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Meta-Analysis
. 2020 Dec 8;12(12):CD009861.
doi: 10.1002/14651858.CD009861.pub3.

Melatonin for preoperative and postoperative anxiety in adults

Bennedikte K Madsen  1 , Dennis Zetner  1 , Ann Merete Møller  2 , Jacob Rosenberg  1   3
Affiliations
Meta-Analysis

Melatonin for preoperative and postoperative anxiety in adults

Bennedikte K Madsen et al. Cochrane Database Syst Rev. .

Abstract
in English, Spanish

Background: Anxiety in relation to surgery is a well-known problem. Melatonin offers an alternative treatment to benzodiazepines for ameliorating this condition in the preoperative and postoperative periods.

Objectives: To assess the effects of melatonin on preoperative and postoperative anxiety compared to placebo or benzodiazepines.

Search methods: We searched the following databases on 10 July 2020: CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science. For ongoing trials and protocols, we searched clinicaltrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform.

Selection criteria: We included randomized, placebo-controlled or standard treatment-controlled (or both) studies that evaluated the effects of preoperatively administered melatonin on preoperative or postoperative anxiety. We included adult patients of both sexes (15 to 90 years of age) undergoing any kind of surgical procedure for which it was necessary to use general, regional, or topical anaesthesia.

Data collection and analysis: One review author conducted data extraction in duplicate. Data extracted included information about study design, country of origin, number of participants and demographic details, type of surgery, type of anaesthesia, intervention and dosing regimens, preoperative anxiety outcome measures, and postoperative anxiety outcome measures.

Main results: We included 27 randomized controlled trials (RCTs), involving 2319 participants, that assessed melatonin for treating preoperative anxiety, postoperative anxiety, or both. Twenty-four studies compared melatonin with placebo. Eleven studies compared melatonin to a benzodiazepine (seven studies with midazolam, three studies with alprazolam, and one study with oxazepam). Other comparators in a small number of studies were gabapentin, clonidine, and pregabalin. No studies were judged to be at low risk of bias for all domains. Most studies were judged to be at unclear risk of bias overall. Eight studies were judged to be at high risk of bias in one or more domain, and thus, to be at high risk of bias overall. Melatonin versus placebo Melatonin probably results in a reduction in preoperative anxiety measured by a visual analogue scale (VAS, 0 to 100 mm) compared to placebo (mean difference (MD) -11.69, 95% confidence interval (CI) -13.80 to -9.59; 18 studies, 1264 participants; moderate-certainty evidence), based on a meta-analysis of 18 studies. Melatonin may reduce immediate postoperative anxiety measured on a 0 to 100 mm VAS compared to placebo (MD -5.04, 95% CI -9.52 to -0.55; 7 studies, 524 participants; low-certainty evidence), and may reduce delayed postoperative anxiety measured six hours after surgery using the State-Trait Anxiety Inventory (STAI) (MD -5.31, 95% CI -8.78 to -1.84; 2 studies; 73 participants; low-certainty evidence). Melatonin versus benzodiazepines (midazolam and alprazolam) Melatonin probably results in little or no difference in preoperative anxiety measured on a 0 to 100 mm VAS (MD 0.78, 95% CI -2.02 to 3.58; 7 studies, 409 participants; moderate-certainty evidence) and there may be little or no difference in immediate postoperative anxiety (MD -2.12, 95% CI -4.61 to 0.36; 3 studies, 176 participants; low-certainty evidence). Adverse events Fourteen studies did not report on adverse events. Six studies specifically reported that no side effects were observed, and the remaining seven studies reported cases of nausea, sleepiness, dizziness, and headache; however, no serious adverse events were reported. Eleven studies measured psychomotor and cognitive function, or both, and in general, these studies found that benzodiazepines impaired psychomotor and cognitive function more than placebo and melatonin. Fourteen studies evaluated sedation and generally found that benzodiazepine caused the highest degree of sedation, but melatonin also showed sedative properties compared to placebo. Several studies did not report on adverse events; therefore, it is not possible to conclude with certainty, from the data on adverse effects collected in this review, that melatonin is better tolerated than benzodiazepines.

