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Published on 1 March 2006

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Treatment of cataplexy in narcolepsy

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John M Shneerson
MA DM FRCP
Consultant Physician/Director
Respiratory Support and Sleep Centre
Papworth Hospital
Cambridge
UK
E:john.shneerson@papworth.nhs.uk

Cataplexy is the sudden onset of muscle weakness during wakefulness.(1) It is almost always triggered by sudden or intense emotion, usually laughter. It is a specific feature of narcolepsy, a condition characterised by fragmentation and instability of rapid eye movement (REM) sleep, such that the muscle atonia which is normal in REM sleep can appear during wakefulness.

Cataplexy may be mild and only cause, for instance, twitching of the face or the upper limbs, but it can lead to generalised muscle weakness in which the subject falls to the ground. Each episode usually lasts for a few seconds or up to two minutes. Recovery is sudden and complete. Patients tend to avoid situations in which sudden or intense emotions may be felt and develop coping techniques of controlling the emotions in order to prevent cataplexy. Episodes can sometimes be aborted by tensing the muscles at the onset of an attack. Attention to sleep hygiene, particularly avoiding sleep deprivation, may help, but nevertheless most subjects require drug treatment, usually in the long term.

The neurological mechanisms underlying cataplexy are complicated. Emotional activity in the limbic system activates the pontine REM sleep centres and nearby regions to increase the activity in the medullary motor centres. This causes glycine-mediated inhibition of the alpha motor neurones in the spinal cord with loss of muscle activity. During wakefulness, the pontine REM sleep centres are inhibited by noradrenaline and serotonin (5HT) released by activity in the locus coeuruleus and raphe nuclei, but in REM sleep and during cataplexy this inhibition ceases.

Several agents are available for treating cataplexy.(2) These can be divided into three groups. First, antidepressants, which have relatively little effect on the excessive daytime sleepiness of narcolepsy but may relieve some of the other REM sleep-related phenomena such as vivid dreams and sleep paralysis as well as cataplexy. Secondly, drugs such as amphetamine and related agents, which are usually prescribed to improve daytime alertness but which also have an anticataplectic action. Lastly, sodium oxybate is a new and unrelated compound that improves cataplexy and other REM sleep-related phenomena, as well as daytime sleepiness.

Antidepressants
Cataplexy is suppressed by drugs that increase 5HT and noradrenergic activity and is worsened by antagonists of these transmitters, such as prazosin, an alpha1-antagonist, and by cholinergic agents. The efficacy of tricyclic antidepressants relates to their noradrenergic and anticholinergic activity. The 5HT-promoting effect is important for selective serotonin reuptake inhibitors (SSRIs). Interestingly, antidepressants almost immediately relieve cataplexy, whereas their action in combating depression may take around one to two weeks to appear. This suggests that the mechanism of action is different in these two situations. Although antidepressants have been widely used for many years to treat cataplexy, there is surprisingly little data about their effectiveness or the comparative value of each drug. Their activity presumably reflects their differing profile at noradrenergic and 5HT synapses and their anticholinergic activity.

Tricyclic antidepressants
Clomipramine is the only tricyclic antidepressant licensed for cataplexy in the UK. It is probably the most effective at suppressing REM sleep,(3) and it blocks 5HT uptake. Common side-effects include weight gain (which is also often a feature of narcolepsy itself), impotence and worsening of daytime sleepiness. Rebound cataplexy can be intense if these drugs are suddenly withdrawn for any reason.

SSRIs
The selective nature of these drugs, acting only on 5HT synapses, may be responsible for their slightly lower effectiveness compared with tricyclic anti‑depressants. Fluoxetine(4) and paroxetine have been the most widely used, and some studies have shown them to be almost as effective as clomipramine.

Other antidepressants
Monoamine oxidase inhibitors such as phenelzine are effective in suppressing REM sleep and cataplexy but are rarely used because of their side-effects. Newer agents, particularly venlafaxine, viloxazine(5) and reboxetine,(6) have been shown to have useful anticataplectic activity and may also improve daytime alertness.

Wakefulness-promoting drugs
Modafinil, which is now the first-line drug for treating daytime sleepiness in narcolepsy, does not have any significant effect on cataplexy. In this respect, it differs from amphetamines and related drugs. These enhance activity at dopamine, noradrenaline and 5HT synapses. They cause presynaptic release of preformed transmitters and inhibit the reuptake of dopamine and noradrenaline, particularly in the ascending reticular activating system and cerebral cortex.

