Oral transmucosal fentanyl citrate for premedication of children undergoing laceration repair

PEDIATRICS/ORIGINAL

CONTRIBUTION

Oral Transmucosal Fentanyl Citrate for Premedication of Children Undergoing Laceration Repair From the Division of Emergency Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts; * Division of Emergency Medicine, Stanford University Hospital and School of Medicine, California;* Department of Anesthesiology, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts;§ and Department of Pediatrics, Saint Francis Hospital Center, and University of Connecticut Health Center, Farmington.

See related editorial, p 1170.

Sara A Schutzman, MD* 9loan Burg, MD t Erica Liebelt, MD* Maureen Stratford, MD* Neil Schechter, MDw Mary Wisk, BS, RN* Gary Fleisher, MD*

Receivedfor publication October 15, 1993. Revision received February 11, 1994. Accepted for publication April 8, 1994. Copyright 9 by the American College of Emergency Physicians.

Study objective: To evaluate the safety and efficacy of two doses of oral transmucosal fentanyl citrate (0TFC)for premedication of children undergoing laceration repair. Design: Prospective, randomized, nonblinded study. Setting: Urban pediatric emergency department.

Participants: Thirty children aged 2 to 8 years requiring laceration repair. Interventions: Premedication with either 10 to 15 pg/kg or 15 to 20 I~g/kg of OTFC. Results: Activity score, vital signs, oxygen saturation, and pain scores were recorded before and after administration of 0TFC. Activity scores decreased significantly 15 to 60 minutes after OTFC. The physician suturing the wound rated the child's sedation/pain control as excellent or good in 83% of patients. Vital signs changes were not clinically remarkable. Oxygen saturations remained at 95% or more except in one child who experienced a transient decrease to 91%. Adverse effects were not serious but included vomiting in 20% of the lower-dose group and 47% of the higher-dose group. There were no significant differences between dose groups for activity or pain score changes, physician assessment, discharge times, or adverse events.

Conclusion: Both doses of OTFCreduced activity with comparable efficacy, with no serious vital signs changes. However, the higher-dose group had a greater number (P=NS) of adverse effects. [Schutzman SA, Burg J, Liebelt E, Stratford M, Schechter N, Wisk M, Fleisher G: Oral transmucosal fentanyl citrate for premedication of children undergoing laceration repair. Ann Emerg Med December 1994;24:1059-1064.]

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INTRODUCTION

MATERIALS AND METHODS

An emergency department visit for repair of a laceration can be a very frightening and painful experience for a child. This often results in the child being less cooperative, making the repair more difficult. Therefore, adequate analgesia, anxiolysis, and sedation are important out of consideration for the feelings of the child and to allow for an easier repair and thus potentially better cosmetic result. Pharmacologic agents can reduce the child's pain and anxiety effectively. However, many current regimens have significant drawbacks; medications administered intravenously or by IM injection are painful, and currently available oral medications have a more prolonged onset of action and may be erratic in their absorption and, consequently, their desired effect. Oral transmucosal fentanyl citrate (OTFC) is a fentanyl-impregnated, sweetened matrix in lozenge form on a holder. It allows administration of a potent opioid through the oral mucosa in a familiar, painless, nonthreatening manner, resulting in analgesia and sedation. The transmucosal route of delivery allows rapid onset of action because of direct absorption into the systemic circulation, avoiding first-pass metabolism by the fiver. Studies have demonstrated that OTFC is safe and effective for children as a premedication before anesthesia and surgery. 1-5 However, controlled studies investigating its use for conscious sedation of children in the ED setting have not been conducted previously The objective of this study was to evaluate and compare the safety and efficacy of two different doses of OTFC for premedication of children undergoing laceration repair in an ED.

The study was approved by the Institutional Review Board of Children's Hospital. Verbal and written consent were obtained from parents or guardians of a convenience sampie of 30 healthy children (American Society of Anesthesiology physical states I and II) who were aged 2 to 8 years, weighed 15 to 50 kg, and were seeking treatment for laceration repair between June 1992 and August 1992 in an urban pediatric ED. Patients with more than momentary loss of consciousness, any neurologic impairment, severe trauma involving more than one body system, suspected internal organ injury, or need for operative intervention and children on anticonvulsants or opioids were excluded. Children were randomized to receive OTFC at either 10 to 15 btg/kg (low dose) or 15 to 20 btg/kg (high dose) according to a randomization schedule supplied to the pharmacy by the sponsor prior to initiation of the study. After randomization, caretakers and evaluators were not blinded to the assignment. OTFC was provided in units containing 200,300,400, or 500 big of fentanyl citrate in lozenge form on a stick. All OTFC units were the same size (1.6 mL). Approximately 30 minutes before the anticipated time of laceration repair, OTFC was administered by asking the patient to rapidly consume the lozenge by sucking without biting or chewing to ensure transmucosal absorption. Selected children also had the topical anesthetic solution TAC (tetracaine, adrenaline, and cocaine) applied to the wound; children not receiving TAC included those with wounds whose location contraindicated its use and children not able to tolerate its application. A minimum of 30 minutes after commencement of OTFC administration, the wound was irrigated and sutured. Patients not receiving TAC and those with incomplete local anesthesia received injected lidocaine. Duration of the procedure was

Figure 1.

