Embed Size (px)
Citation preview
1 RAMELTEON: A MELATONIN RECEPTOR AGONIST
2 Richard Wurtman, M.D.
3 Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
4
5
6
7
8
9
10
11
12
13
14 Keywords: (Ramelteon), melatonin, pineal, MTI receptors, MT2 receptors, sleep,
15 GABA receptors, aging, desensitization
16
17
18
19 Address for correspondence: 77 Mass Ave. 46-5023
20 Cambridge, MA, 02139, USA
21 Telephone: 617-253-6731
22 FAX: 617-253-6882
23 e-mail: [email protected]
----------
1 A. Summary: Ramelteon, the first melatonin receptor agonist to win FDA approval,
2 is presently marketed in the United States; its use is authorized to be marketed in the
3 United States for "..the treatment of insomnia associated with sleep onset". In laboratory
4 tests ramelteon has not exhibited potential for being abused or causing dependency, nor
5 has it been shown to interact with the neurotransmitter receptors that tend to be most
6 associated with these phenomena. Hence unlike other hypnotic agents ramelteon is a non-
7 scheduled drug. Few data have been published in peer-reviewed journals describing
8 ramelteon's efficacy or side-effects in patients who actually suffer from insomnia, and no
9 comparison study has been performed to determine whether, when used at its
10 recommended 8 mg dose, ramelteon has any advantage over physiologic doses of
11 melatonin (0.2 - 0.5 mg), particularly for long-term use in older patients.
2
- -
1
2 B. Introduction
3 Ramelteon is the first FDA-approved agent believed to act by mimicking the
4 effects of the hormone melatonin. It does so, as described below, by combining with and
5 activating melatonin's MT1 and MT2 receptors in the brain, which may mediate
6 melatonin's sleep-promoting effects following its secretion from the pineal
7 gland 1,2,3,4,5,6,7,8.When melatonin is administered to young adults during the daytime or
8 early evening (for example, to those initiating eastbound travel, or undertaking shift
9 work) it promotes sleep onset 4,9;when given at bedtime to older adults who suffer from
10 prolonged nocturnal awakenings, it improves sleep efficiency and increases sleep
11 time 6,10. The fully-effective oral dose of melatonin (0.2-0.5 mg, usually 0.3 mg4,6) is the
12 same for both uses, and is equal to the amount needed to elevate plasma melatonin levels
13 to what they would normally be, during the night, in young adults (about 100-200
14 pcg/ml, up from 2-10 pcg/ml around noon). Among older people whose substantially-
15 calcified pineals secrete less of the hormone, nocturnal plasma melatonin levels may only
16 rise to 25-50 pcg/mlll-14; this deficiency apparently underlies their impairment in sleep
17 efficiencl and their hypnotic response to physiologic doses of melatonin..
18 Melatonin for human consumption is unavailable in most of the world because, to
19 date, few companies have obtained the necessary data and solicited regulatory approval
20 to market it as a drug. The hormone is sold in the United States as an unregulated dietary
21 supplemene of indeterminate purity, usually in doses substantially higher than the
22 submilligram amounts needed to promote sleep. These supraphysiologic doses elevate
23 plasma melatonin levels well beyond their normal range (e.g., to 960-2440 pcg/ml after a
3
1 3 mg dose6,\3), and can cause hypothermia and hyperprolactinemia, among other side
2 effects. Moreover by desensitizing the MT115and MTi6 receptors they lose their ability
3 to promote sleep.
4 Hence, the actual contribution of exogenous melatonin to the treatment of sleep
5 disorders has remained a disappointment. But since it is widely accepted that melatonin
6 does, in fact, promote sleep, this situation has generated a commercial opportunity for
7 synthetic analogs of melatonin - like ramelteon - which, because they would be regulated
8 as a drug, would be of affirmed purity and would be used at a specific recommended
9 dose17. And since ramelteon, like melatonin itself, neither interacts with receptors for
10 GABA or other neurotransmitters, nor predisposes to substance abuse or dependenceI7-2o,
11 it has the great advantage, compared with most other sleep-promoting drugs, of not being
12 a scheduled compound 21-22.Thus, if future clinical experience affirms ramelteon's
13 efficacy and benign side-effect profile use of this drug may expand rapidly.
14 Unfortunately, very little published information is presently available to help
15 physicians decide whether to recommend ramelteon to patients with insomnia - only three
16 peer-reviewed publications. In one ofthese23 healthy, non-insomniac subjects received
17 single doses of the drug; in another 24insomniacs received the ramelteon for just two
18 consecutive days; and in a third25only subjective effects of the drug were described.
