Indian Journal of Pharmacology Home 

RESEARCH ARTICLE
[Download PDF]
Year : 2018  |  Volume : 50  |  Issue : 5  |  Page : 236--241

Efficacy of melatonin on sleep quality after laparoscopic cholecystectomy

Vaibhav Vij, Divya Dahiya, Lileswar Kaman, Arunanshu Behera 
 Department of Surgery, PGIMER, Chandigarh, India

Correspondence Address:
Dr. Divya Dahiya
Department of Surgery, Sector-12, PGIMER, Chandigarh - 160 012
India

Abstract

CONTEXT: Postoperative sleep and circadian rhythm disturbances were associated with prolonged postoperative convalescence, respiratory, and cardiovascular morbidity. Sleep disturbances have been shown to be due to decreased levels of circulating melatonin after surgery. If this sleep pattern and circadian rhythm are recycled, outcome after surgery could be improved. AIMS: The aim of this study was to observe the effect of melatonin on the quality of sleep in patients undergoing laparoscopic cholecystectomy (LC). SUBJECTS AND METHODS: Hundred patients of LC participated in this randomized, placebo-controlled, double-blind, clinical trial. Patients were randomized equally into Group A who received 6 mg melatonin tablets 45 min before sleep for 3 days after surgery and Group B who received placebo. RESULTS: Melatonin usage results in decrease in sleep latency (SL) as compared to placebo (13.6 ± 14.95 vs. 20.10 ± 16.18 min, P = 0.04). There was also increased total sleep duration (TSD) on postoperative day (POD) 1 (P = 0.004) and POD 2 (P = 0.001) in Group A. There was a decrease in daytime naps and night awakenings after surgery in Group A though it was not significant statistically. Subjective assessment of sleep on visual analog scale showed reduced sleep scores (P = 0.001 on POD 1 and 2) and decreased pain (P = 0.02 on POD 1) in Group A. Statistically significant difference was not observed in fatigue or general well-being among groups. CONCLUSIONS: Results in this study could demonstrate that melatonin as a single agent could improve the quality of sleep after LC by decreasing SL and increasing TSD.



How to cite this article:
Vij V, Dahiya D, Kaman L, Behera A. Efficacy of melatonin on sleep quality after laparoscopic cholecystectomy.Indian J Pharmacol 2018;50:236-241


How to cite this URL:
Vij V, Dahiya D, Kaman L, Behera A. Efficacy of melatonin on sleep quality after laparoscopic cholecystectomy. Indian J Pharmacol [serial online] 2018 [cited 2019 Jan 19 ];50:236-241
Available from: http://www.ijp-online.com/text.asp?2018/50/5/236/247533


Full Text



 Introduction



Gallstones are an extremely common clinical entity observed in about 10% to 20% of the adult population.[1] Laparoscopic cholecystectomy (LC) for symptomatic gallstones is the gold standard procedure and also is one of the most commonly performed abdominal surgical procedures. Introduction of minimally invasive surgery and enhanced recovery program has resulted in improved postoperative subjective complaints and reduced morbidity. However, the patients still have short- and long-term subjective discomfort with sleep disturbances for a variable period after minimally invasive surgery and day care surgery.[2],[3]

Sleep disturbance is one of the specific consequences of the stress response to surgery as the entire sleep-wake cycle gets altered after surgery.[4],[5] The postoperative sleep and circadian disturbances might be associated with prolonged postoperative convalescence, respiratory, and cardiovascular morbidity. Several body functions including the circadian rhythms and sleep-wake cycles are regulated by a collection of neurons located in the hypothalamus called the Nucleus Suprachiasmaticus (SCN).[2],[3],[6],[7] Under normal physiological conditions the chief hormone responsible for regulating the circadian rhythm and the sleep wake cycle is Melatonin (N-acetyl-5-metoxytryptamin) which is secreted from the pineal gland.

