A Role for Transmembrane Protein 16C/Slack Impairment in Excitatory Nociceptive Synaptic Plasticity in the Pathogenesis of Remifentanil-induced Hyperalgesia in Rats / 神经科学通报·英文版

Remifentanil is widely used to control intraoperative pain. However, its analgesic effect is limited by the generation of postoperative hyperalgesia. In this study, we investigated whether the impairment of transmembrane protein 16C (TMEM16C)/Slack is required for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) activation in remifentanil-induced postoperative hyperalgesia. Remifentanil anesthesia reduced the paw withdrawal threshold from 2 h to 48 h postoperatively, with a decrease in the expression of TMEM16C and Slack in the dorsal root ganglia (DRG) and spinal cord. Knockdown of TMEM16C in the DRG reduced the expression of Slack and elevated the basal peripheral sensitivity and AMPAR expression and function. Overexpression of TMEM16C in the DRG impaired remifentanil-induced ERK1/2 phosphorylation and behavioral hyperalgesia. AMPAR-mediated current and neuronal excitability were downregulated by TMEM16C overexpression in the spinal cord. Taken together, these findings suggest that TMEM16C/Slack regulation of excitatory synaptic plasticity via GluA1-containing AMPARs is critical in the pathogenesis of remifentanil-induced postoperative hyperalgesia in rats.

The analgesic effect of nefopam combined with low dose remifentanil in patients undergoing middle ear surgery under desflurane anesthesia: a randomized controlled trial / 대한마취과학회지

BACKGROUND: We investigated the effects of the combined administration of nefopam, a N-methyl-D-aspartate receptor antagonist and low dose remifentanil, on early postoperative pain and analgesic requirement. METHODS: Fifty patients scheduled to undergo mastoidectomy and tympanoplasty were randomized to be given either nefopam 40 mg mixed with normal saline 100 ml (Group N) or an equal amount of normal saline (Group C) before anesthesia induction. Anesthesia was maintained with 5-6 vol% desflurane and remifentanil 0.05-0.15 microg/kg/min during the surgery. Postoperative pain was controlled by titration of ketorolac in the postanesthesia care unit (PACU) and ward. We evaluated the intraoperative remifentanil dose, recovery profiles, ketorolac demand in the PACU and ward, numeric rating scale (NRS) for pain at time intervals of every 10 min for 1 h in the PACU, 6, 12, 18 and 24 h in a ward, as well as the time to first analgesic requirement in the PACU and ward. RESULTS: Ketorolac demand and NRS in the PACU were significantly lower in Group N than Group C (P = 0.002, P = 0.005, respectively). The time to first analgesic requirement in the PACU in Group N were significantly longer than Group C (P = 0.046). There were no significant differences in intraoperative remifentanil dose, ketorolac demand, NRS, and the time to first analgesic requirement in the ward between the groups. CONCLUSIONS: Nefopam administration combined with low dose remifentanil infusion reduces pain and analgesic consumption during the immediate postoperative period in patients undergoing middle ear surgery under desflurane anesthesia.

Interaction between postoperative shivering and hyperalgesia caused by high-dose remifentanil / 대한마취과학회지

