Analgesic Efficacy of Melatonin: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials
Abstract
:1. Introduction
2. Materials and Methods
2.1. Data Sources and Searches
2.2. Study Selection and Eligibility
2.3. Assessment of Methodological Quality
2.4. Main and Subgroup Analysis
2.5. Statistical analyses
3. Results
3.1. Identification of Relevant Studies
3.2. General Characteristics of Trials
3.3. Association between the Use of Melatonin and Pain Score Changes
3.4. Association between the Use of Melatonin and Changes in Analgesic Consumption
3.5. Adverse Events
4. Discussion
4.1. Summary of Findings
4.2. Possible Mechanisms for Analgesic Effects of Melatonin
4.3. Comparisons with Previous Studies and Strengths of Our Study
4.4. Possible Reasons for No Analgesic Effect of Melationin in Acute Postoperative or Procedural Pain
4.5. Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Conflicts of Interest
References
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Source | Country | Participants (Mean Age, y; Women, %) | Intervention vs. Control | Duration of Medication | Scoring Instrument (Scale); Endpoint | Change in Pain Score (SD) | |
---|---|---|---|---|---|---|---|
Intervention Group | Placebo Group | ||||||
Altiparmak 2019 [11] | Turkey | 80 patients with neuropathic pain (49.3; 48.8) | Melatonin 3 mg PO + gabapentin 900 mg daily vs.placebo + gabapentin 900 mg daily | 30 days | VRS (0–10); secondary | −4.1 (1.3) | −3.7 (1.3) |
Anderson 2014 [12] | Denmark | 40 patients undergoing laparoscopic cholecystectomy (45; 100) | Melatonin 10 mg IV vs. placebo | At the time of surgical incision | NA | NA | NA |
Borazan 2010 [13] | Turkey | 52 patients undergoing open prostatectomy (57; 0) | Melatonin 6 mg PO vs. placebo | The night before and 60 min before surgery | VAS (0–100); secondary | 27 (1.0) | 47 (2.0) |
Capuzzo 2006 [14] | Italy | 150 patients undergoing surgery (73.2, 52) | Melatonin 10 mg PO vs. placebo | 90 min before surgery | VAS (0–10); secondary | 2 (3.0) | 1 (1.5) |
Caumo 2007 [15] | Brazil | 35 patients undergoing total abdominal hysterectomy (44.8, 100) | Melatonin 5 mg PO vs. placebo | The night before and 60 min before surgery | VAS (0–100); primary | 30 (16.5) | 47 (16.0) |
Caumo 2009 [16] | Brazil | 63 patients undergoing total abdominal hysterectomy (43.4, 100) | Melatonin 5 mg PO vs. clonidine 100 ug PO vs. placebo | The night before and 60 min before surgery | VAS (0–100); primary | 30 (22.4) | 50 (22.4) |
Ebrahimi 2017 [17] | Iran | 105 patients with migraine (38.9, 49) | Melatonin 3 mg PO daily vs. Sodium valproate 200 mg vs. placebo | 8 weeks | VAS (0–10); primary | −3.8 (2.8) | −1.3 (3.4) |
Esmat 2016 [18] | Egypt | 75 patients undergoing lumbar laminectomy (44.6, 48) | Melatonin 7 mg/8 h patch vs. Fentanyl 50 ug/h patch vs. placebo | From 2 h before surgery to 12 h after surgery | VAS (0–10); primary | 3 (0.7) | 4 (0.7) |
Esmat 2016 [19] | Egypt | 62 patients undergoing laparoscopic cholecystectomy (44.3, 100) | Melatonin 7 mg/8 h patch vs. Nicotine 15 mg/16 h patch vs. placebo | From 2 h before surgery to 12 h after surgery | VAS (0–10); primary | 4 (0.7) | 4.5 (2.2) |
Gogenur 2009 [20] | Denmark | 136 patients undergoing laparoscopic cholecystectomy (44, 71) | Melatonin 5 mg PO daily vs. placebo | 3 days | VAS (0–100); secondary | 51 (24.5) | 48 (25.0) |
Gonçalves 2016 [21] | Brazil | 196 patients with migraine (36.9; 44) | Melatonin 3 mg PO daily vs. Amitriptyline 25 mg vs. placebo | 12 weeks | NRS (0–10); secondary | −3.5 (3.95) | −1.8 (3.61) |
