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Adv Biomed Res 2023,  12:185

Perioperative anxiolysis and analgesic effect after premedication with melatonin and pregabalin in total hip arthroplasty under spinal anaesthesia: A prospective comparative trial

Department of Anaesthesiology, King George Medical University, Lucknow, Uttar Pradesh, India

Date of Submission20-Sep-2022
Date of Acceptance04-Apr-2023
Date of Web Publication20-Jul-2023

Correspondence Address:
Dr. Vinod Kumar Srivastava
Department of Anaesthesiology, King George's Medical University, Lucknow, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/abr.abr_323_22

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Background: Preoperative anxiety plays a critical role in post-operative pain response and other outcomes. Melatonin is a naturally secreted hormone which has anxiolytic, sedative, and analgesic properties. Pregabalin, analogue of gabapentin which has property of anxiolytic and analgesic effects.
Materials and Methods: Total 96 patients undergoing total hip arthroplasty, divided into 3 groups of 32 each and were given placebo (group I), melatonin 6 mg (group II), and pregabalin 150 mg (group III). Anxiety level, postoperative pain score, sedation level and duration as well as characteristics of spinal anaesthesia were assessed with other vital parameters.
Results: Group I showed an increment in the anxiety score from baseline whereas in group II and group III, there was a decline in pre-operative anxiety score from baseline at all the periods of observation and more significantly in group III. Visual analogue scale (VAS) score and total dose of rescue analgesia were highest in group I, but group II and group III were comparable to each other. However, the durations of spinal anaesthesia and motor blockade showed a statistically significant difference with maximum duration in group III followed by II and then I. The level of sedation among the three groups were comparable at all the periods of observation.
Conclusions: Pregabalin was found better for perioperative anxiolysis, post-operative analgesia and for prolongation of duration of spinal anaesthesia when compared to melatonin.

Keywords: Anxiety, arthroplasty, melatonin, pregabalin, visual analogue scale

How to cite this article:
Mishra A, Srivastava VK, Prakash R, Mishra NK, Agarwal J, Kabi S. Perioperative anxiolysis and analgesic effect after premedication with melatonin and pregabalin in total hip arthroplasty under spinal anaesthesia: A prospective comparative trial. Adv Biomed Res 2023;12:185

How to cite this URL:
Mishra A, Srivastava VK, Prakash R, Mishra NK, Agarwal J, Kabi S. Perioperative anxiolysis and analgesic effect after premedication with melatonin and pregabalin in total hip arthroplasty under spinal anaesthesia: A prospective comparative trial. Adv Biomed Res [serial online] 2023 [cited 2023 Sep 26];12:185. Available from:

  Introduction Top

For peri-operative physician, two of the major concerns in any patient scheduled for surgery are pre-operative anxiety and postoperative pain. Preoperative anxiety has led to some physiological changes that affect postoperative pain response.[1]

Many pharmacological interventions using drugs like melatonin, gabapentin, pregabalin, midazolam, clonidine, etc., have been done to see effect on perioperative anxiety and subsequently on other outcomes like postoperative pain response, need of analgesia, sensory and motor blockade, and sedation.[2],[3],[4],[5],[6] Melatonin a naturally secreted hormone from the pineal gland of body is an important regulator of sleep wave cycle. Besides anxiolytic and analgesic potential, it also has sedative property without any impairment on cognitive and psychomotor skills.[7] Pregabalin is an r-aminobutyric acid analogue of gabapentin that has anxiolytic and anti-nociceptive properties.[8]

Preoperative use of oral pregabalin has also been reported to lessen the postoperative pain[9],[10] and also enhance total anaesthesia duration produced by single injection peripheral nerve blockade and spinal anesthesia.[11],[12]

The current study was done to ascertain the effect of melatonin and pregabalin on perioperative anxiety, pain, sedation and duration and blockade characteristics of spinal anaesthesia on patients undergoing total hip arthroplasty under spinal anaesthesia.