19 Unreviewed abstracts have also been published describing 35-day studies in insomniacs
20 or shorter studies in healthy subjects required to sleep in a laboratorj6-27, and an FDA
21 report17,briefly summarized two unpublished 35-day polysomnographic studies
22 performed on insomniacs and described the drug as significantly reducing latency to
23 persistent sleep. Apparently no study has examined the effects on sleep of administering
4
1 ramelteon to insomniac patients for more than 35 days, even though nothing in the drug's
2 package insert precludes its likely off-label use by aged insomniacs for prolonged
3 periods. And no study has compared ramelteon's efficacy and safety with that of
4 melatonin, the hormone that the drug was designed to replace2o. Such comparative data
5 would almost certainly have been required before a novel analog of any other hormone
6 would have been granted regulatory approval.
7 Given the paucity of information currently available concerning ramelteon, plus
8 the fact that it and melatonin apparently interact with the same MTI and MT2 receptors,
9 our ability to anticipate ramelteon's clinical effects may be enhanced if we also consider
10 those of melatonin itself. Melatonin does differ from ramelteon in that it also binds to a
11 third protein, sometimes termed the "MT3 receptor" but actually a detoxifying enzyme.
12 However this binding has not been shown to produce functional or behavioral
13 consequences. Hence it seems unlikely that ramelteon's failure to bind to MT3
14 differentiates its clinical effects from those of melatonin.
15 C. Effects ofRamelteon
16 a. Pharmacokinetics and Metabolism
17 When ramelteon [(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-
18 yl)ethyl] propionamide; MW 259.34] is administered at its recommended 8 mg oral
19 dosage it is rapidly absorbed, serum concentrations peaking after 0.5 - 1.5 hrs. at 5,700
20 pg!mI17-19or about 20-40 times nocturnal plasma melatonin levels3,4.Although at least
21 84% of the drug is actually absorbed its oral bioavailability is substantially lower (only
22 1.8%), because of extensive first-pass metabolism17.About 82% ofthe drug in human
23 serum is protein-bound, 70% of this to albumin17. Intravenous ramelteon exhibits a high
5
1 mean volume of distribution in humans (74 liters)17,suggesting that it readily enters most
2 tissues.
3 Ramelteon is metabolized by oxidation to hydroxyl and carbonyl derivatives, and
4 rapidly eliminated, principally as urinary metabolites, within 96 hours of oral
5 administration. Its elimination half-life is short, i.e. 1.0- 2.6 hrsI9,28,suggesting that the
6 drug does not accumulate in the brain after repeated daily dosings, however no data are
7 available on its actual brain levels in animals dosed repeatedly. If the brain does
8 accumulate ramelteon this would increase the likelihood that it - like pharmacologic
9 concentrations of melatonin itself - can desensitize the receptors on which it acts 15,16,29,
10 30,31,32,33.One ramelteon metabolite designated M-II, does exhibit biological activity,
11 binding both to melatonin MTI and MT2 receptors and to serotonin-2B receptorsl7. Its
12 affinities for human MTI and MT2 receptors are approximately one-tenth and one-fifth
13 those ofunmetabolized ramelteon. Although this metabolite is 17-25-fold less potent
14 than ramelteon in in vitro functional assays, it also circulates at much higher
15 concentrations, producing 20-100-fold greater mean systemic exposures. Thus it may
16 contribute to ramelteon' s biological effects. The consequences, if any, of M-II's binding
17 to serotonin receptors await characterization, but could also be important given
18 serotonin's known involvement in sleep.
19 Elderly subjects metabolize ramelteon significantly more slowly than younger
20 subjects, hence their total exposure to any dose (AVC) is almost twice as great17. Total
21 exposure is also increased 4-10-fold among patients with mild or moderate hepatic
22 impairment but not in those with renal disease.17 The metabolic fate of ramelteon is
23 markedly affected by other drugs which happen to interact with CPY-IA2 enzymes, - for
6
1 example, the antidepressant fluvoxamine can cause a 190-fo1dincrease in ramelteon's
2 AUC. Many other drugs (and even a food: grapefruit juice) inhibit or induce CYP1A2,
3 and might thus be expected to affect blood levels oframelteon28.