Authors' conclusions: When compared with placebo, melatonin given as premedication (as tablets or sublingually) probably reduces preoperative anxiety in adults (measured 50 to 120 minutes after administration), which is potentially clinically relevant. The effect of melatonin on postoperative anxiety compared to placebo (measured in the recovery room and six hours after surgery) was also evident but was much smaller, and the clinical relevance of this finding is uncertain. There was little or no difference in anxiety when melatonin was compared with benzodiazepines. Thus, melatonin may have a similar effect to benzodiazepines in reducing preoperative and postoperative anxiety in adults.

Antecedentes: La ansiedad relacionada con la cirugía es un problema conocido. La melatonina ofrece un tratamiento alternativo a las benzodiazepinas para mejorar esta afección en los períodos pre y posoperatorio.

Objetivos: Evaluar los efectos de la melatonina en la ansiedad pre y posoperatoria en comparación con el placebo o las benzodiazepinas. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en las siguientes bases de datos el 10 de julio de 2020: CENTRAL, MEDLINE, Embase, CINAHL y Web of Science. Para los ensayos y protocolos en curso, se buscó en clinicaltrials.gov y en la Plataforma de registros internacionales de ensayos clínicos de la Organización Mundial de la Salud (OMS). CRITERIOS DE SELECCIÓN: Estudios aleatorizados controlados con placebo o controlados con tratamiento estándar, o ambos, que evaluaron los efectos de la melatonina administrada de forma preoperatoria para la ansiedad preoperatoria o posoperatoria. Se incluyeron pacientes adultos de ambos sexos (15 a 90 años de edad) a los que se les realizó cualquier clase de procedimiento quirúrgico donde fue necesario utilizar anestesia general, regional o tópica. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Un autor de la revisión realizó la extracción de los datos por duplicado. Los datos que se extrajeron incluyeron información acerca del diseño del estudio, el país de origen, el número de participantes y los detalles demográficos, el tipo de cirugía, el tipo de anestesia, la intervención y el régimen de dosis, medidas de desenlace de ansiedad preoperatoria y medidas de desenlace de ansiedad posoperatoria.

Resultados principales: Se incluyeron 27 ensayos controlados aleatorizados (ECA), con 2319 participantes, que evaluaron la melatonina para el tratamiento de la ansiedad preoperatoria, la ansiedad posoperatoria o ambas. Veinticuatro estudios compararon la melatonina con el placebo. Once estudios compararon la melatonina con una benzodiazepina (siete estudios con midazolam, tres estudios con alprazolam y un estudio con oxazepam). Otros comparadores en un escaso número de estudios fueron la gabapentina, la clonidina y la pregabalina. No se consideró que ningún estudio tuviera un riesgo bajo de sesgo en todos los dominios. La mayoría de los estudios se consideraron con riesgo incierto de sesgo en general. Se consideró que ocho estudios tenían un alto riesgo de sesgo en uno o más dominios y, por lo tanto, un alto riesgo de sesgo en general. Melatonina versus placebo La melatonina probablemente da lugar a una reducción de la ansiedad preoperatoria medida por una escala visual analógica (EVA, 0 a 100 mm) en comparación con el placebo (diferencia de medias [DM] ‐11,69; intervalo de confianza [IC] del 95%: ‐13,80 a ‐9,59; 18 estudios, 1264 participantes; evidencia de certeza moderada), sobre la base de un metanálisis de 18 estudios. La melatonina podría reducir la ansiedad posoperatoria inmediata medida en una EVA de 0 a 100 mm en comparación con el placebo (DM ‐5,04; IC del 95%: ‐9,52 a ‐0,55; siete estudios, 524 participantes; evidencia de certeza baja), y podría reducir la ansiedad posoperatoria tardía medida seis horas después de la cirugía mediante el State‐Trait Anxiety Inventory (STAI) (DM ‐5,31; IC del 95%: ‐8,78 a ‐1,84; dos estudios; 73 participantes; evidencia de certeza baja). Melatonina versus benzodiazepinas (midazolam y alprazolam) La melatonina probablemente da lugar a poca o ninguna diferencia en la ansiedad preoperatoria medida en una EVA de 0 a 100 mm (DM 0,78; IC del 95%: ‐2,02 a 3,58; siete estudios, 409 participantes; evidencia de certeza moderada) y podría haber poca o ninguna diferencia en la ansiedad posoperatoria inmediata (DM ‐2,12; IC del 95%: ‐4,61 a 0,36; tres estudios, 176 participantes; evidencia de certeza baja). Eventos adversos Catorce estudios no informaron sobre los eventos adversos. Seis estudios informaron específicamente que no se observaron efectos secundarios y los siete estudios restantes informaron casos de náuseas, somnolencia, mareos y cefalea; sin embargo, no se informaron eventos adversos graves. Once estudios midieron la función psicomotora y cognitiva, o ambas, y en general, estos estudios encontraron que las benzodiazepinas deterioraron la función psicomotora y cognitiva más que el placebo y la melatonina. Catorce estudios evaluaron la sedación y en general encontraron que la benzodiazepina causaba el mayor grado de sedación, pero la melatonina también mostró propiedades sedantes en comparación con el placebo. Varios estudios no informaron sobre los efectos adversos; por lo tanto, no es posible concluir con certeza, a partir de los datos sobre los efectos adversos obtenidos en esta revisión, que la melatonina se tolera mejor que las benzodiazepinas.

