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ANALGESIA

Melatonin Improves Tourniquet Tolerance and Enhances Postoperative Analgesia in Patients Receiving Intravenous Regional Anesthesia

From the Department of Anesthesia, King Faisal University, Saudi Arabia.

Abstract

BACKGROUND: Melatonin has anxiolytic and potential analgesic effects. We assessed the efficacy of melatonin premedication in reducing tourniquet-related pain and improving analgesia in patients receiving IV regional anesthesia (IVRA).

METHODS: Forty patients undergoing elective hand surgery under IVRA were randomly assigned into two groups (20 patients each) to receive either melatonin 10 mg (melatonin group) or placebo (control group) as oral premedication. IVRA was achieved with lidocaine, 3 mg/kg, diluted with saline to a total volume of 40 mL. Anxiety scores, hemodynamic changes, sensory and motor block onset and recovery times, tourniquet pain, the quality of intraoperative anesthesia, time to first analgesic request, and 24 h analgesic requirements were recorded.

RESULTS: After premedication, the anxiety scores were significantly reduced in the melatonin group (P = 0.023). During surgery, patients who received melatonin premedication had better tourniquet tolerance (lower verbal pain scores at 30, 40, and 50 min after tourniquet inflation, P < 0.05), lower rescue fentanyl requirements (15.6 ± 21.9 vs 45.7 ± 33.4 µg, P = 0.002), longer time to the first postoperative analgesic request (145.4 ± 20.2 min vs 74.6 ± 12.8, P < 0.001) and lower postoperative diclofenac consumption at 24 h (86.3 ± 27.5 mg vs 116.3 ± 38.3 mg, P = 0.007) compared with the control group.

CONCLUSIONS: Melatonin is an effective premedication before IVRA since it reduced patient anxiety, decreased tourniquet-related pain, and improved perioperative analgesia.

IV regional anesthesia (IVRA) is a simple and reliable local anesthetic technique suitable for short procedures to the extremities. Its limitations include tourniquet pain and minimal postoperative analgesia.1 Premedication with dexmedetomidine and gabapentin have been demonstrated to enhance the quality of anesthesia, tourniquet tolerance and postoperative analgesia in patients receiving IVRA.2,3

Melatonin is a hormone secreted by the pineal gland. This hormone is involved in several biological functions, including circadian rhythms, sleep, and analgesia.4 Systemic or central administration of melatonin produces a dose-dependent antinociception in models of acute and inflammatory pain in animals.5–8 In addition, melatonin enhanced postoperative analgesia in a clinical trial.9 These beneficial effects may be of value when melatonin’s is used as a premedication for IVRA.

The aim of this study was to examine the efficacy of melatonin premedication in reducing tourniquet-related pain and the need for analgesic medication during hand surgery under IVRA and enhancing postoperative analgesia. Secondary objectives included evaluation of melatonin’s effects on anxiety, hemodynamics and onset and recovery of sensory and motor blockade.

METHODS

After obtaining approval of the local Ethics Committee and written informed patient consent, 40 ASA physical status I–II patients scheduled for hand surgery (i.e., carpal tunnel, trigger finger, tendon release or cut tendon repair) were enrolled in this double-blind study. Patients with Raynaud’s disease, sickle cell anemia, chronic pain syndromes, depression or schizophrenia, epilepsy, leukemia, autoimmune disease, diabetes, those who used any analgesic or sedative 24 h before surgery, or those with allergy to any of the study medications or pregnant or breast-feeding women, were excluded from participating in the study. Patients were randomly allocated using an online research randomizer (http://www.randomizer.org) into two equal groups (20 patients each) to receive either melatonin 10 mg (Melatonin®, NATROL, Inc, Chatsworth, CA) (melatonin group) or placebo (control group), orally 90 min before surgery. No other sedative or analgesic premedications were used.

At the preoperative visit, the verbal pain score10 (VPS) of 10 (0 = no pain and 10 = worst pain imaginable) and the level of anxiety using a verbal anxiety score (VAS)11 ranging from 0 to 10 (0 = completely calm, 10 = the worst possible anxiety) were explained to each patient. Baseline heart rate (HR), mean arterial blood pressure (MAP), SaO₂ and anxiety level was recorded for each patient before premedication.

On arrival in the operating room, 90 min after premedication, patients were asked to assess their anxiety level using the VAS. Patients were monitored with an electrocardiogram, noninvasive arterial blood pressure and plethysmographic pulse oximetry using an anesthesia machine (Datex-Ohmeda S/5, ADU, Finland).

