Comparison of inhalational methoxyflurane, intranasal fentanyl, and intravenous morphine for treatment of prehospital acute pain in Norway (PreMeFen): a randomised, non-inferiority, three-arm, phase 3 trial.

# Comparison of inhalational methoxyflurane, intranasal fentanyl, and intravenous morphine for treatment of prehospital acute pain in Norway (PreMeFen): a randomised, non-inferiority, three-arm, phase 3 trial *The Lancet 2025* Articles Comparison of inhalational methoxyflurane, intranasal fentanyl, and intravenous morphine for treatment of prehospital acute pain in Norway (PreMeFen): a randomised, non-inferiority, three-arm, phase 3 trial Randi Simensen, Lars Olav Fjose, Kjetil Thorsen, Inge Christoffer Olsen, Marius Rehn, Jostein Hagemo, Live Smalberget, Fridtjof Heyerdahl Summary Background Adequate pain control is essential; however, acute pain is often undertreated in prehospital care. Lancet 2025; 406: 2957–67 This study aimed to evaluate three analgesic regimens for treating acute pain in an ambulance setting. Published Online November 20, 2025 Methods PreMeFen is a randomised, open-label, non-inferiority, three-arm, phase 3 trial conducted in the working https://doi.org/10.1016/ S0140-6736(25)01575-2 areas of the ground ambulance service of the Innlandet Hospital Trust, Norway. Patients aged 18–69 years and 70 years See Comment page 2870 and older with traumatic or medical acute pain scoring 4 or higher on the Numeric Rating Scale (NRS) were randomly Institute of Clinical Medicine, assigned (1:1:1) to receive in titration doses 3 mL inhalational methoxyflurane, 50 μg or 100 μg intranasal fentanyl, or University of Oslo, Oslo, 0·05 mg/kg or 0·1 mg/kg intravenous morphine, respectively, depending on the age group. The primary endpoint Norway (R Simensen MSc, was change in pain NRS score from baseline to 10 min after treatment start and was analysed per protocol. The non- Prof M Rehn PhD, J Hagemo PhD, inferiority margin was 1·3. This trial is registered with ClinicalTrials.gov (NCT05137184) and is completed. F Heyerdahl PhD); Department of Research and Development, Norwegian Air Ambulance Findings Between Nov 12, 2021, and April 22, 2023, 632 patients were assessed for eligibility, and 338 were randomly Foundation, Oslo, Norway assigned to methoxyflurane (n=112), fentanyl (n=115), or morphine (n=111). 281 patients were included in the per- (R Simensen MSc, protocol population. 145 (52%) of 281 patients were female and 136 (48%) were male. Median age was 61 years L O Fjose CandMed, K Thorsen PhD, Prof M Rehn PhD, (IQR 47–75). The baseline NRS score was 7·6 (SD 1∙8). Mean NRS score changes after 10 min were –3·31 (SD 2·67) J Hagemo PhD, L Smalberget BSc, for methoxyflurane, –1·98 (2·28) for fentanyl, and –2·74 (2∙12) for morphine. Comparing changes in mean NRS F Heyerdahl PhD); Prehospital score while adjusting for baseline showed that methoxyflurane was non-inferior to fentanyl Division, Innlandet Hospital (–1·33 [95% CI –2·01 to –0·64]) and morphine (–0·36 [–1·03 to 0·31]). Intranasal fentanyl was not non-inferior to Trust, Moelv, Norway (R Simensen MSc, L O Fjose MD, morphine at 10 min (0·91 [0·27 to 1·55]). Adverse events occurred in 26 (24%) of 109 patients in the morphine L Smalberget BSc); Division of group, 27 (24%) of 112 in the fentanyl group, and 24 (22%) of 111 in the methoxyflurane group. Two serious adverse Prehospital Services, Oslo events, respiratory depression (grade 2) and loss of consciousness (grade 3), occurred in the same patient in the University Hospital, Oslo, methoxyflurane group. There were no treatment-related deaths. Norway (R Simensen MSc, Prof M Rehn PhD, J Hagemo PhD, F Heyerdahl PhD); Department Interpretation Inhalational methoxyflurane is non-inferior to intranasal fentanyl and intravenous morphine for acute of Research Support for Clinical pain management in the prehospital environment, assessed 10 min after administration. Inhalational methoxyflurane Trials, Oslo University Hospital, serves as a valuable non-intravenous alternative in the early phase of treatment and might bridge the gap to longer- Oslo, Norway (I C Olsen PhD) acting analgesics. Correspondence to: Randi Simensen, Prehospital Division, Innlandet Hospital Funding Norwegian Air Ambulance Foundation and Innlandet Hospital Trust. Trust, Moelv 2390, Norway randi.simensen@norskluft Copyright © 2025 Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, ambulanse.no and similar technologies. Introduction poor access to the patient.7 Nevertheless, the International Pain is frequently encountered among patients receiving Association for the Study of Pain emphasised in the treatment from emergency medical service personnel, Declaration of Montreal that pain management is a with reports of up to 53% of patients having moderate to health challenge and defined access to pain relief as a severe pain.1 Inadequate prehospital treatment of pain is human right.8,9 widespread and well documented,2,3 and it can have Traditionally, prehospital pain management has immediate and long-term consequences.4 Undertreat- mainly involved intravenous opioid administration. ment of pain and variability in pain management However, peripheral venous cannulation has been strategies mirror the differences in competencies among reported to be unsuccessful in 12–26% of adults,10 prehospital personnel, ranging from technicians with resulting in oligoanalgesia. Patients might accordingly basic training to experienced physicians.5,6 The benefit from alternative, non-intravenous analgesic prehospital setting also adds challenges to pain administration routes that are safe, effective, easy to management, including weather, low temperatures, and administer, and fast-acting. Two such alternative Articles Research in context Evidence before this study Added value of this study We searched PubMed with the search terms (“fentanyl” The PreMeFen study contributes to the literature by OR “methoxyflurane”) AND (“intranasal” OR “inhalation”) establishing that methoxyflurane is non-inferior to intravenous AND (“emergency