Untitled Document

doi:10.7508/beat.2015.02.003

Original Article

Bull Emerg Trauma 2015;3(2):46-52.

Analgesic Effects of Inhalation of Nitric Oxide (Entonox) and Parenteral Morphine Sulfate in Patients with Renal Colic; A Randomized Clinical Trial

Hamid Kariman1, Alireza Majidi2*, Sara Taheri1, Ali Shahrami1, Hamid Reza Hatamabadi3

1Department of Emergency Medicine, Imam Hossein Medical Center, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2Department of Emergency Medicine, Shohadaye Tajrish Medical Center, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
3Safty Promotion and Injury Prevention Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

...............................................................

*Corresponding author: Alireza Majidi
Address: Department of Emergency Medicine, Shohadaye Tajrish Medical Center,
Shahid Beheshti University of Medical Sciences, Tehran, Iran. Tel: +98-912-8027014, e-mail: alirezamajidi330@yahoo.com

Received: August 17, 2014
Revised: January 8, 2015
Accepted: February 11, 2015

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Please cite this paper as:
Kariman H, Majidi AR,  Taheri S, Shahrami A, Hatamabadi HR. Analgesic Effects of Inhalation of Nitric Oxide (Entonox) and Parenteral Morphine Sulfate in Patients with Renal Colic; A Randomized Clinical Trial. Bull Emerg Trauma. 2015;3(2):46-52.

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Abstract

Objective: To compare the analgesiceffects of Nitrous oxide and morphine sulfate in patients with acute renal colic due to urolithiasis.
Methods: This  was randomized clinical trial being performed in Imam Hossein hospital affiliated with Shahid Beheshti University  of Medical Sciences during a 1-year period from May2013 to May2014.  A  total of number of 100 patients, with an age range of 20-50 years, who presented with renal colic secondary to urolithiasis confirmed by ultrasonography were randomly assigned to receive morphine sulfate injection (0.1 mg/kg)  with 100 mg diclofenac suppository (n=50) or Entonox exhalation (50% nitric oxide and 50% oxygen)for 30-minutes with 100 mg diclofenac suppository (n=50). Quantitative measurement was of pain was performed according to a visual  analogue scale (VAS), before, 3, 5, 10 and 30-minute after the intervention. The pain severity and side effects were measured between two study groups.
Results: The baseline characteristics of the patients in two study groups were comparable. The frequencies of pain persistence (at least 50%) at 3-, 5-, 10- and 30-minute intervals in morphine sulfategroup were 96%, 80%, 50% and 8%, respectively; these frequencies in Entonex  were 82%, 42%, 12% and 2%, respectively (p<0.001).
Cox regression modeling showed that use of Entonox was the only effective agent in the success of treatment, compared to the use of morphine, i.e. use of Entonox increased the success of treatment up to 2.1 folds compared to the use of morphine (HR=2.1; 95% CI: 1.2-3.6; p=0.006).
Conclusion: The results of the present study demonstrate that inhalation of Entonox is an effective and safe analgesic regimen for acute renal colic. It acts more rapidly and is more potent in relieving renal colic when compared to morphine sulfate.Entonox can be regarded as an appropriate alternative to analgesics like opioids in this ground.

Clinical Trial Registry: The current study is registered with Iranian Registry  for Clinical  Trials  (www.irct.ir; IRCT2014120215620N4)

Keywords: Renal colic; Urolithiasis; Pain relief; Morphine; Entonox; Visual analogue scale (VAS).

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Introduction

Renal  colic  is one  of the most  common  and painful medical emergencies. The incidence and prevalence of renal colic secondary to urolithiasis isincreasing all over the world, affecting almost 10% of the world population at present [1]. Prevalence rate in men is 3-4 times more than women [2]. The recurrence  rate of nephrolithiasis  after  the first episode as high as 50% [3,4]. This condition bring an annual financial toll of $2.1 billion on the health systems some due to lostworking days and decreased productivity in the United States[5]. Renal colic, an intolerable pain, requires immediate intervention in order  to relieve  pain  [6]. Non-steroidal  anti- inflammatory drugs (NSAIDs) are first-line agents. Opioids are other effective analgesic, effectfaster than NSAIDs  although  with higher  side effects [6,7].  The combination  of NSAIDS  and opiates is an acceptable  approach  for reducing  the pain intensityand shortening the length of hospital stay in patients with acute renal colic due to urolithiasis [8]. NSAIDs are associated with several side effects and opioids may cause tolerance and dependence. Thus the optimum regimen for pain control in patients with renal colic is yet to be identified [9,10]. Entonox (mixture of 50% oxygen and 50% nitrous oxide) as an analgesic agent has been widely used for many years in different clinical contextssuch as colonoscopy, urologic procedures and labor pain [11]. Entonox is a relatively safe and effective drug with no serious side effects ifused intermittently [12]. Entonox mechanism is centrally which act rapidly and reaches an effective concentration and clears from the circulation by exhalation with minimum effect on the respiratory system [13,14]. The efficacy of Entonex in pain control has been tested and proved in several clinical conditions [11]. However data regarding its efficacy in acute renal colic is scarce. Thus, we performed the current clinical trial in order to determine the analgesic effects of Entonox when compared to parenteral morphine sulfate in patients with acute renal colicsecondary to urolithiasis.

