The present study demonstrates that long-acting oral melatonin improved VAS pain score and reduced cumulative dose of PCA morphine consumption in 24 hours. These results were similar to the previous studies in other procedures, such as prostatectomy,[20] dental surgery,[15] hand surgery,[21] cataract surgery under topical anesthesia [22] and abdominal hysterectomy.[19,23] In contrast, some studies failed to show the effectiveness of perioperative melatonin in terms of analgesic outcomes.[24,25] The variation of dose, route and timing of melatonin administration might affect these individual results, which remain inconclusive even after systematic review were conducted.[8,26] Caumo et al. revealed the analgesic effect of preoperative oral melatonin. Melatonin reduced pain scores on VAS scale within postoperative period of 48 hours and lowered morphine consumption for 24 hours after abdominal hysterectomy, compared to placebo.[19] Such a study proposed that postoperative anxiolytic effect of melatonin treatment led to anti-nociceptive effect.[19,23] In contrast, this study could not show a significant difference of anxiolysis, as well as VAS pain score after immediate postoperative phase at post-anesthesia care unit arrival. The present study investigated a 4 mg of prolonged-release formulation of melatonin (Circadin®, Neurim Pharmaceuticals, Tel-Aviv, Israel). We chose this dose and form of melatonin because this was the only commercial available form in Thailand. This was a lower dose than other previous studies as premedication for analgesic effect. Forms of melatonin in all previous studies might be a short acting formulation or higher doses. However, from general clinical practice, 2-mg dose once daily of prolonged-release melatonin showed clinical benefits in terms of sleep quality and quality of life in patients aged 55 years and older without unexpected effects.[27] The therapeutic indication of this novel formulation melatonin is primary insomnia in elderly due to long duration of action and safety profiles.[8] Exogenous melatonin modulates via activation of the MT1 and/or MT2 melatonin receptors in the central nervous system.[13,27] In addition, there were several in vitro studies which demonstrated that the anti-nociceptive effects of melatonin could be reversed by various mechanism such as flumazenil, naloxone, potassium or calcium ion-channel-blockers.[12] Moreover, a recent review of literature proposed the synergistic effects of melatonin combined with morphine in terms of hyperalgesia and morphine tolerance reduction.[28] In contrast, another recent meta-analysis could not show the significant association between melatonin use and acute postoperative pain outcome.[29] The present study is the first clinical study of prolonged-release formulation in perioperative period. A recent study in patients who underwent orthognathic surgery showed that prophylactic oral melatonin significantly decreased pain, numbness perception and were also correlated to lower serum hydrogen peroxide but higher antioxidant enzyme levels.[30]
Patients with postoperative sleep disturbance can suffer from delirium, delayed recovery and pain.[31] Correlation between pharmacologic sleep promotion and perioperative pain control are still controversial.[32] The present study failed to demonstrate the improved postoperative sleep quality. Similar to a recent meta-analysis in cholecystectomy, melatonin interventions showed no substantial impact on sleep quality and pain score after 1 and 3 hours.[33] However, Kirksey A. et al concluded melatonin did not have effect on subjective sleep assessment but improved sleep efficiency and sleep time by actigraphy wrist bracelet measurement.[34]
Acute postoperative pain after hysterectomy may be complicated by anxiety state and psychological factors. A qualitative systematic review demonstrated that anxiety was a significant predictor for postoperative pain.[35] Such result was similar to another study in patients who underwent hysterectomy, in which preoperative anxiety was a positive predictor of immediate postoperative pain, pain on wards and also pain at home.[10]Moreover, Pinto et al. showed that anxiety predicted pain intensity at 48 hours after hysterectomy and also mediated pain catastrophizing.[6] In several clinical studies and systematic reviews, the outcome of preoperative melatonin administered to reduce preoperative anxiety was still controversial among varied population and doses.[15,17,19,36] Whereas another systematic review from Cochrane database concluded melatonin can reduce preoperative anxiety at the same rate as standard medication with midazolam if it was given within appropriate timing.[37] However, the present study could not exhibit the benefit of melatonin as an anxiolytic.
In addition, the concept of immune-pineal axis influencing postoperative pain in patients who underwent hysterectomy was proposed. There was an inverse correlation between tumor necrosis factor (TNF) and nocturnal melatonin level. Moreover, the lower melatonin level was accompanied by lower cortisol levels and patients required higher doses of analgesics.[38] Therefore, exogenous melatonin might play a role for perioperative period especially in hysterectomy.
Fatigue has been defined as the lack of energy or exhaustion which is a complex, multifactorial symptom distinct from sleepiness or sadness.[39] The incidence of postoperative fatigue following hysterectomy was frequent regardless of general or spinal anesthesia.[40] Intensity of postoperative fatigue was the result of many biological factors, such as surgical stress response, anemia, declined nutritional status, psychological and social factors.[40] Fatigue was associated to poor quality of life in cancer patients who underwent surgery.[39] From the present study, melatonin enhanced subjective fatigue, general well-being VAS pain score and satisfaction score compared to placebo. These results were different from previous studies. Ivry M. et al. revealed melatonin improved quality of recovery following bariatric surgery in terms of sleep and pain levels.[16] Although differing in definition and measurement, the present study demonstrated advantages of melatonin administration in early postoperative fatigue and recovery, but no improvement of sleep quality. This may be due to lower morphine requirement.
Limitations of this study include the quality of recovery questionnaire in Thai version, which was not validated at the time the study was conducted. Likert and VAS pain score were measured to represent overall subjective recovery condition. The details of each standard domain may be inconclusive. Second, the results were focused only on perioperative and acute postoperative periods. Future studies should evaluate the effect of melatonin on chronic pain after hysterectomy. Third, the present study revealed only benefits of preoperative 2 doses of 4 mg of prolonged-release melatonin. Continuation of melatonin in postoperative period or earlier timing to load rather than one night before the surgery might be more appropriate with melatonin’s pharmacokinetics and patient’s metabolism. Moreover, to our knowledge, the appropriate dose and timing of oral prolonged-released melatonin was not established in perioperative period.