Grima 2018 [22] | Australia | 66 patients with traumatic brain injury (37; 33) | Melatonin 2 mg PO daily vs. placebo | 4 weeks | SF-36 (0–100); secondary | 2.07 (17.64) | 1.27 (17.64) |
Haddadi 2018 [23] | Iran | 180 patients undergoing retrobulbar eye block for cataract surgery (63.6; 56) | Melatonin 6 mg PO vs. placebo | 60 min before surgery | NA | NA | NA |
Hansen 2014 [24] | Denmark | 54 patients undergoing breast cancer surgery (51, 100) | Melatonin 6 mg PO daily vs. placebo | From 1 week before surgery to 12 weeks after surgery | VAS (0–100); secondary | 97 (100.7) | 130 (277.8) |
Ismail 2009 [25] | Saudi Arabia | 40 patients undergoing cataract surgery (72.8, 48) | Melatonin 10 mg PO vs. placebo | 90 min before surgery | VAS (0–100); primary | 30 (14.8) | 30 (11.1) |
Ivry 2016 [26] | Israel | 60 patients undergoing bariatric surgery (43, 46) | Melatonin 5 mg PO vs. placebo | Night before and 2 h before surgery | QoR-15 (0–10); primary | 3.9 (5.4) | 7.5 (4.9) |
Khezri 2013 [27] | Iran | 120 patients undergoing retrobulbar eye block for cataract surgery (73; 38) | Melatonin 6 mg PO vs. gabapentin 600 mg PO vs. placebo | 90 min before surgery | VPS (0–10); primary | 4.0 (5.9) | 4.0 (6.3) |
Khezri 2013 [28] | Iran | 60 patients undergoing cataract surgery (63.5; 60) | Melatonin 3 mg SL vs. placebo | 60 min before surgery | VPS (0–100); secondary | 10.0 (7.4) | 10.0 (7.4) |
Kirksey 2015 [29] | United States | 37 patients undergoing total knee arthroplasty (70; 73.7) | Melatonin 5 mg PO vs. placebo | 6 days | NA | NA | NA |
Laflı 2019 [30] | Turkey | 165 patients undergoing major abdominal surgery (47.3; 75) | Melatonin 6 mg PO vs. Vitamin C 2 g PO vs. Placebo | 1 h before surgery | VAS (0–10); primary | 3.04 (1.82) | 4.75 (2.09) |
Lund 2015 [31] | Denmark | 72 patients with advanced cancer (64; 66) | Melatonin 20 mg PO daily vs. placebo | 15 days | EORTC QLQ-C15-PAL (0–100); secondary | 0.8 (19.3) | 1.9 (22.2) |
Mistraletti 2015 [32] | Italy | 82 critically ill patients requiring invasive or non-invasive respiratory assistance | Melatonin 6 mg PO daily vs. placebo | From the third intensive care unit (ICU) day to ICU discharge | NA | NA | NA |
Mowafi 2008 [33] | Saudi Arabia | 40 patients with tourniquet-related pain for hand surgery (44.6; 45) | Melatonin 10 mg PO vs. placebo | 90 min before surgery | VPS (0–100); primary | 30.0 (7.4) | 40.0 (11.1) |
Palmer 2019 [34] | Brazil | 36 patients with breast cancer receiving adjuvant chemotherapy (54.2; 100) | Melatonin 20 mg PO daily vs. placebo | 10 days | NRS (0–10); primary | −3.25 (1.16) | −1.91 (1.60) |
Schwertner 2013 [35] | Brazil | 40 patients with endometriosis (36.8; 100) | Melatonin 10 mg PO daily vs. placebo | 8 weeks | VAS (0–10); primary | −3.08 (3.62) | −1.16 (3.13) |
Seet 2015 [36] | Singapore | 76 patients undergoing all four third molar teeth extraction (22.7; 33) | Melatonin 6 mg PO vs. placebo | 90 min before surgery | VAS (0–100); primary | 11.3 (11.0) | 13.2 (11.0) |
Song 2005 [37] | Singapore | 42 patients with irritable bowel syndrome (27.2; 60) | Melatonin 3 mg PO daily vs. placebo | 2 weeks | NRS (0–10); primary | −2.35 (1.34) | −0.70 (1.12) |
Varoni 2018 [38] | Italy | 20 patients with burning mouth syndrome (64.4; 80) | Melatonin 12 mg PO daily | 8 weeks | VAS (0–10); Primary | 0.6 (2.2) | 1.2 (1.8) |
Vidor 2013 [39] | Brazil | 32 patients with temporomandibular disorders (32.3; NR) | Melatonin 5 mg PO daily vs. placebo | 4 weeks | VAS (0–10); primary | −2.55 (2.96) | −0.91 (2.92) |
Vij 2018 [40] | India | 100 patients undergoing laparoscopic cholecystectomy (42.8; 74) | Melatonin 5 mg PO daily vs. Placebo | 3 days | VAS (0–100); Secondary | 30.0 (12.5) | 30.0 (15.8) |
