Ultra-low-dose early night ramelteon administration for the treatment of delayed sleep-wake phase disorder: case reports with a pharmacological review

Abstract

Delayed sleep-wake phase disorder (DSWPD) is a common circadian sleep-wake phase disorders brings serious social impairment of the patients. Melatonin is the main medication option; however, it has not been approved in some countries, and over-the-counter melatonin is under poor quality control. The melatonin receptor agonist ramelteon might be a potential treatment option, but there are few reports regarding its use in DSWPD patients. Existing pharmacological and chronobiological studies suggest that an ultra-low dose of ramelteon in the early night is beneficial for DSWPD. Here, we present our clinical experience together with a pharmacological review and discussion. Twenty-three DSWPD patients, of whom 18 patients had a treatment history of a normal dose of ramelteon, were prescribed low-dose ramelteon (median: 0.571 mg, 1/14 of a tablet) to be taken in the early night (mean: 18:10). After the treatment, the mean sleep schedule was significantly advanced, and clinical symptoms were improved.

Citation:

Shimura A, Kanno T, Inoue T. Ultra-low-dose early night ramelteon administration for the treatment of delayed sleep-wake phase disorder: case reports with a pharmacological review. J Clin Sleep Med. 2022;18(12):2861–2865.

INTRODUCTION

Delayed sleep-wake phase disorder (DSWPD [also abbreviated DSPD, DSPS]) is a common circadian rhythm sleep-wake disorder (CRSWD), and is characterized by a delayed habitual sleep schedule relative to the desired or required sleep and wake times.¹ DSWPD patients have difficulty sleeping early, difficulty waking up early, and tend to feel sick in the morning, and have difficulty adapting to their social schedules, such as school or work. This maladaptation leads to multifunctional impairment, such as absenteeism and presenteeism, low academic achievement, or dropping out from school or workplaces, and depression.

To treat DSWPD, oral administration of melatonin is commonly used as a drug therapy.¹ Melatonin, also known as the “hormone of darkness”,² is an endogenous hormone secreted by the pineal gland, and its stimulatory effect on the melatonin receptor MT₂ functions to shift the phase of the circadian rhythm, depending on the administration timing.³ Ramelteon⁴ is a melatonin receptors MT_1/2 agonist, and its use is approved in some countries, such as the United States, Japan, Philippines, Indonesia, and Taiwan. Not only in countries where clinicians cannot use melatonin, but also where melatonin is sold as an over-the-counter drug that is under poor quality control,⁵ ramelteon could be a potential drug option, although there have only been a few reports of its clinical use for DSWPD. The pharmacokinetics of ramelteon are quite different from melatonin. Ramelteon has a much stronger potency for stimulating melatonin receptors and a half-life time longer than that of endogenous melatonin, and its active metabolite M-II has a much longer half-life, and a potency that is only slightly weaker than melatonin.⁶ The pharmacological profile of ramelteon suggests that the normal dosage, 8 mg for insomnia, is excessive for advancing the sleep-wake phase, and hence a smaller amount of ramelteon administered in the early night is expected to be beneficial for the treatment of DSWPD. In this study, we present our clinical experience of ultra-low-dose ramelteon administration to DSWPD patients, including a pharmacological review and discussion.

REPORT OF CASES

From September 2015 to April 2019, 30 patients with DSWPD who were being treated in the sleep clinic were prescribed low-dose ramelteon. The sleep clinic belongs to a general hospital and is also a part of the department of psychiatry. Patients are often referred to this sleep clinic by nearby pediatric or psychiatric hospitals or clinics. These 30 patients had either directly visited the sleep clinic, were referred to the clinic by other hospitals or clinics, or were referred to the clinic by other clinicians in the same hospital for their sleep-wake problems.