department” OR “emergency medical morphine and intranasal fentanyl in the management of acute, services” OR “ambulance” OR “air ambulance” OR “prehospital” moderate to severe traumatic and non-traumatic pain within OR “pre-hospital”) AND (“acute pain” OR “pain management” the prehospital context, as assessed 10 min post- OR “pain treatment” OR “pain therapy” OR “analgesia”) for administration. Notably, while intranasal fentanyl did not show studies published between June 1, 2006, and June 1, 2021, later non-inferiority to intravenous morphine at 10 min, it was updated to June 1, 2025. We focused on clinical studies, clinical shown to be non-inferior at 20 min and 30 min. This study adds trials, randomised controlled trials, reviews, systematic reviews, to existing evidence of non-intravenous alternatives for and meta-analyses. A systematic review indicated that immediate pain relief in prehospital settings, offering real- intranasal fentanyl and intravenous morphine have similar world insights into analgesic regimens pertinent to ambulance analgesic effects, as measured by changes in the Numeric Rating and emergency care environments. To our knowledge, this Scale, within pre-hospital settings. However, the quality of study represents the first randomised trial comparing these evidence was low, and studies did not assess time-to-effect. three treatment regimens. Methoxyflurane has shown significantly inferior analgesic Implications of all the available evidence efficacy compared with opioids at typical doses, but due to its Methoxyflurane and intranasal fentanyl are non-intravenous rapid onset of action it might be valuable for immediate pain alternatives to morphine, which are available and show management when intravenous access is challenging. A large effectiveness for prompt pain relief in prehospital scenarios, retrospective analysis showed that intranasal fentanyl and with few serious adverse events. Our findings suggest that intravenous morphine were more efficacious than methoxyflurane serves as a useful non-intravenous alternative methoxyflurane, with no difference between fentanyl and in the initial phase in which immediate pain relief is crucial and morphine, but time-to-effect again was not assessed. Therefore, intravenous access remains unestablished. Furthermore, it acts as a robust evidence comparing methoxyflurane, intranasal fentanyl, bridge to longer-acting analgesics. Intranasal fentanyl necessitates and intravenous morphine for immediate pain relief in a longer time frame to achieve its analgesic effect, establishing prehospital care is scarce, and no clinical trial has directly its non-inferiority to intravenous morphine after 20 min. performed this comparison. administrations are the intranasal and inhalational Methods routes. Intranasal fentanyl is a highly potent, synthetic Study design and participants lipophilic opioid,11,12 whereas inhalational methoxyflurane The PreMeFen study is a randomised, three-arm, open- is a non-narcotic, volatile anaesthetic often administered label, single-centre, non-inferiority, phase 3 clinical trial in low doses and inhaled through a specialised inhaler.3,13 conducted in three rural and urban areas of the ground Intranasal fentanyl is approved for breakthrough cancer- ambulance service of Innlandet Hospital Trust, Norway. related pain,14 and has been introduced for prehospital The study was performed in line with the published acute pain.15 Methoxyflurane is widely used in prehospital study protocol,21 and according to the principles of the settings in Australia and New Zealand, but to a lesser Helsinki Declaration.22 extent in Europe.16 Although equipotency studies Patients aged 18 years or older with medical or traumatic indicate a modest effect compared with intravenous acute moderate to severe pain scoring 4 or higher on the fentanyl,17 we have shown feasibility and good patient Numeric Rating Scale (NRS) were eligible. Inclusion satisfaction of prehospital methoxyflurane administrated criteria also included normal physiology and ability to for ski-related injuries in an alpine environment.7 provide informed consent. Exclusion criteria included However, systematic reviews suggest the need for life-threatening or limb-threatening conditions, head prehospital studies to establish efficacy and safety for injuries with neurological impairment, and allergies to See Online for appendix these alternatives in the prehospital treatment of acute the treatment medications (appendix p 5). Ambulance pain.18–20 We aimed to compare two non-intravenous personnel assessed inclusion during the primary medical alternatives, methoxyflurane and intranasal fentanyl, examination and obtained oral consent before inclusion with each other and with the established standard of and randomisation. Patients were treated on-site and intravenous morphine. enroute to hospital. End of study was when the patients The objective was to establish whether non-intravenous were handed over to either the emergency department, methoxyflurane and intranasal fentanyl were as effective emergency outpatient clinic, general practitioner, or as intravenous morphine for initial pain treatment for a when left on scene, depending on the patient’s condition. broad spectrum of painful conditions performed by Oral patient consent was obtained, witnessed by the paramedics in real prehospital acute settings. two ambulance personnel on scene and documented in 2958 Articles the case report form (appendix p 2). All patients received administration of study drug and after 5 (only NRS), written information about the study, including details on 10, 20, and 30 min, or when handed over to the emergency how to withdraw from participation. Follow-up phone department (10–160 min after administration; appendix calls were attempted 2 weeks after inclusion for all p 7). Ambulance personnel verbally asked patients to participants. The consent procedure was in line with report pain NRS scores. Vital measurements were Norwegian regulations. The study protocol and consent assessed with Life Pack 