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Nebulized fentanyl vs intravenous morphine for ED patients with acute abdominal pain: a randomized double-blinded, placebo-controlled clinical trial
American Journal of Emergency Medicine xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Nebulized fentanyl vs intravenous morphine for ED patients with acute abdominal pain: a randomized double-blinded, placebo-controlled clinical trial☆ Travis Deaton, MD a, Jonathan D. Auten, DO a, Michael A. Darracq, MD, MPH b,⁎ a b
Naval Medical Center San Diego, Department of Emergency Medicine, 34800 Bob Wilson Drive, San Diego, CA 92134 University of California, San Francisco (UCSF), Fresno Medical Education Program, Department of Emergency Medicine, 155 N Fresno St, Fresno CA 93701
a r t i c l e
i n f o
Article history: Received 3 November 2014 Received in revised form 27 February 2015 Accepted 19 March 2015 Available online xxxx
a b s t r a c t Objectives: Patients with acute abdominal pain commonly present to emergency departments. The safe and effective relief of discomfort is a concern to patients and physicians. Intravenous opioids are the traditional method used to provide pain relief in this setting, but intravenous access is time consuming and not always achievable. Alternative methods of pain control may therefore be necessary for the acute management of painful conditions without adding to the overall physical or psychological discomfort. The purpose of this study was to evaluate the feasibility of nebulized fentanyl (NF) in the alleviation of acute and undifferentiated abdominal pain. We also sought to compare NF with intravenous morphine (IVM) and to assess patient and provider satisfaction with NF. Nebulized fentanyl (2 μg/kg) was compared to IVM (0.1 mg/kg) at 10, 20, 30, and 40 minutes; and patient and physician satisfaction was recorded. The NF group experienced more rapid pain relief and more sustained and clinically significant pain relief over the 40-minute study interval. There were no adverse effects noted in the NF group. Both patient and physician satisfaction scores were higher in the NF group. Fentanyl citrate at a dose of 2 μg/kg through a breath-actuated nebulizer appears to be a feasible and safe alternative to IVM (0.1 mg/kg) in the treatment of acute abdominal pain. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Abdominal pain is among the most common reasons for emergency department (ED) visits in the United States [1]. Between 1998 and 2008, ED visits for which noninjury abdominal pain was the primary reason increased 31.8% from 5.3 million visits in 1999-2000 to 7 million in 2007-2008 [2]. Concurrently, there has been increasing concern about the timely and appropriate treatment of discomfort in the ED [3,4]. The administration of oral or intramuscular medications may be associated with a delayed onset to action and can be difficult to titrate to effect. The standard practice in many EDs is the administration of intravenous (IV) medications for the relief of abdominal pain. In some cases, IV access is not desired, necessary, or feasible, which has led to the search for alternative methods of analgesia delivery [5,6]. Intranasal preparations have been well researched as potential alternate means to deliver adequate pain control to prehospital and ED patients [7–11]. However, this method is limited in the total dose of analgesia that can be administered and is reported to have a delayed onset of analgesia when compared to IV administration [12]. Nebulization of analgesic medications offers another potential route of administration ☆ This research was conducted without any financial support in the form of grants or otherwise. ⁎ Corresponding author. E-mail addresses: [email protected] (T. Deaton), [email protected] (J.D. Auten), [email protected] (M.A. Darracq).
without the limitations of intranasal administration. There is currently a paucity of published literature regarding the use of nebulized fentanyl (NF) in adult ED patients [13,14]. We sought to evaluate the feasibility of NF administration in an adult ED population and to compare NF to IV morphine (IVM) in the treatment of acute abdominal pain. In addition, we sought to evaluate adverse events and patient and provider satisfaction with this novel method of drug delivery. 2. Methods After local institutional review board (IRB) and US Food and Drug Administration (FDA) Investigation New Drug/Device (IND) approval, a randomized, double-blinded, double-placebo–controlled trial was conducted between October 2011 and February 2012. The study occurred in a military treatment facility ED with an annual census of about 75 000 patients. Patients between the ages of 18 and 65 years meeting inclusion criteria were approached to participate in the study. Male and female patients with acute noninjury abdominal pain severe enough to warrant IV opioid analgesia (pain ≥5 out of 10) were considered for enrollment. Pain was of less than 24-hour duration, and patients were without an allergy to morphine sulfate or fentanyl citrate, able to provide informed consent, and not determined to be in extremis. Patients with known impairment in renal or hepatic function, hypothyroidism, Addison disease, prostatic hypertrophy, or urethral stricture were excluded from enrollment. Pregnant or lactating patients were
http://dx.doi.org/10.1016/j.ajem.2015.03.046 0735-6757/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Deaton T, et al, Nebulized fentanyl vs intravenous morphine for ED patients with acute abdominal pain: a randomized double-blinded, placebo-controlled clinical trial, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.03.046
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T. Deaton et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
excluded from the study. A urine pregnancy test was performed in all female patients of childbearing years before enrollment. Patients taking monoamine oxides inhibitors, tricyclic antidepressants, sedative hypnotics, or known cytochrome P450 3A4 inhibitors within 14 days of enrollment or during the study were excluded as required for FDA IND approval. Patients who had taken oral or had been administered IV or intramuscular pain medications before enrollment were also excluded. After informed and written consent, patients were randomized to receive IVM sulfate (0.1 mg/kg) with an equivalent volume of nebulized isotonic sodium chloride solution (group IVM) or NF citrate (2 μg/kg) with an equivalent volume of IV isotonic sodium chloride solution (group NF) using computerized randomization software from our research pharmacist. Both the morphine sulfate (1 mg/mL) and fentanyl citrate (50 μg/mL) used in the present study were standard preparations designed for IV administration and commercially available. All nebulized study medications were delivered over the course of 5 to 10 minutes via the AeroEclipse II Breath Actuated Nebulizer (BAN) (Monaghan Medical Corporation, Plattsburgh, NY). The AeroEclipse II only delivers medications when activated by negative inspiratory pressure on the part of the patient and prevents delivery of medications to the environment at large. All patients were educated on the proper use of the AeroEclipse II nebulizer including reading the package insert, "Place mouthpiece in your mouth, and inhale slowly and deeply. As you inhale, the green button on top of the nebulizer will move into the fully down position, indicating that the AeroEclipse II BAN is producing aerosol in response to inhalation. Exhale normally. A valve on the mouthpiece opens allowing passive exhalation, as the green button returns to the up position indicating no aerosol is being produced. Do not place your lips over the exhalation valve on the bottom of the mouthpiece. Doing so will prevent the valve from functioning