Narcolepsy management in Australia: time to wake up

Australia’s narcolepsy management is inadequate by international standards and should be aligned with that of other first class health services

Narcolepsy types 1 and 2 and idiopathic hypersomnia are central disorders of hypersomnolence. Narcolepsy type 1 is a debilitating disorder of hypersomnolence, associated with selective loss or dysfunction of orexinergic (hypocretinergic) neurons in the hypothalamus.1 Patients with narcolepsy type 1 experience cataplexy and may also demonstrate hypnagogic hallucinations, sleep fragmentation and sleep paralysis. Narcolepsy type 2 may be caused by less extensive injury to orexinergic neurons and is not associated with cataplexy. A diagnosis of narcolepsy is associated with a substantial adverse impact on mental health, health‐related quality of life impairment, long term disability, absenteeism and greater use of health care resources including increased frequency of hospitalisation and emergency department and specialist visits.2,3

The International Classification of Sleep Disorders defines narcolepsy as the presence of excessive daytime sleepiness for > 3 months in association with a mean sleep latency of < 8 minutes and at least two sleep onset rapid eye movement periods on a multiple sleep latency test.4 While the diagnostic criteria for narcolepsy in Australia are in accordance with standard international guidelines, a definitive diagnosis of narcolepsy type 1 may also be made on the basis of low cerebrospinal fluid orexin levels independent of multiple sleep latency test results, although such testing is not available in Australia.1 The HLA‐DQB1*0602 allele is carried by 95% of Caucasian patients with narcolepsy type 1 but is also present in up to 50% of patients with narcolepsy type 2 and 5–38% of the general population.1,5 An idiopathic hypersomnia diagnosis requires demonstration of a mean sleep latency < 8 minutes, but less than two sleep onset rapid eye movement periods.4 Further research is needed to better understand the less defined neurobiological mechanisms of narcolepsy type 2 and idiopathic hypersomnia, with calls for complaint‐driven reclassification of these disorders.6

The prevalence of these disorders in Australia is unclear. There is currently no Australasian narcolepsy or idiopathic hypersomnia data registry. Based on European, North American and Japanese databases, the global prevalence of narcolepsy ranges from 25 to 50 cases per 100 000 population, although a higher prevalence has been found in Japan.7 The prevalence of idiopathic hypersomnia is less well studied.

Effective treatment of narcolepsy can provide long term benefits with improved clinical outcomes, education and employment opportunities, work productivity and quality of life.2 Current first line agents available or under review for management of narcolepsy in North America and Europe include wakefulness promoters, such as modafinil and armodafinil, short‐acting sodium oxybate, pitolisant and solriamfetol.1,8,9 Phase 3 randomised placebo‐controlled safety and efficacy trials have demonstrated significantly improved objective (multiple sleep latency test and/or maintenance of wakefulness test) and subjective measures of sleepiness with the use of wakefulness promoters and a selective dopamine and norepinephrine reuptake inhibitor (solriamfetol).9,10 In addition to improved alertness, a histamine H3 receptor inverse agonist (pitolisant) and a $\gamma$‐hydroxybutyrate (sodium oxybate) reduced weekly cataplexy rates by up to 75%.11,12 Nightly use of sodium oxybate also reduced sleep disruption and improved patient quality of life.13

Sympathomimetic stimulants, including methylphenidate and dexamphetamine, are approved as second or third line agents for narcolepsy overseas.1,14 While these agents are more economical than first line agents and have been available on the market for a significantly longer period, they are associated with several adverse effects including palpitations, weight loss and mental health disturbances.15 The relegation of stimulants to second or third line use in narcolepsy in Europe and North America is also related to their addictive potential and risk of tolerance in up to one‐third of patients.15 The level of evidence supporting their use is not comparable to current first line agents. Head‐to‐head studies comparing stimulants and wakefulness promoters have not been performed.

