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The Influence of Melatonin on Sleep Quality After Laparoscopic Cholecystectomy

A Meta-Analysis of Randomized Controlled Trials

Zhang, Juyi, MD; Wang, Yubin, MD; Xu, Hao, MD; Yang, Juan, MD

Surgical Laparoscopy Endoscopy & Percutaneous Techniques: February 2019 - Volume 29 - Issue 1 - p 1–6
doi: 10.1097/SLE.0000000000000601
Review Article
Free

Introduction: The efficacy of melatonin to improve sleep quality after laparoscopic cholecystectomy remains controversial. We conduct a systematic review and meta-analysis to explore the influence of melatonin intervention versus placebo on sleep quality after laparoscopic cholecystectomy.

Methods: We searched PubMed, EMbase, Web of Science, EBSCO, and Cochrane library databases through July 2018 for randomized controlled trials assessing the effect of melatonin intervention versus placebo on sleep quality after laparoscopic cholecystectomy. This meta-analysis is performed using the random-effect model.

Results: Five randomized controlled trials involving 250 patients are included in the meta-analysis. Overall, compared with control group for laparoscopic cholecystectomy, melatonin intervention shows no substantial impact on well-being [standard mean difference (std MD)=0.05; 95% confidence interval (CI)=−0.26 to 0.36; P=0.76], sleepiness (std MD=−0.10; 95% CI=−0.44 to 0.23; P=0.54), sleep quality (std MD=0.10; 95% CI=−0.21 to 0.41; P=0.53), pain scores after 1 hour (std MD=−0.26; 95% CI=−1.08 to 0.56; P=0.53) and 3 hours (std MD=−0.86; 95% CI=−2.69 to 0.97; P=0.36), headache [risk ratio (RR)=1.25; 95% CI=0.42-3.71; P=0.68], depression (RR=1.03; 95% CI=0.15-7.21; P=0.97), dizziness (RR=1.09; 95% CI=0.14-9.40; P=0.94).

Conclusions: Melatonin intervention has no significant influence on well-being, sleepiness, sleep quality, pain intensity after 1 and 3 hours, headache, depression, and dizziness for laparoscopic cholecystectomy.

Department of General Surgery, Kaizhou People Hospital, Chongqing, China

The authors declare no conflicts of interest.

Reprints: Juyi Zhang, MD, No. 8 Ankang Road, Hanfeng Street, Kaixian, Chongqing 405400, China (e-mail: zjy923@163.com).

Received August 5, 2018

Accepted August 17, 2018

Subjective discomfort and sleep disturbances commonly occur after minimally invasive surgery and ambulatory surgery such as laparoscopic cholecystectomy but the underlying mechanisms have not been fully elucidated.1–3 Pain is believed to be one of the most important contributing factors but some patients with low postoperative pain levels still suffer from poor sleep quality.4,5 Pain remains a substantial problem in the postoperative period after laparoscopic cholecystectomy.6,7 Optimal pain relief benefits to reduce the risk of postoperative complications and induce a more rapid recovery of the patient.8

Some preliminary studies report that circadian disturbances in the synthesis of the pineal hormone melatonin may contribute to postoperative sleep disturbances.9–11 Melatonin is responsible to regulate circadian rhythmicity and the sleep-wake cycle under normal physiological conditions, and melatonin has a hypnotic effect with very low toxicity.12,13 In addition, the endogenous sleep hormone melatonin has a well-documented antinociceptive effect in animal studies,14 and its analgesic effect has been conflicting in human clinical studies.15 This analgesic effect may be associated with central receptor-mediated effects and peripheral anti-inflammatory processes.16,17

The efficacy of melatonin intervention for the improvement of sleep quality and pain relief after laparoscopic cholecystectomy has not been well established. Recently, several studies on the topic have been published, and the results have been conflicting.18–21 With accumulating evidence, we, therefore, perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to investigate the efficacy of melatonin intervention versus placebo for patients with laparoscopic cholecystectomy.

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MATERIALS AND METHODS

Ethical approval and patient consent are not required because this is a systematic review and meta-analysis of previously published studies. The systematic review and meta-analysis are conducted and reported in adherence to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).22

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Search Strategy and Study Selection

Two investigators have independently searched the following databases (inception to July 2018): PubMed, EMbase, Web of Science, EBSCO, and Cochrane library databases. The electronic search strategy is conducted using the following keywords: melatonin and laparoscopic cholecystectomy. We also check the reference lists of the screened full-text studies to identify other potentially eligible trials.

The inclusive selection criteria are as follows: (i) population: patients undergoing laparoscopic cholecystectomy; (ii) intervention: melatonin; (iii) comparison: placebo; (iv) study design: RCT.

