Article, Emergency Medicine

Nebulized fentanyl vs intravenous morphine for ED patients with acute limb pain: a randomized clinical trial

a b s t r a c t

Objective: Intravenous morphine has been used as a common method of pain control in emergency care. nebulized fentanyl is also an effective temporary substitute. This study was designed to compare the effectiveness of nebulized fentanyl with intravenous (IV) morphine on management of acute limb pain.

Methods: This was a placebo-controlled, double-blind randomized clinical trial. Ninety emergency department patients with moderate to severe pain aged 15 to 50 years were blocked randomized and enrolled in this study. Forty-seven patients in the experimental group received nebulized fentanyl (4 ug/kg) and IV normal saline as placebo, and the remaining 43 patients in the control group received IV morphine (0.1 mg/kg) and nebulized normal saline as placebo. All participants’ pain scores were assessed by numerical rating scale before and after intervention at 5-, 10-, 15-, 30-, 45-, and 60-minute intervals. Patients’ vital sign and possible adverse effects were recorded respectively. Finally, all participants were assessed for their satisfaction.

Results: The mean initial pain score in the experimental group was 8.7 and 8.4 in the control group (P = .1). Pain relief in both groups after 5 and 10 minutes were similar (P = .72). Although the pain relief was significantly greater with fentanyl at 15 minutes, this difference is not clinically significant. Pain management in both groups was successful and was more than 3 scores reduction in Numerical Rating Scale. Patient satisfaction in both groups was similar. No adverse effects were reported in the experimental group.

Conclusion: This study suggests that nebulized fentanyl is a rapid, safe, and effective method for temporary control of acute limb pain in emergency department patients.

(C) 2014 /p>

Introduction

Most emergency visits, up to 70%, are due to patients seeking relief from pain [1]. Although the patient easily describes the pain, managing that pain in overcrowded emergency departments is truly challenging. It is desirable to use a rapid, effective, and safe analgesic immediately after triage. Although intravenous (IV) morphine has been used as a common method of pain control in most emergency departments [1], its administration requires the insertion of an IV cannula. This can cause additional distress to the patient and can often be time consuming or unsuccessful. Between 12% and 26% of IV catheter insertions are unsuccessful in adults [2]. As a result, temporary and feasible methods for analgesic administration have been recently considered. One such method, nebulized fentanyl is a convenient and effective temporary relief, which has not been fully studied in adult

* Corresponding author. Emergency Department, Imam Khomeini Complex Hospital, Keshavarz Blvd, Tehran 1419733141, Iran. Tel./Fax: +98 21 66904848,

+ 98 912 1324877 (cell).

E-mail addresses: [email protected], [email protected] (S. Bagheri-Hariri).

emergency departments [3-5]. Fentanyl is a highly potent opioid with considerable Lipid solubility. These features make it an ideal opioid to be administered through inhalation [6]. In this study, the effect of nebulized fentanyl has been compared with the IV administration of morphine in patients with acute pain due to limb trauma in the emergency department of Imam Khomeini Complex Hospital.

Methods

Trial design

This was a double-blind randomized clinical trial.

Participants

A convenience eligible sample of 90 fully cooperative patients aged 15 to 50 years presenting to the emergency department due to limb trauma with acute pain with Numerical Rating Scale score above 5 were enrolled in the study. The numeric verbal scale ranges from 0 to 10, from no pain to most pain. After obtaining a written

http://dx.doi.org/10.1016/j.ajem.2014.05.051

0735-6757/(C) 2014

informed consent, patients were given a full instruction and reassurance about the process of their pain management and how to use the face mask.

Randomization

In this study, block randomization was used. Two sets of treatments were prepared and named package A (experimental) or package B (control). Block sizes were 2 by 2 (23 blocks of 4). Possible sequence for packages within each block was as follows: AABB (1), ABAB (2), BBAA (3), BABA (4), BAAB (5), and ABBA (6). Each acceptable possibility of the blocks had been marked from 1 to 6 as above. Then a dice was used to generate the sequence of the blocks from 1 to 23. At the end, blocks were set by using the generated sequence, and the packages within blocks were sequentially numbered from 1 to 90.

Allocation

Consecutive allocation was used in this study. The patients’ sequences for allocation were generated by the Triage time and date from 1 to 90. The caregiving team then matched the sequentially numbered identical packages from package 1 to package 90 to the consecutive patients, from patient 1 to patient 90.

