Lecture given to the West of Scotland Pain Group on Wednesday 24th November 2010 in the Ebenezer Duncan Centre, Victoria Infirmary, Glasgow by Dr Paul Reading, Consultant Neurologist. In this talk, Dr Reading describes the importance of good quality sleep and how pain and sleep interact. www.wspg.org.uk

1. Sleep, Pain and Drugs
Paul Reading
Department of Neurology
The James Cook
University Hospital

2. 1. defining sleep and the sleep drive
2. how much sleep do we need?
importance of quantity and quality
3. the effects of sleep deprivation
4. the causes of excessive sleepiness
5. the relation between pain and sleep
6. effects of drugs for pain on sleep quality

3. Everyone and every animal
needs to sleep!
If sleep doesn’t serve some vital function it is
the biggest mistake evolution ever made.
Alan Rechtschaffen
Sleep is of the brain, by the brain and
for the brain
William Dement
The best bridge for repair between despair
and hope is a good night’s sleep
Joseph E Crossman

4. 1 2 3 4 5 6 7
Time (hours through night)
WAKING
REM
Sleep
I
II
III
IV
Typical Hypnogram
of Young Adult
REMREM REM REM

5. EEG (central)
EEG (occipital)
OCULOGRAM
CHIN EMG
PHYSIOLOGICAL
CORRELATES
OF SLEEP
STAGES
50%
15%
10%
20%
~5% total sleep

6.  Borbély’s two factor hypothesis (1982) :
the need for sleep dependent on :
• homeostatic factors
(process S)
• “hour glass”
• circadian factors
(process C)
• nadirs of alertness at ~ 4 am & ~ 3 pm
The Triggers for Sleep
SKIN MITOSIS

7.  We still don’t really know!
 There is clear inter-individual variation
e.g. Einstein v Thatcher and Napoleon
but whole populations fairly homogenous :
~ 7 hrs of quality sleep needed for most
 In Western society we [probably] sleep less
than 90 years ago (young adults 6.8 v 8.2h)
 The idea of a chronic “sleep debt” (that must
be repaid) has become a widespread concept …
How much Sleep do we Need?

8. British Medical Journal :
editorial – Sept 29th
“The subject of sleeplessness is once more
under public discussion. The hurry and
excitement of modern life is held to be
responsible for much of the insomnia of which
we hear; and most of the articles and letters
are full of good advice to live more quietly
and of platitudes concerning the harmfulness
of rush and worry. The pity of it is that so
many people are unable to follow this good
advice and are obliged to lead a life of anxiety
and high tension.”
1894

9. 8 hrs/night
0 14 140
6 hrs/night
4 hrs/night
0 hrs/night
Data suggest increasing signs of sleepiness
with regular 6 hours of nocturnal sleep
but subjective sleepiness ≠ objective sleepiness
Van Dongen et al Sleep 2002
PVT = psychomotor vigilance test
How much Sleep does the Brain Need?
0 14 0 14

10.  animals will die in about 2 weeks
• both REM and non-REM needed
• mechanism of death?
Acute Sleep Deprivation
in animals

11. The Effects of Acute Sleep Deprivation
in humans
Sleepy!

12. The risks of sleepiness
Selby Rail Crash
06:12h: car drifts off road, down embankment onto railway.
Hit by passenger train - derailed, then hit by goods train 100 fatal & serious injuries

14.  in late 1960’s landmark studies on prolonged SD
students paid on a sliding pay scale (up to 205 hours)
• day 3 - significant concentration problems,
visual symptoms also prominent
• day 5 - intermittent confusion, numerous lapses
• day 7 - hallucinations / delusions,
psychomotor retardation (“dementia”)
 no consistent biochemical abnormalities (cortisol higher)
 no long lasting psychological / cognitive sequelae
Acute Sleep Deprivation
in humans

15. The Effects of Acute Sleep Deprivation
 Involuntary “micro sleeps” occur
 Reaction times slower
 Attention becomes unstable
• vigilance poor, lapses increase
• short term memory suffers
• unable to sustain performance
• note effects on driving
 Problem solving and judgement deteriorate
• frontal lobe function particularly affected
 Pain threshold reduced?

16. Dawson & Reid (Nature 1997)
Effect of Sleep Deprivation on Psychomotor Performance
Compared With Blood Alcohol Concentration

17. The Effects of Acute Sleep Deprivation
Brain imaging
 after 24hr SD
prefrontal
cortex (PFC)
underactive
 during cognitive tasks
PFC and thalamus
appear overactive
similar to old age
brain has to work
“harder”?

18.  impaired sense of humour (Sleep 2006)
The Effects of Acute Sleep Deprivation
Headline 1:
Vet investigates failed
panda mating
Headline 2:
Panda mating fails:
vet takes over

19.  all drugs improved PVT scores
 placebo performance 1 SD below expected
 modafinil improves visual joke appreciation
due to improved frontal lobe function?
Results

20.  greater risk taking and reduced learning about losses (Sleep 2007)
The Effects of Acute Sleep Deprivation
• If 24h SD, overactivation in nucleus accumbens
when taking a risky gamble
• higher expectation of reward?
• If 24h SD, under-activation of orbitofrontal cortex
following a loss
• reduced learning about losses?