  Materials and Methods Top

The current prospective, randomized, placebo-controlled, clinical trial were conducted in orthopedic surgery department after approval by institutional ethics committee [IRB No. ECR/262/Inst/UP/2013/RR-19] and registration of the study in the clinical trials registry of India (CTRI/2021/02/031574). We designed current comparative study to see the efficiency of melatonin and pregabalin using pre-emptive medication for total hip arthroplasty under spinal anaesthesia. The primary outcome was estimating perioperative anxiety and secondary outcome was postoperative pain along with onset, duration of spinal anaesthesia and level of sedation.

The duration of the study was one year from March 2021 to February 2022.

Sample size was calculated on the basis of variation in anxiety scores of the two groups under study using the following formula:

Where σ1 = 4.5, σ2 = 4.2 are the standard deviations (SDs) of anxiety scores of the two groups,

d = min (σ1, σ2) is the minimum mean difference consider to be clinically significant. Nasr DA et al.[6]

So, the required sample size is

n = 32 each groups.

A total of 96 patients with 30–60 years of age group of either sex with ASA physical status I and II undergoing total hip arthroplasty were enrolled in the study. [Figure 1] Any patient with an absolute contraindication to spinal anaesthesia, acute or chronic neurological or psychiatric disorders, any peripheral neuropathy, on long term analgesics and opioid containing drugs, history of allergy to study drugs, previous history of taking pregabalin or melatonin, history of taking antidepressants, antipsychotics or any medicine with sedative or analgesic properties, those giving negative consent for spinal anaesthesia and inability to communicate were kept out from the trial. Following taking consent from all enrolled 96 patients, were allocated randomly into three groups of 32 patients each. All patients were randomized by using computer generated random numbers sealed in envelopes.
Figure 1: Patient flow diagram

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During pre-anaesthetic visit, detailed history, general physical, and systemic examination along with routine investigations were done for all patients. The drugs melatonin (Melatonin 6 mg, Natrol, USA), pregabalin (pregabid 150, INTAS pharmaceuticals limited, India), and placebo multivitamin (Capsule Becosule Pfizer, limited, India) were prepared by an anaesthetist not involved in any point of the study. Becosules contains vitamins like thiamine, riboflavin, pyridoxine, niacinamide, biotin, methylcobalamin, and ascorbic acid. Drugs administration and recording response done by anesthetist were blinded to group allocation.

  • Group I: Received placebo (multivitamin) orally
  • Group II: Received melatonin 6 mg orally
  • Group III: Received pregabalin 150 mg orally.

We have used pregabalin in the dose of 150 mg orally which is consistent with other studies that have shown that a dose of 150 mg has a better analgesic profile in comparison to 75 mg.[13],[14]

A previous comparative study done with two different doses of oral melatonin for perioperative anxiety showed a more marked anxiolytic property of melatonin with double dose rather than earlier smaller dose.[15] Thus, we have used 6 mg oral melatonin in the current study.

All study drugs and placebo were given approximately for two hours before commencement of surgery in powdered form filled in a similar gelatin capsule with sip of water. So, the above study was double blinded as investigator as well as participant were ignorant about study drugs. The patients who were on any oral analgesic medication for pain related to hip pathology were not given the morning dose of the drug and ensured that atleast 12 hours had elapsed since the last analgesic dose.

Before giving the study drug or placebo, anxiety level was assessed by using beck anxiety inventory (BAI).[16] It contains 21 questions; each has four score from 0 to 3, So total score of BAI may vary from zero to sixty three (0 to 63). There were four level of anxiety level according to score and categorized as minimal (0–7), mild (8–15), moderate (16–25) and severe (26–63).

Anxiety level was reassessed after shifting the patient to the operation theatre, right before giving spinal anaesthesia and just after surgery.

After taking the patient to the operation table (OT), electrocardiography (ECG), non-invasive blood pressure (NIBP), temperature and pulse oximeter were attached and continuously monitored. After securing venous line with 18 g catheter, preloading was done with Ringer's lactate or Sterofundin at the rate of 15 ml/kg before spinal anaesthesia.