Blinding

The size, content, and the sequence of treatment within blocks were masked and concealed from the participants, those administer- ing the intervention, and those assessing the outcomes by the study supervisor. In the experimental treatment, 2 identical-labeled 10-cc syringes were placed, the first one contained fentanyl citrate with the

Allocation

Randomized (n = 90)

Excluded (n = 156)

  • Not meeting inclusion criteria (n = 32): pain score less than 5 NRS
  • Declined to participate (n = 29)
  • Other reasons (n = 95)

Assessed for eligibility (n = 246) Patients aged between 15 and 50 with painful limb

label “nebulize 0.8 cc/kg in 2 to 3 minutes” and in the other syringe, normal saline as a placebo with the label “inject 0.1 cc/kg IV slowly.” The control treatment also contained 2 identical 10-cc syringes, the first one contained normal saline as a placebo with the label of “nebulize 0.8 cc/kg in 2 to 3 minutes” and the other syringe contained morphine with the label “inject 0.1 cc/kg IV slowly.”

Interventions

Patients were randomized to receive either nebulized fentanyl plus IV placebo or IV morphine plus nebulized placebo for their temporary pain management. In both groups, the nebulized drug was administered first, in 2 to 3 minutes depending on its dosage, followed by the slow injection of the IV drug in 2 minutes. The dose for nebulized fentanyl was 4 ug/kg from an IV solution with the concentration of 50 ug/mL, and the dose for IV morphine was 0.1 mg/kg from an IV solution with the concentration of 1 mg/mL. The placebo in both groups was normal saline.

Ultrasonic nebulizers were used in this study (Hikoneb home-type; Kare Medical and Analytical Devices Ltd, Ankara, Turkey [7]). The nebulizers had a high nebulizing performance and low-energy consumption and were capable of nebulizing a small amount of drugs (5-10 mL) in less than 5 minutes. The Continuous mode was selected during the nebulization period. In order to prevent fentanyl vapor accumulation in the experimental group, a highly sealed (disposable silicon) face mask in the well-ventilated room was used.

Outcome

An absolute reduction of pain score from the baseline in NRS was considered as the primary outcome of this study. All participants’ pain

Enrollment

Allocated to experiment (n = 47)

  • Received nebulized fentanyl (n = 47)
  • Did not receive nebulized fentanyl (n = 0)

Allocated to control (n = 43)

  • Received IV morphine (n = 43)
  • Did not receive IV morphine (n = 0)

Analysed (n = 43)

  • Excluded from analysis (n = 0)

Fig. 1. CONSORT diagram of the study.

Analysed (n = 47)

  • Excluded from analysis (n = 0)

Analysis

Lost to follow-up for 60 minutes (n = 0) Complications (n = 0)

Discontinued intervention (n = 0)

Lost to follow-up for 60 minutes (n = 0) complications (n = 4) (mild and self controlled) Discontinued intervention (n = 0)

Follow-Up

scores were assessed using NRS before and after intervention at 10, 15, 30, 45, and 60 minutes after drug administration. If the NRS score remained 5 or more after 15 minutes, 1 mg of morphine was given intravenously as the rescue dose in both groups. The rescue dose was repeated at 5-minute intervals until the pain score dropped to less than 5. During the observation period, the vital signs (blood pressure, pulse oximetry, respiratory rate, and heart rate) were monitored and recorded by the nursing staff. Participants were constantly monitored for adverse effects such as nausea, vomiting, vertigo, pruritus, and decreased level of consciousness. At the end, all participants were verbally assessed for their pain management satisfaction as the secondary outcome. Patients expressed their satisfaction about their pain management ranging from very satisfied to very dissatisfied using a 6-item Likert rating scale.

Analysis

In accordance with similar studies, sample size was calculated as approximately 44 patients in each of the experimental and the control group [8,9]. All data were gathered in individual data sheet for each patient and were analyzed by SPSS 11 using Mann-Whitney test. In order to compare pain relief in both groups over time, repeated- measures analysis of variance was used.

As estimated in this study, the Power of the study (1 – ?) was 80%, the significant level (?) was 5%, and the minimal clinically important difference (?) was 1.3 score (NRS). The minimal clinically significant difference in pain score was considered 1.3 NRS score.

