Acta Pædiatrica ISSN 0803–5253


Comparison of a morphine and midazolam combination with morphine alone for paediatric displaced fractures: a randomized study
Chrystèle Wille-Ledon1*, Hélène Chappuy (,2,3*, Carole Giraud2, Jean-Marc Tréluyer2,3,4†, Gérard Chéron1†
´ diatriques, Ho ˆ pital Necker Enfants Malades, Assistance Publique-Ho ˆ pitaux de Paris, Universite ´ Paris Descartes, Paris, France 1.Service d’Urgences pe ´ Paris Descartes, Paris, France 2.EA3620, Universite ´ de recherche Clinique et Centre d’Investigation Clinique Paris Centre, Paris, France 3.Unite ˆ pitaux de Paris, Universite ´ Paris Descartes, Paris, France 4.Pharmacologie clinique, Groupe hospitalier Cochin-Saint-Vincent-de-Paul, Assistance Publique-Ho

Keywords Analgesia, Fractures, Orthopaedic injury, Pain management, Sedation Correspondence H Chappuy, Paediatric Emergency Department, Necker Enfants Malades Hospital, 149 rue de ` vres, 75743 Paris Cedex 15, France. Se Tel: +33-01-44-49-42-92 | Fax: +33-01-44-49-42-99 | Email: Received 8 December 2010; revised 24 March 2011; accepted 7 April 2011. DOI:10.1111/j.1651-2227.2011.02311.x *Co-first authors. Co-last authors. Identifier: NCT00416039.

ABSTRACT Aim: To compare the efficacy of sublingual midazolam with oral morphine versus
that of oral morphine with placebo in a paediatric population attending an emergency department (ED) with acute long-bone fractures. Methods: A sample of children aged 5–16 years with clinically deformed closed long-bone fractures was randomized to groups receiving either oral morphine (0.5 mg ⁄ kg) ⁄ sublingual placebo or oral morphine (0.5 mg ⁄ kg) ⁄ sublingual midazolam (0.2 mg ⁄ kg). The main exclusion criteria were narcotic or benzodiazepine use, significant head injury, multiple organ failure, femoral fracture and allergy. Pain scores were rated on a 100-mm visual analogue scale (VAS) at 0, 15, 30, 60, 90 and 120 min. Results: Fifty-eight children were enrolled (mean age: 10.5 years, SD 2.7). Fractures concerned the radius or ulna in 43 cases (74.1%), the humerus (22.4%) and the tibia or fibula (3.5%). No significant difference in VAS scores was observed between the two treatment arms (p = 0.72). Drowsiness was significantly more frequent in the midazolam group (p = 0.007) during the first 2 h after administration. No serious adverse event was observed. Conclusion: The analgesic performances of morphine and the combination of morphine with midazolam assessed by VAS were similar in children presenting at the ED with a long-bone fracture.

INTRODUCTION Long-bone fractures are a common reason for visits to paediatric emergency departments. These fractures are often very painful, and the management of this pain frequently requires the use of opiate analgesics administered intravenously or orally (1–3). Oral morphine treatment is effective for the management of pain caused by long-bone fractures in children, with rare minor side effects, such as mild drowsiness. Doctors often prefer this treatment to intravenous treatment. However, it generally takes more than an hour to achieve a satisfactory decrease [visual analogue scale (VAS) < 30] in pain (4). We aimed to decrease this delay by establishing a sedation ⁄ analgesia protocol combining an opiate analgesic, morphine, with a sedative. We chose to combine oral morphine with midazolam, a short-acting benzodiazepine administered sublingually (5,6). Sublingual midazolam has been shown to be useful for the premedication during sedation before surgery, but no previous study has evaluated the efficacy and tolerance of sublingual midazolam used in combination with oral morphine for analgesia in displaced fractures in children. The aim of this study was thus to evaluate the combination of sublingual midazolam and oral morphine for the

management, in the emergency department, of pain owing to displaced fractures, focusing on the difference between VAS score at M0 (just before treatment administration) and that after 30 min (M30) and on safety of use.

MATERIALS AND METHODS Approval was obtained from the Necker-Enfant Malades ethical committee (Paris, France). We carried out a singlecentre, prospective, randomized, double-blind study comparing the combination of oral morphine and sublingual

Key notes
• The objective of the study was to compare the efficacy of sublingual midazolam with oral morphine versus that of oral morphine with placebo in a paediatric population. No significant difference in visual analogue scale scores was observed between the two treatment arms. Drowsiness was significantly more frequent in the midazolam group (p = 0.007) during the first 2 h after administration.

