Evaluation of antihyperalgesic and analgesic effects of 35% nitrous oxide when combined with remifentanil

Abstract

BACKGROUND Remifentanil is an effective drug in peri-operative pain therapy, but it can also induce and aggravate hyperalgesia. Supplemental administration of N2O may help to reduce remifentanil-induced hyperalgesia. OBJECTIVE To evaluate the effect of 35 and 50% N2O on hyperalgesia and pain after remifentanil infusion. DESIGN Single site, phase 1, double-blind, placebo-controlled, randomised crossover study. SETTING University Hospital, Germany from January 2012 to April 2012. PARTICIPANTS Twenty-one healthy male volunteers. INTERVENTIONS Transcutaneous electrical stimulation induced spontaneous acute pain and stable areas of hyperalgesia. Each volunteer underwent the following four sessions in a randomised order: 50 to 50% N2-O2 and intravenous (i.v.) 0.9% saline infusion (placebo); 50 to 50% N2-O2 and i.v. remifentanil infusion at 0.1 μg kg−1 min−1 (remifentanil); 35 to 15 to 50% N2O-N2-O2 and i.v. remifentanil infusion at 0.1 μg kg−1 min−1 (tested drug) and 50 to 50% N2O-O2 and i.v. remifentanil infusion at 0.1 μg kg−1 min−1 (gas active control). Gas mixtures were inhaled for 60 min; i.v. drugs were administered for 30 min. MAIN OUTCOME MEASURES Areas of pin-prick hyperalgesia, areas of touch-evoked allodynia and pain intensity on a visual analogue scale were assessed repeatedly for 160 min. RESULTS Data from 20 volunteers were analysed. There were significant treatment and treatment-by-time effects regarding areas of hyperalgesia (P < 0.001). After the treatment period, the area of hyperalgesia was significantly reduced (P < 0.001) in the tested drug and in the gas active control (30.6 ± 9.25 and 24.4 ± 7.3 cm2, respectively) compared with remifentanil (51.0 ± 17.0 cm2). There was also a significant difference between the gas active control and the tested drug sessions (P < 0.001). For the area of allodynia and pain rating, results were consistent with the results for hyperalgesia. CONCLUSIONS Administration of 35% N2O significantly reduced hyperalgesia, allodynia and pain intensity induced after remifentanil. It might therefore be suitable in peri-operative pain relief characterised by hyperalgesia and allodynia, such as postoperative pain, and may help to reduce opioid demand. TRIAL REGISTRATION EudraCT-No.: 2011-000966-37.

Remifentanil-induced hyperalgesia in healthy volunteers: a systematic review and meta-analysis of randomized controlled trials

“…Therefore, in these conditions, clinicians need to be cautious about the possible occurrence of acute opioid tolerance 24,25,48 and OIH, which may impair pain treatment or even worsen pre-existing pain. According to the previously reported results, coadministration of anaesthetic drugs, such as propofol, 43,45 nitrous oxide, 49 magnesium, 42 ketamine, 5,39 and dexmedetomidine, 50 seem to be helpful to modulate the development of OIH, even if their modulatory effect needs to be further explored. However, there is a lack of validated approaches to diagnose OIH, which may limit the relevance of these results.…”

Efficacy and safety of flurbiprofen‑axetil combined with nalbuphine pretreatment on remifentanil‑induced postoperative hyperalgesia: A randomized clinical trial

“…Due to the complexity of the mechanism of RIH, it may be necessary to use several drugs with different mechanisms to achieve a suitable effect for the prevention of hyperalgesia. Numerous strategies to alleviate RIH have been previously reported, including the use of minimal doses of remifentanil, gradual withdrawal of remifentanil infusion ( 21 , 22 ), multimodal analgesia, as well as alternative therapy, such as propofol ( 23 ), ketamine ( 24-26 ), dexmedetomidine ( 27 ), N 2 O ( 28 ) and COX inhibitors ( 29 ).…”

Effects of different doses of esketamine on hemodynamic indexes, pain stress indexes, and VAS scores in patients with benign ovarian tumors undergoing laparoscopic resection induced by remifentanil

“…In the context of this study, it was observed that patients in Group B displayed significantly lower heart rates at 30 min intraoperatively and 1 h postoperatively compared to Groups A and C. Furthermore, their mean arterial pressure was lower than that of Groups A and C, suggesting that 0.6 mg/kg esketamine for anesthesia could improve hemodynamic stability, possibly due to the potent dissociative anesthetic effects of esketamine, its noncompetitive antagonism of glutamate (mediated by NMDA receptors in the central nervous system), and the maintenance of a 0.6 mg/kg dose, which appears to be more conducive to maintaining hemodynamic stability. Previous studies have also explored the use of low-dose esketamine administered before anesthesia induction in children undergoing surgical procedures and demonstrated the efficacy of low-dose esketamine in suppressing the somatotropic response triggered by propofol [16,17]. Additionally, in a separate investigation, low-dose ketamine in combination with propofol was employed for epidural anesthesia in patients undergoing laparoscopic appendectomy, resulting in a significant reduction in anesthesia recovery time and improved hemodynamic stability [18].…”