15 monitor (Stryker, USA). documents were approved by the Regional Committees Respiratory rate was automatically measured with an for Medical Research Ethics, South-East, Norway (255159) end-tidal carbon monoxide nasal cannula connected to and the Norwegian Medicines Agency (EudraCT Number the monitor. The number of intravenous cannulation 2021-000549-42). The CONSORT checklist for attempts was noted. Adverse events were monitored by randomised controlled trials was used with the extension ambulance personnel throughout the prehospital phase. for non-inferiority trials (appendix pp 3–4). The trial was Adverse events were documented in the patient record registered with ClinicalTrials.gov (NCT05137184) and is and reported according to protocol. Additional timepoints complete. were recorded at scene arrival, study drug administration, rescue medication administration, and handover at Randomisation and masking emergency department or equivalent. Pain diagnoses Patients were randomly assigned (1:1:1) to inhalational were grouped into four: chest pain of cardiac origin, methoxyflurane, intranasal fentanyl, or intravenous traumatic pain, non-traumatic musculoskeletal pain, and morphine by The Department of Clinical Trial Unit, Oslo other non-traumatic pain. These pain diagnoses were University Hospital, using computer-generated block recorded based on hospital records collected within randomisation with variable block size and sealed, opaque 14 days of the event. envelopes. These envelopes were part of the study kit We also recorded patient and ambulance personnel (appendix p 5). Ambulance personnel obtained oral satisfaction with a 5-point Likert Scale. Sex was consent before opening the randomisation envelope. determined from the patient’s national ID number Although this is an open-label study and the ambulance (11 digits) in patient records. The predominant ethnic personnel were not masked to treatment allocation, the group within the catchment area was Norwegian, and statistician was masked to the allocations in the dataset data on race and ethnicity were not collected. Data were until the statistical analysis plan was signed and the collected using paper forms and the electronic ambulance database was locked. patient journal system (EWA version 16) and were entered into a study-specific electronic case report form Procedures (Viedoc version 4.78). Data integrity was ensured through Patients aged 18–69 years received 3 mL inhalational predefined validation checks, batch reviews, and manual methoxyflurane (Medical Developments NED, quality control procedures. Amsterdam, Netherlands), 100 μg intranasal fentanyl Ambulance personnel had a range of levels of education (Takeda Pharma, Vallenback Strans, Denmark), or from emergency medical technicians to paramedics and 0·1 mg/kg intravenous morphine (Abcur, Helsingborg, nurses. Ambulance personnel were required to hold Sweden). Patients aged 70 years or older received 3 mL permanent employment, have the necessary medical inhalational methoxyflurane, 50 µg intranasal fentanyl, or authorisations, and complete 8 h of mandatory training 0·05 mg/kg intravenous morphine. In both groups doses before being permitted to include patients. were repeated if needed, with an interval of 5 min for fentanyl and morphine, and the maximum doses were Outcomes 6 mL methoxyflurane, 500 ug fentanyl, and 0∙5 mg/kg The primary endpoint was mean change in pain on a morphine. The rationale for doses is described in the 0–10-point NRS from baseline to 10 min after protocol (appendix pp 16–95). Dose titration to effect was administration of the study drug. Secondary endpoints allowed and guided by patients’ NRS scores. If pain relief were mean change in pain NRS score at 5, 20, and 30 mins was inadequate despite repeated doses of the study drug, after administration; mean changes in vital parameters; the ambulance personnel were allowed to administer time from arrival to treatment and time from arrival to other analgesics, defined as rescue medication. The 2-point reduction in NRS; need for rescue medication; choice of rescue medication was made at the ambulance time from investigational medicine administration to personnel’s discretion according to local protocols, based rescue medication administration; patient and personnel on the patient symptoms and underlying conditions satisfaction; adverse events; and change in Glasgow (appendix p 6). Although paracetamol normally is Coma Scale (GCS) score. considered a basic component of multimodal analgesia, it Adverse events were coded using Medical Dictionary was not given with the study drugs but was available as for Regulatory Activities (version 25.E) and categorised one of many options of rescue medication. using the National Institutes of Health Division of AIDS Pain NRS, blood pressure, oxygen saturation, pulse table for grading the severity of adult and paediatric rate, and respiratory rate were measured before adverse events (appendix pp 16–95). Respiratory Articles depression was defined as a respiratory rate less than previous hypothesis’ null hypothesis was rejected. A null 10 breaths per min. It was not feasible to register the use hypothesis was rejected, and non-inferiority established, of the diluter hole in the methoxyflurane device if the two-sided 95% CI of the corresponding estimated consistently, and hence, the use of the diluter hole was treatment difference in change in NRS at 10 min was not included in the evaluation of the need for rescue below the prespecified inferiority margin of 1·3. The medication. primary outcomes were also summarised with the number and percentage of patients, mean reduction in Statistical analysis score, and SD for each treatment group. We estimated the sample size using a t test, with effect For continuous secondary outcomes, pain NRS was sizes based on previous studies.3,23,24 The expected analysed similarly to the primary outcome at the other reduction in pain NRS score after 10 min was 3·77 for timepoints 5, 20, and 30 min, and vital parameters were methoxyflurane, 