What this Study Adds
Amantadine, magnesium sulphate, pregabalin, dexmedetomidine, ibuprofen, flurbiprofen plus dexmedetomidine, parecoxib, parecoxib plus dexmedetomidine, and S (+)-ketamine plus methadone show statistically significantly milder pain intensity than placebo. Amantadine ranked the most effective while failed to demonstrate superiority in the incidence of postoperative nausea and vomiting when compared to placebo.
Dexmedetomidine is not the best but the most well-balanced choice for it is the only intervention that is superior to placebo in all indicators.
1. Introduction
As a component of balanced anesthesia, opioids are the main analgesics used during the perioperative period. Timely opioid administration during surgery lessens the requirement of general anesthetics, leading to faster recovery[1], and post-surgery patient-controlled opioid analgesia enhances patient comfort and satisfaction[2]. However, a reduction in nociceptive thresholds and a paradoxical increase in pain after exposure to opioids during surgery[3], referred to as opioid-induced hyperalgesia (OIH), had been demonstrated in animal models[4], human volunteers[5] and surgical patients[6]. Suffering more severe postoperative pain due to nociceptive sensitization may render patients obliged to accept more opioids, unless alternatives are considered[7]. Also, opioid-related adverse drug events have been associated with increased inpatient mortality, prolonged length of stay and high cost of hospitalization[8].
Although the precise molecular mechanism underlying OIH remains unclear, it is commonly suggested to be triggered by neuroplastic altering in the peripheral and central nervous systems[9]. Previous electrophysiological studies using slices of rat spinal cord revealed a cellular mechanism concerning the rapid and persistent up-regulation of N-methyl-D-aspartate (NMDA) receptor function by clinically relevant concentrations of remifentanil through μ- and δ-opioid receptor pathway; mirroring the role of pathologic activation of NMDA receptor in the development of OIH[10, 11]. Therefore, to prevent the development of OIH, clinical explorers mainly followed the idea of manipulating the glutaminergic system through modulation of the NMDA receptor, either directly or indirectly. In light of these, multiple drugs have been shown the potential to attenuate the pain intensity and reduce the demand for postoperative analgesics, such as ketamine, dexmedetomidine and flurbiprofen[12]. Regretfully, limited by small sample sizes and various medication dosages in existing literature, clinical routines are still controversial about the optimal intervention strategy to prevent the increase in postoperative pain intensity due to OIH[13]. Importantly, comparative efficacy of diverse drugs of the prevention and comparisons involving non-NMDA receptor antagonists are urgently needed. As such, the comparative effects of different kinds of medications remains undetermined.
Given these uncertainties, we performed a systematic review and network meta-analysis evaluating different pharmacologic interventions for preventing the increase in postoperative pain intensity caused by OIH in adults after general anesthesia, with the hope to better guide clinical practice for more individualized general anesthesia protocol.