4 b. Neurochemical Effects
5 The ability of ramelteon to bind to brain receptors for melatonin or to
6 numerous other brain proteins (e.g., neurotransmitter receptors; ion channels;
7 neurotransmitter transporters) was examined using, for melatonin receptors, cultured
8 Chinese ovary (CHO) cells cloned to contain MT1 or MT2 receptors or brain
9 homogenates containing "MT3 receptors,,18. Ramelteon binding to other proteins was
10 assessed using commercial assay protocols. Since the binding of authentic melatonin to
11 MT1 or MT2 receptors was known to suppress cyclic AMP production, this effect was
12 also assessed in the CHO cells. (The putative "MT3 receptor" is actually a detoxifying
13 enzyme - quinine reductase 2 - 34which can bind melatonin but which otherwise has no
14 known involvement in melatonin's physiological effects nor in the side-effects (e.g.,
15 hypothermia) produced by pharmacologic doses. Ramelteon failed to bind significantly
16 to this "MT3 receptor", however the significance of this lack of activity - like that of the
17 "MT3 receptor" itself - is uncertain.)
18 A binding protein was considered responsive to ramelteon if, at a 10 micromolar
19 concentration, the drug failed to inhibit by 50% or more the protein's binding to its true
20 ligand. Using this criterion, ramelteon effectively inhibited the binding of radiolabeled
21 melatonin to brain MT1 or MT2 receptors. Also, like melatonin itself, ramelteon
22 inhibited the production of cyclic AMP in cloned CHO cells containing the melatonin
23 receptors. Ramelteon failed to suppress by more than 50% the receptor binding of the
7
-
1 other ligands tested, except for the binding of serotonin to its 5HT-IA receptors, for
2 which the Ki value was 5.6 micromolar. Brain receptors failing to respond to ramelteon
3 included the GABA receptors which mediate the therapeutic actions and side-effects of
4 most other hypnotic agents, and also the receptors for opioids, benzodiazepines,
5 dopamine, and other monoamines (excluding the 5HT-IA receptor). This neurochemical
6 specificity probably explains the drug's low abuse potentialI7and its relatively good side-
7 effect profile, described below.
8 The affinities for ramelteon of the MTI and MT2 receptors are probably greater
9 than those for melatonin itself. For the MTI receptor the Ki's for ramelteon and
10 melatonin are, respectively 14 x 10-12and 80 x 10-12,and for the MT2 receptor they are
11 112 x 10-12and 383 x 10-1218,19.Peak plasma ramelteon levels after a therapeutic (8 mg)
12 dose (i.e., 57,000 pg/ml19)are, however, hundreds of times greater than those generated
13 by nocturnal melatonin secretion in younger people, or by administering a therapeutic
14 (0.3 mg) dose of the hormone to anyone (i.e., 250 pg/ml or lessl\ Since
15 supraphysiologic concentrations of melatonin markedly desensitize the MTI receptor
16 ".. .thereby affecting physiological responses.. ..following activation ofMTI melatonin
17 receptors" 15,and cause a similar long-lasting down-regulation ofMT2 receptors in
18 suprachiasmatic nucleus (SCN) neuronsl6 it seems likely that significant receptor
19 desensitization will develop among patients taking ramelteon for more than a few days -
20 perhaps even exacerbating their insomnia. Hence the drug probably should not be used
21 for prolonged periods, particularly by older people having difficulty staying asleep, until
22 the risk of desensitization has been evaluated.
23 c. Clinical Effects
8
1 A single publication24has presented objective data on the effects of
2 ramelteon on patients with insomnia (N = 107; mean age 37.7 years); another5 has
3 presented subjective data, based on sleep diaries (n=829; all subjects were 65 years of age
4 or older). In the first, subjects received the drug (4,8, 16, or 32 mg, separated by 5- or
5 12-day washout periods) on 2 consecutive evenings, thirty minutes prior to their habitual
6 bedtime, and were monitored polysomnographically for 8 hours. All doses significantly
7 reduced sleep latency by about 13 minutes; increased total sleep time by about 12
8 minutes (i.e., from 400 to 412 minutes); and increased sleep efficiency (from 83.5% to
9 86% for the 8 mg dose). No residual pharmacological effects were noted the following
10 day. In the other publication25,also reanalyzed and described in reference 35, subjects
11 received 4 or 8 mg of ramelteon or placebo nightly for 5 weeks. Significant reductions in
12 subjective sleep latency (by 8 minutes, from 78.5 to 70.2 minutes) after either dose and
13 increases in total sleep time assessed subjectively (by 8-10 minutes), were found after one
14 week oftreatment. The reductions in subjective sleep latency persisted for the 5 weeks of
15 treatment. An unreviewed abstract also described studies on insomniacs in which
16 ramelteon (8 mg and 16 mg) was given for 5 weeks to 405 patients (mean age 39.3
17 years)27. The ramelteon significantly decreased sleep latency, as assessed
18 polysomographically, after 2, 16, or 30 days. Moreover, total sleep time and sleep
19 efficiency were increased after 2 days of treatment, and no rebound insomnia or
20 withdrawal effects were noted after cessation of treatment. Data also have been presented
21 describing sleep-promoting effects oframelteon among non-insomniac subjects in which
22 transient insomnia had been induced by having them sleep in a sleep laboratorl3,27.
