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Article

Analgesic Efficacy of Melatonin: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials

by 1,2, 3,4,5,* and 6
1
Department of Family Medicine, Seoul National University Hospital, Seoul 03080, Korea
2
Department of Medicine, Yonsei University Graduate School, Seoul 03722, Korea
3
Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang 10408, Korea
4
Division of Cancer Epidemiology and Management, Research Institute, National Cancer Center, Goyang 10408, Korea
5
Department of Family Medicine and Center for Cancer Prevention and Detection, Hospital, National Cancer Center, Goyang 10408, Korea
6
Palliative Care Clinic, Hospital, National Cancer Center, Goyang 10408, Korea
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(5), 1553; https://doi.org/10.3390/jcm9051553
Received: 12 April 2020 / Revised: 13 May 2020 / Accepted: 19 May 2020 / Published: 21 May 2020
(This article belongs to the Section Anesthesiology)

Abstract

:
Previous systematic reviews and meta-analyses of randomized controlled trials have reported controversial findings regarding the effects of melatonin on pain reduction. The aim of this study was to evaluate the efficacy of melatonin on pain among adults using a meta-analysis of randomized, double-blind, placebo-controlled trials (RDBPCTs). PubMed, EMBASE, the Cochrane Library, and the bibliographies of relevant articles were searched up to February 2020. Two of the authors independently evaluated eligibility of the studies based on the pre-determined criteria and extracted data. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) for the pain score change were calculated using a random-effects meta-analysis. Out of 463 that met the initial criteria, a total of 30 trials, which involved 1967 participants with 983 in an intervention group and 984 in a control group, were included in the final analysis. In a random-effects meta-analysis, the use of melatonin reduced chronic pain in all the trials (5 studies, SMD −0.65, 95% CI −0.96 to −0.34, I2 = 57.2%) and high-quality trials (4 studies, SMD −0.62, 95% CI −1.01 to −0.23, I2 = 49.3%). Moreover, the use of melatonin significantly reduced acute postoperative pain (11 studies, SMD −0.82, 95% CI −1.40 to −0.25, I2 = 93.0%). However, the subgroup meta-analysis of high-quality RDBPCTs showed no significant association between them (6 studies, SMD −0.21, 95 % CI −0.66 to 0.24, I2 = 82.4%). The current study suggests that melatonin might be used in treatment of chronic pain, while there is no sufficient evidence for acute postoperative or procedural pain. Further trials are warranted to confirm its analgesic effect.

1. Introduction

Melatonin (N-acetyl-5-methoxytryptamine), a hormone secreted by the pineal gland, affects the regulation of circadian rhythms, sleep, and mood in humans [1]. Various synthetic melatonin preparations, which are widely available at health-food stores and drugstores, have been used for the treatment of sleep disorder [1]. Meanwhile, regarding a low intensity of pain perception during the night, the possible analgesic effect of high melatonin during the night has been proposed as a mechanism [2]. Based on this initial observation, a number of experimental studies in animals have reported the role of melatonin in pain modulation [3].
In humans, melatonin has been evaluated as an analgesic for various types of pain. A qualitative systematic review of a total of eight randomized controlled trials with perioperative melatonin reported inconsistent and limited evidence regarding its analgesic effects [4]. Another systematic review and meta-analysis of a total of eight randomized controlled trials with perioperative melatonin concluded that its analgesic effects were uncertain due to the profound heterogeneity [5]. A recent systematic review and meta-analysis of a total of 19 randomized controlled trials with the use of melatonin for various types of pain reported a significant reduction of pain [5,6]. The study, however, included open-label trials and active-control trials, and had not performed subgroup analyses by important factors such as methodological quality. Further, additional randomized controlled trials have been published since, and have reported inconsistent findings on the analgesic effect of melatonin.
The aim of the current study was to evaluate the efficacy of melatonin on pain among adults using a meta-analysis of randomized, double-blind, placebo-controlled trials (RDBPCTs).

2. Materials and Methods

2.1. Data Sources and Searches

The systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [7]. We searched PubMed, EMBASE, and the Cochrane Library using keywords in 11 February 2020. The keywords were as follows: “melatonin” and “pain”. The bibliographies of relevant articles were reviewed to locate additional publications from the previous review articles and reference lists.

2.2. Study Selection and Eligibility

We included RDBPCTs that investigated the effect of melatonin in all types of pain in adults and reported preintervention and postintervention quantitative data. In the current meta-analysis, we excluded open-label trials such as randomized controlled trials that did not use placebos as a control group. Two authors (S.N.O. and S.K.M.) assessed the eligibility of studies by the pre-determined selection criteria. Discrepancies were resolved by discussion.

2.3. Assessment of Methodological Quality

Two authors (S.N.O. and H.J.C.) assessed the methodological quality of RDBPCTs, and disagreements were resolved by consensus in discussion with a third reviewer (S.K.M). We assessed the risk of bias on the basis of Cochrane Risk of Bias Tool [8]. Trials that had a low risk of bias in more than the average number of items in all the trials were considered to have an overall low risk of bias in this study.

2.4. Main and Subgroup Analysis

For the main analysis, we examined the associations between the use of melatonin and the pain score changes as well as those between the use of melatonin and the changes in analgesic consumption. Moreover, subgroup meta-analyses for each outcome were performed according to various factors as follows: pain type (acute procedural pain, acute postoperative pain—local and epidural anesthesia, acute postoperative pain—general anesthesia, chronic pain—defined as pain lasting three months or longer at the time of enrollment, and pain duration not reported) and methodological quality score (number of low risk of bias <6 and ≥6). Furthermore, we extracted data on adverse events.

2.5. Statistical analyses

We calculated pooled standardized mean differences (SMDs) with their corresponding 95% confidence intervals (CIs). A random-effects model meta-analysis based on the Der Simonian and Laird method was used in the current study because individual trials were carried out in the different populations. We transformed median (interquartile range or range) values to mean (standard deviation) values [8]. If more than two doses of melatonin in a trial were used, the dose which was closer to the average dose of all trials was chosen. If a scale decreases with pain intensity, we multiplied the mean values from one set of studies by −1 to make all the scales point in the same direction [8]. For the test of heterogeneity across studies, Higgins I2 was used to measure the percentage of total variation across publications [9]. An I2 value greater than 50% was regarded as substantial heterogeneity [9]. We constructed a funnel plot with 1/(SE), a measure of sample size, plotted against effect size, to examine publication bias [10]. (Supplementary Figure S1) The statistical analysis was performed using Stata SE version 13.1 software package (StataCorp, College Station, TX, USA).

