American Journal of Alzheimer's Disease and Other Dementias http://aja.sagepub.com/
Melatonin and Melatonin Agonist for Delirium in the Elderly Patients Dwaipayan Chakraborti, Deena J. Tampi and Rajesh R. Tampi AM J ALZHEIMERS DIS OTHER DEMEN published online 18 June 2014 DOI: 10.1177/1533317514539379 The online version of this article can be found at: http://aja.sagepub.com/content/early/2014/06/18/1533317514539379
Published by: http://www.sagepublications.com
Additional services and information for American Journal of Alzheimer's Disease and Other Dementias can be found at: Email Alerts: http://aja.sagepub.com/cgi/alerts Subscriptions: http://aja.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Jun 18, 2014 What is This?
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Review
Melatonin and Melatonin Agonist for Delirium in the Elderly Patients
American Journal of Alzheimer’s Disease & Other Dementias® 1-11 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1533317514539379 aja.sagepub.com
Dwaipayan Chakraborti, MD1, Deena J. Tampi, MSN, MBA-HCA, RN2, and Rajesh R. Tampi, MD, MS, FAPA3,4
Abstract The objective of this review is to summarize the available data on the use of melatonin and melatonin agonist for the prevention and management of delirium in the elderly patients from randomized controlled trials (RCTs). A systematic search of 5 major databases PubMed, MEDLINE, PsychINFO, Embase, and Cochrane Library was conducted. This search yielded a total of 2 RCTs for melatonin. One study compared melatonin to midazolam, clonidine, and control groups for the prevention and management of delirium in individuals who were pre- and posthip post-hip arthroplasty. The other study compared melatonin to placebo for the prevention of delirium in older adults admitted to an inpatient internal medicine service. Data from these 2 studies indicate that melatonin may have some benefit in the prevention and management of delirium in older adults. However, there is no evidence that melatonin reduces the severity of delirium or has any effect on behaviors or functions in these individuals. Melatonin was well tolerated in these 2 studies. The search for a melatonin agonist for delirium in the elderly patients yielded 1 study of ramelteon. In this study, ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo. Ramelteon was well tolerated in this study. Keywords melatonin, melatonin agonist, ramelteon, delirium, randomized controlled trials
Introduction Delirium is a common neuropsychiatric syndrome seen in the elderly patients.1 The rates of delirium vary depending upon the population that is being studied.2 The prevalence of delirium among the elderly patients in the community is between 0.4% and 2%, whereas its incidence increases to 11% to 42% during general hospital admissions and 15% to 62% postoperatively.2-4 Current estimates indicate that about one-fifth of the elderly patients who are hospitalized each year in the United States experience complications because of delirium during the hospitalization.2 Available evidence indicates that delirium contributes to poor patient outcomes irrespective of baseline patient characteristics and etiological factors.2 Some individuals with delirium never recover to their baseline level of cognitive function following an episode of delirium.2 The presence of delirium increases nursing time per patient, higher per-day hospital costs, and an increased length of hospital stay.2,5 Delirium increases the risk of dementia, institutionalization, and death independent of the baseline patient characteristics or comorbidities.6 The average cost per day in the hospital for patients with delirium is more than 2.5 times the cost among patients without delirium.7 The cost of delirium is approximately US$6.9 billion for Medicare in-hospital expenditure, and the total the national burden of delirium on the health care system ranges from US$38 billion to US$152 billion per year.7,8
It is estimated that about one-third of the cases of delirium are preventable and that prevention remains the most effective strategy for minimizing the occurrence of delirium and its adverse outcomes.2 A multicomponent targeted risk factor intervention strategy that used standardized protocols for the management of 6 risk factors for delirium, cognitive impairment, sleep deprivation, immobility, visual impairment, hearing impairment, and dehydration, demonstrated that the incidence, the total number of days with delirium, and the total number of episodes of delirium could be significantly reduced by this strategy.9 This intervention also reduced the short-term cost by US$831 per hospitalization for intermediate-risk
1 The Division of Gerontology, Geriatrics and Palliative Care, University of Alabama School of Medicine, Birmingham, AL, USA 2 Behavioral Health Service, Saint Francis Hospital and Medical Center, Hartford, CT, USA 3 Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA 4 Adult Psychiatry Residency, Regional Academic Health Center, Harlingen, TX, USA
Corresponding Author: Rajesh R. Tampi, MD, MS, FAPA, Adult Psychiatry Residency, Regional Academic Health Center, 2102 Treasure Hills Blvd, Harlingen, TX 78550, USA. Email: [email protected]