The patients were diagnosed as having DSWPD according to the criteria of the International Classification of Sleep Disorders,¹ using the information in their sleep logs for at least the preceding 14 days. The diagnosis was made by psychiatrists who specialize in sleep medicine. Sleep hygiene education and interventions, particularly with regard to the light condition, such as avoiding the use of displays or strong room lights in the evening and receiving sunlight in the morning, were provided, but the effects were insufficient and the symptoms of DSWPD continued in these patients. Of these patients, 18 had previously been administered the normal dose (8 mg) of ramelteon before bed, but they did not continue it because of low efficacy or intolerance, such as excessive sleepiness or tiredness. Here, with the agreement of the patients, very low doses of ramelteon were used to avoid low efficacy and adverse effects, and the doctors in charge explained this prescription to patients when obtaining their oral consent. The participants were not recruited for the purpose of the trial but were new clinical patients in the sleep clinic. This study was carried out in accordance with the Declaration of Helsinki, and was approved by the Ethics Committee of Neuropsychiatric Research Center, Tokyo, Japan (study approval number: 177). Patients were informed about the study via the hospital noticeboard, including that they could opt-out from the study at any time.

Ramelteon was prescribed at a low dose (median: 0.571 mg [1/14 of a tablet]; mean: 0.653 mg ± 0.216 mg; range: 0.4–1.142 mg [1/20–1/7 tablets]) in the early night (median: 18:00; mean: 18:10 ± 1:03; range: 15:00–20:00). Pharmacists crushed the ramelteon tablets and dispensed them to the patients as a powder. For example, the prescription of 1/14 of a tablet means a total of 1 tablet taken in 2 weeks, received in 14 portions. The actual amount of low-dose ramelteon prescribed was decided by discussion between each doctor and each patient as shared decision-making. To avoid wasting the remainder of the pills, a dose of 1/14 of a tablet was frequently selected, because patients often visit the outpatient clinic every 2 or 4 weeks. After 2 or more weeks from the beginning of treatment with low-dose ramelteon, each patient’s sleep schedule, daytime function, and adverse events were examined. Then, the amount of ramelteon was reduced if there was unacceptable acute sleepiness after administration, and reexamined after 2 or more weeks.

Chronotype, which is the morningness-eveningness tendency, of the patients was assessed by calculating their “midpoint of sleep on free-days, sleep corrected (MSFsc)”.⁷ The midpoint of sleep on free days (MSF) is considered to indicate the patients’ natural sleep schedules, which are the times at which patients naturally sleep and wake up when they have no particular social requirements or duties. MSFsc is MSF corrected for oversleeping owing to the lack of sleep (sleep debt).

Among the 30 DSWPD patients, 23 patients (76.7%) were followed up for 2 weeks or more, whereas 7 patients (23.3%) were not (never came back to the sleep clinic). The 23 patients comprised 15 men and 8 women. The mean age was 23.5 ± 9.2 years (range: 14–46 years). Regarding their occupations, 15 patients were school students, 6 patients were office workers, 1 patient was a musician, and 1 patient was unemployed. Psychiatric comorbidities were detected in 10 patients (43.5%; depression: 3 patients; bipolar disorder: 5 patients; autism spectrum disorder [ASD] with bipolar disorder: 1 patient; ASD with anxiety disorder: 1 patient) and the patients underwent no new/additional treatments during the observation period.

Table 1 shows the change in sleep schedules of the patients before and after the treatment. The mean duration from the first evaluation to the follow-up evaluation was 40.2 days (± 33.3 days). The mean sleep schedule before the treatment was as follows: on workdays (or school days), sleep: 3:21 am (± 1:55), wake-up: 11:03 am (± 2:21), and total sleep time: 7 hr 42 min (± 2 hr 29 min). On free-days, sleep: 3:45 am (± 1:48), wake-up: 12:30 pm (± 1:25), and total sleep time: 8 hr 44 min (± 1 hr 31 min). The mean MSFsc was 7:41 (± 1:35). The average final dose of ramelteon was 0.586 mg ± 0.168 mg (median: 0.571 mg [1/14 of a tablet]; range: 0.16–1.142 mg [1/50–1/7 tablets]) and average administration clock time of the final dose was 18:10 ± 1:03, which was not different from the initial time. After the treatment (mean: 40.2 days ± 33.3 days), the mean sleep schedule changed to the following: on weekdays, sleep time: 0:17 am (± 1:10), wake-up: 8:43 am (± 1:11), and total sleep time: 8 hr 25 min (± 1 hr 13 min). On free days, sleep: 0:30 am (± 1:17), wake-up: 9:27 am (± 1:13), and total sleep time: 8 hr 57 min (± 1 hr 23 min). The mean MSFsc was 4:46 (± 1:02), which was advanced significantly (P < .001; paired t test).

