a b s t r a c t

Purpose: Midazolam comedication with morphine is a routine practice in pre and postoperative patients but has not been evaluated in prehospital setting. We aimed to evaluate the comedication effect of midazolam in the prehospital traumatic adults.

Methods: A prehospital prospective randomized double-blind placebo-controlled trial of Intravenous morphine 0.10 mg/kg and midazolam 0.04 mg/kg vs morphine 0.10 mg/kg and placebo. pain assessment was done using a validated Numeric rating scale (NRS). The primary end point was to achieve an efficient analgesic effect (NRS <= 3) 20 minutes after the baseline. The secondary end points were treatment safety, total morphine dose required until obtaining NRS <= 3, and efficient analgesic effect 30 minutes after the baseline. Findings: Ninety-one patients were randomized into midazolam (n = 41) and placebo (n = 50) groups. No significant difference in proportion of patients with a pain score <= 3 was observed between midazolam (43.6%) and placebo (45.7%) after 20 minutes (P = .849).

Secondary end points were similar in regard with proportion of patients with a pain score <= 3 at T30, the side effects and adverse events except for drowsiness in midazolam vs placebo, 43.6% vs 6.5% (P b .001). No significant difference in total morphine dose was observed, that is, midazolam (14.09 mg +- 6.64) vs placebo (15.53 mg +- 6.27) (P = .315).

Conclusions: According to our study, midazolam does not enhance pain control as an adjunctive to morphine regimen in the management of trauma-induced pain in prehospital setting. However, such midazolam use seems to be associated with an increase in drowsiness.

(C) 2014

1. Introduction

Today, acute pain management through morphine titration is a common practice in pre and postoperative and emergency settings [1-6]. However, most treated patients continue to complain of pain or are relieved of pain only after a long analgesia administration

? Grant: This study was funded by the French Ministry of Health (PHRCI 2006, GO 20).

The funding agency had no role in design, conduct, or analysis of the study.

?? Clinical trial registration: NCT01731184.

? Author contributions: YA conceived the study, designed the trial, and obtained

research funding. YA, MR, JJ, and FS supervised the conduct of the trial and data collection. YA, MR, JJ, and FS undertook recruitment of participating centers and patients and managed the data. MG and GRJ provided statistical advice on study design and analyzed the data. ZA drafted the manuscript and interpreted the outcomes, and all authors contributed substantially to its revision. YA takes responsibility for the manuscript as a whole.

?? Conflict of interest: The authors declare no conflicts of interest.

* Corresponding author. Brest Medical university hospital.

E-mail address: [email protected] (Z. Alavi).

time [7]. Pain has a very complex neurophysiologic and neuropsy- chologic mechanism. Morphine-midazolam concomitant treatment has been reported to allow a better sedation (use of a lower dose of morphine) and faster pain relief through an analgesic pathway comprising both components of pain mechanism [8,9]. This combination of treatment has been advised by many authors [10- 12] and used widely for pain control in traumatic patients [13,14]. In France, expert guidelines suggest that midazolam is the most appropriate benzodiazepine for sedation [15,16]. Midazolam phar- macologic properties seem interesting: sedative, hypnotic inductor, anxiolytic, Muscle relaxant, and amnesic [17-19]. As a Sedative agent, midazolam has been reported to allow a conscious sedation and a better analgesia [9,20,21]. Furthermore, as a comedication in pre and postoperative settings, midazolam has allowed the use of a lower dose of morphine [21]. Its pharmacologic activity is characterized by its fast action (3 minutes) and by its very short plasma half-life. The presence of an antidote is an additional advantage for its safety of administration [17,20-22]. (See Fig.)

http://dx.doi.org/10.1016/j.ajem.2014.01.048

0735-6757/(C) 2014

Fig. Flowchart showing the flow of participants through each stage of our randomized trial.

Discontinued intervention: Patient received 2 injections of midazolam (n = 2)

Morphine titration was ceased whenover- sedated (Ramsay score? 3) and/or bradyapnea (RR<10/min) and/or saturated oxygen rate (SaO2 < 90%) and/or a clinical state requiring naloxone

Allocated to Morphine + Midazolam (Group Midazolam)

(n = 41)

Received allocated 0.10 mg/kg morphine + 0.04 mg/kg midazolam (n = 41)

Received 3mg / 5 min morphine until NRS ? 3

Assessed (n = 39)

• NRS at T20
• NRS per 5 min during 30 min
• Adverse events
• Total morphine dose until NRS ?3

Analysis

Importance

Follow up

Allocation

Enrollment

Using midazolam as a comedication is common in pre and postoperative patients but nonevaluated in traumatic patients with acute severe pain in prehospital settings. To our knowledge, this is the first study evaluating the adjunctive role of midazolam to morphine for pain control in prehospital management of traumatic severe pain.