3. Results

3.1. Identification of Relevant Studies

Figure 1 shows a flow diagram for the study selection process. A total of 463 articles were identified by the initial search of four databases and hand-searching relevant bibliographies. After excluding 138 duplicated articles, two of the authors independently evaluated eligibility of all studies and excluded an additional 273 articles that did not meet the pre-determined selection criteria depending on the title and abstract of each article. Among them, 22 articles were excluded after reviewing the full texts of the remaining 52 articles for the following reasons: insufficient data (n = 14); conference abstract (n = 4); study protocol (n = 1); and not placebo controlled (n = 3). The remaining 30 RDBPCT were included in the final analysis [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40].

3.2. General Characteristics of Trials

Table 1 shows the general characteristics of 30 RDBPCT included in the final analysis. The included trials were published between 2006 and 2019, and they involved a total of 1967 participants (983 in an intervention group and 984 in a control group). Out of 30 trials, 12 trials investigated acute postoperative pain after the surgery under general anesthesia [12,13,14,15,18,19,20,24,26,30,36,40], four trials did acute postoperative pain after the surgery under local and epidural anesthesia [15,25,28,29], four trials investigated acute procedural pain [23,27,32,33], and five trials investigated chronic pain [17,21,35,37,38]. The duration of pain was not reported in the remaining five trials [11,22,31,34,39]. In the methodological quality score assessed by the Cochrane Risk of Bias Tool, the average number of low risk of bias was 5.8, and 19 trials demonstrated low risk of bias in 6 items or more and were considered to be high quality [14,16,18,19,20,21,22,24,28,29,31,32,33,34,35,36,37,38,39], while the remaining 11 trials demonstrated a low risk of bias in 5 items or less [11,12,13,15,17,23,25,26,27,30,40] (Table 2).

3.3. Association between the Use of Melatonin and Pain Score Changes

As shown in Figure 2, a random-effects meta-analysis of a total of 26 RDBPCTs showed that the use of melatonin significantly decreased pain scores compared with a placebo with substantial heterogeneity (SMD - 0.54, 95% CI −0.81 to −0.27, I2 = 85.8%, n = 26). In the subgroup meta-analysis by pain type, the use of melatonin decreased pain scores in acute postoperative pain after the surgery under general anesthesia (SMD −0.82, 95% CI −1.40 to −0.25, I2 = 93.0%, n = 11), and in chronic pain (SMD −0.65, 95% CI −0.96 to −0.34, I2 = 39.4%, n = 5).
However, in the subgroup meta-analysis for the acute postoperative pain after surgery under general anesthesia by number of items of low risk of bias, although a significantly large pain reduction with the use of melatonin was observed in those with low risk of bias in less than six items (SMD −2.13, 95% CI −3.46 to −0.81, I2 = 96.0%, n = 5), there was no significant pain reduction in the trials with low risk of bias in six or more items. Meanwhile, in the subgroup meta-analysis for the chronic pain by number of items of low risk of bias, melatonin was effective for reducing pain intensity in both the trials with low risk of bias in six or more items (SMD −0.62, 95% CI −1.01 to −0.23, I2 = 49.3%, n = 4) and those with low risk of bias in less than six items (SMD −0.80, 95% CI −1.29 to −0.32, I2 = not applicable, n = 1) (Table 3).

3.4. Association between the Use of Melatonin and Changes in Analgesic Consumption

As shown in Figure 3, a random effect meta-analysis of a total of 11 RDBPCTs showed that the use of melatonin significantly decreased analgesic consumption compared with a placebo with substantial heterogeneity (SMD −2.08, 95% CI −2.97 to −1.19, I2 = 96.0%, n = 11). In the subgroup meta-analysis by pain type, the use of melatonin decreased analgesic consumption in acute postoperative pain after the surgery under general anesthesia (SMD −2.76, 95% CI −4.00 to −1.53, I2 = 96.3%, n = 7), while there was no significant reduction in analgesic consumption in the trials with acute procedural pain and acute postoperative pain after the surgery under local or epidural anesthesia.
Furthermore, in the subgroup meta-analysis for the acute postoperative pain after the surgery under general anesthesia by number of items of low risk of bias, there was a significant reduction of analgesic consumption in both the trials with low risk of bias in six or more items (SMD −4.68, 95% CI −7.55 to −1.81, I2 = 97.9%, n = 4) and those with low risk of bias in less than six items (SMD −1.27, 95% CI −2.09 to −0.46, I2 = 83.6%, n = 3) (Table 4).

3.5. Adverse Events

Fifteen studies out of 30 studies assessed adverse events [12,17,18,19,21,22,24,25,28,29,31,32,33,38,39]. Dizziness [18,19,25,29,33] and drowsiness [17,18,19,33] were found in five studies and four studies, respectively. One study reported fatigue [17], and another reported mild headaches [26,28]. The remaining eight studies reported no serious adverse events [12,21,22,24,31,32,38,39].

4. Discussion

4.1. Summary of Findings

In the current meta-analysis of 30 RDBPCTs, we found that the use of melatonin was associated with the improvement of chronic pain regardless of study quality, specifically in endometriosis, irritable bowel syndrome, and migraines. There was no sufficient evidence that the use of melatonin has beneficial effects for acute postoperative or procedural pain. Although there were effects on pain intensity in acute postoperative pain after surgery under general anesthesia in low-quality studies, there was no effect for it in high-quality studies. Meanwhile, there was an effect on analgesic consumption in acute postoperative pain after surgery under general anesthesia in both high-quality studies and low-quality studies. For acute procedural pain and acute postoperative pain after the surgery under local or epidural anesthesia, there were too few studies to determine its efficacy.