Patients were then given spinal anaesthesia with 15 mg of 0.5% hyperbaric bupivacaine and 25 μg fentanyl in the L3-L4 or L4-L5 interspace using midline approach with a 25-G Quincke needle in sitting position. Then, the patient was made supine for atleast ten minutes followed by lateral decubitus position, keeping operative side up for surgery. Any hypotension was managed with phenylephrine 1 μg/kg, when systolic blood pressure (SBP) reduced by 30% from baseline and mean arterial pressure (MAP) to less than 60 mm Hg. The decrease in heart rate below 50 beats/min was managed with intravenous atropine 0.5 mg. Patients requiring intraoperative sedation were eliminated from the study.

Sensory blockade was estimated by using pinprick test, performed every two minutes to know the time taken for T10 sensory block. Time taken from intrathecal injection to T10 sensory level was recorded which was considered as an onset time of sensory effect. Time of two segment regression from peak sensory level was noted as an estimate of duration of spinal anaesthesia. Patients having sensory blockade below T10 level were excluded from the study.

Modified bromage scale was used for evaluation of motor blockade.[17] The time to achieve IV grade bromage scale was recorded which was considered as a commencement of motor block. Duration of motor blockade was calculated from administration of spinal anaesthesia to the time taken for return to bromage grade II.

Pain grading was estimated by using the visual analogue scale (VAS) score from zero (no pain) to ten (worst pain) after completion of surgery.

Assessment was done every hourly till the first six hours and then two hourly till 24 hours after the surgery. Post-operative pain was managed by rescue analgesics when VAS score ≥4 at any point of assessment or when patient demanded for analgesia in the form of intravenous diclofenac 75 mg administered by hospital personnel. The time of the first postoperative rescue analgesia and total dose of rescue analgesics administered were recorded up-to 24 hours postoperatively. Sedation was assessed by Ramsay sedation scale[18] just after completion of surgery and at 1, 2, 6, 12, and 24-hours in post-operative period. Data were analyzed using SPSS (statistical package for the social sciences) version 21.0 statistical analysis software. Demographic data were analyzed using analysis of variance. ANOVA (analysis of variance) student's t-test, nonparametric, and other appropriate tests were used to analyze data.

Discrete (categorical) data were summarized as in proportions and percentages (%) while quantitative data were summarized as mean ± SD. All P-value of less than 0.05 was considered as statistically significant.

  Results Top

A total 96 patients enrolled for study were allocated into three groups, proceeded further as shown in patients flow diagram. [Figure 1] The baseline and demographic characters like age, gender, and weight were comparable in all the three groups. [Table 1] The baseline anxiety scores (two hours before surgery) of all three groups were comparable. In group I patients, an increase from baseline anxiety score was observed after shifting to OT and before administration of spinal anaesthesia. In group II and group III however, there was a statistically significant decline from the pre-operative anxiety score at all the periods of observation. [Table 2] On inter-group comparison, significant differences were seen at all periods of observation following baseline (P < 0.05) among all the three groups. The mean anxiety score of group I was highest and statistically significant among all groups and in other intergroup comparison, group II has significantly higher than group III. Minimum inter-group difference was observed between group II and III, while maximum between group I and III. Order of anxiety score in above three groups was group III < group II < group I. [Table 3] At almost all-time intervals group I had significantly higher VAS scores among all groups. Postoperatively VAS score in groups II and III were comparable at most intervals except at 3 hr, 4 hr, 10 hr, and 12 hr, where it was significantly higher in group II and at 6 hr, 18 hr, and 20 hr when it was significantly higher in group III. [Table 4] Group I (2.44 ± 0.67) had earliest requirement of rescue analgesia and statistically significant (P < 0.001) when compared to group II (4.91 ± 0.78) and III (6.31 ± 1.24). While comparing intergroup (group II and III) we found that group II (4.91 ± 0.78) required earlier rescue analgesia than group III (6.31 ± 1.24) and it was statistically significant (P < 0.001). [Table 5] The drug dose (IV diclofenac) administered for rescue analgesia postoperatively were compared among the three groups, where group I (210 ± 29.74) had significantly (P < 0.001) greater dose requirement than group II (157.03 ± 39.77) and III (138.28 ± 43.06). The drug dose requirements in group II (157.03 ± 39.77 and III (138.28 ± 43.06) were however, comparable (P = 0.124) [Table 5].
Table 1: Comparison of demographic profile and body weight of study population