properly." Immediately after intranasal medications were initiated, IV medications were given slowly over a 2- to 3-minute push by the bedside nurse. Baseline 100-mm visual analog scale (VAS) scoring of patient pain and vital signs (blood pressure [BP], heart rate, oxygen saturation) were recorded before delivery of study medications. Continuous pulse oximetry during the study interval with audible alarms for oxygen saturation less than 95% was performed. The VAS scores (recorded by the enrolled patient) and vital signs (recorded by the bedside nurse) were recorded every 10 minutes for a total of 40 minutes. Patients and treating providers were blinded to VAS responses from previous time points. For safety reasons, the charge nurse in the ED was not blinded to the investigational drugs being administered. However, the physician, bedside nurse, and patient were blinded. After patient consent and enrollment, the charge nurse opened a randomly assigned computer-generated card placing the patient in a previously determined arm in the study. As fentanyl citrate and morphine sulfate are Schedule II medications, the charge nurse drew the medications from the department Pyxis pharmacy. Intravenous medication was diluted with isotonic sodium chloride to match and equally fill sterile 10-mL placebo syringe. Nebulized medication was diluted with isotonic sodium chloride to match and equally fill sterile 5-mL placebo syringe. Red labels were used to indicate the investigational drug used for IV administration and contained the labeling "Caution: New Drug—Limited by Federal Law to Investigational Use. For intravenous use only." Green labels were used to indicate the investigational drug used for inhalational administration and contained the labeling "Caution: New Drug—Limited by Federal Law to Investigational Use. For use with AeroEclipse II BAN only." Only the charge nurse was aware of what medication or placebo was contained in the labeled syringes. The charge nurse was not directly involved in the care of enrolled patients and maintained awareness of allocation for safety reasons. Naloxone and standard resuscitative equipment and medications were available at all times during the study. The bedside nurse, blinded to treatment allocation, was given both study syringes and administered medication and placebo within minutes of each other. At the completion of 40 minutes, the treating physician and patient were asked whether they believed the medication provided
adequate analgesia. “Rescue” analgesia and antiemetics were available to be administered at any point during the study according to treating physician preference. Descriptive statistics, Student t test for continuous variables, and Fisher exact test for categorical variables was performed. Z test for proportions was performed to compare differences between groups for patient self-identified ethnicity. The primary outcomes of interest were the feasibility and safety of NF in comparison to IVM. Secondary outcomes of interest were the reduction in pain score from baseline at each of the 4 time points. Two-factor analysis of variance with repeated measures of one factor (time) and posttest analysis using Bonferroni correction for repeated comparisons were performed to compare the difference in pain scores from baseline at each of the 10-minute intervals between each of the treatment groups (IVM, NF) [15]. Additional secondary outcomes of interest included physician and patient satisfaction with the administered medication and need for rescue analgesia or antiemetic. These were assessed with the Fisher exact test. Continuous data were analyzed for normality using the ShapiroWilk test. Homogeneity of variance was assessed using the Levine test. Two-tailed P values less than .05 were considered statistically significant. All statistics were completed using SPSS software (v20; IBM Corporation, Armonk, NY). Sample size to detect a difference greater than 15 mm (out of 100 mm) in the VAS was calculated before patient enrollment and was determined to be 16 participants per treatment arm with repeated measurements for time. This assumed moderate effect size (0.5), α of .05, and a power of 0.80 for detecting Type II error [16]. A difference of greater than 15 mm (out of 100) in the VAS score was considered clinically significant [17,18]. 3. Results A total of 40 patients participated in the study (20 patients received IVM and 20 patients received NF]; 3 patients from the IVM and 3 patients from the NF group were not included in data analysis at the request of the local IRB because of discrepancies noted on consent forms. One patient from the IVM and 1 patient from the NF group were not included in data analysis at the request of the local IRB for protocol deviation (receiving incorrect doses of medications [IVM: 0.15 mg/kg and NF: 1.5 μg/kg]) (Figure). Per-protocol analysis of the remaining 32 patients was performed. Demographic features of the 2 treatment arms including age, sex, ethnicity, baseline VAS, and baseline vital signs are presented in Table 1. There was no statistically significant difference in demographics, vital signs, or baseline VAS of participants between the 2 groups. There were also no clinically significant adverse events associated with the administration of NF or IVM. No instances of naloxone administration or resuscitative measures such as intubation or ventilation were necessary in either treatment group. Patients and physicians reported greater satisfaction with NF than with IVM. A greater need for rescue medications was experienced in patients receiving IVM than with NF (Table 2). Patients in the IVM group received at least 1 rescue medication for analgesia (5/16) or antiemesis (7/16) post morphine administration, whereas 1 patient in the NF received ondansetron for nausea. This patient however experienced nausea before administration of fentanyl, and the medication was administered concomitant to fentanyl. Another patient in the NF experienced asymptomatic hypotension (BP before NF, 98/53; BP 10 minutes following NF, 87/49) and received 1 L of NS with immediate improvement in BP. Difference from baseline at time points (10, 30, and 40 minutes) for the morphine treatment arm did not demonstrate normal distribution by the Shapiro-Wilk test, whereas differences from baseline at each of the time points did demonstrate normal distribution for the fentanyl treatment arm. Logarithmic transformation of VAS difference from baseline for both treatments arms was performed with resulting normal distributions for each treatment at each time point. The resulting
Please cite this article as: Deaton T, et al, Nebulized fentanyl vs intravenous morphine for ED patients with acute abdominal pain: a randomized double-blinded, placebo-controlled clinical trial, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.03.046
T. Deaton et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
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Enrollment
Assessed for eligibility (n = 41)
Excluded (n = 1) Not meeting inclusion criteria (n = 0) Declined to participate (n = 1)
Randomized (n = 40) Neb Fentanyl (n = 20)
IV Morphine (n = 20)
Allocation Allocated to intervention (n = 20) Received allocated intervention (n = 20)
Allocated to intervention (n = 20) Received allocated intervention (n = 20)
Did not receive allocated intervention (n = 0)
Did not receive allocated intervention (n = 0)
Follow-Up Lost to follow-up (n = 0)
Lost to follow-up (n = 0)
Discontinued intervention (n = 0)
Discontinued intervention (n = 0)
Analysis Analysed (n = 16) Excluded from analysis (n = 4)
Analysed (n = 16) Excluded from analysis (n = 4)
-Incomplete consent on IRB review (n = 3)
-Incomplete consent on IRB review (n = 3)
-Protocol Deviation (n = 1)
-Protocol Deviation (n = 1)
Figure. Enrollment and analysis flowchart.
