Article, Urology

Atomized intranasal vs intravenous fentanyl in severe renal colic pain management: A randomized single-blinded clinical trial

a b s t r a c t

Objectives: Renal colic is one of the most common painful disorders in patients referred to the emergency department. The main purpose of this study was to compare the efficiency of two methods of intravenous (IVF) and intranasal (INF) fentanyl administration in pain management in patients with severe renal colic.

Materials & methods: This was a single-blind randomized clinical trial performed on patients with severe renal colic. The severity of pain was >=8 based on the numerical rating scale (NRS). The efficacy of pain management was compared within and between the IVF (intramuscular Ketorolac + Intravenous fentanyl) and INF (intramuscular Ketorolac + Intranasal fentanyl) groups at different times points. Oral consent was obtained from all the patients.

Results: Of 220 individuals, 96 (43.60%) were women and 124 (56.40%) were men. There were no significant differences between the two groups regarding the baseline Pain severity, age, sex, history of urolithiasis and body mass index (BMI). The pain severity showed a significant reducing trend in both groups (p b 0.0001). There was also a significant difference comparing the mean pain severity between groups at different times (p b 0.0001). In each group, the severity of pain showed significant reduction compared with its prior measurement (P b 0.0001).

Conclusion: Fentanyl is highly effective in controlling pain in patients with severe renal colic referring to the emergency department. Intranasal administration of fentanyl combination with ketorolac can be an appropriate, non-invasive, easy-to-use and fast alternative to the intravenous method to manage pain in these patients.

(C) 2019

Introduction

Pain is one of the most common complaints of patients referred to emergency departments [1]. Kidney stones affect approximately 1 in 11 people in the United States increasing to 1 in 5 among highest-risk groups [2]. The prevalence of renal stones has been reported as 5.7% in Iran. However, this rate may be influenced by age, sex, weight, diet and underlying diseases [3]. Accordingly, the prevalence of kidney stones increased in the late twentieth and through the twenty-first centuries. This has been attributed to a variety of factors including environmental changes, alterations in dietary habits, and increased prevalence of Metabolic syndrome. Renal colic is among common causes of sudden and severe pain, especially in tropical areas [4]. Proper management of renal colic pain in emergency departments is of particular importance [5].

Combined administration of Nonsteroidal anti-inflammatory drugs and narcotics is a common way to control pain associated

* Corresponding author.

E-mail address: [email protected] (M. Torabi).

with renal colic. The combination of ketorolac, the first line NSAID used in patients with renal colic, and fentanyl, a highly effective and safe narcotic, can be administrated through various routes [6,7]. Intravenous fentanyl is commonly administrated to patients admitted to emergency departments, to control severe pain. Nevertheless, different doses of fentanyl can be delivered through other non- invasive ways such as intranasal route. The Analgesic efficacy of fentanyl administrated through intranasal; however, is unclear [8]. The bioavailability of fentanyl administrated in either intravenous or intranasal (i.e. pulmonary and mucosal absorption) route has been identical suggesting the recent as an appropriate alternative the former method [9,10]. Nevertheless, the onset and duration of Therapeutic effects may be different in these two methods [11]. Overall, intranasal administration of fentanyl provides a safe and satisfactory pain Management strategy [12-14].

The aim of this study was to compare therapeutic efficiencies of intravenous and intranasal routes of fentanyl administration to manage pain and increase patients? satisfactions in those with severe renal colic pain referred to emergency departments. The side effects of fentanyl administration were also compared between these two methods.

https://doi.org/10.1016/j.ajem.2019.158483

0735-6757/(C) 2019

Materials & methods

Study design

This was a single-blinded randomized clinical trial including patients with severe renal colic referred to two emergency departments in Kerman, southeastern Iran during a six-month period from January 2019 to July 2019. Overall, the two departments contain 87 beds and register more than 135,000 patients annually. In the both departments, renal colic had been managing by combined administration of ketorolac and narcotics.