Administration of melatonin is relatively safe and serves as a probable future supplement to other analgesics, hypnotics, anti-inflammatory drugs and sedatives. In the post operative period, it can also serve as a replacement therapy to restore sleep while improving secondary fatigue and general wellbeing.[8] These potential properties of melatonin suggested that melatonin might have beneficial effect on postoperative circadian rhythm. Limited studies are available on melatonin addressing its beneficial effect on its post operative sleep disturbances. Hence, the aim and objective of this study was to observe the efficacy of melatonin on sleep quality on patients undergoing LC besides assessing its efficacy on pain, fatigue after LC and general well-being.

 Subjects and Methods



Study design

The study was a randomized, placebo-controlled, double-blind, clinical trial which was conducted at the institute over 1.5 years. This study included 100 patients who underwent elective LC. Patients were randomized into two equal groups by computer-generated randomized number table. Group A received the melatonin tablets and Group B where placebo was given.

Patient selection

Inclusion criteria

All patients between ages 18 and 80 years who were listed for elective LC and who gave consent for the participation in this study were included in the study.

Exclusion criteria

Patients, who had known sleep disturbances, who were taking hypnotics, sedatives, psychoactive drugs or opioids, beta-blockers, or c such as warfarin, patients who were pregnant or lactating, and who were expected to have compliance problems (psychiatric disorders) or known hypothyroidism, were not included in this study.

Surgery

LC was performed using CO2 for creating pneumoperitoneum, and surgery was performed using four ports as described in American technique. All patients received the standard anesthesia care. Induction was done with 2 mg/kg propofol and maintained with isoflurane and oxygen + N2O (MAC-1–1.2). Neuromuscular block was done by vecuronium 0.1 mg/kg at the time of induction. Neostigmine (50 μg/kg/min) and glycopyrrolate (10 μg/kg/min) were used for reversal before the end of surgery. Prophylactic antibiotic (1.5 g cefuroxime) before surgery and isotonic saline as the maintenance fluid were used. Preperitoneal bupivacaine 2 mg/kg was used for trochar site anesthesia. In the postoperative period, all patients received 75 mg of intravenous diclofenac (voveran) and 4 mg of intravenous ondansetron (emset) for nausea.

Advice on discharge

LC was done on daycare basis, and all patients were discharged on the same day after monitoring vitals and general condition of the patient. On discharge, the patients were advised to take 50 mg voveran peroral three times a day for 4 days. Patients in Group A were also given six tablets of melatonin (each containing 3 mg) and were instructed to take two tablets approximately 40–45 min before going to sleep for 3 nights. Patients in Group B were given placebo (identical multivitamin tablets) and were instructed to take two tablets approximately 40–45 min before going to sleep for 3 nights.[9]

Measurement of outcome

Subjective assessment of sleep was done, and the sleep record was maintained by patients on a sleep diary. Sleep was recorded under following headings: sleep latency (SL), total sleep duration (TSD), night awakenings number (NA) and duration, and day naps number (DN) and duration (DND). Sleep was recorded on the day before surgery and for 3 days postoperatively. The night before surgery was not used in sleep assessment.

Visual analog scale (VAS) was used for sleep, fatigue, pain, and well-being assessment both in the preoperative period and postoperatively for 3 days as explained above. Data were recorded on 100-mm VAS scale (best possible sleep-0 and worst possible sleep-100). Fatigue was assessed on a 10-point ordinal scale (1-fit and 10-fatigued). General well-being was assessed (0-extremely well and 100-extreme malaise). The pain was also assessed on VAS scale (0 mm-no pain and 100 mm-worst possible pain).

Statistical analysis

Analysis of collected data was performed using Statistical Package for the Social Sciences (SPSS) version 22.0 (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.). The Kolmogorov–Smirnov test was applied to check normalcy of the quantitative data. Independent t-test was used to compare the mean of normally distributed quantitative data for age, height, weight, and body mass index (BMI) between the two study groups. Ordinal data for VAS score, DND score were compared using the Mann–Whitney test, and data were represented in median (interquartile range). Chi-square/Fisher exact test was applied to find the association between categorical variables for gender, abdominal pain (yes/no), and vomiting (yes/no) between the two study groups. Two-tailed P < 0.05 was considered statistically significant with 95% confidence interval.