Goals of this investigation

We aimed to test the comedication effect (ie, analgesia and sedation) of midazolam in prehospital setting. Our goals were as follow: pain control and assessment of side effects and adverse events in the trauma-induced pain management in prehospital setting.

1. Methods
   1. Study design

A prospective, multicenteric, randomized double-blind placebo- controlled trial of morphine sulfate at 0.10 mg/kg-midazolam 0.04mg/kg vs morphine-placebo was performed in traumatic patients with acute severe pain (numeric rating scale [NRS] >=6) [23].

Setting

The study was conducted in prehospital emergency services of Brest, Carhaix, Quimper, Concarneau, Douarnenez, and Nantes, between November 5, 2006, and September 30, 2009. Data collection was done by each center’s service mobile d’urgence et de reanimation

physicians (residents). The French SMUR are mobile emergency resuscitation trucks (fully equipped with resuscitation devices) composed of a qualified emergency physician (or an anesthetist), a paramedic specialized nurse, and an emergency medical technician (EMT). These SMUR units provide prehospital emergency care in response to prior emergency medical phone (reached by dialing toll free 15 or 112) assistance by an emergency physician.

Selection of participants

Conscious patients (with a Glasgow Coma Scale [GCS] >=13) ages 18 to 70 years, on spontaneous ventilation with trauma-induced pain (NRS >=6) taken in prehospital care (emergency and intensive care) by SMUR were eligible for inclusion. This comprised all types of trauma. Contraindication to morphine or midazolam was determined through questioning of the patients, for example, history of allergies, severe liver, and kidney failure as well as severe respiratory failure. The above contraindication and other criteria such as being on morphine or treated for chronic pain, pregnant, unable to evaluate their pain, and presence of trauma-induced failures, that is, hemodynamic shock (eg, hypotension, pulse rate, and clinical examination) and/or respiratory failure (eg, clinical examination, saturated oxygen rate [SaO2], and respiratory rate) and/or neurologic impairment (GCS <=8) led to patient's exclusion from the study.

The study was approved by the ethics committee of our center (comite de protection des patients registration no. 444).

Outcome measures

The primary end point was to achieve an efficient analgesic effect (NRS <=3) 20 minutes after the baseline. The secondary end points were as follow:

• Midazolam treatment safety (presence or evolution of adverse events and side effects);

• Total morphine dose required until obtaining NRS less than or equal to 3; and
• Efficient analgesic effect (NRS <= 3) 30 minutes after the baseline.
  1. Interventions

     Patients meeting inclusion criteria (NRS >=6 with trauma-induced pain) were randomly assigned (ie, random allocation blocks of 10 by the sponsoring center) to receive either morphine (morphine sulfate) at 0.10 mg/kg (followed by 3 mg every 5 minutes until obtaining NRS

     <=3) associated to midazolam (midazolam group) at 0.04 mg/kg (only 1 dose at the baseline) or morphine associated to a placebo (placebo group), with an equal probability of assignment to each group. The placebo-normal saline solution-was prepared and injected identical to midazolam.

     Each patient was assigned to a numbered case report form (CRF) allocated to either group. Patient’s randomization was done using sealed envelopes containing patient-assigned group. After patient’s inclusion, the CRF group allocations were de-identified.

     Allocation was concealed (from the patient, physician, and EMT) to prevent any influence of knowledge of treatment assignment on those enrolling the patients in the study except for the nurse preparing the treatment and providing care. The study drug was delivered through an identical indiscernible syringe by the nonblinded paramedic nurse who was placed behind the physician in the emergency truck. The registered nurse nonblinded to the treatment did not participate in data collection and interpretation. The emergency physician was in charge of drug administration, data collection, interpretation (of the NRS, the analgesic, and sedative parameters), and patient follow-up. Because of the baseline pain intensity (NRS >=6), in accordance with

     the ethics committee requirement, the informed consent was obtained postinclusion. Pain assessment was done according to the NRS, ranging from 0 equals to “no pain” to 10 equals to “worst possible pain.”

