A Randomized Controlled Trial Comparing Intranasal Fentanyl to Intravenous Morphine for Managing Acute Pain in Children in the Emergency Department

doi:10.1016/j.annemergmed.2006.06.016

Annals of Emergency Medicine

Volume 49, Issue 3, March 2007, Pages 335-340

Presented at the Australasian College for Emergency Medicine annual scientific meeting, Melbourne, Australia, November 2005.

https://doi.org/10.1016/j.annemergmed.2006.06.016 Get rights and content

Study objective

We compare the efficacy of intranasal fentanyl versus intravenous morphine in a pediatric population presenting to an emergency department (ED) with acute long-bone fractures.

Methods

We conducted a prospective, randomized, double-blind, placebo-controlled, clinical trial in a tertiary pediatric ED between September 2001 and January 2005. A convenience sample of children aged 7 to 15 years with clinically deformed closed long-bone fractures was included to receive either active intravenous morphine (10 mg/mL) and intranasal placebo or active intranasal concentrated fentanyl (150 μg/mL) and intravenous placebo. Exclusion criteria were narcotic analgesia within 4 hours of arrival, significant head injury, allergy to opiates, nasal blockage, or inability to perform pain scoring. Pain scores were rated by using a 100-mm visual analog scale at 0, 5, 10, 20, and 30 minutes. Routine clinical observations and adverse events were recorded.

Results

Sixty-seven children were enrolled (mean age 10.9 years [SD 2.4]). Fractures were radius or ulna 53 (79.1%), humerus 9 (13.4%), tibia or fibula 4 (6.0%), and femur 1 (1.5%). Thirty-four children received intravenous (IV) morphine and 33 received intranasal fentanyl. Statistically significant differences in visual analog scale scores were not observed between the 2 treatment arms either preanalgesia or at 5, 10, 20, or 30 minutes postanalgesia (P=.333). At 10 minutes, the difference in mean visual analog scale between the morphine and fentanyl groups was −5 mm (95% confidence interval −16 to 7 mm). Reductions in combined pain scores occurred at 5 minutes (20 mm; P=.000), 10 minutes (4 mm; P=.012), and 20 minutes (8 mm; P=.000) postanalgesia. The mean total INF dose was 1.7 μg/kg, and the mean total IV morphine dose was 0.11 mg/kg. There were no serious adverse events.

Conclusion

Intranasal fentanyl delivered as 150 μg/mL at a dose of 1.7 μg/kg was shown to be an effective analgesic in children aged 7 to 15 years presenting to an ED with an acute fracture when compared to intravenous morphine at 0.1 mg/kg.

Introduction

In the pediatric emergency department (ED), rapid, effective, and painless delivery of analgesia is desired.1, 2 As a consequence, it is routine in many facilities to give intravenous (IV) morphine to children presenting to the ED in moderate to severe pain.3, 4 However, the insertion of an IV cannula can, at times, require special skills, is time and staff dependent, and is painful and anxiety provoking for some children. Alternative methods of providing safe and effective analgesia include the intranasal route for the administration of opiates such as fentanyl and diamorphine.5, 6, 7, 8, 9 A study in a tertiary pediatric ED illustrated the safety and efficacy of intranasal fentanyl in a pediatric population.⁸ Two other ED studies have compared an intranasal opiate with intramuscular morphine as their criterion standard.5, 6

There has not been a study comparing an intranasal opiate with a drug with a similar onset of action. Intramuscular morphine would be expected to take up to 30 minutes to achieve adequate analgesia, whereas intranasal formulations take 5 to 10 minutes. In addition, if it were possible to provide adequate analgesia without IV access, then the administration of analgesia would be hastened, which would equate to greater patient comfort and satisfaction.

Our objective was to illustrate the comparative effectiveness of intranasal fentanyl to IV morphine in the pediatric ED. The primary endpoint was to demonstrate equivalence in pain control.

Section snippets

Study Design and Setting

This study was a double-blind, placebo-controlled, randomized trial within a tertiary pediatric ED with an annual census of 42,000 attendances. Enrollments were made from September 2001 to January 2005.

