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.