Downloaded from aja.sagepub.com at Maastricht University on June 19, 2014
American Journal of Alzheimer’s Disease & Other Dementias®
2 patients and the long-term cost savings approaching US$10 000 per year from the prevention of long-term nursing home days.10,11 One systematic review specific to the prevention of delirium in the elderly patients concluded that multicomponent interventions to prevent delirium are effective and should be implemented through synergistic cooperation between the various health care disciplines.12 Both nonpharmacological and pharmacological strategies have demonstrated benefit in the management of individuals with delirium.1 Nonpharmacological strategies include frequent reorientation, making eye contact, frequent touching, and using clear verbal instructions when talking to patients.2 Other strategies include the minimizing of sensory impairments comprising vision and hearing loss by the use of assistive devices, reducing the use of physical restraints, providing treatment in a nonstimulating environment, and minimizing staff and room changes.1 Pharmacotherapy in delirium is mainly targeted toward the treatment of its underlying causes.3 However, it is also used to manage the patient’s behaviors when these behaviors cannot be controlled by nonpharmacological means.2 A recent systematic review by Friedman et al indicated that pharmacological strategies show greater success in the prevention of delirium rather than in its management.13 The investigators found evidence for delirium prevention effects with haloperidol, second-generation antipsychotics, gabapentin, and melatonin. It is postulated that sundowning syndrome, the term used to describe complex behavioral symptoms in patients with dementia, is more common in the evening and at night and the alterations in the sleep–wake cycle seen in individuals with delirium have a common neurobiological substrate, that is, a disturbance in the circadian rhythm.14 Melatonin (N-acetyl-5-methoxytryptamine) an endogenous hormone produced by the pineal gland during the hours of darkness is thought to play an important role in the regulation of the circadian rhythm and in maintaining the sleep–wake cycle15,16 It is hypothesized that melatonin secretion is delayed or low in older individuals with delirium.17,18 Available data also indicate that there is a suppression of the nocturnal peak level of melatonin and a decline in the circadian amplitude of the melatonin rhythm in older adults.19 A disruption to the circadian pattern of melatonin secretion has also been noted in individuals with postoperative delirium (POD).17,18 In a recent study, the postoperative plasma concentration of melatonin at 1 hour after surgery was found to be significantly lower in individuals with delirium than in those without delirium.20 The investigators found that after adjustment for relevant confounders, the plasma melatonin concentration was independently associated with the risk of delirium (odds ratio [OR], 0.50; P ¼ .047). In an earlier study, the investigators had found that the urinary excretion of 6-sulfatoxymelatonin (6SMT), the chief metabolite of melatonin which closely parallels the serum melatonin concentrations, was higher in individuals with hypoactive delirium and lower in individuals with hyperactive delirium.21 A recent study of older adults scheduled for major orthopedic surgery or abdominal surgery indicated that in the first week after surgery, postoperative cognitive dysfunction occurred in almost one-third of these individuals and was
linked to a 2-fold fluctuation in their endogenous melatonin levels as measured by the level of urinary 6-SMT.22 A summary of the available evidence indicates that there is a complex relationship between serum melatonin levels and the development of delirium.15 Older adults who have an agerelated suppression of their nocturnal peak levels of melatonin and a decline in the circadian amplitude of the melatonin rhythm are at a higher risk of developing delirium.14 When these individuals encounter a physiologically stressful situation like a medical illnesses or a surgical procedure, where there is a disruption of the circadian rhythm, an episode of delirium develops. The physiological changes that develop during an episode of delirium further disrupt the individual circadian rhythm, thus perpetuating a cycle for maintaining the delirium.23 There is some evidence that melatonin has beneficial effects on circadian rhythm disturbances in dementia. In a systematic review by de Jonghe et al, the investigators found that in 2 of the 4 randomized controlled trials (RCTs) and all 5 of the case series that used melatonin, there was an improvement in sundowning/ agitated behavior in individuals with dementia.14 As circadian rhythm disturbances are seen in both dementia and delirium, the authors postulated that melatonin may have beneficial effects in the management of delirium. A report of 2 cases indicated that melatonin at 2 mg at bedtime orally for 4 days was beneficial in the prevention and management delirium.24 