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SLEEP DISORDERS
What are sleep disorders?
Occasional difficulty in sleeping, or in staying awake when
desired, is a very common experience and may be considered a
normal part of life. However, a prolonged inability to get to sleep
or stay asleep (insomnia), or a sudden and irresistible urge to
fall asleep at inappropriate moments during the day (narcolepsy),
sufficient to disrupt normal life, are considered to be sleep
disorders. They require medical investigation, as do sleepwalking
and recurring sudden inability to breathe during sleep (sleep
apnoea), Restless legs syndrome (a feeling of discomfort in
the legs when in bed that may be alleviated by moving the legs)
is a disorder of the nervous system that commonly results in
disturbed sleep.
There are many factors that may contribute to sleep difficulties,
including the physical environment (room too hot/too light/too
noisy/bed too uncomfortable, etc), medical factors (arthritic or
other pain, waking up at night to urinate, side-effects of
medication, etc), and psychological influences (anxiety,
depression, inter-personal conflict, etc), as well as lifestyle
aspects (irregular routines, shift-working, food or drink consumed
shortly before bedtime, or in excess, and so on) and these must
all be considered and eliminated as possible causes for the sleep
disturbance. Nevertheless, it may prove impossible to resolve all
sleep difficulties without at least short-term use of medication,
and this section considers some of the medicines in use or
development for this purpose.
Who do sleep disorders affect?
Insomnia can affect almost anyone. It is estimated that 10-15 per
cent of the adult population suffers from chronic insomnia and it is
even more frequent later in life. Insomnia is more frequent among
those with obesity, high blood pressure, congestive heart failure
and anxiety or depression. In an Australian survey of people over
60, those reporting sleep difficulties were more than three times
more likely to be depressed than those without such difficulties
and similar data have been reported from other countries.
Narcolepsy is estimated to affect about 1 in 2,000 people in the
UK, but only about 2,500-3,000 have been diagnosed and are
being treated. It is a life-long condition.
Sleep apnoea is most likely to affect people who are overweight or
obese, and the risk increases with age. In a population survey in
the United States, a quarter of those interviewed were judged to
have a high risk of sleep apnoea, including 57 per cent of obese
individuals. Like obesity, sleep apnoea has been associated with a
raised risk of developing diabetes.
Restless legs syndrome has been reported to affect between
3-9 per cent of adults in the general population. It becomes more
common with age and affects women more often than men. It
has been reported to be more common among people with
type 2 diabetes.
Present treatments and shortcomings
Historically, insomnia which was not controlled by improving
sleeping habits and other non-medical measures was most often
treated with barbiturates or benzodiazepine tranquillisers. The
barbiturates are controlled drugs and have fallen from favour
because of their potential for the development of tolerance and
dependence and the dangers of overdose. Benzodiazepines also
have a potential for addiction, but are considered acceptably safe
for short-term use. Short-acting types may be preferred, as they are less likely to cause drowsiness during the day. 'Rebound insomnia'
may occur on discontinuing benzodiazepines, especially if they
have been used for an extended period.
More recently, three hypnotic (sleep-inducing) medicines have
been introduced for insomnia that have a different chemical
structure from benzodiazepines. These are zaleplon (Sonata,
Wyeth), zolpidem (Stilnoct, sanofi-aventis) and zopiclone
(Zimovane, sanofi-aventis). These medicines were developed
to be less likely to induce tolerance and dependence than
benzodiazepines, but they act partly through the same receptors
in the brain, which act on the neurotransmitter gamma-amino
butyric acid (GABA), and are also recommended only to be used
in the short term.
Only one medication is available for the treatment of the excessive
daytime sleepiness associated with narcolepsy and with obstructive
sleep apnoea. This is modafinil (Provigil, Cephalon). How it works
is not precisely known, but it acts as a central stimulant to promote
wakefulness. Obstructive sleep apnoea is otherwise most often
treated mechanically, using a continuous positive air-pressure
(CPAP) pump and face-mask at night, to keep the airways open
during sleep.
Medicines acting on the neurotransmitter dopamine play a central
role in the treatment of restless legs syndrome. Two are available
for use in the UK: pramipexole (Mirapexin, Boehringer Ingelheim)
and the more recently introduced ropinirole (Adartrel,
GlaxoSmithKline). Nausea and other gastrointestinal symptoms,
sleepiness and uncontrolled movements may occur as side-effects
with these medicines.
What's in the development pipeline?
Additional compounds acting on GABA receptors are in
development for treating insomnia. Neurocrine Biosciences has a
new non-benzodiazepine agent (Indiplon) in Phase 3 trial that
acts on GABA receptors believed to be responsible for promoting
sleep. It is being aimed first at insomnia resulting from difficulty
with getting to sleep. Gaboxadol (Merck Sharp & Dohme
/Lundbeck), which is also in Phase 3 trial, appears to interact
directly with GABA receptors different from those on which
benzodiazepines act. It increases the amount of slow-wave (deep)
sleep without affecting REM-sleep. Two other GABA-receptor
agents are in Phase 2 trials: Evotec's EVT-201 and the partial
agonist, Neurogen's NG2-73.
Several compounds are under investigation that interact with
serotonin receptors instead of GABA receptors. These include
eplivanserin (Phase 3) and volinanserin (M-100907, Phase 2) from
sanofi-aventis, Organon's Org 50081 (Phase 3), Lilly's pruvanserin
(Phase 2), Acadia's ACP-103 and Arena's ADP125, both in Phase 2
trials. These offer the prospect of increased slow-wave sleep and
improved treatment of sleep maintenance, i.e. fewer awakenings
and more rapid return to sleep after awakening.
Perhaps the greatest excitement in the treatment of insomnia
revolves around new compounds that act on melatonin receptors.
Melatonin is a naturally occurring hormone that has long been
known to be important for circadian rhythms and the sleep-wake
cycle and receptors in the brain are known to regulate these
circadian rhythms. Takeda has developed a new agent, ramelteon
(Rozerem) that acts selectively on these receptors, which is in
Phase 3 trials in Europe. Results from studies showed that
ramelteon reduced the time it took to fall asleep and its use was
not associated with rebound insomnia or withdrawal symptoms
on stopping treatment.
Two other new agents that act on this system are also in Phase 3
trials. Alliance Pharmaceuticals has synthetic melatonin (Posidorm)
under study in elderly patients with insomnia and in those with
shiftwork-associated sleep disorder and Vanda is studying VEC-162
in transient insomnia. Another melatonin analogue being studied
in elderly patients is Phase2 Discovery's PD-6735, which is in
Phase 2 trial.
New treatments are also being explored for restless legs syndrome.
Schwarz Pharma has a skin patch form of rotigotine (Neupro),
which is already indicated for use in Parkinson's disease, in Phase 3
trial and Newron Pharmaceuticals is developing safinamide, which
has reached Phase 2. It is also in development for treating
Parkinson's disease. Lastly, XenoPort has reported encouraging
results from its Phase 2 trials of XP13512, a derivative of
gabapentin (Neurontin, Pfizer) which has long been used to treat
epilepsy, and XP13512 is now in Phase 3 development in restless
legs syndrome by XenoPort's partner GlaxoSmithKline.
FOR FURTHER INFORMATION CONTACT:
UK NARCOLEPSY ASSOCIATION (UKAN)
PO Box 13842, Penicuik
Lothian, EH26 8WX
Scotland
Phone: 0845 450-0394
Website: www.narcolepsy.org.uk
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