Response to “A Rigorous Evaluation of Methoxyflurane is Needed: Comment on ‘Methoxyflurane Versus Standard of Care for Acute Trauma-Related Pain in the Emergency Setting: Protocol for a Randomised, Controlled Study in Italy (MEDITA)’”

Response to “A Rigorous Evaluation of Methoxyflurane is Needed: Comment on ‘Methoxyflurane... Adv Ther https://doi.org/10.1007/s12325-019-00937-2 LETTER Response to ‘‘A Rigorous Evaluation of Methoxyflurane is Needed: Comment on ‘Methoxyflurane Versus Standard of Care for Acute Trauma-Related Pain in the Emergency Setting: Protocol for a Randomised, Controlled Study in Italy (MEDITA)’’’ . . . . . Andrea Fabbri Giuseppe Carpinteri Germana Ruggiano Elisabetta Bonafede Antonella Sblendido Alberto Farina Amedeo Soldi Received: February 26, 2019 The Author(s) 2019 Keywords: Acute pain; Analgesic; Emergency robust data in the literature (including the department; Inhaled analgesic; Injury; STOP! study [2]) and by extensive experience in Methoxyflurane; Penthrox; Pre-hospital; clinical practice, particularly in Australia. Trauma Although such data are adequate to support the introduction into clinical practice in Europe, further head-to-head studies vs. the best cur- We welcome the critical review by Montassier rently used therapeutic options, in terms of and Freund on our article on the rationale and effectiveness and rapidity of onset, are needed. methods of the ‘‘MEDITA’’ study [1]. Below, we These data will help to identify methoxyflu- provide point-by-point answers to all rane’s place in therapy, which today is a comments. promising option with potential advantages Methoxyflurane is currently being intro- compared with the drugs on the market. There duced in Europe, and its use is supported by are now emerging data in Europe: the ‘‘InMe- diate’’ study [3], which randomised 310 patients Enhanced Digital Features To view enhanced digital with trauma pain to methoxyflurane or stan- features for this article go to https://doi.org/10.6084/ m9.figshare.7808861. dard of care (SoC) analgesia, has recently been completed in Spain. Preliminary results indicate A. Fabbri that methoxyflurane significantly (p \ 0.0001) Department of Emergency Medicine, Morgagni- reduced pain severity compared with SoC up to Pierantoni Hospital Forlı`, Forlı`, Italy 20 min after the start of treatment [4]. Another ongoing study, ‘‘PenASAP’’, will randomise 360 G. Carpinteri Department of Emergency Medicine, Vittorio patients with trauma pain in a double-blind Emanuele University Hospital, Catania, Italy fashion to Penthrox or placebo, administered in addition to SoC [5]. These studies, together with G. Ruggiano Emergency Medicine Department, Santa Maria the MEDITA study, which is the subject of this Annunziata Hospital, Florence, Italy letter [1], all conducted with high method- ological and qualitative standards, aim to E. Bonafede resolve the uncertainties that currently persist. Bioikos Ambiente S.r.l., CRO YGHEA Division, Bologna, Italy Oral analgesia was not used to treat patients with moderate pain (NRS 4–6) in the MEDITA A. Sblendido  A. Farina (&)  A. Soldi study since intravenous (IV) therapy is the Medical Affairs Department, Mundipharma Pharmaceuticals srl, Milan, Italy common clinical practice in Italy where the e-mail: alberto.farina@mundipharma.it Adv Ther study was conducted, although it should be possible, and we agree that third parties have an underlined that there is wide heterogeneity in important role to play in future investigations the therapeutic approach and oligoanalgesia of methoxyflurane. still represents a widespread issue. The use of IV formulations is consistent with Italian Interso- ciety Recommendations on pain management ACKNOWLEDGEMENTS in the emergency setting [6]. Likewise, in the Spanish InMediate study, oral agents were PENTHROX is a registered trademark of Med- administered to only 10.7% of patients in the ical Developments International Ltd. SoC group, although it should be noted that the majority of patients (76.5%) had severe pain Funding. This work was sponsored by Mun- (NRS C 7). Moreover, we think that in the dipharma Pharmaceuticals srl. No article pro- context of a clinical study, to evaluate the net cessing charges were received by the journal for efficacy of the molecule, it is more appropriate the publication of this letter. to use an IV formulation to make the compar- ison more homogeneous and to obtain head-to- Authorship. All named authors meet the head data vs. the most effective therapeutic International Committee of Medical Journal option. A comparison vs. oral drugs would have Editors (ICMJE) criteria for authorship for this given an obvious result because of the latency in article, take responsibility for the integrity of the onset of action. A pharmacoeconomic the work as a whole and have given final analysis will