2·54 for fentanyl, and 2·70 for morphine analysed at 10 min using ANOVA followed by Tukey’s treatment regimens. A common standard variation test. For dichotomous secondary outcomes, rescue of 2·12 was used, with the non-inferiority margin of 1·3.25 medication was analysed with a logistic regression To ensure with 90% power that the upper limit of the model, adjusted for baseline pain scores. For adverse two-sided 95% CI would exclude a difference less than events, no adjustments for baseline scores were made, the margin of 1·3, we needed 88 participants in each and Pearson’s Chi square test was used. Ordinal group. When including around 10% dropouts, the study outcomes were analysed with a proportional odds model required 300 patients for random assignment. The per- and when model assumptions were not met protocol analysis set included all patients who received Kruskal Wallis test or Fisher’s exact test were used. Time- the assigned treatment with no major protocol deviation. to-event was analysed with Cox regression under the Any rescue medication administered before the primary assumption that the group hazards were proportional endpoint assessment at 10 min excluded patients from over time. When this assumption was not met, the the per-protocol analysis set. Protocol deviations are analysis was performed with a log-rank test. A listed in the appendix (p 8). The full analysis set included Kaplan–Meier plot was made for visualisation. For all patients who fulfilled the study criteria and were analysing time from ambulance arrival to a 2-point administered the allocated study drug. The safety analysis reduction in pain NRS score, linear interpolation was set included all patients who received any study drug. used to estimate the exact time this reduction was The primary endpoint was analysed per protocol, and the achieved if it occurred between two timepoints. sensitivity analysis was performed in the full analysis set Predictors for adverse events were examined as with imputations. exploratory endpoints. Null hypotheses (H) were: (1) low-dose methoxyflurane There were, per definition, no missing data for the is inferior to intranasal fentanyl at reducing pain; primary endpoint in the per protocol analysis set. (2) low-dose methoxyflurane is inferior to intravenous However, for the sensitivity analysis in the full analysis morphine at reducing pain; and (3) intranasal fentanyl is set, and for secondary outcomes, missing values inferior to intravenous morphine at reducing pain. These were imputed using multiple imputation (appendix were measured by a change in NRS score from 0 min pp 8–9). All statistical analyses were performed to 10 min after administration: using R version 4.3.3. The Data Monitoring Committee per formed a half-way-inclusion assessment (Sept 1, 2022), H: h: μ –μ ≥δ, h: μ –μ <δ 1 0 methoxyflurane fentanyl I a methoxyflurane fentanyl I and the study was monitored throughout the trial period. No interim efficacy analyses were planned. H: h: μ –μ ≥δ, h: μ –μ <δ 2 0 methoxyflurane morphine I a methoxyflurane morphine I Role of the funding source H: h: μ –μ ≥δ, h: μ –μ <δ 3 0 fentanyl morphine I a fentanyl morphine I The funders of this study had no role in study design, μ is the mean change in pain NRS (NRS at 10 min – NRS data collection, data analysis, data interpretation, or x at 0 min) with study drug (methoxyflurane, fentanyl, or writing of the report. morphine}, and δ is the non-inferiority margin of 1·3 (appendix pp 96–115). Results The primary hypotheses were tested in a hierarchical Between Nov 12, 2021, and April 22, 2023, 632 patients manner according to the protocol.21 For each were assessed for eligibility and 338 were randomly link in the sequence, two study drugs were assigned to methoxyflurane (n=112), fentanyl (n=115), or compared using the linear regressions model morphine (n=111; figure 1). 281 patients were included in DNRS = NRS + randomisation, where NRS is the the per-protocol set, of whom 102 were in the T10 T0 T0 baseline NRS score and DNRS is the change from methoxyflurane group, 89 in the fentanyl group, 90 in T10 baseline to 10 min after administration. Hypotheses were the morphine group. Differences in group sizes were tested sequentially using the Wald test,26 and inferences caused by more dosing errors in the morphine and about the next hypothesis could only be made if the fentanyl groups than in the methoxyflurane group 2960 Articles 1882 patients screened assessed for eligibility 1250 excluded 632 patients screened assessed for eligibility 294 ineligible 148 did not meet inclusion criteria 118 met exclusion criteria 28 declined to participate 338 enrolled 338 randomly assigned 112 assigned to methoxyflurane 115 assigned to fentanyl 111 assigned to morphine 1 did not receive treatment 3 did not receive treatment 2 did not receive treatment 1 withdrew 3 withdrew 2 had NRS score of 0 111 received methoxyflurane and included 112 received fentanyl and included in 109 received morphine and included in in safety analysis set safety analysis set safety analysis set 7 discontinued 9 discontinued 8 discontinued 7 did not meet criteria 9 did not meet criteria 5 received morphine as rescue medication 3 did not meet criteria 104 included in full analysis set 103 included in full analysis set 101 included in full analysis set 2 discontinued 14 discontinued 11 discontinued 2 no NRS collected at 10 min 7 wrong treatment or dose 11 wrong treatment or dose 6 no NRS collected at 10 min 1 other 102 included in per-protocol analysis set 89 included in per-protocol analysis set 90 included in per-protocol analysis set Figure 1: Trial profile NRS=Numeric Rating Scale. (appendix p 8). Overall, 145 (52%) of 281 patients were methoxyflurane changed the mean NRS score by –1·33 female and 136 (48%) were male. Median age was 61 years (95% CI –2·01 to –0·64) compared with intranasal (IQR 47–75; table). fentanyl (figure 3). The upper limit of the 95% CI was Mean pain NRS score before treatment was 7·6 (SD 1·8) below the non-inferiority margin of 1·3, and and mean