ORIGINAL ARTICLE Ramelteon A Novel Hypnotic Lacking Abuse Liability and Sedative Adverse Effects Matthew W. Johnson, PhD; Patricia E. Suess, PhD; Roland R. Griffiths, PhD Context: Ramelteon is a novel MT1 and MT2 melatonin well as assessments of a broad range of stimulant and receptor selective agonist recently approved for insom- sedative subjective effects. Observer-rated measures in- nia treatment. Most approved insomnia medications have cluded assessments of sedation and impairment. Motor potential for abuse and cause motor and cognitive im- and cognitive performance measures included psycho- pairment. motor and memory tasks and a standing balance task. Objective: To evaluate the potential for abuse, subjec- Results: Compared with placebo, ramelteon (16, 80, and tive effects, and motor and cognitive–impairing effects 160 mg) showed no significant effect on any of the sub- of ramelteon compared with triazolam, a classic benzo- jective effect measures, including those related to poten- diazepine sedative-hypnotic drug. tial for abuse. In the pharmacological classification, 79% (11/14) of subjects identified the highest dose of ramelt- Design: In this double-blind crossover study, each par- eon as placebo. Similarly, compared with placebo, ra- ticipant received oral doses of ramelteon (16, 80, or 160 melteon had no effect at any dose on any observer-rated mg), triazolam (0.25, 0.5, or 0.75 mg), and placebo dur- or motor and cognitive performance measure. In con- ing approximately 18 days. All participants received each treatment on different days. Most outcome measures were trast, triazolam showed dose-related effects on a wide assessed at 0.5 hours before drug administration and re- range of subject-rated, observer-rated, and motor and cog- peatedly up to 24 hours after drug administration. nitive performance measures, consistent with its profile as a sedative drug with abuse liability. Setting: Residential research facility. Conclusion: Ramelteon demonstrated no significant ef- Participants: Fourteen adults with histories of seda- fects indicative of potential for abuse or motor and cog- tive abuse. nitive impairment at up to 20 times the recommended therapeutic dose and may represent a useful alternative Main Outcome Measures: Subject-rated measures in- to existing insomnia medications. cluded items relevant to potential for abuse (eg, drug lik- ing, street value, and pharmacological classification), as Arch Gen Psychiatry. 2006;63:1149-1157 NSOMNIA IS THE INABILITY TO FALL First, benzodiazepine receptor ago- or remain asleep or the experi- nists are known to be used nonmedically ence of nonrestorative sleep, re- (ie, abused), particularly by individuals sulting in clinically significant dis- with a history of substance abuse.6-9 Sec- tress or adverse consequences on ond, these compounds can engender daytime functioning.1 This disorder is preva- cognitive impairments, most promi- I 10-14 lent, with 10% to 15% of adults having nently anterograde amnesia. Third, chronic insomnia and another 25% to 35% these agents can produce motor impair- experiencing occasional insomnia.2,3 The ments (eg, poor driving performance15,16 most common pharmacological agents used and falls in older persons17,18). Fourth, in the treatment of insomnia are ␥-amino- benzodiazepine receptor agonists can butyric acid type A (GABAA)modulators act- produce a withdrawal syndrome on dis- ing at the benzodiazepine recognition site continuation of long-term use of thera- Author Affiliations: (ie, benzodiazepine receptor agonists) (eg, peutic or higher doses.8,15,19 Withdrawal Departments of Psychiatry and zolpidem tartrate, eszopiclone, temaze- symptoms include rebound insomnia, Behavioral Sciences pam, and triazolam).4,5 These compounds anxiety, irritability, headache, gastroin- (Drs Johnson, Suess, and Griffiths) and Neuroscience produce several problematic effects that in- testinal disturbance, depersonalization, (Dr Griffiths), The Johns crease the risk of inappropriate use and re- perceptual changes, and, in severe cases, Hopkins University School of strict the populations in which they may be seizures and delirium.6 Pharmacological Medicine, Baltimore, Md. safely prescribed.5 agents without such problematic effects (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, OCT 2006 WWW.ARCHGENPSYCHIATRY.COM 1149 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 could provide a valuable alternative for the treatment of METHODS insomnia. Because of concern about abuse, dependence, and SUBJECTS withdrawal, physicians are frequently discouraged from prescribing benzodiazepine receptor agonists to patients Healthy men and nonpregnant and nonlactating women be- with a history of substance abuse or dependence.8,20,21 