**2. Existing lines of therapy**

As we have already mentioned, current therapies are aimed at the symptomatic treatment of narcolepsy. One key point to take into account is the high degree of inter-individual variability in the clinical presentation of the disease, in terms of the different clinical evolution over the years, and the therapeutic response and possible side effects related to the different treatments.

The first approach should therefore focus on the adoption of nonpharmacological measures, with programmed short-duration daytime naps being one of the most prominent.

Establishment of rigid schedules for waking up and going to bed, attempting to avoid transgressions or sleep deprivation, should be recommended. Like other patients with sleep disorders, avoiding excessive caffeine or alcohol consumption should be recommended. Last, but not least, it is helpful to orient the patient from the point of view of work, providing suggestions as to the jobs that are most advisable and less advisable for patients with narcolepsy. In addition, they should be informed of associations or support groups at the national and international level.

Regarding pharmacological therapy, the different existing lines of therapy can be classified according to their mode of action or according to the type of symptomatology that they are intended to treat (daytime sleepiness, cataplexy, sleep fragmentation, etc.).

#### **2.1 Recommended treatments for excessive daytime sleepiness (EDS)**

1.Modafinil: inhibits the dopamine transporter, facilitating an increase in its concentration, although its mechanism of action is still unclear. Approved by the FDA and EMA. Armodafinil is also FDA approved and the usual doses for adults range from 100 to 250 mg.

Dosage: in tablets of 100–400 mg orally. Initially, treatment is started with 100 mg, which can be divided into two intakes of 50 mg at least 2 hours apart. The dose should later be increased depending on the degree of drowsiness, considering the dose-dependent occurrence of side effects.

Pharmacokinetics: the absorption of modafinil is fast, with a maximum plasma concentration of about 2 to 4 h. The effective elimination half-life of modafinil after multiple doses is approximately 15 h. The main route of excretion is via the liver and part of its metabolites via the kidneys. Patients with severe hepatic impairment should be treated with lower doses. Reversible inhibition of the cytochrome P450 enzyme CYP2C19, as well as CYP3A4, CYP1A2 and CYP2B633 has been observed. Coadministration of modafinil with diazepam, phenytoin and propranolol, which are eliminated via the CYP2C19 enzyme, may increase their levels. It is recommended that alternative methods of contraception be considered during treatment with modafinil and one month after the end of the treatment.

Safety and adverse events: generally well tolerated and the most common adverse events were headache (13%), nervousness (8%) and nausea (5%). Treatment-related cardiovascular events were infrequent, including palpitations (1.5%), hypertension (1%) and tachycardia (1%). Studies with modafinil have shown a potential for dependence, so the possibility of dependence with long-term use cannot be completely ruled out. It is also recommended that an ECG be performed on all patients prior to the start of treatment.

The combination of modafinil with connexin-30 inhibitors is under development (discussed later in the chapter).

2.Methylphenidate: blocks the reuptake of noradrenaline and dopamine (inhibiting the transporters of these neurotransmitters at the presynaptic level) increasing the concentration of dopamine and noradrenaline in the synaptic cleft. Broadly speaking, this generates its stimulant effect within the central nervous system (CNS), primarily in the prefrontal cortex. It is also a weak agonist at the 5-HT1A receptor, which is an additional mechanism that contributes to increased dopamine levels. Before starting any treatment with stimulants, it is advisable to perform at least an electrocardiogram to rule out possible cardiac arrhythmias [4]. Due to the risk of serious side effects, avoiding use with patients with structural heart abnormalities is recommended.

Dosage: doses are administered orally and range between 10 and 60 mg and should not exceed 72 mg. Immediate and extended release are available.

Adverse effects: insomnia and nervousness are the most frequent events, although other effects related to the CNS (dizziness, headache, tics, akathisia), gastrointestinal (nausea/vomiting, dry mouth, decreased appetite, weight loss, abdominal pain) and cardiovascular system (tachycardia and palpitations) have also been reported. Methylphenidate is FDA approved for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults and as a second-line treatment for narcolepsy in adults.


Dosage: doses between 5 and 30 mg orally, twice a day, or 20 mg in a sustained release formulation twice a day are usually used.

