4. Discussion
Since the morbidity concealment, complex pathogenesis and treatment uncertainty for OIH, the best strategy is to prevent its occurrence. This is the first systematic review and network meta-analysis to compare different pharmacological interventions and explore the best strategy for preventing the increase in postoperative pain due to OIH in adults after general anesthesia. Twenty treatments were compared and analyzed from following aspects: pain intensity, opioid-related adverse effects, pain threshold, time to first rescue analgesic and morphine consumption. We found that no such perfect drug that ranked the best in all indicators. This seems to highlight the importance of individualized treatment selection and multimodal approach.
Our results reveal that amantadine, magnesium sulphate, pregabalin, dexmedetomidine, ibuprofen, flurbiprofen plus dexmedetomidine, parecoxib, parecoxib plus dexmedetomidine and S (+)-ketamine plus methadone all show their potential to prevent the increase of postoperative pain intensity, and amantadine seems to be the best option among all 20 interventions included in the analysis. Although the mechanisms for the development of OIH are not completely understood, preclinical models implicate the glutaminergic system and pathologic activation of NMDA receptors in the development of central sensitization[23-25]. Among these effective interventions, amantadine, magnesium sulphate, methadone and S (+)-ketamine are known to be antagonists of NMDA receptor, where its primary effects are thought to occur. Wu L et al. reported that perioperative administration of NMDA receptor antagonists could effectively prevent the increase of postoperative pain intensity and morphine consumption[13]. However, our works draw a partially consistent conclusion that amantadine may be the best option but either ketamine or S (+)-ketamine fails to show significant superiority in deterring the raise of postoperative pain intensity. Possible factors responsible for this discrepancy could be that the conclusion of Wu L et al.’s needs an extraordinary prudent interpretation due to a high heterogeneity even after subgroup analysis; the studies involved were small (only 14 studies included 3 drugs which directly act on NMDA receptors), with possible overestimation of the risk of Type II statistical error. On the other hand, the effect of an intervention may be affected by others to different extents in NMA. Thus, we suggest that future studies should consider confirming our meta-analysis results.
Ibuprofen, flurbiprofen and parecoxib belong to non-steroidal anti-inflammatory drugs (NSAIDs), which are widely used worldwide with potent anti-inflammatory, analgesic and antipyretic activity. It is well known that one of their main mechanisms of action is the inhibition of cyclo-oxygenase (COX), the enzyme involved in biosynthesing prostaglandins and thromboxane[26]. Interestingly, prostaglandins have been proved to modulate nociceptive processing[27] and stimulate the release of the excitatory amino acid glutamate in spinal cord dorsal horns[28]. Furthermore, the antagonize function of COX inhibitors to NMDA receptor in central nervous system also has been revealed[29, 30]. Clinical study or meta-analysis about the effect of COX inhibitors on OIH is still lacking although it has been proved in animal models[31, 32]and human volunteers[33, 34].
It has been indicated that pronociceptive effects caused by opioids result from the central and peripheral nervous system sensitization, which is similar to the mechanism of hyperalgesia associated with nerve injury[35]. Pregabalin is a 3-substituted analogue of γ-aminobutyric acid and treatment of neuropathic pain[36] which shares a close structure and similar mechanism of action with gabapentin but has fewer side effects[37]. The effect of pregabalin to reduce hyperalgesia and allodynia in human volunteers[38]and rat models[39] are acknowledged. However, A J Lederer et al. reviewed the effects of pregabalin on OIH and concluded that, while strongly supported by theoretical considerations, the recommendation as a clinical routine still lack of clinical evidence[40]. Stoicia et al. also draw a similar conclusion that the application of gabapentin in mitigating OIH still needs support from large-scale standardized patient studies[41].
Dexmedetomidine is a potent and highly selective α-2 adrenoceptor agonist with sympatholytic, sedative, amnestic, and analgesic properties[42]. Its anti-hyperalgesia effects are closely related to NMDA receptors. Animal experiments reveal that dexmedetomidine modulates spinal cord NMDA receptors activation via suppressing tyrosine phosphorylation of NR2B in the superficial spinal cord, which was found up-regulated when remifentanil-induced hyperalgesia happens[43], [44]. Likewise, its anti-hyperalgesia effect in clinical routine requires more evaluation of further studies.
The results of this meta-analysis also revealed that, compared with placebo, dexmedetomidine and flurbiprofen plus dexmedetomidine are the only two strategies that are associated with a lower incidence of PONV. It is interesting to note that flurbiprofen alone has no superior effect. This seems to infer that it is dexmedetomidine plays a significant role in preventing PONV. This finding is in line with past studies[45-47]. Jin S et al.[46] investigated the effect of dexmedetomidine on PONV on patients during general anesthesia and reported that dexmedetomidine (irrespective of administration mode) had a significantly lower incidence of PONV than placebo. It was through that this added antiemetic effect may be explained by α2 agonists through inhibition of catecholamine by parasympathetic tone, although the biologic basis remains obscure. Alternatively, consumption of intraoperative anesthetics and opioids, which have been considered risk factors for PONV[48], may be reduced with the use of dexmedetomidine.
Consideration of treatment risk/benefit ratio is an important factor in clinical decision-making. Our results show that, although there is the best option in every index, dexmedetomidine is the only pharmacological intervention that demonstrated superiority to placebo in all indicators. In addition, the multifarious benefit of dexmedetomidine in improving quality of emergence from anesthesia[49], reducing postoperative delirium incidence[50], enhancing recovery after surgery[51] and organ-protective effects[52] has been already fully proved and widely accepted. It is difficult to deny that dexmedetomidine is an attractive anesthetic adjuvant notwithstanding the side effects of hypotension and bradycardia[53].
This network meta-analysis had several possible limitations. First, since multiple interventions were included in the analysis, several had data from only one study and therefore a relatively small sample size, which may have led to possible bias and overestimation of treatment effect. Second, some non-pharmacological interventions were not involved to compare, such as gradual withdrawal of remifentanil[54], opioid rotation[55] and combination with a regional nerve block[56]. Third, variation was presented in the opioid dosage, timing, administration regimens, surgery duration and maintenance of anesthesia. These disparities restrict the amount of data that can be pooled in meta-analysis which present major challenges in interpretation and applicability of the results. Overall, this systematic review and network meta-analysis provides the best summary of the comparative effect of different pharmacological interventions on improving the postoperative pain intensity caused by OIH.