Effect of oral melatonin on postoperative analgesia in mandibular fracture fixation surgery- A randomised controlled study

INTRODUCTION

Pain after any surgical procedure is inevitable and it is controlled by administration of analgesics in most cases. Surgical trauma, the application of heat and chemical stimulation to the wound, and frequently traction and manipulation of soft tissues are the causes of postoperative pain. [1] The anaesthetist and surgeon try their hardest to get rid of postoperative pain without creating new issues such medication tolerance and reliance, gastrointestinal and visceral motility disorders, respiratory or cardiovascular system depression, or coagulation abnormalities.[2] In order to guarantee the best possible recovery and patient satisfaction after surgery, postoperative pain management is essential. A typical operation in maxillofacial surgery, mandibular fracture repair surgery, frequently poses difficulties in attaining efficient pain management. The hormone melatonin, which is mostly linked to the regulation of circadian rhythm, has exhibited possible analgesic effects.

To treat postoperative pain, two drug classes are available: (1) narcotic analgesics, which act directly on opioid receptors in the central nervous system, and (2) nonsteroidal anti-inflammatory drugs (NSAIDs), which act by inhibiting prostaglandin synthesis to achieve analgesic and anti-inflammatory effects.[3] In many different postoperative pain states, NSAIDs are an efficient analgesic, and in certain situations, they have an analgesic effect that is similar to that of opioids. [4] NSAIDs are more tolerable than opioids and have anti-inflammatory, peripheral and central analgesic effects.

Melatonin is one of the medications that is most frequently used to lessen acute pain and enhance analgesic benefits following surgery. The pineal gland in the brain secretes the hormone known as melatonin, also known as n-acetyl methoxy-tryptamine. Melatonin regulates the circadian rhythm and wakefulness due to its significant biological effects on the body.[5,6]  Research has demonstrated the protective effect of melatonin against a range of illnesses, including diabetes, Alzheimer’s disease, cancer, heart disease, fibromyalgia, mood problems, and mental health issues.[6] Research conducted on patients having surgical procedures has demonstrated that melatonin plasma levels have been found to decrease following surgery and anaesthesia. Thus, it is advised that patients having surgery take melatonin in addition to their regular dosage.[7,8] Furthermore, melatonin has been demonstrated in certain studies to have beneficial benefits during anaesthesia and surgery, such as a decrease in pain intensity, preoperative anxiety, postoperative delirium, and the requirement for anaesthetic medications.[9,10] The potential of melatonin as an adjuvant analgesic medication is suggested by its capacity to regulate inflammation and pain perception.  While the precise mechanism of the analgesic effects of melatonin is not fully understood, the stimulation of β-endorphin secretion as well as its effect on various receptors including opioid, benzodiazepines, muscarinic, serotonergic receptors in the posterior horn of the spinal cord, as well as the central nervous system is suggested.[10] Controversial results have been reported in various clinical studies on the postoperative analgesic effects of melatonin in different doses (including 3, 5, 6 and 10 mg).

This investigation aims to elucidate whether oral melatonin supplementation, administered preoperatively, can enhance pain relief and reduce the need for traditional analgesics postoperatively in patients undergoing mandibular fixation surgery under general anaesthesia.

Understanding the role of melatonin in the context of mandibular fracture fixation surgery may contribute to the development of tailored and effective pain management strategies for patients undergoing such procedures. The exploration of melatonin’s analgesic effects in this specific surgical context holds promise for improving patient outcomes and advancing our understanding of alternative approaches to postoperative pain control.

Aims and Objectives

Aim:

·        To assess the efficacy of oral melatonin in enhancing postoperative analgesia following mandibular fracture fixation surgery.

Primary Objective:

·        To measure the total consumption of the rescue analgesic (tramadol) in the first 24 hours among the patients who had taken exogenous melatonin in the preoperative period of their mandibular surgery.