4.2. Possible Mechanisms for Analgesic Effects of Melatonin

There are several possible biological mechanisms for the analgesic effect of melatonin. Previous experimental studies in animals and humans have reported its analgesic effect in various nociceptive and neuropathic pain models. In rodents, melatonin has shown antinociceptive, antihyperalgesic, and antiallodynic effects against various noxious stimuli, inflammation, and nerve injury [41]. One of the most important mechanisms of action is an activation of melatonin receptors, termed MT1 and MT2, distributed in important regions in pain control, such as lamina I-V and X of the spinal cord, thalamus, hypothalamus, spinal trigeminal tract, and trigeminal nucleus [42,43,44]. Activation of melatonin receptors leads to a Gi-protein-mediated decrease of cyclic AMP levels and inhibits Ca2+ channels so that intracellular Ca2+ levels decrease [45]. An increase in intracellular Ca2+ levels beyond a certain threshold has been known to be critical in central sensitization associated with inflammatory and neuropathic pain [46]. The activation of melatonin receptors also activates K+ channels which inhibit an action potential firing in neurons [47]. Several other second messenger molecules like cGMP, diacylglycerol, inositol triphosphate, and arachidonic acid are regulated by melatonin receptors [48]. Melatonin indirectly interacts with other receptor systems including benzodiazepinergic, opioidergic, serotonergic, dopaminergic, adrenergic, glutaminergic, and NO-cyclic GMP-PKG signaling pathway [49].
Melatonin also has anti-inflammatory and antioxidative effects which may affect peripheral nociception and hyperalgesia by reducing inflammation and tissue damage [3]. It might directly interact with specific binding sites in lymphocytes and macrophages and inhibit the production of pro-inflammatory cytokines [50,51]. Melatonin is also a direct free radical scavenger which neutralizes a number of free radicals including reactive oxygen and nitrogen species [52]. It also stimulates antioxidative enzymes like glutathione peroxidase, glutathione reductase, and superoxide dismutase [52].
Moreover, a few human experimental studies have been reported. Stefani et al. reported dose-dependent analgesic effects of melatonin in healthy volunteers [53]. A single dose of sublingual melatonin 0.15 mg/kg and 0.25 mg/kg showed a significant increase in pressure and heat pain threshold and tolerance, and there was a correlation between serum melatonin concentrations and changes in pain threshold and tolerance [53]. However, in a burn injury model in healthy volunteers, Anderson et al. showed no analgesic, antihyperalgesic, or anti-inflammatory effects of intravenous melatonin 10 mg and 100 mg comparing to placebos [54].

4.3. Comparisons with Previous Studies and Strengths of Our Study

In the meantime, previous RDBPCTs have reported inconsistent findings on the analgesic effects of melatonin in various types of pain. Since 2010, several systematic reviews and meta-analyses have been published on this topic. In 2010, a systematic review of randomized trials without meta-analysis reported that five studies showed an opioid-sparing effect or reduced perioperative pain scores, whereas three studies were contradictory [4]. In 2014, a meta-analysis of eight randomized trials reported an analgesic effect of melatonin in postoperative pain [5]. However, the authors concluded that the magnitude of effect was unreliable because of substantial heterogeneity.
A recent meta-analysis of 19 randomized trials published in 2017 showed that melatonin significantly reduced the pain intensity indicated by pain scores in the overall anti-nociception effect and in the subgroup meta-analyses by operation-associated pain, inflammatory pain, and procedural pain [6]. However, it included trials without a placebo control group and assessed the quality of trials using only the Jadad scale, which has been criticized and explicitly discouraged by the Cochrane reviews because of issues with the generic problems of scales, its strong emphasis on reporting rather than on conduct, and it does not cover one of the most important potential biases in randomized trials, i.e., allocation concealment [9].
Unlike these systematic reviews and meta-analyses, we performed subgroup meta-analyses according to various factors including the risk of bias by the Cochrane Risk of Bias Tool [8]. Interestingly, the trials with low risk of bias in six or more items, which are considered as having high quality, showed no significant reduction of pain scores in acute postoperative pain after surgery under general anesthesia, whereas those with low risk of bias in less than 6 items, which are considered as having low quality, showed a large reduction of pain scores. Cochrane reviews explicitly discourage the use of scales or scores for assessing quality or risk of bias because of difficulties in justification of assigning weights to different items in the scale regarding the calculation of a summary score and unreliable assessments of validity by the scales [8]. Despite these limitations, we think that it would be helpful to know if there is any tendency in the study findings according to study quality or bias. Based on the findings from the subgroup meta-analyses by the number of items of low risk of bias, we suggest that melatonin might have no significant effect on acute postoperative pain after surgery under general anesthesia because trials with low risk of bias in six or more items are more likely to show the results closer to the truth than those with low risk of bias in less than six items.

4.4. Possible Reasons for No Analgesic Effect of Melationin in Acute Postoperative or Procedural Pain

There are possible explanations or reasons why no analgesic effect of melatonin was shown in acute postoperative or procedural pain. First, the optimal timing of melatonin administration is not established yet. In most RDBPCTs for perioperative or procedural pain included in the current study, melatonin was administered once orally 60–90 min before the surgery or procedure. Time to maximal plasma concentration is approximately 50 min following oral formulation of melatonin, and elimination half-life is 45 min [55]. Therefore, it might not be appropriate to administer melatonin preoperatively in order to reduce postoperative pain. Second, melatonin might not have a strong analgesic effect compared to other proven analgesics, such as opioids and nonsteroidal anti-inflammatory drugs (NSAIDs). In most trials, the study subjects received those opioids or NSAIDs in both the melatonin and control groups. Thus, melatonin administration as a premedication might not show any additional analgesic effects. Last, melatonin might be ineffective for perioperative or procedural pain. Our findings showed that melatonin was effective for chronic pain. It might be related to the differences in pathophysiology between acute nociceptive pain, such as acute postoperative or procedural pain, and chronic pain [56,57].

4.5. Limitations

Our study has several limitations. First, we included only five studies including 309 patients for chronic pain. Therefore, further large trials are warranted to confirm our findings on the analgesic effect of exogenous melatonin for chronic pain. Second, 10 out of the 26 RDBPCTs included in the current meta-analysis were not designed specifically to investigate the analgesic effect of melatonin as the primary endpoint. In general, findings in the secondary endpoint might be due to chance because the design of the trial is not specifically powered to assess it. Last, we estimated means and standard deviations from median and interquartile ranges or ranges in ten RDBPCTs. If data are skewed, they might not be estimated accurately [8].

5. Conclusions

In summary, melatonin might be used in the treatment of chronic pain, specifically in endometriosis, irritable bowel syndrome, and migraines. There was no sufficient evidence to support the use of melatonin for acute postoperative or procedural pain based on the meta-analysis of high-quality RDBPCTs. However, further trials are warranted to confirm its analgesic effects. Particularly, high methodological quality research is needed regarding acute postoperative pain after surgery under general anesthesia.

