Haemodynamic effects of methoxyflurane versus fentanyl and placebo in hypovolaemia: a randomised, double-blind crossover study in healthy volunteers.

Background: Methoxyflurane is approved for relief of moderate to severe pain in conscious adult trauma patients: it may be self-administrated and is well suited for use in austere environments. Trauma patients may sustain injuries causing occult haemorrhage compromising haemodynamic stability, and it is therefore important to elucidate whether methoxyflurane may adversely affect the haemodynamic response to hypovolaemia. Methods: In this randomised, double-blinded, placebo-controlled, three-period crossover study, inhaled methoxyflurane 3 ml, i.v. fentanyl 25 µg, and placebo were administered to 15 healthy volunteers exposed to experimental hypovolaemia in the lower body negative pressure model. The primary endpoint was the effect of treatment on changes in cardiac output, while secondary endpoints were changes in stroke volume and mean arterial pressure and time to haemodynamic decompensation during lower body negative pressure. Results: There were no statistically significant effects of treatment on the changes in cardiac output, stroke volume, or mean arterial pressure during lower body negative pressure. The time to decompensation was longer for methoxyflurane compared with fentanyl (hazard ratio 1.9; 95% confidence interval 0.4-3.4; P=0.010), whereas there was no significant difference to placebo (hazard ratio -1.3; 95% confidence interval -2.8 to 0.23; P=0.117). Conclusions: The present study does not indicate that methoxyflurane has significant adverse haemodynamic effects in conscious adults experiencing hypovolaemia. Clinical trial registration: ClinicalTrials.gov (NCT04641949) and EudraCT (2019-004144-29) https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004144-29/NO.

Determination of equi-analgesic doses of inhaled methoxyflurane versus intravenous fentanyl using the cold pressor test in volunteers: a randomised, double-blinded, placebo-controlled crossover study.

BACKGROUND: Inhaled methoxyflurane for acute pain relief has demonstrated an analgesic effect superior to placebo. Data comparing methoxyflurane to an opioid are needed. The aim of this study was to determine the equi-analgesic doses of inhaled methoxyflurane vs i.v. fentanyl. Both drugs have an onset within minutes and an analgesic effect of 20-30 min. METHODS: Twelve subjects were included in a randomised, double-blinded, placebo-controlled crossover study with four treatments: placebo (NaCl 0.9%), fentanyl 25 µg i.v., fentanyl 50 µg i.v., or inhaled methoxyflurane 3 ml. The subjects reported pain intensity using the verbal numeric rating scale (VNRS) from 0 to 10 during the cold pressor test (CPT). The CPT was performed before (CPT 1), 5 min (CPT 2), and 20 min (CPT 3) after drug administration. RESULTS: Inhaled methoxyflurane and fentanyl 25 µg reduced VNRS scores significantly compared with placebo at CPT 2 (-1.14 [estimated difference in VNRS between treatment groups with 95% confidence interval {CI}: -1.50 to -0.78]; -1.15 [95% CI: -1.51 to -0.79]; both P<0.001) and CPT 3 (-0.60 [95% CI: -0.96 to -0.24]; -0.84 [95% CI: -1.20 to -0.47]; both P<0.001). There were no significant differences between the two drugs. Methoxyflurane had significantly higher VNRS scores than fentanyl 50 µg at CPT 2 (0.90 [95% CI: 0.54-1.26]; P<0.001) and CPT 3 (0.57 [95% CI: 0.21-0.94]; P<0.001). CONCLUSIONS: Inhaled methoxyflurane 3 ml was equi-analgesic to fentanyl 25 µg i.v. at CPT 2. Both resulted in significantly less pain than placebo. Fentanyl 50 µg i.v. demonstrated analgesia superior to methoxyflurane. CLINICAL TRIAL REGISTRATION: NCT03894800.

Tapentadol versus oxycodone analgesia and side effects after laparoscopic hysterectomy: A randomised controlled trial.

BACKGROUND: Tapentadol is an opioid, which acts as a µ-opioid receptor agonist and inhibits noradrenaline reuptake in the central nervous system. This dual mechanism of action results in synergistic analgesic effects and potentially less side effects. This has been shown in treatment of chronic pain but postoperative studies are sparse. OBJECTIVES: The main aim was to compare the analgesic effect of tapentadol with oxycodone after laparoscopic hysterectomy. Opioid side effects were recorded as secondary outcomes. DESIGN: Randomised, blinded trial. SETTING: Single-centre, Oslo University Hospital, Norway, December 2017 to February 2019. PATIENTS: Eighty-six opioid-naïve American Society of Anesthesiologists physical status 1 to 3 women undergoing laparoscopic hysterectomy for nonmalignant conditions. INTERVENTION: The patients received either oral tapentadol (group T) or oxycodone (group O) as part of multimodal pain treatment. Extended-release study medicine was administered 1 h preoperatively and after 12 h. Immediate-release study medicine was used as rescue analgesia. MAIN OUTCOME MEASURES: Pain scores, opioid consumption and opioid-induced side effects were evaluated during the first 24 h after surgery. RESULTS: The groups scored similarly for pain at rest using a numerical rating scale (NRS) 1 h postoperatively (group T 4.4, 95% CI, 3.8 to 5.0, group O 4.6, 95% CI, 3.8 to 5.3). No statistically significant differences were found between the groups for NRS at rest or while coughing during the 24-h follow-up period (P = 0.857 and P = 0.973). Mean dose of oral rescue medicine was similar for the groups (P = 0.914). Group T had significantly lower odds for nausea at 2 and 3 h postoperatively (P = 0.040, P = 0.020) and less need for antiemetics than group O. No differences were found for respiratory depression, vomiting, dizziness, pruritus, headache or sedation. CONCLUSION: We found tapentadol to be similar in analgesic efficacy to oxycodone during the first 24 h after hysterectomy, but with significantly less nausea. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03314792.