Important decisions in choosing the pharmacotherapy for narcoleptics

KEYWORDS:

• Cataplexy
• excessive daytime sleepiness
• hypocretin
• investigational drugs
• modafinil
• narcolepsy
• pitolisant
• sodium oxybate

1. Introduction

Narcolepsy is a chronic sleep disorder characterized by a pentad of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nocturnal sleep. EDS usually appears first and is required for the diagnosis. Cataplexy occurs in about 60–70% of narcoleptic patients, while the other symptoms are less frequent [1]. Furthermore, narcolepsy presents with additional sleep (obstructive sleep apnea (OSA), restless legs syndrome (RLS), and REM behavior disorder (RBD)), neuropsychiatric (depression, and anxiety), metabolic (obesity, and diabetes mellitus) and cardiovascular disorders [2,3].

The revised International Classification of Sleep Disorders (ICSD-3) diagnostic criteria recognize two types of narcolepsy [4]. In type 1 narcolepsy (NT1), EDS is associated with cataplexy and/or reduced levels of hypocretin in the cerebrospinal fluid (CSF). Type 2 narcolepsy (NT2) is characterized by EDS and abnormal manifestations of REM sleep on polysomnography. Cataplexy is absent and hypocretin levels in the CSF are normal [4].

NT1 is presumed to have an autoimmune basis that induces the loss of hypocretin-producing neurons in genetically predisposed individuals. Hypocretin plays a promoting role in wakefulness and it suppresses REM sleep. At the time of presentation, in most cases, NT1 patients have low or no detectable hypocretin levels in the CSF, indicating that symptoms appear when the destruction of most of the hypocretin-producing cells has occurred [5,6]. The pathogenesis of NT2 remains unknown.

While non-pharmacological treatments (i.e. regular sleep–wake schedules and planned naps) can be helpful, more than 90% of narcoleptic patients require a pharmacological treatment.

2. Treatment of narcolepsy

2.1. Drugs currently used

Current treatment is based on symptoms control, since there is no cure for narcolepsy. The available pharmacologic therapies include medications that have been approved for the treatment of specific symptoms, while others are used based on expert consensus only (Table 1). There are five drugs approved by the US Food and Drug Administration (FDA) for the treatment of narcolepsy. Sodium oxybate (SXB) is indicated for both EDS and cataplexy, while methylphenidate, amphetamines, and modafinil/armodafinil are approved only for EDS [2]. There are three drugs approved by the European Medicines Agency (EMA) for the treatment of narcolepsy: SXB for the treatment of narcolepsy with cataplexy and modafinil to treat EDS. In addition, pitolisant, an inverse agonist of the H3 histamine receptor, has been recently approved by EMA to treat narcolepsy with or without cataplexy.

Table 1. Drugs used for the treatment of narcolepsy.

Drug	Mechanism of action	Dosage	Approval	Indications	Side effects
MODAFINIL	Still debated, probably DA reuptake inhibition	100–400 mg	FDA, EMA	EDS	Nausea, headache, dizziness, diarrhea, anxiety
ARMODAFINIL	Same as modafinil	100–250 mg	FDA	EDS	Same as modafinil
METHYLPHENIDATE	Increase DA transmission presynaptically and inhibit DA > NA ≫ 5-HT reuptake	10–60 mg	FDA	EDS	Nervousness, tremor, tics, anorexia, nausea, insomnia, palpitations, hypertension
DEXTROAMPHETAMINE SULFATE	Increase DA transmission presynaptically and inhibit DA > NA ≫ 5-HT reuptake	5–60 mg	FDA	EDS	Nervousness, tics, anorexia, insomnia, tremor, psychosis, hypertension, cardiac arrhythmias, high potential for abuse
SODIUM OXYBATE	Unclear. Probably acts via GABA-B or specific GHB receptors	4.5–9 g	FDA, EMA	EDS, cataplexy, daytime sleepiness and disrupted sleep. Option for hypnagogic hallucinations and sleep paralysis	Exacerbation of sleep apnea and depressive tendencies, somnolence, dizziness, constipation, nausea, weight loss, enuresis, sleep walking
PITOLISANT	Inverse agonist of the histamine H3 receptor	9–36 mg	EMA	EDS, cataplexy	Headache, insomnia, nausea, dyspepsia, anxiety, dizziness, tremor
VENLAFAXINE	Blocks reuptake of 5-HT ≥ NA	37.5–300 mg	No	Cataplexy. Option for hypnagogic hallucinations and sleep paralysis	Dizziness, nausea, headache, insomnia, sexual dysfunction, dry mouth, blood pressure increase

Abbreviations: 5-HT: serotonin; DA: dopamine, EDS: excessive daytime sleepiness; EMA: European Medicines Agency; FDA: Food and Drug Administration; GABA: γ-aminobutyric acid; GHB: gamma-hydroxybutyric acid; NA: noradrenaline

Although not approved, antidepressants are used off-label to treat cataplexy. Venlafaxine is the most used, but tricyclic antidepressants (e.g. clomipramine) and selective serotonergic reuptake inhibitors (e.g. fluoxetine) are used to treat cataplexy as well. In contrast to SXB, antidepressants can reduce cataplexy quickly (often within a few hours), but the abrupt withdrawal of treatment may result in rebound cataplexy.