Supplementary Materials

The following are available online at https://www.mdpi.com/2077-0383/9/5/1553/s1, Figure S1: Publication bias analysis.

Author Contributions

S.N.O. and S.-K.M. designed the study, analyzed the data, and wrote the manuscript. S.N.O., H.J.J., and S.-K.M. assessed methodological quality. All authors read and approved the final manuscript.

Conflicts of Interest

The authors declare that no actual or potential conflicts of interest exist.

References

  1. Brzezinski, A. Melatonin in humans. N. Engl. J. Med. 1997, 336, 186–195. [Google Scholar] [CrossRef]
  2. Srinivasan, V.; Lauterbach, E.C.; Ho, K.Y.; Acuna-Castroviejo, D.; Zakaria, R.; Brzezinski, A. Melatonin in antinociception: Its therapeutic applications. Curr. Neuropharmacol. 2012, 10, 167–178. [Google Scholar] [CrossRef][Green Version]
  3. Ambriz-Tututi, M.; Rocha-Gonzalez, H.I.; Cruz, S.L.; Granados-Soto, V. Melatonin: A hormone that modulates pain. Life Sci. 2009, 84, 489–498. [Google Scholar] [CrossRef] [PubMed]
  4. 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, 113, 968–976. [Google Scholar] [CrossRef] [PubMed][Green Version]
  5. Andersen, L.P.; Werner, M.U.; Rosenberg, J.; Gögenur, I. A systematic review of peri-operative melatonin. Anaesthesia 2014, 69, 1163–1171. [Google Scholar] [CrossRef] [PubMed]
  6. Zhu, C.; Xu, Y.; Duan, Y.; Li, W.; Zhang, L.; Huang, Y.; Zhao, W.; Wang, Y.; Li, J.; Feng, T.; et al. Exogenous melatonin in the treatment of pain: A systematic review and meta-analysis. Oncotarget 2017, 8, 100582–100592. [Google Scholar] [CrossRef]
  7. Liberati, A.; Altman, D.G.; Tetzlaff, J.; Mulrow, C.; Gøtzsche, P.C.; Ioannidis, J.P.; Clarke, M.; Devereaux, P.J.; Kleijnen, J.; Moher, D. The prisma statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. PLoS Med. 2009, 6, e1000100. [Google Scholar] [CrossRef]
  8. Higgins, J.P.; Green, S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available online: https://training.cochrane.org/handbook/archive/v5.1/ (accessed on 19 February 2020).
  9. Higgins, J.P.; Thompson, S.G. Quantifying heterogeneity in a meta-analysis. Stat. Med. 2002, 21, 1539–1558. [Google Scholar] [CrossRef]
  10. Egger, M.; Davey Smith, G.; Schneider, M.; Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997, 315, 629–634. [Google Scholar] [CrossRef][Green Version]
  11. Altiparmak, B.; Cil, H.; Celebi, N. Effect of melatonin on the daytime sleepiness side-effect of gabapentin in adults patients with neuropathic pain. Rev. Bras. Anestesiol. 2019, 69, 137–143. [Google Scholar] [CrossRef]
  12. Andersen, L.P.; Kucukakin, B.; Werner, M.U.; Rosenberg, J.; Gogenur, I. Absence of analgesic effect of intravenous melatonin administration during daytime after laparoscopic cholecystectomy: A randomized trial. J. Clin. Anesth. 2014, 26, 545–550. [Google Scholar] [CrossRef]
  13. Borazan, H.; Tuncer, S.; Yalcin, N.; Erol, A.; Otelcioglu, S. Effects of preoperative oral melatonin medication on postoperative analgesia, sleep quality, and sedation in patients undergoing elective prostatectomy: A randomized clinical trial. J. Anesth. 2010, 24, 155–160. [Google Scholar] [CrossRef] [PubMed]
  14. Capuzzo, M.; Zanardi, B.; Schiffino, E.; Buccoliero, C.; Gragnaniello, D.; Bianchi, S.; Alvisi, R. Melatonin does not reduce anxiety more than placebo in the elderly undergoing surgery. Anesth. Analg. 2006, 103, 121–123. [Google Scholar] [CrossRef] [PubMed]
  15. Caumo, W.; Torres, F.; Moreira, N.L., Jr.; Auzani, J.A.; Monteiro, C.A.; Londero, G.; Ribeiro, D.F.; Hidalgo, M.P. The clinical impact of preoperative melatonin on postoperative outcomes in patients undergoing abdominal hysterectomy. Anesth. Analg. 2007, 105, 1263–1271. [Google Scholar] [CrossRef] [PubMed]
  16. Caumo, W.; Levandovski, R.; Hidalgo, M.P. 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, 10, 100–108. [Google Scholar] [CrossRef]
  17. Ebrahimi-Monfared, M.; Sharafkhah, M.; Abdolrazaghnejad, A.; Mohammadbeigi, A.; Faraji, F. Use of melatonin versus valproic acid in prophylaxis of migraine patients: A double-blind randomized clinical trial. Restor. Neurol. Neurosci. 2017, 35, 385–393. [Google Scholar] [CrossRef]
  18. Esmat, I.M.; Kassim, D.Y. Comparative study between transdermal fentanyl and melatonin patches on postoperative pain relief after lumber laminectomy, a double-blind, placebo-controlled trial. Egypt. J. Anaesth. 2016, 32, 323–332. [Google Scholar] [CrossRef][Green Version]
  19. Esmat, I.M.; Kassim, D.Y. Comparative study between transdermal nicotine and melatonin patches on postoperative pain relief after laparoscopic cholecystectomy, a double-blind, placebo-controlled trial. Egypt. J. Anaesth. 2016, 32, 299–307. [Google Scholar] [CrossRef][Green Version]
  20. Gogenur, I.; Kucukakin, B.; Bisgaard, T.; Kristiansen, V.; Hjortso, N.C.; Skene, D.J.; Rosenberg, J. The effect of melatonin on sleep quality after laparoscopic cholecystectomy: A randomized, placebo-controlled trial. Anesth. Analg. 2009, 108, 1152–1156. [Google Scholar] [CrossRef]
