Despite advances in treatments for acute pain with new medications and development of widely accepted guidelines, inadequate assessment and management of acute pain still remain major problems in prehospital settings and emergency departments1. Reasons for the high incidence of trauma patients receiving inadequate pain treatment during prehospital emergency care include,
the difficulty of patient care in the out-of-hospital area, the
limited time available for such care, the great variability in the availability of analgesics and adjuvants between the various patient transfer units, and the existence of different action protocols. As a result, the patients present with poorly controlled pain at the time of arrival to the emergency department and even at the time of discharge from the hospital.
If the patient requires fast pain relief for the treatment of traumatic pain, it is often necessary to resort to the administration of parenteral analgesics. This results in
difficulties in the care of patients in the prehospital setting
and consumption of both personnel and material resources in the emergency departments.
In Spain there is not a well-established standard of
analgesic treatment for emergency trauma pain or clinical
guidelines with specific recommendations. The most used analgesics in the emergency departments are Non-Steroids Anti-Inflammatories Drugs (NSAIDs) and opioids
administered parentally. Both of them are very good options, but NSAIDs are not very potent and there are safety concerns with opioids. Transmucosal administration of fentanyl is being using more and more, but it is only approved for the treatment of breakthrough pain in patients with cancer2. The increased use of transmucosal fentanyl in the emergency setting probably reveals the need for potent analgesics that can be administered quickly and comfortably from the perspective of both physicians and patients.
An important addition to the management of pain in patients attending emergency units could be the
availability of a drug: (1) with a noninvasive route
of administration that does not require close patient
monitoring (2) has a rapid onset of action that lasts for a reasonable period of time (3) is well-tolerated and (4) has sufficient analgesic potency across a wide range of pain
types comparable with currently available analgesics. A drug of this kind could reduce the patient’s suffering between the patient’s arrival at emergency services and the administration of drugs after an assessment by
doctors, mainly if it could be self-administered by the
patient, using a light and portable device. Also, if patient cannulation could be avoided, the risks associated with this procedure under suboptimal conditions would be reduced. Finally, the achievement of more rapid pain
relief, in addition to benefiting patients, could also
facilitate an earlier review and treatment by physicians when the patient arrives at the hospital.
Methoxyflurane belongs to the fluorinated hydrocarbon group of volatile anesthetics, and was first introduced as
an inhalation anesthetic in the 1960s3. Among inhalational
fluorinated anesthetics, methoxyflurane is unique in having well-documented analgesic properties at low
doses4. Evidence has shown a large safety margin for
analgesic use of methoxyflurane with a Penthrox® inhaler at the recommended dose of 6 mL/day5. Methoxyflurane has been used extensively in Australia and New Zealand, administered via the handheld Penthrox® inhaler6, and is indicated for the short-term pain relief in emergency
medicine and in minor surgical procedures. The
Penthrox® inhaler is a green, whistle-shaped single-use device that delivers methoxyflurane in analgesic doses7. Although the efficacy and safety of methoxyflurane via a Penthrox® inhaler has been evaluated in a clinical trial
developed in emergency units8, it was compared only with placebo and only in hospital emergency rooms.
This is a randomized, open label trial with two parallel groups, aimed to assess the effectiveness, safety, health economics and patients reported outcomes after using
methoxyflurane. Due to its administration advantages and its good efficacy and safety, the Pain Working Group of the Spanish Society of Emergency Medicine (SEMES) and the Spanish Clinical Research Network (SCReN) are interested in testing methoxyflurane against emergency analgesic standard of care (SoC) treatment in patients
with moderate to severe pain associated with trauma who
are treated in emergency units (hospital and pre-hospital emergency units), before incorporating this drug into their
intervention protocols.
InMEDIATE is an acronym (Inhaled Methoxyflurane: Pain relief in adult trauma patients in Spain; in Spanish) of the study with code MR311-3502, EudraCT 2017-00033870, and ClinicalTrials.gov identifier NCT03256903. It is a
randomized, open label, multicenter trial with two parallel groups. The trial will be conducted at 15 sites in Spain
(three of them pre-hospital emergency units). A total of 310 patients with moderate to severe pain secondary to
trauma are expected to be randomized 1:1 to receive either
methoxyflurane or SoC in the emergency units (Figure 1).
Because there is not a well-recognized SoC in Spain,
each principal investigator was required to report the SoC at their emergency Department for treating emergency moderate and severe pain due to trauma. All of the responses were submitted to the Health Authorities, before the approval of this trial.