 Results



A total of 100 patients were included in this study, and they were equally randomized into two groups with 50 patients in each group. Group A patients received melatonin tablets, and Group B patients received placebo tablets after surgery for 3 consecutive days.

Patient's characteristics

The mean age in Group A was 42.8 ± 9.81 years (median ± standard deviation [SD]) and in Group B was 41.4 ± 10.85 years (median ± SD). Females predominate the study comprising 74% in melatonin group and 82% in placebo group (P = 0.334). BMI was 25.25 ± 3.68 (mean ± SD) in Group A and 24.94 ± 3.53 (mean ± SD) in Group B (P = 0.668). Abdominal pain was the most common clinical presentation; it was present in 96% (n = 48) in Group A and 100% (n = 50) in Group B (P = 0.495). Dyspepsia and vomiting were present in 18%, 18% (n = 9, 9) and 14%, and 30% (n = 7, 15) (P = 0.585, 0.160) in Groups A and B, respectively. There was no significant difference in the presence of comorbidities (diabetes and hypertension) in both groups. Ultrasound findings (presence of gallstones, gallbladder distension and wall thickness, and presence of fatty liver) were not significantly different among the two groups (P = 0.202). There was also no difference among two groups in operative outcome (P = 0.49).

Sleep assessment

SL and TSD: There was decreased SL in Group A as compared to those who received placebo in Group B. SL was significantly lower in the melatonin group on the 1st night after LC compared to placebo group (P = 0.04) [Figure 1]. There was also increased TSD in melatonin group as compared to placebo which reached a significant level on the postoperative day (POD) 1 (P = 0.004) and POD 2 (P = 0.001) [Figure 2]Number and duration of NA: Number of NA was less in melatonin group compared to Group B. However, there was no significant difference among Groups A and B [Table 1]. Duration of NA was also less in melatonin group compared to placebo group, although it was not significant statistically [Table 1]Number and duration of DN: Number of DN was less in melatonin group, although the difference among groups was not significant [Table 2]. Duration of daytime naps was also less in melatonin group compared to the placebo group, although this did not reach statistical significance [Table 2].{Figure 1}{Figure 2}{Table 1}{Table 2}

Subjective assessment of sleep, pain, well-being, and fatigue

The subjective assessment of sleep on VAS scale showed significantly reduced sleep score on POD 1 and POD 2 in Group A as compared to Group B [Table 3]. Subjective assessment of pain on VAS scale also showed significantly decreased pain score in melatonin group as compared to placebo group on POD 1 [Table 3].{Table 3}

Although subjective assessment of well-being on VAS scale showed better well-being in Group A as compared to Group B; however, it did not reach statistical significance [Table 3]. Similarly, subjective assessment of fatigue on VAS scale showed no statistically significant difference among the two groups [Table 3].

 Discussion



A stress response following surgery usually results in sleep disorders by complete elimination of REM sleep and enhancement in light sleep during the postoperative period which in-turn severely impacts the quality of life.[10] Presence of sleeplessness, difficulty in falling asleep, and frequent nocturnal or early morning awakenings have been reported after major noncardiac surgeries by many studies in the early postoperative period. Rosenberg[11] found disturbance in sleep pattern after major noncardiac surgery with initial decrease in REM sleep and a later increase during the 1st week after surgery. Deep sleep was suppressed for many days after surgery along with impaired overall sleep quality. They related alterations in sleep cycle to the amount of trauma, surgical stress response, and/or analgesic use in the postoperative period. In a meta-analysis of 19 studies by Pilcher,[12] the association between sleep deprivation and impaired human functioning was demonstrated.

There are different factors such as environmental noise, uncomfortable bed, incisional pain, and prescription of diuretics, which were assumed to be the cause of sleep disturbances after major cardiac or noncardiac surgery. However, there is ample evidence to support that none of the above-mentioned factors were found statistically significant to cause sleep disturbances.[13] Clinical studies document that there is a decrease in the concentration of melatonin in the perioperative period, and sleep disturbance is the consequence of this effect.[14],[15],[16] Melatonin rhythm is the most reliable maker of the circadian clock which can be easily be measured or monitored in blood while its metabolite aMT6s can be estimated in saliva and urine.