  21. Gonçalves, A.L.; Ferreira, A.M.; Ribeiro, R.T.; Zukerman, E.; Cipolla-Neto, J.; Peres, M.F.P. Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention. J. Neurol. Neurosurg. Psychiatry 2016, 87, 1127–1132. [Google Scholar] [CrossRef]
  22. Grima, N.A.; Rajaratnam, S.M.W.; Mansfield, D.; Sletten, T.L.; Spitz, G.; Ponsford, J.L. Efficacy of melatonin for sleep disturbance following traumatic brain injury: A randomised controlled trial. BMC Med. 2018, 16, 8. [Google Scholar] [CrossRef] [PubMed][Green Version]
  23. Haddadi, S.; Shahrokhirad, R.; Ansar, M.M.; Marzban, S.; Akbari, M.; Parvizi, A. Efficacy of preoperative administration of acetaminophen and melatonin on retrobulbar block associated pain in cataract surgery. Anesth. Pain Med. 2018, 8, e61041. [Google Scholar] [CrossRef][Green Version]
  24. Hansen, M.V.; Andersen, L.T.; Madsen, M.T.; Hageman, I.; Rasmussen, L.S.; Bokmand, S.; Rosenberg, J.; Gogenur, I. Effect of melatonin on depressive symptoms and anxiety in patients undergoing breast cancer surgery: A randomized, double-blind, placebo-controlled trial. Breast Cancer Res. Treat. 2014, 145, 683–695. [Google Scholar] [CrossRef]
  25. Ismail, S.A.; Mowafi, H.A. Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia. Anesth. Analg. 2009, 108, 1146–1151. [Google Scholar] [CrossRef] [PubMed]
  26. Ivry, M.; Goitein, D.; Welly, W.; Berkenstadt, H. Melatonin premedication improves quality of recovery following bariatric surgery—A double blind placebo controlled prospective study. Surg. Obes. Relat. Dis. 2017, 13, 502–506. [Google Scholar] [CrossRef] [PubMed]
  27. Khezri, M.B.; Oladi, M.R.; Atlasbaf, A. Effect of melatonin and gabapentin on anxiety and pain associated with retrobulbar eye block for cataract surgery: A randomized double-blind study. Indian J. Pharmacol. 2013, 45, 581–586. [Google Scholar] [CrossRef] [PubMed][Green Version]
  28. Khezri, M.B.; Merate, H. The effects of melatonin on anxiety and pain scores of patients, intraocular pressure, and operating conditions during cataract surgery under topical anesthesia. Indian J. Ophthalmol. 2013, 61, 319–324. [Google Scholar] [CrossRef]
  29. Kirksey, M.A.; Yoo, D.; Danninger, T.; Stundner, O.; Ma, Y.; Memtsoudis, S.G. Impact of melatonin on sleep and pain after total knee arthroplasty under regional anesthesia with sedation: A double-blind, randomized, placebo-controlled pilot study. J. Arthroplast. 2015, 30, 2370–2375. [Google Scholar] [CrossRef]
  30. Laflı Tunay, D.; Türkeün Ilgınel, M.; Ünlügenç, H.; Tunay, M.; Karacaer, F.; Biricik, E. Comparison of the effects of preoperative melatonin or vitamin c administration on postoperative analgesia. Bosn. J. Basic Med. Sci. 2019, 20, 117–124. [Google Scholar] [CrossRef][Green Version]
  31. Lund Rasmussen, C.; Klee Olsen, M.; Thit Johnsen, A.; Aagaard Petersen, M.; Lindholm, H.; Andersen, L.; Villadsen, B.; Groenvold, M.; Pedersen, L. Effects of melatonin on physical fatigue and other symptoms in patients with advanced cancer receiving palliative care: A double-blind placebo-controlled crossover trial. Cancer 2015, 121, 3727–3736. [Google Scholar] [CrossRef]
  32. Mistraletti, G.; Umbrello, M.; Sabbatini, G.; Miori, S.; Taverna, M.; Cerri, B.; Mantovani, E.S.; Formenti, P.; Spanu, P.; D’Agostino, A.; et al. Melatonin reduces the need for sedation in icu patients: A randomized controlled trial. Minerva Anestesiol. 2015, 81, 1298–1310. [Google Scholar] [PubMed]
  33. Mowafi, H.A.; Ismail, S.A. Melatonin improves tourniquet tolerance and enhances postoperative analgesia in patients receiving intravenous regional anesthesia. Anesth. Analg. 2008, 107, 1422–1426. [Google Scholar] [CrossRef] [PubMed]
  34. Palmer, A.C.S.; Souza, A.; Dos Santos, V.S.; Cavalheiro, J.A.C.; Schuh, F.; Zucatto, A.E.; Biazus, J.V.; Da Torres, I.L.S.; Fregni, F.; Caumo, W. The effects of melatonin on the descending pain inhibitory system and neural plasticity markers in breast cancer patients receiving chemotherapy: Randomized, double-blinded, placebo-controlled trial. Front. Pharmacol. 2019, 10, 1382. [Google Scholar] [CrossRef][Green Version]
  35. Schwertner, A.; Conceicao Dos Santos, C.C.; Costa, G.D.; Deitos, A.; de Souza, A.; de Souza, I.C.; Torres, I.L.; da Cunha Filho, J.S.; Caumo, W. Efficacy of melatonin in the treatment of endometriosis: A phase ii, randomized, double-blind, placebo-controlled trial. Pain 2013, 154, 874–881. [Google Scholar] [CrossRef] [PubMed]
  36. Seet, E.; Liaw, C.M.; Tay, S.; Su, C. Melatonin premedication versus placebo in wisdom teeth extraction: A randomised controlled trial. Singapore Med. J. 2015, 56, 666–671. [Google Scholar] [CrossRef] [PubMed]
  37. Song, G.H.; Leng, P.H.; Gwee, K.A.; Moochhala, S.M.; Ho, K.Y. Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: A randomised, double blind, placebo controlled study. Gut 2005, 54, 1402–1407. [Google Scholar] [CrossRef][Green Version]
  38. Varoni, E.M.; Lo Faro, A.F.; Lodi, G.; Carrassi, A.; Iriti, M.; Sardella, A. Melatonin treatment in patients with burning mouth syndrome: A triple-blind, placebo-controlled, crossover randomized clinical trial. J. Oral Facial Pain Headache 2018, 32, 178–188. [Google Scholar] [CrossRef][Green Version]