Figure 1. Flow diagram of the study
The aim of this trial is to evaluate the change in intensity of traumatic pain in patients treated with inhaled
methoxyflurane against SoC in emergency units in Spain. Primary efficacy variables will be as follows:
• Change in mean pain intensity over 20 min: from
baseline to 3, 5, 10, 15 and 20 minutes after the start of treatment administration (STA).
• Time from STA to the first pain relief.
Considering the broad spectrum of trauma types, the variability of analgesic protocols used in Spanish emergency departments, and taking into account that
methoxyflurane has a vast literature base supporting its safety and efficacy (it has been used in Australia since 1975) 2,8-20, we will define the objectives of primary
interest, focused on clinically relevant aspects, and following IMMPACT recommendations21. The following variables will be taken into consideration:
• Analgesic effectiveness in patients with moderate pain
(numeric rating scale [NRS] 0-10 ≥4 and ≤7), treated with first-step analgesics, assessed as the change between preadministration of the treatment and measures at 3, 5, 10, 15, 20 and 30 min after the start of the treatment.
• Safety in patients with severe pain (NRS 0-10 >7), treated with second- or third-step analgesics, evaluated
as the rate of adverse events that require treatment and/or increased duration of hospital stay.
• Speed of action of analgesia in all patients, assessed
as time since patient randomization until the first
meaningful pain relief, following patient’s criteria.
• Patient-averaged summed pain intensity difference 15
trauma pain in Spanish Emergency Units (InMEDIATE): Study protocol.
min after STA (SPID15), assessed as the cumulative sum
of the recorded difference between pain intensity and
baseline, at each time point to 15 min post dose.
• Pain Responders (with ≥ 30% pain relief compared to baseline) at 20 min
Determine differences between both groups for the
following variables:
patient: -Since randomization -Since STA
intensity at 40, 50 and 60 minutes in those patients
remaining in the emergency units.
the 30 minutes after STA until discharge of the patients.
Patients eligible to be enrolled in this trial are adult patients (≥18 years old) with moderate to severe pain (NRS 0-10 ≥4), secondary to trauma, who do not require surgery or hospitalization longer than 12 h. Patients must
be in an adequate level of consciousness and sign the informed consent. The following criteria exclude patients
from participation: (1) Hypersensitivity to methoxyflurane or any fluorinated anesthetic; (2) malignant hyperthermia;
(3) patients who have a history or show signs of liver damage after previous methoxyflurane or halogenated hydrocarbon anesthetic use; (4) clinically significant renal impairment (for the purposes of the study, patients
receiving treatment for kidney disease or on dialysis will
be considered to suffer from this degree of insufficiency);
(5) pregnant or childbearing potential at time of inclusion; (6) clinically evident cardiovascular instability; (7) clinically evident respiratory depression; (8) patients
taking any other analgesic for the acute traumatic pain
before inclusion; (9) altered level of consciousness due to any cause; (10) degenerative diseases; (11) patients
unable to understand the purpose of the study and
perform self-assessments; and (12) patients who have participated in another clinical trial within 30 days prior to
randomisation.
Patients who meet all inclusion and none exclusion
criteria, who have signed informed consent, will be randomized 1:1 through an envelope system. In one
arm, patients will receive methoxyflurane, while in
the other arm they will receive SoC treatment of the
emergency unit. Patients will be randomized by doctors in
ambulances and in hospital emergency units.
The study visits and procedures will be performed as shown in Figure 2 and Table 1.
Figure 2. Study visits and procedures of the study
Patients in the methoxyflurane arm will receive one inhaler containing 3 mL of methoxyflurane, through which they will be instructed to perform inhalations. Patients are
also advised to exhale through inhaler so unmetabolised
methoxyflurane can be absorbed by AC chamber. Patients
will be instructed to initially perform some continuous inhalations, following by intermittent ones depending on their analgesic request. They will also be advised that they can close dilutor hole if they need stronger analgesia. In
case the patient needs it, a second inhaler with 3 additional ml of methoxyflurane 99,9% will be dispensed (maximum daily dose: up to 6 ml [2 vials of 3 ml]). Patients could
also require rescue medication, if needed.
In the other arm, patients will be treated following the emergency units’ SoC for treating patients with similar clinical characteristics. Any kind of analgesic administered by any route will be valid. Only
administration of one analgesic (or fixed combinations) at
time 0 will be considered SoC. Other required analgesics will be considered rescue medication.
