Sleep-related breathing disorders causing excessive daytime sleepiness are rarely treated with drugs. Sleepiness caused by the night-time disruption of obstructive sleep apnoea syndrome is sometimes not completely abolished by the standard treatment of continuous positive airway pressure overnight, and the use of wake-promoting drugs, e.g. modafinil, is being evaluated in these patients.
Narcolepsy is a chronic neurological disorder and is characterised by excessive daytime sleepiness (EDS), usually accompanied by cataplexy (attacks of weakness on emotional arousal). These symptoms are often associated with the intrusion into wakefulness of other elements of rapid eye movement (REM) sleep, such as sleep paralysis and hypnagogic hallucinations, i.e. in a transient state preceding sleep.
Stimulants are effective in the treatment of EDS due to narcolepsy. Suitable agents include dexamfe-tamine, methylphenidate, and modafinil.
Amfetamines release stored neurotransmitters, primarily dopamine and noradrenaline, in the brain. This causes a behavioural excitation, with increased alertness, elevation of mood, increase in physical activity.
Dexamfetamine, the dextrorotatory isomer of amfetamine, is about twice as active in humans as the laevo isomer and is the main prescribed amfetamine. It is rapidly absorbed and its duration of action varies among individuals; most people with narcolepsy find twice daily dosing optimal to maintain alertness during the day.
About 40% of narcoleptic patients find it necessary to increase their dose, indicating tolerance. Although physical dependence does not occur, there is mental and physical depression on withdrawal.
Unwanted effects include edginess, restlessness, insomnia and appetite suppression, weight loss, and increase in blood pressure and heart rate. Amphetamines are commonly abused because of their stimulant effect but this is rare in narcolepsy.
Methylphenidate releases stored dopamine but most of its action is to inhibit uptake of central neurotransmitters. Its effects and adverse effects are very similar to amphetamines. Methylphenidate has a low systemic availability and slow onset of action, making it less liable to abuse. Its duration of effect is quite short (3-4 h) so patients with narcolepsy need to plan the timing of their tablets to fit with daily activities. It is also used in attention deficit/hyperactivity disorder (see below).
Modafinil is a wake-promoting agent whose specific biochemical mechanism of action is obscure. It increases brain concentrations of dopamine after chronic administration in animals but has no overtly stimulant effect like amphetamines. It appears to have a slow onset and its action lasts 8-12 h; abuse potential is very low. Modafinil is used in narcolepsy and other hypersomnias and has also been studied in normal people who need to stay awake for long periods and function well.
In narcolepsy, patients usually need a stimulant for their hypersomnia and a TCA or SSRI for their cataplexy, so care should be taken when combining these. Dexamfetamine and methylphenidate must not be given with MAOIs. There is potential for interaction between methylphenidate and TCAs (hypertension) and SSRI antidepressants. It appears that modafinil, methylphenidate and dexamfetamine may themselves be combined without adverse outcome (modafinil is occasionally used regularly and dexamfetamine added intermittently when peak alertness is particularly critical). Modafinil accelerates the metabolism of oral contraceptives, reducing their efficacy.
Cataplexy is most effectively treated with 5HT uptake-blocking drugs such as clomipramine or fluoxetine, or some other antidepressant drugs, e.g. reboxetine.
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