Results

A total of 246 patients aged 15 to 50 years who came to the emergency department with acute pain from an isolated limb trauma were considered for the study. Two hundred fourteen of them with pain score above 5 based on NRS [10] were included in this study. Twenty-nine patients refused to participate in the study because of personal reasons. The remaining 185 patients were assessed by the exclusion criteria, and only 90 patients were enrolled in the trial. Exclusion criteria and the number (n) of excluded patients were as follows: recent or history of opioid use or addiction (28), recent or history of tricyclic antidepressant (2), Selective serotonin reuptake inhibitor (3), monoamine oxidase inhibitor (1), antipsychotics (1), and any nonspecified sedative/hypnotic drug use (21), acute or chronic medical health problems with a severity score higher than class 2 according to the American Society of Anesthesiology Classification [11] including upper or lower respiratory tract infection (3), acute or chronic liver or kidney disease (3), reactive airway disease (6), unknown allergies (10), a known pregnancy (3), or lactation (9) (Fig. 1).

Forty-seven patients in the experimental group received nebulized fentanyl. The remaining 43 patients received IV morphine, in the control group, for their pain management. Baseline characteristics including age, sex, and body mass index were similar in both groups (P N .05; Table 1). Causes of acute pain in both groups were categorized into 3 different classes; first, wound and soft tissue

Table 1

Baseline characteristics of patients in the nebulized fentanyl (experimental) and IV morphine (control) groups

Characteristics

Experimental group

Control group

P

Female, n (%)

8 (17)

7 (16.3)

.92

Age (y), mean +- SD

26.80 +- 7.45

26.86 +- 7.73

.88

Height (cm), mean +- SD

169.74 +- 6.70

168.60 +- 5.46

.43

Weight (kg), mean +- SD

75.53 +- 13.04

72.67 +- 11.88

.31

BMI (kg/m2), mean +- SD

26.04 +- 2.96

25.42 +- 2.96

.44

BMI, body mass index.

Table 2

Causes of acute pain in the experimental and control groups

Nebulized fentanyl

IV morphine

Total

Wound and soft tissue injuries

8 (17%)

15 (34.9%)

23 (25.6%)

Fractures

23 (48.9%)

18 (41.9%)

41 (45.6%)

Sprains and strains

16 (34%)

10 (23.3%)

26 (28.9%)

Total

47

43

90

injuries; second, fractures; and third, sprains and strains. All were similarly distributed in both groups (Table 2). The initial pain scores for the experimental and control groups were similar (8.7 +- 1 vs 8.4 +- 0.8, respectively; P = .1). There were no significant changes in pain relief at 5 and 10 minutes between the groups. Although the absolute reduction in pain scores in the experimental group at 15, 30, 45, and 60 minutes was statistically significant, these differences do not appear to be clinically significant (Table 3; Fig. 2).

For any given time interval during the observation, there was no significant change in vital signs and oxygen saturation as measured by pulse oximetry in either group. No adverse effects for fentanyl were reported in the experimental group. Four patients receiving IV morphine had nausea, vertigo, and a slight decrease in the level of consciousness (Ramsay level 3) [12], which were not life-threatening and were self-limited and were managed conservatively (Table 4). As a result, the adverse effects were significantly higher in the control group (P = .048). Four patients (8.5%) in the experimental group and 3 patients (7%) in the control group received 1 mg of IV morphine as the rescue dose after 15 minutes (P = 1). Patient satisfaction from their pain management was similar in both groups (P = .67; Table 5).

Discussion

This study was designed as a double-blind, placebo-controlled randomized clinical trial in an adult population and compared the effectiveness of IV morphine, as the standard of pain management [1] to nebulized fentanyl, as a temporary pain controller until further evaluation and management could take place. Intravenous morphine (0.1 mg/kg) and IV fentanyl (1-1.5 ug/kg) could be used for acute pain management [1]. Considering the fact that only 20% of nebulized fentanyl enters the circulation [13], the equiAnalgesic dose of 1 ug/kg

IV fentanyl would be 5 ug/kg of nebulized fentanyl. In order to minimize Possible complications, a lower dose of nebulized fentanyl (4 ug/kg) was used to determine whether satisfactory analgesia could be reached. The patients were observed for an hour. The duration of analgesia is approximately 0.5 to 1.5 hours after fentanyl administra- tion [1]. Our study supported that in the patients with moderate to

Table 3

Decrease of NRS pain score from the base in time intervals after drug administration in both groups

Groups 5 min 10 min 15 min 30 min 45 min 60 min IV morphine

No.

43

43

43

43

43

43

Mean

2.0

3.7

4.3

4.5

4.6

4.6

CI

1.8-2.5

3.4-3.9

4.1-4.6

4.3-4.8

4.4-4.9

4.3-4.9

Nebulized fentanyl

No.