cumulative doses given up to 10 min were methoxyflurane was non-inferior (and showed even 3·0 mL (0·3) methoxyflurane, 153 µg (53·19) fentanyl, superiority) to fentanyl in reducing pain at 10 min. and 8·7 mg (4·03) morphine. The total mean cumulative Methoxyflurane changed the mean NRS score by –0·36 doses at the end of the study were 3·5 mL (1·2) (95% CI –1·03 to 0·31) compared with morphine and methoxyflurane, 293 µg (132) fentanyl, and 13·8 mg (7·0) was non-inferior to morphine. Fentanyl changed the morphine. At 10 min after administration, the mean mean NRS score by 0·91 (0·27 to 1·55) compared with change in NRS score was –3·31 (2·67) for methoxyflurane, morphine, with the 95% CI crossing the non-inferiority –1·98 (2·28) for fentanyl, and –2·74 (2·12) for morphine margin, and hence, we could not conclude on non- (figure 2; appendix p 8). In the linear model, at 10 min, inferiority at 10 min. The 95% CI was in favour of Articles Morphine group (n=90) Fentanyl group (n=89) Methoxyflurane group (n=102) Sex Male 38 (42%) 47 (53%) 51 (50%) Female 52 (58%) 42 (47%) 51 (50%) Age, years 64 (48–76) 61 (50–75) 60 (47–74) Weight, kg Median 76 (68–92) 80 (73–93) 81 (70–90) Missing 1 (1%) 4 (4%) 9 (9%) Diagnosis category* Chest pain of cardiac origin 3 (3%) 5 (6%) 6 (6%) Trauma or injury pain 35 (39%) 30 (34%) 29 (28%) Non-traumatic musculoskeletal 18 (20%) 28 (31%) 28 (27%) Other non-traumatic pain 34 (38%) 26 (29%) 39 (38%) Systolic blood pressure, mm Hg 150 (23·2) 153 (25·5) 151 (24·3) Diastolic blood pressure, mm Hg 86 (17·8) 86 (14·3) 84 (15·2) Pulse rate, min–¹ 80 (70–94) 80 (70–93) 80 (69–89) Respiratory rate, min–¹ 18 (16–20) 18 (16–20) 18 (16–20) Oxygen saturation Median 97% (95–99) 98% (96–99) 97% (96-99) Missing 0 0 1 (1%) Glasgow Coma Scale 15 (15–15) 15 (15–15) 15 (15–15) Numeric Rating Scale 7 (5–9) 8 (7–9) 8 (6–9) Data are n (%), median (IQR), or mean (SD). Baseline data were collected during screening. There were no missing data for variables unless included in the table. *Full diagnosis overview is provided in the appendix (p 15). Table: Demographic and baseline characteristics of the per-protocol population and –0·47 (–1∙10 to 0∙18) compared with morphine, whereas intranasal fentanyl was inferior to morphine 0 with a pain reduction difference of 1·14 (0∙62 to 1∙66) in favour of morphine. The differences levelled at 20 min –1 and 30 min, however, confirming non-inferiority for all three comparisons (figure 3). The sensitivity analysis on –2 all timepoints performed in the full analysis set supported –3 the results from the per-protocol analysis set analyses (appendix p 9). Subgroup analyses for the primary –4 endpoint at 10 min were performed on sex, age, and diagnostic categories. In general, the main findings were –5 consistent across all subgroups, although for –6 methoxyflurane, non-inferiority was not determined for some of the diagnostic categories with fewest patients –7 (figure 4). –8 None of the patients in the per-protocol analysis set 0 5 10 20 30 Emergency received any rescue medication during the first 10 min, department arrival and the primary endpoint was, hence, a result of the allocated study drug. Subsequently, rescue medication was given to 14 (16%) of 90 patients in the morphine group, 26 (29%) of 89 in the fentanyl group, and 41 (40%) of 102 in the methoxyflurane group (appendix p 10). In a logistic regression model with adjustment for baseline pain NRS score, methoxyflurane was a morphine. At 5 min after administration, methoxyflurane significant predictor for needing rescue medication, with showed an even larger margin. On average, an odds ratio (OR) of 3·4 (p=0·0008), whereas intranasal methoxyflurane changed mean pain NRS scores by –1·70 fentanyl had an OR of 2·0 (p=0·060). The median time (–2∙30 to –1∙10) compared with intranasal fentanyl from administration of study drug to rescue medication 2962 SRN ni egnahC Methoxyflurane Fentanyl Morphine Time (min) Figure 2: Pain relief efficacy measured by change in NRS score over time The figure shows the change in mean pain NRS score for morphine (red), fentanyl (blue), and methoxyflurane (green). Timepoints are time since administration of study medication. Lines represent mean change, and bars represent change by 1 SD. NRS=Numeric Rating Scale. Articles was significantly shorter for methoxyflurane than for the Comparison Average marginal Null hypothesis other groups (hazard ratio 2·5 [95% CI 1·37 to 4·66]; effect (95% CI) rejected p=0·0030; appendix p 11). The mean cumulative doses of study drug received by the time of first administration of 5 min Methoxyflurane vs fentanyl –1·70 (–2·30 to –1·10) ·· 5 min Methoxyflurane vs morphine –0·47 (–1·11 to 0·18) ·· rescue medication were 13·4 mg (SD 6·8) morphine, 5 min Fentanyl vs morphine 1·14 (0·62 to 1·66) ·· 287 µg (128·8) fentanyl, and 3·5 mL (1·1) methoxyflurane. Vascular access was established, or attempted to be 10 min Methoxyflurane vs fentanyl –1·33 (–2·01 to –0·64) Yes established, in 211 (75%) of 281 patients, of whom 10 min Methoxyflurane vs morphine –0·36 (–1·03 to 0·31) Yes 10 min Fentanyl vs morphine 0·91 (0·27 to 1·55) No 59 (28%) needed more than one cannulation attempt. In 68 (24%) of 281 patients, vascular access was not 20 min Methoxyflurane vs fentanyl –0·27 (–0·99 to 0·46) ·· attempted: two (2%) of 90 in the morphine group (for 20 min Methoxyflurane vs morphine 0·09 (–0·60 to 0·77) ·· whom intravenous access was already established), 20 min Fentanyl vs morphine 0·35 (–0·39 to 1·08) ·· 28 (31%) of 89 in the fentanyl group, and 38 (37%) of 102 30 min Methoxyflurane vs fentanyl 0·07 (–0·71 to 0·85) ·· in the methoxyflurane group. 