geometric mean with 95% confidence intervals (CIs) is presented in Table 3. The Levene test demonstrated equal variance between the 2 treatment arms for each of the repeated-measures time points. Between-variance comparison demonstrated P values less than .05. Posttest analysis using Bonferroni correction for repeated comparisons demonstrated statistically significant differences between NF and IVM at all time points (Table 3).
Table 1 Demographics of study participants
Age (y) Mean (±SD) 95% CI Sex Female (%) Baseline vital signs Heart rate, beats per min (95% CI) Systolic BP, mm Hg (95% CI) Baseline VAS (mm, 100 mm max) Mean (±SD) 95% CI Ethnicity (%) White African American Hispanic Asian American ⁎ Student t test. † Fisher exact test. ‡ Z test of proportions.
IVM (n = 16)
NF (n = 16)
32.38 (10.76) 26.64-38.11
30.19 (10.7) 24.48-35.89
.71⁎
10 (62.5)
.72†
77.2 (71.4-85)
76.8 (71.5-82.2)
.85⁎
128 (120.2-134.7)
122.9 (118.7-137.8)
.76⁎
8 (50)
P
4. Discussion The present study was designed to assess the feasibility of NF in the alleviation of painful acute abdominal complaints as measured by the VAS. We also sought to compare the efficacy of NF administration and to assess patient and provider satisfaction with this method of drug delivery in an ED setting. The VAS is validated as an accurate and reliable measure of acute pain in an ED setting [19]. At all the time points measured, a single dose of NF (2 μg/kg) resulted in clinically significant pain relief from baseline (VAS difference of 15 mm or greater) with relief achieved within 10 minutes of administration. In contrast, IVM at a dose of 0.1 mg/kg did not achieve clinically significant pain relief until 30 minutes postadministration and no longer demonstrated clinically significant improvement after 30 minutes. Despite the availability of rescue analgesia and more frequent administration, patients in the IVM treatment group experienced less improvement in pain as measured by the VAS in comparison to the NF group. They also experienced a decrement in pain relief after 30 minutes, whereas the NF group Table 2 Patient and physician satisfaction with treatment and need for "rescue" medication
74.94 (16.41) 66.19-83.68 12 (75) 2 (12.5) 1 (6.25) 1 (6.25)
65.81 (13.25) 58.75-72.87 9 (56) 2 (12.5) 4 (25) 1 (6.25)
.09⁎
.26‡ 1.00‡ .14‡ 1.00‡
Patient satisfaction Not very satisfied Satisfied Physician satisfaction Not very satisfied Satisfied Administration of "rescue" medication
IVM (n = 16)
NF (n = 16)
P
12 4
3 13
.004⁎
8 8 9
1 15 1
.016⁎ .006⁎
⁎ Fisher exact test.
Please cite this article as: Deaton T, et al, Nebulized fentanyl vs intravenous morphine for ED patients with acute abdominal pain: a randomized double-blinded, placebo-controlled clinical trial, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.03.046
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T. Deaton et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
Table 3 Differences in VAS from baseline Difference (NF − IVM) (95% CI of difference)
Change in VAS IVM (n = 16), from baseline geometric mean (mm) (95% CI)
NF (n = 16), geometric mean (95% CI)
10 min 20 min 30 min 40 min
15.20 (11.92-19.67) 3.90 (3.3-4.47) 27.66 (22.15-35.12) 15.75 (15.18-16.32) 36.29 (29.67-43.88) 19.67 (19.09-20.24) 37.48 (28.65-49.57) 27.36 (26.79-27.93)
11.30 (5.42-18.88) 11.92 (2.78-25.74) 16.63 (7.39-30.71) 10.12 (2.38-20.48)
experienced more rapid pain relief, more sustained and clinically significant pain relief over the 40-minute study interval, and a trend toward continued improvement over time without additional “rescue” analgesia or antiemetic administration. More providers and patients were satisfied with the analgesia afforded by NF than with IVM, and no adverse events were observed with NF administration. Previous research has compared intranasal fentanyl to IVM in the treatment of painful conditions in both children and adults [9,20]. Doses in the range of 1.7 μg/kg of intranasal fentanyl were shown to be equivalent to 0.1 mg/kg morphine in pediatric long-bone fractures [20]. The use of alternate delivery of fentanyl has been shown to lead to quicker pain control and decrease the need for IV access by 50% [21]. Standard concentrations of 50 μg/mL have been shown to be safe and effective with no adverse effects noted [22,23]. However, intranasal administration has limitations; it is limited to 1 mL per nostril because of liquid run-off problems [24]. In the absence of compounded moreconcentrated preparation of fentanyl, the standard preparation of 50 μg/mL limits each dose to 100 μg in adults. Intranasal fentanyl has also been shown to have a slower onset of action than IV fentanyl [12]. Nebulization of analgesic medications offers another potential route of administration without these limitations of intranasal administration. Nebulized fentanyl was first reviewed as a method of analgesic delivery in the 1990s for postoperative patients [25,26]. It has more recently been researched as an equivalent to slightly superior way to deliver fentanyl in pediatric patients with acute painful conditions [27]. In adults with undifferentiated abdominal pain, similar to our cohort, inhaled fentanyl was found to be equivalent to IV fentanyl [13]. In pediatric and adult patients with long-bone fractures, inhaled fentanyl was found to be superior to IVM [14,27]. Our study is the first to compare NF to IVM in adults with undifferentiated abdominal pain and to suggest this as an alternate method for early control of pain.