Materials and Methods

Study Population
This was a prospective, single blind, randomized clinical trial being performed in emergency department  of Imam  Hossein  hospital  affiliated with Shahid Beheshti University of Medical Sciences during a 1-year period from May 2013 to May 2014. We included a total number of 100 adult patients (18-50 years of age) with acute renal colic secondary to urolithiasis presenting consecutively to emergency department of our center during the study period. All patients were hemodynamically stable (pulse rate=60-100 beat/min; systolic blood pressure ≥90 2mmHg; SPO ≥90%; respiratory rate=8-22 per min). We excluded pregnant women, those with a history of asthma, chronic pulmonary obstruction, intestinal obstruction, hypertension, cardiac failure, those who had undergone surgery on kidneys and the urinary tract, those with peptic ulcers and gastrointestinal hemorrhages  and those with a history of allergy to aspirin, NSAIDs and morphine. A decrease in consciousness  level, trauma to the head and the thoracic  cavity,  pneumocephalus,  pneunothorax (or entrapment  of air in any part  of the body), drug abuse, tenderness  and rebound tenderness, abdominal guarding, delayed menstruation and use of any analgesic within the previous 24-hourwere also excluded from the study. The study protocol was approved by medical Ethics Committee and institutional review board (IRB) of Shahid Beheshti University  of Medical Sciences. All the patients provided their informed written consents before inclusion  in the study.  During  the whole  study period, the researchers were committed to observing all the ethical principles of Helsinki Declaration in a clinical trial study. The study protocol was registered by Iranian registry of clinical trial (IRCT2014120215620N4; www.irct.ir).

Study Protocol
The patients were diagnosed clinically by determining a detailed history and complete physical examination by single emergency medicine resident. The findings were recorded in a questionnaire which consisted of 3 sections. The first section consisted of demographic data and habits such as smoking. The second section included brief history of patient such as location of pain (flank, abdomen), prior history of renal stone, familial history of renal stone and physical examination and vital signs (blood pressure, pulse rate, respiratory  rate, temperature,  arterial oxygen saturation percentages). In the third section, stone, size, location and grading of hydronephrosis based on ultrasound or CT-scan and also laboratory findings such as hematuria were recorded. In this section, the severity of pain based on VAS scale at first visit, 3, 5, 10 and 30-minute after intervention was recorded. The validity of the questionnaire was confirmed by Cronbach’s alpha coefficient of 0.88. The  urolithiasis  and  hydronephrosis  was confirmed in all the patients with abdominopelvic ultrasonography or/and computerized tomography (CT) scan. The patients were randomly assigned to two study groups using a computer-based random digit generator. Those who were assigned to first group received intramuscularmorphine  injection (0.1 mg/kg) along with 100 mg suppository of diclofenac.  Those assigned  to the second  group received 30-minute of self-administered Entonox inhalation (containing 50% oxygen and 50% nitric oxide) via mask [15] along with100mg of suppository diclofenac.
Quantitative measurement of pain was performed according  to visual  analogue  scale  (VAS)  [16], beforeand  3-,  5-,  10-  and  30-minute  after  the intervention. Pain scores were based on a standard 10-cm  VAS.  Treatment  success  was  defined as achieving at least 50% of pain subsidence. The need for administration of rescue analgesics was evaluated for 2 hours. Any symptoms including nausea, vomiting, dizziness, unconsciousness and apnea, were evaluated and recorded in the data sheets. The length of hospitalization was also recorded.