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Data Extraction and Outcome Measures

We have extracted the following information: author, number of patients, age, body mass index, American Society of Anesthesiologists (ASA) class I/II and detail methods in each group etc. Data have been extracted independently by 2 investigators, and discrepancies are resolved by consensus. We also contact the corresponding author to obtain the data when necessary. No simplifications and assumptions are made.

The primary outcomes are well-being, sleepiness, and sleep quality after 3 days. Secondary outcomes include pain scores after 1 and 3 hours, headache, depression, dizziness.

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Quality Assessment in Individual Studies

Methodological quality of the included studies is independently evaluated using the modified Jadad scale.23 There are 3 items for Jadad scale: randomization (0 to 2 points), blinding (0 to 2 points), dropouts and withdrawals (0 to 1 points). The score of Jadad Scale varies from 0 to 5 points. An article with Jadad score ≤2 is considered to be of low quality. If the Jadad score ≥3, the study is thought to be of high quality.24

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Statistical Analyses

We estimate the standard mean difference (std MD) with 95% confidence interval (CI) for continuous outcomes (well-being, sleepiness, and sleep quality after 3 d, pain scores after 1 and 3 h) and risk ratio (RR) with 95% CIs for dichotomous outcomes (headache, depression, and dizziness). A random-effects model is used regardless of heterogeneity. Heterogeneity is reported using the I 2 statistic, and I 2>50% indicates significant heterogeneity.25 Whenever significant heterogeneity is present, we search for potential sources of heterogeneity via omitting a study in turn for the meta-analysis or performing subgroup analysis. Publication bias is not evaluated because of the limited number (<10) of included studies. All statistical analyses are performed using Review Manager Version 5.3 (The Cochrane Collaboration, Software Update, Oxford, UK).

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RESULTS

Literature Search, Study Characteristics, and Quality Assessment

A detailed flowchart of the search and selection results is shown in Figure 1. In total, 403 potentially relevant articles are identified initially. Finally, 5 RCTs that meet our inclusion criteria are included in the meta-analysis.18–21,26

FIGURE 1

FIGURE 1

The baseline characteristics of the 5 eligible RCTs in the meta-analysis are summarized in Table 1. The 5 studies are published between 2004 and 2015, and sample sizes range from 41 to 121 with a total of 250. Melatonin is administered by oral and intravenous approaches and its doses range from 5 to 10 mg. Two RCTs report the same patient sample but focus on different outcome data.

TABLE 1

TABLE 1

TABLE 1

TABLE 1

Among the 5 studies included here, 2 studies report well-being, sleepiness, and sleep quality after 3 days,19,21 2 studies report pain scores after 1 and 3 hours,18,21 and 2 studies report headache, depression, dizziness.20,21 Jadad scores of the 5 included studies vary from 3 to 5, and all 5 studies are considered to be high-quality ones according to quality assessment.

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Primary Outcomes: Well-being, Sleepiness, and Sleep Quality After 3 Days

These outcome data are analyzed with the random-effects model, and the pooled estimate of the 2 included RCTs suggested that compared with control group after laparoscopic cholecystectomy, melatonin intervention shows no significant influence on well-being (std MD=0.05; 95% CI=−0.26 to 0.36; P=0.76) with no heterogeneity among the studies (I 2=0%; heterogeneity P=0.33) (Fig. 2), sleepiness (std MD=−0.10; 95% CI=−0.44 to 0.23; P=0.54) with low heterogeneity among the studies (I 2=9%; heterogeneity P=0.29) (Fig. 3) and sleep quality (std MD=0.10; 95% CI=−0.21 to 0.41; P=0.53) with no heterogeneity among the studies (I 2=0%; heterogeneity P=0.92) (Fig. 4) after 3 days.

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

FIGURE 4

FIGURE 4

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Sensitivity Analysis

Low and even no heterogeneity is observed among the included studies for the primary outcomes, and thus we do not perform sensitivity analysis via omitting one study in turn to detect the heterogeneity.

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Secondary Outcomes

Compared with control group after laparoscopic cholecystectomy, melatonin intervention has no remarkable impact on pain scores after 1 hour (std MD=−0.26; 95% CI=−1.08 to 0.56; P=0.53; Fig. 5) and 3 hour (std MD=−0.86; 95% CI=−2.69 to 0.97; P=0.36; Fig. 6), headache (RR=1.25; 95% CI=0.42-3.71; P=0.68; Fig. 7), depression (RR=1.03; 95% CI=0.15-7.21; P=0.97; Fig. 8), dizziness (RR=1.09; 95% CI=0.14-9.40; P=0.94; Fig. 9).