9
1 A laboratory study on ramelteon's abuse potential, perfonned on 14 subjects with
2 a history of sedative/hypnotic or anxiolytic drug use, uncovered no differences in
3 subjective test responses between those receiving ramelteon and those on placebo; the
4 positive control drug used in the study, triazolam, did consistently demonstrate
5 differences from placebo36.
6 Some evidence of small, next-day residual effects was observed among insomniac
7 subjects receiving ramelteon for 35 days: At week one those receiving ramelteon (8 mg)
8 had higher VAS scores - a measure of fatigue - than those on placebo, and at week three
9 those on ramelteon exhibited lower immediate word recalll7. No evidence has been
10 presented suggesting rebound insomnia or withdrawal effects among subjects receiving
11 ramelteon for 35 days. The most common side-effects (compared with placebo) noted in
12 Phase 1-3 studies on ramelteon have been somnolence, fatigue, dizziness, and an
13 exacerbation ofinsomnial7.
14 D. Effects of Melatonin
15 Two physiologic effects have been consistently noted following melatonin administration:
16 promotion of sleep onset and maintenance2-1O,and the phase-shifting of circadian rhythms,
17 including the melatonin rhythm37,38.Both effects are produced by physiologic doses, i.e., 0.1 -
18 0.3 mg for sleep, and 0.3 - 0.5 mg for phase-shifting. Melatonin's actions on sleep reflect both of
19 these effects, - a direct action which decreases sleep latency, increases sleep efficiency, and
20 increases total sleep time; and an indirect action on the phasing of sleep onset and offset,
21 mediated by changes in the timing ofthe sleep rhythm.
22 a. Sleep
23 A 1997 articleSon melatonin and sleep listed 24 papers, almost all of
10
1 which described sedation, fatigue, decreased alertness, increased reaction time, shortened
2 sleep latency (i.e., number of minutes needed to fall asleep), increased sleep efficiency
3 (i.e., percent ofthe total sleep period actually spent sleeping), and/or increased total sleep
4 time. A 2005 meta-analysis? of 17 studies involving 284 subjects who satisfied inclusion
5 criteria, demonstrated a statistically significant decrease in sleep latency (by 4 minutes;
6 95% Confidence Interval 2.5-5.4) and significant increases in sleep efficiency (2.2%;
7 Confidence Interval 0.2-4.2) and total sleep duration (12.8 minutes; Confidence Interval
8 2.9-22.8) (Table 1). The inclusion criteria required that a study include at least 6
9 subjects, all adults; be randomized and double-blinded; involve placebo-controlled
10 clinical trials; and use objective measures of sleep evaluation. Studies could utilize
11 crossover or parallel group designs, however case reports were excluded. It was perhaps
12 noteworthy that statistical significance was attained in spite of major variations among
13 the studies in melatonin doses and routes of administration used; the general health of the
14 subjects; and the measures used to evaluate sleep.
15 The effects of exogenous melatonin on sleep have been examined under three
16 types of experimental conditions.
17 1) After administration of the hormone during the daily light period. This causes
18 blood melatonin levels to be transiently elevated, but then to return to baseline before the
19 initiation of nocturnal melatonin secretion. Such experiments have been used to
20 demonstrate that melatonin can decrease sleep latency at any time in the afternoon or
21 evening, and that this effect is independent of any action the hormone might have on
22 sleep rhythms (since no treatment can immediately shift the phase of a circadian rhythm
23 by 8-10 hrS.)3.
11
1 2) After administration of the hormone late enough in the daily light period, such that
2 blood melatonin levels are still elevated when nocturnal melatonin secretion starts39. The period
3 during which plasma melatonin levels are continuously elevated is thus prolonged. Such
4 experiments have simulated the use of melatonin to decrease sleep latency and maintain
5 continuous sleep in, for example, a shift-worker or an eastbound world traveler required to start
6 sleeping earlier in the evening.
7 3) After administration of the hormone at the end ofthe light period6 , e.g., to
8 older insomniacs with low nighttime plasma melatonin levels. The intent has been to
9 prolong the portion of the night during which their plasma melatonin concentrations are
10 elevated to the same range as those of non-insomniac young adults.