5. Limitations The results of this study cannot be generalized to other painful conditions such as orthopedic injury or trauma. However, NF has been demonstrated to be effective in the treatment of pediatric and adult long-bone fractures, suggesting that NF offers analgesia in a variety of painful conditions [14,27]. To meet requirements for the FDA IND, a number of exclusions were included in patient enrollment. The effect of concomitant use of monoamine oxides inhibitors, tricyclic antidepressants, sedative-hypnotics, and known cytochrome P450 3A4 inhibitors on the efficacy of or complications related to the use of NF is unknown. Similarly, the efficacy and potential complications of NF in the pregnant or lactating patient were not evaluated in the present study. Our study only looked at pain scores from 0 to 40 minutes. The peak effect of fentanyl is seen at 3 to 5 minutes, whereas morphine may take up to 20 minutes to reach peak effect. The timing of administration and peak effect of both medications may have factored into the patients favoring fentanyl over morphine. The analgesic effect of morphine can last 4 to 5 times longer than fentanyl, and providers may elect to choose this medication over fentanyl based on this property alone. The nebulizer used in the present study is designed to deliver 100% of its contents to the patient; and therefore, a standard nebulizer
may deliver less than the 2-μg/kg dose of fentanyl administered in the present study and therefore demonstrate reduced efficacy in pain relief. A higher dose may be necessary with a standard nebulizer to achieve similar results. The taste or smell of NF vs nebulized saline was not matched by pharmacy, and it is possible that study participants were aware of what active medication they received based on these differences. Patients did not appear however to be able to differentiate if the IV or the nasal preparation contained the active medication. A potential loss of blinding may have occurred as a result of the manner in which study medications were drawn and mixed by the charge nurse but administered by the treating nurse. Because there were no safety concerns and no reason for the charge nurse to reveal allocation, we feel that this is unlikely. We did not follow patients after their initial ED evaluation; we therefore cannot comment on any delayed complications that may have resulted from administration of NF. The patients were also evaluated for generalized abdominal pain, and specific pathologic conditions were not recorded. As the etiologies for acute abdominal pain are diverse and were not recorded in the present study, the resulting reduction in pain scores seen between groups may reflect differences in the etiology of abdominal pain between groups rather than effects of administered medication. As the mean age of enrolled patients was roughly 30 ± 10 years, the effects of NF on pediatric or elderly patients cannot be described with the present study. Administration of 2 μg/kg NF in an elderly patient may have additional adverse effects, and caution is advised. 6. Conclusion Fentanyl citrate at a dose of 2 μg/kg through a breath-actuated nebulizer appears to be a feasible and safe alternative to IVM (0.1 mg/kg) in the treatment of acute abdominal pain in adult patients and is associated with more rapid and sustained pain relief, greater patient and provider satisfaction, and less need for additional doses of analgesia or antiemetics. The opinions and assertions contained herein are the views of the authors and are not to be construed as official or reflecting the views of the Department of the Navy, Department of Defense, or the US Government. References [1] National hospital ambulatory medical care survey: 2010 emergency department summary. CDC Web site. Available at: http://www.cdc.gov/nchs/data/ahcd/ nhamcs_emergency/2010_ed_web_tables.pdf. [Accessed 5 September, 2014]. [2] Bhuiya FA, Pitts SR, McCaig LF. Emergency department visits for chest pain and abdominal pain: United States, 1999-2008. Available at: http://www.cdc.gov/nchs/ data/databriefs/db43.pdf. [Accessed 5 September, 2014]. [3] Motov SM, Khan A. Problems and barriers of pain management in the emergency department: are we ever going to get better? J Pain Res 2009;2:5–11. [4] Allione A, Melchio R, Martini G, Dutto L, Ricca M, Bernardi E, et al. Factors influencing desired and received analgesia in emergency department. Intern Emerg Med 2011; 6(1):69–78. [5] Karlsen AP, Pedersen DM, Trautner S, Dahl JB, Hansen MS. Safety of intranasal fentanyl in the out-of-hospital setting: a prospective observational study. Ann Emerg Med 2014;63(6):699–703. [6] Graudins A, Meek R, Egerton-Warburton D, Seith R, Furness T, Chapman R. The PICHFORK (Pain In CHildren Fentanyl OR Ketamine) trial comparing the efficacy of intranasal ketamine and fentanyl in the relief of moderate to severe pain in children with limb injuries: study protocol for a randomized controlled trial. Trials 2013;14:208. [7] Steenblik J, Goodman M, Davis V, Gee C, Hopkins CL, Stephen R, et al. Intranasal sufentanil for the treatment of acute pain in a winter resort clinic. Am J Emerg Med 2012;30(9):1817–21. [8] Stephen R, Lingenfelter E, Broadwater-Hollifield C, Madsen T. Intranasal sufentanil provides adequate analgesia for emergency department patients with extremity injuries. J Opioid Manag 2012;8(4):237–41. [9] Rickard C, O'Meara P, McGrail M, Garner D, McLean A, Le Lievre P. A randomized controlled trial of intranasal fentanyl vs intravenous morphine for analgesia in the prehospital setting. Am J Emerg Med 2007;25(8):911–7. [10] Johnston S, Wilkes GJ, Thompson JA, Ziman M, Brightwell R. Inhaled methoxyflurane and intranasal fentanyl for prehospital management of visceral pain in an Australian ambulance service. Emerg Med J 2010;28(1):57–63. [11] Middleton PM, Simpson PM, Sinclair G, Dobbins TA, Math B, Bendall JC. Effectiveness of morphine, fentanyl, and methoxyflurane in the prehospital setting. Prehosp Emerg Care 2010;14(4):439–47. [12] Wolfe TR, Braude DA. Intranasal medication delivery for children: a brief review and update. Pediatrics 2010;126:532–7.
