Sleep well

• Sleep


  A reversible behavioral state of perceptual disengagement from and unresponsiveness to the environment

  
• Sleep is not a passive state

  
• Circadian rhythms


  Endogenous autonomous oscillations in physiological activities/behaviours following the ~24 hours cycles

  
• Circadian rhythms


  • Inputs
  • Core oscillator
  • Outputs (i.e., the rhythm)
• Circadian rhythms - the physiology

  1. Input (Zeitgebers)

  2. Master Clock

  3. Physiological outputs cycles

  
• Two-process model


  1. Homeostatic (Process S) – energy debt

  2. Circadian (Process C) – clock based drive
• Circadian rhythms and Sleep – the link

  Energy debt (S)

  Melatonin (C)

  Energy debt/adenosine? (S)

  Melatonin (C)

  Energy debt (S)

  Melatonin (C)
• The neurobiology of sleep

  1. Orexin Neurons

  2. Monoaminergic neurons

  3. VLPO

  4. Limbic System

  5. SCN –master clock

  6. Energy balance

  7. Thalamus

  Cortex

  
• Flip-flop switch regulating sleep-wake

  Mutual inhibition of sleep and wake promoting regions

  
• The functions of sleep

  • Emotional regulation
  • Metabolic function regulation
  • Macromolecule biosynthesis
  • Toxic bi-product/metabolic waste removal
  • Prophylactic cellular maintenance

  Memory functions/consolidation

  Energy balance
• Sleep Architecture


  SOL – sleep onset latency

  WASO – wake after sleep onset

  TST – total sleep time

  SE – sleep efficiency

  REM – Rapid eye movement sleep

  NREM – Non-road eye moement sleep

  N1, N2, N3 stages of sleep

  
• Classification of sleep disorders

  • Insomnias
  • Sleep-related breathing disorders
  • Hypersomnias: narcolepy
  • Circadian rhythm sleep disorders
  • Parasomnias
  • Sleep-related movement disorders: RLS

  Isolated symptoms, & other

  
• Insomnia Disorder - 3rd Edition ICSD/DSM-5

  Difficulty initiating sleep

  Difficulty maintaining sleep continuity

  Poor sleep quality

  The above difficulty occurs despite adequate opportunity and circumstances for sleep

  
• Insomnia Disorder - 3rd Edition ICSD

  • Fatigue/Malaise
  • Attention concentration or memory impairment
  • Social/vocational dysfunction or poor school performance
  • Mood disturbance/irritability
  • Daytime sleepiness
  • Motivation/energy/initiative reduction
  • Proneness for errors/accidents at work/driving
  • Tension headaches and or GI/Symptoms in response to sleep loss

  Concerns or worries about sleep

  
• Insomnia is made on a clinical history (subjective reports of sleep behaviour/sleep diaries) – there is no need for a sleep study

  
• DSM-5 accords insomnia as a disorder in its own right- the terminology primary/secondary insomnia is now outdated
• Epidemiology and risk factors of insomnia

  • Female gender

  Advancing Age

  Occupational Status

  Education Level

  Economic status
• Insomnia overall: 10-30%, Chronic Insomnia: 10-15%, Insomnia Disorder: 3-5%
• 1. 8 million Australians on a particular night would be experiencing insomnia symptoms

  Australian surveys show that between 13-33% of the population report regular difficulty either getting to sleep or staying asleep
• Consequences of insomnia


  • Sleep continuity disturbance

  Insufficient sleep duration

  Circadian phase shifts

  Nocturnal wakefulness

  Cognitive and mood disturbance

  Poor work performance

  Poor work function

  Major depression/anxiety disorders

  Chronic Pain

  Hypertension and CVD

  Diabetes

  Cognitive impairment and dementia

  
• Neurobiology of insomnia


  • Circadian process misalignment

  Delayed or advanced melatonin secretion

  Homoeostatic process irregularities

  Maladaptive sleep health behaviours/altered cognitive pattern

  Overactivity in the hypothalamus, hippocampus, amygdala or prefrontal cortices

  Cognitive, emotional, behavioural and autonomous hyperactivity

  Comorbid psychological or medical issues

  
• Circadian dysregulation


  Sleep disorders

  Genetic chronotype

  Shift work

  Jet lag

  Social jet lag
• Homoeostatic - misalignment


  Irregular sleep wake patterns

  Irregular diet, exercise patterns

  Napping

  Caffeine
• Neuro-psychological models – conceptual cognitive frameworks

  Predisposing factors

  Precipitating factors

  Perpetuating factors
• Hyperarousal stress in insomnia

  Psychological stress, problem solving, worry

  Attention to sleep stimuli/consequences of sleep disturbance

  Behaviour adaptation

  Conditioning

  Mood disorders, Anxiety, Stress, Addiction
• Australian guidelines for insomnia care published in MJA 2013 clearly state that behavioural treatments (CBTi) should be first line and offered along with any pharmacological support
• Long term use of pharmacotherapy is not recommended
• Mood disorders