66 (35%) of 191 patients in 30 min Methoxyflurane vs morphine 0·55 (–0·20 to 1·30) ·· the two non-intravenous groups did not receive any 30 min Fentanyl vs morphine 0·45 (–0·34 to 1·23) ·· vascular access attempt, and invasive procedure was –2 –1 0 1 2 avoided (appendix p 12). There was a significant difference in the time from the Greater NRS reduction Less NRS reduction ambulance arriving at the scene to administering study Figure 3: Estimated difference in NRS score between treatment groups in the per-protocol analysis set drug, with a median time of 22·5 min (95% CI 21–26) for The average marginal effect is measured across all observations using a balanced grid of covariates (if applicable). intravenous morphine, 17 min (15–19) for fentanyl, and Change in NRS score at 10 min is the primary outcome. The other timepoints are secondary outcomes. For each 18 min (17–20) for methoxyflurane (p=0·0020; appendix timepoint, hypotheses 1–3 were tested sequentially and therefore no further adjustment for multiple testing were done. The dashed line represents the non-inferiority margin. NRS=Numeric Rating Scale. p 11). The median time from administration of the first dose of study drug to a 2-point reduction in pain NRS score was 30·0 min (95% CI 27·5–34·0) in the morphine but after administration of rescue medication. There group, 29·0 min (26·3–35·0) in the intranasal were no treatment-related deaths. A purposeful selection fentanyl group, and 25·3 min (22·3–32·5) in the method in a logistic regression model was used to methoxyflurane group (p=0·70; appendix p 11). Patient identify predictors of adverse events, testing baseline satisfaction was good or better for 67 (77%) of 87 patients NRS scores, treatment group, sex, provider education in the morphine group, 63 (71%) of 89 in the fentanyl level, age, and rescue medication before the adverse group, and 68 (69%) of 99 in the methoxyflurane group. event. The most parsimonious model retaining predictive Excellent satisfaction was highest in the methoxyflurane value included only sex: women had a higher risk for group (42 [42%] of 99), but poor satisfaction was also the adverse events than men (OR 2·07; p=0·013). highest in this group (21 [21%] of 99). These findings are also reflected in the corresponding study worker Discussion satisfaction scoring (appendix p 12). This randomised, non-inferiority trial shows that Of all patients, only one had a 2-point reduction in GCS methoxyflurane is non-inferior to intravenous morphine score and nine had a 1-point reduction at 10 min. Only and intranasal fentanyl for treating acute moderate to 1-point reductions in GCS were observed thereafter. severe pain, measured 10 min after administration. Eight (80%) of ten reductions in GCS score at 10 min Although methoxyflurane showed equal superiority to were in the methoxyflurane group, but the overall intranasal fentanyl, the study design only allowed for difference between the three groups was not significant conclusion of non-inferiority. Notably, methoxyflurane (p=0·051). There were no significant differences in showed effectiveness shortly after administration reduction of systolic blood pressure or change in compared with opioids. The differences in effectiveness respiratory rates between the groups (appendix p 13). between groups levelled after 20 and 30 min, but the non- In total, 94 adverse events were recorded in inferiority of methoxyflurane to intravenous morphine 77 (23%) of 332 patients: 24 (22%) of 111 in the and intranasal fentanyl remained. Intranasal fentanyl was methoxyflurane group, 27 (24%) of 112 in the fentanyl not shown to be non-inferior to intravenous morphine at group, and 26 (24%) of 109 in the morphine group 10 min. (appendix pp 13–14). There were no differences between A systematic review20 suggests that methoxyflurane is a the groups and frequency of adverse events (p=0·89). short-acting, single analgesic that bridges intravenous The overall most common adverse events were vomiting access with administration of other analgesics. This (36 [11%] of 332), nausea (15 [5%]), respiratory depression recommendation is based on a few low-quality studies. (12 [4%]), and dizziness (six [18%]). Only two events were Our trial provides high-quality evidence supporting these defined as severe adverse events with respiratory previous findings. In a randomised crossover study, depression and loss of consciousness. Both occurred in inhaled methoxyflurane was equianalgesic to 25 μg the same patient in the methoxyflurane treatment group, intravenous fentanyl during a cold pressor test.17 Our Articles Comparison n (%) Average marginal effect (95% CI) Sex Male Methoxyflurane vs fentanyl 98 (51%) –1·32 (–2·28 to –0·37) Female Methoxyflurane vs fentanyl 93 (49%) –1·34 (–2·32 to –0·35) Age category 18–69 years Methoxyflurane vs fentanyl 131 (69%) –1·26 (–2·09 to –0·44) ≥70 years Methoxyflurane vs fentanyl 60 (31%) –1·52 (–2·77 to –0·28) Diagnosis Chest pain of cardiac origin Methoxyflurane vs fentanyl 11 (6%) –0·82 (–3·67 to 2·03) Trauma or injury pain Methoxyflurane vs fentanyl 59 (31%) –1·01 (–2·23 to 0·21) Non-traumatic musculoskeletal pain Methoxyflurane vs fentanyl 56 (29%) –1·04 (–2·29 to 0·22) Other non-traumatic pain Methoxyflurane vs fentanyl 65 (34%) –1·82 (–3·01 to –0·64) Sex Male Methoxyflurane vs morphine 89 (46%) 0·00 (–0·98 to 0·98) Female Methoxyflurane vs morphine 103 (54%) –0·61 (–1·52 to 0·30) Age category 18–69 years Methoxyflurane vs morphine 129 (67%) –0·27 (–1·08 to 0·54) ≥70 years Methoxyflurane vs morphine 63 (33%) –0·59 (–1·76 to 0·58) Diagnosis Chest pain of cardiac origin Methoxyflurane vs morphine 9 (5%) 0·85 (–2·36 to 4·05) Trauma or injury pain Methoxyflurane vs morphine 64 (33%) –0·30 (–1·44 to 0·85) Non-traumatic musculoskeletal pain Methoxyflurane vs morphine 46 (24%) 0·22 (–1·15 to 1·59) Other non-traumatic pain Methoxyflurane vs morphine 73 (38%) –0·61 (–1·67 to 0·45) Sex Male Intranasal fentanyl vs morphine 85 (47%) 1·24 (0·32 to 2·17) Female Intranasal fentanyl vs morphine 94 (53%) 0·69 (–0·19 to 1·57) Age category 18–69 years Intranasal fentanyl vs morphine 128 (72%) 0·97 (0·23 to 1·72) ≥70 years Intranasal fentanyl vs morphine 51 (28%) 0·79 (–0·41 to 1·99) Diagnosis Chest pain of cardiac origin Intranasal fentanyl vs morphine 8 (4%) 1·64 (–1·42 to 4·69) Trauma or injury pain Intranasal fentanyl vs morphine 65 (36%) 0·60 (–0·46 to 1·66) Non-traumatic musculoskeletal pain Intranasal fentanyl vs morphine 46 (26%) 1·24 (–0·03 