Activity and pain scales. Activity scale 1: Asleep, not readily arousable 2: Asleep, slowly responds to verbal instructions 3: Drowsy, readily responds to verbal instructions 4: Awake, calm 5: Awake, active CHEOPS scale (Observer pain scale; range, 4 to 13) Behaviors assessed Cry(1 to3) Facial expression (0 to 2) Verbal remarks (0 to 2) Torso movement (1 to 2) Leg movement (1 to 2) Reaching (1 to 2) Oucher scale (Self-reporLed pain scale; range, 0 to 100) Visual scale of incremental degrees of pain by facial expression

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Table 1.

Characteristics of low-dose and high-dose OTFC groups. Characteristic No. of patients Mean dose of fentanyl (FLg/kg)* Mean age (yr) Time to consume OTF[; (min) Time to laceration repair (rain) Laceration size (cm) Procedure duration (rain) Discharge time (rain) *,~ P=-NSfar all othercomparisons.

Low Dose

High Dose

15 13.0+1.7 5.8+1.3 13+2 34+6 2.0+1.0 25+12 99+38

15 16.9+1.0 5.6+1.3 17+1 37+9 1.9+1.0 30+20 87+28

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considered the time from the first painful stimulus (irrigation or lidocaine injection) to time of dressing placement after the completion of wound repair. Each patient had baseline systolic and diastolic arterial blood pressures, pulse, and respiratory rate measured prior to OTFC administration and at 15-minute intervals until ED discharge. Oxygen saturation and pulse were monitored continuously by pulse oximeter from the onset of OTFC administration to the end of the procedure or until the patient was awake and alert. Patients with an oxygen saturation persistently below 95% were instructed to breathe deeply (if able to comply) and/or given supplemental oxygen. The degree of sedation was measured by an activity scale (Figure 1) at 15-minute intervals. Pain was assessed by an observer using the Children's Hospital of Eastern Ontario Pain Scale 6 (CHEOPS, Figure 1) before OTFC administration and during laceration repair. Self-reported pain scores were determined using the Oucher Score 7 before and after the procedure on children with appropriate cognitive capabilities (Figure 1). Patients were discharged from the ED when they were awake or easily aroused, were able to ambulate (consistent with age and physical condition), and had normal vital signs and oxygen saturation above 95%, Time to discharge, defined as the interval from the beginning of OTFC administration until the time of discharge, was recorded. Side effects and adverse events such as pruritus, low oxygen saturation, nausea, and vomiting were recorded. Follow-up calls were made the following day (or until a caretaker was reached) to the children's homes to document additional adverse effects. Continuous and ordered data were analyzed using the Wilcoxon signed rank test and the Mann-Whitney ranksum test given the small numbers. Categorical data were analyzed by Z 2. Data were analyzed using SPSS/PC+ version 3.1. Values are reported as mean_iSD. P<.05 was considered significant.

RESULTS

Thirty children aged 2.3 to 8.4 years (mean, 5.7 years) were enrolled and randomized to receive 10 to 15 pg/kg (15) or 15 to 20 btg/kg (15) of fentanyl. Twenty-seven children consumed the OTFC unit by licking or sucking; two children (one each from the low-dose and high-dose groups) bit and chewed the unit, and one child from the high-dose group consumed only 80%. Twenty-eight children had TAC applied to their lacerations before repair; the two who did not were in the low-dose group. Thirteen children exhibited no response to the first painful stimulus, five winced but had no verbal complaint, four winced and complained verbally, and eight patients cried. There was no significant difference in patient characteristics, laceration size, or consumption/procedure times between the two dosage groups (Table 1). A decrease in activity score occurred in 22 patients after OTFC administration; 20 (67%) became drowsy or fell asleep (Figure 2). Level of activity decreased significantly in both groups compared to baseline at 15 to 60 minutes after OTFC commencement (P<.01), with no significant intergroup difference. Mean time to lowest activity score was 30 minutes after OTFC, and the mean decrease was 1.5 points (on a five-point scale, Figure 1). Children's pain, as assessed by an observer (CHEOPS score), showed no significant increase during the laceration repair as compared to baseline in either group (Table 2). Self-reported pain (Oucher score) decreased significantly from pre-OTFC to postprocedure evaluation (P<.01) in both groups (Table 2). The physicians performing the laceration repair assessed the child's degree of comfort and cooperation as excellent Figure 2. Sedation

807~ Of children drowsy or asleep OTFCadministered 704

Table 2.

after OTFC. *

1

50-1

Mean pain scores.