In another case report, the investigators found that melatonin given at 4 mg a day orally was beneficial in an individual with dementia and sundowning syndrome and possible delirium.25 Interestingly, there is emerging evidence that the melatonin agonist, ramalteon, has some benefit in the management of delirium. In a case series of 3 women aged between 59 and 83 years, the use of ramelteon at 8 mg a day orally was found to be beneficial in the management of delirium.26 A case series of 4 men and 1 woman aged between 71 and 91 years indicated that ramelteon at 8 mg at bedtime orally was beneficial in the management of delirium, and it was well tolerated.27 In a retrospective review, the investigators found that among elderly individuals with delirium and insomnia after an acute stroke (7 individuals, mean age 76 years), the use of ramelteon was beneficial in managing their behaviors, and no adverse effects were noted with the medication.28 In another case report, a 100-yearold Japanese man with delirium who had not responded to management with risperidone 0.5 mg once daily orally responded to a switch to ramelteon at 8 mg at bedtime orally.29 The authors of this report indicate that the symptoms of delirium improved without any adverse effects from ramelteon (Table 1). It is postulated that ramelteon exerts its hypnotic action by the suppression of electrical activity via the melatonin 1 (MT1) receptor, and the circadian phase shifts due to its action on the melatonin 2 (MT2) receptor in the suprachiasmatic nucleus.30 Ramelteon is also noted to have a 6-fold higher affinity for MT1 receptors and 3-fold affinity for MT2 receptors with a longer half-life than melatonin.31 The higher affinity of ramelteon for the melatonin receptors is thought to have beneficial effects on delirium.27 Ramelteon appears be fairly well tolerated, and it does not impair next-day cognitive or motor
Downloaded from aja.sagepub.com at Maastricht University on June 19, 2014
Chakraborti et al
3
Table 1. Case Reports and Case Series for Melatonin and Melatonin Agonist for Delirium. Name of the Study
Type of Report
Hanania and Kitain24 Hanania and Kitain24
Case report 53-year-old, male
Lammers and Ahmed25 Kimura et al26
Case report 81-year-old, male
Furuya et al27
Case series
Ohta et al28
Case series
Tusuda et al29
Case report
Age of Individual (s), Sex
Case report 78-year-old, male
Case series
Drug and Dosage
Outcome
Side Effects
Melatonin, 2 mg at bedtime orally Melatonin, 2 mg at bedtime orally
Improvement in symptoms of delirium including sleep Prevented an episode of delirium in this individual with a history of postoperative delirium Improvement in the symptoms of delirium including sleep Improvement in the symptoms of delirium including sleep Improvement in the symptoms of delirium including sleep Improvement in the symptoms of delirium including sleep
None reported
Improvement in the symptoms of delirium
None reported
Melatonin, 2 mg twice daily orally 3 individuals, 69.3 + 12.34 Ramelteon, 8 mg at years, females bedtime orally 5 individuals, 82.4 + 8.3 Ramelteon 8 mg at years, bedtime orally Ramelteon 8 mg at 7 individuals, 76 + 6.5 bedtime orally years, 4 males and 3 females 100 years, male Ramelteon 8 mg at bedtime orally
performances and is not associated with withdrawal symptoms, rebound insomnia, or abuse potential.32 Given the growing body of evidence that melatonin and the melatonin agonist ramelteon may show some benefit in individuals with delirium, we wanted to review the data on their use in older adults with delirium from RCTs.
Search Strategy The purpose of this review is to summarize the data from RCTs on the use of melatonin and melatonin agonist ramelteon for delirium in older adults. We performed a literature search of 5 major databases: PubMed, MEDLINE, PsychINFO, Embase, and Cochrane Library. Search terms were ‘‘delirium,’’ ‘‘melatonin,’’ ‘‘melatonin agonist,’’ and ‘‘ramelteon.’’ The databases were searched through March 31, 2014. There was no language limit set in order to be as inclusive as possible with the search strategy. Each author independently searched the 5 databases for studies with the search terms. Abstracts of all of the studies that were noted on the initial screening were retrieved for further evaluation. Studies were selected for full-text review if they involved patients who were 60 years of age, were diagnosed as having delirium by any diagnostic criteria, were prevention or management studies, used melatonin or a melatonin agonist, and had an RCT design. Case reports, case series, database reviews, population-based reviews, systematic reviews, and meta-analysis were also excluded, but the data available from these studies were to be used as a comparison to the data available from this review. Disagreements between the authors regarding the study selection for this review were resolved through consensus. We operationalized prevention as a strategy to avoid the development of a new episode of delirium or to avoid the recurrence of another episode of delirium. Management was operationalized as a strategy to control the symptoms of delirium once they occurred.
