my patient can’t sleep – how can we avoid over-use of
TRANSCRIPT
West M
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My patient can’t sleep – how can
we avoid over-use of sleeping pills?
Robin Ferner
University of Birmingham
West M
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Declarations
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I have provided medico-legal opinions on
harm from drugs
I generally sleep soundly
West M
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Do you sleep soundly:
3
POLL
OPEN
1 Always18.18%
2 Usually45.45%
3 Sometimes27.27%
4 Rarely9.09%
5 Never0%
West M
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Sleep
Definition – tricky
Physical quiescence + arousal threshold + rapid reversibility
Functions of sleep – speculative, e.g.
Neuronal housekeeping: brain repair, network reorganization
Cleansing: removing free radicals, neurotoxins
Energy allocation: physiological function -v- energy conservation
&c
4
Assefa. AIMS Neuroscience 2015; 2: 155-171
West M
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Neurobiology of wakefulness & sleep
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Orexin
Ascending reticular
activating system
Melatonin
(REM) sleep
GABA
Adrenaline
Serotonin
SleepWakefulness
West M
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Stages of sleep
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Stage 1 Stage 2 Stage 3
2
Rapid Eye
Movement
2 2 22
Most drugs disturb “sleep architecture”
“sleep architecture”
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Insomnia
7 Tobaldini. Nature Reviews Cardiology 2019; 16: 213-224
Clinical feature Experimental measure
Difficulty in going to sleep sleep onset latency
Difficulty staying asleep waking after sleep onset
total sleep time
Unrefreshing sleep Pittsburgh Sleep Quality Index
Maximum (worst) 21/21
Incidence – up to 1/3 of all adults, increases with age
Effects – bad for psyche, performance, physiology
depression, errors, cardiometabolic risk
West M
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Treatment: NICE Knowledge Summary
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1. Remove underlying causes if possible
4. Advise good sleep hygiene
2. Give advice on driving
3. Refer for Cognitive Behavioural Therapy
5. If Severe symptoms or
Acute exacerbation… short-term ℞
West M
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Potentially alleviable impediments to normal sleep (PAINS)
Pain, pruritus, prostatism…
Anxiety
Insomnia syndromes
Nuisances, neighbours, noisiness
Stimulants
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1. Remove underlying causes if possible
West M
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Insomnia syndromes
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Sleep-related
breathing disorders
Central
hypersomnolence
Circadian rhythm
disorders
Sleep-related
movement disorders
Parasomnias
‘Insomnia disorder’
Narcolepsy
(orexin deficiency)
JW Waterhouse 1872 Undine
1RY central sleep
apnoea
Jet lag
Sleep-related
bruxism
Sleepwalking
Sateia. International Class-
ification of Sleep Disorders-
Third Edition. Chest 2014;
146: 1387-94
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Cochrane review of 6 trials, total 224 patients over 60
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“The data suggest a mild effect of CBT for different aspects of the
sleep problems in older adults.”
ψ 3. Refer for Cognitive Behavioural Therapy
Change, CBT -v- control
Sleep onset latency NS
Wake after sleep onset
Sleep duration
-21% (NS at 12/12)
NS
Montgomery. Cochrane Database Systematic Rev 2003:
CD003161.
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50 students – poor sleepers in three groups
“choose an image; focus on it for 120 s”
“think over the day”
“no instruction”
Concrete imagery and sleep
Sleep latency (min)
Harvey. Behaviour Res Therap 2002; 40: 267–277
“brief training in the identification and elaboration of an
engaging and interesting imagery task … reduced
discomfort associated with unwanted pre-sleep
cognitive activity and reduced sleep onset latency.”
ψ
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https://www.nhs.uk/live-well/sleep-and-tiredness/10-tips-to-beat-insomnia/
4. Advise good sleep hygiene
West M
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A review of empirical evidence
…though epidemiologic and experimental research
generally supported an association between individual
sleep hygiene recommendations and nocturnal sleep, the
direct effects of individual recommendations on sleep
remains largely untested in the general population.