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Table 2: Comparison of anxiety score of study population at different time intervals

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Table 3: Intergroup comparison of anxiety score at different time intervals

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Table 4: Intergroup differences in pain at different time intervals

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Table 5: Between group comparison of rescue analgesia

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Onset of sensory effect in Group I was 4.10 ± 0.28 min as compared to Group II (3.96 ± 0.30 min) and Group III (3.95 ± 0.30 min), but this difference was statistically insignificant (P = 0.085). Onset of motor effect was also slower in Group I (8.01 ± 0.41 min) as compared to Group II (7.98 ± 0.39 min) and Group III (7.85 ± 0.34 min), difference was also statistically insignificant (P = 0.212) [Table 6].
Table 6: Between group comparison of different anaesthetic parameters

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Duration of spinal anaesthesia was longest in group III (251.72 ± 25.79 min) followed by that in group II (238.78 ± 17.44 min) and shortest in group I (212.03 ± 16.83 min). In intergroup comparison of the duration among all groups was statistically significant (P < 0.001) [Table 6].

Duration of motor blockade was statistically significant in intergroup comparison among all three groups. It was longest in group III (185.34 ± 19.07 min) followed by that in group II (174.13 ± 17.11 min) and shortest in group I (163.25 ± 15.83 min). [Table 6] Level of sedation among three groups was comparable at all the periods of observation. None of the intergroup or between group differences were found to be statistically significant (P-value > 0.05) [Table 7].
Table 7: Between group differences in level of sedation at different time intervals

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  Discussion Top

Our study showed that perioperative anxiolysis is more effective in pregabalin group followed by melatonin and less in placebo group. This is similar to the results obtained by Abbasivash et al.[2] who concluded that melatonin is associated with less perioperative anxiety and better analgesia as compared to placebo. Similar results were also reported by Caumo et al.[7] when melatonin was given preoperatively for anxiolysis in patients undergoing abdominal hysterectomy. A systemic review by Madsen et al.[19] also showed that preoperative melatonin reduces perioperative anxiety more compared to placebo or benzodiazepine.

In concordance with our results, Bala et al.[20] and Altiparmak et al.[21] reported in their respective studies that pregabalin reduces perioperative anxiety. On the contrary, another study by White et al.[22] showed that after administration of oral pregabalin in doses from 75 to 300 mg, had no any remarkable change in anxiety and postoperative pain in minor surgical procedures. Although previous literature disfavor our study but used the simple VAS score for estimating anxiety which could be less accurate than the beck's anxiety inventory score[16] used in our study.

However, contrary to our results, Nasr et al.[6] and Khanna et al.[23] concluded their studies that premedication with melatonin and pregabalin are comparable in their effects on perioperative anxiety. This could be due to the different anxiety scores used in these studies.

Post-operative analgesia and consumption of rescue analgesics:

Need of first dose of rescue analgesia was earliest in group I followed by group II and last in group III. Also, total dose of rescue analgesia required by group I was significantly higher than that by group II and group III while that required by groups II and III were comparable. Our results are consistent with the results of Rajappa et al.[13] and Jokela et al.[14] who have observed significant reduction in VAS as well as need for rescue analgesia in patients receiving pregabalin. Studies conducted with melatonin have also shown similar results.[2],[15],[24]

Javaherforooshzadeh et al.[25] compared the efficacy of melatonin and gabapentin which is a pregabalin analogue, in reducing postoperative pain in lumbar spine surgery. Their results showed that both melatonin and gabapentin can be used in reducing pain when compared to placebo. The pain score was significantly lower in the gabapentin group than melatonin group and this result reflects our finding.

In a study comparing melatonin, gabapentin, and clonidine for postoperative pain and anxiety, Hoseini et al.[5] concluded that all three had a similar efficacy in reducing postoperative pain and also reducing narcotic consumption when compared to placebo which is consistent with the results of our study. Contrary to our result, the comparable efficacy of melatonin and pregabalin may be due to a difference in sample size (22 per group).