Source | Random Sequence Generation | Allocation Concealment | Blinding of Participants, and Personnel | Blinding of Outcome Assessment | Incomplete Outcome Data | Selective Reporting | Other Bias | No. of Low Risk of Bias |
---|---|---|---|---|---|---|---|---|
Altiparmak 2019 [11] | low | unclear | unclear | unclear | low | low | low | 4 |
Anderson 2014 [12] | low | unclear | unclear | unclear | low | low | low | 4 |
Borazan 2010 [13] | low | unclear | unclear | low | low | low | low | 5 |
Capuzzo 2006 [14] | low | low | low | low | low | low | low | 7 |
Caumo 2007 [15] | low | unclear | unclear | low | low | low | low | 5 |
Caumo 2009 [16] | low | low | unclear | low | low | low | low | 6 |
Ebrahimi 2017 [17] | low | low | unclear | low | unclear | low | low | 5 |
Esmat 2016 [18] | low | low | unclear | low | low | low | low | 6 |
Esmat 2016 [19] | low | low | unclear | low | low | low | low | 6 |
Gögenur 2009 [20] | low | low | low | low | low | low | low | 7 |
Gonçalves 2016 [21] | low | low | low | low | low | low | low | 7 |
Grima 2018 [22] | unclear | low | low | low | low | low | low | 6 |
Haddadi 2018 [23] | unclear | unclear | unclear | unclear | low | low | low | 3 |
Hansen 2014 [24] | low | low | low | low | low | low | low | 7 |
Ismail 2009 [25] | low | unclear | high | low | low | low | low | 5 |
Ivry 2016 [26] | low | unclear | unclear | low | low | low | low | 5 |
Khezri 2013 [27] | low | low | unclear | low | low | low | low | 6 |
Khezri 2013 [28] | low | unclear | unclear | low | low | low | low | 5 |
Kirksey 2015 [29] | unclear | low | low | low | low | low | low | 6 |
Laflı 2019 [30] | low | unclear | unclear | low | low | low | low | 5 |
Lund 2015 [31] | low | low | low | low | low | low | low | 7 |
Mistraletti 2015 [32] | low | low | low | low | low | low | low | 7 |
Mowafi 2008 [33] | low | low | unclear | low | low | low | low | 6 |
Palmer 2019 [34] | low | low | low | low | low | low | low | 7 |
Schwertner 2013 [35] | low | low | low | low | low | low | low | 7 |
Seet 2015 [36] | low | low | low | low | low | low | low | 7 |
Song 2005 [37] | unclear | low | low | low | low | low | low | 6 |
Varoni 2018 [38] | low | unclear | low | low | low | low | low | 6 |
Vidor 2013 [39] | low | low | low | low | low | low | low | 7 |
Vij 2018 [40] | low | unclear | unclear | unclear | unclear | low | low | 3 |
Type of Pain | No. of Low Risk of Bias | No. of Trials | Summary SMD (95% CI) | Heterogeneity, I2 (%) |
---|---|---|---|---|
Acute pain—postoperative, local or epidural anesthesia | ≥ 6 | 1 [15] | −0.893 (−1.544, −0.241) | NA |
< 6 | 2 [23,26] | 0.000 (−0.392, 0.392) | 0 | |
Acute pain—postoperative, general anesthesia | ≥ 6 | 6 [13,17,18,19,22,32] | −0.212 (−0.664, 0.240) | 82.4 |
< 6 | 5 [12,14,24,27,36] | −2.134 (−3.456, −0.812) | 96.0 | |
Chronic pain | ≥ 6 | 4 [20,31,33,34] | −0.618 (−1.011, −0.225) | 49.3 |
< 6 | 1 [16] | −0.803 (−1.291, −0.316) | NA |
Type of Pain | No. of Low Risk of Bias | No. of Trials | Summary SMD (95% CI) | Heterogeneity, I2 (%) |
---|---|---|---|---|
Acute pain—procedural | ≥ 6 | 2 [32,33] | −0.527 (−1.517, 0.464) | 84.0 |
< 6 | 1 [23] | −3.262 (−3.818, −2.706) | NA | |
Acute pain—postoperative, general anesthesia | ≥ 6 | 4 [12,18,19,20] | −4.676 (−7.546, −1.806) | 97.9 |
< 6 | 3 [13,25,30] | −1.271 (−2.087, −0.455) | 83.6 |
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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
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 StyleOh, 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