This meta-analysis included 39 RCTs that compared postoperative pain outcomes after propofol-based anesthesia with that after inhalational anesthesia. Use of propofol was associated with lower postoperative pain scores at rest and opioid consumption. In addition, fewer patients required rescue analgesics in the propofol group, as evidenced by the longer time to first analgesic administration. None of the differences remain significant, however, when a conservative P value of <.01 was applied.
In this meta-analysis, we found lower pain scores and reduced pain intensity at rest (from 0.48 U at 30 minutes to 0.08 U at 24 hours postoperatively) associated with propofol anesthesia compared with inhalational anesthesia. Further, the use of propofol was associated with a lower morphine-equivalent consumption in the first 24 hours after surgery (MD, 2.68 mg), which indicates an opioid-sparing effect. Slightly superior postoperative pain relief with propofol anesthesia is indicated by reduced pain intensity and opioid consumption, a reduction in the use of rescue analgesia, and a longer time to first analgesia after surgery. This meta-analysis demonstrates for the first time the possible superiority of propofol anesthesia over inhalational anesthesia with respect to the analgesic effect, particularly in the early postoperative period. Although most of our results do indicate a benefit of propofol in this regard, it is noteworthy that all the differences are small and statistically nonsignificant if a P value cutoff of <.01 is used. Therefore, these differences may arguably not be clinically significant either.
Several possible mechanisms may help explain the effects of propofol and volatile agents on acute postoperative pain. Volatile agents are known to suppress the propagation of sensory afferent stimuli to the nervous system at anesthetic concentrations.49,50 It is worth noting that inhaled anesthetics tend to cause hyperalgesia at 0.1 minimum alveolar concentrations, which may be responsible for increased pain perception during recovery from anesthesia.51 The increased sensitivity to pain is mediated by modulation of central adrenergic and cholinergic transmission, as well as by 5-HT3 receptor–mediated currents.52,53 In contrast, propofol exhibits short-lasting analgesic properties with a trend toward reduced hyperalgesia and allodynia in healthy volunteers.54 In animal models, propofol suppresses nociception induced by spinal sensitization and decreases the lumbar dorsal horn neuronal responses to noxious stimuli.55,56 In addition, antioxidant and neuroprotective effects of propofol also have been documented.57,58
Use of opioids is the cornerstone of analgesic therapy for moderate-to-severe pain. Acute and chronic exposure to opioids, however, is associated with the development of hyperalgesia because of involvement of N-methyl-D-aspartate (NMDA) receptor in pain facilitating systems.59 Remifentanil, an ultra short–acting opioid, causes opioid-induced hyperalgesia through a cellular mechanism that involves rapid and prolonged up-regulation of NMDA receptor function.60,61 Moreover, propofol directly activates γ-aminobutyric acid type A receptors, inhibits NMDA receptors, and modulates calcium influx through the slow calcium–ion channels.62 Finally, maintenance of general anesthesia with propofol has been shown to prevent remifentanil-induced hyperalgesia.43,63
The subgroup analyses revealed better postoperative analgesia with propofol in patients who received concomitant intraoperative remifentanil. These findings suggest a synergistic effect between propofol and remifentanil leading to a more potent NMDA antagonistic effect on opioid-associated hyperalgesia than that observed with volatile agents.
There are several limitations of our study. First, when applying a conservative P value of <.01, the main differences between propofol and inhalational anesthesia are small and not statistically significant. The clinical relevance of these results needs to be further investigated. Second, there is difficulty in attributing the analgesic properties of propofol or hyperalgesic effects of sevoflurane, although there is evidence to support both. Complex interaction exists between general anesthetics and opioids in the pain facilitating systems. Third, the opioids used for postoperative pain relief varied between the studies, and the calculation of morphine-equivalents may have introduced a bias. Fourth, a multimodal analgesic approach with local anesthetics, NSAIDS, and opioids could mask any marginal difference that might exist between propofol and volatile agents. Fifth, despite subgroup analyses according to different techniques or analgesia regimens, this meta-analysis was affected by heterogeneity because of varied surgical procedures, different volatile anesthetics studied, various perioperative analgesic regimens used, and different indices used for titration of anesthesia depth; therefore, the results should be interpreted with caution. Finally, our study did not evaluate the effects of propofol or volatile agents on the long-term outcomes such as chronic pain. Further studies with adequate power to investigate long-term and short-term pain outcomes after propofol or inhalational anesthesia are required.
This meta-analysis did not demonstrate significant differences in postoperative pain control between propofol anesthesia and inhalational anesthesia because of substantial heterogeneity among studies. Large RCTs may be needed to verify whether the choice of anesthetics may contribute to a multimodal pain management and improved patient outcomes.
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