Pain intensity will be measured at 0, 3, 5, 10, 15, 20 and 30 minutes after receiving medication, and at discharge
time, using a NRS0-10 scale. It will be also recorded time
to first pain relief and time to first meaningful pain relief, following IMMPACT recommendations. If the patient
is still at the hospital pain intensity will be also recorded
at 40, 50 and 60 minutes after STA (Figure 1). Sedation rate will be evaluated at baseline and 30 minutes after
STA, using Ramsay scale. Also measured will be patient
satisfaction (using a NRS0-10 scale), patient fulfillment of expectation (evaluated with the CEP scale) and patient global impression of change (PGIC) at 30 minutes after STA (evaluated using PGIC scale). Fourteen days (±2) after discharge, a safety visit will be
performed at the hospital or by telephone. Laboratory samples for hematology will be collected at the start of
the trial and at the safety visit (details of the evaluated parameters are included in table 1). During the entire trial,
any adverse events will be recorded and reported to the
sponsor and the health authorities (when applicable).
Some 310 patients are expected to be recruited over 4
months. This number was calculated to meet the primary
objectives of the study by attaching a significance level of 2.5% and a 90% confidence interval (Bonferroni method). The assumptions for the methoxyflurane group are based
on data obtained in a pivotal study of this drug, assuming
a difference of 20% with respect to the data expected in the comparator group, for both objectives. With these
data, we would need to include a total of 295 patients.
Assuming a 5% loss, a total of 310 included patients
would be required for the trial.
The analysis of the primary variable of efficacy will be made on an intention-to-treat (ITT) basis. It will include
all the patients who are randomized, whether they have received the study treatment or not.
In addition, the analysis of efficacy will also be performed in the “evaluable” or per protocol population (PP). This is a subgroup of the ITT population defined as those
patients who meet the trial selection criteria, who have not received rescue medication and who comply with the
protocol-defined monitoring scheme (at least baseline visit and after 3, 5, 10, 15 and 20 min complete).
The safety analyses (intermediate and final) will be held in
the safety population, which includes patients who receive at least one dose of the drug during the study.
The statistical analysis will be performed by members of the SCReN.
All patients who meet the selection criteria will be
included in the analysis. Patients who are removed
from the analysis, along with the reason they have been eliminated, will be detailed. No values will be allocated for unavailable data.
The quantitative variables will be defined using the mean, median, standard deviation and confidence interval for the mean with a confidence level of 95%. The contrast
of the distribution between dichotomous and categorical variables will be performed using contingency tables
with the statistical chi-squared or Fisher’s exact test, as
appropriate.
The comparison of means between groups of qualitative
variables, using Student’s t-test, will be performed when
comparing two groups, and a single factor analysis of variance when comparing more than two groups, if the normality criteria are met.
To evaluate the primary objective, an analysis of covariance will be performed, using a mixed model of repeated measures analysis of covariance will be carried
out for 3, 5, 10, 15 and 20 minutes. Missing data major
will not be imputed, and will be left as lost. In the analysis
of repeated measures will be included fixed-effect terms
for treatment and time random central effect and pain
baseline value (0 minutes).
Regarding other primary endpoint, time to first pain relief, a time to event analysis will be performed using time-toevent methodology, including a Cox Proportional Hazards
model with treatment and qualifying pain intensity at
randomisation as fixed effects and center as a random effect. Pre-dose pain baseline intensity (at 0 minutes) will be added as a covariate. Weibull assumption model will be checked and used when it holds. A Kaplan-Meier analysis
will also be performed to evaluate the average time until
first pain relief and first clinically meaningful pain relief.
Cost of pain relief by time unit will be calculated as
follows: Cost of treatment (drugs+fungible+nurse time..) = C; Pain relief (difference between baseline and time t) = PRt; known time= t. Then C / PRt [€ / cm] gives us costs (in euros) to reduce one cm of pain; And C / PRt / t [(€ / cm) / (min)] = [€ / cm min], is cost to reduce 1 cm of pain
in one minute.
All statistical analyses of secondary efficacy endpoints will be performed on the ITT and PP population and will be exploratory with no aim to draw confirmatory conclusions. All secondary efficacy endpoint data will
be summarized descriptively by treatment group and
time point (where applicable). All endpoints will be
analyzed using appropriate statistical models, in order
to get estimates (differences or ratios) and two-sided 95% confidence intervals for the treatment effects. All exploratory p-values will be from 2-sided tests and no
adjustments for multiplicity will be performed.
