General aspects of management and treatment
– Information about the disease should be provided to the patients and relatives.
– Acceptance of the diagnosis is crucial and facilitates adherence to therapeutic advices.
– There are only two treatment modalities with proven efficacy: lifestyle advice and pharmacological therapy.
Patients should provide themselves the opportunity to have enough nocturnal sleep, and live a regular life: going to bed at the same hour each night, and getting up at the same time each morning as much as possible. Scheduled daytime naps or short naps just before certain activities demanding a high degree of attention temporarily improve sleepiness in most patients. Alcohol and sedating daytime medication should preferably be avoided.
Treatment of excessive daytime sleepiness (EDS)
Stimulants are the main treatment for EDS. These include dexamphetamine (5-60 mg /day), methylphenidate (10-60 mg / day), modafinil (100-400 mg / day), and armodafinil (150-250 mg / day). These drugs enhance the release and inhibit the re-uptake of catecholamine and to a lesser extent of serotonin in the central nervous system and the periphery. Side-effects and tolerance are major drawbacks in the use of stimulants. Addiction does not seem to be a problem in narcoleptics though data are limited. Long-acting agents (modafinil, armodafinil, dexamphetamine, and sustained release formulations of methylphenidate) seem to be better tolerated than short acting drugs (methylphenidate). Dexamphetamine and sustained release formulations are off-label in most European countries. The quick and short acting stimulants can be used to good effect when ‘targeted’ at social events or difficult periods during the day. The possibility of induction of human hepatic cytochrome P450 enzymes by modafinil should be borne in mind. Modafinil for example increases the metabolism of oral contraceptives.
Sodium oxybate, acting as an agonist at the GABAB receptor is effective in reducing EDS, particularly at dosages of 6-9 grams per night (divided in 2 doses, the second dose must be ingested 3-4 hours after the first). Efficacy and side-effects are both dose-dependent. Side-effects are usually mild, particularly when compared to those occurring with other drugs. Nevertheless, sodium oxybate has a black box warning because it is a potent CNS depressant with abuse potential. While the most frequent side effect is nausea, the most disabling ones are enuresis and sleep walking. Weight loss can occur. Sodium oxybate should not be used in conjunction with other sedatives or alcohol. In patients with OSAS, co-treatment with continuous positive airway pressure (CPAP) is often indicated. The effect of high dosages on EDS is comparable to that of modafinil. However, combination therapy with modafinil is even more effective.
Pitolisant, an inverse H3 agonist, has been approved for the treatment of excessive daytime sleepiness in Europe in 2016. At doses of 18-36 mg/day it has a good efficacy as measured by the MWT and Epworth Sleepiness Scale.
Treatment of cataplexy, hypnagogic hallucination and sleep paralysis
Most studies concerning the treatment of the REM sleep dissociation phenomena have focused on cataplexy, but most drugs reduce hypnagogic hallucinations and sleep paralysis as well. Sodium oxybate and tricyclic antidepressants are considered the most effective treatments for cataplexy. The different tricyclic antidepressants all inhibit the re-uptake of norepinephrine and serotonin and are potent REM sleep inhibitors. The most commonly used ones are imipramine (10-100 mg / day), and clomipramine (10-150 mg / day). Many clinicians consider low dosages of clomipramine to be the treatment of choice. As with stimulants, side effects, and to a lesser extent tolerance, are the major drawbacks. Side-effects are largely due to the anticholinergic properties; the most frequently reported ones are a dry mouth, increased sweating, sexual dysfunction (impotence, delayed orgasm, erection and ejaculation dysfunction), weight gain, tachycardia, constipation, blurred vision, and urinary retention. Tricyclic antidepressants should never be stopped abruptly because of the risk of severe aggravation of cataplexy, which may even lead to a ‘status cataplecticus’.
There is some experience with alternative antidepressants, especially selective serotonin re-uptake inhibitors and more selective noradrenergic reuptake inhibitors such as fluoxetine, zimelidine, viloxazine, femoxitine, fluvoxamine, paroxetine, venlafaxine, and atomoxetine (all medication off-label in Europe) in a relative higher dosage than the tricyclics.
Sodium oxybate (4.5 – 9 gram / night) is the best studied anti-cataplectic drug and is a potent inhibitor of cataplexy. In resistant cases, a combination of an antidepressant and sodium oxybate may be considered.
Several drugs may theoretically be expected to aggravate cataplexy, but the only one for which this is reliably documented is prazosin, an alpha-1 antagonist used to treat hypertension.
Disturbed nocturnal sleep
Sodium oxybate is the only drug with a proven long-term effect on nocturnal sleep. Short term beneficial effects of benzodiazepines have been described as well. Although nocturnal sleep may sometimes be improved with benzodiazepines, improvement of EDS is uncommon.