Role of Inhaled Methoxyflurane in the Management of Acute Trauma Pain.
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ABSTRACT:
SUBMITTER: Fabbri A
PROVIDER: S-EPMC7323816 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
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Role of Inhaled Methoxyflurane in the Management of Acute Trauma Pain.
Fabbri Andrea A Ruggiano Germana G Garcia Collado Sergio S Ricard-Hibon Agnes A Restelli Umberto U Sbrana Giovanni G Marinangeli Franco F Farina Alberto A Coffey Frank F
Journal of pain research 20200625
Adequate treatment of trauma pain is an integral part of the management of trauma patients, not just for ethical reasons but also because undertreated pain can lead to increased morbidities and worse long-term outcomes. Trauma pain management presents challenges in the pre-hospital setting, particularly in adverse or hostile environments as well as in busy emergency departments (EDs). Inhaled methoxyflurane, administered at analgesic doses via a disposable inhaler, has recently become available ...[more]
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Project description:Methoxyflurane is an inhaled analgesic administered via a disposable inhaler which has been used in Australia for over 40 years for the management of pain associated with trauma and for medical procedures in children and adults. Now available in 16 countries worldwide, it is licensed in Europe for moderate to severe pain associated with trauma in conscious adults, although additional applications are being made to widen the range of approved indications. Considering these ongoing developments, we reviewed the available evidence on clinical usage and safety of inhaled analgesic methoxyflurane in trauma pain and in medical procedures in both adults and children. Published data on methoxyflurane in trauma and procedural pain show it to be effective, well tolerated, and highly rated by patients, providing rapid onset of analgesia. Methoxyflurane has a well-established safety profile; adverse events are usually brief and self-limiting, and no clinically significant effects on vital signs or consciousness levels have been reported. Nephrotoxicity previously associated with methoxyflurane at high anesthetic doses is not reported with low analgesic doses. Although two large retrospective comparative studies in the prehospital setting showed inhaled analgesic methoxyflurane to be less effective than intravenous morphine and intranasal fentanyl, this should be balanced against the administration, supervision times, and safety profile of these agents. Given the limitations of currently available analgesic agents in the prehospital and emergency department settings, the ease of use and portability of methoxyflurane combined with its rapid onset of effective pain relief and favorable safety profile make it a useful nonopioid option for pain management. Except for the STOP! study, which formed the basis for approval in trauma pain in Europe, and a few smaller randomized controlled trials (RCTs), much of the available data are observational or retrospective, and further RCTs are currently underway to provide more robust data.
| S-EPMC6200081 | biostudies-other
Project description:IntroductionEvidence on the use of inhaled methoxyflurane in the management of trauma pain is conflicting and obfuscated. This study aimed to determine the efficacy and safety of inhaled methoxyflurane for trauma pain on the basis of published randomized controlled trials (RCTs).MethodsRCTs assessing the efficacy of methoxyflurane in adults or adolescents with acute trauma pain published in PubMed, Web of Science, Embase, Cochrane Library, and Google Scholar were searched. The control groups were those that received placebo or standard analgesic treatment (SAT). The primary outcome was the change from baseline in pain scores during the first 30 min of treatment. Secondary outcomes included time to first pain relief, the proportion of patients experiencing pain relief, rescue analgesia rate, the treatment satisfaction of patients and investigators, and the methoxyflurane-related treatment-emergent adverse events (TEAEs).ResultsA total of nine RCTs (1806 patients) were identified. Results revealed that methoxyflurane provided a clinically unimportant benefit by improving the mean difference of change from baseline in pain intensity (from - 0.44 to - 1.23 cm, p < 0.001) at various time points within the first 20 min compared to control treatment. Besides, methoxyflurane decreased the time of onset of pain relief (mean difference - 5.29 min; 95% CI - 6.97 to - 3.62) and the proportion of patients who needed rescue analgesic medication (risk ratio 1.41; 95% CI 1.17-1.70) despite it increasing the risk of non-severe TEAEs (risk ratio 3.09; 95% CI 1.72-5.57). Notably, the benefit of almost all secondary pain-related outcomes was rendered clinically nonsignificant between methoxyflurane and SAT strata besides the time of onset of pain relief. The quality of evidence was low or very low in all outcomes.ConclusionsIn emergency situations without effective therapy, this systematic review and meta-analysis provides low-quality evidence that methoxyflurane can be used as a rapid-acting and effective treatment for acute trauma pain, although its utilization is associated a risk of non-severe TEAEs. However, the current evidence does not support the notion that inhaled methoxyflurane offered superior analgesic efficacy to SAT.Clinical trial numberPROSPERO registration number CRD42020223000.
