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PEDIATRICS Vol. 109 No. 5 May 2002, pp. 894-897

A Randomized, Clinical Trial of Oral Midazolam Plus Placebo Versus Oral Midazolam Plus Oral Transmucosal Fentanyl for Sedation During Laceration Repair

Eileen J. Klein, MD, MPH*, Douglas S. Diekema, MD, MPH*, Carolyn A. Paris, MD, MPH*, Linda Quan, MD*, Morty Cohen, RPh{ddagger} and Kristy D. Seidel, MPH§

* Department of Pediatrics, University of Washington and Children’s Hospital and Regional Medical Center, Seattle, Washington
{ddagger} Investigational Drug Service, Children’s Hospital and Regional Medical Center, Seattle, Washington
§ General Clinical Research Center, University of Washington and Children’s Hospital and Regional Medical Center, Seattle, Washington

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   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. To determine whether a combination of oral transmucosal fentanyl (Fentanyl Oralet, Abbott Laboratories, North Chicago, IL) plus oral midazolam has an acceptable safety profile and is more effective than oral midazolam alone for sedation during laceration repair in a pediatric emergency department (ED).

Methods. Randomized, double-blind, placebo-controlled, clinical trial. Patients between 2 and 8 years of age who weighed >10 kg and presented to the ED with a laceration in need of repair under sedation were eligible for inclusion. All patients received oral midazolam (0.5 mg/kg; maximum dose 10 mg) and either fentanyl (5–10 µg/kg) or placebo in oralet form. Data collected every 5 minutes included the following: heart rate, oxygen saturation, respiratory rate, pain as measured on a Children’s Hospital of Eastern Ontario Pain Score (CHEOPS) scale (range: 4–13), and an activity scale (range: 1–5). Effectiveness of sedation was measured by CHEOPS and activity scores compared between the treatment groups.

Results. Fifty-one patients were randomized to receive oral midazolam plus fentanyl (N = 28) or oral midazolam plus placebo (N = 23). Age, weight, gender, or baseline pain and activity scores did not differ between the 2 groups. Seven patients in the fentanyl group vomited compared with 0 patients in the placebo group. Three patients in the fentanyl group and no patients in the placebo group had brief oxygen saturation below 93% on room air. The mean pain score within 5 minutes of the start of the procedure did not differ between the 2 groups (fentanyl group, 9.4 versus placebo group, 8.8). Mean activity scores within 5 minutes of the start of the procedure were also similar (fentanyl group, 4.3 versus placebo group, 4.3).

Conclusions. The addition of oral transmucosal fentanyl to oral midazolam did not improve pain or activity scores in pediatric patients given sedation for laceration repair. Patients who received Fentanyl Oralet suffered significantly more side effects despite the relatively low doses administered in this study. Oral transmucosal fentanyl should not be used for procedural sedation in the ED.

Key Words: sedation • Fentanyl Oralet • midazolam

Abbreviations: ED, emergency department • CHEOPS, Children’s Hospital of Eastern Ontario Pain Score • MPC, meperidine, promethazine, chlorpromazine


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sedation is often needed for young children undergoing minor procedures in the emergency department (ED). Oral midazolam is a commonly used sedative for children undergoing procedures such as laceration repair. The reported efficacy of oral midazolam for procedural sedation is 60% to 76%.1,2 Oral transmucosal fentanyl has also been used successfully for procedural sedation in the ED. Although its efficacy as a sedative lies between 69% and 75%, the use of oral transmucosal fentanyl has been accompanied by an unacceptable level of complications. As many as 45% of children sedated with oral transmucosal fentanyl in the ED suffer vomiting, and up to 65% suffer facial pruritis.3–17