be conducted separately at the end approval to the version to be published. of the study. The primary pain intensity end point in the Disclosures. Elisabetta Bonafede is an ‘‘MEDITA’’ study is assessed over the first 10 min employee of the clinical research organization because of the rapid action of the drug and conducting the study. Antonella Sblendido is an represents the most challenging comparison for employee of Mundipharma Pharmaceuticals srl. methoxyflurane. By definition, IV medicinal Amedeo Soldi is an employee of Mundipharma products are immediately ready to act. This also Pharmaceuticals srl. Alberto Farina is an correlates with the indication of methoxyflu- employee of Mundipharma Pharmaceuticals srl. rane: emergency relief of moderate-to-severe Andrea Fabbri, Giuseppe Carpinteri and Ger- pain in conscious adult patients with trauma mana Ruggiano have nothing to disclose. and associated pain and the unmet need of receiving an easy-to-use, rapid-acting and Compliance with Ethics Guidelines. This effective first-line analgesic treatment for article is based on previously conducted studies trauma-related pain. Methoxyflurane is already and does not contain any studies with human known to be effective at 30 min, so the 10-min participants or animals performed by any of the end point in the MEDITA trial provides addi- authors. tional information about its efficacy profile. Long duration of action is not the goal of Peer Review. Please note, contrary to the methoxyflurane treatment. In any case, inter- journal’s standard single-blind peer review pro- mittent administration produces a longer anal- cess, as a letter this article underwent review by gesic effect, and if required there is the option a member of the journal’s Editorial Board. to administer a second 3-ml dose in clinical Open Access. This article is distributed practice. While the Penthrox inhaler indeed requires responsible disposal [7], other anal- under the terms of the Creative Commons Attribution-NonCommercial 4.0 International gesics also have challenges in terms of con- sumables that are single use and non-recyclable License (http://creativecommons.org/licenses/ (e.g. syringes, flasks, cannulas, needles, etc.). by-nc/4.0/), which permits any noncommercial Finally, Mundipharma strongly encourages use, distribution, and reproduction in any and supports independent research as far as medium, provided you give appropriate credit Adv Ther Emergency Units (InMEDIATE): study protocol. IBJ to the original author(s) and the source, provide Clin Pharmacol. 2017;1:e0008. a link to the Creative Commons license, and indicate if changes were made. 4. Borobia Pe´rez A, Garcı´a Collado S, Carballo Cardona C, Capilla Pueyo R, Ferna´ndez Alonso C, Pe´rez Torres I, et al. InMEDIATE: results of a phase IIIB, open label randomised clinical trial to compare pain relief between methoxyflurane and standard of care anal- REFERENCES gesia for treating patients with trauma pain in Spanish emergency departments. Basic Clin Pharma- col Toxicol. 2018;123(Suppl. 4):16. 1. Fabbri A, Carpinteri G, Ruggiano G, Bonafede E, Sblendido A, Farina A, Soldi A, MEDITA Study Group. 5. Efficacy and Safety of Penthrox Combined With a Methoxyflurane versus standard of care for acute Standard Analgesia (SoC) in Adult Patients Admitted trauma-related pain in the emergency setting: proto- to the Emergency Department With Moderate to col for a randomised, controlled study in Italy Severe Pain Associated With Trauma (Pen ASAP). (MEDITA). Adv Ther. 2019;36(1):244–56. NCT03798899. https://clinicaltrials.gov/ct2/show/ NCT03798899?term=methoxyflurane&rank=8. 2. Coffey F, Wright J, Hartshorn S, Hunt P, Locker T, Accessed 26 Feb 2019. Mirza K, Dissmann P. STOP!: a randomised, double- blind, placebo-controlled study of the efficacy and 6. Raccomandazioni Intersocietarie Italiane (SIAARTI, safety of methoxyflurane for the treatment of acute SIMEU, SIS 118, AISD, SIARED, SICUT, IRC) sulla pain. Emerg Med J. 2014;31(8):613–8. gestione del dolore in emergenza. 2014. http://www. aisd.it/e107_files/downloads/raccintersocietarie_it_ 3. Borobia Perez AM, Capilla Pueyo R, Casal Codesido complete31052014.pdf Accessed 26 Feb 2019. JR, InMEDIATE Group, et al. Phase IIIb, open label randomised clinical trial to compare pain relief 7. Penthrox summary of product characteristics. 2016. between methoxyflurane and standard of care for https://www.medicines.org.uk/emc/medicine/31391. treating patients with trauma pain in Spanish Accessed 26 Feb 2019. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Advances in Therapy Springer Journals

Response to “A Rigorous Evaluation of Methoxyflurane is Needed: Comment on ‘Methoxyflurane Versus Standard of Care for Acute Trauma-Related Pain in the Emergency Setting: Protocol for a Randomised, Controlled Study in Italy (MEDITA)’”