Secondary Objective:

·        To measure the Visual Analogue score - VAS among the patients in postoperative period 

·        To calculate the Ramsay sedation score among the patients in postoperative period              

·        To measure the total consumption of opioids in the intraoperative period

·        To measure the level of anxiety through verbal assessment of anxiety

REVIEW OF LITERATURE

Borazan et al (2010)¹¹ to assess the effectiveness of preoperative oral melatonin medication on sedation, sleep quality, and postoperative analgesia in patients undergoing elective prostatectomy.  Fifty-two ASA I-II patients undergoing elective prostatectomy were included in this study, randomly divided into two groups. Patients received an oral placebo (n = 26) or 6 mg melatonin (n = 26) the night before and 1 h before surgery. All patients received a standard anesthetic protocol. At the end of surgery, all patients received tramadol i.v. via a PCA device. Extubation time, intraoperative fentanyl consumption, and recovery time were assessed at the end of the operation. Pain scores, tramadol consumption, and sedation scores were assessed at 1, 2, 4, 6, 12, 18, and 24 h postoperatively, and sleep quality and subjective analgesic efficacy were assessed at 24 h after surgery. There were no significant differences in demographic data between the groups. Extubation time and recovery time from anesthesia were significantly longer in the melatonin group (P < 0.05). Intraoperative fentanyl usage, pain scores, and tramadol consumption were significantly lower in the melatonin group (P < 0.05). The postoperative sleep quality of patients was significantly better in the melatonin group than in the control group (P < 0.05). Postoperative VAS of pain was significantly lower in the melatonin group compared with the control group at 1, 2, 4, 6, 12, 18, and 24 h postoperatively (P < 0.05). Subjective analgesic efficacy of patients was significantly different between groups (P < 0.05). The sedation scores were significantly higher in the melatonin group than in the control group at 1 h and 2 h after surgery (P < 0.05).  Preoperative oral melatonin administration decreased pain scores and tramadol consumption and enhanced sleep quality, sedation scores, and subjective analgesic efficacy during the postoperative period.

Jain et al (2017) 12 to critically compare the postoperative analgesic efficacy of small doses of intravenous TRAMADOL (opioid analgesic) versus LORNOXICAM (NSAID) in patients with mandibular trauma undergoing open reduction and internal fixation (ORIF) and to assess the presence of any adverse effects due to NSAID or opioid use. Forty adult ASA grade I–II patients with mandibular trauma, scheduled for ORIF under general anesthesia in the Department of Oral and Maxillofacial Surgery, College of Dental Sciences, Davangere, were selected for the study. The patients were randomly assigned into a tramadol group (Group T) and a lornoxicam group (Group L) and were administered intravenous tramadol 50 mg and intravenous lornoxicam 8 mg, respectively, at specific postoperative intervals. Pain intensity was quantitatively assessed at the 2nd, 4th, 6th, 12th, and 24th postoperative hours using a visual analog scale of 10 cm. Adverse effects of the analgesics were also recorded and compared. Both the drugs resulted in a significant decrease in pain intensity from 2nd to 24th postoperative hours, but better pain control was observed in Group L at 24th postoperative hour. Only two patients experienced nausea and vomiting in Group T and one patient experienced gastric acidity in Group L. The comparative results clearly demonstrate that pain control by intravenous lornoxicam is significantly better than by intravenous tramadol at 24th postoperative hour after ORIF of mandibular trauma. Side effects produced by both the drugs were minor and had no apparent effect on the study results.

Lee et al (2020) 13 studied that the neurosensory assessments and biochemical assays to evaluate the efficacy of melatonin on nerve healing following orthognathic surgery. Thirty randomly allocated orthognathic patients were prophylactically administered either oral melatonin or identical placebo for 21 consecutive days. Pre- and post-surgical clinical parameters included subjective pain, numbness, and objective neurosensory function. Pre- and post-surgical biochemical parameters were serum hydrogen peroxide and antioxidant enzyme levels. Melatonin was found to significantly reduce subjective pain perception by 50% in the early postoperative days. A 30% reduction in subjective numbness perception was observed at 1-week postoperative, increasing to an over 80% reduction by 3 months postoperative (P < 0.00001). Objective neurosensory testing showed a significant improvement in healing profile in the melatonin group. Postoperatively, the hydrogen peroxide concentration was lower in the melatonin group (P < 0.00001), and the levels of antioxidant enzymes were higher (P < 0.00001). The strong correlations between clinical outcomes and biochemical changes suggest a link between antioxidant effects and reduced postsurgical pain and sensory recovery. The study findings suggest that the prophylactic administration of melatonin confers significant clinical benefits in terms of reduced postoperative pain and opioid use and improved sensory recovery following surgery.