Dexamphetamine is most commonly used in narcolepsy and has a significant anticataplectic action, presumably because of its effect on nor‑adrenergic synapses. Similar but less well-documented effects are seen with selegiline.(7) The risk of dependency in narcoleptics appears to be low, but tolerance develops in around 30% of subjects.

Sodium oxybate
This Schedule 4 controlled drug is unrelated to antidepressants or any other drug used in the treatment of narcolepsy. It is licensed for use in cataplexy in the USA and Europe, including the UK. Sodium oxybate is a four-carbon fatty acid and a natural metabolite of GABA (gamma- aminobutyrate). The peak plasma concentration is attained around one hour after ingestion. It has a short half-life, but its clinical effects are prolonged and are unrelated to plasma concentration. Its mechanism of action is uncertain, but it probably works through specific GHB (gamma- hydroxybutyrate) receptors. It increases the total sleep time and shortens the duration of REM sleep.

Initial studies have shown that it has a dose-related action in relieving cataplexy and that this increases gradually over several weeks.(8) The effect appears to be greater than that of antidepressants and other drugs.(9) There is no rebound worsening of cataplexy after discontinuing sodium oxybate.(10) The usual dose is 4.5–9g, with half taken before sleep and the other half 2.5–4 hours later.

There is little evidence for dependency or tolerance in therapeutic doses,(8) but it has been used ­illicitly to facilitate sexual assault and as a bodybuilding drug in view of its effect on growth hormone. Side-effects include nausea, abdominal pain, headaches, dizziness, nocturnal confusion and nocturnal ­enuresis.(11) It should be avoided in pregnancy and during breast-feeding. It does not interact with modafinil or tricyclic antidepressants and can be used in combination with these, but its effects are potentiated by alcohol and hypnotics, with which it should not be taken.

Conclusions
Cataplexy is often the most intrusive symptom of narcolepsy, but there are several ­pharmacological options for its treatment. Antidepressants are most commonly prescribed, but dexamphetamine taken primarily to reduce daytime sleepiness also has a useful anticataplectic effect.

Recent studies of sodium oxybate have suggested that it is the most effective treatment of cataplexy. It can be used in combination with antidepressants or wakefulness-promoting drugs, but careful patient selection is required in view of its possible side-effects and interaction with alcohol.

References

  1. Shneerson JM. Sleep medicine: a guide to sleep and its disorders. 2nd ed. Oxford: Blackwell Publishing; 2005.
  2. Houghton WC, Scammell TE, Thorpy M. Pharmacotherapy for cataplexy. Sleep Med Rev 2004;8:355-66.
  3. Chen CN. The use of clomipramine as a REM sleep suppressant in narcolepsy. Postgrad Med J 1980;56 Suppl 1:86-9.
  4. Langdon N, Shindler J, Parkes JD, Bandak S. Fluoxetine in the treatment of cataplexy. Sleep 1986;9:371-3.
  5. Guilleminault C, Mancuso J, Salva MA, et al. Viloxazine hydrochloride in narcolepsy: a preliminary report. Sleep 1986;9:275-9.
  6. Larrosa O, de al Llave Y, Bario S, et al. Stimulant and anticataplectic effects of reboxetine in patients with narcolepsy: a pilot study. Sleep 2001;24:282-5.
  7. Roselaar SE, Langdon N, Lock CB, et al. Selegiline in narcolepsy. Sleep 1987;10:491-5.
  8. US Xyrem Multicenter Study Group. A 12-month, open-label, multicenter extension trial of orally administered sodium oxybate for the treatment of narcolepsy. Sleep 2003;26:31-5.
  9. Xyrem International Study Group. Further evidence supporting the use of sodium oxybate for the treatment of cataplexy: a double-blind, placebo-controlled study in 228 patients. Sleep Med 2005;6:415-21.
  10. US Xyrem Multicenter Study Group. The abrupt cessation of therapeutically administered sodium oxybate (GHB) does not cause withdrawal symptoms. J Toxicol Clin Toxicol 2003;41:131-5.
  11. The US Xyrem Multicenter Study Group. A ­randomized, double-blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep 2002;25:42-9.


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