FIGURE 5

FIGURE 5

FIGURE 6

FIGURE 6

FIGURE 7

FIGURE 7

FIGURE 8

FIGURE 8

FIGURE 9

FIGURE 9

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DISCUSSION

Postoperative pain, preoperative anxiety, and reduced sleep quality are known as the most common and most predictable perioperative problems, and they may increase the risk of surgical complications.27 Acute pain after laparoscopic cholecystectomy has a complex nature and is not similar to pain in other laparoscopic procedures.7 Melatonin is known as an endogenous sleep hormone secreted from the pineal gland in response to darkness.28 The analgesic melatonin has been extensively studied in terms of the effects of sleep disturbances, anxiolytic effects, antidepressive effects, and anti-inflammatory/antioxidative effects.15,29,30

In a study, 5 mg oral melatonin administered the night before and 1 hour before abdominal hysterectomy reveals a significantly improved postoperative rest/activity rhythm due to the anxiolytic and analgesic effect of melatonin.31 Doses of 0.3 to 10 mg melatonin are found to have some ability to improve hypnotic effectiveness after the surgery.32 Our meta-analysis suggests melatonin intervention shows no substantial influence on sleep quality as the meta-analysis of well-being, sleepiness, and sleep quality after 3 days after laparoscopic cholecystectomy.

The mechanisms mediating the analgesic effect of melatonin are not well elucidated. Both central and peripheral processes may be involved. The central effect is caused by the activation of widespread specific melatonin receptors in the central nervous system and modulation of other receptor systems, such as the opioid system.14 The peripheral analgesic action may account for the antioxidative/anti-inflammatory effects of melatonin at the site of injury.17 Finally, the well-documented anxiolytic actions of melatonin may be associated with the perception of pain in the clinical setting.15 Several studies have reported that the intensity of postoperative pain has been significantly decreased after melatonin intervention.33,34 However, in another study on 44 females with laparoscopic cholecystectomy, intravenous administration of melatonin shows no significant effect on postoperative pain.19 There is no significant difference in pain intensity after 1 and 3 hours between melatonin intervention and control group for laparoscopic cholecystectomy based on the results of our meta-analysis.

Although there is no significant heterogeneity, this low inconsistency may be caused by several reasons. First, different routes of melatonin administration are involved in our included RCTs. Second, the doses of melatonin intervention range from 5 to 10 mg. Most human clinical studies have focused on the doses of 3 to 15 mg melatonin but its doses are up to 300 mg/kg in experimental animal studies.14 Optimal dosing and a strict dose-response relationship remain to be investigated further. Third, the different timing of administration is critical for the analgesic effect. In addition, studies have reported that the administration of melatonin is a safe drug, without serious adverse effects.35 Our meta-analysis finds no increase in adverse events including headache, depression, and dizziness after melatonin intervention for laparoscopic cholecystectomy.

This meta-analysis has several potential limitations that should be taken into account. First, our analysis is based on only 5 RCTs and 3 of them have a relatively small sample size (n<100). More RCTs with large samples should be conducted to confirm this issue. Next, different administration and timing of melatonin intervention in included RCTs are different, which may have an influence on the pooling results. Finally, the doses of melatonin included in our meta-analysis may be not sufficient for laparoscopic cholecystectomy, and dose-efficacy relationship needs to be explored.

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CONCLUSIONS

Melatonin intervention provides no significant benefits for laparoscopic cholecystectomy.

