Effect of Preoperative Melatonin on Quality of Recovery After Elective Laparoscopic Cholecystectomy

1. INTRODUCTION

1.1 Background

Recovery after surgery cannot be adequately captured by traditional clinical measures alone. Mortality, morbidity, and length of stay, while important, tell us very little about how patients actually feel during the recovery period. Recovery is a complex, multidimensional process shaped by physiological, psychological, and environmental factors. The Quality of Recovery (QoR) concept was developed to address this gap, including physical comfort, emotional well-being, psychological state, and functional independence.

Among available QoR instruments, the Quality of Recovery-15 (QoR-15) questionnaire is a validated 15 item patient reported outcome measure assessing recovery across five clinically relevant domains: physical comfort, emotional state, physical independence, psychological support, and pain. Items are scored 0-10 (total range 0-150, where higher scores reflect better recovery). The QoR-15 shows strong validity, reliability, and responsiveness across different surgical populations, both elective and emergency, in various healthcare settings. Critically, its minimal clinically important difference (MCID) is formally established at 6.0 to 8.0 points, making it ideal for evaluating the impact of perioperative interventions. Pharmacological agents including ketamine and dexamethasone, for instance, have been evaluated using QoR-15 based outcome measures in recent trials.

Laparoscopic cholecystectomy is the gold standard surgical treatment for symptomatic gallstone disease. While it offers clear advantages over open surgery like reduced pain, shorter hospital stay, fewer wound complications, and faster recovery, a significant number of patients experience unpleasant postoperative symptoms that compromise their quality of recovery.

Postoperative Pain remains a persistent clinical challenge. A significant proportion of patients experience moderate to severe pain within the first 24 hours. The pain is particularly complex, arising from multiple sources: parietal pain from port-site incisions, visceral pain from gallbladder bed dissection, and referred shoulder-tip pain from diaphragmatic irritation caused by residual carbon dioxide. This multicomponent nature means single-target analgesic strategies are insufficient, creating a strong theoretical foundation for multimodal interventions.

Sleep Disturbance is another neglected issue, with incidence rates reaching up to 90% in surgical populations. Poor postoperative sleep increases pain sensitivity, cognitive dysfunction, and delirium while delaying recovery. The causes are multifactorial: surgical stress triggers systemic inflammation; pain disrupts sleep architecture; and environmental factors like noise, lighting, nursing interventions further impair sleep quality.

Anxiety and other postoperative symptoms - nausea, fatigue, and psychological distress add further to these challenges, collectively compromising overall quality of recovery and patient satisfaction. These problems are not confined to elective cases; similar findings have been reported in emergency settings as well.

Despite advances in minimally invasive techniques and anaesthetic practice, and the widespread adoption of Enhanced Recovery after Surgery (ERAS) protocols across surgical specialties, postoperative discomfort and impaired recovery in the early period remain persistent clinical concerns. This emphasizes the need for simple, effective adjunctive interventions that can be integrated into existing frameworks.

Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous indolamine hormone produced by the pineal gland, best known for regulating circadian rhythm and the sleep-wake cycle. However, emerging evidence reveals a much broader pharmacological profile directly relevant to perioperative recovery.

Melatonin possesses multimodal properties addressing several postoperative challenges simultaneously:

Analgesic: Acts through MT1 and MT2 receptor activation and modulation of endogenous opioid pathways.

Anxiolytic: Modulates GABAergic neurotransmission and reduces sympathetic nervous system activity.

Anti-inflammatory: Suppresses pro-inflammatory cytokines (interleukin-6, tumour necrosis factor-α) and modulates immune responses.

Antioxidant: Acts as a direct free-radical scavenger and stimulates endogenous antioxidant enzyme systems Sedative-hypnotic: May improve postoperative sleep quality This wide range of action is particularly valuable because surgery and anaesthesia themselves disrupt endogenous melatonin secretion through hospital lighting, clinical interventions, surgical stress, and anaesthetic agents. Surgical trauma triggers a systemic inflammatory cascade characterized by elevated pro-inflammatory cytokines and reactive oxygen species; melatonin has been shown to attenuate these responses in clinical studies and to reduce measurable oxidative stress markers. There is also emerging evidence that melatonin may reduce neuroinflammation associated with postoperative delirium and cognitive dysfunction, though the data in this area remain preliminary. Supplemental melatonin may simultaneously address circadian disruption, pain, anxiety, inflammation, and oxidative stress through a single, well-tolerated oral dose.