47

47

47

47

47

47

Mean

1.9

3.6

4.7

5.0

5.2

5.2

CI

1.7-2.2

3.3-3.9

4.5-5.0

4.7-5.2

4.9-5.4

4.9-5.4

Total

No.

90

90

90

90

90

90

Mean

1.9889

3.6444

4.5333

4.7778

4.9111

4.9000

P

.72

.72

.011

.006

b.001

b.0001

CI, confidence interval.

0

-1.5

Reduction on NRS scores

-1.95

-2.02

-3.69

-3.59

-4.32

-4.55

-4.62

-4.6

-4.72

-4.97

IV Morphine Nebulize Fentanyl

-3

-4.5

-5.17 -5.17

-6

5min 10min 15min 30min 45min 60min

Time intervals

Fig. 2. Reduction on pain score (NRS) in time intervals between 2 groups.

severe limb pain (NRS N 5), both IV morphine (0.1 mg/kg) and nebulized fentanyl (4 ug/kg) were successful pain management methods for the first 60 minutes (pain score reduction N 3 NRS after 5 minutes). No changes in vital signs and no adverse effects were reported on those received nebulized fentanyl.

Other studies have been done to evaluate the analgesic effect of nebulized fentanyl. In a study done by Mather et al [14], the pharmacokinetics of nebulized fentanyl was compared with the IV form, and in both groups, the time-averaged bioavailability was 100%. No difference between the nebulized and systemic administration of fentanyl was noted. This study also demonstrated that the peak fentanyl concentration and effectiveness was 4 to 9 minutes. Another study that was done by Higgins et al [15] showed the effectiveness of nebulized fentanyl in postoperative pain relief.

The randomized, double-blinded, double-placebo-controlled study of Bartfield et al [9] compared the effect of nebulized and IV fentanyl in relieving abdominal pain, with a dosage of 1.5 ug/kg. Fifty patients were included in the study and were followed up for 30 minutes. They concluded that in the first 15 minutes of their study, IV fentanyl was significantly more efficacious than nebulized fentanyl, but by the end of 30 minutes, there was no significant clinical and statistical difference between nebulized and IV fentanyl administration. They believed that the special specifications and the selected mode (on demand) of the nebulizer helped them use lower doses of nebulized fentanyl (1.5 ug/kg). In our study, the nebulizer was an ordinary nebulizer and was used with continued nebulizing mode.

Studies have been done in the pediatric population, which have compared intranasal and nebulized fentanyl with IV morphine for acute pain management. In one study done among pediatric patients with limb trauma, administration of nebulized fentanyl with the dosage of 4 ug/kg via a standard nebulizer resulted in significant improvement in pain score compared with IV morphine [8]. In another study, Intranasal fentanyl with the dose of 1.7 ug/kg from a solution with a concentration of 150 ug/mL was an effective analgesic compared with IV morphine in children with limb fractures [16].

Table 4

Number of patients with complications or need for rescue dose (IV morphine 1 mg) in

both groups during the observation period

Nebulized fentanyl

IV morphine

Nausea, vomiting

0

2 (4%)

Lightheadedness, loss of consciousness

0

2 (4%)

Need for rescue dose

4 (8.5%)

3 (7%)

Considering the effective dose of intranasal fentanyl, Crellin et al [6] reported that 1.5 ug/kg of intranasal fentanyl from a 50-ug/mL concentration, which is the standard concentration, had a satisfactory result compared with higher concentrated solutions.

Considering the above studies, our study was one of the few studies that compared nebulized fentanyl with IV morphine in an adult setting using a controlled double-blind randomized clinical trial. Moreover, the patients in this study were observed and monitored for an hour for any possible complications, which is by far longer than any other studies.

Considering this study and previous studies, nebulized fentanyl could be used as a temporary substitute for rapid pain relief immediately after triage in different age groups ranging from children to adults. As far as our study shows, this route of fentanyl administration is safe, fast, and significantly effective in temporary acute pain management until insertion of an IV cannula is possible.

Trial registration

The study protocol was approved by Clinical Ethics Board of Imam Khomeini Complex Hospital and the affiliated Tehran University of Medical Sciences. The RCT was registered and approved by blinded registry of clinical trials (IRCT2012111710585N1) ([email protected]). Administration of fentanyl is subject to the joint commission’s authorization from the directors of the board of narcotics of the Imam Khomeini Complex Hospital.