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Irish. Sleep Medicine Reviews 2015;22: 23-36
West M
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Exercise and sleep
16 weeks of exercise in 43 older people
Walking 30–40 min x 4/week
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Active Control
Sleep latency 15 min 24 min
Sleep duration 6.8 h 6.0 h
Pittsburgh Index* 5.4 8.8
King. JAMA1997;277:32-7
*Pittsburgh Sleep Quality Index:
questionnaire, maximum (worst) score is 21/21
West M
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Exercise and sleep
Chronic exercise
Total sleep time (?)
Sleep onset latency (?)
Episodes of wakefulness (?)
A catch:
May not make (middle-aged ♀) patients feel better
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Driver. Sleep Med Rev 2000; 4: 387-402
Rubio-Arias. Maturitas 2017; 100: 49-56
West M
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T’ai chi and sleep
Change,
T’ai Chi
Change,
Control
Sleep latency -23 min -5.6 min
Sleep duration +0.87 h +0.06 h
Pittsburgh Index -0.92 -0.18
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6 months T’ai chi -v- 6 months low intensity exercise
62 -v- 56; mean age 75 y
Li. J Am Geriatr Soc 52:892–900, 2004
West M
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Favours music Favours control
Music and sleep
Five trials of listening to pre-recorded music once a day for ¾ h
Heterogeneous music types
Active 134 patients, control 130 patients: mean difference -2.8
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Jespersen. Cochrane 2015; CD010459
Mean Δ in Pittsburgh Index
Random, 95% CI
West M
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Malted milk drink at bed-time and sleep
Horlicks®
Placebo
Hour of sleep1st 6th
Mean
minutes of
intervening
wakefulness
2
4
6
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Bŕezinóva BMJ 1972; 2: 431-433
We are indebted to Beecham Inc., Clifton, New
Jersey, U.S.A, for supplies of Horlicks powder
8 subjects
West M
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Spicy meals and sleep
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Spicy meal Control
Sleep latency 34.8 min 16.1 min
Sleep duration 423 min 445 min
Time awake 43 min 25 min
Edwards. Int J Psychophysiol 1992;13: 97-100
Six young men
Cross-over study
With or without Tabasco® + mustard
West M
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Non-pharmacological measures have failed
Use cheapest Z-drug/short-acting benzo
Insomnia is interfering with normal daily life
Treatment is for a short period only
Switch only if there is an ADR
5. Short-term ℞
West M
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Drugs inducing sleep
• γ-amino-butyric acid
• Barbiturates
• Benzodiazepines
• Ethanol
• Meprobamate
• Neurosteroids
• Propofol
• Z-drugs
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Cl-
Melatonin
receptor
agonists
GABAA agonists
Orexin
receptor
antagonists
Anti-
depressants
West M
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Barbiturates – 1904
At least 50 marketed
They work
Veronal® (barbitone) – British Pharmacopoeia 1914
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Jordan AC. BMJ 1904 (2253):538-9
West M
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Barbiturate deaths, England and Wales
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López-Muñoz. Neuropsych Dis Treat 2005; 1:329–343
West M
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Benzodiazepines - 1960
Augment the effects of GABA at the receptor
Safe in overdose
Anxiolytic
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extends into the field of the sedativescovers the field of meprobamateextends into the field of the phenothiazinesexerts an effect in some cases that respond to reserpine
West M
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Benzodiazepines – 20 years on
‘Evidence is rapidly accumulating that benzodiazepines are
potentially drugs of dependence, that chronic use is
associated with adverse effects, and that withdrawal may
produce a definite abstinence syndrome.'
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Ashton H. BMJ 1984; 288: 1135-1140
‘Because of the risk of dependence on benzodiazepines
these agents should probably not be given as regular daily
treatment for chronic anxiety.’ Petursson H. BMJ 1981; 283: 643-645
West M
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Benzodiazepines now
Temazepam indicated for:
The short-term treatment of insomnia only when
it is severe, disabling, or subjecting the individual
to extreme stress, especially for those patients in
whom the persistence of a hypnotic effect would
be undesirable.