The patients were randomly assigned to either intramuscular ketorolac + intravenous fentanyl (IVF) (i.e. control) or intramuscular ketorolac + intranasal fentanyl (INF) (i.e. intervention) group. The analgesic efficiency of each method was measured at specific time points in post-intervention period.

Ethics committee approval

The study was approved by the Ethics Committee of Kerman University of Medical Sciences [IR.KMU.AH.REC.1397.116] and Iranian Registry of Clinical Trials (IRCT20150509022181N4). Oral consent was obtained from each patient.

Date collection form

Adult patients (i.e. N18 years old) with severe renal colic pain referred to the emergency departments were enrolled in the study. After excluding acute abdominal pain, the diagnosis was confirmed based on clinical sign and symptoms (i.e. severe flank pain radiating inferiorly and anteriorly, nausea and vomiting, urinary symptoms, and previous history), as well as ultrasound and urinary analyses.

The minimization randomization was used to allocate the patients to each group to obtain a balanced distribution of variables. Addiction, acute abdominal pain, uncertain diagnosis of renal colic, unresponsiveness to primary therapeutics, hypersensitivity to NSAIDs or narcotics, receiving either monoamine oxides inhibitors, triCyclic antidepressants, hypnotic sedatives or Cytochrome P450 inhibitors within the past two weeks, asthma, age b18 years old, pregnancy and lactation, and finally unwillingness to participate in the study were considered as exclusion criteria (Fig. 1).

Study protocol

Overall, 220 patients with renal colic were randomly allocated to either control (i.e. IVF) or intervention (i.e. INF) group (n = 110 per group). In the IVF group, the patients were injected with 60 mg intramuscular ketorolac (30 mg/ml, Iran Hormone Co, Iran,) and 1 ug/kg intravascular fentanyl (50 ug/ml, Fentanyl, Durogestic). On the other hand, the patients in INF group received 60 mg intramuscular ketorolac along with 2 ug/kg intranasal fentanyl. Intranasal fentanyl was administrated using a nasal atomizer (LMA(R) MAD NASAL(TM), TELEFLEX, USA) [12]. The drugs had been kept at 4 ?C during the study. The drugs were administrated by two Trained nurses. The data was collected using a questionnaire by a emergency medicine senior resident (PGY3). The resident was blinded to the study. If the pain did not subside at 30 min post administration, investigators offered IV morphine (0.1 mg/kg) as the rescue analgesic. The patients received morphine were excluded from the study.

Pain intensity measurement

The pain intensity and fluctuations were measured using the Numerical Rating Scale . One-third reduction in pain compared with baseline was considered as statistically significant. The validity of

Fig. 1. Consolidated standards of reporting trials flow diagram.

Table 1

Baseline characteristics, Comparison between IVF1 and INF2 groups.

Variables

IVF group n (%)

INF group n (%)

P-value

Age (years)

0.28

<=48

51(46.4)

59(53.6)

N48

59(53.6)

51(46.4)

Gender

1.00

Male

62(56.4)

62(56.4)

Female

BMI3

48(43.6)

48(43.6)

0.78

18.5-24.99

41(37.3)

43 (39.3)

>=25

69(62.7)

67(60.9)

History of urinary stone

0.78

Yes

65(59.1)

47(42.7)

No

45(40.9)

63(57.3)

1 Ketorolac IM + Fentanyl IV.

2 Ketorolac IM + Fentanyl IN.

3 Body mass index.

NRS system is similar to the Visual analog scale . Patients with severe renal colic pain (i.e. NRS >= 8) were included in this study [15]. The severity of pain was measured by the senior emergency medicine resident at baseline, as well as 10, 20, 30, 40, and 60 min after the interventions.

Outcome measurement

The pain score was determined during a 60-minute period. The primary outcome included reduction in pain intensity. Patient?s Satisfaction rate and drug adverse effects included secondary outcomes. The patients? satisfaction was documented at the end of study. Any adverse effect was recorded during and upon completion of the trial.

