Anesthesiology, Article

Nebulized fentanyl vs intravenous morphine for ED patients with acute abdominal pain: a randomized double-blinded, placebo-controlled clinical trial

a b s t r a c t

Objectives: Patients with acute abdominal pain commonly present to emergency departments. The safe and effec- tive 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 ug/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 ug/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.

(C) 2015

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 in- travenous (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 alter- nate means to deliver adequate pain control to prehospital and ED pa- tients [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 satisfac- tion with this Novel method of drug delivery.

Methods

After local institutional review board (IRB) and US Food and Drug Administration Investigation New Drug/Device (IND) approval, a randomized, double-blinded, double-placebo-controlled trial was conducted between October 2011 and February 2012. The study oc- curred 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 consi- dered for enrollment. Pain was of less than 24-hour duration, and pa- tients 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, hypothy- roidism, 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/(C) 2015

excluded from the study. A urine pregnancy test was performed in all fe- male patients of childbearing years before enrollment. Patients taking monoamine oxides inhibitors, triCyclic antidepressants, sedative hyp- notics, or known Cytochrome P450 3A4 inhibitors within 14 days of en- rollment 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 ug/kg) with an equivalent volume of IV isotonic sodium chloride solution (group NF) using computerized randomization software from our re- search pharmacist. Both the morphine sulfate (1 mg/mL) and fentanyl citrate (50 ug/mL) used in the present study were standard preparations designed for IV administration and commercially available. All nebu- lized study medications were delivered over the course of 5 to 10 minutes via the AeroEclipse II Breath Actuated Nebulizer (BAN) (Monaghan Medi- cal Corporation, Plattsburgh, NY). The AeroEclipse II only delivers medica- tions 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 but- ton on top of the nebulizer will move into the fully down position, indica- ting 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 indica- ting no aerosol is being produced. Do not place your lips over the exhala- tion valve on the bottom of the mouthpiece. Doing so will prevent the valve from functioning properly.” Immediately after intranasal medica- tions were initiated, IV medications were given slowly over a 2- to

3-minute push by the bedside nurse.

Baseline 100-mm Visual analog scale 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 satu- ration 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 physi- cian, 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 deter- mined 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 pa- tient 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 pro- portions was performed to compare differences between groups for pa- tient self-identified ethnicity. The primary outcomes of interest were the feasibility and safety of NF in comparison to IVM. Secondary out- comes 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 inter- vals between each of the treatment groups (IVM, NF) [15]. Additional secondary outcomes of interest included physician and patient satisfac- tion 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 Shapiro- Wilk test. Homogeneity of variance was assessed using the Levine test. Two-tailed P values less than .05 were considered statistically signi- ficant. 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), ? 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].

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 pa- tients from the NF group were not included in data analysis at the re- quest 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 proto- col deviation (receiving incorrect doses of medications [IVM: 0.15 mg/kg and NF: 1.5 ug/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 de- mographics, 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 adminis- tration 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 pa- tients 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 re- ceived ondansetron for nausea. This patient however experienced nau- sea before administration of fentanyl, and the medication was administered concomitant to fentanyl. Another patient in the NF expe- rienced asymptomatic hypotension (BP before NF, 98/53; BP 10 minutes following NF, 87/49) and received 1 L of NS with immediate improve- ment 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

Follow-Up

Lost to follow-up (n = 0) Discontinued intervention (n = 0)

Lost to follow-up (n = 0) Discontinued intervention (n = 0)

Analysis

Analysed (n = 16)

Excluded from analysis (n = 4)

-Incomplete consent on IRB review (n = 3)

Protocol deviation (n = 1)

Analysed (n = 16)

Excluded from analysis (n = 4)

-Incomplete consent on IRB review (n = 3)

-Protocol Deviation (n = 1)

Figure. Enrollment and analysis flowchart.