Subgroup analyses and sensitivity analyses, in particular with respect to different approaches for handling of
missing data, will also be applied for specific endpoints.
An interim analysis will be performed to assess treatment safety only, when 100 patients have completed the study.
Coordination, management and monitoring of the study will be performed by the SCReN.
The researchers will adhere strictly to the provisions of this protocol and will complete the case report forms. The study will be performed according to the recommendations for clinical studies and the evaluation of drugs in humans, as contained in the Declaration of
Helsinki (revised in successive world assemblies) and in
the current Spanish and European legislation on clinical
studies and patient data confidentiality. The study will follow the principles of Good Clinical Practice. This
study has been approved by the Clinical Research Ethics
Committee of La Paz University Hospital (Madrid, Spain)
and by the Spanish Agency of Medication and Health
Products, and has been registered in Eudra CT (Eudra CT: 2017-000338-70) and clinicaltrial.gov (identifier NCT03256903).
Methoxyflurane was initially developed as an inhalational
anesthetic agent. It was later discovered that it had good analgesic properties at lower doses, with a good
safety profile. It is currently used in countries including
Australia, where it is routinely used in ambulance services because its low doses can achieve rapid analgesia, with easy administration. It has been recently launched in four
European countries (UK, Ireland, Belgium and France),
and approval is expected in the rest of Europe by the end of 2017, through a decentralized procedure.
Despite the fact that methoxyflurane has been marketed in
Australia and New Zealand for treating emergency pain
due to trauma for more than 40 years, no randomized
clinical trials to evaluate analgesic its effectiveness compared to active treatment have been published in this setting. Observational studies have shown that
methoxyflurane has an analgesic effect superior to
intramuscular tramadol, lower than strong opioids but faster than intranasal fentanyl, but none of them have been carried out in Europe. The only randomized trial to evaluate the change in pain intensity developed in Europe was a placebo controlled trial, and it was performed only in emergency hospital departments8.
To the best of our knowledge, the described Spanish
trial will be the first randomized clinical trial in Europe comparing methoxyflurane to active treatment, in the
emergency treatment of trauma pain.
In Spain there are no clinical guidelines for managing
trauma pain. A large multicenter study carried out in 33
Spanish hospitals, including more than 1600 patients
with acute minor trauma, showed that less than 50% of
the patients received analgesic treatment, and the most used painkillers were NSAID26. During the last few years
pain management in emergency setting has significantly
improved with more opioids being used for treating severe pain, but we are far from achieving a standard of care,
supported by strong scientific evidence.
The present trial will help us to compare different
analgesic protocols versus methoxyflurane ,used in both, hospital and pre-hospital Spanish setting.
Methoxyflurane is the most used analgesic for treating
patients with emergency pain in the prehospital setting in Australia17, and those Australian patients have a mean
pain intensity above 8 (scored using a verbal numeric rating scale 0-10). We think that our trial will confirm methoxyflurane as a good option for being a first-line
analgesic for treating acute pain in the Spanish emergency departments.
This protocol was authorized on 18 March 2017 by the Spanish Medicine Agency in its initial version. The
protocol described here corresponds to version 1.1 (18 May 2017). Proposed dates for the study are listed below:
Opening of the first site: June 2017
End of the inclusion period: October 2017 End of database: December 2017
Data analysis and final report: January 2018
The Scientific Committee of the study is made up
of members of SEMES and SCReN. Mundipharma
Pharmaceuticals S.L funds the study according to
the guidelines of the current protocol. Mundipharma
Pharmaceuticals S.L agrees not to interfere in the selection
processes of the patients, analysis of the data and/or publication of the results, or any other process that might come into play with the results of the study. Funding will be independent of the results of the study.
The Spanish Clinical Research Network (SCReN), PT12/0002, is funded by the PE of I+D+I 2013-2016 and by the Subdirección General de Evaluación y Fomento de la Investigación – Instituto de Salud Carlos III (ISCIII). It is also co-financed with funding from FEDER.
® PENTHROX is a registered trade mark of Medical
Developments International Limited.
Alberto M. Borobia, MD, PhD Clinic Pharmacology Department. La Paz University
Hospital.
Spanish Clinical Research Network (SCReN). Spanish Society of Emergency Medicine (SEMES)
Rosa Capilla Pueyo, MD
Emergency Department.