Conclusiones de los autores: Cuando se compara con el placebo, la melatonina administrada como premedicación (en forma de comprimidos o sublingual) probablemente reduce la ansiedad preoperatoria en los adultos (medida entre 50 y 120 minutos después de la administración), lo que es potencialmente relevante desde el punto de vista clínico. El efecto de la melatonina sobre la ansiedad posoperatoria en comparación con el placebo (medido en la sala de recuperación y seis horas después de la cirugía) también fue evidente, pero fue mucho menor, y la relevancia clínica de este hallazgo no está clara. Hubo poca o ninguna diferencia en la ansiedad cuando la melatonina se comparó con las benzodiazepinas. Por lo tanto, la melatonina puede tener un efecto similar al de las benzodiazepinas en la reducción de la ansiedad pre y posoperatoria en los adultos.

Trial registration: ClinicalTrials.gov NCT01126294 NCT02415309 NCT02451293 NCT03966950 NCT02386319.

PubMed Disclaimer

Conflict of interest statement

B. Madsen: none known.

A. Møller: none known.

J. Rosenberg: none known.

D. Zetner: has received a PhD grant from RepoCeuticals ApS. RepoCeuticals ApS had no involvement with the Cochrane Review and has not in any way been able to influence this process.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 Melatonin versus placebo, outcome: 1.1 Preoperative anxiety (VAS) (mm) with subgroup 1.1.1 Final VAS scores and subgroup 1.1.2 Change VAS scores.
5
5
Funnel plot of comparison: 1 Melatonin versus placebo, outcome: 1.1 Preoperative anxiety (VAS) [mm].
6
6
Forest plot of comparison: 2 Melatonin versus benzodiazepine ‐ preoperative anxiety, outcome: 2.1 Preoperative anxiety (VAS) [mm].
1.1
1.1. Analysis
Comparison 1: Melatonin versus placebo, Outcome 1: Preoperative anxiety (VAS)
1.2
1.2. Analysis
Comparison 1: Melatonin versus placebo, Outcome 2: Postoperative anxiety (VAS) [mm]
1.3
1.3. Analysis
Comparison 1: Melatonin versus placebo, Outcome 3: Postoperative anxiety (STAI)
2.1
2.1. Analysis
Comparison 2: Melatonin versus benzodiazepine, Outcome 1: Preoperative anxiety (VAS) [mm]
2.2
2.2. Analysis
Comparison 2: Melatonin versus benzodiazepine, Outcome 2: Postoperative anxiety (VAS) [mm]
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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Acil 2004 {published data only}
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Hoseini 2015 {published data only}
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Ionescu 2008 {published data only}
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Ismail 2009 {published data only}
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Jain 2019 {published data only}
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Javaherforooshzadeh 2018 {published data only}
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Khanna 2019 {published data only}
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Khezri 2013 {published data only}
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Khezri 2013b {published data only}
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Khezri 2016 {published data only}
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Marzban 2016 {published data only}
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Mowafi 2008 {published data only}
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Naguib 1999 {published data only}
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Naguib 2000 {published data only}
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Naguib 2006 {published data only}
    1. Naguib M, Samarkandi AH, Moniem MA, Mansour Eel-D, Alshaer AA, Al-Ayyaf HA, et al. The effects of melatonin premedication on propofol and thiopental induction dose-response curves: a prospective, randomized, double-blind study. Anesthesia and Analgesia 2006;103(6):1448-52. [PMID: ] - PubMed
Norouzi 2019 {published data only}
    1. Norouzi A, Fateh S, Modir H, Kamali A, Akrami L. Premedication effect of melatonin on propofol induction dose for anesthesia, anxiety, orientation and sedation after abdominal surgery: a double-blinded randomized trial. Medical Gas Research 2019;9(2):62-7. [PMID: ] - PMC - PubMed
Patel 2015 {published data only}
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Pokharel 2014 {published data only}
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Seet 2015 {published data only}
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Torun 2019 {published data only}
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Turkistani 2007 {published data only}
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References to studies excluded from this review