2.2. Drugs in development

The discovery that most of NT1 symptoms are directly explained by hypocretin deficiency raised hopes that restoration of hypocretin signaling could lead to causative therapy. Central administration of hypocretin-1 reverses narcolepsy in animal models, but unfortunately the hypocretin peptide does not cross the blood-brain barrier (BBB). Administration of hypocretin-1 intranasally holds promise as this route delivers the compound directly into the brain, bypassing the BBB. However, intranasal administration in animals and narcoleptic patients showed limited success [7].

Replacement with hypocrein receptor agonists represents one option for the future. Other more difficult options might be gene therapy and transplantation of hypocretin-producing neurons generated from pluripotent stem cell. A phase I trial started in 2017 to evaluate safety, tolerability, and pharmacokinetics of TAK-925, an hypocretin 2 receptor agonist, administered to NT1 patients and healthy participants.

GABA-B agonism with R-baclofen, the active R-enantiomer of baclofen, was evaluated in a narcoleptic mice showing that R-baclofen was more effective than SXB at increasing the duration, intensity, and consolidation of NREM sleep. R-baclofen was also more effective than SXB at reducing cataplexy [8]. Further research is needed to evaluate the role of R-baclofen in human narcolepsy.

JZP-110 is a phenylalanine derivative that acts as a dopamine and noradrenaline reuptake inhibitor. It was successfully assessed for treatment of EDS in two phase II, placebo-controlled trials, while there was no significant effect on cataplexy [9,10]. An initial report of a phase III trial, confirmed the positive results obtained with previous studies [11].

Given that NT1 is due to an autoimmune attack, immunotherapies could modify the natural history of the disease. Treatments with steroids, intravenous immunoglobulins, plasmapheresis and alemtuzumab have shown variable efficacy [12,13]. Immunotherapy is believed to be helpful when administered close to disease onset to prevent neuronal death. Further well-designed immunotherapy studies are needed.

Other therapeutic options are expected to emerge in the next few years: longer-acting formulation of SXB (a phase III trial is currently ongoing) and modafinil combined with connexin inhibitors. A phase II trial to evaluate the efficacy and safety of THN102, a combination of modafinil and flecainide, is currently recruiting participants.

JZP-258, an investigational oxybate product candidate with 90 percent less sodium content than SXB oral solution, is currently evaluated in a phase III study as a potential treatment for cataplexy and EDS in narcoleptic patients.

2.3. Treatment and comorbidities

No single management strategy is available for initiating treatment for narcolepsy, medications should be tailored to each patient’s characteristics and symptoms, as well as on drugs available in each part of the world. Patient’s characteristics include the patient’s age and lifestyle as well as substance use, such as caffeine, nicotine, alcohol, and cannabis. For example, SXB should not be used in conjunction with other sedatives or alcohol. Regarding women of childbearing age, it should be mentioned that modafinil induces the cytochrome P450 enzymes and can reduce the effectiveness of hormonal oral contraceptives. In addition to EDS, clinicians should investigate the presence and severity of other REM-sleep phenomena and additional symptoms. The symptom that is most incapacitating is to be targeted first. Ancillary symptoms can be addressed gradually in a step-wise manner [14]. If EDS is present in the absence of cataplexy, treatment can be initiated with monotherapy using a stimulant, either modafinil or pitolisant. When monotherapy is not completely effective for symptomatic relief, combination of medications can be useful. The coadministration of modafinil and SXB has showed synergistic effect [15]. Even a combination of modafinil and pitolisant seem to be feasible [2]. Older narcolepsy medications, such as methylphenidate and amphetamines, should be regarded as second- or third-line treatment options.

If a patient presents with EDS and cataplexy, first-line options are SXB or pitolisant that act on both symptoms. The use of other agents depends on persistence of symptoms and their impact on patient function, guiding the choice of combination therapy [1]. In any case, regular assessment after initiation of treatment is a useful approach to drive changes in therapy such as dose adjustment, medication switches and the use of multiple medications [1].