to 2·50) Other non-traumatic pain Intranasal fentanyl vs morphine 60 (34%) 1·18 (0·09 to 2·27) –4 –2 0 2 4 Greater NRS reduction Less NRS reduction Figure 4: Subgroup analysis 10 min after first dose of study drug The average marginal effect is measured across all observations using a balanced grid of covariates (if applicable). Differences in change in NRS score 10 minutes after first study drug dose between treatment groups, stratified by subgroups, using the per-protocol analysis set. The dashed line represents the non-inferiority margin. NRS=Numeric Rating Scale. clinical study showed a notable timely difference in appear inadequate compared with the total accumulated effectiveness compared with fentanyl and morphine and dose. non-inferiority to a higher dose than 25 μg intravenous The need for rescue medication is a surrogate marker fentanyl. This finding suggests that the rapid onset of of the effectiveness of the allocated analgesic treatment. effect and the self-administration of methoxyflurane In our study, 76 (84%) of 90 patients in the morphine might enhance its perceived analgesic properties in a group, 63 (71%) of 89 in the fentanyl group, and clinical prehospital setting. The titration of analgesics is 61 (60%) of 102 in the methoxyflurane group did not crucial for an effective pain relief strategy, which need any rescue medication throughout the prehospital contrasts with experimental studies with single doses.27 phase. The difference in the need for rescue medication Our individualised management of intravenous between the fentanyl and morphine groups was not morphine and intranasal fentanyl regimens resulted in significant. This finding is in line with a literature review4 higher accumulated doses than those in previous that found that intravenous morphine and intranasal literature.18,27,28 However, given the dosage restrictions fentanyl had similar effects. Although most of the imposed by the device, which are limited to 50 or 100 μg patients with non-intravenous analgesics were managed per dose for intranasal fentanyl, the initial dosage might adequately without rescue medication, the differences in 2964 Articles need for rescue medication suggests that methoxyflurane credible consent, providing written information to all might not provide adequate pain control during the patients about how to withdraw from the study, and whole prehospital phase. We cannot rule out that the establishing a protocol for the study team to attempt large number of patients who received rescue medication follow-up calls with all patients 2 weeks post-inclusion. in the methoxyflurane group affected the non-inferiority Obtaining consent in the acute prehospital setting is result at 20 and 30 min. However, with its rapid onset of challenging; however, we believe that our implemented effect, methoxyflurane could serve as a good option for measures effectively balance these ethical considerations, the early stages of treatment. ensuring appropriate medical treatment and informed Overall, all three study drug regimens had mild, consent. Ultimately, seven patients withdrew from the transient adverse events that were consistent with study: five during treatment, one during the 2-week expected pharmacological action. The frequency of these follow-up call, and one post-treatment through the contact adverse events was similar across treatment groups and details provided in the written information. are consistent with earlier studies.11,20 It is noteworthy The open-label design might introduce expectation that motion sickness during transport and pain itself can bias but was chosen due to practical and ethical cause nausea and vomiting, as described in the most considerations. A double-blinded, triple-dummy study frequent adverse events. The only significant predictor would be too complicated and time-consuming in the for adverse events in our study was female sex, which is acute prehospital setting. Our real-life approach is, in line with a retrospective study.29 however, pragmatic and corresponds to standard medical No subgroup analyses differed distinctly from the main practice. Additionally, the primary outcome of change in findings, but there were wider 95% CIs in the smaller NRS score after 10 min, represents a highly relevant, subgroups, such as in the category of diagnosis of chest subjective patient-reported outcome. The 10-min pain (figure 4). It is noteworthy that the effectiveness in timepoint was selected due to its clinical and operational the young and old subgroups was identical for all relevance in the acute prehospital setting, where prompt three comparisons. Although methoxyflurane is analgesic effect is essential. However, this early approved in Europe for moderate to severe pain in adult assessment is limited by the pharmacodynamic and patients with trauma-associated pain, our results indicate pharmacokinetic properties of the three study drugs, a rapid onset of action across all diagnostic groups. particularly before full effect is achieved for some of Studies suggest there should be more focus on non- them. Notably, inhalation administration typically has a opioid analgesia to treat chest pain due to the concern of shorter time-to-effect, whereas intranasal administration increased myocardial infarction severity by higher opioid has a longer onset. The experience of pain includes doses.30 In our study, the subgroups with chest pain of objective and subjective elements, influenced by the cardiac origin were too small to conclude whether there situation, pain response, and patient experience. All was any difference in effect between the study drugs. personnel received specific training and simulation In addition to evaluating pain levels using the NRS, we exercises in how to score NRS. Although this was a assessed satisfaction levels (using a Likert Scale) among single-centre study, it was conducted across personnel and patients, recognising that these measures three different locations, covering both urban and rural are distinct. Our findings show a notable dichotomy in