Non-24-Hour Sleep-Wake Disorder: Disease Overview and Treatment Options

ABSTRACT: Non-24-hour sleep-wake disorder (Non-24) occurs when a person’s circadian rhythm is not entrained to the environmental 24-hour sleep-wake cycle. Most commonly, Non-24 occurs in totally blind persons due to their inability to perceive light. Limited treatment options exist for the management of this disorder. Light therapy may be useful in sighted patients. Melatonin has been studied, but its ideal dosage and duration are unknown. There are two melatonin agonists currently available, ramelteon and tasimelteon, but tasimelteon is the only drug FDA-approved for the treatment of Non-24. Recommended treatments include trying several regimens of melatonin supplementation initially. If that course is unsuccessful, tasimelteon 20 mg should be taken 1 hour prior to desired bedtime for at least 6 months.

Most societies operate on a calendar with a 24-hour day. However, without synchronization from environmental stimuli, humans will have a circadian rhythm that is predetermined by genetics.¹ This means that the circadian rhythm will be “free-running.” Most free-running human circadian rhythms are slightly shorter or longer than 24 hours. An individual’s circadian period is known as tau. Since most people would have a tau that is not exactly 24 hours, the circadian rhythm needs to be entrained to the environmental 24-hour cycle. Entrainment occurs through exposure to light, timing of meals, social interactions, and other external stimuli.

Light is the strongest stimulus that allows for synchronization to the 24-hour sleep-wake cycle in humans.² When lights are dimmed or the sun sets, melatonin is released from the pineal gland and signals the body that it is time to sleep.

Non-24-Hour Sleep-Wake Disorder (Non-24)

Non-24 is one of four endogenous circadian rhythm sleep disorders (CRSDs) described in the International Classification of Sleep Disorders. Characteristics of endogenous CRSD are provided in TABLE 1.³

Non-24 is a CRSD that occurs when a person’s circadian rhythm is not entrained to the environmental 24-hour sleep-wake cycle.⁴ An individual’s tau remains longer or shorter than 24 hours due to the lack of entrainment and results in the inability to adjust to the established 24-hour day.⁵ Further, a patient will shift in and out of sync with our social calendar. For example, a person with a tau of 24.5 hours will be off by 30 minutes today, 1 hour tomorrow, and 1.5 hours the next day. In that case, it will take a total of 48 days for that individual to cycle back to a sleep-wake schedule in sync with our established calendar. Of those 48 days, only 16 will be relatively close to a normal day for entrained individuals. This also means that part of the cycle will be in direct opposition to a normal day. As such, patients will cycle in and out of symptoms of this disorder. This irregular sleeping schedule can lead to insomnia and excessive daytime sleepiness, which can then lead to troubles with work, school, relationships, and other everyday tasks that are normally taken for granted.¹

Symptoms of Non-24 will be unique to each person and may vary based on where patients are in their sleep-wake cycle relative to our established 24-hour day. Most commonly, patients may complain of disrupted nighttime sleep, daytime napping, and irritability. Minimum diagnostic criteria for Non-24 include a complaint of either difficulty falling asleep or difficulty waking up, progressively delayed sleep onset and offset, an inability to maintain entrainment to a 24-hour sleep-wake schedule, and a duration of 6 or more weeks of this irregular sleep pattern.⁶ Because each individual’s tau and total cycle will vary, Non-24 is likely underdiagnosed.

Most commonly, Non-24 occurs in totally blind persons because of their inability to perceive light. Of the 1.3 million blind individuals in the United States, approximately 65,000 to 95,000 are diagnosed with Non-24.⁷

Non-24 is not just a sleep disorder, it is a circadian rhythm disorder. This means that treatment is more complicated than simply using standard sedative hypnotics. In this disorder, it is important to try to treat the underlying cause and not just the symptoms. The American Academy of Sleep Medicine (AASM) provides recommendations for the evaluation and treatment of Non-24, which were last updated in 2007.⁸ The remainder of this article will discuss the safety and efficacy of currently available treatment options and provide recommendations for implementing them in practice.

Light Therapy

The AASM suggests that light therapy may be a potential treatment option in sighted patients with Non-24.⁸ Case reports in a total of two individuals have shown that timed morning-light exposure in sighted patients with Non-24 was able to entrain these individuals’ circadian rhythms.^9,10 Both reports involved light therapy for 2 to 3 hours daily.

PHARMACOLOGIC TREATMENT OPTIONS

Available agents for the treatment of Non-24 disease are discussed in the following sections and summarized in TABLE 2.