Andersen 2014 {published data only}
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Andersen 2015 {published data only}
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Bourne 2006 {published data only}
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Cardinali 2002 {published data only}
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CTRI/2018/02/012032 {unpublished data only}
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CTRI/2019/08/020502 {unpublished data only}
    1. CTRI/2019/08/020502. Comparative study between oral melatonin and oral pregabalin on preoperative anxiety and perioperative sedation in surgeries under regional anaesthesia [Comparative study between oral melatonin and oral pregabalin on preoperative anxiety perioperative sedation and postoperative analgesia in surgeries under regional anaesthesia- a randomised control study]. https://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2019/08/020502 (first received 1 August 2019).
de Carvalho 2019 {published data only}
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Dwaich 2016 {published data only}
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Fan 2017 {published data only}
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Ford 2020 {published data only}
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Ghaeli 2015 {published data only}
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Ghaeli 2018 {published data only}
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Gogenur 2009 {published data only}
    1. Gogenur I, Kucukakin B, Bisgaard T, Kristiansen V, Hjortso NC, Skene DJ, et al. The effect of melatonin on sleep quality after laparoscopic cholecystectomy: a randomized, placebo-controlled trial. Anesthesia and Analgesia 2009;108(4):1152-6. [PMID: ] - PubMed
Haddadi 2018 {published data only}
    1. Haddadi S, Shahrokhirad R, Ansar MM, Marzban S, Akbari M, Parvizi A. Efficacy of preoperative administration of acetaminophen and melatonin on retrobulbar block associated pain in cataract surgery. Anesthesiology and Pain Medicine 2018;8(5):e61041. [PMID: ] - PMC - PubMed
Hansen 2014 {published data only}
    1. Hansen MV, Andersen LT, Madsen MT, Hageman I, Rasmussen LS, Bokmand S, et al. Effect of melatonin on depressive symptoms and anxiety in patients undergoing breast cancer surgery: a randomized, double-blind, placebo-controlled trial. Breast Cancer Research and Treatment 2014;145:683-95. [PMID: ] - PubMed
Hansen 2014a {published data only}
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IRCT20141009019470N82 {unpublished data only}
    1. IRCT20141009019470N82. Comparative effect of melatonin, gabapentin and dexmedetomidine on post-operative pain and anxiety in patients undergoing laminectomy [Comparative effect of melatonin, gabapentin and dexmedetomidine on post-operative pain and anxiety in patients undergoing laminectomy]. https://apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT20141009019470N82 (first received 29 June 2019).
IRCT201602147202N10 {unpublished data only}
    1. IRCT201602147202N10. Comparison between melatonin and zolpidem in improving sleep quality, anxiety and depression [Comparison of the effect of melatonin and zolpidem in improving quality of sleep, anxiety and depression in colorectal cancer patients receiving chemotherapy]. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT201602147202N10 (first received 10 September 2017).
IRCT201701304365N20 {unpublished data only}
    1. Baradari AG, Habibi MR. Effect of melatonin on pain intensity after lumbar disc surgery [Effect of preoperative melatonin on pain intensity after lumbar disc surgery]. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT201701304365N20 (first received 16 April 2017).
Ivry 2017 {published data only}
    1. Ivry M, Goitein D, Welly W, Berkenstadt H. Melatonin premedication improves quality of recovery following bariatric surgery - a double blind placebo controlled prospective study. Surgery for Obesity and Related Diseases 2017;13(3):502-6. [PMID: ] - PubMed
