Pharmacological management of narcolepsy with and without cataplexy

Abstract

Narcolepsy is an orphan neurological disease and presents with sleep-wake, motoric, neuropsychiatric and metabolic symptoms. Narcolepsy with cataplexy is most commonly caused by an immune-mediated process including genetic and environmental factors, resulting in the selective loss of hypocretin-producing neurons. Narcolepsy has a major impact on workableness and quality of life. Areas covered: This review provides an overview of the temporal available treatment options for narcolepsy (type 1 and 2) in adults, including authorization status by regulatory agencies. First- and second-line options are discussed as well as combination therapies. In addition, treatment options for frequent coexisting co-morbidities and different phenotypes of narcolepsy are presented. Finally, this review considers potential future management strategies. Non-pharmacological approaches are important in the management of narcolepsy but will not be covered in this review. Expert opinion: Concise evaluation of symptoms and type of narcolepsy, coexisting co-morbidities and patients´ distinct needs is mandatory in order to identify a suitable, individual pharmacological treatment. First-line options include Modafinil/Armodafinil (for excessive daytime sleepiness, EDS), Sodium Oxybate (for EDS and/with cataplexy), Pitolisant (for EDS and cataplexy) and Venlafaxine (for cataplexy (off-label) and co-morbid depression). New symptomatic and causal treatment most probably will be completed by hypocretin-replacement and immune-modifying strategies.

Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy

“…Pitolisant may be considered as a promising first-line option for daytime somnolence and cataplexy, even though the short-term duration of the studies, the lack of data demonstrating the non-inferiority of pitolisant versus active drugs and/or in case of failure or intolerance to alternative drugs (ie, modafinil, sodium oxybate, and methylphenidate) should be taken into account as well-recognized issues of rare diseases 43,48,65. Although the non-inferiority compared to modafinil, as measured by means of ESS score changes, failed to be demonstrated in pivotal studies, the historical comparison from six RCTs with modafinil, to which the Harmony I and Ibis studies were added, indicates that the effect of pitolisant on EDS in narcolepsy, when used up to 40 mg/day, is of the same degree as modafinil 34.…”

Important decisions in choosing the pharmacotherapy for narcoleptics

“…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.…”

“…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.…”

“…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.…”

“…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].…”