| S-EPMC8119536 | biostudies-literature
Project description:BackgroundMore than 75% of patients presenting to the Emergency Department are suffering symptoms of pain. Despite this, 67% will not receive any analgesia. Methoxyflurane is a fluorinated hydrocarbon gas which has analgesic properties when inhaled. Penthrox is a methoxyflurane autoinhaler recently licenced in Europe. Its ease of administration, safety, and fast onset of action make it of particular relevance to emergency medicine. Additionally, outside the hospital, it has the advantage of increased temperature stability and portability over current standard care. New evidence of its efficacy is emerging; however, currently, its use in Europe is not widespread. The objective of this study will be to systematically evaluate the evidence on inhaled methoxyflurane to determine if it is a superior analgesia in the acute trauma setting.MethodsWe designed and registered a study protocol for a systematic review and meta-analysis on randomised controlled trials, comparing inhaled methoxyflurane and either placebo or standard care. A comprehensive search will be conducted from database inception onwards in MEDLINE, Embase, and the Cochrane CENTRAL database, concurrent with a search of the grey literature for other relevant studies, including clinical trial databases. Only randomised controlled trials will be included. No limitations will be imposed on publication status or language of publication. The primary outcome will be mean difference in patient-reported pain at time points within the first 30 min of administration. Secondary outcomes will be mean difference in time to clinically significant pain relief and relative risk of adverse effects. Two reviewers will independently screen all returned studies and collect data. Disagreements will be resolved through discussion or referral to a third reviewer. Individual study methodological quality will be appraised using an appropriate tool. If feasible, we will conduct a random effects meta-analysis; if this is not possible, we will construct a narrative synthesis.DiscussionThis systematic review will summarise the best available evidence and definitively establish if inhaled methoxyflurane is a superior analgesia to standard care in the acute trauma setting. This knowledge will directly impact emergency care in the UK and worldwide and may require amendments to European pain relief guidelines.Systematic review registrationPROSPERO CRD42020189119 .
| S-EPMC7860209 | biostudies-literature
Project description:PurposeAcute trauma pain management in the elderly population is a challenge. Inhaled methoxyflurane represents a promising treatment option; however, data in the elderly population are limited.Patients and methodsSubgroup, post hoc analysis including 69 patients aged ≥65 years from a randomized, active-controlled, open-label study in the emergency setting. Key inclusion criterion was moderate-to-severe pain (Numerical Rating Scale [NRS] score ≥ 4]) secondary to trauma in a single limb. Patients received inhaled methoxyflurane (3 mL) or standard analgesic treatment (SAT; IV paracetamol 1 g or ketoprofen 100 mg for moderate pain [NRS 4-6] and IV morphine 0.1mg/kg for severe pain [NRS ≥7]). The primary endpoint was the overall change in visual analog scale (VAS) pain intensity from randomization to the next 3, 5, and 10 min. Secondary endpoints included time to onset of pain relief (TOPR), efficacy up to 30 min, judgment of operators and patients, and safety.ResultsPain reduction over time was similar in both groups. Median TOPR was shorter for methoxyflurane (9 min; 95% CI: 7.8, 10.2 min) than SAT (15 min; 95% CI: 10.2, 19.8 min). In terms of treatment satisfaction, patients and operators rated treatment efficacy and practicality, respectively, as "Excellent" or "Very good" 5.7 times and 3.4 times more frequently than SAT. A similar rate of adverse events (methoxyflurane: 6 events; SAT: 7 events) was recorded, all non-serious. No clinically significant changes in vital signs parameters were observed, and methoxyflurane did not result in cases of bradycardia or hypotension.ConclusionIn elderly patients with trauma pain, inhaled methoxyflurane shows similar pain relief and safety compared to SAT, offering advantages in terms of onset of effect and user's satisfaction. Although this analysis presents some methodological limitations, it provides the first specific evidence of the use of inhaled methoxyflurane in the elderly population.Trial registrationEudraCT number: 2017-001565-25; Clinicaltrials.gov identifier NCT03585374.