11 In all of these situations, exogenous melatonin has decreased sleep latency and,
12 when tested, increased sleep duration and sleep efficiency. A 0.2-0.5 mg dose was
13 usually found to be either as effective as, or more effective than6,higher pharmacologic
14 doses, which tend to lose efficacy when administered for several days. The physiologic
15 dose has no effect on body temperature, affirming that, while pharmacologic doses do
16 cause hypothermia, melatonin's ability to promote sleep is not mediated by such a
17 change, as had been suggested. The hormone tends to have no consistent effect on sleep
18 architecture (Table 1),neither increasing nor decreasing the portion of the sleep period
19 during which subjects exhibit REM. Its effects, in general, have differed from those
20 usually associated with hypnotic drugs, since after melatonin subjects can readily keep
21 from falling asleep if they so choose, and their cognitive abilities the morning after
22 receiving the hormone are unchanged or improved3.
12
1 A relatively large (N = 30) study 6,was performed on people who were 50 years
2 of age or older; did or did not suffer from clinically-significant insomnia (i.e. sleep
3 efficiencies of 70-80% in the insomniacs vs. 92% in controls); and received each of four
4 randomized doses of melatonin (0; 0.1; 0.3; or 3.0 mg;) orally for a week, separated by
5 one-week washout periods. The hormone was found to produce statistically and
6 clinically significant improvements in sleep efficiency among the insomniacs, with the
7 0.3 mg dose causing the greatest effect (P 0.0001) (Table 1): total sleep time increased
8 by 19minutes, and sleep efficiency rose from 78% to 88%. The effect of the melatonin
9 was greatest during the middle portion of the nocturnal sleep period, when sleep
10 efficiency was increased from 70% to 92%. No effects were noted in subjects without
11 insomnia, and among the insomniacs there were no changes in total sleep time; latency to
12 sleep onset (which is not abnormal in this population) or to REM sleep; or percent time
13 spent in any of the sleep stages. Dose-related increases in plasma melatonin levels were
14 observed, the 0.3 mg dose causing peak levels in the range usually observed nocturnally
15 among young adults. By ten hours after administration of the 0.1 or 0.3 mg doses plasma
16 melatonin levels did not differ from those after placebo treatment; however after the 3.0
17 mg dose plasma melatonin levels remained significantly elevated for much of the
18 following day. This high dose but not the other two also caused significant hypothermia.
19 The study concluded that many older people with poor sleep efficiency might benefit if
20 their low nocturnal melatonin levels were corrected.
21 A prolonged-release preparation containing 2 mg of melatonin has recently been
22 shown to improve sleep quality and next-morning alertness in insomniac patients aged 55
23 years or 0Ider4o,41,using a sleep evaluation questionnaire, a diary and other subjective
13
1 measurements. This preparation elevates plasma melatonin levels to 390 pcg/ml after
2 1.5-2.5 hours and sustains plateau levels for 3.1-4.4 hours, after which they decay to
3 baseline within 9-10 hours (N. Zisapel, personal communication).
4 b. Circadian Rhythms: Phase-Shifting and Jet Lag
5 That exogenous melatonin can synchronize and shift the phases of various human
6 circadian rhythms is generally accepted. As little as 0.5 mg of pure melatonin42,or 0.05 mg of
7 melatonin in com oil43(which causes earlier peaks in, and the more rapid disappearance of,
8 elevated plasma melatonin levels) advanced the onset of nocturnal melatonin secretion when
9 administered at 5 PM, and larger doses caused greater phase advances. (The hormone shifted the
10 core body temperature rhythm, however a statistically significant effect was found only after a
11 dose that elevated plasma melatonin levels well beyond their normal range, i.e., to 1327 pcg/ml
12 42),affirming that physiologic elevations in plasma melatonin fail to affect body temperature.
13 Melatonin can also control the timing of the sleep and sleepiness rhythms, - an effect readily
14 demonstrated among blind people with free-running melatonin and sleep rhythms43but also
15 among sighted individuals. Moreover physiologic doses (0.3 mg) reportedly entrain a variety of
16 otherwise free-running rhythms in blind people44.