Jahromi 2016 {published data only}
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Kirksey 2015 {published data only}
    1. Kirksey MA, Yoo D, Danninger T, Stundner O, Ma Y, Memtsoudis SG. Impact of melatonin on sleep and pain after total knee arthroplasty under regional anesthesia with sedation: a double-blind, randomized, placebo-controlled pilot study. Journal of Arthroplasty 2015;30(12):2370-5. [PMID: ] - PubMed
Madsen 2016 {published data only}
    1. Madsen MT, Hansen MV, Andersen LT, Hageman I, Rasmussen LS, Bokmand S, et al. Effect of melatonin on sleep in the perioperative period after breast cancer surgery: a randomized, double-blind, placebo-controlled trial. Journal of Clinical Sleep Medicine 2016;12(2):225-33. [PMID: ] - PMC - PubMed
Nasr 2014 {published data only}
    1. Nasr DA, Abdellatif AA. Efficacy of preoperative melatonin versus pregabalin on perioperative anxiety and postoperative pain in gynecological surgeries. Egyptian Journal of Anaesthesia 2014;30:89-93.
NCT01126294 {unpublished data only}
    1. NCT01126294. Perioperative melatonin in lumbar laminectomy [Perioperative analgesic and anxiolytic effect of melatonin in patients undergoing lumbar laminectomy]. https://clinicaltrials.gov/show/NCT01126294 (first received 19 May 2010).
NCT02415309 {unpublished data only}
    1. NCT02415309. Premedication with melatonin in lumbar medial branch block procedure [Premedication with melatonin vs. placebo in patients undergoing interventional pain procedure]. https://clinicaltrials.gov/show/NCT02415309 (first received 14 April 2015).
NCT02451293 {unpublished data only}
    1. NCT02451293. The effect of melatonin on depression, anxiety, circadian and sleep disturbances in patients after acute myocardial syndrome (MEDACIS) [The Effect of MElatonin on Depression, Anxiety, CIrcadian and Sleep Disturbances in Patients After Acute Myocardial Syndrome]. https://clinicaltrials.gov/show/NCT02451293 (first received 15 May 2015).
NCT03966950 {unpublished data only}
    1. NCT03966950. Use of melatonin for preventing POCD in transurethral prostate resection under spinal anesthesia [Use of melatonin for prevention of POCD after TURP surgery under spinal anesthesia for elderly patients]. https://clinicaltrials.gov/show/NCT03966950 (first received 10 May 2019).
Radwan 2010 {published data only}
    1. Radwan K, Youssef M El-Tawdy A, Zeidan M, Kamal N. Melatonin versus gabapentin. A comparative study as preemptive medications. Internet Journal of Anesthesiology 2010;23:19.
Rokhtabnak 2017 {published data only}
    1. Rokhtabnak F, Ghodraty MR, Kholdebarin A, Khatibi A, Seyed Alizadeh SS, Koleini ZS, et al. Comparing the effect of preoperative administration of melatonin and passiflora incarnata on postoperative cognitive disorders in adult patients undergoing elective surgery. Anesthesiology and Pain Medicine 2017;7(1):e41238. [PMID: ] - PMC - PubMed
Schemmer 2008 {published data only}
    1. Schemmer P, Nickkholgh A, Schneider H, Sobirey M, Weigand M, Koch M, et al. PORTAL: pilot study on the safety and tolerance of preoperative melatonin application in patients undergoing major liver resection: a double-blind randomized placebo-controlled trial. BMC Surgery 2008;8:2. [PMID: ] - PMC - PubMed
TCTR20140516001 {unpublished data only}
    1. TCTR20140516001. Effectiveness preemptive of melatonin on acute postoperative analgesia in patients undergoing abdominal hysterectomy with or without ovarian surgery. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=TCTR20140516001 (first received 16 may 2014).
Vij 2018 {published data only}
    1. Vij V, Dahiya D, Kaman L, Behera A. Efficacy of melatonin on sleep quality after laparoscopic cholecystectomy. Indian Journal of Pharmacology 2018;50(5):236-41. [PMID: ] - PMC - PubMed
Wawrzyniak 2014 {published data only}
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References to studies awaiting assessment