University Hospital Puerta de Hierro-Majadahonda Coordinator of the Pain Group of SEMES
Jose Ramón Casal Codesido, MD
Emergency Department. El Bierzo Hospital
Coordinator of the Pain Group of SEMES
Anselma Fernández Testa, MD Emergency Department. Complejo Asistencial of Zamora
Secretary of the Pain Group of SEMES
Antonio J. Carcas-Sansuán, MD, PhD Clinic Pharmacology Department. La Paz University Hospital.
SCReN
José Carlos Martínez Ávila, PhD Clinic Pharmacology Department. La Paz University Hospital.
SCReN
María Teresa García. MSc Scientific Support Unit: Epidemiology, Bioinformatics
and Biostatistics
12 de Octubre University Hospital
SCReN
César Carballo Cardona La Paz University Hospital (Madrid)
Rosa Capilla Pueyo Puerta de Hierro-Majadahonda University Hospital (Madrid)
Cesáreo Fernández Alonso
Clínico San Carlos University Hospital (Madrid)
Pedro Llorens Soriano General University Hospital of Alicante (Alicante)
José Ramón Casal Codesino El Bierzo Hospital (León)
Sergio García Collado Campo Grande Hospital (Valladolid)
Anselma Fernández Testa
Health complex of Zamora (Zamora)
Antonio Cid Dorribo
Emergency Medical Service of Madrid, SUMMA 112 (Madrid)
Amaia Etxebarria Gulias Emergencies 112 - Osakidetza (Vizcaya)
Aitor Odiaga
Gernika Hospital (Vizcaya)
Luis Sánchez Santos
Public Foundation of health emergencies of Galicia-061 (Vigo)
Luis Amador Barcela
Álvaro Cunqueiro Hospital (Vigo)
Ignacio Pérez Torres Virgen del Rocío University Hospital (Sevilla)
María Arranz Viladecans Hospital (Barcelona)
Carmen del Arco
La Princesa University Hospital (Madrid)
[1]. Marinangeli F, Narducci C, Ursini ML, Paladini A, Pasqualucci A, Gatti A, Varrassi G. Acute pain and availability of analgesia in the prehospital emergency setting in Italy: a problem to be solved. Pain Pract. 2009 Jul;9(4):282-8
[2]. Bendall JC, Simpson PM, Middleton PM. Effectiveness of prehospital morphine, fentanyl, and
methoxyflurane in pediatric patients. Prehosp Emerg Care. 2011 Apr;15(2):158-65 [3]. Tomlin PJ. Methoxyflurane. Br J Anaesth.1965;37:706–9. [4]. Tomi K, Mashimo T, Tashiro C, Yagi M, Pak M,
Nishimura S, Nishimura M, Yoshiya I. Alterations in pain threshold and psychomotor response associated with subanaesthetic concentrations of
inhalation anaesthetics in humans. Br J Anaesth. 1993 Jun;70(6):684-6.
[5]. Dayan AD. Analgesic use of inhaled methoxyflurane: Evaluation of its potential nephrotoxicity. Hum Exp Toxicol. 2016 Jan;35(1):91
[6]. Medical Developments International Pty.Ltd., 2009, PENTHROX® (methoxyflurane) Inhalation. Product information: Australia.
[7]. Penthrox British Summary of Product
Characteristics October 2015. http://www.mhra.
gov.uk/home/groups/spcpil/documents/spcpil/con
1460695399101.pdf. Accessed 07 Aug 2016. [8]. Coffey F, Wright J, Hartshorn S, Hunt P, Locker T, Mirza K, et al. STOP!: a randomised, double-blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain. Emerg Med J. 2014 Aug;31(8):613-8
[9]. Babl F, Barnett P, Palmer G, Oakley E, Davidson A. A pilot study of inhaled methoxyflurane for procedural analgesia in children. Paediatr Anaesth. 2007 Feb;17(2):148-53.
[10]. Babl FE, Jamison SR, Spicer M, Bernard S. Inhaled methoxyflurane as a prehospital analgesic in children. Emerg Med Australas. 2006 Aug;18(4):404-10
[11]. Buntine P, Thom O, Babl F, Bailey M, Bernard
S. Prehospital analgesia in adults using inhaled methoxyflurane. Emerg Med Australas. 2007 Dec;19(6):509-14.
[12]. Gaskell AL, Jephcott CG, Smithells JR, Sleigh JW. Self-administered methoxyflurane for procedural analgesia: experience in a tertiary Australasian centre. Anaesthesia. 2016 Apr;71(4):417-23.