BACKGROUND: High-dose remifentanil-based anesthesia is associated with opioid-induced hyperalgesia (OIH) and postanesthetic shivering (PAS). These effects can be prevented by N-methyl-d-aspartate (NMDA) receptor antagonists. This study aimed to investigate correlations between OIH and PAS caused by high-dose remifentanil and the effects of low-dose ketamine on OIH and PAS. METHODS: Seventy-five patients scheduled for single-port laparoscopic gynecologic surgery were randomly allocated into three groups, each of which received intraoperative remifentanil: group L at 0.1 microg/kg/min; group H at 0.3 microg/kg/min; and group HK at 0.3 microg/kg/min plus 0.25 mg/kg ketamine just before incision, followed by a continuous infusion of 5 microg/kg/min ketamine until skin closure. RESULTS: PAS, postoperative tactile pain threshold, and the extent of hyperalgesia in group H were significantly different (P < 0.05) than in the other two groups. PAS was significantly correlated with OIH, including mechanically evoked pain such as postoperative tactile pain threshold (r = -0.529, P = 0.01) (r = -0.458, P = 0.021) and the extent of hyperalgesia (r = 0.537, P = 0.002) (r = 0.384, P = 0.031), respectively, in group H and group HK. Notably, both groups were treated with high-dose remifentanil. Tympanic membrane temperature, time to first postoperative analgesic requirement, postoperative pain scores, analgesic consumption, and cumulative patient-controlled analgesia volume containing morphine were comparable in all three groups. CONCLUSIONS: OIH, including the enhanced perception of pain, and PAS were both associated with high-dose remifentanil, were significantly correlated and were attenuated by a low dose of ketamine. This suggests that a common mechanism in part mediated through activation of the central glutamatergic system (e.g., NMDA receptors), underlies the two effects caused by high doses of remifentanil.

Effect of oral pregabalin on opioid-induced hyperalgesia in patients undergoing laparo-endoscopic single-site urologic surgery / 대한마취과학회지

BACKGROUND: Pregabalin is an antiepileptic drug that is effective for treating postoperative pain, neuropathic pain, anxiety, and hemodynamic instability. The aim of this study was to investigate the effect of a single preoperative dose of pregabalin in patients with opioid-induced hyperalgesia (OIH). METHODS: Ninety ASA I-II patients undergoing laparoendoscopic single-site urologic surgery were randomly assigned to one of the following three groups that received either pregabalin or placebo 1 h before anesthesia and an intraoperative remifentanil infusion. Group plL received placebo and 0.05 microgram/kg/min remifentanil, group plH received placebo and 0.3 microgram/kg/min remifentanil, and group prH received 300 mg pregabalin plus 0.3 microgram/kg/min remifentanil. The primary endpoint was pain intensity upon movement 1, 6, 12, and 24 h after surgery. Secondary endpoints were the area of hyperalgesia and mechanical hyperalgesia threshold 24 h after surgery, time to first postoperative analgesic requirement, and cumulative postoperative volume of morphine administered via a patient-controlled analgesia (PCA) pump over 24 h. RESULTS: The time to first postoperative analgesic requirement in group plH was significantly shorter than that in group plL. The injected PCA volume was significantly greater in group plH than that in the other two groups. Postoperative pain intensity in group plH was significantly greater than that in the other two groups at 6, 12, and 24 h after surgery. The mechanical hyperalgesia threshold and the area of hyperalgesia around the surgical incision 24 h after surgery in group plH differed significantly from those in the other two groups, which were not significantly different. Adverse effects were comparable among groups. CONCLUSIONS: High-dose remifentanil induced hyperalgesia, including increased pain intensity, increased area of hyperalgesia, and decreased mechanical hyperalgesia threshold. These effects were attenuated by oral administration of a single preoperative dose of pregabalin (300 mg) in patients undergoing laparo-endoscopic single-site urologic surgery.

Antihyperalgesic effects of dexmedetomidine on high-dose remifentanil-induced hyperalgesia / 대한마취과학회지