None reported
None reported None reported None reported None reported
Results For melatonin, the search strategy yielded a total of 250 possible articles. This included 66 articles in PubMed, 22 articles in MEDLINE, 6 articles in PsychINFO, 148 articles in Embase, and 8 articles in Cochrane Library. After a review of the abstracts, 8 articles were obtained for a full-text review. Of these, 6 articles were excluded as they were case reports, editorial, or reviews. Only 2 articles met the inclusion criteria. No additional articles were retrieved from the bibliographic search of the relevant articles. The search strategy yielded a total of 7 articles for the melatonin agonist ramelteon. Of the 7 articles, 6 were obtained from PubMed. No articles were obtained from the search of MEDLINE, PsychINFO, or Embase databases. One article was obtained from the search of Cochrane Library. After a review of the abstracts, 5 articles were obtained for a full-text review. Of these, only 1 article met the inclusion criteria. The other articles were 2 case series and 2 case reports. No additional articles were retrieved from the bibliographic search of the relevant articles. To aid with the evaluation of data, we organized the studies in a chronological manner with the older study being the first to the most recent study being the last. The quality of data was evaluated using the criteria developed by the Centre for Evidence Based Medicine (CEBM) for RCT evaluation (Table 2).33
Melatonin In the study by Sultan, 300 individuals 65 years of age who were scheduled for hip arthroplasty were screened for inclusion into this study.34 Abbreviated Mental Test (AMT), a test approved by the Royal College of Physicians and the British Geriatric Society for routine assessment of cognitive function in the elderly patients, was conducted in all individuals. Those individuals with scores
Melatonin and Melatonin Agonist for Delirium in the Elderly Patients Dwaipayan Chakraborti, Deena J. Tampi and Rajesh R. Tampi AM J ALZHEIMERS DIS OTHER DEMEN published online 18 June 2014 DOI: 10.1177/1533317514539379 The online version of this article can be found at: http://aja.sagepub.com/content/early/2014/06/18/1533317514539379
Published by: http://www.sagepublications.com
Additional services and information for American Journal of Alzheimer's Disease and Other Dementias can be found at: Email Alerts: http://aja.sagepub.com/cgi/alerts Subscriptions: http://aja.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Jun 18, 2014 What is This?
Downloaded from aja.sagepub.com at Maastricht University on June 19, 2014
Review
Melatonin and Melatonin Agonist for Delirium in the Elderly Patients
American Journal of Alzheimer’s Disease & Other Dementias® 1-11 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1533317514539379 aja.sagepub.com
Dwaipayan Chakraborti, MD1, Deena J. Tampi, MSN, MBA-HCA, RN2, and Rajesh R. Tampi, MD, MS, FAPA3,4
Abstract The objective of this review is to summarize the available data on the use of melatonin and melatonin agonist for the prevention and management of delirium in the elderly patients from randomized controlled trials (RCTs). A systematic search of 5 major databases PubMed, MEDLINE, PsychINFO, Embase, and Cochrane Library was conducted. This search yielded a total of 2 RCTs for melatonin. One study compared melatonin to midazolam, clonidine, and control groups for the prevention and management of delirium in individuals who were pre- and posthip post-hip arthroplasty. The other study compared melatonin to placebo for the prevention of delirium in older adults admitted to an inpatient internal medicine service. Data from these 2 studies indicate that melatonin may have some benefit in the prevention and management of delirium in older adults. However, there is no evidence that melatonin reduces the severity of delirium or has any effect on behaviors or functions in these individuals. Melatonin was well tolerated in these 2 studies. The search for a melatonin agonist for delirium in the elderly patients yielded 1 study of ramelteon. In this study, ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo. Ramelteon was well tolerated in this study. Keywords melatonin, melatonin agonist, ramelteon, delirium, randomized controlled trials