areas. The modest eligibility rate (632 [34%] of the methoxyflurane group, with a predominance of 1882 patients) could be affected by the study setting, excellent and poor scores among personnel and patients. where the threshold for including patients is dependent This finding suggests a dual phenomenon associated on high motivation among the study workers. In with methoxyflurane: although its overall analgesic addition, many patients with acute pain were not eligible effectiveness over time is lower than that of opioids for inclusion due to dementia, confusion, language (ie, necessitating additional rescue medication for some problems, or complex symptoms, and the ambulance individuals), its rapid onset of pain relief and provision workers might have avoided active exclusion for various for self-administration might empower patients by reasons. We have no reason to believe that the study enhancing their perceived control. population diverges from the patient population of This study used oral consent from the patients, which interest. The manual entry of data into the database represents a departure from the conventional requirement presents a potential risk to data integrity. Nonetheless, for written consent. The ethical considerations surround- predefined validation checks and rigorous quality control ing the recruitment of patients with moderate to severe procedures were implemented to ensure reliability of pain for a clinical study are complex. They involve the data. balancing the need to minimise delays in acute care In conclusion, the PreMeFen study showed that against the imperative to ensure that patients fully methoxyflurane was non-inferior to intravenous understand what they are consenting to. Consequently, morphine and intranasal fentanyl for treating acute we implemented several mitigating measures, including moderate to severe traumatic and non-traumatic pain in exclusion criteria guided by contextual judgement, the prehospital setting 10 min after administration. specialised training for study personnel on obtaining Intranasal fentanyl was, however, not shown as Articles non-inferior to intravenous morphine at 10 min. Although 7 Rydlöv HS, Fjose LO, Heyerdahl F. Pain management with the non-inferiority of methoxyflurane remained through- inhalation of methoxyflurane administrated by non-medical ski patrol: a quality assessment study. Pain Ther 2023; 12: 1455–63. out the observation time, patients in the methoxyflurane 8 Raja SN, Carr DB, Cohen M, et al. The revised International group needed more rescue medication than those in the Association for the Study of Pain definition of pain: concepts, morphine group. challenges, and compromises. Pain 2020; 161: 1976–82. 9 International Pain Summit of the International Association for the Contributors Study Of Pain. Declaration of Montréal: declaration that access to FH and LOF contributed to the conceptualisation of the study. FH and pain management is a fundamental human right. ICO were responsible for the study design. FH and LOF developed the J Pain Palliat Care Pharmacother 2011; 25: 29–31. methodology. RS managed the day-to-day operations of the study. RS 10 Sabri A, Szalas J, Holmes KS, Labib L, Mussivand T. Failed attempts and LS collated data. KT conducted the statistical analyses. ICO and improvement strategies in peripheral intravenous independently checked the primary analysis. RS, LS, and KT catheterization. Biomed Mater Eng 2013; 23: 93–108. performed data validation. RS wrote the original draft. FH and LOF 11 Friesgaard KD, Vist GE, Hyldmo PK, et al. Opioids for treatment of contributed to writing of the original draft. All authors participated in pre-hospital acute pain: a systematic review. Pain Ther 2022; the review and editing of the paper. FH and RS had final responsibility 11: 17–36. for the decision to submit for publication. RS, FH, LS, and KT 12 Grape S, Schug SA, Lauer S, Schug BS. Formulations of fentanyl accessed and verified the data. All authors had full access to all the for the management of pain. Drugs 2010; 70: 57–72. included data and approved the final submitted version of the report. 13 Williams OD, Pluck G. The use of methoxyflurane (Penthrox) for procedural analgesia in the emergency department and pre-hospital Declaration of interests environment. Trauma 2020; 22: 85–93. We declare no competing interests. 14 European Medicines Agency. Instanyl. 2024. https://www.ema. Data sharing europa.eu/en/medicines/human/EPAR/instanyl (accessed Anonymised individual data and data dictionary will be available for Nov 8, 2024). research purposes by request to the corresponding author. Clinical study 15 Rickard C, O’Meara P, McGrail M, Garner D, McLean A, results will be posted in the European Clinical Trials Database. Le Lievre P. A randomized controlled trial of intranasal fentanyl vs intravenous morphine for analgesia in the prehospital setting. Acknowledgments Am J Emerg Med 2007; 25: 911–17. We want to express our gratitude to all patients who consented to 16 Trimmel H, Egger A, Doppler R, Pimiskern M, Voelckel WG. participate in our study. A special thanks to the study workers and their Usability and effectiveness of inhaled methoxyflurane for supervisors at Innlandet Hospital Trust for their hard work throughout prehospital analgesia: a prospective, observational study. the data collection period. We are grateful to Arne Skulberg and BMC Emerg Med 2022; 22: 8. Lars Øivind Høiseth for their contribution to the preliminary phase of 17 Lenz H, Høiseth LØ, Comelon M, Draegni T, Rosseland LA. the trial. We also appreciate the support from Oslo University Hospital Determination of equi-analgesic doses of inhaled methoxyflurane Clinical Trial Unit with the database and monitoring. 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Pain Res Manag 2015; 20: 23–28. --- [PDF原文](https://sci-net.xyz/storage/8010893/41db0bb846f651039b5da585daa550948aa8fe7397ec9ae152552063d88753bb/Comparison-of-inhalational-methoxyflurane-intranasal-fentanyl-and-intravenous-morphine-for.pdf) DOI: 10.1016/S0140-6736(25)01575-2