Physiol. Res. 69: 157-164, 2020 https://doi.org/10.33549/physiolres.934133 Regulatory Effects of Propofol on High-Dose Remifentanil-Induced Hyperalgesia Xiaohu SU1, Wei ZHU2, Yufeng TIAN1, Lei TAN1, Hao WU1, Lei WU1 1Department of Anesthesiology, Suqian First Hospital, Suqian, Jiangsu Province, P. R. China, 2Department of Anesthesiology, Jiangsu Province Hospital, Nanjing, Jiangsu Province, P. R. China Received February 1, 2019 Accepted November 20, 2019 Epub Ahead of Print December 19, 2019 Summary Key words We aimed to evaluate the regulatory effects of propofol on high- Remifentanil • Hyperalgesia • Propofol dose remifentanil-induced hyperalgesia. A total of 180 patients receiving laparoscopic cholecystectomy were randomly divided Corresponding author into sevoflurane + high-dose remifentanil (SH) group, W. Zhu, Department of Anesthesiology, Jiangsu Province sevoflurane + low-dose remifentanil (SL) group and propofol + Hospital, Nanjing 210029, Jiangsu Province, P. R. China. E-mail: high-dose remifentanil group (PH) group (n=60). After [email protected], Y. Tian, Department of Anesthesiology, intravenous administration of midazolam, SH and SL groups were Suqian First Hospital, Suqian 223800, Jiangsu Province, induced with sevoflurane and remifentanil, and PH group was P. R. China. E-mail: [email protected] induced with propofol and remifentanil. During anesthesia maintenance, SH and SL groups were given 0.3 μg/kg/min and Introduction 0.1 μg/kg/min sevoflurane and remifentanil respectively, and PH group was given 0.3 μg/kg/min propofol and remifentanil. Opioids, as the most commonly used analgesic The three groups had significantly different awakening time, drugs in clinical practice, are widely used for general extubation time and total dose of remifentanil (P<0.001). anesthesia, postoperative analgesia and chronic pain Compared with SL group, periumbilical mechanical pain alleviation. However, opioids may cause acute tolerance thresholds 6 h and 24 h after surgery significantly decreased in and hyperalgesia. Acute opioid tolerance (AOT) refers to SH group (P<0.05), and the visual analog scale (VAS) scores reduction in the therapeutic effects, requiring higher significantly increased 30 min, 2 h and 6 h after surgery doses to maintain the analgesic effects. Opioid-induced (P<0.05). Compared with SH group, periumbilical mechanical hyperalgesia (OIH) is a state of pain sensitization, which thresholds 6 h and 24 h after surgery were significantly higher in is manifested as decrease in the threshold of pain, with PH group (P<0.05), and VAS scores 30 min, 2 h and 6 h after a shift in the stimulus-pain curve to the left, i.e. stimulus surgery were significantly lower (P<0.05). PH group first used with the same intensity may induce more intense pain. patient-controlled intravenous analgesia pump significantly later Specifically, patients may become more sensitive to than SL group did (P<0.05). The total consumptions of sufentanil painful stimuli after using opioids for treatment (Bekhit in PH and SL groups were significantly lower than that of 2010). SH group (P<0.05). The incidence rates of bradycardia and As an ultra-short-acting μ opioid receptor postoperative chill in PH and SH groups were significantly higher agonist, remifentanil is widely used for general anesthesia than those of SL group (P<0.05). Anesthesia by infusion of high- due to fast onset, short half-life of elimination, no dose remifentanil plus sevoflurane caused postoperative accumulation, metabolism through non-specific esterases hyperalgesia which was relieved through intravenous anesthesia in plasma and tissues, and constant context-sensitive half- with propofol. time. Basic and clinical studies have verified that PHYSIOLOGICAL RESEARCH • ISSN 1802-9973 (online) 2020 Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic Fax +420 241 062 164, e-mail: [email protected], www.biomed.cas.cz/physiolres 158 Su et al. Vol. 69 AOT and/or OIH occurred after continuous propofol plus remifentanil on remifentanil-induced administration of remifentanil (Lee et al. 2011, Ishida hyperalgesia. et al. 2012). Intraoperative use of high-dose remifentanil may induce postoperative acute pain and hyperalgesia, Subjects and Methods leading to poor outcomes of early postoperative analgesia (Fletcher and Martinez 2014). The mechanisms of Baseline clinical data remifentanil-induced AOT and/or OIH remain unclear A total of 180 patients (20-60 years old) with and may be associated with opioid receptor changes, ASA grade I-II, who received laparoscopic cholecystec- activation of the NMDA receptor system, reduction of tomy, were randomly divided into a sevoflurane + high- γ-aminobutyric acid receptor, as well as increased release dose remifentanil group (SH group), a sevoflurane + low- of opioid peptides, neuropeptides, nociceptin, dynorphin dose remifentanil group (SL group) and a propofol + A and cellular inflammatory factors (prostaglandin, high-dose remifentanil group (PH group) (n=60). interleukin-1, interleukin-6) (Yu et al. 2016). Exclusion criteria: Severe cardiopulmonary diseases, Remifentanil activates inhibitory G protein by stimulating hypertension, diabetes, alcohol or drug abuse, history of μ receptor, exerting analgesic effects through down- acute or chronic pain, current administration of regulation of intracellular cAMP. Long-term continuous analgesics, obesity (body mass index (BMI)>30 kg/m2), administration of remifentanil can reduce the number of and incorrect use of patient-controlled intravenous produced receptors and cause opioid tolerance. Then analgesia (PCIA) pump. This study has been approved by rapid metabolism of remifentanil leads to compensatory the ethics committee of our hospital, and written up-regulation of cAMP bypass and induces acute informed consent has been obtained from all patients. tolerance. Besides, remifentanil binds μ receptor and activates active G protein to induce hyperalgesia. Methods Activation of the NMDA receptor system may be one of The patients fasted and water-deprived before the main mechanisms for acute tolerance and/or surgery. The venous access was established after entering hyperalgesia (Kaye et al. 2014). Remifentanil can the operating room, and vital signs were routinely enhance NMDA receptor function by promoting the monitored, including blood pressure, oxyhemoglobin expressions of NR2B subunits in spinal cord neurons, and saturation, electrocardiogram, anesthetic gas concentra- facilitate pain signal transduction and central tion monitoring (Detax-Ohmeda S/5 monitor, USA) and sensitization, finally resulting in hyperalgesia. In bispectral index (BIS) measurement (Vista Covidien, addition, remifentanil can agonize μ receptor, inhibit the USA). After intravenous administration with 2-3 mg of glutamate transport system, and increase the glutamate midazolam, SH and SL groups were induced by inhaling content supplied to NMDA receptors for activation. sevoflurane, and the circuit was flushed for 3 min with Remifentanil is often used in combination with 7 l/min of oxygen and 7 % sevoflurane. The patients propofol for general anesthesia. Propofol can inhibit the inhaled sevoflurane by mask for induction, accompanied involvement of NMDA glutamate subtype receptors in by assisted ventilation. Two minutes after the start of regulating hyperalgesia (Ahmed et al. 2016). Moreover, induction, 4 l/min of oxygen and 3 % sevoflurane were propofol can delay and attenuate remifentanil-induced used. Meanwhile, 2 μg/kg remifentanil was slowly hyperalgesia (Rivosecchi et al. 2014), but related clinical administered and then changed to 0.5 μg/kg/min for indices are mainly postoperative visual analog scale induction. The PH group was injected slowly with (VAS) score and postoperative consumption of 2 mg/kg propofol and 2 μg/kg remifentanil, and then analgesics. In fact, if the threshold for pain is not directly pumped with 0.5 μg/kg/min remifentanil for induction. measured, it is difficult to objectively assess the When BIS was lower than 50, 0.9 mg/kg rocuronium was relationship between use of remifentanil and given intravenously, followed by endotracheal intubation. postoperative hyperalgesia, because one of the The SH group was anesthetized with 0.3 μg/kg/min characteristics of hyperalgesia is the decrease of pain sevoflurane and remifentanil for anesthesia maintenance, threshold. Therefore, we herein employed electronic von the SL group was given 0.1 μg/kg/min sevoflurane and Frey (EVF) to detect postoperative pain threshold. In remifentanil, and the PH group was given 0.3 μg/kg/min combination with postoperative pain score and analgesic propofol and remifentanil. The end-tidal carbon dioxide consumption, we evaluated the effects of anesthesia using pressure (PETCO2) was maintained at 35-45 mm Hg 2020 Effects of Propofol on Hyperalgesia 159 during surgery. BIS was adjusted within the range of incision. The measurement was performed before and 6 h 40-60 by increasing or decreasing the concentration of and 24 h after surgery, respectively. The total dose of sevoflurane or propofol. If hypotension remifentanil, first time of using PCIA pump, total (MAP<60 mm Hg) occurred and was not relieved after postoperative sufentanil consumption, awakening time 5 min of rapid infusion, 10 mg ephedrine was (from stopping using anesthetics to opening eyes by intravenously given. When bradycardia (HR<45 bpm) being woken up) and extubation time (from stopping took place, 0.5 mg atropine was intravenously given. using