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Please cite this article as: Deaton T, et al, Nebulized fentanyl vs intravenous morphine for ED patients with acute abdominal pain: a randomized double-blinded, placebo-controlled clinical trial, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.03.046
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Nebulized fentanyl vs intravenous morphine for ED patients with acute abdominal pain: a randomized double-blinded, placebo-controlled clinical trial☆ Travis Deaton, MD a, Jonathan D. Auten, DO a, Michael A. Darracq, MD, MPH b,⁎ a b
Naval Medical Center San Diego, Department of Emergency Medicine, 34800 Bob Wilson Drive, San Diego, CA 92134 University of California, San Francisco (UCSF), Fresno Medical Education Program, Department of Emergency Medicine, 155 N Fresno St, Fresno CA 93701
a r t i c l e
i n f o
Article history: Received 3 November 2014 Received in revised form 27 February 2015 Accepted 19 March 2015 Available online xxxx
a b s t r a c t Objectives: Patients with acute abdominal pain commonly present to emergency departments. The safe and effective relief of discomfort is a concern to patients and physicians. Intravenous opioids are the traditional method used to provide pain relief in this setting, but intravenous access is time consuming and not always achievable. Alternative methods of pain control may therefore be necessary for the acute management of painful conditions without adding to the overall physical or psychological discomfort. The purpose of this study was to evaluate the feasibility of nebulized fentanyl (NF) in the alleviation of acute and undifferentiated abdominal pain. We also sought to compare NF with intravenous morphine (IVM) and to assess patient and provider satisfaction with NF. Nebulized fentanyl (2 μg/kg) was compared to IVM (0.1 mg/kg) at 10, 20, 30, and 40 minutes; and patient and physician satisfaction was recorded. The NF group experienced more rapid pain relief and more sustained and clinically significant pain relief over the 40-minute study interval. There were no adverse effects noted in the NF group. Both patient and physician satisfaction scores were higher in the NF group. Fentanyl citrate at a dose of 2 μg/kg through a breath-actuated nebulizer appears to be a feasible and safe alternative to IVM (0.1 mg/kg) in the treatment of acute abdominal pain. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Abdominal pain is among the most common reasons for emergency department (ED) visits in the United States [1]. Between 1998 and 2008, ED visits for which noninjury abdominal pain was the primary reason increased 31.8% from 5.3 million visits in 1999-2000 to 7 million in 2007-2008 [2]. Concurrently, there has been increasing concern about the timely and appropriate treatment of discomfort in the ED [3,4]. The administration of oral or intramuscular medications may be associated with a delayed onset to action and can be difficult to titrate to effect. The standard practice in many EDs is the administration of intravenous (IV) medications for the relief of abdominal pain. In some cases, IV access is not desired, necessary, or feasible, which has led to the search for alternative methods of analgesia delivery [5,6]. Intranasal preparations have been well researched as potential alternate means to deliver adequate pain control to prehospital and ED patients [7–11]. However, this method is limited in the total dose of analgesia that can be administered and is reported to have a delayed onset of analgesia when compared to IV administration [12]. Nebulization of analgesic medications offers another potential route of administration ☆ This research was conducted without any financial support in the form of grants or otherwise. ⁎ Corresponding author. E-mail addresses: [email protected] (T. Deaton), [email protected] (J.D. Auten), [email protected] (M.A. Darracq).
without the limitations of intranasal administration. There is currently a paucity of published literature regarding the use of nebulized fentanyl (NF) in adult ED patients [13,14]. We sought to evaluate the feasibility of NF administration in an adult ED population and to compare NF to IV morphine (IVM) in the treatment of acute abdominal pain. In addition, we sought to evaluate adverse events and patient and provider satisfaction with this novel method of drug delivery. 2. Methods After local institutional review board (IRB) and US Food and Drug Administration (FDA) Investigation New Drug/Device (IND) approval, a randomized, double-blinded, double-placebo–controlled trial was conducted between October 2011 and February 2012. The study occurred in a military treatment facility ED with an annual census of about 75 000 patients. Patients between the ages of 18 and 65 years meeting inclusion criteria were approached to participate in the study. Male and female patients with acute noninjury abdominal pain severe enough to warrant IV opioid analgesia (pain ≥5 out of 10) were considered for enrollment. Pain was of less than 24-hour duration, and patients were without an allergy to morphine sulfate or fentanyl citrate, able to provide informed consent, and not determined to be in extremis. Patients with known impairment in renal or hepatic function, hypothyroidism, Addison disease, prostatic hypertrophy, or urethral stricture were excluded from enrollment. Pregnant or lactating patients were
http://dx.doi.org/10.1016/j.ajem.2015.03.046 0735-6757/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Deaton T, et al, Nebulized fentanyl vs intravenous morphine for ED patients with acute abdominal pain: a randomized double-blinded, placebo-controlled clinical trial, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.03.046
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T. Deaton et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
excluded from the study. A urine pregnancy test was performed in all female patients of childbearing years before enrollment. Patients taking monoamine oxides inhibitors, tricyclic antidepressants, sedative hypnotics, or known cytochrome P450 3A4 inhibitors within 14 days of enrollment or during the study were excluded as required for FDA IND approval. Patients who had taken oral or had been administered IV or intramuscular pain medications before enrollment were also excluded. After informed and written consent, patients were randomized to receive IVM sulfate (0.1 mg/kg) with an equivalent volume of nebulized isotonic sodium chloride solution (group IVM) or NF citrate (2 μg/kg) with an equivalent volume of IV isotonic sodium chloride solution (group NF) using computerized randomization software from our research pharmacist. Both the morphine sulfate (1 mg/mL) and fentanyl citrate (50 μg/mL) used in the present study were standard preparations designed for IV administration and commercially available. All nebulized study medications were delivered over the course of 5 to 10 minutes via the AeroEclipse II Breath Actuated Nebulizer (BAN) (Monaghan Medical Corporation, Plattsburgh, NY). The AeroEclipse II only delivers medications when activated by negative inspiratory pressure on the part of the patient and prevents delivery of medications to the environment at large. All patients were educated on the proper use of the AeroEclipse II nebulizer including reading the package insert, "Place mouthpiece in your mouth, and inhale slowly and deeply. As you inhale, the green button on top of the nebulizer will move into the fully down position, indicating that the AeroEclipse II BAN is producing aerosol in response to inhalation. Exhale normally. A valve on the mouthpiece opens allowing passive exhalation, as the green button returns to the up position indicating no aerosol is being produced. Do not place your lips over the exhalation valve on the bottom of the mouthpiece. Doing so will prevent