Table 1.

Sleep schedule changes of the patients.

	Before Treatment (n = 23)		After Treatment (n = 23)
	Mean	SD	Mean	SD
Sleep Schedules
Sleep (workdays, 24-hour time)	3:21	1:55	0:17*	1:10
Wake (workdays, 24-hour time)	11:03	2:21	8:43*	1:11
Sleep (free days, 24-hour time)	3:45	1:48	0:30*	1:17
Wake (free days, 24-hour time)	12:30	1:25	9:27*	1:13
MSFsc (24-hour time)	7:41	1:35	4:46*	1:02
Ramelteon Treatment
Duration from the first medication (days)	−	−	40.2	33.3
First and last dosage (mg/d)	0.653	0.216	0.586	0.168
(tablets/d)	0.082	0.027	0.073	0.021
Administration time (24-hour time)	18:10	1:03	18:10	1:03

*Significantly advanced, P < .001 (paired t test). MSFsc, midpoint of sleep on free-days, sleep corrected, SD = standard deviation.

As for DSWPD symptoms, all of the patients (100%) reported difficulties in waking up in the morning at the desired time and were frequently late for school or work before the administration of ramelteon. After the treatment, 14 patients (60.9%) responded completely to the treatment, and their difficulty in waking up and being late for school or work disappeared. Six patients (26.1%) partially responded to the treatment, and their symptoms improved but not completely. Three patients (13.0%) did not respond to the treatment. Regarding other symptoms, obvious sleep drunkenness in the morning (eg, confusion, irritability, aggressiveness, personality changes, and amnesia) was confirmed in 16 patients (69.6%) before the treatment. After the treatment, symptoms disappeared in 14 patients (87.5%) and remained in 2 patients (12.5%). Headache in the morning or at the time of waking up was observed in 8 patients (34.8%) before the treatment. After the treatment, it disappeared in 4 patients (50.0%) and remained in 4 patients (50.0%). Nausea in the morning or at the time of waking up was observed in 7 patients (30.4%) before the treatment. After the treatment, it disappeared in all patients (100.0%).

Regarding adverse events, a sense of fatigue and acute transient drowsiness immediately after the administration of ramelteon were observed in 5 patients (21.7%), but these symptoms disappeared within several days or after reducing the dose of ramelteon.

DISCUSSION

To our knowledge, this is the first report of ramelteon being prescribed to a relatively large number of DSWPD patients; it demonstrates a statistically significant advance in patients’ sleep schedules, and adds a pharmacological discussion. Few melatonin agonists have been approved as medical drugs, and the practical use of ramelteon, as described in this study, may be beneficial for the treatment of DSWPD and circadian rhythm sleep-wake disorder.

Ramelteon is a melatonin receptors MT_1/2 agonist, and its active metabolite M-II is also an agonist. M-II has agonist activity for MT₂ receptors, which are involved in the adjustment of circadian rhythm, and are 0.615 times as potent as melatonin.⁶ The half maximal inhibitory concentration (IC₅₀) of these molecules are as follows: melatonin, 904 pmol/L; ramelteon, 53.4 pmol/L (× 16.93 potency of ramelteon); and M-II, 1,470 pmol/L (× 0.615 potency of ramelteon). When administrating one-tablet (8mg) ramelteon, the average maximum (or peak) serum concentration (C_max) of M-II is 54,180 pg/mL (196,774 pmol/L) and this is approximately 200–2,000 times higher than the peak concentration of physiologically secreted melatonin. Ramelteon has a half-life of 0.92 hours and, if taken at night, will have disappeared from the plasma by the morning. However, M-II has a half-life of 2.1 hours, and thus even 12 hours after the administration, which will be in the morning or midday, there will still be more than 1/64 of the M-II dose remaining, which is approximately 738 pg/mL (2,680 pmol/L). This concentration and receptor activity during the daytime is also much higher than the physiological level of melatonin activity at midnight (Figure 1).

Figure 1. Estimated plasma concentrations and MT₂ receptor-stimulating potencies of 1 tablet (8 mg) of ramelteon administered to patients at 20:00.