ª2011 The Author(s)/Acta Pædiatrica ª2011 Foundation Acta Pædiatrica 2011 100, pp. e203–e207


We collected the following data to evaluate tolerance: respiratory rate (RR).Sedation analgesia in paediatric long-bone fractures Wille-Ledon et al. Student’s t-tests were used to compare between the two groups. 90 (M90) and 120 (M120) min after treatment administration. A nursing assistant. All the patients had an ASA physical status score of 1. Qualitative values were compared with Fisher’s exact tests.0 and the alternative hypothesis that the mean of group 2 is 28. As a result of this estimation. nausea and vomiting. midazolam with the combination of oral morphine and a placebo. the means of the differences between VAS scores at different time points.0 and with a significance level (alpha) of 0. As midazolam has a very bitter taste. this procedure was carried out between 30 and 120 min after treatment administration. This analysis was carried out with NCSS 2007 software. Detailed information regarding therapy prior to the initiation of study drug. We considered 15 mm to be a clinically significant value for the difference between the two groups.05 using a two-sided Student’s t-test. France. vomiting and skin reactions. oxygen saturation (SaO2).1%). However.5 mg ⁄ kg) and sublingual midazolam (0. multiple organ failure. The fractures were of the radius or ulna in 43 cases (74. The treatment was administered by the investigative doctor. All patients were randomized using a computer-generated schedule with sequentially numbered containers prepared by the Clinical Research Unit. Statistical analysis The quantitative data are expressed as means ± standard deviation.5 mL of 30% glucose to make this drug more acceptable to the patients. owing to withdrawal of parental consent for two patients in group A. e203–e207 . pp. A nitrous oxide–oxygen mixture (Entonox) was administered to the child during the reduction procedure.5%). We measured heart and respiratory rates. M90 and M120. The midazolam and placebo were prepared and administered by the doctor in the absence of the nurse responsible for pain evaluation. Drug administration The midazolam group (MDZ) received oral morphine (0. were included in the study once the parent or parents present had been informed about the procedure and had signed an informed consent form. assuming that the true distribution is uniform. 1 for flow chart and Table 1 for patient characteristics). significant head injury. it was decided to include 30 patients in each group. The control group (placebo) received the same dose of morphine orally and sublingual saline. pain was evaluated with a 100-mm VAS. heart rate (HR). M60. Eligible patients were randomized 1:1 to receive midazolam or placebo. consciousness (drowsiness or agitation). we added 0. and qualitative data are expressed as percentages with a 95% confidence interval. the injured limb was provisionally immobilized with a pneumatic splint on the arrival in the emergency department. in the presence of the paediatrician from the emergency department.0 with known group standard deviations of 19. baseline demographics and illness were obtained at the time of enrolment. Sample size calculation According to a previous study.2 mg ⁄ kg). trained to recognize the secondary effects of sedation and who had successfully completed the paediatric resuscitation course (EPLS) of the European Resuscitation Council. Immediately after reduction. Data collection On arrival at the emergency department (M0) and then 15 (M15). Randomization and baseline data collection Patients and all study personnel except the investigative doctor were blinded to treatment assignment. only 58 patients were analysed (see Fig. consciousness. neither the patient nor the person responsible for noting VAS score in the observation notebook was aware of the group to which the patient had been assigned. accompanied by at least one of their parents and seen consecutively in the emergency department for a displaced fracture of a long bone requiring morphine analgesia. The fracture was displaced in 53 patients. femoral fracture. The primary endpoint was the difference between VAS score at M0 (just before treatment administration) and that at M30. the difference between VAS score at M0 (just before treatment administration) and that at M30 was )13 ± 19 mm in the control group (4). If reduction in the fracture was indicated in the emergency department. Children between the ages of five and 16 years. Different syringes were used for morphine and midazolam or placebo. This study was carried out in the paediatric emergency department of Necker-Enfants Malades Hospital in Paris.0 between the null hypothesis that both group means are 13. RESULTS Characteristics of the patients Sixty patients were randomized. Patients with a VAS score of 30 or lower at the various times points were identified. The exclusion criteria were patients with ASA score >2. The volume of liquid was the same for midazolam and placebo. 19 of whom underwent e204 ª2011 The Author(s)/Acta Pædiatrica ª2011 Foundation Acta Pædiatrica 2011 100. and M15. The secondary endpoints were the differences in VAS score between M0. who was therefore blind to the contents of the syringe used. under the supervision of Paris Descartes Clinical Research Unit.4%) and the tibia or fibula in two cases (3. 30 (M30). Group sample sizes of 26 give a power of 81% to detect a difference of 15. oxygen saturation. the child was asked whether he or she was willing to undergo the procedure again if necessary. or allergy to opiates or benzodiazepine. remained with the child for the 2 h following administration of the treatment. 60 (M60). narcotic analgesia in the 6 h before arrival or benzodiazepine use in the 24 h before arrival. nausea. In all cases. the humerus in 13 cases (22. by an orthopaedic surgeon. Thus. and the VAS was collected by a nurse blinded to the treatment assignment.

