Dataset Information

Comparison of inhalational methoxyflurane (Penthrox®) and intramuscular tramadol for prehospital analgesia.

ABSTRACT:

Introduction

Treatment of pain is an important component of prehospital care. Inhalational analgesia agents have attractive strengths, but there is a paucity of studies comparing these with more conventional agents. We aimed to compare inhalational methoxyflurane and intramuscular (IM) tramadol as first-contact analgesia in the Singapore national ambulance service.

Methods

Ambulances were randomised to carry either methoxyflurane or IM tramadol for the first six months and crossed over to the other arm after six months. Patients aged ≥ 16 years, with acute pain arising from musculoskeletal trauma with Numerical Rating Scale (NRS) score ≥ 3 were enrolled. Variables included NRS reduction, time variables, adverse effects, Ramsay Sedation Scores, and patient and paramedic satisfaction scores on a Likert scale.

Results

A total of 369 patients were enrolled into this study, but 26 patients were excluded due to missing data. The methoxyflurane arm had a shorter median time taken from arrival at the scene to drug administration (9.0 [interquartile range 6.0-14.0] minutes vs. 11.0 [interquartile range 8.0-15.0] minutes). For patients who achieved reduction in NRS ≥ 3 within 20 minutes, those in the methoxyflurane arm took a shorter time. However, the methoxyflurane (46.7%) arm experienced lower proportion of patients not achieving NRS reduction ≥ 3 when compared to the tramadol (71.6%) arm after over 20 minutes. The methoxyflurane arm had significantly higher paramedic and patient satisfaction scores.

Conclusion

For the doses of medication used in this implementation study, methoxyflurane was superior in efficacy, speed of onset and administration, but had more minor adverse effects when compared to IM tramadol.

SUBMITTER: Lim KJ

PROVIDER: S-EPMC8801836 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

Comparison of inhalational methoxyflurane (Penthrox®) and intramuscular tramadol for prehospital analgesia.

Lim Kegan Jianhong KJ Koh Zhi Xiong ZX Ng Yih Yng YY Fook-Chong Stephanie S Ho Andrew Fu Wah AFW Doctor Nausheen Edwin NE Said Nur Ain Zafirah Mohd NAZM Ong Marcus Eng Hock MEH

Singapore medical journal 20200317 6

<h4>Introduction</h4>Treatment of pain is an important component of prehospital care. Inhalational analgesia agents have attractive strengths, but there is a paucity of studies comparing these with more conventional agents. We aimed to compare inhalational methoxyflurane and intramuscular (IM) tramadol as first-contact analgesia in the Singapore national ambulance service.<h4>Methods</h4>Ambulances were randomised to carry either methoxyflurane or IM tramadol for the first six months and crossed ...[more]

PMID: 32179922

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Project description:Oligoanalgesia, the undertreatment of trauma-related pain using standard analgesics in prehospital and emergency departments, has been extensively documented as one of the major challenges affecting the effective treatment of trauma-related pain. When administered in low doses, methoxyflurane has been highlighted by numerous medical works of literature to provide an effective, nonopioid, nonnarcotic treatment alternative to standard analgesics for prehospital and emergency department use. Low-dose methoxyflurane has been associated with fast-pain relief in adult patients manifesting moderate-to-severe pain symptoms. This systematic review and meta-analysis aimed to assess the clinical implication of low-dose methoxyflurane use in prehospital and emergency departments in adult patients with moderate-to-severe trauma-related pain. Moreover, the review aimed at assessing the risk stratification associated with using low-dose methoxyflurane in prehospital and emergency departments. The systematic review and meta-analysis performed a comprehensive search for pertinent literature assessing the implications and risks of using low-dose methoxyflurane in adult patients exhibiting moderate-to-severe trauma-related pain in prehospital settings. A comparison between the use of low-dose methoxyflurane and standard-of-care analgesics, placebo, in prehospital settings was reported in four clinically conducted randomized controlled trials (RCTs). These RCTs included the STOP! trial, InMEDIATE, MEDIATA, and the PenASAP trials. A meta-analysis comparing the time taken to achieve first pain relief on initial treatment of patients with moderate-to-severe trauma-related pain favored the use of low-dose methoxyflurane to the standard-of-care analgesics (mean difference = -6.63, 95% confidence interval = -7.37, -5.09) on time taken to establish effective pain relief. Low-dose methoxyflurane has been associated with superior and faster pain relief in prehospital and emergency departments in adult patients exhibiting moderate-to-severe trauma-related pain compared to other standard analgesics.

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.

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 .