Kiabi et al (2021)14 conducted a double-blind randomized controlled clinical study, 204 patients undergoing elective cesarean section with class 1 and 2 anesthesia (ASA) were enrolled. Patients were randomly divided into 3 groups of 68 patients. Patients in group A were given 5 mg melatonin tablets, patients in group B were given 10 mg melatonin tablets, and group C was given placebo. All patients underwent spinal anesthesia with the same anesthesia protocol. Pain intensity, nausea, vomiting, pruritus and headache were assessed and recorded 2, 6, 12 and 24 h after surgery. The time of first dose of analgesia, the amount of opioid consumed within 24 h, and the time to resume physical activity was also recorded. Statistical analysis of data was performed using SPSS 20 software. Repeated measurements of pain intensity during the study showed that in all 3 groups pain intensity was significantly reduced during the study, p < 0.001, respectively. The intensity of pain was significantly different in groups B and C, groups B and A and groups A and C, P < 0.001, respectively. The pain reduction was greatest in group B, followed by group A and group C, respectively. The time interval between the end of surgery and the patient’s need for analgesia was significant in group B compared to group A (P = 0.035) and C (P < 0.001) and also in group A compared to group C (P = 0.011). The mean dose of opioid was significantly least in group B, p < 0.001. The mean time to resume physical activity was also shortest in group B, p < 0.001 Headache and nausea/vomiting were observed in 7 patients (10.7%) group A and 7 patients (10.7%) in group C. None of the patients in group B developed complications. The results of the present study showed that the use of 10 mg of melatonin before cesarean section with spinal anesthesia is not only safe, but also reduces the severity of patients’ pain, increases the duration of postoperative analgesia, reduces the need for analgesics after surgery and resumption of physical activity.

Baradari et al (2022)15 conducted a double blinded randomized controlled clinical trial 80 patients undergoing an elective mini-open microdiscectomy surgery at Imam Khomeini educational hospital in Sari, Iran, were selected and randomly assigned into one of four groups. Patients in group A, B, C, and D received 3, 5 and 10 mg melatonin or placebo tablets one hour before surgery, respectively. Using the visual analogue scale (VAS) the severity of pain, nausea and vomiting, pruritus, and use of narcotics were assessed immediately after surgery and before leaving the post-anesthesia care unit, 6, 12 and 24 hours postoperatively.  In all three groups receiving melatonin at all three different doses, postoperative pain was significantly less than the placebo group (P<0.01). There were no statistically significant differences in postoperative pain level between the three groups receiving melatonin (P>0.05). The amount of opioid received by the patients within 24 hours after surgery had statistically significant differences within the groups (P=0.043, F=2.58). The results of post hoc analysis in terms of postoperative pain intensity showed statistically significant differences between the two groups receiving melatonin at a dose of 5 mg and the placebo group (P=0.04). No serious side effects reported in four groups.  The use of oral melatonin with a dose of 5 mg, 1 hour before the surgery as an inexpensive method can effectively reduce pain intensity as well as the amount opioid use after lumbar laminectomy and discectomy

Gandhi et al (2022)16 conducted a randomised controlled study between June 2020 to June 2021, at Mahatma Gandhi Memorial Medical College and M.Y. Hospital, Indore, Madhya Pradesh, India. Total 100 patients belonging to American Society of Anaesthesiologists (ASA) grade I and II of either gender, of age 18-60 years who were planned for elective surgery under general anaesthesia were randomly divided into two groups. Group M (n=50) was given 6 mg oral melatonin (two capsules of 3 mg each), and group C (n=50) was given multivitamin capsules, 90 minutes before induction of anaesthesia. General anaesthesia was induced using standard method for both the groups. Sedation score was assessed in preoperative period as well as after giving drugs and till four hours postoperatively by using Ramsay Sedation score. Pain was evaluated by Visual Analogue Scale (VAS) score till 8 hours postoperatively. Time of request of first rescue analgesia was noted and compared to that of control group.  At preoperative time sedation score was comparable between both the groups. At postoperative time, sedation score 4 was seen in significantly higher number of patients of group M in comparison to group C, while at all the other time intervals, sedation scores were comparable between the two groups. Mean VAS score was found to be significantly higher in group C (3.2±0.4) in comparison to group M (3.02±0.14), four hours postoperatively. The mean time to request for first rescue analgesia in group M was 7.27±1.01 hours and in group C was 5.40±0.78 hour (p-value=0.001).  Preoperative oral melatonin can be used to effectively reduce the postoperative pain without producing undue sedation.