Introduction Delirium is a common neuropsychiatric syndrome seen in the elderly patients.1 The rates of delirium vary depending upon the population that is being studied.2 The prevalence of delirium among the elderly patients in the community is between 0.4% and 2%, whereas its incidence increases to 11% to 42% during general hospital admissions and 15% to 62% postoperatively.2-4 Current estimates indicate that about one-fifth of the elderly patients who are hospitalized each year in the United States experience complications because of delirium during the hospitalization.2 Available evidence indicates that delirium contributes to poor patient outcomes irrespective of baseline patient characteristics and etiological factors.2 Some individuals with delirium never recover to their baseline level of cognitive function following an episode of delirium.2 The presence of delirium increases nursing time per patient, higher per-day hospital costs, and an increased length of hospital stay.2,5 Delirium increases the risk of dementia, institutionalization, and death independent of the baseline patient characteristics or comorbidities.6 The average cost per day in the hospital for patients with delirium is more than 2.5 times the cost among patients without delirium.7 The cost of delirium is approximately US$6.9 billion for Medicare in-hospital expenditure, and the total the national burden of delirium on the health care system ranges from US$38 billion to US$152 billion per year.7,8
It is estimated that about one-third of the cases of delirium are preventable and that prevention remains the most effective strategy for minimizing the occurrence of delirium and its adverse outcomes.2 A multicomponent targeted risk factor intervention strategy that used standardized protocols for the management of 6 risk factors for delirium, cognitive impairment, sleep deprivation, immobility, visual impairment, hearing impairment, and dehydration, demonstrated that the incidence, the total number of days with delirium, and the total number of episodes of delirium could be significantly reduced by this strategy.9 This intervention also reduced the short-term cost by US$831 per hospitalization for intermediate-risk
1 The Division of Gerontology, Geriatrics and Palliative Care, University of Alabama School of Medicine, Birmingham, AL, USA 2 Behavioral Health Service, Saint Francis Hospital and Medical Center, Hartford, CT, USA 3 Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA 4 Adult Psychiatry Residency, Regional Academic Health Center, Harlingen, TX, USA
Corresponding Author: Rajesh R. Tampi, MD, MS, FAPA, Adult Psychiatry Residency, Regional Academic Health Center, 2102 Treasure Hills Blvd, Harlingen, TX 78550, USA. Email: [email protected]
Downloaded from aja.sagepub.com at Maastricht University on June 19, 2014
American Journal of Alzheimer’s Disease & Other Dementias®
2 patients and the long-term cost savings approaching US$10 000 per year from the prevention of long-term nursing home days.10,11 One systematic review specific to the prevention of delirium in the elderly patients concluded that multicomponent interventions to prevent delirium are effective and should be implemented through synergistic cooperation between the various health care disciplines.12 Both nonpharmacological and pharmacological strategies have demonstrated benefit in the management of individuals with delirium.1 Nonpharmacological strategies include frequent reorientation, making eye contact, frequent touching, and using clear verbal instructions when talking to patients.2 Other strategies include the minimizing of sensory impairments comprising vision and hearing loss by the use of assistive devices, reducing the use of physical restraints, providing treatment in a nonstimulating environment, and minimizing staff and room changes.1 Pharmacotherapy in delirium is mainly targeted toward the treatment of its underlying causes.3 However, it is also used to manage the patient’s behaviors when these behaviors cannot be controlled by nonpharmacological means.2 A recent systematic review by Friedman et al indicated that pharmacological strategies show greater success in the prevention of delirium rather than in its management.13 The investigators found evidence for delirium prevention effects with haloperidol, second-generation antipsychotics, gabapentin, and melatonin. It is postulated that sundowning syndrome, the term used to describe complex behavioral symptoms in patients with dementia, is more common in the evening and at night and the alterations in the sleep–wake cycle seen in individuals with delirium have a common neurobiological substrate, that is, a disturbance in the circadian rhythm.14 Melatonin (N-acetyl-5-methoxytryptamine) an endogenous hormone produced by the pineal gland during the hours of darkness is thought to play an important role in the regulation of the circadian rhythm and in maintaining the sleep–wake cycle15,16 It is hypothesized that melatonin secretion is delayed or low in older individuals with delirium.17,18 Available data also indicate that there is a suppression of the nocturnal peak level of melatonin and a decline in the circadian amplitude of the melatonin rhythm in older adults.19 A disruption to the circadian pattern of