     Safety was monitored by continuous pulse oximetry, monitoring of respiratory rate and pulse rate, noninvasive blood pressure, and Ramsay score [24] monitoring every 5 minutes for 30 minutes. These data as well as the presence of nausea, vomiting, apnea, pruritus, and drowsiness were recorded.

     Morphine titration was ceased upon any signs of adverse events and side effects: Ramsay score at least 3 (to avoid oversedation) [4] and/or NRS less than or equal to 3 and/or bradypnea (b 10/minute) [4] and/or SaO2(b 90% for at least 10 seconds) [4] and/or a clinical state requiring antidote administration: naloxone (Narcan) at 1 ug/kg direct intravenous injection (DIV). Metoclopramide (primperan, 1 vial by DIV) was to be administered if the patient vomited more than once.

     Methods of measurement

     Doses of morphine (morphine sulfate) at 0.10 mg/kg and midazolam (midazolam group) at 0.04 mg/kg were chosen respectively in line with the literature [1,3,9,10,12-16,25,26]. We chose to assess pain intensity according to NRS and not according to the Visual analogue scale (VAS). Both are used worldwide, by emergency department (ED) physicians, but the former seems to be a more reliable and valid tool for pain management in a wide population range (from children to the elderly and those with speech problems). Although both scales offer identical high differentials, the VAS acceptation by the elderly remains uncom- mon. According to Ricard-Hibon et al and Berthier et al [7,23,25], VAS requires an abstracting capacity hard to obtain in the elderly. Moreover, they reported a higher failure rate of VAS in traumatology [23].

     Data collection and processing

     The CRFs were filled in by the physician in the truck. The data were entered into an Excel spreadsheet, and statistical analysis was conducted in SAS (Statistical Analysis System Version 9.3; SAS Institute, Cary, NC).

     1. Statistical analysis

     A sample size of 166 patients was calculated to provide 80% power (? risk of 5%) to detect a 20% difference in the proportion of patients with a pain score NRS less than or equal to 3 after 20 minutes, that is, 85% in midazolam group and 65% in the placebo group. Patient characteristics, age, and sex were collected.

     The quantitative variables were described as mean +- standard deviation (SD) and qualitative variables as percentage and frequency. Proportion of patients (%), with efficient analgesic effect (NRS <=3),

     20 minutes from the baseline (primary outcome) were compared between the 2 groups. Mean values and proportion of side effects and adverse events as well as total morphine dose until obtaining NRS less than or equal to 3 (secondary outcomes) were compared between the 2 groups. Proportions were compared using the ?² test or Fisher exact test as appropriate, and means were compared using the t test. Sensitivity analyses were performed to evaluate the impact of missing data. We assumed the best possible scenario for midazolam (success for missing data in midazolam group vs failure in placebo) and the worst possible scenario for midazolam (failure for missing data in midazolam vs success in placebo). An intention-to-treat analysis was performed given the sedative safety criteria.

     1. Results

     Participant flow is summarized in the Consort diagram (Fig.). Of 97 patients assessed for eligibility, 91 were enrolled in the study. Six patients were excluded: 2 refused to participate and 4 did not meet the inclusion criteria. Random allocation resulted in 41 patients

     Table 1

     Patients’ description

     Table 3

     Comparison of different analgesic and sedative parameters between the midazolam and placebo groups

     Placebo group Midazolam group P

     ^b t test.

     		Placebo group		Midazolam group	P
     		(n = 46)		(n = 39)
     Sex	Male	38 (82.6%)		29 (76.3%)	.475a
     	Female	8 (17.4%)		9 (23.7%)
     Age	Mean +- SD	40.4 +- 15.6		43.3 +- 18.6	.443 b
     a ?2 test.

     assigned to the midazolam group and 50 to the placebo group. All randomized patients for whom data were available for the primary outcome were included in the analysis (n = 85).

     There was neither a significant difference in age and sex between

     Respiratory rate, breaths per minute (mean +- SD) no.

