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Low-dose methoxyflurane analgesia in adolescent patients with moderate-to-severe trauma pain: a subgroup analysis of the STOP! study.

ABSTRACT: Introduction:The 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 methods:Three 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. Results:Mean 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. Conclusion:This 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 registration:Clinicaltrials.gov identifier: NCT01420159, EudraCT number: 2011-000338-12.

SUBMITTER: Hartshorn S

PROVIDER: S-EPMC6388743 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Low-dose methoxyflurane analgesia in adolescent patients with moderate-to-severe trauma pain: a subgroup analysis of the STOP! study.

Hartshorn Stuart S Dissmann Patrick P Coffey Frank F Lomax Mark M

Journal of pain research 20190215

<h4>Introduction</h4>The 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.<h4>Patients and methods</h4>Three hundred patients (96 in the adolescent subgroup) aged ≥12 years requiring analgesia for acute trauma pain (pain score of 4-7 ...[more]

PMID: 30863141

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Project description:IntroductionAcute pain remains highly prevalent in the Emergency Department (ED) setting. This double-blind, randomized, placebo-controlled UK study investigated the efficacy and safety of low-dose methoxyflurane analgesia for the treatment of acute pain in the ED in the adult population of the STOP! trial.MethodsPatients presenting to the ED requiring analgesia for acute pain (pain score of 4-7 on the Numerical Rating Scale) due to minor trauma were randomized in a 1:1 ratio to receive methoxyflurane (up to 6 mL) or placebo (normal saline), both via a Penthrox® (Medical Developments International Limited, Scoresby, Australia) inhaler. Rescue medication (paracetamol/opioids) was available immediately upon request. Change from baseline in visual analog scale (VAS) pain intensity was the primary endpoint.Results300 adult and adolescent patients were randomized; data are presented for the adult subgroup (N = 204). Mean baseline VAS pain score was ~66 mm in both groups. The mean change from baseline to 5, 10, 15 and 20 min was greater for methoxyflurane (-20.7, -27.4, -33.3 and -34.8 mm, respectively) than placebo (-8.0, -11.1, -12.3 and -15.2 mm, respectively). The primary analysis showed a highly significant treatment effect overall across all four time points (-17.4 mm; 95% confidence interval: -22.3 to -12.5 mm; p < 0.0001). Median time to first pain relief was 5 min with methoxyflurane [versus 20 min with placebo; (hazard ratio: 2.32; 95% CI: 1.63, 3.30; p < 0.0001)]; 79.4% of methoxyflurane-treated patients experienced pain relief within 1-10 inhalations. 22.8% of placebo-treated patients requested rescue medication within 20 min compared with 2.0% of methoxyflurane-treated patients (p = 0.0003). Methoxyflurane treatment was rated 'Excellent', 'Very Good' or 'Good' by 77.6% of patients, 74.5% of physicians and 72.5% of nurses. Treatment-related adverse events (mostly dizziness/headache) were reported by 42.2% of patients receiving methoxyflurane and 14.9% of patients receiving placebo; none caused withdrawal and the majority were mild and transient.ConclusionThe results of this study support the evidence from previous trials that low-dose methoxyflurane administered via the Penthrox inhaler is a well-tolerated, efficacious and rapid-acting analgesic.FundingMedical Developments International (MDI) Limited and Mundipharma Research GmbH & Co.KG.Trial registrationClinicaltrials.gov identifier: NCT01420159, EudraCT number: 2011-000338-12.

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: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.

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.

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:BackgroundThe buprenorphine transdermal system (BTDS) is approved in the US for the management of chronic pain. Due to its high affinity for μ-opioid receptors with a slow dissociation profile, buprenorphine may potentially displace or prevent the binding of competing μ-opioid-receptor agonists, including immediate-release (IR) opioids, in a dose-dependent manner. Health care professionals may assume that the use of IR opioids for supplemental analgesia during BTDS therapy is not acceptable.Materials and methodsThis post hoc analysis evaluated the use of IR opioids as supplemental analgesia during the management of moderate-severe chronic pain with BTDS at 52 US sites (BUP3015S, NCT01125917). Patients were categorized into IR-opioid and no-IR-opioid groups. At each visit of the extension phase, adverse events, concomitant medications, and information from the Brief Pain Inventory (BPI) were recorded.ResultsThe most common supplemental IR opioids prescribed during BTDS treatment (n=354) were hydrocodone-acetaminophen and oxycodone-acetaminophen. The mean daily dose of IR opioids (morphine equivalents) for supplemental analgesia was 22 mg. At baseline, BPI - pain intensity and BPI - interference scores were higher for patients in the IR-opioid group. In both treatment groups, scores improved by week 4, and then were maintained throughout 6 months of the open-label extension trial. The incidence of treatment-emergent adverse events was similar in both groups.ConclusionPatients who were prescribed IR opioids reported lower scores for BPI pain intensity and pain interference to levels similar to patients receiving BTDS without IR opioids, without increasing the rate or severity of treatment-emergent adverse events. Patients prescribed concomitant use of IR opioids with BTDS had greater treatment persistence. The results of this post hoc analysis provide support for the concomitant use of IR opioids for supplemental analgesia during the management of moderate-severe chronic pain with BTDS.

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.

Dataset Information

Low-dose methoxyflurane analgesia in adolescent patients with moderate-to-severe trauma pain: a subgroup analysis of the STOP! study.

Publications

Low-dose methoxyflurane analgesia in adolescent patients with moderate-to-severe trauma pain: a subgroup analysis of the STOP! study.

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