melatonin secretion has also been noted in individuals with postoperative delirium (POD).17,18 In a recent study, the postoperative plasma concentration of melatonin at 1 hour after surgery was found to be significantly lower in individuals with delirium than in those without delirium.20 The investigators found that after adjustment for relevant confounders, the plasma melatonin concentration was independently associated with the risk of delirium (odds ratio [OR], 0.50; P ¼ .047). In an earlier study, the investigators had found that the urinary excretion of 6-sulfatoxymelatonin (6SMT), the chief metabolite of melatonin which closely parallels the serum melatonin concentrations, was higher in individuals with hypoactive delirium and lower in individuals with hyperactive delirium.21 A recent study of older adults scheduled for major orthopedic surgery or abdominal surgery indicated that in the first week after surgery, postoperative cognitive dysfunction occurred in almost one-third of these individuals and was
linked to a 2-fold fluctuation in their endogenous melatonin levels as measured by the level of urinary 6-SMT.22 A summary of the available evidence indicates that there is a complex relationship between serum melatonin levels and the development of delirium.15 Older adults who have an agerelated suppression of their nocturnal peak levels of melatonin and a decline in the circadian amplitude of the melatonin rhythm are at a higher risk of developing delirium.14 When these individuals encounter a physiologically stressful situation like a medical illnesses or a surgical procedure, where there is a disruption of the circadian rhythm, an episode of delirium develops. The physiological changes that develop during an episode of delirium further disrupt the individual circadian rhythm, thus perpetuating a cycle for maintaining the delirium.23 There is some evidence that melatonin has beneficial effects on circadian rhythm disturbances in dementia. In a systematic review by de Jonghe et al, the investigators found that in 2 of the 4 randomized controlled trials (RCTs) and all 5 of the case series that used melatonin, there was an improvement in sundowning/ agitated behavior in individuals with dementia.14 As circadian rhythm disturbances are seen in both dementia and delirium, the authors postulated that melatonin may have beneficial effects in the management of delirium. A report of 2 cases indicated that melatonin at 2 mg at bedtime orally for 4 days was beneficial in the prevention and management delirium.24 In another case report, the investigators found that melatonin given at 4 mg a day orally was beneficial in an individual with dementia and sundowning syndrome and possible delirium.25 Interestingly, there is emerging evidence that the melatonin agonist, ramalteon, has some benefit in the management of delirium. In a case series of 3 women aged between 59 and 83 years, the use of ramelteon at 8 mg a day orally was found to be beneficial in the management of delirium.26 A case series of 4 men and 1 woman aged between 71 and 91 years indicated that ramelteon at 8 mg at bedtime orally was beneficial in the management of delirium, and it was well tolerated.27 In a retrospective review, the investigators found that among elderly individuals with delirium and insomnia after an acute stroke (7 individuals, mean age 76 years), the use of ramelteon was beneficial in managing their behaviors, and no adverse effects were noted with the medication.28 In another case report, a 100-yearold Japanese man with delirium who had not responded to management with risperidone 0.5 mg once daily orally responded to a switch to ramelteon at 8 mg at bedtime orally.29 The authors of this report indicate that the symptoms of delirium improved without any adverse effects from ramelteon (Table 1). It is postulated that ramelteon exerts its hypnotic action by the suppression of electrical activity via the melatonin 1 (MT1) receptor, and the circadian phase shifts due to its action on the melatonin 2 (MT2) receptor in the suprachiasmatic nucleus.30 Ramelteon is also noted to have a 6-fold higher affinity for MT1 receptors and 3-fold affinity for MT2 receptors with a longer half-life than melatonin.31 The higher affinity of ramelteon for the melatonin receptors is thought to have beneficial effects on delirium.27 Ramelteon appears be fairly well tolerated, and it does not impair next-day cognitive or motor
Downloaded from aja.sagepub.com at Maastricht University on June 19, 2014
Chakraborti et al
3
Table 1. Case Reports and Case Series for Melatonin and Melatonin Agonist for Delirium. Name of the Study
Type of Report
Hanania and Kitain24 Hanania and Kitain24
Case report 53-year-old, male
Lammers and Ahmed25 Kimura et al26
Case report 81-year-old, male