Enrollment

Allocation

Allocated to intervention (n = 20) Received allocated intervention (n = 20)

Did not receive allocated intervention (n = 0)

Allocated to intervention (n = 20) Received allocated intervention (n = 20)

Did not receive allocated intervention (n = 0)

IV Morphine (n = 20)

Neb Fentanyl (n = 20)

Randomized (n = 40)

Excluded (n = 1)

Not meeting inclusion criteria (n = 0) Declined to participate (n = 1)

Assessed for eligibility (n = 41)

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

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 de- livery 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 mea- sured, a single dose of NF (2 ug/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

IVM (n = 16)

NF (n = 16)

P dose of 0.1 mg/kg did not achieve clinically significant pain relief until

Age (y)

Mean (+-SD)

32.38 (10.76)

30.19 (10.7)

30 minutes postadministration and no longer demonstrated clinically

.71? significant improvement after 30 minutes. Despite the availability of

95% CI

26.64-38.11

24.48-35.89

rescue analgesia and more frequent administration, patients in the

IVM treatment group experienced less improvement in pain as mea- sured by the VAS in comparison to the NF group. They also experienced a decrement in pain relief after 30 minutes, whereas the NF group

Sex

Female (%)

8 (50)

10 (62.5)

.72+

Baseline vital signs

Heart rate, beats per min

77.2 (71.4-85)

76.8 (71.5-82.2)

.85?

(95% CI)

Systolic BP, mm Hg (95% CI)

128 (120.2-134.7)

122.9 (118.7-137.8)

.76?

Baseline VAS

(mm, 100 mm max)

Mean (+-SD)

74.94 (16.41)

65.81 (13.25)

.09?

95% CI

66.19-83.68

58.75-72.87

Table 2

Patient and physician satisfaction with treatment and need for “rescue” medication

IVM (n = 16) NF (n = 16) P

* Student t test.

+ Fisher exact test.

? Z test of proportions.

Satisfied 8 15 .016? Administration of “rescue” medication 9 1 .006?

* Fisher exact test.

Ethnicity (%) White

12 (75)

9 (56)

.26?

Patient satisfaction Not very satisfied

12

3

African American

2 (12.5)

2 (12.5)

1.00?

Satisfied

4

13

.004?

Hispanic

1 (6.25)

4 (25)

.14?

Physician satisfaction

Asian American

1 (6.25)

1 (6.25)

1.00?

Not very satisfied

8

1

Table 3

Differences in VAS from baseline

may deliver less than the 2-ug/kg dose of fentanyl administered in the present study and therefore demonstrate reduced efficacy in pain relief.

Change in VAS from baseline (mm)

IVM (n = 16),

geometric mean (95% CI)

NF (n = 16),

geometric mean (95% CI)

Difference (NF – IVM) (95% CI of difference)

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

10 min 11.30 (5.42-18.88) 15.20 (11.92-19.67) 3.90 (3.3-4.47)

20 min 11.92 (2.78-25.74) 27.66 (22.15-35.12) 15.75 (15.18-16.32)

30 min 16.63 (7.39-30.71) 36.29 (29.67-43.88) 19.67 (19.09-20.24)

40 min 10.12 (2.38-20.48) 37.48 (28.65-49.57) 27.36 (26.79-27.93)

experienced more rapid pain relief, more sustained and clinically significant pain relief over the 40-minute study interval, and a trend to- ward 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 ug/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 ug/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 more- concentrated preparation of fentanyl, the standard preparation of 50 ug/mL limits each dose to 100 ug 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 de- livery in the 1990s for postoperative patients [25,26]. It has more re- cently 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, in- haled fentanyl was found to be equivalent to IV fentanyl [13]. In pedia- tric 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.

Limitations

The results of this study cannot be generalized to other painful con- ditions 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 antide- pressants, sedative-hypnotics, and known cytochrome P450 3A4 inhi- bitors 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 adminis- tration and peak effect of both medications may have factored into the patients favoring fentanyl over morphine. The analgesic effect of mor- phine 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

aware of what active medication they received based on these differ- ences. Patients did not appear however to be able to differentiate if the IV or the nasal preparation contained the active medication. A po- tential 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 complica- tions that may have resulted from administration of NF. The patients were also evaluated for generalized abdominal pain, and specific patho- logic conditions were not recorded. As the etiologies for acute abdomi- nal pain are diverse and were not recorded in the present study, the resulting reduction in pain scores seen between groups may reflect dif- ferences 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 ug/kg NF in an elderly patient may have additional adverse effects, and caution is advised.

Conclusion

Fentanyl citrate at a dose of 2 ug/kg through a breath-actuated nebu- lizer 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 au- thors 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.

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