BACKGROUND: Dexmedetomidine is a highly selective alpha2 adrenergic agonist that has been shown to decrease the intensity of opioid-induced hyperalgesia (OIH). We aimed to investigate the antihyperalgesic effects of dexmedetomidine on high-dose remifentanil-induced hyperalgesia. METHODS: Ninety American Society of Anesthesiologists physical status I-II patients undergoing laparoscopically assisted vaginal hysterectomy (LAVH) were randomly assigned to one of the following three groups, each of which received either dexmedetomidine (an initial dose of 1.0 microg/kg for 10 min, followed by a continuous infusion of 0.7 microg/kg/hr) or placebo saline 15 min before the induction of anesthesia and intraoperative remifentanil infusion: group C received a placebo and 0.05 microg/kg/min remifentanil; group RH received a placebo and 0.3 microg/kg/min remifentanil; and group DRH received dexmedetomidine and 0.3 microg/kg/min remifentanil. RESULTS: The mechanical hyperalgesia threshold 24 hr after surgery was significantly lower in group RH than in the other two groups. Postoperative pain intensity using visual analog scale (VAS) and cumulative volume of a patient-controlled analgesia (PCA) containing morphine over 24 hr were significantly greater in group RH than in group DRH. The time to the first postoperative analgesic requirement was significantly shorter in group RH than in the other two groups. The desflurane requirement was significantly greater in group C than in the other groups. The frequency of hypotension and bradycardia was significantly higher, but shivering and postoperative nausea and vomiting were significantly lower in group DRH than in the other two groups. CONCLUSIONS: High-doses of remifentanil induced hyperalgesia, which presented a decreased mechanical hyperalgesia threshold, enhanced pain intensity, a shorter time to first postoperative analgesic requirement, and greater morphine consumption, but dexmedetomidine efficiently alleviated those symptoms. Dexmedetomidine may be a novel and effective treatment option for preventing or attenuating OIH.

Pain managements in pancreatic cancer patient with opioid-induced hyperalgesia: A case report

Opioids are generally used to treat severe cancer pain. Usually, it is common to increase the dose of opioids to maintain analgesia. Opioid-induced hyperalgesia (OIH) is a paradoxical response to opioid resulting in increased perception of pain rather than antinociceptive effect. A 64-year-old female with pancreatic cancer was suffering from whole abdominal pain. She took massive opioid therapy, however, her pain had been worse and widen in the 3 months. Radiologic imaging was performed to exclude metastatic cancer. The result was negative. We suspected OIH, and reduced the amount of opioids, then, added to adjuvant analgesics. And also we performed celiac plexus neurolysis with the use of alcohol and continuous epidural catheter insertion. Her numeric rating pain scale (NRS) decreased from 9/10 to 3/10. This case suggests that adjuvant analgesics and interventional treatments can resolve a OIH patient with intractable cancer pain.

The Effects of Intraoperative Adenosine Infusion on Acute Opioid Tolerance and Opioid Induced Hyperalgesia Induced by Remifentanil in Adult Patients Undergoing Tonsillectomy

BACKGROUND: Adenosine has been shown to have a wide spectrum of unique pain-relieving effects in various clinical situations. The aim of this study was to investigate the effects of intraoperative adenosine infusion on acute opioid tolerance and opioid induced hyperalgesia induced by remifentanil in adult patients undergoing tonsillectomy. METHODS: For this study, ninety patients were randomly allocated into groups that receive either adenosine (adenosine group) or saline (remifentnail group) intravenously under remifentanil based anesthesia and saline (sevoflurane group) under sevoflurane anesthesia. The patients in adenosine group received adenosine at dose of 80 microg/kg/min, and those in remifentnail group and sevoflurane group received an equal volume of saline 10 minutes after the induction of anesthesia until the end of surgery. Intraoperative evaluation included time weighted mean remifentanil dose, and postoperative evaluations included degree of pain severity at 1, 6, 12, and 24 hours, time to first postoperative requirement, and analgesic dose required during 24 hours after operation. RESULTS: Time weighted mean remifentanil dose during intraoperative period in adenosine group was significantly lower than that of remifentnail group (P = 0.00). The first postoperative analgesic were required earlier in remifentanil group than sevoflurane group or adenosine group (P = 0.00). Pethidine requirement during 24 hours in sevoflurane group and adenosine group was significantly lower than that of remifentnail group (P = 0.00). The visual analog scale scores for pain in sevoflurane group and adenosine group were significantly lower than those of remifentnail group for 12 hours after operation (P = 0.00). Incidence of hypotension (P = 0.024) and number of ephedrine administered (P = 0.011) in adenosine group were significantly higher than those of sevoflurane group. CONCLUSIONS: The above results suggest that intraoperative adenosine infusion prevent acute opioid tolerance and opioid induced hyperalgesia induced by remifentanil.