the valve from functioning properly." Immediately after intranasal medications were initiated, IV medications were given slowly over a 2- to 3-minute push by the bedside nurse. Baseline 100-mm visual analog scale (VAS) scoring of patient pain and vital signs (blood pressure [BP], heart rate, oxygen saturation) were recorded before delivery of study medications. Continuous pulse oximetry during the study interval with audible alarms for oxygen saturation less than 95% was performed. The VAS scores (recorded by the enrolled patient) and vital signs (recorded by the bedside nurse) were recorded every 10 minutes for a total of 40 minutes. Patients and treating providers were blinded to VAS responses from previous time points. For safety reasons, the charge nurse in the ED was not blinded to the investigational drugs being administered. However, the physician, bedside nurse, and patient were blinded. After patient consent and enrollment, the charge nurse opened a randomly assigned computer-generated card placing the patient in a previously determined arm in the study. As fentanyl citrate and morphine sulfate are Schedule II medications, the charge nurse drew the medications from the department Pyxis pharmacy. Intravenous medication was diluted with isotonic sodium chloride to match and equally fill sterile 10-mL placebo syringe. Nebulized medication was diluted with isotonic sodium chloride to match and equally fill sterile 5-mL placebo syringe. Red labels were used to indicate the investigational drug used for IV administration and contained the labeling "Caution: New Drug—Limited by Federal Law to Investigational Use. For intravenous use only." Green labels were used to indicate the investigational drug used for inhalational administration and contained the labeling "Caution: New Drug—Limited by Federal Law to Investigational Use. For use with AeroEclipse II BAN only." Only the charge nurse was aware of what medication or placebo was contained in the labeled syringes. The charge nurse was not directly involved in the care of enrolled patients and maintained awareness of allocation for safety reasons. Naloxone and standard resuscitative equipment and medications were available at all times during the study. The bedside nurse, blinded to treatment allocation, was given both study syringes and administered medication and placebo within minutes of each other. At the completion of 40 minutes, the treating physician and patient were asked whether they believed the medication provided
adequate analgesia. “Rescue” analgesia and antiemetics were available to be administered at any point during the study according to treating physician preference. Descriptive statistics, Student t test for continuous variables, and Fisher exact test for categorical variables was performed. Z test for proportions was performed to compare differences between groups for patient self-identified ethnicity. The primary outcomes of interest were the feasibility and safety of NF in comparison to IVM. Secondary outcomes of interest were the reduction in pain score from baseline at each of the 4 time points. Two-factor analysis of variance with repeated measures of one factor (time) and posttest analysis using Bonferroni correction for repeated comparisons were performed to compare the difference in pain scores from baseline at each of the 10-minute intervals between each of the treatment groups (IVM, NF) [15]. Additional secondary outcomes of interest included physician and patient satisfaction with the administered medication and need for rescue analgesia or antiemetic. These were assessed with the Fisher exact test. Continuous data were analyzed for normality using the ShapiroWilk test. Homogeneity of variance was assessed using the Levine test. Two-tailed P values less than .05 were considered statistically significant. All statistics were completed using SPSS software (v20; IBM Corporation, Armonk, NY). Sample size to detect a difference greater than 15 mm (out of 100 mm) in the VAS was calculated before patient enrollment and was determined to be 16 participants per treatment arm with repeated measurements for time. This assumed moderate effect size (0.5), α of .05, and a power of 0.80 for detecting Type II error [16]. A difference of greater than 15 mm (out of 100) in the VAS score was considered clinically significant [17,18]. 3. Results A total of 40 patients participated in the study (20 patients received IVM and 20 patients received NF]; 3 patients from the IVM and 3 patients from the NF group were not included in data analysis at the request of the local IRB because of discrepancies noted on consent forms. One patient from the IVM and 1 patient from the NF group were not included in data analysis at the request of the local IRB for protocol deviation (receiving incorrect doses of medications [IVM: 0.15 mg/kg and NF: 1.5 μg/kg]) (Figure). Per-protocol analysis of the remaining 32 patients was performed. Demographic features of the 2 treatment arms including age, sex, ethnicity, baseline VAS, and baseline vital signs are presented in Table 1. There was no statistically significant difference in demographics, vital signs, or baseline VAS of participants between the 2 groups. There were also no clinically significant adverse events associated with the administration of NF or IVM. No instances of naloxone administration or resuscitative measures such as intubation or ventilation were necessary in either treatment group. Patients and physicians reported greater satisfaction with NF than with IVM. A greater need for rescue medications was experienced in patients receiving IVM than with NF (Table 2). Patients in the IVM group received at least 1 rescue medication for analgesia (5/16) or antiemesis (7/16) post morphine administration, whereas 1 patient in the NF received ondansetron for nausea. This patient however experienced nausea before administration of fentanyl, and the medication was administered concomitant to fentanyl. Another patient in the NF experienced asymptomatic hypotension (BP before NF, 98/53; BP 10 minutes following NF, 87/49) and received 1 L of NS with immediate improvement in BP. Difference from baseline at time points (10, 30, and 40 minutes) for the morphine treatment arm did not demonstrate normal distribution by the Shapiro-Wilk test, whereas differences from baseline at each of the time points did demonstrate normal distribution for the fentanyl treatment arm. Logarithmic transformation of VAS difference from baseline for both treatments arms was performed with resulting normal distributions for each treatment at each time point. The resulting
Please cite this article as: Deaton T, et al, Nebulized fentanyl vs intravenous morphine for ED patients with acute abdominal pain: a randomized double-blinded, placebo-controlled clinical trial, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.03.046
T. Deaton et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
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Enrollment
Assessed for eligibility (n = 41)
Excluded (n = 1) Not meeting inclusion criteria (n = 0) Declined to participate (n = 1)
Randomized (n = 40) Neb Fentanyl (n = 20)
IV Morphine (n = 20)
Allocation Allocated to intervention (n = 20) Received allocated intervention (n = 20)
Allocated to intervention (n = 20) Received allocated intervention (n = 20)
Did not receive allocated intervention (n = 0)
Did not receive allocated intervention (n = 0)
Follow-Up Lost to follow-up (n = 0)
Lost to follow-up (n = 0)
Discontinued intervention (n = 0)
Discontinued intervention (n = 0)
Analysis Analysed (n = 16) Excluded from analysis (n = 4)
Analysed (n = 16) Excluded from analysis (n = 4)
-Incomplete consent on IRB review (n = 3)
-Incomplete consent on IRB review (n = 3)
-Protocol Deviation (n = 1)
-Protocol Deviation (n = 1)
Figure. Enrollment and analysis flowchart.