4O4

CHEOPS Score (4-13)* Low-Dose High-Dose Group Group

Oucher Score (O-100)t Low-Dose High-Dose Group Group

3O4

104 ',

Before OTFC After 0TFC

7.2+2.7 7.7+3.0

7.8+2.2 7.5+2.1

22+22 4+9

* There were no significant intragroup or intergroup differences. t Intragroupdifferenceswere significant (P<.Ol);no significant differences betweengroups,

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18• 2•

0:'00

0:15

0:30

0:45 1:00 1:15 Time(hr) mLow-dose group [ ~ q High4ose group

1:30

* There were no significant group differences.

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or good in 25 (83%) and fair or poor in 5, with no significant difference between dosage groups. Pulse changes from baseline (98_+12) in the low-dose group were significant only at 15 minutes (92_+13) and 30 minutes (89_+12) after OTFC administration (P<.05). There were no significant changes in pulse from baseline in the high-dose group. Differences in pulse between dosage groups occurred only at 30 minutes (89+12 for the low-dose group versus 102+18 for the high-dose group), with borderline significance (P=.05). At no time in the study was any child bradycardic. The only significant change in systolic blood pressure compared to baseline was in the low-dose group at 60 minutes after OTFC, increasing to 113_+11 mm Hg compared to a baseline mean of 104_+8 mm Hg (P=.02). There was no significant change in systolic blood pressure in the high-dose group compared to baseline and no significant difference between the two dosage groups at any time. No child in the study became hypotensive. Respiratory rate decreased significantly from baseline in both groups alter OTFC (Figure 3); however, there was little clinically important effect on oxygen saturation (Figure 4). Only one child (in the low-dose group) had an oxygen saturation persistently below 95% in room air and was given supplemental oxygen for 5 minutes for a transient decrease in oxygen saturation to 91%. No statistical difference in respiratory rate or oxygen saturation existed at any time between the two dosage groups. Although side effects or adverse events occurred in 23 patients, none were serious; the majority were pruritus and vomiting (Table 3). Although not statistically significant, more than double (47% versus 20%) the number of high-dose patients vomited than those who had received

low-dose OTFC. In addition, all three of the low-dose patients who vomited did so only once, whereas three of seven high-dose patients vomited repeatedly. Time to onset of vomiting was 90 to 300 minutes after OTFC administration and did not differ significantly between groups. Pruritus was common and did not differ significantly between groups (Table 3). Mean time to onset of itching was 23_+15 minutes; the average duration was 20 minutes, lasting more than 60 minutes in only three patients, one of whom was given an oral antihistamine. One patient (in the high-dose group) who had been discharged awake and alert though nauseated after OTFC administration and repair of head laceration (secondary to being hit with a large rock) returned 5 hours later with lethargy and persistent vomiting. Described as "awake but dazed," he received naloxone. During the IM injection of the medication the child yelled; however, it was unclear if the naloxone had any persistent effect on his mental status. The child then received IV hydration, had a normal head computed tomography scan, and was discharged from the second visit after several hours of observation in stable condition with no further problems. Mean time to discharge from the ED was 93+33 minutes (range, 55 to 215 minutes) with 29 of 30 children discharged by 140 minutes after OTFC administration. There was no significant difference in time to discharge between the two dosage groups (Table 1). Telephone follow-up elicited a higher number of adverse events after discharge in the high-dose group (P=.05). Of the 15 patients in the low-dose group, 11 had no problems after Figure 4. Oxygen saturation. ~

Figure 3. 100- Mean oxygen saturation

Respiratory rate.

99V]ean respiratory rate 24

98

97

20

96-

16-

12 0:00

0:15

0:30 I

1:00

1:15

Time {hrl Low-dosegroup .....+-----High-dose group

*lntragroup decrease from baseline (,~

1 0 62

0:45

There was no significant difference be~een groups.