17 Melatonin's ability to phase-shift circadian rhythms underlies its common use to
18 prevent or treat "jet lag" -particularly that associated with eastbound travel (possibly
19 because the melatonin can be taken while the traveler is still awake): A 1999 review45
20 cited 9 placebo-controlled field studies on this use, of which 7 were successful in that
21 improvements were noted in subjective (and in one case objective) measures of sleep and
22 alertness. Adequate data are not available on the relationship between the efficacies of a
23 particular melatonin dose in treating jet lag and in raising plasma melatonin levels. Some
14
1 investigators recommend taking the melatonin at a specific time [e.g., at 2 AM in the
2 traveler's new geographic environment]; others simply propose "..a... pre-flight early
3 evening treatment before an eastbound flight, followed by treatment at bedtime for four
4 days after arriva1.45Westbound, the traveler is advised to take the melatonin late in the
5 evening, in order to sustain nocturnal plasma melatonin levels for as long into the night as
6 possible. A 2003 Cochrane Review on "Melatonin for the prevention and treatment of jet
7 lag" concluded that "Melatonin is remarkably effective in preventing or reducing jet
8 lag...46.A more recent (2006) meta-analysis concluded that melatonin has not been
9 shown to be effective in treating sleep disorders such as jet lag and shift work disorder,
10 nor insomnias secondary to e.g., neurologic disease47. This review failed to include many
11 publications in which melatonin had been found effective for jet lag, nor to consider the
12 prior meta-analyses which concluded that the hormone is efficacious. Moreover almost
13 all of the studies it did cite had utilized very high, probably desensitizing melatonin
Other Reported Effects
It has been suggested48,49that melatonin is a potent antioxidant, and that
17 melatonin supplements may protect against such age-related diseases as atherosclerosis,
18 cancer, and Alzheimer's disease. None ofthese proposed uses has been tested in a
19 controlled clinical trial nor, of course, has any been approved by the FDA. And all remain
20 questionable because of their lack of confirmations; the enormous melatonin
21 concentrations or doses needed to produce the effect; the failure of the investigators to
22 provide data on actual blood or tissue melatonin concentrations after treatment; and the
23 lack of studies comparing melatonin's effects with those of known antioxidants like
15
14 doses.
15 c.
16
1 Vitamins C or E. It has usually been possible to demonstrate antioxidant or free radical
2 scavenger effects in vitr048,however, such demonstrations generally have required
3 melatonin concentrations 1,000 - 100,000times those ever occurring in viv050.Similarly,
4 while high doses of melatonin (10-450 mglkg body weight parenterally) have sometimes
5 been shown to elicit antioxidant effects in experimental animals in vivo, neither their
6 long-term safety nor their effects on the animals' blood melatonin levels have been
7 characterized. In humans such megadoses might ultimately be expected to impair sleep
8 or various circadian rhythms by desensitizing melatonin receptors.
9 In several small studies melatonin was found to reduce blood pressure when given
10 to normotensive men or women in daytime or early evening,51or to patients with
11 essential hypertension. This possible effect should be explored further in subjects given
12 ramelteon, as should whether therapeutic doses of the drug cause hypothermia.
13 D. Conclusions
14 Ramelteon, a potent agonist for melatonin's MTI and MT2 receptors, shares with
15 melatonin the ability to reduce sleep latency, and is approved for this use by the FDA. It
16 is not an agonist for benzodiazepine or GABA receptors, nor for those of other
17 neurotransmitters thought to mediate the hypnotic effects or addictive potential of most
18 hypnotic drugs; moreover, ramelteon has not manifested abuse potential in laboratory
19 tests. Hence, probably unique among prescription hypnotics, ramelteon is a non-
20 scheduled drug. The longest, still-unpublished studies on ramelteon's use in insomniacs
21 have lasted only 35 days, and in the longest such study described in a peer-reviewed
22 publication the drug was administered for only two days. Hence it is not yet possible to
23 conclude that, with chronic administration, ramelteon will retain its efficacy and
16
1 propensity for causing only benign side effects. That ramelteon might indeed lose
2 efficacy with repeated use is suggested by its relatively high peak blood levels (compared
3 with those of melatonin) after a standard therapeutic dose, and by the tendency of the
4 MT1 and MT2 receptors to become desensitized when exposed to supraphysiologic
5 levels of their agonist.
17
1 Acknowledgements
2 Studies perfonned in the author's laboratory were supported by the U.S. National
3 Institutes of Health. The Massachusetts Institute of Technology owns a U.S. patent on the
4 use of melatonin to promote sleep.
18
1 References
2 1. Lynch HJ, Wurtman RJ, Moskowitz MA, et ai1yrhythm in human urinary
3 melatonin. Science 1975;187:169-71
Brzezinski A. Melatonin in humans. N En)!!Med 1997;336:186-95
Wurtman, R.J. Melatonin. In P. Coates, et al. eds. Encvclopedia of Diet v
, Marcel Dekker, Inc. 2005:457-66
Dollins AB, Zhdanova IV, Wurtman RJ, et I. Effect of inducing nocturnal serum
8 melatonin concentration in daytime on sleep, mood, body temperature and performance.