     T0 17.02 +- 5.08 (n = 45) 16.92 +- 5.24 (n = 36) .927^a

     T20 15.14 +- 3.28 (n = 43) 15.5 +- 5.11 (n = 32) .729^a

     T30 15.14 +- 3.17 (n = 43) 15.03 +- 5.46 (n = 31) .922^a

     Pulse rate, beats per minute (mean +- SD) no.

     T0 85.67 +- 17.63 (n = 46) 85.79 +- 17.78 (n = 38) .976^a

     T20 82.95 +- 16.60 (n = 44) 82.21 +- 15.80 (n = 34) .841^a

     T30 81.93 +- 16.40 (n = 40) 81.30 +- 16.40 (n = 33) .872^a

     Systolic blood pressure, mm Hg (mean +- SD) no.

     T0 135.50 +- 20.67 (n = 45) 135.70 +- 19.96 (n = 38) .957^a

     T20 131.00 +- 17.05 (n = 42) 130.80 +- 19.44 (n = 37) .944^a

     T30 133.80 +- 20.83 (n = 39) 136.20 +- 21.89 (n = 33) .637^a

     Diastolic blood pressure, mm Hg (mean +- SD) no.

     placebo and midazolam groups (40.4 +- 15.6 vs 43.3 +- 18.6, P = .443) T0		78.69 +- 13.79 (n = 45)		80.66 +- 15.19 (n = 38)	.538a
     (82.6% vs 76.3% men, P = .475) (Table 1) nor in other baseline T20		75.36 +- 11.8 (n = 42)		76.73 +- 15.21 (n = 37)	.653a
     T30		77.69 +- 13.63 (n = 39)		78.39 +- 13.31 (n = 33)	.914a
     parameters (Table 3). Ramsay score median (range) no.
     No significant difference (P = .849) in the proportion of patients	T0	1	43.5% (20)	48.7% (19)	.906b
     with a pain score less than or equal to 3 was observed between		2	54.3% (25)	51.3% (20)

     midazolam (43.6%) and placebo (45.7%) after 20 minutes (Table 2). Sensitivity analysis results were as follow: for the best possible

     3 2.2% (1) 0.0% (0)

     4 0.0% (0) 0.0% (0)

     T20 1 8.7% (4) 17.9% (7) .066^b

     scenario midazolan, placebo 42% vs midazolam 46.3% (n = 21 vs n =	2	76.1% (35)	76.9% (30)
     19; P = .678) and for the worst possible scenario midazolam, placebo	3	15.2% (7)	2.6% (1)
     50% vs 41.5% midazolam (n = 25 vs n = 17; P = .416). Analysis of the	4	0.0% (0)	2.6% (1)

     analgesic and sedative parameters (Table 3) showed similar results in regard with all the side effects and adverse events except for the proportion of patients with drowsiness in midazolam vs placebo: 43.6% vs 6.5% (P b .001).

     None of the patients required administration of metoclopramide and naloxone. We observed a SaO2 less than 90% for 1 patient (2.2%) in placebo group vs for 5 patients (12.8%) in midazolam group (P =

     .089). Total morphine dose between midazolam and placebo (14.09 mg +- 6.64 vs 15.53 mg +- 6.27, P = .315) and proportion of patients with a pain score less than or equal to 3 at T30 (60% vs 60%, P = 1.000) were comparable.

     1. Discussion

     To date, this study is one of the first studies designed to systematically evaluate the Analgesic efficacy and safety of midazolam and the evolution of morphine dose in morphine-midazolam concomitant treatment in posttraumatic patients with acute pain in prehospital setting. Evolution of morphine dose was reported to be similar in 2 groups. Our results are consistent with those in the literature [26-28] reporting that a well-managed morphine titration failed to relieve pain (score <=3) in comparable percentages of patients (35%-40%) with ours (54.3% at T20 and 40% at T30).

     There was no significance difference in proportion of patients with a pain score less than or equal to 3 observed in our traumatic patients between the 2 groups.

     On the other hand, proportion of patients experiencing drows- iness was significantly higher in midazolam group (43.6 % vs 6.5%, P b .001). This safety monitoring observation was not consistent with

     Table 2

     Between-group difference in number of patients (%) with efficient analgesic effect (NRS

     <=3) 20 minutes and 30 minutes after the baseline

     	Placebo group	Midazolam group	P
     Efficient analgesic effect	21 (45.7%)	17 (43.6%)		.849b
     (NRS <=3) 20 mina	[31.3%-60.1%]	[28.0%-49.2%]

     T30	1	4.6% (2)	14.7% (5)	.245b
     	2	79.5% (35)	79.4% (27)
     	3	13.6% (6)	5.9% (2)
     	4	2.3% (1)	0.0% (0)

     Side effects % (no.)