1:30

95 0:00

0115

0':30 I

O:a,5

1:00

1:15

1:30

Time (hr) Low dose group .....+-----High-dose group

*There were no significant differences between groups

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discharge, 3 vomited once after ED discharge, and 1 was "not eating quite right." Telephone follow-up of the highdose group revealed that seven patients vomited after ED discharge (one of whom returned for evaluation of persistent vomiting and lethargy), one had significant total body pruritus lasting 12 hours, and one was "irritable" the next day. DISCUSSION

Fentanyl citrate, the pharmacologically active compound of OTFC, is a synthetic opioid 80 to 100 times more potent than morphine. Many of fentanyl's pharmacodynamic properties, including rapid onset of action, short duration of clinical effect, ease of reversibility, and limited cardiovascular effects, are desirable in the ED. When incorporated into a sweetened matrix, fentanyl citrate can be administered transmucosally, allowing for rapid, reliable absorption of the medication in a pleasant way that is painless, nonthreatening, and perhaps in itself anxietyrelieving to the child. OTFC has been shown to produce dose-dependent increases in sedation and analgesia in adult volunteers 8 with peak serum levels at a mean of 23 minutes after administration. 9 In an open study evaluating OTFC at different doses (ranging from 5 to 25 ~tg/kg) as a preoperative medication in children, the drug also was found to cause a dose-dependent reduction in activity, with peak clinical effects at mean times of 34 to 39 minutes for those receiving 10 to 20 btg/kg. 1 In several randomized, double-blind studies comparing OTFC to placebo as a preoperative medication, children receiving OTFC had significantly more sedation and less apprehension. 2-4 Other studies comparing OTFC to oral meperidine/diazepam/atropine as a preanesthetic medication found OTFC to be of equivalent efficacy for sedation. 5,1~ Reports of OTFC use in children other than as a preoperative medication have been limited. Lind et a111 found OTFC effective in reducing pain and sedating ten ED patients aged 6 to 34 years; however, to date there has been no study of OTFC in children in an ED setting. We evaluated OTFC at two different doses as premedication for sedation in 30 children undergoing laceration repair in an ED and found that OTFC decreased activity scores within 30 minutes. Although the children's CHEOPS scores (pain and anxiety behaviors) during suturing showed no significant change from baseline, one might expect that without medication children would have had an increase in the score while being sutured compared to having no intervention. This interpretation is supported

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by the suturing physician's assessment of 83% of children having excellent or good comfort and cooperation, although there was obviously no control group. Because topical and local anesthetics were used in this study, the efficacy of OTFC as an analgesic is obscured; however, its sedative and anxiolytic effects are clear. Because OTFC is a relatively new medication with limited use in children, particularly in the ED, there are various dosage recommendations in the literature, ranging from 10 to 20 p.g/kg. 1,4 We evaluated two different doses of OTFC and found no significant difference in children receiving 10 to 15 ~tg/kg versus 15 to 20 btg/kg with regard to sedating effect, CHEOPS score difference, or physician assessment of the child's behavior. Although no serious adverse event occurred in either group, children in the higher-dose group did have a larger number of side effects. It is important to note that because both doses were within ranges with an overlapping cutoff (at 15 t.tg/kg), dose differences were not large between some children in the different groups. Potential obstacles to safe and efficient ED care with the use of OTFC would be vital sign changes, oxygen desaturation, excessive or prolonged sedation, and side effects such as pruritus and vomiting. Although some statistically significant changes in pulse and blood pressure occurred, they were not clinically significant. The respiratory rate slowing occurred in both groups; however, it was of limited clinical significance as only one child had an oxygen saturation below 95%. Despite the low incidence of clinically important respiratory depression in this study, we believe that children receiving OTFC should have vital signs and oxygen saturation monitored and that naloxone and resuscitation equipment should be available. 12 Table 3.

Adverse events and side effects. Adverse Events and Side Effects No. in Low-Dose Group (%) Pruritus Facial GeneraFized Vomiting One episode Repeatedvomiting Nausea/gagging Abdominal pain Low oxygen saturation Delayed lethargy Vertigo None

10 (67) 5 5 3 (20) 3 0 1 (7) 1 (7) 1 (7) 0 0 5 (33)

No. in High-Dose Group (%) 9 (60) 7 2 7 (47) 4 3 2 (13) 1 (7) 0 1 (13) 2 (13) 2 (13)