Furuya et al27
Case series
Ohta et al28
Case series
Tusuda et al29
Case report
Age of Individual (s), Sex
Case report 78-year-old, male
Case series
Drug and Dosage
Outcome
Side Effects
Melatonin, 2 mg at bedtime orally Melatonin, 2 mg at bedtime orally
Improvement in symptoms of delirium including sleep Prevented an episode of delirium in this individual with a history of postoperative delirium Improvement in the symptoms of delirium including sleep Improvement in the symptoms of delirium including sleep Improvement in the symptoms of delirium including sleep Improvement in the symptoms of delirium including sleep
None reported
Improvement in the symptoms of delirium
None reported
Melatonin, 2 mg twice daily orally 3 individuals, 69.3 + 12.34 Ramelteon, 8 mg at years, females bedtime orally 5 individuals, 82.4 + 8.3 Ramelteon 8 mg at years, bedtime orally Ramelteon 8 mg at 7 individuals, 76 + 6.5 bedtime orally years, 4 males and 3 females 100 years, male Ramelteon 8 mg at bedtime orally
performances and is not associated with withdrawal symptoms, rebound insomnia, or abuse potential.32 Given the growing body of evidence that melatonin and the melatonin agonist ramelteon may show some benefit in individuals with delirium, we wanted to review the data on their use in older adults with delirium from RCTs.
Search Strategy The purpose of this review is to summarize the data from RCTs on the use of melatonin and melatonin agonist ramelteon for delirium in older adults. We performed a literature search of 5 major databases: PubMed, MEDLINE, PsychINFO, Embase, and Cochrane Library. Search terms were ‘‘delirium,’’ ‘‘melatonin,’’ ‘‘melatonin agonist,’’ and ‘‘ramelteon.’’ The databases were searched through March 31, 2014. There was no language limit set in order to be as inclusive as possible with the search strategy. Each author independently searched the 5 databases for studies with the search terms. Abstracts of all of the studies that were noted on the initial screening were retrieved for further evaluation. Studies were selected for full-text review if they involved patients who were 60 years of age, were diagnosed as having delirium by any diagnostic criteria, were prevention or management studies, used melatonin or a melatonin agonist, and had an RCT design. Case reports, case series, database reviews, population-based reviews, systematic reviews, and meta-analysis were also excluded, but the data available from these studies were to be used as a comparison to the data available from this review. Disagreements between the authors regarding the study selection for this review were resolved through consensus. We operationalized prevention as a strategy to avoid the development of a new episode of delirium or to avoid the recurrence of another episode of delirium. Management was operationalized as a strategy to control the symptoms of delirium once they occurred.
None reported
None reported None reported None reported None reported
Results For melatonin, the search strategy yielded a total of 250 possible articles. This included 66 articles in PubMed, 22 articles in MEDLINE, 6 articles in PsychINFO, 148 articles in Embase, and 8 articles in Cochrane Library. After a review of the abstracts, 8 articles were obtained for a full-text review. Of these, 6 articles were excluded as they were case reports, editorial, or reviews. Only 2 articles met the inclusion criteria. No additional articles were retrieved from the bibliographic search of the relevant articles. The search strategy yielded a total of 7 articles for the melatonin agonist ramelteon. Of the 7 articles, 6 were obtained from PubMed. No articles were obtained from the search of MEDLINE, PsychINFO, or Embase databases. One article was obtained from the search of Cochrane Library. After a review of the abstracts, 5 articles were obtained for a full-text review. Of these, only 1 article met the inclusion criteria. The other articles were 2 case series and 2 case reports. No additional articles were retrieved from the bibliographic search of the relevant articles. To aid with the evaluation of data, we organized the studies in a chronological manner with the older study being the first to the most recent study being the last. The quality of data was evaluated using the criteria developed by the Centre for Evidence Based Medicine (CEBM) for RCT evaluation (Table 2).33
Melatonin In the study by Sultan, 300 individuals 65 years of age who were scheduled for hip arthroplasty were screened for inclusion into this study.34 Abbreviated Mental Test (AMT), a test approved by the Royal College of Physicians and the British Geriatric Society for routine assessment of cognitive function in the elderly patients, was conducted in all individuals. Those individuals with scores
