Study of Melatonin on Sleep, Pain, and Confusion After Joint Replacement Surgery

Study Overview
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Brief Summary
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Pain, confusion, and breaks in normal sleep cycles have been challenges commonly faced by patients after undergoing joint surgeries. To address these issues, melatonin, an inexpensive over-the-counter supplement, has shown in previous to help manage sleep disorders, prevent and treat post-operative confusion in patients over 70 years of age, and reduce pain. The purpose of this study is to establish whether melatonin can aid in reducing pain and post-operative confusion and improve sleep quality after total knee replacement

Detailed Description
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Sleep disruption is a challenge commonly faced by patients and care providers in the perioperative period [1,2] and has been shown to affect postoperative performance after total knee arthroplasty [3] . Postoperative sleep disruption is likely influenced by environmental factors [4] and anesthetic exposure [5,6] and is known to be exacerbated by postoperative pain [7] . In a reciprocal manner, sleep disruption has been shown to exacerbate pain perception [8,9] . Melatonin is an inexpensive over-the-counter dietary supplement with an established safety profile [10] that has shown promise in managing sleep disorders and amelioration of chronic and acute pain. Evidence suggests that exogenous melatonin can be efficacious in improving sleep disruption in tracheostomized patients in the ICU [11] as well as those experiencing jet lag [12,13] . Previous studies have found conflicting results regarding the potential for melatonin to improve sleep and pain in the perioperative period [14] . These discrepancies may result from differences in surgical and anesthetic conditions, differences in melatonin dose and administration regimens, variations in study quality, different methods of assessing pain and sleep quality, and different patient populations. There is no consensus as to what dose, duration, and timing of melatonin administration in the perioperative period are most likely to improve sleep quality or quantity. This study was designed to explore the effect of a stable regimen of exogenous perioperative melatonin, administered over 6 consecutive nights, on postoperative pain, sleep quality, and sleep efficiency in patients undergoing total knee arthroplasty under regional anesthesia with sedation. To our knowledge, this study is the first to examine perioperative subjected sleep quality as well as sleep time and efficiency as measured by the validated objective tool of wrist actigraphy in this population. This study examined the hypotheses that sleep disruption occurs in the context of total knee arthroplasty performed under regional anesthesia with sedation and that perioperative melatonin can modulate pain and sleep disruption after total knee arthroplasty. Gogenur I., Bisgaard T., Burgdorf S., et. al.: Disturbances in the circadian pattern of activity and sleep after laparoscopic versus open abdominal surgery. Surg Endosc 2009; 23: pp. 1026. Kain Z.N., Caldwell-Andrews A.A.: Sleeping characteristics of adults undergoing outpatient elective surgery: a cohort study. J Clin Anesth 2003; 15: pp. 505. Cremeans-Smith J.K., Millington K., Sledjeski E., et. al.: Sleep disruptions mediate the relationship between early postoperative pain and later functioning following total knee replacement surgery. J Behav Med 2006; 29: pp. 215. Lane T., East L.A.: Sleep disruption experienced by surgical patients in an acute hospital. Br J Nurs 2008; 17: pp. 766. Tung A., Mendelson W.B.: Anesthesia and sleep. Sleep Med Rev 2004; 8: pp. 213. Nelson L.E., Guo T.Z., Lu J., et. al.: The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway. Nat Neurosci 2002; 5: pp. 979. Wylde V., Rooker J., Halliday L., et. al.: Acute postoperative pain at rest after hip and knee arthroplasty: severity, sensory qualities and impact on sleep. Orthop Traumatol Surg Res 2011; 97: pp. 139. Tiede W., Magerl W., Baumgartner U., et. al.: Sleep restriction attenuates amplitudes and attentional modulation of pain-related evoked potentials, but augments pain ratings in healthy volunteers. Pain 2010; 148: pp. 36. Raymond I., Nielsen T.A., Lavigne G., et. al.: Quality of sleep and its daily relationship to pain intensity in hospitalized adult burn patients. Pain 2001; 92: pp. 381. Dietary supplements: a framework for evaluating safety.2005.The National Academies Press Washington, DC Bourne R.S., Mills G.H., Minelli C.: Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care 2008; 12: pp. R52. Suhner A., Schlagenhauf P., Hofer I., et. al.: Effectiveness and tolerability of melatonin and zolpidem for the alleviation of jet lag. Aviat Space Environ Med 2001; 72: pp. 638. Suhner A., Schlagenhauf P., Johnson R., et. al.: Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag. Chronobiol Int 1998; 15: pp. 655. Andersen L.P., Rosenberg J., Gogenur I.: Perioperative melatonin: not ready for prime time. Br J Anaesth 2014; 112: pp. 7.

Official Title
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Effects of Perioperative Melatonin on Sleep, Pain, and Confusion After Joint Replacement Surgery

Conditions
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Delirium, Postoperative Pain, Confusion, Sleep

Intervention / Treatment
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* Drug: Melatonin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 18-90 years old undergoing elective, primary total knee replacement American Society of Anesthesiologists (ASA) Physical Status I-III Epidural anesthesia/Patient Controlled Analgesia candidate Exclusion Criteria: Mental impairment Pre-operative use of benzodiazepines, narcotics, or prescription/over-the counter (OTC) sleep aids Pre-operative use of calcium channel blockers Insomnia Recent drug or alcohol abuse Psychiatric disorders other than anxiety, including depression Diabetes

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study: Melatonin<br> | Drug: Melatonin<br>* 5mg of melatonin will be taken by the subject for 3 nights prior and continuing 3 nights after surgery as tolerated.<br>|
| Placebo Comparator: Control: Placebo<br> | Drug: Placebo<br>* 5mg of placebo will be taken by the subject 3 nights prior to surgery and continuing 3 nights after surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Perioperative Sleep Efficiency | Sleep time change from 96 hours before surgery to 72 hours after surgery | 96 hours before surgery to 72 hours after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Perioperative Effects of Melatonin on Post-operative Pain Scores | A difference in 25% in average pain score at each time point be considered clinically significant. | Up to postoperative day 3 | 
| Melatonin Effects on Delirium During Post-operative Inpatient Stay Based on Clinical Assessment in Patients 65 and Older | A difference of 25% will be considered clinically important. | Up to postoperative day 3 | 
| Melatonin Effects on Daytime Activity | A 20% difference will be considered clinically important. | Up to postoperative day 3 | 
| Melatonin Effects on Patient Controlled Analgesia and Postoperative Narcotic Usage | A 25% in narcotic usage will be considered clinically important | Up to 3 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Total Knee Replacement, Pain, Confusion, Sleep