Adverse effects: decreased appetite, nausea, vomiting, insomnia, headache, increased blood pressure and heart rate, etc.

Safety: has a high potential for abuse, can cause psychosis and manic episodes.

## **2.2 Recommended treatments for cataplexy and symptoms resulting from dysregulation of REM sleep**

1.Sodium oxybate (Xyrem®): this is the sodium salt of gamma-hydroxybutyrate (GHB). GHB is synthesised in neurons throughout the CNS and is an active metabolite of gamma-aminobutyric acid (GABA). It inhibits noradrenergic neurons in the locus coeruleus during sleep, with a rebound effect of these neurons during the day thus promoting wakefulness, although its mechanism of action remains unclear. One of the hypotheses about the mechanism of action on the control of EDS and cataplexy postulates that it could be mediated through GABA-B agonist actions on dopaminergic, noradrenergic, as well as thalamocortical neurons. In 1998, the FDA granted permission to test oxybate as an orphan drug for narcolepsy. In 2002 it developed a distribution program through hospital pharmacies only. And in Europe, it is available under restricted prescription and special situation. It also has a risk management and pharmacovigilance program.

Dosage: it is an oral solution (500 mg/ml). The recommended initial dose is 4.5 g/night (divided into 2 doses, each of 2.25 grams) spaced at least 2.5– 4 hours apart before the new dose, so that most of the drug has been eliminated when the patient wakes up. Up to a maximum of 9 g/day (7 g/day in children <12 years).

Pharmacokinetics: it is rapidly absorbed with a maximum plasma concentration (tmax) of 1.5–2 h. Less than 5% of the unaltered drug appears in the urine 6–8 h after dosing. No active metabolites. Also does not induce cytochrome P450 enzymes. In patients with cirrhosis of the liver, a lower dose should be started because a doubling of the area under the curve, reduced oral clearance and prolonged elimination half-life have been observed.

Safety: the most frequent adverse effects were: headache (11.6%), nasopharyngitis (6.4%), dizziness (5.2%), weight loss (5.2%), nausea (5.1%), urinary incontinence in (2.4%) and sleepwalking in (3.1%). Serious adverse events included depression, angina, inguinal hernia, psychosis or attempted suicide. In addition, the European Medicines Agency (EMA) recommends assessing the risk/benefit in patients with obstructive sleep apnoea syndrome (OSA), especially in doses higher than 6 g/night. On the other hand, it is important to control daily salt intake in patients with heart failure, hypertension or renal failure because the molecule has a high salt content. It also must be taken under consideration the potential for abuse, before being administered, the patient's medical history should be reviewed.

Recently, a multi-centre, randomised, placebo-controlled trial involving children and adolescents with narcolepsy with cataplexy was developed examining efficacy and safety. Based on this study, the FDA approved the use of sodium oxybate in paediatric patients with narcolepsy beginning at seven years of age.

There are now new therapeutic lines with controlled-release GHB (see below).


Dosage: initially 37.5 mg, sometimes requiring higher doses (75–300 mg). The extended-release form is preferable.

Safety: It can be administered to children and is not recommended for pregnant women.

4.Fluoxetine and Citalopram: are selective serotonin reuptake inhibitors (SSRIs). A crossover study comparing clomipramine and fluvoxamine showed that

SSRIs improved cataplexy, but were less active than the antidepressant. Studies have been carried out with femoxetine, zimelidine and escitalopram showing a clear anticataplectic effect and good tolerance.


Dosage: between 10 and 150 mg, generally lower doses than those used as an antidepressant are needed to be effective in controlling cataplexy and its effects are very fast (only a few days) compared to the effects as an antidepressant. Several antidepressants have been tried, but clomipramine has been the most commonly used TCA.

Safety: if the antidepressant is abruptly discontinued, an elevated risk of rebound cataplexy or "status cataplecticus" has been observed.

It should be noted that the Class I evidence for Narcolepsy with cataplexy (NT1) and without cataplexy (NT2) was obtained for the previously described psychostimulant drugs and for sodium oxybate. Oxybate therefore remains the first-line treatment of choice in NT1, especially for the control of cataplexy, although as we will see below, pitolisant demonstrated efficacy similar to oxybate in patients with NT1 in a recent randomised placebo-controlled clinical trial.