Selection of Participants

A convenience sample of children aged 7 to 15 years, presenting with clinically deformed closed long-bone fractures, was identified at triage and invited to join the study. Verbal consent was obtained from both the accompanying parent and the child, when appropriate. Written consent was not

Results

We enrolled 67 children between September 2001 and January 2005 (Figure 2). Baseline characteristics were similar between groups (Table 2).

The visual analog scale scores during the 5 periods at which pain was assessed and between intranasal fentanyl and IV morphine are illustrated in Figure 3. Overall, no statistically significant differences in visual analog scale scores between the 2 treatment arms either preanalgesia or at 5, 10, 20, or 30 minutes postanalgesia were observed (P=.333).

Limitations

We used the visual analog scale as our pain measurement tool because it has been validated in recent studies.¹¹ In the clinical setting, it is a somewhat cumbersome tool, requiring a 100-mm diagram and the child to mark his or her pain level. Children older than 6 years were included to avoid difficulty with understanding a pain measurement tool in the acute setting without previous education.13, 14 The verbal 0-to-10 scale (numeric rating scale) has been less validated in the pediatric

Discussion

Intranasal drug administration has been studied widely in postoperative patients16, 17, 18 and burn patients.19, 20, 21 To our knowledge, this study is the first to compare directly intranasal fentanyl with IV morphine in a pediatric population. We were able to demonstrate equivalence in pain scores at all intervals during the study. The combined visual analog scale score showed significant reduction at all intervals postanalgesia except at 30 minutes, which reflects reduction in pain for both

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Cited by (233)