Statistical analysis

The data was analyzed using IBM SPSS statistics (version 21). Descriptive statistics were used to report the mean, SD and prevalence. Chi-square test was used to compare the prevalence between groups. Linear regression was used to compare mean adjusted pain score between the two groups. Considering the repeated measures of outcome variable, the Generalized Estimating Equation (GEE) was to estimate the parameters. ANCOVA (Analysis of Covariance) was used to compare adjusted mean pain score between the groups at individual time points.

Results

Of 220 patients included in the study, 96 (43.60%) and 124 (56.4%) were women and men respectively. The two groups were homogeneous in terms of baseline variables (i.e. (age, sex, body mass index (BMI), and history of urolithiasis).

The means of baseline pain intensity score were 9.22 +- 0.62 and

9.22 +- 0.51 in the IVF and INF groups respectively (p = 1, Table 1). Linear regression analysis was used to assess adjusted pain score between the two groups controlling the effects of other variables. Accordingly, the pain score was 0.57 unit lower in the IVF than INF group. The mean pain score was 0.18 lower in patients aged <=48 than those aged N48 years old. The pain score consecutively reduced by an average of 1.1 unit at any time point post-intervention. pain reduction was positively correlated with the duration of treatment. By increasing one unit in the baseline pain score, the final pain score increased by 0.15 unit (Table 2).

Overall, the mean pain score was higher in the INF than IVF group at all post-intervention times points except for 30 min post-treatment (Table 3). Nevertheless, the pain intensity significantly and consecutively reduced in both groups during the study (p b 0.001, Table 4 and Fig. 2).

There was no significant difference between the two groups in terms of patient?s satisfaction rate (Table 5) or incidence of therapy adverse effects (Table 6).

Discussion

In this study, the analgesic efficiencies of two methods of fentanyl administration (i.e. intravenous and intranasal) were assessed in patients with severe renal colic pain referred to two emergency departments in Kerman, Iran. Two study groups included IVF (i.e. intramuscular ketorolac + intravenous fentanyl) and INF (i.e. intramuscular ketorolac + intranasal fentanyl). Pain intensity was measured during a 60-minute period at post-intervention. Our results indicated that although intravenous administration of fentanyl was more efficient in reducing pain the analgesic effects of the two methods was were comparable. In Similar to the IVF group, the pain intensity continuously reduced in the INF group at all the times post intervention. Furthermore, larger reductions were seen at later times (i.e. 40- and 60- min post-intervention).

In emergency departments, the initial management of renal colic is based on rational and fast diagnosis, as well as rapid and effective pain control. Fentanyl is a common drug in used to control pain in patients with renal colic, especially in cases with severe pain. In combination with NSAIDs, fentanyl can be administrated in a variety of routes.

Table 2

Comparing pain score in IVF1 and INF2 groups by multiple regression and GEE3 method.

Variables

Coefficient

CI (95%)

P-value

Intercept

6.91

(5.83, 7.99)

b0.0001

Groups

IVF

-0.57

(-0.7, -0.43)

b0.0001

Age

INF

<=48

Reference

-0.18

(-0.34 , -0.02)

0.02

BMI4

N48

18.5-24.99

Reference

0.09

(-0.07, -0.27)

0.26

>=25

Reference

History of stone

Yes

0.03

(-0.2, 0.12)

0.65

No

Reference

Gender

Female

0.11

(0.27, 2.1)

0.14

Male

Reference

Time

NRS5 in baseline

-1.1

0.15

(-1.15, -1.05)

(0.04, 0.27)

b0.0001 0.008

1 Ketorolac IM + Fentanyl IV.

2 Ketorolac IM + Fentanyl IN.

3 Generalized estimated equation.

4 Body mass index.

5 Numerical rating scale.

Table 3

Pain intensity changes in different times in IVF and INF groups. *(Ketorolac + Fentanyl IN) – (Ketorolac + Fentanyl IV).

