Melatonin is a hormone produced by the pineal gland in the brain that regulates the body’s circadian rhythm, the 24-hour internal clock that controls the sleep-wake cycle. Peak levels of melatonin production occur in response to darkness, while melatonin production is decreased in response to light.1 It can be produced synthetically, and supplements can help those with insomnia, jet lag, or other sleep disorders improve the duration and quality of sleep. Melatonin has also drawn interest for its links to certain aspects of anesthesia.
Melatonin has a multifaceted relationship with anesthesia. General anesthesia has been found to disrupt the circadian rhythm of melatonin secretion.2 One study showed, for example, that adults administered anesthesia before knee surgery, whether general or spinal, experienced a delay in the onset of nighttime melatonin secretion.3 Separately, stress and inflammation induced surgery can lead to an increase of the hormone cortisol in the body, which suppresses the activity of the enzyme N-acetyltransferase that ultimately suppresses melatonin synthesis.4
Additionally, administering melatonin in the perioperative period can reduce anxiety before surgery. One prospective clinical study found that administering melatonin to adult patients two hours before surgery was more effective at reducing anxiety compared with the anti-anxiety medication alprazolam.5 Melatonin also resulted in a lower degree of sedation and better preserved cognitive and motor function. In addition to reducing anxiety before surgery, perioperative melatonin also can reduce the dosage of intraoperative propofol and does not prolong recovery time.4 Interestingly, the anti-anxiety effect does not appear to be as strong in children, up to 65% of whom experience anxiety throughout the perioperative period. A study from the University of California Irvine School of Medicine showed that midazolam is more effective than melatonin in reducing children’s anxiety at induction of anesthesia.6
Melatonin can also reduce pain following surgery, though the exact mechanisms of this effect have not been resolved. One team of researchers found that patients who took 5 mg of oral melatonin both the night before and one hour before undergoing abdominal hysterectomy experienced decreased pain and anxiety in the first 24 hours after surgery, and better recovery of circadian rhythms in the first week after surgery.7
Postoperative delirium, which refers to reduced awareness of surroundings, poor memory, and behavioral changes following surgery, is another complication that melatonin can help alleviate, possibly due to its ability to restore circadian rhythms disrupted by anesthesia. The University of California study showing that melatonin was less effective in reducing perioperative anxiety in children also found that melatonin was better than midazolam in lowering the rates of postoperative delirium. The results, however, are not conclusive; a study from the Amsterdam Delirium Study Group found that melatonin, compared to placebo, did not significantly reduce postoperative delirium in patients undergoing surgery for hip fracture.8
While the natural biological function of melatonin is mostly understood, and the use of melatonin supplements for sleep is well established, the effect of anesthesia on melatonin, and vice versa, remains an area of active research. Future research will help further clarify the relationship between the two, with the ultimate aim of improving patient outcomes before, during, and after surgery.
References
1. Zisapel, N. New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. Br. J. Pharmacol. 175, 3190 (2018), DOI: 10.1111/bph.14116
2. Mowafi, H. A. & Ismail, S. A. The Uses of Melatonin in Anesthesia and Surgery. Saudi J. Med. Med. Sci. 2, 134 (2014), DOI: 10.4103/1658-631X.142495
3. Guo, R., Ye, J., Liao, B., Luo, X. & Rao, P. The relationship between anesthesia and melatonin: a review. Front. Pharmacol. 14, (2023), DOI: 10.3389/fphar.2023.1255752
4. van Faassen, M., Bischoff, R. & Kema, I. P. Relationship between plasma and salivary melatonin and cortisol investigated by LC-MS/MS. Clin. Chem. Lab. Med. 55, 1340–1348 (2017), DOI: 10.1515/cclm-2016-0817
5. Khare, A. et al. Comparison of Effects of Oral Melatonin with Oral Alprazolam used as a Premedicant in Adult Patients Undergoing Various Surgical Procedures under General Anesthesia: A Prospective Randomized Placebo-Controlled Study. Anesth. Essays Res. 12, 657–662 (2018), DOI: 10.4103/aer.AER_90_18
6. Kain, Z. N. et al. Preoperative Melatonin and Its Effects on Induction and Emergence in Children Undergoing Anesthesia and Surgery. Anesthesiology 111, 44–49 (2009), DOI: 10.1097/ALN.0b013e3181a91870
7. Caumo, W. et al. The clinical impact of preoperative melatonin on postoperative outcomes in patients undergoing abdominal hysterectomy. Anesth. Analg. 105, 1263–1271, table of contents (2007), DOI: 10.1213/01.ane.0000282834.78456.90
8. Jonghe, A. de et al. Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial. CMAJ 186, E547–E556 (2014), DOI: 10.1503/cmaj.140495