| S-EPMC7371437 | biostudies-literature
Project description:Purpose:Opioid analgesics remain the cornerstone of treatment for severe trauma pain in the emergency setting, but there are barriers to their use. This post hoc analysis of a previously reported trial (MEDITA) investigated the efficacy and safety of low-dose methoxyflurane versus intravenous (IV) morphine for severe trauma pain. Patients and Methods:MEDITA was a Phase IIIb, randomized, active-controlled, parallel-group, open-label study in Italian pre-hospital units and emergency departments (EudraCT: 2017-001565-25; NCT03585374). Adult patients (N=272) with moderate-to-severe trauma pain (score ?4 on the Numerical Rating Scale [NRS]) were randomized 1:1 to inhaled methoxyflurane (3 mL) or standard analgesic treatment (SAT; IV paracetamol 1g or ketoprofen 100mg for moderate pain [NRS 4-6] and IV morphine 0.1mg/kg for severe pain [NRS ?7]). Analyses were performed for the severe pain subgroup. The primary efficacy variable was the overall change from baseline in visual analog scale (VAS) pain intensity at 3, 5 and 10min post-randomization. Non-inferiority of methoxyflurane versus morphine was concluded if the upper 95% confidence interval (CI) for the treatment difference was <1; superiority was concluded if the upper 95% CI was <0. Results:Ninety-three patients (methoxyflurane: 49; SAT: 44) were included in the severe pain intention-to-treat population. The reduction in VAS pain intensity over the first 10min was superior for methoxyflurane versus morphine (adjusted mean treatment difference: -5.54mm; 95% CI: -10.49, -0.59mm; p=0.029). Median time to onset of pain relief was 9min for methoxyflurane and 15min for morphine. Patients rated treatment efficacy and physicians rated treatment practicality "Excellent" or "Very good" for more methoxyflurane-treated patients (42.8% and 67.3%) than morphine-treated patients (18.1% and 22.8%). Adverse events, all non-serious, were reported in 20.4% of methoxyflurane-treated patients and in 4.8% of morphine-treated patients. Conclusion:Methoxyflurane provided superior short-term pain relief to IV morphine in patients with severe trauma pain and offers an effective non-narcotic treatment option.
| S-EPMC7064290 | biostudies-literature
Project description:IntroductionInhaled low-dose methoxyflurane is approved in Europe for emergency relief of moderate-to-severe trauma-related pain in adults, but data versus active comparators are sparse. The phase IIIb Methoxyflurane in Emergency Department in ITAly (MEDITA) trial investigated the analgesic efficacy, practicality and safety of methoxyflurane versus standard analgesic treatment (SAT) for acute trauma pain.MethodsThis was a randomised, active-controlled, parallel-group, open-label trial conducted in 15 Italian emergency units. Adults with limb trauma and pain score ≥ 4 on numerical rating scale (NRS) were randomised 1:1 to inhaled methoxyflurane 3 mL or SAT [intravenously administered (IV) morphine 0.1 mg/kg for severe pain (NRS ≥ 7); IV paracetamol 1 g or IV ketoprofen 100 mg for moderate pain (NRS 4-6)]. The primary endpoint was overall change in visual analogue scale (VAS) pain intensity from baseline (time of randomisation) to 3, 5 and 10 min. Non-inferiority and superiority of methoxyflurane versus SAT were concluded if the upper 95% confidence interval (CI) for the treatment comparison (methoxyflurane-SAT) was less than 1 and less than 0, respectively.ResultsBetween 8 February 2018 and 8 February 2019, 272 patients were randomised (136 per treatment group). A total of 270 patients (mean age 51 years; 49% male; 34% with severe pain; mean baseline VAS 67 mm) were treated and analysed for efficacy and safety. Superiority of methoxyflurane was demonstrated for moderate-to-severe pain (adjusted mean treatment difference - 5.94 mm; 95% CI - 8.83, - 3.06 mm), moderate pain (- 5.97 mm; 95% CI - 9.55, - 2.39 mm) and severe pain (- 5.54 mm; 95% CI - 10.49, - 0.59 mm). Median onset of pain relief was 9 min for methoxyflurane and 15 min for SAT. Practicality of methoxyflurane treatment was rated "Excellent", "Very Good" or "Good" by 90% of clinicians vs. 64% for SAT. Adverse events (all non-serious) were reported by 17% of methoxyflurane-treated patients and 3% of SAT-treated patients.ConclusionMethoxyflurane provided superior pain relief to SAT in patients with moderate-to-severe trauma pain and may offer a simple, fast, effective non-opioid treatment option.Trial registrationTrial registered with EudraCT (2017-001565-25) on 2 March 2018 and ClinicalTrials.gov (NCT03585374) on 13 July 2018.FundingMundipharma Pharmaceuticals S.r.l.