Cronin et al.[15] found significantly (P = 0.005) lower nocturnal concentrations of melatonin on the 1st night following surgery compared to the levels on 2nd or 3rd nights and concluded that melatonin suppression might be prevented by melatonin replacement which in turn may prevent the associated sleep alterations in the postoperative period. Kärkelä et al.[16] established that the circadian rhythm of melatonin was influenced both by anesthesia and surgery by measuring melatonin concentration both in saliva and urine. They found significantly decreased levels of melatonin in saliva during the first evening following surgery as compared to that in the preoperative evening. There was also a significant decline in aMT6s levels in nocturnal urine after surgery compared to preoperative levels. Based on these findings, it was concluded that anesthesia along with surgery can acutely disturb circadian rhythm by delaying the onset of nocturnal melatonin secretion.

During the first night after surgery, alternation in the circadian rhythm of melatonin secretion was observed with a phase delay and reduced amplitude; hence it was proposed that reduced melatonin amplitude during the night may be associated with sleep disturbances. It was also thought that melatonin replacement therapy could have an effect on subjective recovery parameters in the preoperative, perioperative, and postoperative periods to restore sleep.[17] It was hypothesized that pharmacological substitution with oral melatonin would restore the endogenous melatonin levels and improve sleep, secondary fatigue, and general well-being after surgery. A meta-analysis of 24 studies compared the benefits and adverse events associated with the use of sedative-hypnotics and observed that although there was a better quality of sleep, with less arousals compared with placebo, there were adverse cognitive and psychomotor events with increased daytime fatigue; its use was associated with statistically significant increased risk of adverse events.[18] Melatonin conversely has a very low toxicity profile, with fewer cognitive side effects but with hypnotic effects which are comparable to the newly developed hypnotics (zaleplon, zolpidem, and zopiclone).[18],[19] Melatonin also has a significant anxiolytic effect.[20]

In the present study, melatonin use results in significant decrease in SL as compared to placebo group and also increased TSD on POD 1 (P = 0.004) and POD 2 (P = 0.001) in melatonin group. Subjective sleep assessment on VAS showed better sleep in melatonin group on POD 1 and POD 2 compared to placebo group. Subjective assessment on VAS scale also showed a significant decreased pain score in melatonin group on POD 1. There was no statistically significant difference was observed in fatigue or general well-being between the two groups.

In a recent placebo-controlled randomized trial, oral melatonin improved sleep quality, measured by the electroencephalography-derived bispectral index in intensive care unit patients.[17] In this study, melatonin use results in decreased number and duration of DN, although it was not significant. Similar results were also obtained for number and duration of NA. Both were less in melatonin group; however, this difference was not significant. Subjective assessment of sleep on VAS scale showed significantly reduced sleep score on POD 1 (P = 0.001) and POD 2 (P = 0.02) in melatonin group compared to placebo group.

To achieve maximal hypnosis, the dosage of melatonin ranges between 0.3 and 10 mg per day. There may be a possibility that better results can be obtained regarding better general well-being and reduced fatigue by dose escalation. There is a decrease in endogenous production of melatonin with age which may also contribute to insomnia. This may demand a higher dose of melatonin in elderly. However, there is evidence where considerable inter-individual variability of circulating melatonin and overlap between ages has been found. The dosage of 5 mg or above is considered sufficient for an adult in various studies. The hypnotic effect of melatonin can produce sleep within 1–2 h of administration of the drug. Therefore, the timing of administration 1 h before sleep was found appropriate.[21] In this study, 6 mg of melatonin was given 40–45 min before sleep for 3 days.

There were some limitations of this study. Although melatonin administration showed some improvement in the sleep quality after LC in this study, this was an objective assessment by the patient; not the objective assessment by polysomnography or actigraphy. There are reports mentioning that there is a decrease in the levels of circulating melatonin and decrease in the receptor sensitivity for melatonin with increasing age. Another limitation was that in this study melatonin levels were not measured.