Variables

IVF

(mean +- SD)

INF

(mean +- SD)

Difference* (95%CI)

P-Value

Baseline

9.22 +- 0.62

9.22 +- 0.52

0.00 (-0.15-0.15)

1.00

10

6.89 +- 1.05

7.5 +- 0.97

0.61 (0.34-0.87)

b0.0001

20

5.09 +- 1.19

5.99 +- 1.09

0.90 (0.59-1.20)

b0.0001

30

4.35 +- 0.80

4.44 +- 0.53

0.09 (-0.09-0.27)

0.32

40

3.19 +- 1.10

3.84 +- 0.62

0.65 (0.40-0.88)

b0.0001

60

2.47 +- 1.06

3.00 +- 0.4

0.53 (0.31-0.74)

b0.0001

Table 4

Pain intensity changes compared to prior time in IVF and INF groups.

Difference time

IVF (95%CI)

P-Value

INF (95%CI)

P-value

20-10

1.80(1.54-2.05)

b0.0001

1.50(1.33-1.68)

b0.0001

30-20

1.64(1.42-1.86)

b0.0001

2.30(2.15-2.46)

b0.0001

40-30

2.25(2.04-2.46)

b0.0001

2.10(1.99-2.28)

b0.0001

60-40

2.40(2.20-2.60)

b0.0001

2.40(2.30-2.58)

b0.0001

Fig. 2. Plot of two group displaying the change in pain intensity from baseline to 60 min.

Although intravenous administration is the common route, other administration methods can also be used in certain conditions. For example, intranasal administration can be beneficial in patients who have needle phobia. In addition, intranasal administration of fentanyl can help to effectively relive the pain when emergency departments are overcrowded both [16,17]. In a study by Belkouch et al., intranasal administration of fentanyl was effective in controlling pain in patients with renal colic.

Intranasally administrated fentanyl can be immediately absorbed through the nasal cavity [18]. Due to high blood flow in nasal epithelium, fentanyl is readily absorbed from the nasal mucosa reaching to peak Blood concentration within 5 min. This phenomenon can partly explain the fast and effective analgesic effect of the intranasal route [19]. In addition, intranasal administration of fentanyl is highly safe, and due to the non-invasive nature of the procedure, it can increase patient?s satisfaction. This is especially important in patients with anxiety, severe

pain, or those who have inaccessible veins [20-24]. In a study by Fendter et al., intranasally administrated fentanyl was more effective than intravenous morphine in reducing pain in patients with renal colic [25]. Considering the rapid and effective pain reducing impact of intranasally administrated fentanyl, this method may be an appropriate strategy for controlling pain in patients with renal colic [26,27]. In this study, we first compared pain score reduction between the two groups. The findings showed greater pain reduction in patients administrated with intravenous than intranasal fentanyl. However, pain intensity reduction was equal in the groups at 30 min post-intervention. Comparing the pain score between consecutive times post-treatment showed that pain severity significantly reduced in each time point in comparison with its prior occasion in both groups. This indicated a continuous pain reduction pattern in the both groups highlighting the efficacy of both administration routes to relieve pain in patients with severe renal colic. Therefore, intranasal administration of fentanyl can

Table 5

Patient satisfaction with treatment in IVF and INF groups.

Variables IVF INF P-Value Not very satisfied 10 (9.1) 14 (12.7) 0.38

Satisfied 67 (60.9) 71 (64.5)

Very satisfied 33 (30) 25 (22.7)

Declaration of Competing Interest

The authors declared that there is no conflict of interest.

Appendix A. Supplementary material

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2019.158483.

Table 6

Adverse effects in IVF and INF groups.

Characteristics N (%)

IVF INF

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    Our study had several limitations. We excluded patients with mild to moderate pain. The patients who needed high dose escalation also were excluded from the study. Although, selection bias was a possibility, but considered to be low based on the number of patients excluded for Rescue analgesia. The study was single-blinded as it was not possible to blind nurses who administrated intranasal or intravenous fentanyl. The optimal dose of intranasal fentanyl was not established. The patients? satisfaction may has been influenced by painful Intramuscular injections. The application and preparation of the nasal automizer device was somehow problematic. Finally, the patients were not followed up for delayed complications.

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    Fentanyl can provide a highly effective drug to control pain in patients with severe renal colic referred to emergency departments. Intranasal administration of this drug in combination with ketorolac is a fast-acting, non-invasive, convenient, and effective method to manage pain in these patients.

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