Sensory and motor blockade:

Our study showed durations of sensory and motor blockade were least in placebo group and highest in pregabalin group supported by Park et al.[12] and Omara et al.[26] Similarly, Abdelrahman et al.[27] have also concluded that preoperative melatonin causes prolongation of sensory and motor blockade of spinal anaesthesia compared to placebo.


Firstly, we had a relatively small sample size and secondarily our study was single center study. It could be possible that what we got outcomes, might be influenced due to the small sample size and single center study. Lastly, the follow-up period for post-operative observation in our study was relatively short.

  Conclusion Top

Thus, we concluded that preoperative administration of 6 mg melatonin and 150 mg pregabalin orally significantly reduces perioperative anxiety, post-operative pain and rescue analgesic requirement as compared to placebo. Both the drugs also prolonged the duration of spinal anaesthesia without having any remarkable changes on onset of sensory and motor blockade when compared to placebo. However, while comparing both the drugs pregabalin was found better for perioperative anxiolysis, post-operative analgesia and for prolongation of duration of spinal anaesthesia when compared to melatonin.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Stamenkovic DM, Rancic NK, Latas MB, Neskovic V, Rondovic GM, Wu JD, et al. Preoperative anxiety and implications on postoperative recovery: what can we do to change our history. Minerva Anestesiol 2018;84:1307-17.  Back to cited text no. 1
Abbasivash R, Salimi S, Ahsan B, Moallemi N, Sane S. The effect of melatonin on anxiety and pain of tourniquet in intravenous regional anesthesia. Adv Biomed Res 2019;8:67.  Back to cited text no. 2
Eapen I, Veerasamy RS, Hamsenandinie C, Anand S. Comparative study between oral melatonin and oral pregabalin on preoperative anxiety, perioperative sedation and postoperative analgesia in surgeries done under regional anaesthesia: A randomized control study. Ann Trop Med Public Health 2020;23.  Back to cited text no. 3
Ahmed Makki MF, Rani S, Kumar S, Bansal P, Saini R, Goyal A. A prospective randomized single-blind study comparing alprazolam versus clonidine and pregabalin as preanaesthetic medication in patients undergoing elective lower limb surgeries. Asian J Pharm Clin Res 2022;16:12-4.  Back to cited text no. 4
Hoseini VS, Yekta RA, Marashi S, Marashi SM. The efficacy of melatonin, clonidine, and gabapentin in reducing Preoperative Anxiety and postoperative pain in patients undergoing laparoscopic cholecystectomy: A randomized clinical trial. Archives of anesthesiology and critical care. Autumn 2015;1:120-125.  Back to cited text no. 5
Nasr DA, Abdellatif AA. “Efficacy of preoperative melatonin versus pregabalin on perioperative anxiety and postoperative pain in gynecological surgeries.” Egypt J Anaesth 2014;30:89-93.  Back to cited text no. 6
Caumo W, Torres F, Moreira NL, Auzani JA, Monteiro CA, Londero G, et al. The clinical impact of preoperative melatonin on postoperative outcomes in patients undergoing abdominal hysterectomy Anesth Analg 2007;105:1263-71.  Back to cited text no. 7
Kavoussi R. Pregabalin: From molecule to medicine. Eur Neuropsychopharmacol 2006;16:128–33.  Back to cited text no. 8
Clarke H, Pagé GM, McCartney CJL, Huang A, Stratford P, Andrion J, et al. Pregabalin reduces postoperative opioid consumption and pain for 1 week after hospital discharge, but does not affect function at 6 weeks or 3 months after total hip arthroplasty. Br J Anaesth 2015;115:903-11.  Back to cited text no. 9
Lam DMH, Choi SW, Wong SSC, Irwin MG, Cheung CW. Efficacy of pregabalin in acute postoperative pain under different surgical categories: A meta-analysis: A meta-analysis. Medicine (Baltimore) 2015;94:e1944.  Back to cited text no. 10