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Publisher
Springer Journals
Copyright
Copyright © 2019 by The Author(s)
Subject
Medicine & Public Health; Internal Medicine; Oncology; Cardiology; Rheumatology; Endocrinology; Pharmacology/Toxicology
ISSN
0741-238X
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1865-8652
D.O.I.
10.1007/s12325-019-00937-2
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Abstract

Adv Ther https://doi.org/10.1007/s12325-019-00937-2 LETTER Response to ‘‘A Rigorous Evaluation of Methoxyflurane is Needed: Comment on ‘Methoxyflurane Versus Standard of Care for Acute Trauma-Related Pain in the Emergency Setting: Protocol for a Randomised, Controlled Study in Italy (MEDITA)’’’ . . . . . Andrea Fabbri Giuseppe Carpinteri Germana Ruggiano Elisabetta Bonafede Antonella Sblendido Alberto Farina Amedeo Soldi Received: February 26, 2019 The Author(s) 2019 Keywords: Acute pain; Analgesic; Emergency robust data in the literature (including the department; Inhaled analgesic; Injury; STOP! study [2]) and by extensive experience in Methoxyflurane; Penthrox; Pre-hospital; clinical practice, particularly in Australia. Trauma Although such data are adequate to support the introduction into clinical practice in Europe, further head-to-head studies vs. the best cur- We welcome the critical review by Montassier rently used therapeutic options, in terms of and Freund on our article on the rationale and effectiveness and rapidity of onset, are needed. methods of the ‘‘MEDITA’’ study [1]. Below, we These data will help to identify methoxyflu- provide point-by-point answers to all rane’s place in therapy, which today is a comments. promising option with potential advantages Methoxyflurane is currently being intro- compared with the drugs on the market. There duced in Europe, and its use is supported by are now emerging data in Europe: the ‘‘InMe- diate’’ study [3], which randomised 310 patients Enhanced Digital Features To view enhanced digital with trauma pain to methoxyflurane or stan- features for this article go to https://doi.org/10.6084/ m9.figshare.7808861. dard of care (SoC) analgesia, has recently been completed in Spain. Preliminary results indicate A. Fabbri that methoxyflurane significantly (p \ 0.0001) Department of Emergency Medicine, Morgagni- reduced pain severity compared with SoC up to Pierantoni Hospital Forlı`, Forlı`, Italy 20 min after the start of treatment [4]. Another ongoing study, ‘‘PenASAP’’, will randomise 360 G. Carpinteri Department of Emergency Medicine, Vittorio patients with trauma pain in a double-blind Emanuele University Hospital, Catania, Italy fashion to Penthrox or placebo, administered in addition to SoC [5]. These studies, together with G. Ruggiano Emergency Medicine Department, Santa Maria the MEDITA study, which is the subject of this Annunziata Hospital, Florence, Italy letter [1], all conducted with high method- ological and qualitative standards, aim to E. Bonafede resolve the uncertainties that currently persist. Bioikos Ambiente S.r.l., CRO YGHEA Division, Bologna, Italy Oral analgesia was not used to treat patients with moderate pain (NRS 4–6) in the MEDITA A. Sblendido  A. Farina (&)  A. Soldi study since intravenous (IV) therapy is the Medical Affairs Department, Mundipharma Pharmaceuticals srl, Milan, Italy common clinical practice in Italy where the e-mail: alberto.farina@mundipharma.it Adv Ther study was conducted, although it should be possible, and we agree that third parties have an underlined that there is wide heterogeneity in important role to play in future investigations the therapeutic approach and oligoanalgesia of methoxyflurane. still represents a widespread issue. The use of IV formulations is consistent with Italian Interso- ciety Recommendations on pain management ACKNOWLEDGEMENTS in the emergency setting [6]. Likewise, in the Spanish InMediate study, oral agents were PENTHROX is a registered trademark of Med- administered to only 10.7% of patients in the ical Developments International Ltd. SoC group, although it should be noted that the majority of patients (76.5%) had severe pain Funding. This work was sponsored by Mun- (NRS C 7). Moreover, we think that in the dipharma Pharmaceuticals srl. No article pro- context of a clinical study, to evaluate the net cessing charges were received by the journal for efficacy of the molecule, it is more appropriate the publication of this letter. to use an IV formulation to make the compar- ison more homogeneous and to obtain head-to- Authorship. All named authors meet the head data vs. the most effective therapeutic International Committee of Medical Journal option. A comparison vs. oral drugs would have Editors (ICMJE) criteria for authorship for this given an obvious result because of the latency