Pharmacological options for narcolepsy: are they the way forward?

ABSTRACT

Introduction

Narcolepsy is an under-recognized, rare neurologic disorder of hypersomnolence that is associated with increased mortality and medical and psychiatric co-morbidities. Narcolepsy exerts a substantial economic burden on patients and society. There is currently no cure, and life-long symptomatic therapy is needed. Available drugs do not modify the disease course.

Areas Covered

This manuscript provides an overview of narcolepsy symptoms, diagnosis, pathophysiology, current pharmacotherapies, and emerging treatments. Gaps and unresolved issues in diagnosis and management of narcolepsy are discussed to answer whether pharmacological options are the way forward.

Expert opinion

Diagnostic criteria for narcolepsy (ICSD-3) need revision and greater clarity. Improved recognition of cataplexy and other symptoms through educational outreach, new biomarkers, improved test scoring through artificial intelligence algorithms, and use of machine learning may facilitate earlier diagnosis and treatment. Pharmacological options need improved symptomatic therapy in addition to targeted therapies that address the loss of hypocretin signaling. Optimal narcolepsy care also needs a better understanding of the pathophysiology, recognition of the different phenotypes in narcolepsy, identification of at-risk individuals and early recognition of symptoms, better diagnostic tools, and a database for research and disease monitoring of treatment, side-effects, and comorbidities.

KEYWORDS:

• drugs
• emerging treatments
• hypocretin replacement
• immunotherapy
• narcolepsy
• neuromodulator treatment
• pharmacotherapy
• update

Article highlights

• Narcolepsy is a life-long hypothalamic disorder characterized by sleep-wake instability that manifests as excessive daytime sleepiness (EDS), cataplexy, sleep paralysis (SP), hypnagogic/hypnopompic hallucinations (HH), and disrupted night sleep (DNS).

• Two phenotypes are recognized by the International Classification of Sleep Disorders (ICSD)-3: narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2) [6]. NT1 is associated with death of hypothalamic hypocretin-producing neurons that is attributed to an autoimmune process [11]. NT2 is probably a heterogeneous disorder, and the cause is unknown [51].

• Narcolepsy is associated with various comorbidities, including cardiovascular and cerebrovascular disease, insulin resistance, obesity, neuropsychiatric conditions, and other sleep disorders [1,2,167].

• Narcolepsy currently has no cure. Pharmacologic treatments are the mainstay of treatment. First-line therapies for EDS in adults are modafinil, pitolisant, solriamfetol, and sodium oxybate (SXB), while methylphenidate, amphetamine, and dextroamphetamine are deemed second-line therapies [39,69]. For cataplexy and EDS, pitolisant and SXB are first-line therapies. Selective serotonin norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants (TCAs) are used off label in the US to treat cataplexy, while SSRIs and TCAs are approved to treat cataplexy in many European countries [74].

• Improvements in narcolepsy care will need clearer diagnostic criteria, reduction of the diagnostic delay, new biomarkers or other tests, improved automatic scoring of tests using artificial intelligence algorithms, and use of machine learning.

• Pharmacological options need improved symptomatic therapies: Histamine H3 (H3) receptor agonists/inverse agonists for EDS are under investigation; AXS-12 (reboxetine) is undergoing clinical trials. Replacement therapy using hypocretin agonists is undergoing investigation. Immunomodulator therapy and neuromodulator therapy need more research/trials. Cell replacement therapies, stem cells, and gene therapies are still experimental.

Declaration of interest

VC Abad is a consultant/faculty lecturer for Medscape/WebMD. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This manuscript was not funded.