geometric mean with 95% confidence intervals (CIs) is presented in Table 3. The Levene test demonstrated equal variance between the 2 treatment arms for each of the repeated-measures time points. Between-variance comparison demonstrated P values less than .05. Posttest analysis using Bonferroni correction for repeated comparisons demonstrated statistically significant differences between NF and IVM at all time points (Table 3).
Table 1 Demographics of study participants
Age (y) Mean (±SD) 95% CI Sex Female (%) Baseline vital signs Heart rate, beats per min (95% CI) Systolic BP, mm Hg (95% CI) Baseline VAS (mm, 100 mm max) Mean (±SD) 95% CI Ethnicity (%) White African American Hispanic Asian American ⁎ Student t test. † Fisher exact test. ‡ Z test of proportions.
IVM (n = 16)
NF (n = 16)
32.38 (10.76) 26.64-38.11
30.19 (10.7) 24.48-35.89
.71⁎
10 (62.5)
.72†
77.2 (71.4-85)
76.8 (71.5-82.2)
.85⁎
128 (120.2-134.7)
122.9 (118.7-137.8)
.76⁎
8 (50)
P
4. Discussion The present study was designed to assess the feasibility of NF in the alleviation of painful acute abdominal complaints as measured by the VAS. We also sought to compare the efficacy of NF administration and to assess patient and provider satisfaction with this method of drug delivery in an ED setting. The VAS is validated as an accurate and reliable measure of acute pain in an ED setting [19]. At all the time points measured, a single dose of NF (2 μg/kg) resulted in clinically significant pain relief from baseline (VAS difference of 15 mm or greater) with relief achieved within 10 minutes of administration. In contrast, IVM at a dose of 0.1 mg/kg did not achieve clinically significant pain relief until 30 minutes postadministration and no longer demonstrated clinically significant improvement after 30 minutes. Despite the availability of rescue analgesia and more frequent administration, patients in the IVM treatment group experienced less improvement in pain as measured by the VAS in comparison to the NF group. They also experienced a decrement in pain relief after 30 minutes, whereas the NF group Table 2 Patient and physician satisfaction with treatment and need for "rescue" medication
74.94 (16.41) 66.19-83.68 12 (75) 2 (12.5) 1 (6.25) 1 (6.25)
65.81 (13.25) 58.75-72.87 9 (56) 2 (12.5) 4 (25) 1 (6.25)
.09⁎
.26‡ 1.00‡ .14‡ 1.00‡
Patient satisfaction Not very satisfied Satisfied Physician satisfaction Not very satisfied Satisfied Administration of "rescue" medication
IVM (n = 16)
NF (n = 16)
P
12 4
3 13
.004⁎
8 8 9
1 15 1
.016⁎ .006⁎
⁎ Fisher exact test.
Please cite this article as: Deaton T, et al, Nebulized fentanyl vs intravenous morphine for ED patients with acute abdominal pain: a randomized double-blinded, placebo-controlled clinical trial, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.03.046
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T. Deaton et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
Table 3 Differences in VAS from baseline Difference (NF − IVM) (95% CI of difference)
Change in VAS IVM (n = 16), from baseline geometric mean (mm) (95% CI)
NF (n = 16), geometric mean (95% CI)
10 min 20 min 30 min 40 min
15.20 (11.92-19.67) 3.90 (3.3-4.47) 27.66 (22.15-35.12) 15.75 (15.18-16.32) 36.29 (29.67-43.88) 19.67 (19.09-20.24) 37.48 (28.65-49.57) 27.36 (26.79-27.93)
11.30 (5.42-18.88) 11.92 (2.78-25.74) 16.63 (7.39-30.71) 10.12 (2.38-20.48)
experienced more rapid pain relief, more sustained and clinically significant pain relief over the 40-minute study interval, and a trend toward continued improvement over time without additional “rescue” analgesia or antiemetic administration. More providers and patients were satisfied with the analgesia afforded by NF than with IVM, and no adverse events were observed with NF administration. Previous research has compared intranasal fentanyl to IVM in the treatment of painful conditions in both children and adults [9,20]. Doses in the range of 1.7 μg/kg of intranasal fentanyl were shown to be equivalent to 0.1 mg/kg morphine in pediatric long-bone fractures [20]. The use of alternate delivery of fentanyl has been shown to lead to quicker pain control and decrease the need for IV access by 50% [21]. Standard concentrations of 50 μg/mL have been shown to be safe and effective with no adverse effects noted [22,23]. However, intranasal administration has limitations; it is limited to 1 mL per nostril because of liquid run-off problems [24]. In the absence of compounded moreconcentrated preparation of fentanyl, the standard preparation of 50 μg/mL limits each dose to 100 μg in adults. Intranasal fentanyl has also been shown to have a slower onset of action than IV fentanyl [12]. Nebulization of analgesic medications offers another potential route of administration without these limitations of intranasal administration. Nebulized fentanyl was first reviewed as a method of analgesic delivery in the 1990s for postoperative patients [25,26]. It has more recently been researched as an equivalent to slightly superior way to deliver fentanyl in pediatric patients with acute painful conditions [27]. In adults with undifferentiated abdominal pain, similar to our cohort, inhaled fentanyl was found to be equivalent to IV fentanyl [13]. In pediatric and adult patients with long-bone fractures, inhaled fentanyl was found to be superior to IVM [14,27]. Our study is the first to compare NF to IVM in adults with undifferentiated abdominal pain and to suggest this as an alternate method for early control of pain.