CTRI/2017/08/009245 {unpublished data only}
    1. CTRI/2017/08/009245. Study of possible beneficial effects of melatonin and gabapentin on patients blood pressure during anesthesia [Comparative efficacy of oral melatonin vs gabapentin for attenuation of haemodynamic response to direct laryngoscopy and endotracheal intubation]. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2017/08/009245 (first received 3 Agust 2017).
IRCT20160430027677N8 {unpublished data only}
    1. Sane S. Clinical trial evaluation the effect of melatonin on analgesia and intraocular pressure in patient with cataract surgery under topical anesthesia [The effect of melatonin on analgesia and intraocular pressure in cataract surgery with topical anesthesia]. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT20160430027677N8 (first received 10 September 2018).

References to ongoing studies

CTRI/2018/02/011895 {unpublished data only}
    1. CTRI/2018/02/011895. Can music and a drug (melatonin)help in decreasing nervousness before operation? [To assess the effect of preoperative melatonin and music on anxiety and recovery profile in patients undergoing day care surgery: a randomized control trial.]. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2018/02/011895 (first received 13 Februrary 2018).
CTRI/2018/04/012960 {unpublished data only}
    1. CTRI/2018/04/012960. Effect of melatonin on anxiety and pain in patient undergoing eye surgery [Effect of preoperative melatonin on anxiety and pain in patient undergoing Phacoemulsification cataract surgery]. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2018/04/012960 (first received 4 March 2018). [CTRI/2018/04/012960]
CTRI/2018/08/015192 {unpublished data only}
    1. CTRI/2018/08/015192. A clinical trial to study the effects of pre operative tablet melatonin in patients undergoing infra umbilical surgeries under spinal anaesthesia. [Efficacy of pre-operative oral melatonin on post-operative pain in patients undergoing infra-umbilical surgeries under subarachnoid block- a double blind randomised control study]. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2018/08/015192 (first received 8 June 2018).
CTRI/2018/08/015537 {unpublished data only}
    1. CTRI/2018/08/015537. Effect of melatonin premedication on propofol consumption in GA [To assess the effect of oral melatonin premedication on propofol requirement for induction in entropy guided general anaesthesia- a randomised double blind study]. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2018/08/015537 (first received 30 August 2018).
CTRI/2018/10/015917 {unpublished data only}
    1. Ranaganath N. Comparison of two separate doses of melatonin as a drug used before anesthesia in cancer patient. [A Comparative Study of Two Doses of Melatonin as Oral Premedication in Oncoanaesthesia; A Randomized Single Blind Control Study]. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2018/10/015917 (first received 10 May 2018).
CTRI/2019/12/022358 {unpublished data only}
    1. CTRI/2019/12/022358. Comparing the effects of melatonin with alprazolam to reduce anxiety before surgery and pain after surgery in adults undergoing laparoscopic removal of gall bladder under general anaesthesia [Comparison of effects of melatonin and alprazolam on pre-operative anxiety in adult patients undergoing laparoscopic cholecystectomy under general anaesthesia]. https://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2019/12/022358 (first received 13 December 2019).
CTRI/2020/02/023330 {unpublished data only}
    1. CTRI/2020/02/023330. A study to evaluate the effect of two doses of oral melatonin on anxiety and pain relief in patients undergoing lower limb surgeries [A study to evaluate clinical impact of two doses of oral melatonin on preoperative anxiety and postoperative pain relief in patients undergoing orthopaedic surgeries]. https://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2020/02/023330 (first received 14 February 2020).
IRCT20100707004345N6 {unpublished data only}
    1. IRCT20100707004345N6. The effect of melatonin on anxiety before hysterectomy [Investigating the effect of melatonin on reducing preoperative anxiety in abdominal hysterectomy; a double blinded clinical trial study]. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT20100707004345N6 (first received 11 April 2019).
IRCT20190120042432N1 {unpublished data only}
    1. IRCT20190120042432N1. Comparison of two oral precursors of melatonin and gabapentin in female candidates for cesarean section under spinal anesthesia [Comparison of two oral precursors of melatonin and gabapentin in female candidates for cesarean section under spinal anesthesia]. https://apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT20190120042432N1 (first received 21 July 2019).
NCT02386319 {unpublished data only}
    1. NCT02386319. Anxiolytic and analgesic effects of melatonin [Anxiolytic and analgesic effects of melatonin: a randomized, double-blinded, placebo-controlled clinical study]. https://clinicaltrials.gov/show/NCT02386319 (first received 11 March 2015).

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References to other published versions of this review

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    1. Hansen MV, Halladin NL, Rosenberg J, Gögenur I, Møller AM. Melatonin for pre‐ and postoperative anxiety in adults. Cochrane Database of Systematic Reviews 2015;(4). [DOI: 10.1002/14651858.CD009861.pub2] [CD009861] - DOI - PMC - PubMed

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