Two IV cannulae were placed, one in a vein on the dorsum of the operative hand for the IVRA, and the second in the opposite hand for administering supplemental medications and fluids during the operation. After a pneumatic double tourniquet had been placed around the upper arm, the extremity was elevated and exsanguinated with an Esmarch bandage. The proximal cuff was then inflated to 250 mm Hg (or 100 mm Hg above the systolic blood pressure), and the circulatory isolation of the arm was verified by inspection, absence of radial pulse, and loss of the pulse oximetry tracing in the ipsilateral index finger. The IVRA was performed using lidocaine, 3 mg/kg, diluted with saline to a total volume of 40 mL and injected over 90 s.

Sensory block was assessed every 30 s after injection of the lidocaine using a standardized pinprick technique with a 22-gauge short-beveled needle. The patient’s response was evaluated in the dermatomal sensory distribution of the medial and lateral antebrachial cutaneous, ulnar, median, and radial nerves. Motor function was assessed by asking the subject to flex and extend their wrist and fingers at 30 s intervals, and complete motor block was recorded when no voluntary movement was present. The onset time for sensory blockade was defined as the time elapsed from injection of the lidocaine until a complete sensory block was achieved in all dermatomes, and the onset time for motor blockade was the time elapsed from injection of lidocaine to achieving a complete motor block. When an adequate surgical block was achieved, the operative tourniquet (i.e., distal cuff) was inflated to 250 mm Hg and then the proximal cuff was released.

The MAP, HR, and oxygen saturation (Spo₂) values were recorded before and immediately after tourniquet inflation, at 10, 20, 30, 40, and 50 min thereafter, and after release of the tourniquet. Assessments of tourniquet-related pain were performed using VPS immediately after tourniquet inflation, at 10, 20, 30, 40, and 50 min thereafter. The initial time to tourniquet pain, defined as the time elapsed between the distal cuff inflation and the patient’s initial complaint of tourniquet pain, was recorded. When the tourniquet pain score was reported to be >4, the patient was given IV 0.5 µg/kg bolus of fentanyl, which was repeated after 5 min if pain was not improved. The total intraoperative fentanyl consumption was calculated.

The distal tourniquet was not deflated until a minimum of 30 min after the lidocaine injection. At the end of surgery, tourniquet deflation was performed using a cyclic deflation technique over 1–2 min. Sensory recovery time was defined as the time elapsed after tourniquet deflation until recovery of sensation in all dermatomes as determined using the pinprick technique at 30 s intervals.

Motor block recovery time was defined as the time elapsed after tourniquet deflation until return of movement in the fingers. The time until the first analgesic requirement was noted as the time elapsed after tourniquet release until the patient’s initial request for pain-relieving medication postoperatively. Patients were given diclofenac, 75 mg IM. PRN every 8 h when the VAS >4 and the total diclofenac dosage at 24 h was recorded. All the evaluations were performed by a blinded observer.

The occurrence of nausea, vomiting, skin rash, tachycardia (HR >100 bpm), bradycardia (HR <50 bpm), hypotension (MAP <60 mm Hg), excessive sleepiness, hypertension (MAP >120 mm Hg), headache, dizziness, tinnitus, and hypoxemia (Spo₂ <90%), as well as any surgical complications (e.g., wound hematoma), were noted upon discharge from the recovery room and at the end of the first postoperative 24 h.

Statistical Analysis
Power analysis was based on a previous study,3 which showed that 20 patients were required in each group to have an 80% chance of detecting a 25% reduction in the mean tourniquet VPS at the 5% level of significance. Data were tested for normal distribution using the Kolmogorov-Smirnov test. Gender and the incidence of complications were analyzed using ² test. Two-way repeated measure analysis of variance was used for continuous parametric variables as HR and MAP and the differences were then calculated by post hoc testing (Newman-Keuls test). Friedman repeated measures analysis of variance followed by Newman-Keuls test were used for within-group comparison of nonparametric variables as pain scores and Mann-Whitney rank-sum test for the comparison of values between the groups. A P value <0.05 was considered significant. Analysis was performed using Statistica software version 7.0 for windows (Statsoft, Inc).

RESULTS

The demographic characteristics and surgery times were similar in the two groups (Table 1). The types of surgery were also matched in both groups. Anxiety scores were similar in both groups (median, Interquartile range = 5, 3.5–6 and 5, 4–6 in the control and melatonin groups respectively). These were reduced after administration of melatonin (P = 0.023; Table 2).

Melatonin premedication reduced MAP compared to the control group. HR and MAP increased significantly in the control group after tourniquet inflation. These increases were not observed in the melatonin group (Fig. 1). No incidence of hypotension or bradycardia requiring intervention was reported in either groups.

View larger version (14K): [in this window] [in a new window]   Figure 1. Changes in heart rate (HR) and mean arterial blood pressure (MAP) in the control and melatonin groups. Measurements were recorded before premedication (BP), before tourniquet application (BT), 10, 20, 30, 40, 50 min after tourniquet inflation and after release of tourniquet (AR). Vertical bars denote 0.95 confidence intervals. *Significant difference compared to baseline before premedication (BP). #Significant difference between the melatonin and control groups.