2) or in the percentage of patients with a VAS score below 30 at any time point (see Table 2).93 0. seven from each group. The difference remained non-significant if we considered only children with an initial VAS score >30 or >70 (data not shown). reduction by an orthopaedic surgeon in the emergency department after M30: eight in the MDZ group and 11 in the placebo group. Safety The most frequently observed adverse effect was drowsiness. the only adverse effect was vomiting (n = 2). Efficacy There were 28 patients in the MDZ and 30 patients in the placebo group.0 0.73 5. 95% CI: 8–38%) (p = 0.2 33.72)19.1–10. e203–e207 e205 . and two children.42 0.11 0.53 0.08–14.7–10.5 ± 2.4 ± 12. one from each group.–7.2 0. pp.87 )26.2 Number of patients with VAS score <30 MDZ (n = 28) 2 (7%) 5 (18%) 9 (32%) 11 (39%) 15 (54%) Placebo (n = 30) 5 (16%) 8 (27%) 10 (33%) 19 (63%) 14 (47%) p value 0.2–15.77). which was never more than moderate.3 17–70 21 ⁄ 7 24 (86%) 69 ± 18 30–100 Placebo group (n = 30) 9. All the somnolent patients were easy to wake with stimulation (level 3 of the Ramsay sedation score). No significant relationship was evidenced between drowsiness and VAS score (data not shown).5 0. that they would. a limited skin rash without oedema or signs of severity (n = 3) and moderate agitation for <30 min (n = 2).6 37.007).92 5. 95% CI: 28–52%): 17 in the MDZ group (59%.79 MDZ = midazolam group. max) Sex ratio M ⁄ F Number of displaced fractures VAS M0 (min. No apnoea or desaturation was noted during the observation period in any of the children included.1–14. It affected 24 children (40%. max) 10. In the MDZ group. There was no significant difference between the two groups for mean VAS score at any of the times considered (see Fig. The difference in VAS score between M0 and M30 did not differ significantly between the two groups: )25 ± 28 vs.48 ± 2. VAS = visual analogue scale.5–3. Sedation analgesia in paediatric long-bone fractures 80 60 randomized patients 70 60 50 Morphine Morphine+midazolam VAS Group A: Two parental consent withdrawn 28 patients received treatment Group B: 30 patients received treatment 40 30 20 10 0 0 20 40 60 80 100 120 140 Time (min) Two hours follow up 28 attended Two hours follow up 30 attended Figure 2 Progression of the mean value of the visual analogue scale score (±SD) over the 120 min following treatment in the two groups.3 0. After reduction in the fracture by an orthopaedic surgeon in the emergency department. Table 2 Changes in VAS score Difference from initial VAS score (M0) Table 1 Description of the population MDZ group (n = 28) Age of the patients (years) (min. 16 of the 19 children were asked whether they would agree to undergo the same procedure again. said that they would not. Periods of inclusion and follow-up were 21 months and 2 h.17 MDZ = midazolam group. respectively. max) Weight (kg) (min.34)201. VAS = visual analogue scale.80)14.18 0. No serious adverse effect or hospitalization linked to treatment was observed. Figure 1 Flowchart of the study population.43 MDZ (n = 28) M15 M30 M60 M90 M120 )15 )25 )35 )41 )44 ± ± ± ± ± 15 28 26 28 28 Placebo (n = 30) )15 )22 )27 )41 )38 ± ± ± ± ± 17 25 27 25 28 p value 95% CI of the mean 0. In the placebo group. 0.2 ± 13. 95% CI: 41–77%) and seven in the placebo group (23%. the adverse effects were vomiting (n = 1). )22 ± 25 (p = 0. Fourteen children.1 17–60 17 ⁄ 13 29 (97%) 63 ± 25 15–100 p value 0. said DISCUSSION The oral administration of morphine combined with the sublingual administration of midazolam resulted in ª2011 The Author(s)/Acta Pædiatrica ª2011 Foundation Acta Pædiatrica 2011 100.Wille-Ledon et al.77 )16.