Vitamin B₁₂

The AASM lists vitamin B₁₂ as a treatment option for patients with Non-24. However, evidence supporting its use is conflicting, and there is little rationale to explain its effectiveness.⁸

Melatonin Supplementation

The AASM recommends melatonin for the treatment of Non-24 in both blind and sighted individuals. It has been studied in case reports and small studies. In one case report, the authors hypothesized that too large a dose of melatonin may lead to “spill over” into the wrong area of the melatonin phase-response curve.¹¹ As such, they suggest that physiological doses (0.3 mg) may be more effective than pharmacologic doses (usually >2 mg). Other case studies reported dosages of melatonin ranging from 3 to 5 mg daily for 2 weeks, 1 month, or an undisclosed period of time, leading to entrainment or significant improvement in circadian rhythm in six blind and sighted individuals with Non-24.^12-16

A crossover study was conducted by Sack et al to determine whether or not melatonin could entrain the circadian rhythms of seven totally blind individuals with Non-24.¹⁷ Participants were treated with either 10 mg of melatonin or placebo 1 hour prior to their desired bedtime for 3 to 9 weeks depending on their free-running circadian period. Out of these seven individuals, six achieved a circadian period of 24.0 hours (P <.001) and one achieved a circadian period of 24.3 hours.

A placebo-controlled, single-blind study was conducted by Hack et al to determine the efficacy of low-dose 0.5 mg melatonin in 10 totally blind individuals with Non-24.¹⁸ These subjects received 0.5 mg of melatonin or placebo daily at 21:00 hours (9 pm) for 26 to 81 days based on their baseline circadian period. Out of these 10 subjects, six were successfully entrained to a normal circadian period (P-value was not provided).

Based on this available evidence, the AASM recommends melatonin as an option for sighted individuals at a dose of 3 mg.⁸ For blind patients, it acknowledges that a variety of regimens have been studied, but suggests that lower doses may be more effective. This suggestion is based on the single case report described above.

Melatonin Agonists

There are two melatonin agonists currently available on the market, ramelteon (Rozerem) and tasimelteon (Hetlioz). Both drugs were approved after the most recent AASM guidelines were released.⁸

Ramelteon: Ramelteon has a high affinity for melatonin receptors 1 and 2 (MT₁ and MT₂) with full agonistic activity at these receptors.¹⁹ MT₁ and MT₂ receptors are thought to play a significant role in regulating the circadian rhythm and sleep-wake cycle. Ramelteon’s major metabolite, M-II, also has activity at the M₁ and M₂ receptors but at a significantly lower binding affinity than the parent drug. M-II is also much less potent than ramelteon but circulates at higher concentrations, providing greater systemic exposure than ramelteon. After fasting administration, ramelteon peaks in 30 minutes to 1.5 hours with an elimination half-life of 1 to 2.6 hours.

Ramelteon is currently only FDA-approved for the treatment of insomnia and has not been studied in patients with Non-24. Common side effects include somnolence, dizziness, fatigue, nausea, and exacerbated insomnia.¹⁹

Tasimelteon: Tasimelteon is also an MT₁ and MT₂ receptor agonist with higher affinity for the MT₂ receptor.²⁰ In January 2014, the FDA approved tasimelteon specifically for the treatment of Non-24 in adults.²¹ Metabolites of tasimelteon have some affinity for the MT₁ and MT₂ receptors but at less than one-tenth the affinity of the parent drug. After fasting administration, tasimelteon peaks in 30 minutes to 3 hours with a mean elimination half-life of 1.3 hours. Tasimelteon should only be taken immediately before bedtime.²⁰

Strong CYP1A2 inhibitors, such as fluvoxamine, may significantly increase tasimelteon exposure and increase the risk of adverse events. The efficacy of tasimelteon may be reduced in smokers.²⁰ Strong CYP3A4 inducers, such as rifampin, may significantly reduce tasimelteon concentrations and reduce efficacy. Animal studies suggest that it may cause fetal harm and so it should be avoided in pregnancy. Tasimelteon has not been studied in nursing mothers or children. Exposure is increased by approximately twofold in geriatric patients, so the risk of adverse events may be greater. No dose adjustment is required for renal impairment or mild-to-moderate hepatic impairment, but tasimelteon has not been studied in patients with severe hepatic impairment.²⁰

Safety and Efficacy of Tasimelteon (SET) Trial: A randomized, multicenter, parallel, placebo-controlled trial was conducted by Vanda Pharmaceuticals to determine the safety and efficacy of tasimelteon in the treatment of Non-24 in blind patients.²² The average age of all participants in the trial was 50 years, and approximately 60% were males.