tween 18 and 60 years of age without a current clinically sig- The 2005 Physicians’ Desk Reference, for example, pro- nificant medical or psychiatric condition other than substance vides the following caution to physicians when pre- abuse or dependence were eligible to participate in this study. scribing the benzodiazepine receptor agonist zolpidem: Subjects fulfilled criteria for DSM-IV current or past psycho- “Because persons with a history of addiction to, or active substance abuse or dependence and reported nonmedi- abuse of, drugs or alcohol are at increased risk of cal use of a sedative drug within the last year. On enrollment, subjects were required to have a negative urine drug screen, habituation and dependence, they should be under demonstrate negative test results for breath ethanol, and show careful surveillance when receiving zolpidem or any no signs or symptoms of drug withdrawal. Subjects with ab- 22(p2982) [italics added] other hypnotic.” Compliance with normal findings on physical or clinical laboratory evaluations such recommendations is difficult considering that 46% were excluded. Subjects gave their written informed consent of the US population reports some use of illicit drugs before beginning the study and were paid for their participa- during their lifetimes and 9% meet criteria for past-year tion. The Western Institutional Review Board of Olympia, Wash, abuse of or dependence on any illicit drug or alcohol.23 approved this study. Furthermore, patients may not disclose such histories of nonmedical use. PROCEDURES Ramelteon, an agent recently approved for the treat- ment of insomnia characterized by difficulty with sleep This study was conducted following general procedures simi- lar to those described previously.34,35 Research subjects re- onset, is a novel MT1 and MT2 melatonin receptor selec- sided on a 14-bed research unit for approximately 18 days. For tive agonist and has minimal affinity for other sites im- a few days before and throughout the study, subjects were given plicated in potential for abuse and impairment, such as a caffeine-free diet but were allowed to smoke tobacco ciga- benzodiazepine receptors, dopamine receptors, opiate re- rettes except when engaged in experimental procedures. Sub- ceptors, ion channels, and various receptor transport- jects and research staff were instructed that possible drugs to 24 ers. The MT1 and MT2 receptors are located in the su- be tested included sedatives, anesthetics, muscle relaxants, anti- prachiasmatic nucleus of the hypothalamus and are psychotics, antianxiety drugs, antihistamines, analgesics, stimu- involved in maintaining the circadian sleep-wake cycle.25 lants, weight loss medications, and placebo. Subjects were also In double-blind studies26-29 analyzing doses from 4 to 64 told that they would receive ramelteon (identified as TAK- 375), an investigational drug being evaluated for treatment of mg, ramelteon was efficacious in reducing latency to per- sleep disorders. Subjects were told that the objective of the study sistent sleep and, although less consistently, in increas- was to learn more about the effects of drugs on mood and per- ing total sleep time in individuals with and without formance during various tasks. No instructions were provided chronic insomnia. as to what outcomes might be expected. Evidence to date suggests that ramelteon administra- During the days in which sessions were conducted, sub- tion may lack several of the problematic effects associ- jects were required to remain in the dayroom of the residen- ated with benzodiazepine receptor agonists used in treat- tial unit from 6:45 AM until 5 PM. Subjects ate a small, low-fat ing insomnia. In preclinical studies of rhesus monkeys, breakfast, which was finished at least 1.5 hours before drug ad- ministration. No additional food was allowed until after 12:45 ramelteon was found to have no reinforcing effect in an PM 30 . Subjects ingested study medications orally at approxi- intravenous drug self-administration procedure, was mately 8:45 AM. As described in more detail herein, various mea- similar to the vehicle in a benzodiazepine vs vehicle drug sures were assessed 0.5 hours before drug administration and discrimination procedure,31 and showed no evidence of repeatedly up to 24 hours after drug administration. withdrawal symptoms during intermittent abstinence pe- Sessions were conducted every day except weekends and riods throughout 1 year of administration.32 In clinical holidays. Before the first experimental session, subjects com- trials in subjects with chronic insomnia, ramelteon treat- pleted practice sessions for the purpose of training and adap- ment was not associated with rebound insomnia or with tation to procedures; no placebo