The efficacy of using oral midazolam and oral transmucosal fentanyl together for procedural sedation has not been studied. We hypothesized that a combination of oral midazolam and oral transmucosal fentanyl would provide superior sedation to either drug alone. Furthermore, given the relationship between dose and the development of side effects related to transmucosal fentanyl, we hypothesized that using a lower dose of oral transmucosal fentanyl than that used in other studies would lead to a decrease in side effects related to this medication. Identification of a sedation regimen with improved efficacy and an acceptable safety profile could positively impact the patient and physician experience during laceration repair in the ED.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We conducted a randomized, double-blind, placebo-controlled trial to compare oral midazolam plus oral transmucosal fentanyl with oral midazolam plus placebo. The study population included children between 2 and 8 years of age presenting to the ED at Children’s Hospital and Regional Medical Center who were perceived by the parent and ED physician to require sedation for laceration repair. Patients were excluded if they had major injuries in addition to the laceration, weighed <10 kg, had eaten a meal in the last 2 hours, had a closed head injury associated with loss of consciousness, had an abnormal neurologic examination in a previously normal child, had significant developmental delay or baseline neurologic deficit, had severe trauma with suspected internal injuries, or had acute or chronic respiratory, renal, or hepatic abnormalities. Parental consent was obtained in all cases.

All enrolled patients received oral midazolam in a dose of 0.5 mg/kg (maximum 10 mg), the standard sedation for laceration repair in the ED. Patients were randomized by the hospital pharmacist in blocks of 4 to receive oral transmucosal fentanyl (Fentanyl Oralet, Abbott Laboratories, North Chicago, IL) or placebo. The pharmacist was the only person aware of the randomization status of the patient. Oral transmucosal fentanyl (Fentanyl Oralet) and placebo lozenges were provided by the manufacturer. Fentanyl Oralet was supplied for this study in 100, 200, and 300-µg lozenges. Patients randomized to receive Fentanyl Oralet were given whichever strength lozenge fell within the 5 to 10-µg/kg dosage range. Therefore, some patients received a dose closer to 5 µg/kg and some closer to 10 µg/kg.

ED nursing staff administered all medications. Study personnel noted compliance with medication (including length of time to consume lozenge and whether it was chewed). Data were retained for analysis regardless of whether the patient consumed the lozenge (based on "intention to treat").

Oral midazolam (0.5 mg/kg; maximum 10 mg) was administered first. The patient was then given the fentanyl or placebo lozenge, and ED nursing staff applied lidocaine, epinephrine, and tetracaine to the wound (if appropriate). Intradermal buffered lidocaine (1%) was administered if additional analgesia was necessary for either irrigation or suturing.

Laceration repair was performed by an ED physician not involved in data collection and was expected to take place within 20 to 30 minutes after administration of midazolam and study medication.

All patients had cardiorespiratory and oxygen saturation monitoring from the time of drug administration. A study nurse remained with the patient from the time of sedative medication administration until the patient was discharged. Study personnel documented vital signs, oxygen saturation, activity scores (Fig 1), and scores Children’s Hospital of Eastern Ontario Pain Score (CHEOPS; Fig 1).3 The activity score is commonly used as a measure of sedation in studies of children. The CHEOPS score is a well-validated score of behavior related to pain and anxiety. Documentation of study measures occurred before sedative administration, at the time of sedative administration, and every 5 minutes thereafter until the patient was discharged from the ED. The study nurse also documented the presence of complications (oxygen desaturation, vomiting, pruritis). Procedure time was documented and was defined as the time from the draping of the patient for suturing until the time when the drape was removed. Attempts were made to contact parents within 3 days of the ED visit to determine their satisfaction with sedation and the presence of complications after discharge.



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  		Fig 1. Activity scale and CHEOPS scale.

 
Data were analyzed using t tests for continuous data and Fisher exact test for categorical data.

This study was approved by the Children’s Hospital and Regional Medical Center Institutional Review Board.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 57 patients were enrolled. One patient did not consume the lozenge, and data were mistakenly not collected. In addition, consent forms from 5 patients were misplaced, and in consultation with the institutional review board it was decided that data on those patients be destroyed. Thus, it was necessary to eliminate those patients from the final analysis. This left a total of 51 patients for analysis; 28 received oral transmucosal fentanyl oralet and 23 received placebo oralet.