9 Proc Nat
10 5.
11 BioI Rhvt
12 6.
1994;91:1824-28
Zhdanova IV, Wurtman RJ. Efficacy of melatonin as a sleep-promoting agent. .f.
1997; 12:644-50
Zhdanova IV, Wurtman RJ, Regan MM, et Melatonin treatment for age-
13 related insomnia. J Gin Endocrin Met 2001; 86(10):4727-30
14 7. Brzezinski A, Vangel MG, Wurtman RJ. et l. Effects of exogenous melatonin
15 on sleep - a meta-analysis.. Sleep Med Rev 2005;9:41-50
16 8. Stone BM, Turner C, Mills SL, et ypnotic activity of melatonin. Sleep
17 2000;23:663-9
18 9. Zhdanova IV, Wurtman RJ, Lynch HJ, et effects of low doses
19 of melatonin ingested in the evening. Gin Pharmacol Ther 1995;57:552-58
20 10. Haimov I, Laudon M, Zisapel N, et rders and melatonin rhythms in
21 elderly people. BMJ 1994;309:167
22 11. Touitou Y. Some aspects ofthe circadian time structure in the elderly.
23 Geront 1982;28 (Suppl1):53-67
19
4 2.
5 3.
6 u
7 4.
1 12. Iguchi H, Kato KI, Ibayashi H. Age-dependent reduction in serum melatonin
2 concentrations in healthy human subjects. J Clin Endocrinol Met 1982;55:27-9
3 13. Zhdonova IV, Wurtman RJ, Balcioglu A, et ndogenous melatonin levels and
4 the fate of exogenous melatonin: age effects. J Geront 1998;53A:B293-B298
5 14. Sack RL, Lewy AJ, Erb DL, et onin production decreases with
6 age. J Pineal Res 1986;3:379-88
7 15. Gerdin MJ, Masana MI, Dubocovich ML. Melatonin-mediated regulation of
8 human MT) melatonin receptors expressed in mammalian cells. Biochem Pharmacol
9 2004;67:2023-30
10 16. Gerdin MJ, Masana MI, Rivera-Bermudez MA, et al. Melatonin desensitizes
11 endogenous MT 2 receptors in the rat suprachiasmatic nucleus: relevance for defining the
12 periods of sensitivity of the mammalian circadian clock to melatonin. FASEB J
13 1004;18:1646-56
14 17. FDA. Center for Drug Evaluation and Research. Application number 21-782:
15 Ramelteon (TAK-375). Medical Review [online]. Available from URL: (Accessed 2006
16 Feb 15).
17 18. Kato K, Hirai K, Nishiyama K, et chemical properties of ramelteon
18 (TAK-375), a selective MT)/MT2receptor agonist. Neu 2005;48:301-10
19 19. Stevenson S, Bryson S, Amakye D, et Yto investigate the absolute
20 bioavailability of a single oral dose of ramelteon (TAK-375) in healthy male subjects.
21 Clinical Pharmacology and TheraTJeu 2004;75:P22
22 20. Cajochen TC. TAK-375. Cu s 2005;6: 114-21
23 21. ROZEREM™ (ramelteon) Tablets. 2005;Package Insert
20
1 22. Ramelteon (Rozerem) for Insomnia. The Medical Let
2 Therapeu 2005;47: 89-91
3 23. Roth T, Stubbs C, Walsh JK. Ramelteon (TAK-375) A selective MTl/MT2-
4 receptor agonist, reduces latency to persistent sleep in a model of transient insomnia
5 related to a novel sleep environment. Sleep 2005;28:303-7
6 24. Erman M, Seiden D, Zammit G, et cy, safety, and dose-response
7 study of Ramelteon in patients with chronic primary insomnia. Sleep Medicine
8 2006;7:17-24
9 25. Roth T, Seiden D, Sainati S, et amelteon on patient-reported sleep
10 latency in older adults with chronic insomnia. Sleep Medicine 2006;7:312-8
11 26. Zammit G, Roth T, Erman M, et controlled
12 polysomnography and outpatient trial to evaluate the efficacy and safety of Ramelteon in
13 adult patients with chronic insomnia. Sleep 2005;28:Abstract Supplement, 0680, A228-
14 A229
15 27. Zammit G, Schwartz H, Roth T, et III study ofRamelteon in a first-
16 night-effect model of transient insomnia. Sleep Medicine 2005;6S2:550, 0007
17 28. McGeehan A, Wellington K. Ramelteon. CNS Dru 2005;19:1057-65
18 29. Witt-Enderby P, Bennett J, Jarzynka M, et at. Melatonin receptors and their
19 regulation: biochemical and structural mechanisms. Life Sciences 2003;72:2183-98
20 30. Gauer F, Masson-Pevet M, Skene D, et Daily rhythms of melatonin binding
