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

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

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

Study Overview

• Status: Completed
• Conditions: Delirium; Confusion; Postoperative Pain; Sleep
• Intervention / Treatment: Drug: Melatonin; Drug: Placebo

Detailed Description

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.

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2. 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.
3. 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.
4. Lane T., East L.A.: Sleep disruption experienced by surgical patients in an acute hospital. Br J Nurs 2008; 17: pp. 766.
5. Tung A., Mendelson W.B.: Anesthesia and sleep. Sleep Med Rev 2004; 8: pp. 213.
6. 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.
7. 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.
8. 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.
9. 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.
10. Dietary supplements: a framework for evaluating safety.2005.The National Academies Press Washington, DC
11. 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.
12. 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.
13. 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.
14. Andersen L.P., Rosenberg J., Gogenur I.: Perioperative melatonin: not ready for prime time. Br J Anaesth 2014; 112: pp. 7.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10021
      • Hospital For Special Surgery

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Study: Melatonin	Drug: Melatonin; 5mg of melatonin will be taken by the subject for 3 nights prior and continuing 3 nights after surgery as tolerated.
PLACEBO_COMPARATOR: Control: Placebo	Drug: Placebo; 5mg of placebo will be taken by the subject 3 nights prior to surgery and continuing 3 nights after surgery

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hospital for Special Surgery, New York

Publications and helpful links

General Publications

• Shigeta H, Yasui A, Nimura Y, Machida N, Kageyama M, Miura M, Menjo M, Ikeda K. Postoperative delirium and melatonin levels in elderly patients. Am J Surg. 2001 Nov;182(5):449-54. doi: 10.1016/s0002-9610(01)00761-9.
• Ozler M, Simsek K, Ozkan C, Akgul EO, Topal T, Oter S, Korkmaz A. Comparison of the effect of topical and systemic melatonin administration on delayed wound healing in rats that underwent pinealectomy. Scand J Clin Lab Invest. 2010 Oct;70(6):447-52. doi: 10.3109/00365513.2010.506926.
• Gitto E, Romeo C, Reiter RJ, Impellizzeri P, Pesce S, Basile M, Antonuccio P, Trimarchi G, Gentile C, Barberi I, Zuccarello B. Melatonin reduces oxidative stress in surgical neonates. J Pediatr Surg. 2004 Feb;39(2):184-9; discussion 184-9. doi: 10.1016/j.jpedsurg.2003.10.003.
• Gitto E, Karbownik M, Reiter RJ, Tan DX, Cuzzocrea S, Chiurazzi P, Cordaro S, Corona G, Trimarchi G, Barberi I. Effects of melatonin treatment in septic newborns. Pediatr Res. 2001 Dec;50(6):756-60. doi: 10.1203/00006450-200112000-00021.
• Gitto E, Reiter RJ, Cordaro SP, La Rosa M, Chiurazzi P, Trimarchi G, Gitto P, Calabro MP, Barberi I. Oxidative and inflammatory parameters in respiratory distress syndrome of preterm newborns: beneficial effects of melatonin. Am J Perinatol. 2004 May;21(4):209-16. doi: 10.1055/s-2004-828610.
• Kucukakin B, Wilhelmsen M, Lykkesfeldt J, Reiter RJ, Rosenberg J, Gogenur I. No effect of melatonin to modify surgical-stress response after major vascular surgery: a randomised placebo-controlled trial. Eur J Vasc Endovasc Surg. 2010 Oct;40(4):461-7. doi: 10.1016/j.ejvs.2010.06.014. Epub 2010 Jul 17.
• Kucukakin B, Klein M, Lykkesfeldt J, Reiter RJ, Rosenberg J, Gogenur I. No effect of melatonin on oxidative stress after laparoscopic cholecystectomy: a randomized placebo-controlled trial. Acta Anaesthesiol Scand. 2010 Oct;54(9):1121-7. doi: 10.1111/j.1399-6576.2010.02294.x.
• Yin YQ, Luo AL, Guo XY, Li LH, Huang YG. Postoperative neuropsychological change and its underlying mechanism in patients undergoing coronary artery bypass grafting. Chin Med J (Engl). 2007 Nov 20;120(22):1951-7.
• Karkela J, Vakkuri O, Kaukinen S, Huang WQ, Pasanen M. The influence of anaesthesia and surgery on the circadian rhythm of melatonin. Acta Anaesthesiol Scand. 2002 Jan;46(1):30-6. doi: 10.1034/j.1399-6576.2002.460106.x.
• Caumo W, Torres F, Moreira NL Jr, Auzani JA, Monteiro CA, Londero G, Ribeiro DF, Hidalgo MP. The clinical impact of preoperative melatonin on postoperative outcomes in patients undergoing abdominal hysterectomy. Anesth Analg. 2007 Nov;105(5):1263-71, table of contents. doi: 10.1213/01.ane.0000282834.78456.90.
• Caumo W, Levandovski R, Hidalgo MP. Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy: a double-blind, randomized, placebo-controlled study. J Pain. 2009 Jan;10(1):100-8. doi: 10.1016/j.jpain.2008.08.007. Epub 2008 Nov 17.
• Wilhelmsen M, Amirian I, Reiter RJ, Rosenberg J, Gogenur I. Analgesic effects of melatonin: a review of current evidence from experimental and clinical studies. J Pineal Res. 2011 Oct;51(3):270-7. doi: 10.1111/j.1600-079X.2011.00895.x. Epub 2011 May 26.
• Papp M, Litwa E, Gruca P, Mocaer E. Anxiolytic-like activity of agomelatine and melatonin in three animal models of anxiety. Behav Pharmacol. 2006 Feb;17(1):9-18. doi: 10.1097/01.fbp.0000181601.72535.9d.
• Yousaf F, Seet E, Venkatraghavan L, Abrishami A, Chung F. Efficacy and safety of melatonin as an anxiolytic and analgesic in the perioperative period: a qualitative systematic review of randomized trials. Anesthesiology. 2010 Oct;113(4):968-76. doi: 10.1097/ALN.0b013e3181e7d626.
• Al-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin SM, Esbaugh J, Dasgupta M. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry. 2011 Jul;26(7):687-94. doi: 10.1002/gps.2582. Epub 2010 Sep 15. Erratum In: Int J Geriatr Psychiatry. 2014 May;29(5):550.
• Sultan SS. Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth. 2010 Sep;4(3):169-73. doi: 10.4103/1658-354X.71132.

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (ACTUAL): June 1, 2013
• Study Completion (ACTUAL): June 1, 2013

Study Registration Dates

• First Submitted: January 4, 2012
• First Submitted That Met QC Criteria: January 4, 2012
• First Posted (ESTIMATE): January 6, 2012

Study Record Updates

• Last Update Posted (ACTUAL): May 11, 2022
• Last Update Submitted That Met QC Criteria: April 19, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Pain; Sleep; Confusion; Total Knee Replacement
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Consciousness Disorders; Confusion; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: 2012-032