Project description:BACKGROUND:Pain from injuries is one of the commonest symptoms in children attending emergency departments (EDs), and this is often inadequately treated in both the pre-hospital and ED settings, in part due to challenges of continual assessment and availability of easily administered analgesic options. Pain practices are therefore a key research priority, including within the field of paediatric emergency medicine. Methoxyflurane, delivered via a self-administered Penthrox® inhaler, belongs to the fluorinated hydrocarbon group of volatile anaesthetics and is unique among the group in having analgesic properties at low doses. Despite over 30 years of clinical acute analgesia use, and a large volume of evidence supporting its safety and efficacy, there is a paucity of randomised controlled trial data for Penthrox®. METHODS:This is an international multi-centre randomised, double-blind, placebo-controlled phase III trial assessing the efficacy and safety of methoxyflurane delivered via the Penthrox® inhaler for the management of moderate to severe acute traumatic pain in children and young people aged 6-17 years. Following written informed consent, eligible participants are randomised to self-administer either inhaled methoxyflurane (maximum dose of 2 × 3 ml) or normal saline placebo (maximum dose 2 × 5 ml). Patients, treating clinicians and research nurses are blinded to the treatment. The primary outcome is the change in pain intensity at 15 min after the commencement of treatment, as measured by the Visual Analogue Scale (VAS) or the Wong-Baker FACES® Pain Rating scale, with the latter converted to VAS values. Secondary outcome measures include the number and proportion of responders who achieve a 30% reduction in VAS score compared to baseline, rescue medication requested, time and number of inhalations to first pain relief, global medication performance assessment by the patient, clinician and research nurse, and evaluation of adverse events experienced during treatment and during the subsequent 14 ± 2 days. The primary analysis will be by intention to treat. The total sample size is 110 randomised and treated patients per treatment arm. DISCUSSION:The Methoxyflurane AnalGesia for Paediatric InjuriEs (MAGPIE) trial will provide efficacy and safety data for methoxyflurane administered via the Penthrox® inhaler, in children and adolescents who present to EDs with moderate to severe injury-related pain. TRIAL REGISTRATION:EudraCT, 2016-004290-41 . Registered on 11 April 2017. ClinicalTrials.gov, NCT03215056 . Registered on 12 July 2017.

Project description:BackgroundEarly termination of prolonged seizures with intravenous administration of benzodiazepines improves outcomes. For faster and more reliable administration, paramedics increasingly use an intramuscular route.MethodsThis double-blind, randomized, noninferiority trial compared the efficacy of intramuscular midazolam with that of intravenous lorazepam for children and adults in status epilepticus treated by paramedics. Subjects whose convulsions had persisted for more than 5 minutes and who were still convulsing after paramedics arrived were given the study medication by either intramuscular autoinjector or intravenous infusion. The primary outcome was absence of seizures at the time of arrival in the emergency department without the need for rescue therapy. Secondary outcomes included endotracheal intubation, recurrent seizures, and timing of treatment relative to the cessation of convulsive seizures. This trial tested the hypothesis that intramuscular midazolam was noninferior to intravenous lorazepam by a margin of 10 percentage points.ResultsAt the time of arrival in the emergency department, seizures were absent without rescue therapy in 329 of 448 subjects (73.4%) in the intramuscular-midazolam group and in 282 of 445 (63.4%) in the intravenous-lorazepam group (absolute difference, 10 percentage points; 95% confidence interval, 4.0 to 16.1; P<0.001 for both noninferiority and superiority). The two treatment groups were similar with respect to need for endotracheal intubation (14.1% of subjects with intramuscular midazolam and 14.4% with intravenous lorazepam) and recurrence of seizures (11.4% and 10.6%, respectively). Among subjects whose seizures ceased before arrival in the emergency department, the median times to active treatment were 1.2 minutes in the intramuscular-midazolam group and 4.8 minutes in the intravenous-lorazepam group, with corresponding median times from active treatment to cessation of convulsions of 3.3 minutes and 1.6 minutes. Adverse-event rates were similar in the two groups.ConclusionsFor subjects in status epilepticus, intramuscular midazolam is at least as safe and effective as intravenous lorazepam for prehospital seizure cessation. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, ClinicalTrials.gov NCT00809146.).

Project description:BackgroundPre-hospital pain management has traditionally been performed with intravenous (IV) morphine, but oligoanalgesia remain a recognized problem. Pain reduction is essential for patient satisfaction and is regarded as a measure of successful treatment. We aim to establish whether non-invasive methods such as inhalation of methoxyflurane is non-inferior to intranasal fentanyl or non-inferior to the well-known IV morphine in the pre-hospital treatment of acute pain.Method/designThe PreMeFen study is a phase three, three-armed, randomized, controlled, non-inferiority trial to compare three regimens of analgesics: inhalation of methoxyflurane and intranasal (IN) fentanyl versus IV morphine. It is an open-label trial with a 1:1:1 randomization to the three treatment groups. The primary endpoint is the change in pain numeric rating scale (NRS) (0-10) from baseline to 10 min after start of investigational medicinal product administration (IMP). The non-inferiority margin was set to 1.3, and a sample size of 270 patients per protocol (90 in each treatment arm) will detect this difference with 90% power.DiscussionWe chose a study design with comparison of analgesic regimens rather than fixed doses because of the substantial differences in drug characteristics and for the results to be relevant to inform policymakers in the pre-hospital setting. We recognize that easier administration of analgesics will lead to better pain management for many patients if the regimens are as good as the existing, and hence, we chose a non-inferiority design. The primary endpoint, the change in pain (NRS) after 10 min, is set to address the immediate need of pain reduction for patients with acute prehospital pain. On a later stage, more analgesic methods are often available. PreMeFen is a non-inferiority randomized controlled trial comparing three analgesic regimens aiming to establish whether inhalation of methoxyflurane or intranasal fentanyl is as good as IV morphine for fast reduction of acute pain in the prehospital setting.