  39. Vidor, L.P.; Torres, I.L.; Custodio de Souza, I.C.; Fregni, F.; Caumo, W. Analgesic and sedative effects of melatonin in temporomandibular disorders: A double-blind, randomized, parallel-group, placebo-controlled study. J. Pain Symptom Manage. 2013, 46, 422–432. [Google Scholar] [CrossRef]
  40. Vij, V.; Dahiya, D.; Kaman, L.; Behera, A. Efficacy of melatonin on sleep quality after laparoscopic cholecystectomy. Indian J. Pharmacol. 2018, 50, 236–241. [Google Scholar]
  41. Srinivasan, V.; Pandi-Perumal, S.R.; Spence, D.W.; Moscovitch, A.; Trakht, I.; Brown, G.M.; Cardinali, D.P. Potential use of melatonergic drugs in analgesia: Mechanisms of action. Brain Res. Bull. 2010, 81, 362–371. [Google Scholar] [CrossRef][Green Version]
  42. Weaver, D.R.; Rivkees, S.A.; Reppert, S.M. Localization and characterization of melatonin receptors in rodent brain by in vitro autoradiography. J. Neurosci. 1989, 9, 2581–2590. [Google Scholar] [CrossRef] [PubMed]
  43. Williams, L.M.; Hannah, L.T.; Hastings, M.H.; Maywood, E.S. Melatonin receptors in the rat brain and pituitary. J. Pineal Res. 1995, 19, 173–177. [Google Scholar] [CrossRef]
  44. Zahn, P.K.; Lansmann, T.; Berger, E.; Speckmann, E.J.; Musshoff, U. Gene expression and functional characterization of melatonin receptors in the spinal cord of the rat: Implications for pain modulation. J. Pineal Res. 2003, 35, 24–31. [Google Scholar] [CrossRef] [PubMed]
  45. Ayar, A.; Martin, D.J.; Ozcan, M.; Kelestimur, H. Melatonin inhibits high voltage activated calcium currents in cultured rat dorsal root ganglion neurones. Neurosci. Lett. 2001, 313, 73–77. [Google Scholar] [CrossRef]
  46. Latremoliere, A.; Woolf, C.J. Central sensitization: A generator of pain hypersensitivity by central neural plasticity. J. Pain 2009, 10, 895–926. [Google Scholar] [CrossRef][Green Version]
  47. Nelson, C.S.; Marino, J.L.; Allen, C.N. Melatonin receptors activate heteromeric g-protein coupled kir3 channels. Neuroreport 1996, 7, 717–720. [Google Scholar] [CrossRef]
  48. Vanecek, J. Cellular mechanisms of melatonin action. Physiol. Rev. 1998, 78, 687–721. [Google Scholar] [CrossRef]
  49. Mantovani, M.; Kaster, M.P.; Pertile, R.; Calixto, J.B.; Rodrigues, A.L.; Santos, A.R. Mechanisms involved in the antinociception caused by melatonin in mice. J. Pineal Res. 2006, 41, 382–389. [Google Scholar] [CrossRef]
  50. Garcia-Perganeda, A.; Guerrero, J.M.; Rafii-El-Idrissi, M.; Paz Romero, M.; Pozo, D.; Calvo, J.R. Characterization of membrane melatonin receptor in mouse peritoneal macrophages: Inhibition of adenylyl cyclase by a pertussis toxin-sensitive g protein. J. Neuroimmunol. 1999, 95, 85–94. [Google Scholar] [CrossRef]
  51. Pozo, D.; Reiter, R.J.; Calvo, J.R.; Guerrero, J.M. Inhibition of cerebellar nitric oxide synthase and cyclic gmp production by melatonin via complex formation with calmodulin. J. Cell. Biochem. 1997, 65, 430–442. [Google Scholar] [CrossRef]
  52. Reiter, R.J.; Tan, D.X.; Qi, W.; Manchester, L.C.; Karbownik, M.; Calvo, J.R. Pharmacology and physiology of melatonin in the reduction of oxidative stress in vivo. Biol. Signals Recept. 2000, 9, 160–171. [Google Scholar] [CrossRef]
  53. Stefani, L.C.; Muller, S.; Torres, I.L.; Razzolini, B.; Rozisky, J.R.; Fregni, F.; Markus, R.; Caumo, W. A phase ii, randomized, double-blind, placebo controlled, dose-response trial of the melatonin effect on the pain threshold of healthy subjects. PLoS ONE 2013, 8, e74107. [Google Scholar] [CrossRef] [PubMed]
  54. Andersen, L.P.; Gogenur, I.; Fenger, A.Q.; Petersen, M.C.; Rosenberg, J.; Werner, M.U. Analgesic and antihyperalgesic effects of melatonin in a human inflammatory pain model: A randomized, double-blind, placebo-controlled, three-arm crossover study. Pain 2015, 156, 2286–2294. [Google Scholar] [CrossRef] [PubMed]
  55. Harpsoe, N.G.; Andersen, L.P.; Gogenur, I.; Rosenberg, J. Clinical pharmacokinetics of melatonin: A systematic review. Eur. J. Clin. Pharmacol. 2015, 71, 901–909. [Google Scholar] [CrossRef] [PubMed]
  56. Knaggs, R.D. Pain after surgery. Br. J. Pain 2017, 11, 159. [Google Scholar] [CrossRef] [PubMed]
  57. Woolf, C.J. Central sensitization: Implications for the diagnosis and treatment of pain. Pain 2011, 152, S2–S15. [Google Scholar] [CrossRef]
Figure 1. Diagram of the study selection process.
Figure 1. Diagram of the study selection process.
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Figure 2. Use of melatonin and change of pain score in a random-effects meta-analysis of randomized, double-blind, placebo-controlled trials.
Figure 2. Use of melatonin and change of pain score in a random-effects meta-analysis of randomized, double-blind, placebo-controlled trials.
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Figure 3. Use of melatonin and change of analgesic consumption in a random-effects meta-analysis of randomized, double-blind, placebo-controlled trials.
Figure 3. Use of melatonin and change of analgesic consumption in a random-effects meta-analysis of randomized, double-blind, placebo-controlled trials.