5. Limitations The results of this study cannot be generalized to other painful conditions such as orthopedic injury or trauma. However, NF has been demonstrated to be effective in the treatment of pediatric and adult long-bone fractures, suggesting that NF offers analgesia in a variety of painful conditions [14,27]. To meet requirements for the FDA IND, a number of exclusions were included in patient enrollment. The effect of concomitant use of monoamine oxides inhibitors, tricyclic antidepressants, sedative-hypnotics, and known cytochrome P450 3A4 inhibitors on the efficacy of or complications related to the use of NF is unknown. Similarly, the efficacy and potential complications of NF in the pregnant or lactating patient were not evaluated in the present study. Our study only looked at pain scores from 0 to 40 minutes. The peak effect of fentanyl is seen at 3 to 5 minutes, whereas morphine may take up to 20 minutes to reach peak effect. The timing of administration and peak effect of both medications may have factored into the patients favoring fentanyl over morphine. The analgesic effect of morphine can last 4 to 5 times longer than fentanyl, and providers may elect to choose this medication over fentanyl based on this property alone. The nebulizer used in the present study is designed to deliver 100% of its contents to the patient; and therefore, a standard nebulizer
may deliver less than the 2-μg/kg dose of fentanyl administered in the present study and therefore demonstrate reduced efficacy in pain relief. A higher dose may be necessary with a standard nebulizer to achieve similar results. The taste or smell of NF vs nebulized saline was not matched by pharmacy, and it is possible that study participants were aware of what active medication they received based on these differences. Patients did not appear however to be able to differentiate if the IV or the nasal preparation contained the active medication. A potential loss of blinding may have occurred as a result of the manner in which study medications were drawn and mixed by the charge nurse but administered by the treating nurse. Because there were no safety concerns and no reason for the charge nurse to reveal allocation, we feel that this is unlikely. We did not follow patients after their initial ED evaluation; we therefore cannot comment on any delayed complications that may have resulted from administration of NF. The patients were also evaluated for generalized abdominal pain, and specific pathologic conditions were not recorded. As the etiologies for acute abdominal pain are diverse and were not recorded in the present study, the resulting reduction in pain scores seen between groups may reflect differences in the etiology of abdominal pain between groups rather than effects of administered medication. As the mean age of enrolled patients was roughly 30 ± 10 years, the effects of NF on pediatric or elderly patients cannot be described with the present study. Administration of 2 μg/kg NF in an elderly patient may have additional adverse effects, and caution is advised. 6. Conclusion Fentanyl citrate at a dose of 2 μg/kg through a breath-actuated nebulizer appears to be a feasible and safe alternative to IVM (0.1 mg/kg) in the treatment of acute abdominal pain in adult patients and is associated with more rapid and sustained pain relief, greater patient and provider satisfaction, and less need for additional doses of analgesia or antiemetics. The opinions and assertions contained herein are the views of the authors and are not to be construed as official or reflecting the views of the Department of the Navy, Department of Defense, or the US Government. References [1] National hospital ambulatory medical care survey: 2010 emergency department summary. CDC Web site. Available at: http://www.cdc.gov/nchs/data/ahcd/ nhamcs_emergency/2010_ed_web_tables.pdf. [Accessed 5 September, 2014]. [2] Bhuiya FA, Pitts SR, McCaig LF. Emergency department visits for chest pain and abdominal pain: United States, 1999-2008. Available at: http://www.cdc.gov/nchs/ data/databriefs/db43.pdf. [Accessed 5 September, 2014]. [3] Motov SM, Khan A. Problems and barriers of pain management in the emergency department: are we ever going to get better? J Pain Res 2009;2:5–11. [4] Allione A, Melchio R, Martini G, Dutto L, Ricca M, Bernardi E, et al. Factors influencing desired and received analgesia in emergency department. Intern Emerg Med 2011; 6(1):69–78. [5] Karlsen AP, Pedersen DM, Trautner S, Dahl JB, Hansen MS. Safety of intranasal fentanyl in the out-of-hospital setting: a prospective observational study. Ann Emerg Med 2014;63(6):699–703. [6] Graudins A, Meek R, Egerton-Warburton D, Seith R, Furness T, Chapman R. The PICHFORK (Pain In CHildren Fentanyl OR Ketamine) trial comparing the efficacy of intranasal ketamine and fentanyl in the relief of moderate to severe pain in children with limb injuries: study protocol for a randomized controlled trial. Trials 2013;14:208. [7] Steenblik J, Goodman M, Davis V, Gee C, Hopkins CL, Stephen R, et al. Intranasal sufentanil for the treatment of acute pain in a winter resort clinic. Am J Emerg Med 2012;30(9):1817–21. [8] Stephen R, Lingenfelter E, Broadwater-Hollifield C, Madsen T. Intranasal sufentanil provides adequate analgesia for emergency department patients with extremity injuries. J Opioid Manag 2012;8(4):237–41. [9] Rickard C, O'Meara P, McGrail M, Garner D, McLean A, Le Lievre P. A randomized controlled trial of intranasal fentanyl vs intravenous morphine for analgesia in the prehospital setting. Am J Emerg Med 2007;25(8):911–7. [10] Johnston S, Wilkes GJ, Thompson JA, Ziman M, Brightwell R. Inhaled methoxyflurane and intranasal fentanyl for prehospital management of visceral pain in an Australian ambulance service. Emerg Med J 2010;28(1):57–63. [11] Middleton PM, Simpson PM, Sinclair G, Dobbins TA, Math B, Bendall JC. Effectiveness of morphine, fentanyl, and methoxyflurane in the prehospital setting. Prehosp Emerg Care 2010;14(4):439–47. [12] Wolfe TR, Braude DA. Intranasal medication delivery for children: a brief review and update. Pediatrics 2010;126:532–7.
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Please cite this article as: Deaton T, et al, Nebulized fentanyl vs intravenous morphine for ED patients with acute abdominal pain: a randomized double-blinded, placebo-controlled clinical trial, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.03.046