Cegin MB, Soyoral L, Yuzkat N, Baydi V, Goktas U. Pregabalin administered as an anxiolytic agent in ultrasound-guided infraclavicular block: A controlled, double-blind, dose-ranging trial. Eur Rev Med Pharmacol Sci 2016;20:568-74.  Back to cited text no. 11
Park M, Lee H, Jeon Y. Preoperative pregabalin prolongs duration of spinal anesthesia and reduces early postoperative pain A double-blind, randomized clinical CONSORT study. Medicine (Baltimore) 2016;95:e4828.  Back to cited text no. 12
Rajappa GC, Vig S, Bevanaguddaiah Y, Anadaswamy TC. Efficacy of pregabalin as premedication for post-operative analgesia in vaginal hysterectomy. Anesth Pain Med 2016;6:e34591.  Back to cited text no. 13
Jokela R, Ahonen J, Tallgren M, Haanpää M, Korttila K. Premedication with pregabalin 75 or 150 mg with ibuprofen to control pain after day-case gynaecological laparoscopic surgery. Br J Anaesth 2008;100:834-40.  Back to cited text no. 14
Lotfy M, Ayaad M. Preoperative oral melatonin can reduce preoperative anxiety and postoperative analgesia in a dose-dependent manner. Ain-Shams J Anaesthesiol 2021;13:32.  Back to cited text no. 15
Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: Psychometric properties. J Consult Clin Psychol 1988;56:893-7.  Back to cited text no. 16
Graham AC, McClure JH. Quantitative assessment of motor block in labouring women receiving epidural analgesia. Anaesthesia 2001;56:470-6.  Back to cited text no. 17
Dawson R, von Fintel N, Nairn S. Sedation assessment using the Ramsay scale. Emerg Nurse 2010;18:18-20.  Back to cited text no. 18
Madsen BK, Zetner D, Møller AM, Rosenberg J. Melatonin for preoperative and postoperative anxiety in adults. Cochrane Database Syst Rev 2020;12:CD009861.  Back to cited text no. 19
Bala R, Kaur J, Sharma J, Singh R. Comparative evaluation of pregabalin and clonidine as preemptive analgesics for the attenuation of postoperative pain following thoracolumbar spine surgery. Asian Spine J 2019;13:967-75.  Back to cited text no. 20
Altiparmak B, Güzel Ç, Gümüş Demirbilek S. Comparison of preoperative administration of pregabalin and duloxetine on cognitive functions and pain management after spinal surgery: A randomized, double-blind, placebo-controlled study. Clin J Pain 2018;34:1114-20.  Back to cited text no. 21
White P, Tufanogullari B, Taylor J. Klein K. The effect of pregabalin on preoperative anxiety and sedation levels: A dose-ranging study. Anesth Analg 2009;108:1140-5.  Back to cited text no. 22
Khanna J, Katoch M, Rajpur S. Comparative evaluation of melatonin, pregabalin and alprazolam as premedicants for perioperative anxiety and post operative pain for laparoscopic surgeries. JK Science 2019;21:64-71.  Back to cited text no. 23
Caumo W, Levandovski R, Hidalgo MPL. 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;10:100-8.  Back to cited text no. 24
Javaherforooshzadeh F, Amirpour I, Janatmakan F, Soltanzadeh M. Comparison of effects of melatonin and gabapentin on post operative anxiety and pain in lumbar spine surgery: A randomized clinical trial. Anesth Pain Med 2018;8:e68763.  Back to cited text no. 25
Omara AF, Ahmed SA, Abusabaa MM. The effect of the use of pre-emptive oral pregabalin on the postoperative spinal analgesia in patients presented for orthopedic surgeries: Randomized controlled trial. J Pain Res 2019;12:2807-14.  Back to cited text no. 26
Abdelrahman AMF, Omara AFAS, Elzohry AAM. Safety and efficacy of oral melatonin when combined with thoracic epidural analgesia in patients with bilateral multiple fracture ribs. Local Reg Anesth 2020;13:21-8.  Back to cited text no. 27


  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]


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