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Table 1. General characteristics of randomized, double-blind, placebo-controlled trials included in the final analysis.
Table 1. General characteristics of randomized, double-blind, placebo-controlled trials included in the final analysis.
SourceCountryParticipants (Mean Age, y; Women, %)Intervention vs. ControlDuration of MedicationScoring Instrument (Scale); EndpointChange in Pain Score (SD)
Intervention GroupPlacebo Group
Altiparmak 2019 [11]Turkey80 patients with neuropathic pain (49.3; 48.8)Melatonin 3 mg PO + gabapentin 900 mg daily vs.placebo + gabapentin 900 mg daily30 daysVRS (0–10); secondary−4.1 (1.3)−3.7 (1.3)
Anderson 2014 [12]Denmark40 patients undergoing laparoscopic cholecystectomy (45; 100)Melatonin 10 mg IV vs. placeboAt the time of surgical incisionNANANA
Borazan 2010 [13]Turkey52 patients undergoing open prostatectomy (57; 0)Melatonin 6 mg PO vs. placeboThe night before and 60 min before surgeryVAS (0–100); secondary27 (1.0)47 (2.0)
Capuzzo 2006 [14]Italy150 patients undergoing surgery (73.2, 52)Melatonin 10 mg PO vs. placebo90 min before surgeryVAS (0–10); secondary2 (3.0)1 (1.5)
Caumo 2007 [15]Brazil35 patients undergoing total abdominal hysterectomy (44.8, 100)Melatonin 5 mg PO vs. placeboThe night before and 60 min before surgeryVAS (0–100); primary30 (16.5)47 (16.0)
Caumo 2009 [16]Brazil63 patients undergoing total abdominal hysterectomy (43.4, 100)Melatonin 5 mg PO vs. clonidine 100 ug PO vs. placeboThe night before and 60 min before surgeryVAS (0–100); primary30 (22.4)50 (22.4)
Ebrahimi 2017 [17]Iran105 patients with migraine (38.9, 49)Melatonin 3 mg PO daily vs. Sodium valproate 200 mg vs. placebo8 weeksVAS (0–10); primary−3.8 (2.8)−1.3 (3.4)
Esmat 2016 [18]Egypt75 patients undergoing lumbar laminectomy (44.6, 48)Melatonin 7 mg/8 h patch vs. Fentanyl 50 ug/h patch vs. placeboFrom 2 h before surgery to 12 h after surgeryVAS (0–10); primary3 (0.7)4 (0.7)
Esmat 2016 [19]Egypt62 patients undergoing laparoscopic cholecystectomy (44.3, 100)Melatonin 7 mg/8 h patch vs. Nicotine 15 mg/16 h patch vs. placeboFrom 2 h before surgery to 12 h after surgeryVAS (0–10); primary4 (0.7)4.5 (2.2)
Gogenur 2009 [20]Denmark136 patients undergoing laparoscopic cholecystectomy (44, 71)Melatonin 5 mg PO daily vs. placebo3 daysVAS (0–100); secondary51 (24.5)48 (25.0)
Gonçalves 2016 [21]Brazil196 patients with migraine (36.9; 44)Melatonin 3 mg PO daily vs. Amitriptyline 25 mg vs. placebo12 weeksNRS (0–10); secondary−3.5 (3.95)−1.8 (3.61)
Grima 2018 [22]Australia66 patients with traumatic brain injury (37; 33)Melatonin 2 mg PO daily vs. placebo4 weeksSF-36 (0–100); secondary2.07 (17.64)1.27 (17.64)
Haddadi 2018 [23]Iran180 patients undergoing retrobulbar eye block for cataract surgery (63.6; 56)Melatonin 6 mg PO vs. placebo60 min before surgeryNANANA
Hansen 2014 [24]Denmark54 patients undergoing breast cancer surgery (51, 100)Melatonin 6 mg PO daily vs. placeboFrom 1 week before surgery to 12 weeks after surgeryVAS (0–100); secondary97 (100.7)130 (277.8)
Ismail 2009 [25]Saudi Arabia40 patients undergoing cataract surgery (72.8, 48)Melatonin 10 mg PO vs. placebo90 min before surgeryVAS (0–100); primary30 (14.8)30 (11.1)
Ivry 2016 [26]Israel60 patients undergoing bariatric surgery (43, 46)Melatonin 5 mg PO vs. placeboNight before and 2 h before surgeryQoR-15 (0–10); primary3.9 (5.4)7.5 (4.9)
Khezri 2013 [27]Iran120 patients undergoing retrobulbar eye block for cataract surgery (73; 38)Melatonin 6 mg PO vs. gabapentin 600 mg PO vs. placebo90 min before surgeryVPS (0–10); primary4.0 (5.9)4.0 (6.3)
Khezri 2013 [28]Iran60 patients undergoing cataract surgery (63.5; 60)Melatonin 3 mg SL vs. placebo60 min before surgeryVPS (0–100); secondary10.0 (7.4)10.0 (7.4)
Kirksey 2015 [29]United States37 patients undergoing total knee arthroplasty (70; 73.7)Melatonin 5 mg PO vs. placebo6 daysNANANA
Laflı 2019 [30]Turkey165 patients undergoing major abdominal surgery (47.3; 75)Melatonin 6 mg PO vs. Vitamin C 2 g PO vs. Placebo1 h before surgeryVAS (0–10); primary3.04 (1.82)4.75 (2.09)
Lund 2015 [31]Denmark72 patients with advanced cancer (64; 66)Melatonin 20 mg PO daily vs. placebo15 daysEORTC QLQ-C15-PAL (0–100); secondary0.8 (19.3)1.9 (22.2)
Mistraletti 2015 [32]Italy82 critically ill patients requiring invasive or non-invasive respiratory assistanceMelatonin 6 mg PO daily vs. placeboFrom the third intensive care unit (ICU) day to ICU dischargeNANANA
Mowafi 2008 [33]Saudi Arabia40 patients with tourniquet-related pain for hand surgery (44.6; 45)Melatonin 10 mg PO vs. placebo90 min before surgeryVPS (0–100); primary30.0 (7.4)40.0 (11.1)
Palmer 2019 [34]Brazil36 patients with breast cancer receiving adjuvant chemotherapy (54.2; 100)Melatonin 20 mg PO daily vs. placebo10 daysNRS (0–10); primary−3.25 (1.16)−1.91 (1.60)
Schwertner 2013 [35]Brazil40 patients with endometriosis (36.8; 100)Melatonin 10 mg PO daily vs. placebo8 weeksVAS (0–10); primary−3.08 (3.62)−1.16 (3.13)
Seet 2015 [36]Singapore76 patients undergoing all four third molar teeth extraction (22.7; 33)Melatonin 6 mg PO vs. placebo90 min before surgeryVAS (0–100); primary11.3 (11.0)13.2 (11.0)