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SPC Temazepam
West M
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‘The dark side of benzodiazepines’
Hangover effects
Cognitive impairment
Memory impairment
Falls
Road traffic collisions (RR ~ 2)
Rebound insomnia, dependence, abuse
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AtkinT. Pharmacol Rev 2018; 70: 197-245
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Temazepam prescribing in England
2014 - 2019
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0
30,000
60,000
90,000
120,000
150,000
10/06/2014 15/07/2015 18/08/2016 22/09/2017 27/10/2018 01/12/2019
https://openprescribing.net/
Items
Benzodiazepine prescriptions for at least 3 years:
120,000 patients in England Public Health England September 2019
West M
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The Z-drugs
Bind mainly at GABAA α1 subunit
(benzos bind at α1, 2, 3, 5)
Sedative and hypnotic, but less anxiolytic
ADRs very similar to benzodiazepines
30
West M
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Risk of hip fracture with hypnotics
Benzodiazepines or Z-drugs
Use up to 14 days: RR 2.4 [1.9–3.1]
Z-drugs
Use up to 14 days : RR 2.4 [1.7–3.3]
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Donnelly. 2017. PlosOne 12(4): e0174730
West M
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Zolpidem and sleep
6 patients with insomnia
Treated for 18 nights, then withdrawn over 3 nights
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Baseline Zolpidem Withdrawal
Sleep latency 65.7 min 24.3 min 53.8 min
Sleep duration 333 min 385 min 354 min
Monti. Eur J Clin Pharm 1989; 36: 461-466
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Melatonin and sleep
33 Wade BMC Medicine 2010, 8:51
930
373
373
534
177
Active
Pla
cebo
SR
melatonin
Control
Δ Sleep latency -26 min -8.3 min P <0.001
Δ Sleep duration +0.64 h +0.41 h NS
Pittsburgh index -0.39 -0.17 NS
Adults aged 65–80 years 159 active -v- 61 placebo
West M
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Melatonin and sleep
Four trials (845 patients), evidence ‘weak, in favour’
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Costello. Nutrition J 2014; 13: 106
West M
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Antidepressants and sleep
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“There may be a small improvement in sleep quality with
short‐term use of low‐dose doxepin and trazodone
compared with placebo.”
Everitt. Cochrane 2018;CD010753
West M
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Suvorexant* and sleepAn orexin antagonist
Suvorexant
(290)
Control
(193)
Δ Sleep latency -35 min - 27 min
Δ Sleep duration + 51 min + 41 min
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Belsomra® Label
*Unlicensed medicine
West M
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So
There are few satisfactory trials
Usually short
Often small
Uncommonly in insomniacs
Measures are either subjective or complex
Objective and subjective measures conflict
The trials don’t measure dependence
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West M
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Conclusions
At least sleep hygiene, exercise, and music
aren’t “odious”
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Carswell BMJ 1927;i: 1163
“Every hypnotic has been "scientifically”
condemned, and the condemnation has
always been accompanied by a certain
suggestion that the prescriber as well as the
patient is, or is likely to become, an odious
person.”
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West M
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Alcohol and sleep
Standard view:
Alcohol sleep latency, then waking later in the night
(?acute alcohol withdrawal)
But
Dose required to sleep latency is lower
67% insomniac patients slept ‘better’ with alcohol
40
Roehrs T, Roth T. Sleep, sleepiness, sleep disorders and
alcohol use and abuse. Sleep Med Rev 2001;5:287e97.
Pressman. Alcohol and Sleep Review: Flawed Design, Methods, and
Statistics Cannot Support Conclusions. Alc Clin Exp 2015; 39: 941-3
Ebrahim. Alcohol and Sleep I: Effects on Normal Sleep. Alc Clin Exp 2013
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Z-drug prescribing in England
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0
200,000
400,000
600,000
10/06/2014 15/07/2015 18/08/2016 22/09/2017 27/10/2018 01/12/2019
Items
West M
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Blue light and sleep
Bright blue-enriched polychromatic light is no more
effective than standard bright light therapy for phase
advancing circadian rhythms at commonly used
therapeutic light levels
42
Smith. Sleep Med. 2009 March ; 10(3): 287–294