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Excessive or prolonged sedation was not problematic during the initial ED visit in that no patient required naloxone or stimulation at that time, and 29 of the 30 patients were ready for discharge by 140 minutes after administration of OTFC. It is impossible to know if the one child who returned after the initial visit with persistent vomiting had prolonged symptomatology due to the OTFC administered or his concomitant head injury:. Although pruritus occurred in 63% of patients (a rate similar to those in prior OTFC studies1,2,1~ the majority of pruritic episodes were mild (eg, rubbing one's nose), did not appear bothersome to the patients, and did not interfere with the procedure, although two patients did experience significant generalized pruritus. Vomiting occurred in one third of patients, a rate similar to those in previous studies. 2,9,m The incidence was more than double in the high-dose group compared to the lowdose group. Although this was only a trend and not of statistical significance, given the small numbers, this may represent a Type 2 error. The majority of children who vomited did so only once, and because the earliest onset was 90 minutes after OTFC administration, it did not interfere with the procedure, although it may have delayed discharge. No child aspirated the vomitus. Although no serious adverse events occurred, given the sample size of 30 patients, the 95% confidence interval was 0% to 10%. Possible pitfalls of this study include the fact that participants were enrolled as a convenience sample (and perhaps not representative of the entire population), an alternative medication and/or placebo control was not used, and a double-blind approach was not used for administration of the medication and evaluation of the patients. Because of limited clinical experience with OTFC in children in an ED setting and the lack of a clearly recommended dose, the design was open and without comparison groups to evaluate safety and help determine a suitable dose (based on efficacy and adverse events) for future studies that would be blinded and have comparison groups. Although it is possible that the lack of blinding may have allowed for observer bias, we believe that the data are valuable because the scoring systems used well-defined end points, vital signs and oxygen saturation are objective measurements, and most side effects were either present or absent. While the results of this study suggest that OTFC may be safe and effective as a sedative for children undergoing laceration repair, additional studies using larger numbers and comparing OTFC to other forms of sedation must be conducted before the advantages and disadvantages of OTFC in outpatients are well established.

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CONCLUSION

We conclude that OTFC provided sedation for children undergoing laceration repair with comparable effectiveness in both dosage groups. No serious alterations in vital signs or oxygen saturation occurred. Children receiving the higher dose of OTFC experienced more adverse effects than those receiving the lower dose. REFERENCES 1. Streisand JB, Stanley TH, Hague B, et al: Oral transmucosal fentanyl citrate premedication in children. Anesth Analg 1989;69:28-34. 2. Feld LH, Chanpeau MW, Van Steennis CA, et al: Preanesthetic medication in children: A comparison of oral transmucosal fentanyl citrate versus placebo. Anesthesiology1989;71:374-377, 3. Stanley TH, Leiman BC, Rawal N, et al: The effects of oral transmucosal fentanyl citrate premedication on preoperative behavior responses and gastric volume acidity in children. Anesth Analg 1989;69:328-335, 4. Ashburn MA, Streisand JB, Tarver SD, et al: Oral transmucosal fentanyl citrate for premedication in paediatric outpatients. Can J Anaesth 1990;37:857-866, 5. Nelson PS, Streisand JB, Mulder SM, et al: Comparison of oral transmucosal fentanyl citrate and an oral solution of meperidine, diazepam, and atropine for premedication in children. Anesthesiology 1989;70:616-621. 6. McGrath PJ, Johnson 6, 6oodman JT, et al: CHEOPS: A behavioral scale for rating postoperative pain in children, in Fields HL, Eubner R, Cervero R (eds): Advances in Pain Research and Therapy, voL 9. New York, Raven Press, 1985, p 395-402. 7. Beyer JE, Aradine CR: Patterns of pediatric pain intensity: A methodological investigation of a self-report scale. Clirr JPaizr 1987;3:130-141. 8. Stanley TH, Hague B, Mock DL, et al: Oral transmucosal fentanyl citrate (lollipop) premedication in human volunteers. Anesth Analg 1989;69:21-27. 9. Streisand JB, Varvel JR, Stanski DR, et al: Absorption and bioavailability of oral transmucosal fentanyl citrate. Anesthesiology 1991 ;74:223-229. 10. Goldstein-Dresner MC, Davis PJ, Kretchman s et al: Double-blind comparison of oral transmucosal fentanyl citrate with oral meperidine, diazepam, and atropine as preanesthetic medication in children with congenital heart disease. Anesthesiology1991;74:28-33. 11. Lind GH, Marcus MA, Ashburn MA, et al: Oral transmucosal fentanyl citrate for analgesia and sedation in the emergency department. Ann Emerg Med 1991;20:1117-1120, 12. American Academy of Pediatrics, Committee on Drugs: 6uidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics 1992;89:1110-1115. The authors thank Mary Wisk, RN, and Pauline Scopton, FIN, for their contributions to this study and thank the ED staff for their assistance and cooperation.

Reprint no. 47/1/58637 Address for reprints: SaraA Schutzman,MD Divisionof EmergencyMedicine Children'sHospital 300 LongwoodAvenue Boston,Massachusetts02115 617-735-6624 Fax617-735-6625

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