{"paper_id":"463cbe14-e93c-4b6f-bf35-5c5a51cd9d2b","body_text":"Original Article | JOGCR. 2024; 9(1): 29-35 \n     Volume 9, January – February 2024       Journal of Obstetrics, Gynecology and Cancer Research \n Journal of Obstetrics, Gynecology and Cancer Research | ISSN: 2476-5848 \n \nPreventive Dose of Melatonin on Postoperative Pain in Total Abdominal \nHysterectomy: A Clinical Trial Study \n \nKatayoun Haryalchi1 , Mandana Mansour Ghanaei2 , Mohammad Rajabi3 , Maryam Ghazizadeh4 ,  \nFakhroddin Aghajanpour5 , Pouya Koochakpoor3 , Mahmood Abedinzade6*  \n \n1. Department of Anesthesiology, Reproductive Health Research Center, Al -Zahra Hospital, School of Medicine, Guilan \nUniversity of Medical Sciences, Rasht, Iran   \n2. Department of Obstetrics and Gynecology, Reproductive Health Research Center, Alzahra Hospital, School of Medicine, \nGuilan University of Medical Sciences, Rasht, Iran \n3. Department of Anesthesia, School of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran  \n4. Department of Biostatics, School of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran  \n5. Department of Reproductive Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical \nSciences, Tehran, Iran  \n6. Department of Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran \n \nArticle Info  ABSTRACT \n  \n          10.30699/jogcr.9.1.29 \n \n \n \nBackground & Objective: Studies have shown contradictory results regarding the use \nof pregabalin and melatonin as analgesic agents. Because the analgesic effects of these \ndrugs as preemptive have not been compared in abdominal hysterectomy, one of the \nmost common surgical procedures in women with moderate to severe pain, under \ngeneral anesthesia. The aim of this study was to compare the pretreatment effects of \nmelatonin and pregabalin on postoperative pain intensity in total abdominal \nhysterectomy (TAH). \nMaterials & Methods: Ninety Patients were randomly divided into three groups \n(N=30): t\nhe first group received oral melatonin (6 mg), the second group received \npregabalin (50 mg), and the third one who took no drug. Serum melatonin and beta -\nendorphin levels were measured before and after the surgery. Pain intensity was \nassessed by the Numerical Rating Scale at 1,6,12, and 24 hours after the surgeries. \nResults: At 12 hrs after the surgery, mean pain intensity in the melatonin group was \nsignificantly lower than the pregabalin group, and in the pregabalin group was \nsignificantly lower than the third group (P<0.05). At 24 hrs after the TAH, the mean \npain intensity in the melatonin group was significantly lower than the third group \n(P<0.05).  \nConclusion: injection preventive melatonin is more effective than pregabalin to \nreduce pain throughout the first 24 hrs after the TAH. \nKeywords: Hysterectomy, Melatonin, Pain, Pregabalin  \nReceived:  2023/05/05; \nAccepted: 2023/12/24; \nPublished Online: 22 Jan 2024; \n \n \nUse your device to scan and read the \narticle online \n \n \nCorresponding Information:  \nMahmood Abedinzade, \nDepartment of Physiology, School of \nMedicine, Guilan University of Medical \nSciences, Rasht, Iran \n \nEmail: mahmood.abedinzade@gmail.com \n   \n \nCopyright © 2024, This is an original open-access article distributed under the terms of the Creative Commons Attribution-noncommercial 4.0 International License \nwhich permits copy and redistribution of the material just in noncommercial usages with proper citation. \n \n \nIntroduction\nNowadays, postoperative pain control is one of the \nmost important concerns of the medical team. They are \nlooking for the best and the most affordable ways for \npostoperative pain management. In addition to the best \nkind of  pain control, reduction of the side effects of \ndrugs also minimizes the costs imposed on hospitals \nand patients (1, 2) . Currently, the most common \nmethods of pain management are the use of opioid \nanalgesics, non-drug analgesics, and local anesthetics \nused in regional anesthesia. Although opioids have \nserious side effects, they are still commonly prescribed \nfor pain management (3). Recent studies have been \npresented, the commencement of pain control before \nthe surgery is one of the most important factors to  \nreduce postoperative pain and stress. According to this \nhypothesis, analgesia will be more effective when \nbegins before the initial surgical stimulation. \nPrescribing analgesic agents before the onset of pain \ngives the drug enough time to reach the proper serum \nlevel before patients complain of pain. In this case, pain \ncontrol can be better, faster, and more effective (4, 5).  \nMelatonin (N -acetyl-5-methoxytryptamine), a \nhormone secreted by the pineal gland, is a good option \nfor use as a preemptive due to its sedative, analgesic, \nand its anti stress effects. Melatonin is made from the \namino acid tryptophan in the pineal gland and presents \n\n\nKatayoun Haryalchi et al. 30 \n      Volume 9, January – February 2024       Journal of Obstetrics, Gynecology and Cancer Research \nas a hormone and antioxidant in all tissues of the body \n(6, 7) . Although the results of several studies have \nshown; preoperative melatonin administration reduces \nopioid consumption and postoperative pain, its \nanalgesic effects have not yet been fully elucidated. \nTherefore, it is necessary to compare the \nantinociceptive effects of melatonin alone with other \ndrugs prescribed as pain medication (8). \nAnticonvulsant drugs are prescribed to control \nchronic neuropathic pain. These drugs, such as \npregabalin, appear to be effective to control and \nmanage postoperative pain (9). Pregabalin is a gamma \naminobutyric acid (GABA) analogue. Past studies have \nshown that this drug has a high affinity for binding to \nthe α2 -δ protein. This protein is found in calcium \nvoltage channels in the central nervous system (10, 11). \nThis drug inhib its the release of many \nneurotransmitters, including glutamate, noradrenaline, \nand substance p. It is used to control neuropathic pain, \ngeneralized and partial seizures, and post -operative \npain (12). Studies have shown contradictory results \nregarding the u se of pregabalin and melatonin as \nanalgesic agents. Also, the analgesic effects of these \ndrugs as preemptive have not been compared in \nabdominal hysterectomy, one of the most common \nsurgical procedures in women with moderate to severe \npain, under general anesthesia. We designed this study \nto compare the effects of melatonin and pregabalin as \na preventive drug to postoperative pain control in \npatients undergoing Total abdominal hysterectomy \n(TAH). \n \nMethods \nAfter approval by the University Ethics Committee \n(ethical code: IR.GUMS.REC.1394.230 & IRCT \nregistration number: IRCT2015090816325N3), 90 \npatients candidates for elective TAH THA with \nphysical status I, II according to American Society of \nAnesthesiologists criteria were enrolled in a double -\nblind clinical trial study with informed consent. During \n2017-2018, these patients were referred to Al -Zahra \nObstetrics and Gynecology Center (Rasht, Iran) for \ntreatment of uterine fibroids, uterine prolapse, \nendometriosis, persistent prolonged bleeding. Patients \nwith cardiac, pulmonary, hepatic, renal, autoimmune, \npsychiatric disorders, diabetes, gastrointestinal, \nseizure, leukemia, allergy, sleep disorders, and chronic \nhistory of analgesic and psychotropic medication usage \nduring one week before the surgery were not inc luded \nin the study (13-15).  \nThe night before the surgery, patients were randomly \ndivided into three groups: melatonin, pregabalin, and \nno drug. In the melatonin group, patients received 6 mg \nof melatonin (two pills each one with the dosage of 3 \nmg) (16, 17) , 2 hrs before the surgery, and in the \npregabalin group, patients received 50 mg of \npregabalin and the third group did not receive any drug \n(18, 19). The volunteers in the study were unaware of \nthe groups, and the medication was administered by a \nmember of the treatment staff who was not aware of the \ngrouping. To prevent dehydration, Ringer intravenous \ninjection was started before induction of anesthesia for \nall three groups. \nAnesthesia was induced with fentanyl (as opioid) \"2 \nμg / kg\", thiopental (as hyp notic) \"5 mg / kg\" and \natracurium (as relaxant) \"0.6 mg / kg\". Maintenance \nwas followed with Isoflurane with a MAC dose of 1 -\n1.5, 50% / 50% N2O / O2, and fentanyl maintenance \ndoses of \"1 µg / kg\" (if heart rate increases by more \nthan 20% above baseline bef