intramuscular and intravenous) and its safety of use provided that the conditions of use are respected (5. as this previous study used a colour analogue scale rather than the VAS. Wille(Contrat d’Initiation a ´ ron from Assistance Publique Ho ˆ pitLedon and Prof. midazolam had a notable sedative effect: the number of drowsy children was significantly higher in the MDZ than in placebo group. ACKNOWLEDGEMENTS This study was supported by a ‘clinical research contract’ ` la Recherche Clinique) to Dr. the number of displaced fractures was similar in the two groups. Arch Pe atr 2005. 5. to our knowledge. The National Agency for Health Accreditation and Evaluation. The two treatments gave similar measurable analgesia in the first hour of treatment. DeQuad Arnette 2004: 115– techniques a 22. However. The discrimination of this score decreases with the age of the patients (15). Cravero JP. Philbrook L. Arch Pe 2001. Zempsky WT. Geldner G. but the decrease in VAS score seemed to be faster. there are some conflicting findings concerning the consequences of GABA receptor activation according to receptor subtype and localization. 7: 103–9. In: Du´ JL. Sublingual midazolam premedication in children: a dose responsive study. The mean age of the patients. Evaluation and management strategies for acute pain in ambu´ diatr latory care of children aged 1 month to 15 years. its short duration of action. In addition. Knoll R. In another study comparing the efficacy for pain reduction of oxycodone and codeine in children aged four to 17 years with suspected forearm fractures. Chuang AZ. In this study. It would be informative to study the association of the two. the combination treatment more frequently caused drowsiness. Wood C. 2 min following IV administration of a dose of 0.Sedation analgesia in paediatric long-bone fractures Wille-Ledon et al. rectal. No difference between the two treatment groups was observed. However. This drowsiness was mild. No other major cardiorespiratory effect or profound sedation was observed. Douleurs aigue casse ¨ s en situation d’urgence: des ` la de ´ marche qualite ´ . with verbal stimulation sufficient to wake the child. Bocquet N. We choose to use midazolam as the benzodiazepine for this study. Friday et al. However. but this is the first study. as they have different mechanisms of action. ´ ron G. our results suggest that oral glucose has little or no effect for children in situations such as bone fractures. We chose to evaluate pain with VAS as this scale is valid for children aged 4 years and older. The two treatments that appear to be most effective in children for acute pain associated with long-bone fractures are ibuprofen and morphine. Jennings C. Comparison between three transmucosal routes of administration of midazolam in children. editor. owing to its relatively short time to action (10 min following the sublingual administration of a dose of 0. Oral mor4. very few data for children are available (8–10). The combination of midazolam and morphine did not improve analgesia over that achieved with morphine alone in the population studied. Many published studies have reported an analgesic effect of benzodiazepines. However.3 mg ⁄ kg. because. sublingual. Our study provides no evidence of a relationship between analgesia and sedation. morphine and the combination of morphine and midazolam performed similarly in terms of analgesic efficacy in children with long-bone fractures. e203–e207 . analgesic effects similar to those obtained with morphine alone in terms of the time lag to action and efficacy. Relief of pain and anxiety in pediatric patients in emergency medical system. oxycodone tended to give greater pain reduction and less itching than codeine (12). CONFLICT OF INTEREST There are no potential conflicts of interest. Wagner K. but in our study. compared ibuprofen and paracetamol–codeine in patients aged five to 17 years with acute traumatic pain in the extremities. Paediatr Anaesth 1998. e206 ª2011 The Author(s)/Acta Pædiatrica ª2011 Foundation Acta Pædiatrica 2011 100. evaluating this biotherapy in the management of acute pain in children or adults and the interaction between sedation and analgesia. Cojocaru B. As midazolam and oral glucose were used together in this study. pp. Other combinations of treatments have been evaluated for the management of pain associated with fractures in children. 6. Khalil S. Suc A. The use of oral glucose as an analgesic for newborns and infants is fully supported by the literature. Rabb M. Other combinations should be evaluated to decrease the percentage of children with insufficient analgesia on morphine alone following limb fractures. 3. it is difficult to compare the results of the two studies. but uncertainties include effectiveness beyond the newborn ⁄ infant period (14). intranasal. France. et al. Paediatr Anaesth 1997. Morphine derivatives and benzodiazepines are frequently used together. either through their GABAergic activity or through interaction between sedation and analgesia (7). Jacobi K. their association may provide improved analgesia for children with broken legs or arms. Treatment of acute pain in children. no effect on the pain measured on the VAS was observed. (13) compared the efficacy of intranasal fentanyl and intravenous morphine for managing acute pain in children with deformed long-bone fractures. 8: 420–32. and the Committee on Pediatric Emergency Medicine and Section on Anesthesiology and Pain Medicine. However. 8: 461–5. with minimal adverse effects (11). 114: 1348–56.1 mg ⁄ kg).6). the ages of the patients in the two groups were similar. Leis A. Another source of potential bias in our study was the heterogeneity of the fractures as we included displaced and nondisplaced fractures. the multiple possible routes of administration (oral. Pediatrics 2004. real or perceived. References 1. initial VAS scores and mean decrease in VAS score were similar to those of our population. Hubmann M. Che ´ diphine administration for children’s traumatic pain. Wille C. Borland et al. 2. In conclusion. with a nadir obtained after 20 min in this previous study. 12: 248–53. Che aux de Paris. Morphine derivatives and benzodiazepines are thus often used together.

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