Clinical and pharmacokinetics overview of intranasal administration of fentanyl
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Due to the presence of large surfaces and high blood supply, drug delivery through the nasal route of administration is the appropriate route to administrate drugs with rapid onsets of action. Bypassing first-pass metabolism can increase drug bioavailability. The physicochemical properties of fentanyl led to a need to develop formulations for delivery by multiple routes. Several approved inter-nasal fentanyl products in Europe and the USA have been used in prehospital and emergency departments to treat chronic cancer pain and used to treat severe acute abdominal and flank pain. Analgesia durations and onsets were not significantly different between intranasal and intravenous fentanyl in patients with cancer breakthrough pain and were well-tolerated in the long term. Intranasal Fentanyl (INF) at a 50 μg/ml concentration decreased renal colic pain to the lowest level in 30 min. Possible adverse effects specific to INF are epistaxis, nasal wall ulcer, rhinorrhea, throat irritation, dysgeusia, nausea, and vomiting. However, there is limited available literature about the serious adverse effects of INF in adults and children. Intranasal Fentanyl Spray (INFS) results in significantly higher plasma concentrations and has a lower T_max than oral transmucosal formulation, and the bioavailability of fentanyl in intranasal formulations is very high (89 %), particularly in pectin-containing formulations such as PecFent and Lazanda.
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Nanotechnology has proved its tremendous worth in the field of drug delivery and targeting. Nano formulations have improved the safety and efficacy of various conventional drugs. Brain targeting is one such domain that has been studied using nanotechnology for the treatment of various Central Nervous System Disorders. However, when approached through oral or intravenous route of drug administration brain targeting is limited due to the presence of physiological barriers such as Blood Brain Barrier. The Intranasal (IN) route has been studied widely as it has the potential to bypass the existing brain barriers and delivers the drug to different areas of the brain through the olfactory or trigeminal pathway. We have discussed nanotechnology-based strategies to deliver drugs to the brain. Surface modification of nanocarriers through different approaches has also been discussed under different heads. Future perspectives and market trends for intranasal drug delivery and products associated with it have also been enlightened.
Additive Value of Intranasal Fentanyl on Ibuprofen for Pain Management of Children With Moderate to Severe Headaches: A Randomized Controlled Trial
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Few studies have evaluated the rapid pain improvement provided by medications for children presenting to an emergency department (ED) with headaches.
Our aim was to evaluate pain reduction provided by intranasal fentanyl (INF) compared with placebo in addition to ibuprofen.
A single-center, double-blinded, randomized, placebo-controlled clinical trial was conducted in a tertiary care pediatric ED. All children aged 8–17 years presenting with a moderate to severe headache were eligible. Study participants were randomly allocated to receive INF 1.5 µg/kg (maximum dose of 100 µg) or similar placebo solution. Co-administration of oral ibuprofen 10 mg/kg (maximum dose of 600 mg) was also provided. The primary outcome was the mean pain rating reduction at 15 min.
Among the 62 participants, the median age was 14 years (interquartile range [IQR] 12–16 years in both groups) and the median initial visual analog scale (VAS) score was 64 (IQR 55–72 in the intervention group; IQR 50–81 in the control group). There was no difference in the mean pain score reduction at 15 min between the two groups (mean difference 2 mm; 95% CI –7 to 11 mm). Mean VAS score reductions were also similar at 30 and 60 min. Adverse events were more frequent in the INF group (risk ratio 2.8; 95% CI 1.29 to 6.22), but all events were minor and transient. No significant differences were found in other outcomes.
This study did not find a benefit from INF for providing additional pain relief in children presenting to ED with headaches.
Intranasal fentanyl for first-trimester uterine aspiration pain: A randomized controlled trial
2022, Contraception
Citation Excerpt :
Researchers showed pain improvement 10 minutes after intranasal fentanyl administration without significant changes in blood pressure, oxygenation, respiratory rate, or pulse. In subsequent studies, Borland and colleagues [23] found intranasal fentanyl comparable to oral morphine for pediatric burn dressing changes, comparable to intravenous morphine for pain associated with fractures, and that standard concentrations of intravenous fentanyl could be used intranasally instead of highly concentrated, specialty formulations [24–25]. Despite the safety demonstrated by the pediatrics studies, only a few studies have explored intranasal fentanyl's obstetric applications, and none have explored intranasal fentanyl for gynecology or abortion.
To evaluate whether administration of intranasal fentanyl reduces reported pain during first-trimester uterine aspiration.
We conducted a multicenter, randomized, double-blind, placebo-controlled trial of patients with pregnancies less than or equal to 14 weeks gestation seeking uterine aspiration for induced abortion, early pregnancy loss, or failed medication abortion. We randomized participants 1:1 to either intranasal fentanyl 100 mcg or intranasal placebo. All participants received ibuprofen and a standardized paracervical block. The primary outcome was pain indicated at the time of uterine aspiration on a 100 mm visual analog scale (VAS). We designed the study to detect a 15 mm difference in mean pain scores, which required 53 people in each arm for a total of 106 participants. Secondary outcomes included postprocedure pain and patient satisfaction with pain control.
From March 2017 through June 2018, we screened 355 people for eligibility and enrolled 107 participants. Those who received intranasal fentanyl reported similar uterine aspiration pain to participants who received placebo (58.4 ± 28.0 fentanyl vs 58.6 ± 24.5 placebo, p = 0.97). Participants who received intranasal fentanyl also reported similar postprocedure pain scores compared to participants who received placebo (19.1 ± 19.4 fentanyl vs 17.2 ± 19 placebo, p = 0.63), and were equally satisfied with procedure pain control (66.8 ± 31.2 fentanyl vs 63.3 ± 29.2 placebo, p = 0.57).
Intranasal fentanyl did not decrease reported pain with first-trimester uterine aspiration, nor did it decrease postprocedure pain compared to placebo. As an adjunct to ibuprofen and paracervical block, intranasal fentanyl did not improve patient satisfaction with pain control.
Intranasal fentanyl does not reduce reported pain with first-trimester uterine aspiration, however abortion-seeking patients are amenable to receiving intranasal medications for pain management.
Intranasal Fentanyl for On-the-Hill Analgesia by Ski Patrol
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Intranasal fentanyl offers a means for safe and effective pain management in austere environments. Prehospital analgesia traditionally involves intravenous or intramuscular medication. However, for wilderness rescuers, these methods are often impractical.
We conducted a retrospective review of health records to evaluate the safety and efficacy of intranasal fentanyl administered by EMT-Basic certified ski patrollers. Our primary aim was to measure the reduction in initial pain scores to subsequent measurements at 5, 10, and 15 min using the pain numeric rating scale (0–10). Clinically significant reduction in severe pain has been established as ≥1.8 points. We used paired t-tests and multilevel modeling to measure statistical significance and potential interactions and reviewed patient charts for adverse events, including respiratory depression or the use of naloxone.
We compiled the results from the winter seasons for 2007 through 2012 and 2016 through 2020. A total of 247 patients were included. The initial pain score was 8.6±1.5 (mean±SD). The decrease in pain scores from 0 to 5, 10, and 15 min, respectively, was –1.8, –2.4, and –2.9 (P<0.0001), which demonstrated a clinically and statistically significant decrease in pain scores. There were no adverse events.
Traditional standard of care analgesics are invasive, elongate scene times, and increase the risk of environmental exposure and provider needlestick. Intranasal fentanyl offers a safe, noninvasive, and rapid analgesia that is well-suited for austere winter environments, such as those encountered at ski resorts. This study demonstrates the safety and efficacy of the administration of intranasal fentanyl by EMT-Basic certified providers.
Intranasal Fentanyl and Midazolam Use in Children 3 Years of Age and Younger in the Emergency Department
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Although the efficacy and safety profiles of both intranasal fentanyl and midazolam are well studied in pediatric patients, few studies examine their use in younger children.
To examine and report our experiences in a pediatric emergency department (ED) with intranasal fentanyl and midazolam in children aged 3 years and younger.
This retrospective study investigated intranasal fentanyl and midazolam administration, alone and in combination, in children 3 years and younger treated in a pediatric ED.
Of 6198 patients included, 1762 received intranasal fentanyl alone, 1115 received intranasal midazolam alone, and 3321 received combination therapy. The median (interquartile range [IQR]) patient age was 2.2 (1.5–3) years. Initial median (IQR) fentanyl dose was 2.7 (2, 3) µg/kg, with 13.3% receiving a repeat dose. Initial median (IQR) midazolam dose was 0.3 (0.2–0.3) mg/kg, with 3.3% receiving a second dose. Children receiving both fentanyl and midazolam had median (IQR) initial doses of 2.8 (2.1–3) µg/kg and 0.3 (0.2–0.3) mg/kg, respectively. Of these, 3.2% received repeat doses of both medications. Laceration repairs (33.8%) and incision and drainage (22.2%) accounted for the majority of indications. Only 2.9% (n = 178) received additional opioids. No serious adverse events requiring a reversal agent or respiratory support were reported.
Intranasal fentanyl and midazolam, alone and in combination, can provide analgesia and anxiolysis to children aged 3 years and younger in the ED setting. Further prospective studies are needed to better evaluate their safety and efficacy in this younger population.