in article, take responsibility for the integrity of the onset of action. A pharmacoeconomic the work as a whole and have given final analysis will be conducted separately at the end approval to the version to be published. of the study. The primary pain intensity end point in the Disclosures. Elisabetta Bonafede is an ‘‘MEDITA’’ study is assessed over the first 10 min employee of the clinical research organization because of the rapid action of the drug and conducting the study. Antonella Sblendido is an represents the most challenging comparison for employee of Mundipharma Pharmaceuticals srl. methoxyflurane. By definition, IV medicinal Amedeo Soldi is an employee of Mundipharma products are immediately ready to act. This also Pharmaceuticals srl. Alberto Farina is an correlates with the indication of methoxyflu- employee of Mundipharma Pharmaceuticals srl. rane: emergency relief of moderate-to-severe Andrea Fabbri, Giuseppe Carpinteri and Ger- pain in conscious adult patients with trauma mana Ruggiano have nothing to disclose. and associated pain and the unmet need of receiving an easy-to-use, rapid-acting and Compliance with Ethics Guidelines. This effective first-line analgesic treatment for article is based on previously conducted studies trauma-related pain. Methoxyflurane is already and does not contain any studies with human known to be effective at 30 min, so the 10-min participants or animals performed by any of the end point in the MEDITA trial provides addi- authors. tional information about its efficacy profile. Long duration of action is not the goal of Peer Review. Please note, contrary to the methoxyflurane treatment. In any case, inter- journal’s standard single-blind peer review pro- mittent administration produces a longer anal- cess, as a letter this article underwent review by gesic effect, and if required there is the option a member of the journal’s Editorial Board. to administer a second 3-ml dose in clinical Open Access. This article is distributed practice. While the Penthrox inhaler indeed requires responsible disposal [7], other anal- under the terms of the Creative Commons Attribution-NonCommercial 4.0 International gesics also have challenges in terms of con- sumables that are single use and non-recyclable License (http://creativecommons.org/licenses/ (e.g. syringes, flasks, cannulas, needles, etc.). by-nc/4.0/), which permits any noncommercial Finally, Mundipharma strongly encourages use, distribution, and reproduction in any and supports independent research as far as medium, provided you give appropriate credit Adv Ther Emergency Units (InMEDIATE): study protocol. IBJ to the original author(s) and the source, provide Clin Pharmacol. 2017;1:e0008. a link to the Creative Commons license, and indicate if changes were made. 4. Borobia Pe´rez A, Garcı´a Collado S, Carballo Cardona C, Capilla Pueyo R, Ferna´ndez Alonso C, Pe´rez Torres I, et al. InMEDIATE: results of a phase IIIB, open label randomised clinical trial to compare pain relief between methoxyflurane and standard of care anal- REFERENCES gesia for treating patients with trauma pain in Spanish emergency departments. Basic Clin Pharma- col Toxicol. 2018;123(Suppl. 4):16. 1. Fabbri A, Carpinteri G, Ruggiano G, Bonafede E, Sblendido A, Farina A, Soldi A, MEDITA Study Group. 5. Efficacy and Safety of Penthrox Combined With a Methoxyflurane versus standard of care for acute Standard Analgesia (SoC) in Adult Patients Admitted trauma-related pain in the emergency setting: proto- to the Emergency Department With Moderate to col for a randomised, controlled study in Italy Severe Pain Associated With Trauma (Pen ASAP). (MEDITA). Adv Ther. 2019;36(1):244–56. NCT03798899. https://clinicaltrials.gov/ct2/show/ NCT03798899?term=methoxyflurane&rank=8. 2. Coffey F, Wright J, Hartshorn S, Hunt P, Locker T, Accessed 26 Feb 2019. Mirza K, Dissmann P. STOP!: a randomised, double- blind, placebo-controlled study of the efficacy and 6. Raccomandazioni Intersocietarie Italiane (SIAARTI, safety of methoxyflurane for the treatment of acute SIMEU, SIS 118, AISD, SIARED, SICUT, IRC) sulla pain. Emerg Med J. 2014;31(8):613–8. gestione del dolore in emergenza. 2014. http://www. aisd.it/e107_files/downloads/raccintersocietarie_it_ 3. Borobia Perez AM, Capilla Pueyo R, Casal Codesido complete31052014.pdf Accessed 26 Feb 2019. JR, InMEDIATE Group, et al. Phase IIIb, open label randomised clinical trial to compare pain relief 7. Penthrox summary of product characteristics. 2016. between methoxyflurane and standard of care for https://www.medicines.org.uk/emc/medicine/31391. treating patients with trauma pain in Spanish Accessed 26 Feb 2019.

Journal

Advances in TherapySpringer Journals

Published: Mar 30, 2019

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