There was no difference in age, gender, or laceration size between the fentanyl and placebo groups (Table 1). It took significantly longer for patients in the fentanyl group to consume the lozenge, although procedure duration and time from start of the lozenge to the completion of the procedure did not differ between the 2 groups. ED stay from the start of the procedure was also no different between the 2 groups (Table 2).


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  		TABLE 1. Demographics

 

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  		TABLE 2. Oralet Consumption Time and Procedure Times (Median)

 
Although we expected activity and pain scales to be maximal early into the procedure, there was no obvious maximal point of anxiety or pain at any time during the procedure in either the fentanyl plus midazolam or placebo plus midazolam groups. We evaluated pain and sedation scores at the start of the procedure (time 0) and 5 minutes into the procedure. Both the fentanyl plus midazolam and placebo plus midazolam groups had similar activity and pain (CHEOPS) scores at the beginning of the procedure and 5 minutes into the procedure (Table 3).


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  		TABLE 3. Sedation

 
Patients receiving oral transmucosal fentanyl suffered significantly more complications than patients in the control group did. Seven patients in the fentanyl group vomited compared with no patients in the placebo group (P = .01). Three patients who received fentanyl had oxygen saturation drop below 93%, whereas none of the patients in the placebo (midazolam alone) group had oxygen desaturation. The 3 patients with oxygen desaturation required only time, stimulation, or blow-by oxygen to increase oxygen saturation. Finally, 4 patients in the fentanyl group and 2 patients in the placebo group experienced pruritis (Table 4). Thirteen (46%) of 28 patients in the fentanyl group experienced a complication (vomiting, pruritis, or decreased oxygen saturation), whereas only 2 (9%) of 23 patients in the placebo group suffered a complication (P = .005).


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  		TABLE 4. Complications

 
There was no difference between parental rating of sedation or satisfaction with sedation between the fentanyl and placebo groups. Twenty-seven percent (9/21) of parents whose child received oral transmucosal fentanyl plus midazolam rated their child as completely sedated, whereas 43% (9/21) of parents whose child received placebo plus midazolam rated their child as completely sedated (P = .43). In addition, 73% (19/26) of parents whose child received oral transmucosal fentanyl plus midazolam stated they were satisfied with their child’s sedation compared with 86% (18/21) of parents whose child received placebo plus midazolam were satisfied with the sedation (P = .56).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Oral transmucosal fentanyl has been used in adults and children as a preanesthetic medication, for postoperative pain, and for cancer pain.3–14 More recently it has been used in children for sedation and analgesia during painful procedures.15–17 Success rates for anxiolysis have ranged from 56% to 100% in published randomized clinical trials. The main complications of oral transmucosal fentanyl include vomiting and pruritis (mainly facial). Vomiting occurs in approximately 40% of patients (range: 0%–65%), usually in the postoperative or postprocedure period, and pruritis occurs in approximately 60% of patients (range: 3%–81%).3–13,15–17,19–21 Oxygen desaturation below 94% has been rare (range: 0%–24%) and never required more than blowby oxygen or brief stimulation.

Two studies have examined the use of oral transmucosal fentanyl for premedication of children undergoing laceration repair. In a randomized, unblinded study involving 30 children, sedation with oral transmucosal fentanyl was found to be adequate in 52% of those receiving 10 to 15 µg/kg compared with 60% of those receiving 15 to 20 µg/kg. Vomiting and facial pruritis occurred in 20% and 67% of the low-dose group, respectively, compared with 47% and 60% of the high-dose group. One patient (in the low-dose group) experienced oxygen saturation <95%, which was treated only with supplemental oxygen. The authors concluded that efficacy at the 2 doses was comparable, but that side effects are higher when higher doses were used.15