The Effects of Intraoperative Adenosine Infusion on Acute Opioid Tolerance and Opioid Induced Hyperalgesia Induced by Remifentanil in Adult Patients Undergoing Tonsillectomy

BACKGROUND: Adenosine has been shown to have a wide spectrum of unique pain-relieving effects in various clinical situations. The aim of this study was to investigate the effects of intraoperative adenosine infusion on acute opioid tolerance and opioid induced hyperalgesia induced by remifentanil in adult patients undergoing tonsillectomy. METHODS: For this study, ninety patients were randomly allocated into groups that receive either adenosine (adenosine group) or saline (remifentnail group) intravenously under remifentanil based anesthesia and saline (sevoflurane group) under sevoflurane anesthesia. The patients in adenosine group received adenosine at dose of 80 microg/kg/min, and those in remifentnail group and sevoflurane group received an equal volume of saline 10 minutes after the induction of anesthesia until the end of surgery. Intraoperative evaluation included time weighted mean remifentanil dose, and postoperative evaluations included degree of pain severity at 1, 6, 12, and 24 hours, time to first postoperative requirement, and analgesic dose required during 24 hours after operation. RESULTS: Time weighted mean remifentanil dose during intraoperative period in adenosine group was significantly lower than that of remifentnail group (P = 0.00). The first postoperative analgesic were required earlier in remifentanil group than sevoflurane group or adenosine group (P = 0.00). Pethidine requirement during 24 hours in sevoflurane group and adenosine group was significantly lower than that of remifentnail group (P = 0.00). The visual analog scale scores for pain in sevoflurane group and adenosine group were significantly lower than those of remifentnail group for 12 hours after operation (P = 0.00). Incidence of hypotension (P = 0.024) and number of ephedrine administered (P = 0.011) in adenosine group were significantly higher than those of sevoflurane group. CONCLUSIONS: The above results suggest that intraoperative adenosine infusion prevent acute opioid tolerance and opioid induced hyperalgesia induced by remifentanil.

The effects of magnesium sulfate infiltration on perioperative opioid consumption and opioid-induced hyperalgesia in patients undergoing robot-assisted laparoscopic prostatectomy with remifentanil-based anesthesia / 대한마취과학회지

BACKGROUND: Opioids not only exert an antinociceptive effect, but also modulate central N-methyl-D-aspartate (NMDA) receptors, resulting in hyperalgesia and acute opioid tolerance. This study was aimed to investigate the effect of the NMDA receptor antagonist, magnesium in preventing remifentanil-induced hyperalgesia. METHODS: For this study, 75 patients scheduled for robot-assisted laparoscopic prostatectomy were randomly allocated into three groups of patients whose incision sites were infiltrated: Group M, with 25% magnesium sulfate 80 mg/kg; Group S, with the same volume of saline under remifentanil-based anesthesia, and Group D, with the same volume of saline under desflurane based anesthesia. All three groups were infiltrated into incision sites after pneumoperitoneum. Intraoperative evaluation included mean remifentanil dose, and postoperative evaluation included pain severity at time intervals of 30 min, 6, 12, 24 and 36 hours, time to first postoperative analgesic requirement, and analgesic dosage required during 24 hours. RESULTS: Mean remifentanil doses during the intraoperative periods in group M were significantly lower than those in group S (P < 0.001). The time to first postoperative analgesic requirement in postoperative period in groups M and D was significantly longer than that in group S (P < 0.001). Visual analog scale scores for pain in groups M and D were significantly lower than those in group S for 12 hours after operation. CONCLUSIONS: A relatively high dose and continuous infusion of remifentanil were associated with opioid induced hyperalgesia. Wound infiltration with magnesium sulfate decreased opioid consumption and reduces opioid induced hyperalgesia.