Limitations and suggestions

In this study, in order to avoid confounding factors, the included patients were otherwise healthy individuals between the ages of 15 and 50 years with acute limb pain. The study group was followed up for an hour after drug administration. This limits our knowledge about the effectiveness and possible adverse effects of nebulized fentanyl compared with IV morphine, after an hour. Further studies could be done in multiple centers considering different age groups with underlying chronic health problems; moreover, with increasing the sample size and prolonged observation, some adverse effects of nebulized fentanyl might be reported. We designed this study as a temporizing measure in rapid pain management, especially when used with on-demand nebulizer mode (intermittent activation with deep breath in by the patient). The cost-benefit of the ultrasonic nebulizer should be judged before considering this method as a long term and definite method of pain management, especially in crowded emergency departments for more than 1 patient at the same time. Finally, because administration of nebulized fentanyl requires the

Table 5

Patients’ satisfaction with regard to pain control based on a 6-item Likert rating scale

Group

Extremely satisfied

Very satisfied

Somewhat satisfied

Somewhat dissatisfied

Very dissatisfied

Extremely dissatisfied

IV morphine

2.3%

41.9%

46.5%

9.3%

0

0

Nebulized fentanyl

6.4%

53.2%

29.8%

10.6%

0

0

availability of an ultrasonic nebulizer, providing and testing a simpler fentanyl inhaler in another study could be a breakthrough in acute pain management in emergency department.

Acknowledgments

The authors would like to express their gratitude to Mr Arvin Farahmand and Ms Merritt Lander for editing the manuscript.

References

  1. Miner J, Paris P, Yealy D. Pain management: Rosen’s emergency medicine, concepts and critical practice. 7th ed. Mosby/Elsevier; 2010 2410-28.
  2. Sabri A, Sazals J, Holmes KS, et al. Failed attempts and improvement strategies in peripheral intravenous catheterization. Biomed Mater Eng 2013;23(1-2):93-108.
  3. Worsley MH, McLeod AD, Brodie MJ, et al. Inhaled fentanyl as a method of analgesia. Anaesthesia 1990;45(6):449-51.
  4. Peng PW, Sandler AN. A review of the use of fentanyl analgesia in the management of acute pain in adult. Anesthesiology 1999;90(2):576-99.
  5. Miner JR, Kletti C, Herold M. Randomized clinical trial of nebulized fentanyl citrate versus i.v. fentanyl citrate in children presenting to emergency department with acute pain. Acad Emerg Med 2007;14(10):895-8.
  6. Crellin D, Ling RX, Babl FE. Does the standard intravenous solution of fentanyl (50 ug/ml) administered intranasally have Analgesic efficacy? Emerg Med Australas 2010;22(1):62-7.
  7. www.karemedical.eu.
  8. Furyk JS, Grabowski WJ, Black LH. Nebulized fentanyl versus intravenous morphine in children with suspected limb fractures in the emergency department: a randomized controlled trial. Emerg Med Australas 2009;21(3):203-9.
  9. Bartfield JM, Flint RD, McErlean M, et al. Nebulized fentanyl for relief of abdominal pain. Acad Emerg Med 2003;10:215-8.
  10. Fink R. pain assessment: the cornerstone to optimal pain management. BUMC Proc

    2000;13:236-9.

    Saubermann AJ, Lagasse RS. Prediction of rate and severity of adverse perioperative outcomes: “normal accidents” revisited. Mt Sinai J Med 2012;79(1):46-56.

  11. Van Dishoeck AM, Der Hooft Van, Simoons ML, et al. Reliable assessment of sedation level in routine clinical practice by adding an instruction to the Ramsay Scale. Eur J Cardiovasc Nurs 2009;8(2):125-8.
  12. Furyk JS, Grabowski WJ, Black LH. Nebulized fentanyl versus intravenous morphine in children with suspected limb fracture in the emergency department: randomized controlled trial. Emerg Med Australas 2009;21(3):203-9.
  13. Mather LE, Woodhouse A, Ward ME, et al. Pulmonary administration of aerosolized fentanyl: pharmacokinetic analysis of systemic delivery. Br J Clin Pharmacol 1998;46(1):37-43.
  14. Higgins MJ, Asbury AJ, Brodie MJ. Inhaled nebulized fentanyl for postoperative analgesia. Anaesthesia 1991;46(11):973-6.
  15. Borland M, Jacobs I, King B, et al. A randomized controlled trail comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department. Ann Emerg Med 2007;49(3):335-40.

Leave a Reply

Your email address will not be published. Required fields are marked *