  • Anxiety
  • Stress
  • Addiction
• Neurotransmitters


  • Monoamine
  • Cortisol
  • Orexin
  • Adenosine
  • 5HT
• Acute changes in ARAS/VLPO


  1. Acute cortical hyperarousal

  2. Process S and C misalignment
• Chronic changes


  1. ARAS/VLPO

  2. Cortical hyperarousal
• Hippocampal volume


  Memory consolidation
• Stages


  • ACUTE
  • SUB-CHRONIC
  • CHRONIC
• Australian guidelines for insomnia care published in MJA 2013 in a special sleep supplement clearly state that behavioural treatments (CBTi) should be first line and offered along with any pharmacological support
• Benzodiazepine receptor agonists (BDZs/Z-drugs)


  • Sleep effect: SOL, N1 ↓ N2 ↓ REM ↓, SWS ↓ TST ↓ WASO ↓
  • Mechanism of action – activate VLPO (GABAergic inhibition – GABAA)
  • Most common drugs used – temazepam/oxazepam/zolpidem/zopiclone
  • Evidence based recommendation – short term use (<2-4 weeks) – then deprescribe
  • Issues – serious adverse effects, misuse, tolerance
• Orexin receptor antagonists


  • Sleep effect: SOL ↓, N1 ↓ N2 ↓ REM ↓, SWS ↑ TST ↑ WASO ↓
  • Mechanism of action – block actions of orexin (OX1 and OX2)
  • Drugs available – suvorexant, lemborexant
  • Evidence based recommendation – assess use after 7-10 days +re-evaluate use in 3 months
  • Issues – adverse effects – dependence (less potential than BDZ/Z-drugs) abnormal dreams, fatigue, dizziness, sleep paralysis, hallucinations during sleep, suicidal ideation
• Off-label use


  • Amitriptyline/Doxepin
  • Mirtazapine
  • Agomelatine
  • Quetiapine
• Antihistamines


  • Mechanism of action – Histamine mediates wakefulness – blockers of H1 receptors can mediate sleep
  • Tolerance develops very quickly even in 4 days (e.g. for diphenhydramine)
  • Most common drugs used – doxylamine/diphenhydramine etc.
  • Evidence based recommendation (poor evidence) – short term use (<10 consecutive days) for 'acute' insomnia
  • Sleep effect: REM ↓ and augments NREM – better for sleep maintenance
  • Issues – serious adverse effects, misuse, tolerance

  
• Melatonin


  • Chronobiotic – "a drug able to influence the phase and/or the period of the circadian clock and adjust directly or indirectly the timing of internal rhythms"
  • Functionality range – environmental cues to master to peripheral clock synchrony + physiological control, gene expression, anti-oxidant, links master clock with brain sleep centres
  • Clinical use – insomnia in adults/older people, CRDs, also trialled in dementia, schizophrenia, depression and metabolic disorders
  • Mechanism of action – exogenous melatonin attenuates the wake-promoting drive through the circadian system – therefore promoting sleep (MT1 and MT2 receptor agonist)
  • Drug available – melatonin-controlled release (melatonin has short half life of 40 mins)
  • Evidence based recommendation – limited benefit in insomnia disorder>55 years
  • Issues – good A/E profile, no dependence/withdrawal rebound insomnia (arthralgia, back pain, weakness etc)
  • Sleep effect: SOL ↓, sleep architecture is maintained, subjective sleep quality ↑

  
• Melatonin (Rx –specialist care)


  • Evidence for use in children with neurodevelopmental disorders where abnormal melatonin secretion and circadian rhythmicity is noticeable
  • 2–18 years: extended-release formulation 1 mg and 5 mg): oral, initially 2 mg at night, 30–60 minutes before bed; after 3 weeks, increase if necessary to 5 mg at night (maximum 10 mg). Review every 3 months and 6 months safety data for up to 2 years of use