Refahee et al (2023)17 conducted a prospective, randomized, blinded trial comprised of patients who required removal of the impacted mandibular third molar. The patients were divided into two groups (n = 19) as follows: melatonin group (3 mg of melatonin into 2 ml of 2% hydroxyethyl cellulose gel was packed into the socket) and placebo group (2 ml of 2% hydroxyethyl cellulose gel was placed in the socket). Thirty-eight patients (25 female and 13 males) with a median age of 27 years were enrolled in the study. There was no statistical significance in bone density observed in both groups [melatonin group: 978.5(951.3-1015.8), control group: 965.8 (924.6-998.7), P = .1]. Alternatively, there were statistically significant improvements in osteoprotegerin levels (on week 4), MMO (on day1), and swelling (on day 3) in the melatonin group compared to those in the placebo group [1.9(1.4-2.4), 39.68 Â± 1.35, and 14.36 Â± 0.80 versus 1.5(1.2-1.4); 38.33 Â± 1.20, and 14.88 Â± 0.59; P = .02, .003, 0.031, respectively]. The pain values showed statistically significant improvement throughout the follow-up period in the melatonin group compared to the placebo group [5(3-8), 2(1-5), and 0(0-2) versus 7(6-8), 5(4-6), and 2(1-3); P < .001, respectively]. The results support the anti-inflammatory effect of melatonin in reducing the pain scale and swelling. Furthermore, it plays a role in the improvement of MMO. On the other hand, the osteogenic activity of melatonin could not be detected.

MATERIAL AND METHODS

Study Settings: The study will be conducted in Department of Anesthesiology, King George’s Medical University, Lucknow.

Study design:  Prospective Randomized controlled study

Study duration: 1.5 years

Sample size: 20 in each group

The sample size formulae used are as follows: (Bernard, 5th edition) [10]

                                      n=

n= (0.76.6²+58.9²)/1(1.645+0.84)²

54.2²

n= (5867.56+3469.21)/1(6.18)

2937.64

       n= (9336.77) (6.18) = 57701.2386 = 19.687≈20 in each group

                                               2937.64              2937.64

n= Sample size

σ₁ = Estimated Standard Deviation cases [=76.6]

σ_{2 =} Estimated Standard Deviation control [=58.9]

∆ = Difference of means [=54.2]

κ= Ratio [=1]

Z_1-α/2= Two-sided Z value [=1.645]

Z_1-β= Power [=0.84]

  Inclusion criteria:

â–ª         Patients of age above 18-65 years of either gender.

â–ª         Patients with ASA grade I and II.

â–ª         Patients undergoing Mandibular fracture surgery

â–ª         Patients who give consent form.

Exclusion criteria:

●       Coagulopathy, chronic use of opioid analgesia or opioid analgesic, analgesic intolerance.

STUDY PROTOCOL

Ethical clearance and Written and Informed consent will be taken. The study will be done at King George Medical University, Lucknow.  A total number of 60 patients who are planned for mandibular fracture surgery will be enrolled in the study and will be randomly allocated to one of the three groups. Study will be double blinded, neither the researcher nor the participants know treatment groups.

Group A: 5mg melatonin tablet

Group B: 10 mg melatonin tablet

Group C: Placebo

In operating room, all patients will be placed under general anesthesia using a similar anesthetic protocol including midazolam (0.1mg/kg), fentanyl (2µ/kg), Propofol(1.5-2 mg/kg), atracurium (0.5 mg/kg). Anaesthesia would be maintained with O2 50% and 50% N2O, Sevoflurane and atracurium based on the patient need. All surgeries will be performed by one surgeon via a same approach.