| S-EPMC6822789 | biostudies-literature
Project description:IntroductionThe inhalational analgesic low-dose methoxyflurane has been widely used by Australian ambulance services since 1975 and is now approved in Europe for emergency relief of moderate-to-severe trauma-related pain in conscious adult patients. The use of methoxyflurane in hostile environments is of special interest given its portability, ease of use and rapid onset of action. This trial will investigate the efficacy, tolerability and practicality of use of inhaled methoxyflurane in patients with moderate-to-severe trauma-related pain rescued from hostile mountainous environments by the Helicopter Emergency Medical Service (HEMS) in Italy.MethodsMETEORA is a phase IIIb, prospective, single-arm, multicentre trial. Approximately 200 adult patients with a pain score of at least 4 on the numerical rating scale (NRS) due to limb trauma rescued by HEMS will be enrolled. Patients will receive up to 2 × 3 mL methoxyflurane, self-administered by the patient by inhalation under medical supervision. Rescue medication will be permitted if required.Planned outcomesPain intensity will be measured using a 100-mm visual analogue scale (VAS) at baseline, at 5, 10, 15, 20, 30, 45 and 60 min after the start of methoxyflurane inhalation and when positioning the patient on a spinal board or stretcher; and also using the NRS at enrolment and at 10 min. Use of rescue medication (yes/no) will be recorded. The patient will rate efficacy and the healthcare professional will rate practicality of methoxyflurane treatment at 30 and 60 min using a 5-point Likert scale. Vital signs will be measured at baseline, 10, 30 and 60 min. Assessments after 30 min will only be performed for patients using a second inhaler. Adverse events will be recorded until safety follow-up at 3 ± 1 days. The primary endpoint is the percentage of patients achieving at least 30% improvement from baseline in VAS pain intensity within the first 10 min of methoxyflurane administration.Trial registrationEudraCT number: 2017-004601-40.FundingMundipharma Pharmaceuticals, srl. Plain language summary available for this article.
| S-EPMC6223977 | biostudies-literature
Project description:BACKGROUND:Acute trauma pain is poorly managed in the emergency department (ED). The reasons are partly organizational: ED crowding and rare trauma care pathways contribute to oligoanalgesia. Anticipating the organizational impact of an innovative care procedure might facilitate the decision-making process and help to optimize pain management. METHODS:We used a multiple criteria decision analysis (MCDA) approach to consider the organizational impact of methoxyflurane (self-administered) in the ED, introduced alone or supported by a trauma care pathway. A MCDA experiment was designed for this specific context, 8 experts in emergency trauma care pathways (leading physicians and pharmacists working in French urban tertiary hospitals) were recruited. The study involved four steps: (i) Selection of organizational criteria for evaluating the innovation's impact; (ii) assessment of the relative weight of each criterion; (iii) choice of appropriate scenarios for exploring the organizational impact of MEOX under various contexts; and (iv) software-assisted simulation based on pairwise comparisons of the scenarios. The final outcome measure was the expected overall organizational impact of methoxyflurane on a 0-to-100 scale (score >50: positive impact). RESULTS:Nine organizational criteria were selected. "Mean length of stay in the ED" was the most weighted. Methoxyflurane alone obtained 59 as a total score, with a putative positive impact for eight criteria, and a neutral effect on one. When a trauma care pathway was introduced concomitantly, the impact of methoxyflurane was greater overall (score: 75) and for each individual criterion. CONCLUSIONS:Our model highlighted the putative positive organizational impact of methoxyflurane in the ED-particularly when supported by a trauma care pathway-and the relevance of expert consensus in this particular pharmacoeconomic context. The MCDA approach could be extended to other research fields and healthcare challenges in emergency medicine.