 Conclusions



Results in this study could demonstrate that melatonin as a single agent could improve the quality of sleep by decreasing SL and increasing TSD. There was also decrease in day time naps, night awakenings and pain after surgery in the melatonin group. Trials with larger number of patients and various dosage schedules are required to confirm the results of this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Beal JM. Historical perspective of gallstone disease. Surg Gynecol Obstet 1984;158:181-9.
2Antoniadis EA, Ko CH, Ralph MR, McDonald RJ. Circadian rhythms, aging and memory. Behav Brain Res 2000;114:221-33.
3Borbély AA, Achermann P. Sleep homeostasis and models of sleep regulation. J Biol Rhythms 1999;14:557-68.
4Gögenur I, Rosenberg-Adamsen S, Kiil C, Kjaersgaard M, Kehlet H, Rosenberg J, et al. Laparoscopic cholecystectomy causes less sleep disturbance than open abdominal surgery. Surg Endosc 2001;15:1452-5.
5Kain ZN, Caldwell-Andrews AA. Sleeping characteristics of adults undergoing outpatient elective surgery: A cohort study. J Clin Anesth 2003;15:505-9.
6Buijs RM, Hermes MH, Kalsbeek A. The suprachiasmatic nucleus-paraventricular nucleus interactions: A bridge to the neuroendocrine and autonomic nervous system. Prog Brain Res 1998;119:365-82.
7Cagnacci A. Influences of melatonin on human circadian rhythms. Chronobiol Int 1997;14:205-20.
8Fraser S, Cowen P, Franklin M, Franey C, Arendt J. Direct radioimmunoassay for melatonin in plasma. Clin Chem 1983;29:396-7.
9Gögenur I, Kücükakin B, Bisgaard T, Kristiansen V, Hjortsø NC, Skene DJ, et al. The effect of melatonin on sleep quality after laparoscopic cholecystectomy: A randomized, placebo-controlled trial. Anesth Analg 2009;108:1152-6.
10Gögenur I, Bisgaard T, Burgdorf S, van Someren E, Rosenberg J. Disturbances in the circadian pattern of activity and sleep after laparoscopic versus open abdominal surgery. Surg Endosc 2009;23:1026-31.
11Rosenberg J. Sleep disturbances after non-cardiac surgery. Sleep Med Rev 2001;5:129-37.
12Pilcher JJ, Huffcutt AI. Effects of sleep deprivation on performance: A meta-analysis. Sleep 1996;19:318-26.
13Redeker NS, Hedges C. Sleep during hospitalization and recovery after cardiac surgery. J Cardiovasc Nurs 2002;17:56-68.
14Gögenur I, Middleton B, Kristiansen VB, Skene DJ, Rosenberg J. Disturbances in melatonin and core body temperature circadian rhythms after minimal invasive surgery. Acta Anaesthesiol Scand 2007;51:1099-106.
15Cronin AJ, King TS, Keifer JC, Bixler EO, Davies MF. Melatonin secretion after surgery. Lancet 2001;357:557-8.
16Kärkelä 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;46:30-6.
17Bourne RS, Mills GH, Minelli C. Melatonin therapy to improve nocturnal sleep in critically ill patients: Encouraging results from a small randomised controlled trial. Crit Care 2008;12:R52.
18Glass J, Lanctôt KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older people with insomnia: Meta-analysis of risks and benefits. BMJ 2005;331:1169.
19Furio AM, Brusco LI, Cardinali DP. Possible therapeutic value of melatonin in mild cognitive impairment: A retrospective study. J Pineal Res 2007;43:404-9.
20Caumo W, Torres F, Moreira NL Jr., Auzani JA, Monteiro CA, Londero G, et al. The clinical impact of preoperative melatonin on postoperative outcomes in patients undergoing abdominal hysterectomy. Anesth Analg 2007;105:1263-71.
21Arendt J. Melatonin and human rhythms. Chronobiol Int 2006;23:21-37.