Sensory and motor block onset and recovery times were similar in the two study groups (Table 2). However, VPS scores for tourniquet pain were significantly less in the melatonin group at 30, 40, and 50 min after tourniquet inflation (Fig. 2). These lower pain scores were also reflected in the smaller supplemental fentanyl requirements during surgery in the melatonin group (P = 0.002; Table 2). The time to first postoperative analgesic request was prolonged in the melatonin group when compared with the control group (P < 0.001). Postoperative diclofenac consumption was significantly reduced in the melatonin group (P = 0.007).

View larger version (12K): [in this window] [in a new window]   Figure 2. Verbal pain scores (VPS) in the control and melatonin groups. Scores were recorded immediately after tourniquet application (AT), 10, 20, 30, 40, 50 min after tourniquet inflation. Data are represented as median and interquartile range. P values shown represent the levels of statistical significance between the two groups.

There were no statistically significant differences between groups with respect to adverse effects reported during the 24-h postoperative observation period. One patient complained of dizziness and two in the melatonin group had excessive sleepiness.

DISCUSSION

The main findings in this study were that melatonin premedication reduced anxiety, decreased tourniquet-related pain, and enhanced intraoperative and postoperative analgesia without producing clinically significant side effects.

The level of anxiety scores for the patients in the melatonin group was lower than those in the control group. Melatonin’s anxiolytic effect is supported with previous clinical trials in adults.12,13 On the contrary; Capuzzo et al.14 reported that melatonin premedication did not reduce anxiety more than placebo in elderly patients undergoing surgery. However, in their study the level of anxiety scores decreased 33% after melatonin premedication.

The beneficial effect of melatonin on tourniquet-related pain in our study was clinically evident by lower pain scores, a longer time to fentanyl rescue and a reduction in intraoperative fentanyl consumption. Tourniquet-related pain is a limiting factor for IVRA techniques. This distress may be caused via multiple factors, including neuropathic pain produced by nerve compression stimulation of nerve endings in cutaneous tissue,15 skeletal muscle ischemia,16 and local metabolic changes.17 Melatonin may be effective in the relief of tourniquet pain, since it has been shown that it significantly depresses nociceptive discharges of spinal dorsal horn neurons that follow stimulation of C fibers18 and inhibits synaptic potentiation (wind-up) in the spinal cord.19 Moreover, melatonin was able to reduce tactile allodynia induced by ligation of L5/L6 spinal nerves20 and by thermal hyperalgesia in neuropathic mice with partial tight ligation of the sciatic nerve.21

Another main finding in this study is that the time to first request of postoperative analgesic medication was prolonged in the melatonin group with lower postoperative analgesic consumption. Several animal studies have shown that systemic melatonin provided dose-dependent antinociception and enhanced morphine analgesia.5–8 Moreover, in a recent clinical work on female patients undergoing abdominal hysterectomy under epidural anesthesia, Caumo et al., demonstrated that melatonin premedication enhanced postoperative analgesia.9 We are not aware of previous clinical studies evaluating the efficacy of melatonin in reducing tourniquet-related pain during IVRA and in providing residual analgesia in the early postoperative period.

The precise mechanism and site of action of melatonin antinociception are not completely obvious. However, several studies on experimental animals tried to clarify the mechanisms. Melatonin may enhance the levels of β-endorphin and the antinociception induced by opioid receptor agonists.5 In addition, it could activate MT₂ melatonin receptors in the dorsal horn of the spinal cord.22 Other mechanisms might be mediated via an interaction with the adrenergic (₂–adrenoceptors), dopaminergic (D₂-receptors), serotonergic (5-HT_2a receptors), and opioid systems, in addition to the l-arginine-nitric oxide pathway.23 All these sites could be reached considering the high lipid-solubility of melatonin.

The selected dose of oral melatonin (10 mg) was based on a previous premedication study. Several earlier clinical trials administered different sublingual doses of melatonin.12,13 Further studies may be required to determine the optimum dose and route of administration of melatonin as premedication for IVRA. Although the incidence of adverse effects was similar in both groups, this study was not powered to evaluate the potential side effects of melatonin.

In conclusion, premedication with a single oral dose of melatonin (10 mg) before IVRA alleviates patients’ anxiety, diminishes tourniquet-related pain, and moderates intraoperative and postoperative analgesic consumption.

Footnotes

Accepted for publication May 23, 2008.

Address correspondence and reprint requests Dr. Hany A. Mowafi, Department of Anesthesiology, King Fahd University Hospital, P O Box 40081, Al-Khobar 31952, Saudi Arabia. Address e-mail to hany_mowafi{at}hotmail.com.

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