21 sites in the rat pars tuberalis and suprachiasmatic nucleus; evidence for a regulation of
22 melatonin receptors by melatonin itself. Neu o 1993;57:120-6
21
1 31. Hazlerigg D, Gonzalez-Brito A, Lawson W, et ed exposure to
2 melatonin leads to time-dependent sensitization of adenylate cyclase and down-regulates
3 melatonin receptors in pars tuberalis cells from ovine pituitary. Endocrinolof!V
4 1993;132:285-92
5 32. Jones M, Melan M, Witt-Enderby P. Melatonin decreases cell proliferation and
6 transformation in a melatonin receptor-dependent manner. Cancer Let 2000; 151: 133-
7 43
8 33. Witt-Enderby P, MacKenzie R, McKeon R, et
9 filamentous structures in non-neuronal cells that is dependent on the expression ofthe
10 human mt! melatonin receptor. Cell Mot 2000;46:28-42
11 34. Nosjean 0, Ferro M, Coge F, et Identification of the melatonin-binding site
12 MT3 as the quinine reductase 2. J Bioi Chem 2000;275:31311-17
13 35. Mini LJ, Wang-Weigand S, Zhang J. Self-reported efficacy and tolerability of
14 ramelteon 8 mg in older adults experiencing severe sleep-onset difficulty. Am J Geriat
15 Pharmacot 2007;5: 177 -84
16 36. Griffiths R, Suess P, Johnson M. Ramelteon and triazolam in humans: Behavioral
17 effects and abuse potential. SleeT)2005;28: Abstract Supplement, 0132
18 37. Arendt J. Importance and relevance of melatonin to human biological rhythms.
19 J. Neu 2003;15:427-31
20 38. Herxheimer A, Petrie KJ. Melatonin for preventing and treating jet lag.
21 Cochrane Dat Rev.2001;(I):, CD001520
22
1 39. Zhdanova IV, Wurtman RJ, Morabito C, et l. Effects oflow oral doses of
2 melatonin, given 2-4 hours before habitual bedtime, on sleep in normal young humans.
3 Sleep 1996;19:423-31
4 40. Lemoine P, Nir T, Laudon M, Zisapel N. Prolonmged-release melatonin
5 improves sleep quality and morning alertness in patients aged 55 years and older and has
6 no withdrawal effects. J Sleep Research 2007;16:372-80
7 41. Wade AG, Ford I, Crawford G, McMahon A, Nir T, Laudon M, Zisapel N.
8 Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of
9 sleep and next-day alertness outcomes. Cu ch Opinions 2007;23:2597-
10 2605
11 42. Deacon S, Arendt J. Melatonin-induced temperature suppression and its acute
12 phase-shifting effects correlate in a dose-dependent manner in humans. Brain Res
13 1995;688:77-85
14 43. Arendt J, Aldhous M, Wright J. Synchronization of a disturbed sleep-wake cycle
15 in a blind man by melatonin treatment. LancetI988;1(8588):772-3
16 44. Lewy AJ, Emens JS, Lefler BJ et trains free-running blind
17 people according to a physiological dose-response curve. ChronobiolInt 2005;22:1093-
18 1206
19 45. Arendt J. Jet-lag and shift work: (2) therapeutic use of melatonin. JRoval Soc
20 Med. 1999;92:402-5
21 46. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag
22 (Cochrane Review). The Cochrane Library 2003; Issue 4:CD001520
23
1 47. Buscemi N, Vandermeer B, Hooton N, et l. Efficacy and safety of exogenous
2 melatonin for secondary sleep disorders and sleep disorders accompanying sleep
3 restriction: meta-analysis. BMJ2006;332:385-93
4 48. Reiter RJ. Oxidative damage in the central nervous system: protection by
5 melatonin. Prog in Neu 1998;56:359-84
6 49. Rodriguez C, Mayo JC, Sainz RM et Regulation of antioxidant enzymes: a
7 significant role for melatonin. J Pineal Res 2004;36:1-9
8 50. Duell PB, Wheaton DL, Shultz A, et nhibition ofLDL oxidation by
9 melatonin requires supraphysiologic concentrations. Clin Chem 1998;44:1931
10 51. Cagnacci A, Cannoletta M, Renzi A et ged melatonin administration
11 decreases nocturnal blood pressure in women. Am J Hvper! 2005;18:1614-18
24
