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.