| S-EPMC7159203 | biostudies-literature
Project description:IntroductionLow-dose methoxyflurane, administered via a hand-held inhaler, has been used for short-term pain relief in emergency medicine in Australia and New Zealand for over 40 years, and was recently approved in Europe for the rapid relief of moderate-to-severe trauma-related pain in adults. There is currently a lack of data for methoxyflurane versus active comparators, therefore this trial will investigate the efficacy and safety of inhaled methoxyflurane compared with standard of care (SoC) in the treatment of acute trauma-related pain in pre-hospital and ED settings in Italy.MethodsMEDITA (Methoxyflurane in Emergency Department in ITAly) is a Phase IIIb, prospective, randomised, active-controlled, parallel-group, open-label, multicentre trial. A total of 272 adult patients with moderate-to-severe pain [score ≥ 4 on the Numerical Rating Scale (NRS)] due to limb trauma will be randomised 1:1 to receive 3 mL methoxyflurane (self-administered by the patient via inhalation under supervision of a trained person) or medications that currently comprise the SoC in Italy [intravenous (IV) morphine for severe pain (NRS ≥ 7); IV paracetamol or ketoprofen for moderate pain (NRS 4-6)], administered as soon as possible after randomisation.Planned outcomesPain intensity will be measured using a 100-mm visual analogue scale (VAS) at baseline (time of randomisation) and at intervals up to 30 min. Time of onset of pain relief as reported by the patient and use of rescue medication will be recorded. The patient will rate the efficacy and the healthcare professional will rate the practicality of study treatment at 30 min after randomisation using a 5-point Likert scale. Adverse events will be recorded until safety follow-up at 14 ± 2 days. Vital signs will be measured at baseline, 10 and 30 min. The primary aim is to demonstrate non-inferiority of methoxyflurane versus SoC for the change in VAS pain intensity from baseline (randomisation) to 3, 5 and 10 min.Trial registrationEudraCT number: 2017-001565-25. Clinicaltrials.gov identifier: NCT03585374.FundingMundipharma Pharmaceuticals srl.
| S-EPMC6318254 | biostudies-literature
Project description:BackgroundWe aimed to investigate clinical benefits and economic costs of inhaled methoxyflurane when used by ambulance staff for prehospital emergency patients with trauma. Comparison is to usual analgesic practice (UAP) in the UK in which patient records were selected if treatment had been with Entonox® or intravenous morphine or intravenous paracetamol.MethodsOver a 12-month evaluation period, verbal numerical pain scores (VNPS) were gathered from adults with moderate to severe trauma pain attended by ambulance staff trained in administering and supplied with methoxyflurane. Control VNPS were obtained from ambulance database records of UAP in similar patients for the same period. Statistical modelling enabled comparisons of methoxyflurane to UAP, where we employed an Ordered Probit panel regression model for pain, linked by observational rules to VNPS.ResultsOverall, 96 trained paramedics and technicians from the East Midlands Ambulance Service NHS Trust (EMAS) prepared 510 doses of methoxyflurane for administration to a total of 483 patients. Comparison data extracted from the EMAS database of UAP episodes involved: 753 patients using Entonox®, 802 patients using intravenous morphine, and 278 patients using intravenous paracetamol. Modelling results included demonstration of faster pain relief with inhaled methoxyflurane (all p-values < 0.001). Methoxyflurane's time to achieve maximum pain relief was estimated to be significantly shorter: 26.4 min (95%CI 25.0-27.8) versus Entonox® 44.4 min (95%CI 39.5-49.3); 26.5 min (95%CI 25.0-27.9) versus intravenous morphine 41.8 min (95%CI 38.9-44.7); 26.5 min (95%CI 25.1-28.0) versus intravenous paracetamol 40.8 (95%CI 34.7-46.9). Scenario analyses showed that durations spent in severe pain were significantly less for methoxyflurane. Costing scenarios showed the added benefits of methoxyflurane were achieved at higher cost, eg versus Entonox® the additional cost per treated patient was estimated to be £12.30.ConclusionWhen administered to adults with moderate or severe pain due to trauma inhaled methoxyflurane reduced pain more rapidly and to a greater extent than Entonox® and parenteral analgesics. Inclusion of inhaled methoxyflurane to the suite of prehospital analgesics provides a clinically useful addition, but one that is costlier per treated patient.
| S-EPMC9261021 | biostudies-literature