Demographic data of the patients, as well as signs and symptoms, number of surgical accesses, number of fixations will be recorded. The patients level of anxiety will be  measured preoperatively through verbal assessment of anxiety that ranged from no anxiety, moderate anxiety, and severe anxiety. The pain variable will be  quantified using the Visual Analog Scale (VAS). This scale is used in the form of a ruler, presented to the individual with the numbers from zero (without pain) to ten (unbearable pain). The patient will be asked to indicate the intensity of his pain immediate after surgery(0hr) at 1hr,4hr, 8hr, 12hr, 18hr, and 24hr. Ramsay sedation score (RSS) would be measured at immediate after surgery(0hr) at 1hr,4hr, 8hr, 12hr, 18hr, and 24hr To control postoperative pain, all patients will receive injection paracetamol 1 gm intravenously every 6 hours. If any patient would be having VAS> 3, Inj tramadol 2mg/kg will be given iv. and total consumption of tramadol will be documented.

All post-operative patients will be transported to the PACU.  We will also record incidences of postoperative nausea, and vomiting. Ondansetron is administered to patients who experience nausea or vomiting. We will also record intraoperative fentanyl, propofol and vecuronium consumption. Intraoperative and postoperative vitals will be recorded and any incidence of hypotension or bradycardia will be reported.

Statistical analysis

Statistical analysis will be performed by the SPSS version 23^rd version. Continuous variables were presented as mean±SD and categorical variables were presented as absolute numbers and percentage. Normally distributed continuous variables and categorical variables were compared using appropriate statistical test. P value less than 0.05 was taken as significant.

REFERENCES

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10. Mowafi HA, Ismail SA. The uses of melatonin in anesthesia and surgery. Saudi J Med Med Sci. 2014;2:134–141. 

11. 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 Apr;24(2):155-60. doi: 10.1007/s00540-010-0891-8. Epub 2010 Feb 26. PMID: 20186437.

12. Jain AD, Vsm R, Ksn SB, Km S, Tewathia N. A Comparative Assessment of Postoperative Analgesic Efficacy of Lornoxicam versus Tramadol after Open Reduction and Internal Fixation of Mandibular Fractures. Craniomaxillofac Trauma Reconstr. 2017 Sep;10(3):171-174. doi: 10.1055/s-0037-1600901. Epub 2017 Mar 22. PMID: 28751939; PMCID: PMC5526686.

13. Lee TYC, Curtin JP. The effects of melatonin prophylaxis on sensory recovery and postoperative pain following orthognathic surgery: a triple-blind randomized controlled trial and biochemical analysis. Int J Oral Maxillofac Surg. 2020 Apr;49(4):446-453. doi: 10.1016/j.ijom.2019.07.006. Epub 2019 Aug 14. PMID: 31420120.

14. Kiabi FH, Emadi SA, Jamkhaneh AE, Aezzi G, Ahmadi NS. Effects of preoperative melatonin on postoperative pain following cesarean section: A randomized clinical trial. Ann Med Surg (Lond). 2021 May 12;66:102345. doi: 10.1016/j.amsu.2021.102345. PMID: 34040762; PMCID: PMC8141662.

15. Baradari AG, Habibi MR, Aarabi M, Sobhani S, Babaei A, Emami Zeydi A, Ghayoumi F. The Effect of Preoperative Oral Melatonin on Postoperative Pain after Lumbar Disc Surgery: A Double-Blinded Randomized Clinical Trial. Ethiop J Health Sci. 2022 Nov;32(6):1193-1202. doi: 10.4314/ejhs.v32i6.17. PMID: 36475244; PMCID: PMC9692143.

16. Gandhi M, Singh S, Arora KK, Barde R.Effect of Preoperative Oral Melatonin on Postoperative Sedation and Analgesia among Patients undergoing Elective Surgery under General Anaesthesia: A Randomised Controlled StudyJ Clin of Diagn Res.2022; 16(8):UC01-UC04. https://www.doi.org/10.7860/JCDR/2022/56679/16682

17. Refahee SM, Aboulmagd I, Ragab R, Abdel Aziz O, Ahmed WAEA, Shabaan AA. The Effect of Local Melatonin Application Following the Removal of an Impacted Mandibular Third Molar. J Oral Maxillofac Surg. 2023 May;81(5):622-631. doi: 10.1016/j.joms.2023.01.010. Epub 2023 Feb 13. PMID: 36796435.