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REFERENCES

1. Kain ZN, Caldwell-Andrews AA. Sleeping characteristics of adults undergoing outpatient elective surgery: a cohort study. J Clin Anesth. 2003;15:505–509.
2. Vinden C, Nash DM, Rangrej J, et al. Complications of daytime elective laparoscopic cholecystectomies performed by surgeons who operated the night before. JAMA. 2013;310:1837–1841.
3. Gogenur I. Postoperative circadian disturbances. Dan Med Bull. 2010;57:B4205.
4. Pavlin DJ, Chen C, Penaloza DA, et al. A survey of pain and other symptoms that affect the recovery process after discharge from an ambulatory surgery unit. J Clin Anesth. 2004;16:200–206.
5. Rawal N, Hylander J, Nydahl PA, et al. Survey of postoperative analgesia following ambulatory surgery. Acta Anaesthesiol Scand. 1997;41:1017–1022.
6. Bisgaard T, Kehlet H, Rosenberg J. Pain and convalescence after laparoscopic cholecystectomy. Eur J Surg. 2001;167:84–96.
7. Bisgaard T. Analgesic treatment after laparoscopic cholecystectomy: a critical assessment of the evidence. Anesthesiology. 2006;104:835–846.
8. Kehlet H, Wilmore DW. Evidence-based surgical care and the evolution of fast-track surgery. Ann Surg. 2008;248:189–198.
9. Cronin AJ, Keifer JC, Davies MF, et al. Melatonin secretion after surgery. Lancet. 2000;356:1244–1245.
10. Gogenur I, Middleton B, Kristiansen VB, et al. Disturbances in melatonin and core body temperature circadian rhythms after minimal invasive surgery. Acta Anaesthesiol Scand. 2007;51:1099–1106.
11. Gogenur I, Ocak U, Altunpinar O, et al. Disturbances in melatonin, cortisol and core body temperature rhythms after major surgery. World J Surg. 2007;31:290–298.
12. Zhdanova IV. Melatonin as a hypnotic: pro. Sleep Med Rev. 2005;9:51–65.
13. Seabra ML, Bignotto M, Pinto LR Jr, et al. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res. 2000;29:193–200.
14. Srinivasan V, Pandi-Perumal SR, Spence DW, et al. Potential use of melatonergic drugs in analgesia: mechanisms of action. Brain Res Bull. 2010;81:362–371.
15. Yousaf F, Seet E, Venkatraghavan L, et al. Efficacy and safety of melatonin as an anxiolytic and analgesic in the perioperative period: a qualitative systematic review of randomized trials. Anesthesiology. 2010;113:968–976.
16. Shavali S, Ho B, Govitrapong P, et al. Melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by increasing the release of beta-endorphin an endogenous opioid. Brain Res Bull. 2005;64:471–479.
17. Esposito E, Paterniti I, Mazzon E, et al. Melatonin reduces hyperalgesia associated with inflammation. J Pineal Res. 2010;49:321–331.
18. Hosseini VS, Yekta RA, Marashi S, et al. The efficacy of melatonin, clonidine and gabapentin in reducing preoperative anxiety and postoperative pain in patients undergoing laparoscopic cholecystectomy: a randomized clinical trial. Arch Anesth Crit Care. 2015;1:120–125.
19. Andersen LP, Kucukakin B, Werner MU, et al. Absence of analgesic effect of intravenous melatonin administration during daytime after laparoscopic cholecystectomy: a randomized trial. J Clin Anesth. 2014;26:545–550.
20. Kucukakin B, Klein M, Lykkesfeldt J, et al. No effect of melatonin on oxidative stress after laparoscopic cholecystectomy: a randomized placebo-controlled trial. Acta Anaesthesiol Scand. 2010;54:1121–1127.
21. Gogenur I, Kucukakin B, Bisgaard T, et al. The effect of melatonin on sleep quality after laparoscopic cholecystectomy: a randomized, placebo-controlled trial. Anesth Analg. 2009;108:1152–1156.
22. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62:1006–1012.
23. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.
24. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med. 2001;135:982–989.
25. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–1558.
26. Acil M, Basgul E, Celiker V, et al. Perioperative effects of melatonin and midazolam premedication on sedation, orientation, anxiety scores and psychomotor performance. Eur J Anaesthesiol. 2004;21:553–557.
27. Beattie WS, Buckley DN, Forrest JB. Epidural morphine reduces the risk of postoperative myocardial ischaemia in patients with cardiac risk factors. Can J Anaesth. 1993;40:532–541.
28. Skene DJ, Lockley SW, Arendt J. Use of melatonin in the treatment of phase shift and sleep disorders. Adv Exp Med Biol. 1999;467:79–84.
29. Capuzzo M, Zanardi B, Schiffino E, et al. Melatonin does not reduce anxiety more than placebo in the elderly undergoing surgery. Anesth Analg. 2006;103:121–123.
30. Gitto E, Karbownik M, Reiter RJ, et al. Effects of melatonin treatment in septic newborns. Pediatr Res. 2001;50:756–760.
31. Caumo W, Torres F, Moreira NL Jr, et al. The clinical impact of preoperative melatonin on postoperative outcomes in patients undergoing abdominal hysterectomy. Anesth Analg. 2007;105:1263–1271.
32. Arendt J. Melatonin and human rhythms. Chronobiol Int. 2006;23:21–37.
33. Ionescu D, Bãdescu C, Ilie A, et al. Melatonin as premedication for laparoscopic cholecystectomy: a double-blind, placebo-controlled study. South Afr J Anaesth Analg. 2008;14:8–11.
34. Srivastava U, Kumar A, Saxena S, et al. Effect of preoperative gabapentin on postoperative pain and tramadol consumption after minilap open cholecystectomy: a randomized double-blind, placebo-controlled trial. Eur J Anaesthesiol. 2010;27:331–335.
35. Kucukakin B, Lykkesfeldt J, Nielsen HJ, et al. Utility of melatonin to treat surgical stress after major vascular surgery—a safety study. J Pineal Res. 2008;44:426–431.
Keywords:

melatonin; sleep quality; laparoscopic cholecystectomy; randomized controlled trials; meta-analysis

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