25% Hospital population2 23% Chronic lung disease3 50% Cancer2 70% HIV/AIDS3 75% Hemodialysis3 77% Depression3 90% (1) Bastien et al. (2003). (2) Miller & Arnold (2011). (3) Hanks et al. (2010)
    7. 7. Activated HPA axis Increased metabolic rate Increased autonomic nervous system Psychophysiologic Hyperarousal Increased sleep EEG frequency Increased cerebral blood flow Hanks et al. (2010).
    8. 8. Situation Sitting and reading Watching TV Sitting inactive in a public place (e.g. theater or a meeting) As a passenger in a car for an hour without a break Lying down to rest in the afternoon Sitting and talking to someone Sitting quietly after a lunch without alcohol In a care, while stopped for a few minutes in traffic Miller & Arnold (2011).
    9. 9. Hygiene  Chronology  Environment  Physical Symptoms  Medical Conditions  Spiritual Concerns  Miller & Arnold (2011).
    10. 10. Persistent Medical, neurologic or psychiatric Difficulty staying asleep Nightmares, OSA Frequent awakening Medications Early morning awakening Depression Day-night reversal Delirium Miller & Arnold (2011).
    11. 11. Hugel et al. (2004).
    12. 12. Hugel et al. (2004).
    13. 13. 38% What do you think would help you sleep? • Symptom control 21% • Address worry 19% • Combination of measures 13% • Don’t know 4% • Sleep medications Hugel et al. (2004).
    14. 14. Disease Mgmt Loss, gri ef End-oflife/death mgmt Physical issues Patient/Family Characteristics Practical issues Psych & cognitive issues Social issues Spiritual issues Adapted from EPEC-O. (2007)
    15. 15. Relaxation therapies  Sleep restriction therapy  Stimulus control therapy  Cognitive behavioral therapy  BiPAP  Palatoplasty  Miller & Arnold (2011).
    16. 16. Hanks et al. (2010).
    17. 17. “Patients may be able to avoid [spiritual] concerns during the day through the distraction of daily activities but have difficulty ignoring them at night. Thus, it is important to directly address a patient’s spiritual concerns, worries, and fears about dying during the day.” Miller & Arnold (2011).
    18. 18. Consider stopping:  Steroids  Stimulant antidepressants  Bronchodilators  Diuretics 
    19. 19. Sanna & Brurera (2002).
    20. 20. Increase stage 2 (N2)  Decrease stages 3 and 4 (N3)  Interfere with slow-wave sleep  Bastien et al. (2003).
    21. 21. Medication Dosage Half-life Tmax Metabolites Comments Other benzodiazepine receptor agonists Zolpidem 5 1.5-4 1-1.5 No Zaleplon 5 1 0.5-1 No Eszopiclone 2 5-7 0.5-2 Minimal Ambien®; imidazopyridine Sonata®; pyrazolopyrimidine Lunesta®; cyclopyrrolone Melatonin agonists Ramelteon 8 1-2 0.5-1 No Rozerem®; Not a controlled substance Adapted from Table 10.12.7, Hanks et al. (2010).
    22. 22. Studied only in depressed insomniacs  25-100mg may improve sleep*  Biphasic half-life (3-6h, 5-9h) 
    23. 23. Proven phase-shifting capability  Mixed evidence for benefit in elderly  Poorly-regulated formulations 
    24. 24.  Sedative-hypnotics Falls  Hip fracture  Cognitive impairment   Preferred Zolpidem (Ambien)  Eszopiclone (Lunesta)  Ramelteon (Rozerem)  Hanks et al. (2010).
    25. 25. Great source of oracles to human kind, when stealing soft, and whispering to the mind, through sleep’s sweet silence, and the gloom of night, thy power awakes the intellectual sight; to silent souls the will of heaven relates, and silently reveals their future fates.
    26. 26. Sleep and it’s disturbance are physiologically complex  Begin with a thorough history and sleep hygiene counseling  Pharmaceuticals are only one treatment, even in palliative care 
    27. 27.   Bastien CH et al. (2003). Sleep EEG power spectra, insomnia and chronic use of benzodiazepines. Sleep. 26(3): 313-317. Carol E (2011). "How Much Sleep Do We Really Need?". National Sleep Foundation. Undated. http://www.sleepfoundation.org/article/how-sleepworks/how-much-sleep-do-we-really-need. Retrieved 2012-09-18.        Davidson JR, MacLean AW, Brundage MD & K Schulze (2002). Sleep disturbance in cancer patients. Soc Sci Med. 54: 1309-1321. EPEC-O (2007). Module 1: Comprehensive Assessment. Hanks G et al., Ed. (2010). Oxford Textbook of Palliative Medicine: Sleep in palliative care. New York, NY. 1059-1083. Hugel H, et al. (2004). The prevalance, key causes and management of insomnia in palliative care patients. J Pall Symp Mgmt. 27(4): 316-321. Maslow A (1954). Motivation and Personality. New York: Harper. Pp 236. Miller M & R Arnold (2011). Fast Facts and Conceps #101, 104, 105. Insomnia: Patient assessment, Non-parmacologic treatments & Phamacological Therapies. EPERC. Sanna P & E Brurera (2002). Insomnia and sleep disturbances. Eur J Pall Care. 9(1): 8-12.
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