ore anesthesia), and \natracurium (0.2 mg/kg). Neuromuscular block was \nreversed at the end of surgery with Neostigmine 0.02 \nmg / kg + Atropine 0.04 mg / kg. \nDuring anesthesia and surgery, monitoring was \nperformed by ECG, SaO2, and capnography to \ndetermine CO2 (35-34) and non -invasive blood \npressure monitoring every five minutes. The amount of \nneuromuscular block was assessed by a nerve \nstimulator. The duration  of surgery, the time of \nanesthesia, and the amount of fentanyl dosage were \ncarefully recorded. Postoperative pain was controlled \nusing 1 µg / kg fentanyl injections in consideration of \nNRS ≥ 4. In the early hours after the surgery, heart rate, \nmean arteri al pressure, respiratory rate, SpO2, and \nfentanyl levels were recorded. Any side effects \nincluding nausea, vomiting, respiratory depression, \ndizziness, diplopia, itching, and tremor were recorded \nand reported to the anesthesiologist. Ondansetron with \na dosage of 4 mg IV injection is used to control nausea. \nPain severity was measured with the numeric rating \nScale (NSR) at 1, 6, 12, and 24 hours after the surgery. \nThe NSR contains 10 points that patients report using \ntheir pain level. The number 0 is considered as painless, \n1-3 mild pain, 4-6 moderate pain, and 7-10 severe pain. \nSerum melatonin and beta- endorphin levels were \nmeasured immediately before and after the surgery \nwith 5 cc blood samples in all three groups. The \nsamples were then centrifuged at 3500 rpm for 15 \nminutes. Isolated serum was stored at -20 ° C. ELISA \ntechnique was used to measure serum melatonin \n(EASTBIOPHARM melatonin (H) _96Test) and beta-\nendorphin (EASTBIOPHARM Beta -Endorphin (H) \n_96Test) levels. \nStatistical analysis \nThe results of this study were evaluated using SPSS \n(Statistic Package for Social Science) software, version \n16.0 (IBM, USA).  ANOVA test was used to compare \nthe severity of pain in the postoperative hours after the \nsurgery and to compare the beta- endorphin and \nmelatonin lev els before and after the surgery. The \nresults were expressed as mean and standard deviation \nand the significance level was considered as less than \n5 percent in all tests. \n \nResults \nPostoperative Pain intensity  \n\n31 Melatonin and Postoperative Pain in Hysterectomy \n      Volume 9, January – February 2024       Journal of Obstetrics, Gynecology and Cancer Research \nThe mean pain intensity at 1, 6, 12, and 24 hr s after \nthe surgery was compared between three groups and \ndata analysis showed a significant difference in pain \nintensity. The results presented; the pain intensity at \none hour after the surgery in the melatonin group was \nlower than the third group signifi cantly (P = 0.01). At \n12 hours after the surgery, the mean pain intensity in \nthe melatonin group was lower than the pregabalin \ngroup significantly (P = 0.001) and in the pregabalin \ngroup was lower than the third group significantly (P = \n0.004). At 24 hrs a fter the surgery, the mean pain \nintensity in the melatonin group was significantly \nlower than the third group (P = 0.003) (Table 1\n). \n \nTable 1. Comparison of pain intensity in the first 24 hours after surgery between the three groups (Mean ± SD) \nPain Intensity \nStudy Groups \nP value \nMelatonin Pregabalin Placebo \n1 hour  after surgery 4.8 ± 2.41 5.8 ± 2.48 8.2 ± 1.39 0.009 \n6 hour after surgery 5.85 ± 1.95 7 ± 1.41 7.1 ± 1.59 0.3 \n12 hour after surgery 4.14 ± 1.95 8 ± 1 5 ± 1.15 0.001 \n24 hour after surgery 1.28 ± 0.48 2.2 ± 0.83 3.9 ± 1.79 0.002 \n \nSerum Beta-Endorphin levels before and after the \nsurgery \nComparing the mean beta- endorphins of the three \ngroups before surgery did not show a significant \ndifference ( Table 2 ). Comparison of postoperative \nbeta-endorphin levels showed a significant difference \nbetween melatonin and the third group (P = 0.04). \n \nTable 2. Serum beta-endorphin level before and after surgery (Mean ± SD) \nGroups before surgery after surgery \nMelatonin 37.52 ± 27.43 42.33 ± 30.31 \nPregabalin 57.74 ± 40.13 63.1 ± 33.87 \nPlacebo 77.85 ± 59.4 94.19 ± 67.94 \nP value 0.09 0.04 \n \nSerum melatonin levels before and after the \nsurgery \nComparison of mean melatonin levels in three \ngroups showed no significant difference before and \nafter the surgery (Table 3). \n \nTable 3. Serum melatonin levels before and after surgery (Mean ± SD) \nGroup before surgery after surgery \nMelatonin 32.52 ± 20.07 33 ± 13.79 \nPregabalin 37.46 ± 18.02 36.77 ± 13.47 \nPlacebo 36.46 ± 24.94 48.39 ± 26.19 \nP value 0.8 0.1 \n \n \nDiscussion \nIn the present study, we assessed mean postoperative \npain intensity, and compared serum melatonin and \nbeta-endorphin levels throughout the preoperative and \npostoperative periods in patients undergoing total \nabdominal hysterectomy. The results illustrated; \npatients receiving melatonin before the surgery have \nless pain intensity than other groups during the first 24 \nhours after the surgery, which could reduce opioid \nconsumption during this period. \nWe have shown in previous studies that the use of \nanesthetic supplements such as magnesium sulfate \nreduces the severity of postoperative pain and opiate \nconsumption (13). In this study, we evaluated the \nseverity of postoperative pain following melatonin and \npregabalin administrat ion. Some studies show that \nmelatonin reduces the intensity of pain induced by \nelectrical, mechanical, chemical, and surgical stimuli \n(20). Caumo et al. investigated the antinociceptive \n\nKatayoun Haryalchi et al. 32 \n      Volume 9, January – February 2024       Journal of Obstetrics, Gynecology and Cancer Research \neffects of preoperative administration of melatonin. \nThe results showed that melatonin reduces the severity \nof pain and drug usage in the first two hrs after the \nsurgery, which is in line with the results of the present \nstudy (21). Hosseini, Yekta (22)  studied the analgesic \neffects of preoperative melatonin administration at a \ndose of 5 mg on patients undergoing laparoscopic \ncholecystectomy. They observed that melatonin \nreduces pain intensity and opioid consumption after the \nsurgery (22). Nethra and cow orkers concluded; \npreemptive melatonin with a dosage of 3 mg produced \nanalgesia within six hrs after the surgery, so the need \nfor analgesics decreased throughout the 24 hours. The \nresults were the same as ours (23). A study by Khezri \net al. showed sublingu al usage of melatonin with a \ndosage of 30 mg could not make analgesia after \nCesarean Section, which was contrary to our findings \nand may be due to differences in the type of surgery \nand anesthesia (24). \nIn animal studies, the antinociceptive effects of \nmelatonin have been shown to be dose-dependent. The \nmechanism of the analgesic effects of melatonin is not \nwell understood (25) . Melatonin exerts analgesic \neffects through GABA -B receptors, opiate receptors, \nand activation of melatonin receptors. Melatonin al so \nreduces the pain intensity by suppressing the \nexpression of TNF -alpha and other inflammatory \nfactors (26).  \nIn our study, the mean pain intensity in patients \nreceiving pregabalin was lower than the third group, \nbut there was no significant difference between the two \ngroups. The results of the study of Imam et al. showed \nthat administration of 150 mg of pregabali n before the \nsurgery reduces the severity of pain in the first 24 hrs \nafter abdominal hysterectomy, which was the same as \nours (27). The results of the Ghai et al. study showed \nprescribing 300 mg of pregabalin one hour before the \nabdominal hysterectomy, reduces preoperative anxiety \nand pain without unpleasant sedative effects in the first \nhours of recovery (28). In the study of Jokela et al., \npreoperative administration of 300 mg pregabalin in \npatients undergoing laparoscopic abdominal \nhysterectomy reduced postoperative pain and opioid \nconsumption, which is consistent with the results of the \npresent study (29).  \nPregabalin seems to have analgesic effects by \nbinding to the α1,2- δ subunit of the voltage -gated \ncalcium channel. Chronic administration of pregabalin \nalso reduces the level of expression of this subunit in \nthe dorsal horn of the spinal cord and presynaptic nerve \nterminals and controls pain, especially chronic pain \n(30, 31) . In this study, we measured and compared \nserum levels of melatonin and beta -endorphin before \nand after the surgery to evaluate the antinociceptive \neffect of melatonin and pregabalin. There was no \nsignificant difference between preoperative and \npostoperative melatonin levels, but beta -endorphin \nlevels were significantly different in the three groups. \nAlso, the beta -endorphin level after the surgery was \nhigher than the pre -surgical level. Studies show that \nbeta-endorphin levels increase following abdominal \nsurgery (32). The beta- endorphin antinociceptive \nmechanism in the central nervous system is well -\ndefined, but the plasma analgesic effects of beta-\nendorphin are not fully understood (33). \nIt seems in this study, preoperative administration of \nmelatonin and pregabalin increases the endogenous \nopioid, which reduces postoperative pain intensity and \nopioid consumption. Previous studies have also \nillustrated beta -endorphin levels increases after \nmelatonin administration (34) . In this regard, maybe \nmeasurement of plasma level of beta- endorphin could \nbe used to assess acute and chronic postoperative pain. \nIn a study by Popovic et al., measurement of serum \nbeta-endorphin levels before and after abdominal \nsurgery showed; the level of this endogenous opioid \nincreased within the first 24 hrs after the surgery, which \nis consistent with the results of our study (35) . Beta-\nendorphin levels increase following general anesthesia, \nand opioid consumption inhibits this increase severely, \nbut nonopioid supplement agents did not decrease \nserum beta-endorphin levels in this study (36).  \nOur results showed; there was no significant \ndifference between serum melatonin levels before and \nafter the surgery. Although opiate drugs increase serum \nmelatonin levels, in this study, its serum level did not \nchange significantly following the administration of \nmelatonin and pregabalin. Factors such as anesthesia \nand surgery affect serum melatonin levels (37). It has \nbeen proved that following general anesthesia, serum \nmelatonin levels decrease on the first night after the \nsurgery, causing sleep disturbances in patients. In a \nstudy on patients undergoing orthopedic surgery, urine \nsulfatoxymelatonin (the main metabolite of melatonin) \ndecreased in the early hours after the surgery following \ngeneral anesthesia with thiopental and isoflurane (38) . \nHowever, some studies reported conflicting results. For \nexample, during anesthesia with fentanyl and \nthiopental, serum melatonin levels increased, which is \nin agreement with our study.  Anesthetic drugs are \neffective at the serum melatonin levels. For example, \nisoflurane increases melatonin level during the surgery \nand sevoflurane decreases its level (39).  \nIn conclusion, preoperative administration of \nmelatonin and pregabalin reduces the pain intensity \nthroughout the first 24 hrs after the abdominal \nhysterectomy under general anesthesia. B ut further \nclinical studies on the beneficial effects of melatonin in \ndifferent surgical procedures are recommended. \n \nConclusion \nPreoperative administration of both melatonin and \npregabalin reduces the pain intensity throughout the \nfirst day after the TAH under GA, but preventive \nmelatonin is more effective than pregabalin to reduce \npain in the patients.  \n \n\n33 Melatonin and Postoperative Pain in Hysterectomy \n      Volume 9, January – February 2024       Journal of Obstetrics, Gynecology and Cancer Research \nAcknowledgments \nWe appreciate all the kind co -operation of all our \ncolleagues, without whom this research was not \npossible to be conducted properly. \n \nConflict of Interest \nThe authors report no conflict of interest regarding \npublication of this paper. \nFunding \nThis study was financially supported by the Vice -\nChancellorship of Research and Technology, Guilan \nUniversity of Medical Science. \n \n \n \n \n1. 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J Anesth. 2004;18:228-31.  \n[DOI:10.1007/s00540-004-0249-1] [PMID]\n \nHow to Cite This Article:  \nHaryalchi, K., Mansour Ghanaei, M., Rajabi, M., Ghazizadeh, M., Aghajanpour, F., Koochakpo or, P., et al. \nPreventive Dose of Melatonin on Postoperative Pain in Total Abdominal Hysterectomy: A Clinical Trial Study . J \nObstet Gynecol Cancer Res. 2024;9(1):29-35. \nDownload citation:                             RIS | EndNote | Mendeley |BibTeX |","source_license":"CC0","license_restricted":false}