Project description:BackgroundLow-dose analgesic methoxyflurane (Penthrox®) was approved in Europe for emergency relief of moderate to severe pain in conscious adults with trauma in 2015. A comparative post-authorisation safety study (PASS) was conducted to assess the risk of hepatotoxicity and nephrotoxicity with methoxyflurane during routine clinical practice.MethodsThis was a comparative hybrid prospective-retrospective cohort study. The comparative cohorts consisted of adults who were given methoxyflurane (methoxyflurane cohort) or another analgesic (concurrent cohort) routinely used for moderate to severe trauma and associated pain in the emergency setting (ambulance and Emergency Department) in the UK between December 2016 and November 2018. Hepatic and renal events were captured in the ensuing 12 weeks. A blinded clinical adjudication committee assessed events. A historical comparator cohort (non-concurrent cohort) was identified from patients with fractures in the English Hospital Episode Statistics (HES) accident and emergency database from November 2013 and November 2015 (before commercial launch of methoxyflurane). Hepatic and renal events were captured in the ensuing 12 weeks via linkage with the Clinical Practice Research Datalink (CPRD) and HES hospital admissions databases.ResultsOverall, 1,236, 1,101 and 45,112 patients were analysed in the methoxyflurane, concurrent and non-concurrent comparator cohorts respectively. There was no significant difference in hepatic events between the methoxyflurane and concurrent cohorts (1.9% vs. 3.0%, P = 0.079) or between the methoxyflurane and non-concurrent cohorts (1.9% vs. 2.5%, P = 0.192). Renal events were significantly less common in the methoxyflurane cohort than in the concurrent cohort (2.3% vs. 5.6%, P < 0.001). For methoxyflurane versus non-concurrent cohort the lower occurrence of renal events (2.3% vs. 3.2%, P = 0.070) was not statistically significant. Multivariable adjustment did not change these associations.ConclusionsMethoxyflurane administration was not associated with an increased risk of hepatotoxicity or nephrotoxicity compared with other routinely administered analgesics and was associated with a reduced risk of nephrotoxicity compared with other routinely administered analgesics.Trial registrationStudy registered in the EU PAS Register (ENCEPP/SDPP/13040).

Project description:IntroductionThe undertreatment of acute pain presents a significant challenge in the Emergency Department. This post hoc subgroup analysis of a previously reported randomized controlled UK study reports the efficacy and safety of low-dose methoxyflurane analgesia in treating adolescent patients with moderate-to-severe trauma pain.Patients and methodsThree hundred patients (96 in the adolescent subgroup) aged ≥12 years requiring analgesia for acute trauma pain (pain score of 4-7 on the Numerical Rating Scale) at triage were randomized 1:1 to methoxyflurane (up to 6 mL) or placebo (normal saline), both administered using a Penthrox® inhaler. The patient could request rescue medication (paracetamol/opioids) at any time. The primary endpoint was the change from baseline in visual analog scale (VAS) pain intensity.ResultsMean VAS pain score for the adolescent subgroup at baseline was ~ 61 mm. Adjusted mean change in VAS pain intensity from baseline to 5, 10, 15, and 20 minutes was -24.5, -28.1, -31.6, and -31.7 mm for methoxyflurane and -14.6, -18.8, -19.2, and -23.7 mm for placebo, with a statistically significant treatment effect in favor of methoxyflurane overall across all four time points (-9.9 mm; 95% CI: -17.4, -2.4 mm; P=0.0104). Median time to first pain relief was significantly shorter with methoxyflurane (1 minute) than placebo (3 minutes, P<0.0001). Pain relief was reported within 1-10 inhalations in 95.7% of methoxyflurane-treated patients and 64.6% of placebo-treated patients. Rescue medication was requested by two (4.3%) methoxyflurane-treated patients and three (6.3%) placebo-treated patients. Over 95% of patients, physicians, and nurses rated methoxyflurane treatment as "Excellent", "Very Good" or "Good" compared with between 64% and 68% for placebo. The incidence of adverse events was higher with methoxyflurane (51%) than placebo (42%), mostly comprising mild/transient dizziness and headache.ConclusionThis subgroup analysis shows that low-dose inhaled methoxyflurane is a rapid-acting and effective analgesic in adolescent patients presenting with moderate-to-severe trauma pain.Trial registrationClinicaltrials.gov identifier: NCT01420159, EudraCT number: 2011-000338-12.

Dataset Information

Comparison of inhalational methoxyflurane (Penthrox®) and intramuscular tramadol for prehospital analgesia.

Introduction

Methods

Results

Conclusion

Publications

Comparison of inhalational methoxyflurane (Penthrox®) and intramuscular tramadol for prehospital analgesia.

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