21. The Effects of Acute Sleep Deprivation
• After 24h SD, “angry” and “happy” emotions less recognised
recovery after sleep period

22. The Adverse “Emotional” Effects of
Sleep Deprivation
 Sleep loss in medical residents amplified negative emotional
consequences of disruptive daytime experiences while positive
benefits of rewarding activities were blunted (Zohar 2005)
 In test of emotional memory,
f-MR scans show limbic areas
overactive to negative stimuli
> 1 night SD (Yoo et al 2007)
 “hyper-limbic state”
 due to loss of functional
connectivity with PFC?
note similarities to depression
i.e. over-reactive to negative events

23. Does chronic severe sleep deprivation
and/or pain shrink (age) the brain?
gray matter changes in
brains of severe OSA in
middle-age men
Eun Yeon Joo et al
Sleep 2010
gray matter changes in
brains of sufferers of
chronic back pain and
fibromyalgia
Apkarian et al
J Neurosci 2004
Kuchinad et al
J Neurosci 2007

24. (Possible) Systemic Effects of
Chronic (partial) Sleep Deprivation
 Sleep loss may affect metabolism
• resistance to insulin, pre-diabetic state
due to increased sympathetic activity / cortisol?
especially in OSA + metabolic syndrome
• hunger signals increased
resistance to leptin, the “satiety hormone”
 Sleep loss and inflammatory responses
• altered immunity
e.g. less effective vaccinations, increased cancer? (note Danish ruling)
• inflammatory markers in blood increased (e.g. CRP)
blood “stickier”, vascular complications

25. Chronic Sleep Deprivation
don’t forget children!
 growth hormone deficiency?
hGH spurt with
first SWS period

26. The Causes of Excessive Sleepiness
Primary Sleep Disorders
with sleep-wake dysregulation
• Narcolepsy
• Idiopathic hypersomnolence
Sleepiness Secondary to a
Chronic Disorder
• Obstructive Sleep
apnoea/hypopnoea
syndrome
• Restless legs syndrome
• Parkinson’s disease
• Depression
• Myotonic dystrophy
• Multiple sclerosis
Circadian Misalignment
• Shift work sleep
disorder
• Delayed sleep phase
syndrome
In real life? (voluntary) sleep restriction
the environment
pain
other medical conditions
5% of population?

27. “Secondary” Insomnia
Medical causes
• Obstructive sleep apnoea
• Asthma
• Oesophageal reflux
• Prostatism / nocturia
• Pain syndromes
diabetic neuropathy,
fibromyalgia
Neurological causes
• Restless legs syndrome
• Parkinson’s disease
• Dementia
• Morvan’s syndrome
• Fatal familial insomnia
Psychiatric causes
• Medication related
(stimulating anti-
depressants)
• Withdrawal-related
• Anxiety disorders
• Mood disorders “sleep toxins”

28. Pain and Sleep
Genetics

29. Pain and Sleep
a bi-directional relationship
Pain ↑ → Sleep ↓
5-HT ↓ → Pain ↑ and Sleep ↓
Sleep ↓ → Pain ↑
 Clinical observations in burns patients (Raymond et al Pain 2001)
subjective sleep quality predicts pain scores subsequent day
but pain intensity during day does not predict sleep quality
 Sleep deprivation in animals (REM) lowers pain threshold
and reduces opiate efficacy
pressure pain and heat tolerance affected, not general sensation

30.  Sleep deprivation (REM?) decreases pain thresholds
poor sleep quality also affects QOL and ability to cope
Roehrs et al Sleep 2006
Pain and Sleep
0 hrs8 hrs 4 hrs
8 hrs NRem Rem 0 hrs

31.  commonly used drugs to treat nocturnal pain may
facilitate sleep onset and increase duration
but not improve its quality :
 Opiates REM ↓↓ SWS ↓↓ arousals ↑↑↑
 AED’s REM ↓ SWS ↑
 Anti-dep REM ↓(↓) SWS ↓↔ sleep maintenance ↓↔
 BZ’s / alc REM ↓ SWS ↓ sleep maintenance ↑
Pain, Drugs and Sleep

32.  Sleep architecture “improved” by Pregabalin
Pregabalin compared to placebo and BZ over 3 nights in volunteers
Hindmarch et al Sleep 2005
after pregabalin, control subjects have:
1. increased SWS (absolute and proportional values)
2. reduced overall sleep latency and REM latency
3. sleep reported as more “refreshing”
Pregabalin and Sleep

33.  RCT (n=370)
• twice daily PGB
• improved pain
scores
• improved sleep
interference
(sleep diaries)
Van van Seventer et al 2006
Pregabalin, Pain and Sleep Interference
in post-herpetic neuralgia

34.  Gabapentin
 Tiagabine (Gabatril)
 Xyrem (sodium oxybate, GHB)
 Melatonin?
 Cannabis?
Other drugs that “improve” or increase
deep (slow wave ) sleep

35. Fibromyalgia
 Fibromyalgia common (3%?)
 Defined by pain symptoms but sleep abnormal
poor sleep efficiency, reduced stage 4
“alpha intrusions” into stage 4, fewer spindles (stage 2)
 Several studies have looked at Pregabalin
recent phase III, 748 patients, pain and sleep improved
Mease et al, J Rheumatology (Mar 2008)
 Sodium Oxybate also appears effective
small open study (n=18) but sleep, pain and fatigue improved

36. Fibromyalgia
 Very recent randomised controlled trial
Moldofsky J Rheum 2010
 195 FM patients randomised to
oxybate (4.5, 6G) or placebo
fatigue improved on VAS
pre-Rx: sleep efficiency 76%
SWS 41 min
post-Rx: sleep efficiency 85%
6G SWS 61 min
subjective sleep ratings correlated
with pain scores

37. anxiety
poor
sleep
pain
Pain should not be
treated in isolation
DON’T FORGET SLEEP!
quantity and quality...