Another randomized study compared oral transmucosal fentanyl (10–15 µg/kg) with intramuscular meperidine, promethazine, and chlorpromazine (MPC) for sedation in 40 children undergoing laceration repair. Adequate sedation was attained in 75% of children in the fentanyl group and 69% of children in the MPC group. Vomiting and pruritis occurred in 45% and 60% of the fentanyl group respectively compared with 5% and 21% of the MPC group. Two patients in the fentanyl group experienced oxygen saturation <95%, which was treated only with supplemental oxygen. Prolonged somnolence was noted in the MPC group.17

Schechter et al16 conducted a randomized, clinical trial in children evaluating the usefulness of oral transmucosal fentanyl citrate as an analgesic for lumbar puncture or bone marrow aspiration. They found significantly less pain in the fentanyl group compared with placebo. No alternative analgesia was given in the placebo control group. Two patients (4%) in the fentanyl group had transient oxygen desaturation (<95%). Thirty-one percent of patients in the fentanyl group vomited compared with 0% in the placebo group, and 65% experienced pruritis compared with 8% in the placebo group.16

Although we hypothesized that a combination of oral midazolam and oral transmucosal fentanyl would offer improved sedation to children undergoing laceration repair, we found no difference in sedation or analgesia between children receiving that combination and those receiving midazolam alone. We may not have had sufficient power in this study to detect clinically significant differences in pain scores between the fentanyl plus midazolam and the placebo plus midazolam group in this study; however, we had 80% power to detect a 2.4-point difference in mean pain score between the 2 groups. We did have sufficient power to detect a clinically significant difference in sedation scores between the fentanyl plus midazolam and the placebo plus midazolam group. There was 80% power to detect a 0.7-point difference between the 2 groups.

It is possible that sedation would have been superior had a higher dose of oral transmucosal fentanyl been used, but we would also have expected a larger number of side effects with higher doses. It is also possible that the length of time from medication administration to the start of the procedure may have been a factor. We anticipated that the procedure would begin an average of 20 to 30 minutes after initiation of sedation, but in fact, procedures did not begin until a median of 36 minutes after administration of sedative medication.

Complications in this study resembled those found in previous studies of oral transmucosal fentanyl. In a previous study comparing oral transmucosal fentanyl and intramuscular MPC for sedation of children undergoing laceration repair the authors conclude: "The high incidence of vomiting may limit the utility of oral transmucosal fentanyl citrate as a conscious sedation agent in outpatient settings." Our findings support the conclusion that side effects related to use of oral transmucosal fentanyl for sedation for painful procedures seems unacceptably high and further suggest that oral transmucosal fentanyl in combination with oral midazolam does not improve sedation compared with midazolam alone. We recommend that oral transmucosal fentanyl not be used in the emergency department setting for procedural sedation. Fentanyl Oralet has recently been discontinued by the manufacturer. We believe that "off-label" use of other formulations of oral transmucosal fentanyl for sedation should be avoided.a Future research should focus on the safety and efficacy of other single or multiple agents for sedation for laceration repair. Evaluation of oral midazolam at higher doses than are currently being used may be the next step.


   ACKNOWLEDGMENTS
 
This study was supported by the Children’s Hospital and Regional Medical Center Research Endowment Fund. A portion of this work was conducted through the Clinical Research Center Facility at the University of Washington and supported by the National Institutes of Health grant M01-RR-00037. Fentanyl Oralet and placebo were provided by the manufacturer.

We thank Dawn Cotter, RN, and the Clinical Research Center at the University of Washington for research assistance, and Gini Scott for assistance with manuscript preparation.


   FOOTNOTES
 
Received for publication Sep 6, 2001; Accepted Dec 3, 2001.

Reprint requests to (E.J.K.) Children’s Hospital and Regional Medical Center, 4800 Sand Point Wy NE, Mailstop CH-04, Seattle, WA 98105-0371. E-mail: eklein{at}chmc.org

a The production of Fentanyl Oralet has recently been discontinued by the manufacturer for financial reasons. A new formulation of oral transmucosal fentanyl is being marketed for breakthrough cancer pain, but not for sedation. Back


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics

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