Song 2005 [37]Singapore42 patients with irritable bowel syndrome (27.2; 60)Melatonin 3 mg PO daily vs. placebo2 weeksNRS (0–10); primary−2.35 (1.34)−0.70 (1.12)
Varoni 2018 [38]Italy20 patients with burning mouth syndrome (64.4; 80)Melatonin 12 mg PO daily8 weeksVAS (0–10); Primary0.6 (2.2)1.2 (1.8)
Vidor 2013 [39]Brazil32 patients with temporomandibular disorders (32.3; NR)Melatonin 5 mg PO daily vs. placebo4 weeksVAS (0–10); primary−2.55 (2.96)−0.91 (2.92)
Vij 2018 [40]India100 patients undergoing laparoscopic cholecystectomy (42.8; 74)Melatonin 5 mg PO daily vs. Placebo3 daysVAS (0–100); Secondary30.0 (12.5)30.0 (15.8)
Abbreviation: FLACC, the face, legs, activity, cry, consolability scale; EORTC QLQ-C15-PAL, European organization for research and treatment of cancer quality of life questionnaire core 15 palliative version; FPS, faces pain scale; NR, not reported; NRS, numeric rating scale; QoR-15, quality of recovery 15 questionnaire score; SD, standard deviation; VAS, visual analog scale; VPS, verbal pain score; VRS, verbal rating scale.
Table 2. Summary of risk of bias assessment for randomized, double-blind, placebo-controlled trials. (a)
Table 2. Summary of risk of bias assessment for randomized, double-blind, placebo-controlled trials. (a)
SourceRandom Sequence GenerationAllocation ConcealmentBlinding of Participants, and PersonnelBlinding of Outcome AssessmentIncomplete Outcome DataSelective ReportingOther BiasNo. of Low Risk of Bias
Altiparmak 2019 [11]lowunclearunclearunclearlowlowlow4
Anderson 2014 [12]lowunclearunclearunclearlowlowlow4
Borazan 2010 [13]lowunclearunclearlowlowlowlow5
Capuzzo 2006 [14]lowlowlowlowlowlowlow7
Caumo 2007 [15]lowunclearunclearlowlowlowlow5
Caumo 2009 [16]lowlowunclearlowlowlowlow6
Ebrahimi 2017 [17]lowlowunclearlowunclearlowlow5
Esmat 2016 [18]lowlowunclearlowlowlowlow6
Esmat 2016 [19]lowlowunclearlowlowlowlow6
Gögenur 2009 [20]lowlowlowlowlowlowlow7
Gonçalves 2016 [21]lowlowlowlowlowlowlow7
Grima 2018 [22]unclearlowlowlowlowlowlow6
Haddadi 2018 [23]unclearunclearunclearunclearlowlowlow3
Hansen 2014 [24]lowlowlowlowlowlowlow7
Ismail 2009 [25]lowunclearhighlowlowlowlow5
Ivry 2016 [26]lowunclearunclearlowlowlowlow5
Khezri 2013 [27]lowlowunclearlowlowlowlow6
Khezri 2013 [28]lowunclearunclearlowlowlowlow5
Kirksey 2015 [29]unclearlowlowlowlowlowlow6
Laflı 2019 [30]lowunclearunclearlowlowlowlow5
Lund 2015 [31]lowlowlowlowlowlowlow7
Mistraletti 2015 [32]lowlowlowlowlowlowlow7
Mowafi 2008 [33]lowlowunclearlowlowlowlow6
Palmer 2019 [34]lowlowlowlowlowlowlow7
Schwertner 2013 [35]lowlowlowlowlowlowlow7
Seet 2015 [36]lowlowlowlowlowlowlow7
Song 2005 [37]unclearlowlowlowlowlowlow6
Varoni 2018 [38]lowunclearlowlowlowlowlow6
Vidor 2013 [39]lowlowlowlowlowlowlow7
Vij 2018 [40]lowunclearunclearunclearunclearlowlow3
(a) Based on the Cochrane Risk of Bias Tool.
Table 3. Use of melatonin and pain score change in the subgroup meta-analysis of randomized, double-blind, placebo-controlled trials.
Table 3. Use of melatonin and pain score change in the subgroup meta-analysis of randomized, double-blind, placebo-controlled trials.
Type of PainNo. of Low Risk of BiasNo. of TrialsSummary SMD (95% CI)Heterogeneity, I2 (%)
Acute pain—postoperative, local or epidural anesthesia≥ 61 [15]−0.893 (−1.544, −0.241)NA
< 62 [23,26]0.000 (−0.392, 0.392)0
Acute pain—postoperative, general anesthesia≥ 66 [13,17,18,19,22,32]−0.212 (−0.664, 0.240)82.4
< 65 [12,14,24,27,36]−2.134 (−3.456, −0.812)96.0
Chronic pain≥ 64 [20,31,33,34]−0.618 (−1.011, −0.225)49.3
< 61 [16]−0.803 (−1.291, −0.316)NA
Abbreviations: NA, not applicable; SMD, standardized mean difference; CI, confidence interval.
Table 4. Use of melatonin and analgesic consumption change in the subgroup meta-analysis of randomized, double-blind, placebo-controlled trials.
Table 4. Use of melatonin and analgesic consumption change in the subgroup meta-analysis of randomized, double-blind, placebo-controlled trials.
Type of PainNo. of Low Risk of BiasNo. of TrialsSummary SMD (95% CI)Heterogeneity, I2 (%)
Acute pain—procedural≥ 62 [32,33]−0.527 (−1.517, 0.464)84.0
< 61 [23]−3.262 (−3.818, −2.706)NA
Acute pain—postoperative, general anesthesia≥ 64 [12,18,19,20]−4.676 (−7.546, −1.806)97.9
< 63 [13,25,30]−1.271 (−2.087, −0.455)83.6
Abbreviation: NA, not applicable; SMD, standardized mean difference; CI, confidence interval.

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Oh, S.N.; Myung, S.-K.; Jho, H.J. Analgesic Efficacy of Melatonin: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials. J. Clin. Med. 2020, 9, 1553. https://doi.org/10.3390/jcm9051553

AMA Style

Oh SN, Myung S-K, Jho HJ. Analgesic Efficacy of Melatonin: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials. Journal of Clinical Medicine. 2020; 9(5):1553. https://doi.org/10.3390/jcm9051553

Chicago/Turabian Style

Oh, Si Nae, Seung-Kwon Myung, and Hyun Jung Jho. 2020. "Analgesic Efficacy of Melatonin: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials" Journal of Clinical Medicine 9, no. 5: 1553. https://doi.org/10.3390/jcm9051553

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