The use of high‐dose melatonin in liver resection is safe: first clinical experience

Abstract

Experimental data suggest that melatonin decreases inflammatory changes after major liver resection, thus positively influencing the postoperative course. To assess the safety of a preoperative single dose of melatonin in patients undergoing major liver resection, a randomized controlled double-blind pilot clinical trial with two parallel study arms was designed at the Department of General and Transplantation Surgery, Ruprecht-Karls-University, Heidelberg. A total of 307 patients, who were referred for liver surgery, were screened. One hundred and thirteen patients, for whom a major liver resection (≥3 segments) was scheduled, were eligible. Sixty-three eligible patients refused to participate, and therefore, 50 patients were randomized. A preoperative single dose of melatonin (50 mg/kg BW) dissolved in 250 mL of milk was administered through the gastric tube after the intubation for general anesthesia. Controls were given the same amount of microcrystalline cellulose. Primary endpoint was safety. Secondary endpoints were postoperative complications. Melatonin was effectively absorbed with serum concentrations of 1142.8 ± 7.2 ng/mL (mean ± S.E.M.) versus 0.3 ± 7.8 ng/mL in controls (P < 0.0001). Melatonin treatment resulted in lower postoperative transaminases over the study period (P = 0.6). There was no serious adverse event in patients after melatonin treatment. A total of three infectious complications occurred in either group. A total of eight noninfectious complications occurred in five control patients, whereas three noninfectious complications occurred in three patients receiving preoperative melatonin (P = 0.3). There was a trend toward shorter ICU stay and total hospital stay after melatonin treatment. Therefore, a single preoperative enteral dose of melatonin is effectively absorbed and is safe and well tolerated in patients undergoing major liver surgery.

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…In healthy women given 300 mg melatonin/day for 4 months there were no side effects [214]. In a randomized controlled double-blind clinical trial on 50 patients referred for liver surgery a single preoperative enteral dose of 50 mg/kg melatonin was safe and well tolerated [215]. This underlines the urgent need for large clinical trials in the field of melatonin and cancer [216,217].…”

A systematic review of peri‐operative melatonin

“…One study gave melatonin daily for one month pre-operatively [28], whereas four studies gave melatonin the night before surgery, in addition to the immediate pre-operative dose [5,6,13,15]. Three studies gave melatonin at surgical incision [25,26] or after intubation [32]. One study gave three separate melatonin doses on the first three postoperative nights [16].…”

“…One study gave 3500 mg orally [32] and one study gave 50 mg intravenously [26]. Most studies gave melatonin 30-100 min before surgery [4, 12, 14, 17-24, 27, 29-31].…”

“…Participants had various operations: abdominal [15][16][17]25, Full-text studies excluded (n = 17) -10 studies did not investigate surgical patients -3 studies were protocol studies -2 studies were not randomised -2 studies used melatonin only in combination with other drug interventions 32]; dental [27]; gynaecological [5,6,18,19,30]; ophthalmological [4,14]; orthopaedic [12]; thoracic [28,29]; urological [13]; vascular [26]; and mixed [20][21][22][23][24]31]. The anaesthetic techniques included: general anaesthesia [13,[15][16][17][18][19][20][21][22][23][24][25][26][28][29][30][31][32]; intravenous regional anaesthesia [12]; neuraxial block [5,6,20,26,31]; sedation …”

Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial

“…The study had no data safety or monitoring board because melatonin was considered safe. 28,29 We reported all serious adverse events to the Medical Ethics Committee and had a protocol to break the randomization code in case of a suspected unex pected serious adverse reaction. This trial was registered with the Netherlands Trial Registry (NTR1576) and was funded by an unrestricted grant (no.…”