The presence of ancillary symptoms or comorbid conditions might have an impact on the determination of treatment. SXB represent a good choice if disrupted night-time sleep and stage shifts are present, while in general treatment that improves cataplexy also lead to a reduction of hypnagogic/hypnopompic hallucinations and sleep paralysis.

RBD is a common symptom in narcolepsy. Conventional treatment with melatonin or clonazepam is reported to be effective, but also SXB could be a good option [2]. On the other hand RBD may be induced by antidepressants. Also RLS and periodic limb movements (PLMs) can be exacerbated by antidepressants and SXB.

Depressive symptoms are frequent in patients with narcolepsy. In this case, antidepressants may be helpful in the treatment of both depression and cataplexy, while most stimulants and SXB might worsen depression. Compared to controls, patients with NT1 and NT2 were associated with a higher frequency of chronic pain and fatigue. Depression possibly influences pain perception in these patients [16]. In the case of a comorbid ADHD, methylphenidate seems the best first-line option. Comorbid metabolic conditions such as diabetes may be of particular relevance to narcolepsy because of the associated obesity and weight control issues. Most antidepressants may cause an increase of appetite and weight gain, while treatment with SXB is often associated with weight loss. However, SXB can exacerbate OSA. OSA has a high prevalence in narcolepsy, due to its relationship with obesity. The presence of moderate or severe OSA should be determined before prescribing SXB, and sleep apnea must be treated prior to initiating therapy [13].

Paediatric recommendations for the treatment of narcolepsy have not been established, and while few drugs have been evaluated for efficacy or toxicity in children, treatment of paediatric narcolepsy is generally considered similar to that of adults [1]. Limited clinical reports of children with narcolepsy suggest the efficacy and tolerability of modafinil for EDS, venlafaxine for cataplexy, and SXB for most symptoms, although multiple medications are used in some patients [17–19]. A recent double-blind, placebo-controlled, randomised-withdrawal study showed the clinical efficacy of SXB in the treatment of both EDS and cataplexy in narcoleptic children. The safety profile of SXB was consistent with that observed in adult patients [20].

3. Conclusion

Treatment of narcolepsy remains challenging and current therapy is strictly symptomatically based. In this manuscript we briefly overviewed the current and emerging treatments of narcolepsy. Moreover, we highlighted that treatment decisions should be based on a patient-centric approach. It is important to consider the primary symptomatic complaint, but the choice of therapy depends not only on factors related to the disease, but also on comorbidities and patient’s characteristics. Narcolepsy management requires a regular evaluation of symptoms to drive changes in therapy.

4. Expert opinion

Narcolepsy is a chronic and lifelong condition. Nowadays the primary goal of treatments and behavioral strategies is to reduce or eliminate symptoms and improve patient sleep and quality of life. Narcolepsy is an active area for drug development, with an increasing number of symptomatic medications. An ideal therapeutic agent could treat EDS, cataplexy, and sleep fragmentation with minimal side effects and a low dosing frequency. SXB is one of the most effective single agents for simultaneously treating all symptoms of narcolepsy. Because of its short half-life (30 min), it typically needs to be administered twice during the night. Moreover, with its administration, patients may need to alter their lifestyle. They should avoid alcohol and sedating medications, and the profound sedation of SXB means that patients sometimes have to change living arrangements [21]. Therefore it is far from being the ideal solution.

Pitolisant represents a novel drug target. Pitolisant has shown to be equal in its efficacy to treat EDS compared to modafinil [22]. In a recent study, pitolisant was more effective than placebo in reducing cataplexy [23]. Future comparative studies with SXB are needed to evaluate its efficacy in the treatment of cataplexy. Longer term effects, particularly in terms of potential for tolerance are also needed.

JZP-110 acts as a dopamine and noradrenaline reuptake inhibitor. If the currently ongoing phase III trial will confirm its efficacy and safety, JZP-110 would be a new therapeutic option for the treatment of EDS in the coming years. It could also open the opportunity for new combination therapies.

The pathophysiology of NT2 is still unknown. In contrast, most of the symptoms in NT1 are directly explained by hypocretin deficiency. On a long-term basis, the gold standard for narcolepsy treatment is likely to aim at replacing the missing causal neurotransmitter, hypocretin. Disease-specific therapies need further development and testing before they can be clinically relevant. Replacement with hypocretin receptor agonists represent the most practicable option for the future, and a phase I trial is currently ongoing.

Based on an autoimmune etiology of narcolepsy, immunotherapy holds the promise of preventing disease onset. However attempts to modify the immune process to treat narcolepsy have given equivocal results. Immunotherapy in the earliest stages of the disease could be an effective option, although further studies are needed [24]. More information would be necessary to provide a better understanding of the underlying immune mechanism and how it can be altered for therapeutic benefits.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

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