Out of 84 eligible participants, 42 were randomized to receive tasimelteon 20-mg capsules, and 42 patients were assigned to receive placebo capsules. Both treatments were administered by mouth daily 1 hour before bedtime for 6 months. Patients, providers, and outcomes assessors were all blinded to treatment assignments.²²

The trial had two primary outcomes. The first primary outcome was the percentage of patients entrained. Entrainment was defined as having a postbaseline tau value of <24.1 hours. Urinary aMT6, a major metabolite of melatonin, was used to determine tau. The other primary outcome was the percentage of patients achieving a clinical response. At one month, 20% (n = 8) in the tasimelteon group achieved the primary outcome of entrainment compared to 2.6% (n = 1) in the placebo group (P = 0.029). At 6 months, 23.7% (n = 9) of patients in the tasimelteon group had achieved a clinical response, compared to 0% of patients in the placebo group (P = .0025).²²

Adverse events were similar in each group. The most common adverse events reported in the tasimelteon group were headache, increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and abnormal dreams. In summary, this small study showed that approximately one in four blind patients with Non-24 treated with tasimelteon for 6 months will achieve a clinical response.²²

Randomized Withdrawal Study of the Efficacy and Safety of Tasimelteon (RESET) Trial: Another randomized, parallel, placebo-controlled trial was conducted by Vanda Pharmaceuticals to demonstrate the maintenance effect of tasimelteon in the treatment of Non-24 in blind patients.²³ The average age of all participants in the trial was 52 years, and approximately 60% were males.

Ten patients were randomized to receive 20 mg of tasimelteon and 10 patients were to receive placebo.²³ Patients, providers, and outcomes assessors were all blinded to treatment assignments. The primary outcome of this trial was the maintenance of entrainment using urinary aMT6, similar to the SET trial. At this time, nine patients in the tasimelteon group remained entrained compared to only two in the placebo group (P = .0055).

 Adverse events were similar across the two groups. The most commonly reported adverse events in the tasimelteon group were nasopharyngitis, arthralgia, headache, diarrhea, and constipation.²³

In summary, this small study showed that for every two patients treated with tasimelteon 20 mg daily for an additional 8 weeks, one will maintain entrainment. Patients who were entrained after taking tasimelteon 20 mg daily relapsed after a median of 25 days on placebo. This means that patients should continue treatment with tasimelteon in order to maintain entrainment.²³

DISCUSSION

Limited options exist for the treatment of Non-24, and there are limited trials to draw conclusions regarding which option may be the most effective in successfully entraining an individual’s circadian rhythm. Further, the most recent guidelines from the AASM do not discuss melatonin agonists. Although vitamin B₁₂ is mentioned in the AASM guidelines, it is probably not worthwhile to try it considering the lack of rationale for and evidence to support its use. Light therapy is an option only in sighted individuals with Non-24, thus limiting its use in a significant population of patients with the disorder. Even though there are a limited number of trials to support the safety and efficacy of the melatonin agonist tasimelteon in the treatment of Non-24, the small trials that have been conducted support the use of tasimelteon in totally blind patients with Non-24. With the high cost of tasimelteon, it may be appropriate to have a trial of treatment with melatonin initially since it is a fraction of the cost with a similar mechanism of action. However, melatonin is available OTC and therefore is not regulated the same way as prescription drugs. Further, it has not been FDA-approved in patients with Non-24, and the ideal dose and duration of treatment are unknown.

It is reasonable to suggest that the melatonin agonist ramelteon may be effective in the treatment of Non-24. It is pharmacologically and pharmacokinetically similar to tasimelteon and is a much more cost-effective option than tasimelteon. A month’s supply of ramelteon 8-mg capsules is approximately $250, which is still quite expensive but nowhere near as costly as tasimelteon ($9,728.60/month),²⁴ which is considered a specialty drug. However, ramelteon has never been studied in patients with Non-24.

CONCLUSION

In blind patients with Non-24, initially trying a few regimens of daily melatonin ranging from 0.5 to 10 mg daily 1 hour prior to desired bedtime for at least 1 month is recommended. If these regimens do not result in entrainment, a trial of tasimelteon may be initiated at 20 mg 1 hour prior to desired bedtime for at least 6 months. After 6 months of treatment, if the individual is entrained, additional maintenance therapy may be required for an unknown duration of treatment. It is unclear as to how long a patient will need to continue taking tasimelteon to maintain entrainment after initially becoming entrained.

Further research should focus on determining the most effective and safest treatment regimen for patients diagnosed with Non-24. The small population of patients who have Non-24, the difficulty in diagnosing the disorder, and the difficulty determining a baseline tau all complicate research in this area. Long-term randomized, controlled trials in larger patient populations would be ideal. Controlled studies of melatonin with similar endpoints, including entrainment based on urinary aMT6, would be helpful. Dose-finding studies of melatonin are still needed and would likely help determine its role in this disorder. Studies of ramelteon may also be a promising area of future research.

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