The Australian Therapeutic Guidelines16 recommend the wakefulness promoters modafinil and armodafinil as first line and the best tolerated agents in the management of narcolepsy and idiopathic hypersomnia. The stimulants methylphenidate and dexamphetamine are described as alternate agents, available for prescription by experts in the field.16 However, the Pharmaceutical Benefits Scheme (PBS) only allows access to wakefulness promoters if stimulants pose an unacceptable medical risk or have resulted in the development of intolerance necessitating stimulant treatment withdrawal. Pragmatically, this positions stimulants as first line and wakefulness promotors as second line, even though clinical guidelines place them equally as first line agents in Australia. No other PBS‐subsidised medications to overcome excessive daytime sleepiness are available for use in Australian patients with narcolepsy. For the management of cataplexy, clomipramine is approved on the PBS.

While short‐acting sodium oxybate is available in Australia via the Special Access Scheme, the prohibitive out‐of‐pocket cost for patients (typically $15 000–22 000 per year)17 limits its use. For international pharmaceutical companies, introduction of these new drugs into Australia is limited by them not yet having an orphan drug designation. Orphan drug designation in Australia requires that < 5 in 10 000 individuals must have a seriously debilitating disorder (such as narcolepsy type 1) for which the specific drug offers effective treatment, the drug is not financially viable for the manufacturer/sponsor to market in Australia, and there is no plausibility of the drug treating individuals outside of the orphan indication.18 Other rare diseases including hypereosinophilic syndrome, Crohn disease and cystic fibrosis have obtained access to life‐altering chemotherapy, disease‐modifying antirheumatic drugs or targeted genetic modulator therapy respectively through the PBS via this pathway.18 Without a national narcolepsy and idiopathic hypersomnia data registry and no current clinical access to cerebrospinal fluid orexin testing, we are unable to objectively determine the number of patients with narcolepsy types 1 and 2 and idiopathic hypersomnia in Australia, or determine the financial viability for the manufacturer or sponsor. Further, for these aforementioned drugs, there is a possibility of treating sleepiness symptoms in populations other than those with narcolepsy. As a result, progressing the availability of these agents to Australian patients under the orphan drugs scheme remains difficult.

Safe and efficacious cutting edge medications are already available in other modern health care systems for narcolepsy types 1 and 2. Australia boasts a first class health care system but its approach to narcolepsy management is manifestly inadequate. Current prescribing restrictions, the cost of unsubsidised medications and the absence in Australia of the novel agents available overseas leaves narcolepsy management in this country behind the times and doctors unable to provide evidence‐based, best practice care for patients. Narcolepsy is often comorbid with neuropsychiatric, metabolic and autonomic disturbances, and parasomnias. It is therefore imperative that appropriate models of multidisciplinary care be developed for hastening diagnosis and enhancing treatment efficacy, and to have access to safe and effective treatment.1

Due to the coronavirus disease 2019 pandemic, it is unclear whether funding for narcolepsy and idiopathic hypersomnia research will be impacted or whether Australian Government‐led progression to Therapeutic Goods Administration approval for sodium oxybate (as recommended by the 2019 Parliamentary Inquiry into Sleep Health Awareness17) will come to fruition. We seek, in the first instance, to raise awareness of the current state of limited access to appropriate pharmacotherapeutic agents for the management of a group of uncommon but significant and debilitating diseases. We call upon the Department of Health to work alongside clinicians, patient advocacy groups and pharmaceutical companies to bring currently available therapeutics for narcolepsy and other hypersomnias of central origin into alignment with other first class health care systems internationally. To determine the prevalence of narcolepsy and disorders of central hypersomnolence and improve access to orexin testing, government and private funding for the establishment of a national data registry and national reference centre for orexin testing would be needed. Alternatively, reasonable extrapolation of prevalence from comparable countries should be allowed. Streamlined processes obviating the need for multiple drug registration and PBS reimbursement applications should be considered if a drug treats symptoms that occur across several diseases. In summary, Australia is behind in the area of narcolepsy management and it is time to wake up to this.