(A) Concentrations of ramelteon, endogenous melatonin, and its metabolite M-II after ramelteon administration. (B) MT₂ receptor–stimulating potency of each compound. The solid line indicates the physiological melatonin secretion pattern. The dotted line indicates the plasma concentration and the melatonin equivalent for MT₂ receptor agonist potency of ramelteon, and the bold solid line indicates that of M-II. The graphs were created by the authors based on the pharmacological information of ramelteon, as well as a previous pharmacological study of melatonin ad M-II.⁶ Melatonin equivalents were calculated from MT₂ receptor agonist potencies (half maximal inhibitory concentration [IC₅₀]/pmol). The figures also indicate the phase shift effect of oral melatonin administration (0.5–3 mg) at each clock time (dim-light melatonin onset = ∼21:00) according to the phase response curve.⁸ M-II = active metabolite of ramelteon, MT_{2 =} melatonin receptor 2.

According to the melatonin phase-response curve,⁸ the administration of melatonin in the morning delays the circadian rhythm. Thus, it may be inappropriate to use 8 mg of ramelteon to advance the circadian rhythm, because this may result in too much stimulation of MT₂ by the remaining ramelteon and M-II. In fact, a previous study showed that 8 mg of ramelteon did not change the circadian rhythm significantly, whereas a lower dose of ramelteon advanced it.⁹ In a previous clinical review, Lewy also recommended lower doses of melatonin, such as 0.5 mg, for circadian rhythm sleep-wake disorders and that high doses of melatonin causes a “spillover” to the delay zone.¹⁰ Besides M-II, ramelteon itself has 16.9 times higher MT₂ receptor–stimulating potency than melatonin (15.2 times by mass, molar weight adjusted). Combining the effects of ramelteon and M-II, it is theoretically possible to use 32 μg ramelteon (4/1,000 of a tablet) to advance the circadian rhythm, although it is unrealistic to divide a tablet equally into 250 portions.

Melatonin is frequently used as a supplement to improve sleep quality; however, existing supplements sometimes have quality problems.⁵ As nonguaranteed supplements may have unstable efficacy and unexpected adverse events, the development of melatonin agonists as quality-controlled and approved drugs should be considered.

This study has some limitations. First, this is a retrospective study using an open-label case-series without a control group or randomization. To confirm the efficacy of the ultra-low-dose and early night administration of ramelteon, a placebo-controlled randomized trial is needed. Second, the sample size was small and a substantial number of patients (n = 7, 23.3%) were lost to follow-up. Therefore, our results do not confirm that this method is effective for every DSWPD patient, and the actual effectiveness may be overestimated. Third, the patients described in this study were non- or poor responders to the instructions provided regarding light exposure. This may be a characteristic of this group and may bias the responses to the treatment. Fourth, the monitoring of sleep and measurement of the effect was based on sleep logs, not using wearable devices, such as by actigraphy. Therefore, there might be a problem with objectivity. Fifth, drug adherence was not monitored. The exact time of the administration and whether the patients actually took the ramelteon or not remain unclear.

CONCLUSIONS

Our results, together with the pharmacological profiles of ramelteon and the melatonin phase-response curve, indicate that an ultra-low-dose and early night administration of ramelteon may be beneficial and safe for the treatment of DSWPD patients.

DISCLOSURE STATEMENT

All authors have read and approved this manuscript. Akiyoshi Shimura reports personal fees from Dainippon Sumitomo Seiyaku and Eisai outside the submitted work. Takeshi Inoue reports personal fees from Mochida Pharmaceutical, Takeda Pharmaceutical, Eli Lilly, Janssen Pharmaceutical, MSD, Taisho Toyama Pharmaceutical, Yoshitomiyakuhin, and Daiichi Sankyo, grants from Shionogi, Astellas, Tsumura, and Eisai, grants and personal fees from Otsuka Pharmaceutical, grants and personal fees from Dainippon Sumitomo Pharma, Mitsubishi Tanabe Pharma, Kyowa Pharmaceutical Industry, Pfizer, Novartis Pharma, and Meiji Seika Pharma, outside the submitted work. The authors have no conflicts of interest directly relevant to the contents of this article.

ABBREVIATIONS

DSWPD

delayed sleep-wake phase disorder

MSF

midpoint of sleep on free days