[13]. Huang S, Pepdjonovic L, Konstantatos A, Frydenberg M, Grummet J. Penthrox alone versus Penthrox plus periprostatic infiltration of local analgesia for analgesia in transrectal ultrasound-guided prostate biopsy. ANZ J Surg. 2016 Mar;86(3):139-42.
[14]. Johnston S, Wilkes GJ, Thompson JA, Ziman M, Brightwell R. Inhaled methoxyflurane and intranasal fentanyl for prehospital management of visceral pain in an Australian ambulance service. Emerg Med J. 2011 Jan;28(1):57-63.
[15]. Konkayev AK, Baymagambetov SHA, Sainov MS, Bekmagambetova NV, Akhmetova AZH. Evaluation of clinical effectiveness of inhalatory analgesic “Penthrox” for pain relief in ankle injuries. Archives of the Balkan Medical Union 2013;48(S3):239-43.
[16]. Lee C, Woo HH. Penthrox inhaler analgesia in transrectal ultrasound-guided prostate biopsy. ANZ J Surg. 2015 Jun;85(6):433-7.
[17]. Middleton PM, Simpson PM, Sinclair G, Dobbins TA, Math B, Bendall JC. Effectiveness of morphine, fentanyl, and methoxyflurane in the prehospital setting. Prehosp Emerg Care. 2010 Oct;14(4):439-47
[18]. Nguyen NQ, Toscano L, Lawrence M, Moore J, Holloway RH, Bartholomeusz D, et al. Patientcontrolled analgesia with inhaled methoxyflurane versus conventional endoscopist-provided sedation for colonoscopy: a randomized multicenter trial.
Gastrointest Endosc. 2013 Dec;78(6):892-901. [19]. Oxer HF. Effects of Penthrox® (methoxyflurane)
as an analgesic on cardiovascular and respiratory
functions in the pre-hospital setting. Journal of
Military and Veterans’ Health. 2016;24(2):14-20.
[20]. Spruyt O, Westerman D, Milner A, Bressel M, Wein S. A randomised, double-blind, placebocontrolled study to assess the safety and efficacy of methoxyflurane for procedural pain of a bone marrow biopsy. BMJ Support Palliat Care. 2014 Dec;4(4):342
8.
[21]. Cooper SA, Desjardins PJ, Turk DC, Dworkin RH, Katz NP, Kehlet H, et al. Research design considerations for single-dose analgesic clinical trials in acute pain: IMMPACT recommendations. Pain. 2016 Feb;157(2):288-301.
[22]. Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J. 1974 Jun 22;2(5920):656-9.
[23]. Pujiula-Maso J, Suñer-Soler R, Puigdemont-Guinart M, Grau-Martín A, .Bertrán-Noguer C, et al. [The satisfaction of hospitalized patients as an indicator of
quality of care]. Enferm Clin 2006;16(1):19-26. [24]. Hurst H, Bolton J. Assessing the clinical significance
of change scores recorded on subjective outcome
measures. J Manipulative Physiol Ther. 2004
Jan;27(1):26-35.
[25]. R Core Team. A language and environment for statistical computing; R Foundation for Statistical Computing, Vienna, Austria (2013)
[26]. García-Castrillo L, Andrés-Gómez M, Rubini Puig S, Juárez-González E, Skaf Peters E, García-Cases C. [Pain in mild acute traumatic processes]. Emergencias 2006;18: 19-27.
Phase IIIb, open label randomised clinical trial to compare pain relief between methoxyflurane and standard of care for treating patients with trauma pain in Spanish Emergency Units (InMEDIATE): Study protocol.
Table 1. Activity Calendar per visit
1: The length of the administration of the analgesic trial treatment, as well as trial medication, will be recorded in the case report form (CRF).
2: The first draw could be performed before or post-administration of the analgesic trial treatment. In both analyses, the following variables will be measured: alkaline phosphatase, Gamma-Glutamyl Transferase (GGT), Glutamate Pyruvate Transaminase (GPT); Glutamate Oxalacetate Transaminase (GOT); Blood Urea Nitrogen (BUN), calcium, chloride, creatinine, albumin, glucose, potassium, sodium, bilirubin, total protein, erythrocytes, leucocytes, hemoglobin, hematocrit, platelets, Mean Corpuscular Volume (MCV) and Mean Corpuscular Hemoglobin (MCH). 3 In case of suspicion of a pregnancy, a pregnancy test will be performed from urine prior to analgesic trial treatment administration. If positive, the patient would not participate in the trial.
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