Oral melatonin has a short elimination half-life (30-60 minutes) and peak plasma concentration within 30-90 minutes. In perioperative trials, doses range from 3-10 mg, administered 60-120 minutes before surgery. A 6 mg dose, administered 60 minutes before anaesthetic induction, has shown significant improvements in postoperative sleep quality and pain outcomes and matches the protocol of the most directly comparable trial.

A meta-analysis of 11 randomized controlled trials (782 participants, heterogeneous surgical populations) found that melatonin significantly improved postoperative sleep, with 6 mg doses showing particularly favourable results. A second meta-analysis of 16 randomized controlled trials (1,053 patients) demonstrated meaningful reductions in postoperative pain intensity and perioperative opioid consumption following melatonin. Ismail et al. (2025) reported anxiolytic effects comparable to benzodiazepines without residual sedation or dependence potential.

The most directly relevant study is a double-blind, placebo-controlled trial in 63 patients undergoing laparoscopic bariatric surgery. Preoperative melatonin 6 mg produced a statistically significant QoR-15 improvement of approximately 10 points at 24 hours, exceeding the established MCID. However, bariatric surgery patients differ substantially from cholecystectomy patients in body mass index, comorbidity burden, surgical complexity, and recovery trajectory. The trial's small sample size also limits precision and precludes meaningful subgroup analysis.

Melatonin's safety profile is excellent. A systematic review of 37 randomized controlled trials (>2,000 participants) found adverse event incidence comparable to placebo, with reported side effects being mild and self-limiting (drowsiness, headache, occasional dizziness). Serious adverse events from single-dose perioperative melatonin are very uncommon.

A critical gap exists in the literature is that no published study has evaluated the effect of preoperative melatonin on comprehensive postoperative recovery using the QoR-15 in patients undergoing laparoscopic cholecystectomy. Moreover, evidence examining melatonin's effect on multiple recovery outcomes like pain, sleep, anxiety, opioid consumption, and PONV in this population is absent.

A further limitation is the near total absence of data from South Asian populations. CYP1A2, the enzyme principally responsible for melatonin metabolism, is subject to clinically relevant genetic polymorphisms that vary in prevalence across ethnic group. Differences in baseline melatonin secretion, dietary melatonin intake, and habitual light exposure may influence both baseline recovery profiles and clinical response to exogenous supplementation. Findings from predominantly Western populations cannot be directly applied to South Asian clinical settings without local evidence.

The MEL-REC trial (Melatonin for Enhanced Laparoscopic Recovery) is designed to evaluate whether preoperative oral melatonin (6 mg) improves postoperative quality of recovery, as measured by QoR-15 score at 24 hours after surgery, in adult patients undergoing elective laparoscopic cholecystectomy under general anaesthesia

1.2 Rationale of the study The rationale for this trial is based on three lines of evidence that join together. First, inspite of being classified as a minimally invasive procedure, laparoscopic cholecystectomy is associated with clinically significant postoperative discomfort - parietal, visceral, and referred pain; disrupted sleep; anxiety; nausea; and fatigue which impairs recovery quality in a significant proportion of patients and is not fully addressed by current standard care. Second, melatonin's pharmacological profile is wide, combining anxiolytic, analgesic, anti-inflammatory, antioxidant, and chronobiotic properties in a single, well-tolerated oral agent. This multimodal action enables it to target several of the pathophysiological mechanisms that underlie poor postoperative recovery - a characteristic that few other available perioperative adjuncts can meet. Third, while preliminary evidence from a bariatric surgery population supports the idea that melatonin can improve global postoperative recovery as measured by the QoR-15, confirmatory evidence in the laparoscopic cholecystectomy population is lacking. The existing evidence base is further limited by heterogeneous surgical populations, variable dosing regimens, and a predominant focus on isolated outcome domains rather than comprehensive, patient centred recovery assessment. The near total absence of data from South Asian populations - in whom pharmacogenomic and environmental factors may influence melatonin's effects - restricts the generalizability of the available evidence to the clinical setting of the present study.

From a practical perspective, the justification for investigating melatonin in this context is compelling. Laparoscopic cholecystectomy is performed in very high volumes globally. Melatonin is inexpensive, widely available, easily administered orally, and has a well-established safety profile. If a clinically meaningful improvement in postoperative recovery can be established, the implications for perioperative practice - including potential inclusion in ERAS protocols - would be considerable. This study is therefore designed to address the identified evidence gap through a double-blind, placebo-controlled randomized trial.