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: Supervising editor: Steven M. Green, MD

: Author contributions: MB conceived, designed, and conducted the study and undertook article writing and acts as guarantor. IJ assisted in planning and manuscript revision and undertook statistical analysis. BK conducted patient enrollments and article revision. DO'B was involved in planning, obtaining funding, and article revision.

: Reprints not available from the authors.

: Funding and support: Funded by an ACEM Morson Taylor Research Grant.

View full text

Pediatrics/original researchA Randomized Controlled Trial Comparing Intranasal Fentanyl to Intravenous Morphine for Managing Acute Pain in Children in the Emergency Department

Study objective

Methods

Results

Conclusion

Introduction

Section snippets

Study Design and Setting

Selection of Participants

Results

Limitations

Discussion

Pediatr Clin North Am

Ann Emerg Med

Ann Emerg Med

Ann Emerg Med

Burns

Burns

Only one fifth of A&E departments were found to have pain control policy for children [letter]

BMJ

Pediatric emergency department analgesic practice

Pediatr Emerg Care

The management of pain in the emergency department

Pediatr Clin North Am

A prospective randomised pilot comparison of intranasal fentanyl and intramuscular morphine for analgesia in children presenting to the emergency department with clinical fractures

Emerg Med (Fremantle)

Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures

BMJ

Pediatrics/original research
A Randomized Controlled Trial Comparing Intranasal Fentanyl to Intravenous Morphine for Managing Acute Pain in Children in the Emergency Department