     Nausea OR:1.54 (0.38-6.20)

     No 91.3% (42) 87.2% (34) .726^b

     Yes 8.7% (4) 12.8% (5)

     Vomiting OR: 1.18 (0.07-19.58)

     No 97.8% (45) 97.4% (38) 1.000^b

     Yes 2.2% (1) 2.6% (1)

     Pruritus No	100.0% (46)	OR: noncalculable 97.4% (38)	1.000b
     Yes Apneac	0.0% (0)	2.6% (1) OR: noncalculable

     No	100.0% (46)	100.0% (39)	1.000b
     Yes	0.0% (0)	0.0% (0)
     Drowsiness No	93.54% (43)	OR: 11.08 (2.93-41.90) 56.4% (22)	b.001b
     Yes	6.5% (3)	43.6% (17)
     SaO2 b90% No	97.8% (45)	OR: 6.62 (0.74-59.29) 87.24% (34)	.089b
     Yes	2.2% (1)	12.8% (5)

     Total morphine dose until obtaining NRS <=3

     15.53 +- 6.27 (n = 46) 14.09 +- 6.64 (n = 37) .315^a

     Abbreviation: OR, odds ratio.

     ^a t test.

     ^b Fisher exact test.

     ^c Lack of spontaneous respiratory effort for 15 seconds.

     that found in the literature [20,21,29] recommending the use of midazolam as a safe analgesia. However, our sedative effect results were consistent with those reported by Shafer et al [22] and more recently by Wille-Ledon et al and Sundstrom et al [28,30]. The latter studies, comparing midazolam-morphine combination to morphine alone in a randomized study of respectively pediatric displaced fractures and prehospital (ED) pain management of acute coronary pain reported no significant analgesic effect but a significant sedative effect (ie, drowsiness).

     This study provides patient-specific (prehospital traumatic) and helpful information to the literature evaluating the benefits of

     Efficient analgesic effect (NRS <=3) 30 min^a

     27 (60.0%) 21 (60.0%) 1.000^b

     [45.7%-74.3%] [43.8%-76.2%]

     midazolam [10,12,15,16]. Our safety monitoring results are not consistent with those reported by Gilliland et al, Cragg et al, Shah et

     ^a n (%) [95% confidence interval].

     ^b ? ² test.

     al, and Atallah et al [9,20,21,29]. Our secondary end point findings are not unexpected given midazolam pharmacologic property (a

     sedative benzodiazepine) and mechanism of action (3 minutes, yet with a very short plasma half-life). Our results difference with the operating context may be explained by the difference in the primary objective between the settings. Prehospital care aims at achieving a tolerable pain score (analgesic effect) and/or rapid and conscious sedation, whereas operating setting aims at improving wake-up and extubation time. Gilliland et al [21] reported a better sedation, yet short-lived morphine sparing effect of midazolam in pre and postoperating setting. Atallah et al [9] reported a better postoperative recovery (less amnesic effect) with midazolam and using a low dose of postoperative morphine.

     Limitations

     Our study was underpowered both from an enrollment perspec- tive as well as an overestimation of the likely difference in proportions of patients achieving NRS less than 3 between the 2 groups. The former limitation can be explained by the prehospital urgent care setting for trauma-induced pain. The latter may be explained by the lack of appropriate knowledge and guidelines at the time of our study. There were missing data for the primary end point. However, our sensitivity analysis demonstrated that the results were not sensitive to missing data. Furthermore, our study lacked complete description of patient characteristics, which can be explained by the prehospital emergency setting of the study.

     Conclusions

     This study did not find any benefit of midazolam adjunctive therapy to morphine in pain control despite of its common use in pain management. Furthermore, in this adjunctive therapy, midazolam was not found to be the most appropriate benzodiazepine for sedation. In prehospital traumatic setting, clinically, we do not recommend the use of midazolam, given the lack of analgesic benefit and the significant increase in drowsiness. A larger study, recording and comparing more detailed patient characteristics and with a lower estimate of success would be required to better evaluate our goal and confirm our clinical outcomes.

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