<p>Remifentanil-Induced Secondary Hyperalgesia Is Not Prevented By Preoperative Acetazolamide Administration In Patients Undergoing Total Thyroidectomy: A Randomized Controlled Trial</p>

Abstract

PurposeAcute administration of remifentanil may lead to opioid-induced hyperalgesia (OIH). Studies in mice suggest that OIH is mediated by impaired anionic homeostasis in spinal lamina I neurons due to a down-regulation of the K+-Cl− co-transporter KCC2, which was reverted using acetazolamide (ACTZ), a carbonic anhydrase inhibitor. We propose that ACTZ prevents remifentanil-mediated OIH in humans.Patients and methodsWe conducted a randomized, double-blind, placebo-controlled clinical trial between December 2016 and September 2018. Patients were randomly allocated to receive ACTZ (250 mg of ACTZ 2 h before surgery) or placebo. To detect hyperalgesia, mechanical pain threshold (MPT) were measured before and after surgery using hand-held von Frey filaments in the forearm. Anesthesia was maintained with remifentanil at a target effect site of 4.5 ± 0.5 ng/mL, and sevoflurane at an end-tidal concentration of 0.8 MAC corrected for age.ResultsIn total, 47 patients completed the study. Both groups were comparable in the baseline characteristics and intraoperative variables. Baseline MPT were similar in both groups. However, MPT in the forearm significantly diminished in the time in both groups. Finally, postoperative pain and morphine consumption were similar between groups.ConclusionBoth groups developed remifentanil-mediated OIH at 12–18 h after surgery. However, ACTZ did not prevent the MPT reduction in patients undergoing total thyroidectomy.

Knowing the Enemy Is Halfway towards Victory: A Scoping Review on Opioid-Induced Hyperalgesia

“…Most of the studies showing OIH after surgery involve the use of intraoperative remifentanil [ 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ] ( Table 2 ). In fact, remifentanil is the only opioid analgesic for which a clear clinical OIH-inducing property has been demonstrated by a meta-analysis ( Table 3 ) [ 10 ].…”

“…Antinociceptive actions mediated through GABA receptors on neurons were posed to be impaired and therefore to contribute further to LTP in hyperalgic signaling, enhancing perpetuation of OIH [ 93 , 94 ]. The impairment of GABA receptors in these conditions, while experimentally achieved through induction of inhibitory neuronal KCC2 channels [ 2 , 95 ], was not shown to be clinically applicable in acute OIH using acetazolamide, a pharmacological inhibitor of carbonic anhydrase in clinical use [ 67 , 96 ]. In an RCT involving patients under surgical analgesia using remifentanil, concomitantly revealing hyperalgic manifestations compatible with OIH, acetazolamide was unsuccessful in reverting these disturbances through the additional use of this substance [ 67 ], unlike other substances applied in similar conditions as mentioned in Table 2 .…”