Statistical Analysis
The sample size was estimated to be 49 patients in each group, considering the treatment success rate of 13% in the placebo and 43% in Entonox groups [15], by 90% power (β=0.1), 95% confidence interval (α=0.05), and 15% withdrawal rate.
All the statistical  analyses  were performed  by statistical package for social sciences (SPSS Inc., Chicago, USA). The parametric data was compared with independent t-test. The pain scores were compared within groups by means of paired sample t-test. Non-parametric  data was compared  using chi-square test. Treatment success percentages were evaluated by Kaplan-Meier  curves and log rank test was used to compare  the curves. Cox regression model was used for data modeling and the consistency hypothesis of hazard ratios (HR) was confirmed by using the graphic method of the scatter (t) diagram of Log (-log) on log (t) and observing the parallelism of the graphs. We report HR with 95% confidence interval (CI). A two sided p-value of less than 0.05 was considered statistically significant.

Results

Overall  117 patients were screened for the study out of whom  100 full  filled the study criteria and were randomly assigned to two study groups each containing  50  patients.  All   the patients finished the study  and thus the total number  of patients included in the final analysis  were 100 (Figure  1). Gender distribution of the patient were significantly different between two study groups (p=0.02). The demographic and baseline clinical characteristics of the patients are summarized in Table 1. The frequency of hematuria (p=0.62),  hydronephrosis  (p=0.070), stone size (p=0.17)  and concomitant presence of multiple stones (p=0.488) were not differed between two groups. The location of pain was the flank region in 21 (43.8%) patients in morphine sulfate group and 27 (54.0%)  patients in Entonox (p=0.23).
The  pain  scores  after  the  intervention  is  also demonstrated in Table 1. We found that the pain intensity significantly decreased in both study groups. Pain persistence frequencies (at least 50%) at 3-, 5-, 10- and 30-minute intervals in the morphine groupwere 96% (95% CI: 95.9-96.1%), 80% (95% CI: 79.8-80.2),  50% (95% CI: 49.9-50.1)  and 8% (95% CI: 7.95-8.06). While in the Entonox group these values were82% (95% CI: 81.96-82.04), 42% (95% CI: 41.7-42.3), 12% (95% CI: 11.9-12.1) and 2% (95% CI: 1.8-2.2), respectively ( p<0.001, based on long rank test) (Figure 2). There were no significant adverse effects during 2-hour of observation after drug administration. Rescue dose was given in 6 patients (54.6%) in morphine sulfate group and 5 patients (45.4%) in Entonox group ( p=0.72). In the final step, using Cox regression analysis we tried to determine whether any of the baseline characteristics could be responsible for the significant difference between the two groups. As seen in Table 2 and 3, the only factor found to be responsible for this difference was treatment type (HR=2.1; 95% CI: 1.2-3.6; p=0.006).

Fig. 1. CONSORT flow diagram of the study.

 

Table 1. The baseline characteristics and outcome of 100 patients with acute renal colic secondary to urolithiasis receiving morphine sulfate (n=50) or Entonox (n=50) as analgesia.

 

Morphine (n=50)

Entonox (n=50)

p-value

Age (years)

34.7± 8.3

32.1 ± 8.3

0.120

Gender

 

 

 

Men (%)

39 (79.6%)

29 (58.0%)

0.021

Women (%)

10 (20.4%)

21 (42.0%)

 

Smoking (%)

15 (30.6%)

21 (42.0%)

0.211

Multiple stone

14 (29.2%)

11 (22.0%)

0.488

Stone size (mm)

5.98 ± 3.9

7.9 ± 9.0

0.170

Hydronephrosis

 

 

 

Mild (%)

34 (68.0%)

32 (61.5%)

0.070

Moderate (%)

13 (26.0%)

9 (17.3%)

 

Severe (%)

3 (6.0%)

11 (21.2%)

 

VASa score

 

 

 

On admission

9.6 ± 0.8

9.6 ± 0.7

0.94

3-minute after intervention

8.6 ± 1.6

6.4 ± 1.9

<0.001

5-minute after intervention

6.95 ± 2.4

5.3 ± 2.3

0.007

10-minute after intervention

5.0 ± 2.5

3.6 ± 1.8

0.002

30-minute after intervention

2.0 ± 1.8

1.8 ± 1.3

0.525

aVAS: Visual analogous scale

Fig. 2. A  graph representing time intervals of pain relief in patients with renal colic. Treatment failure was defined as no decrease in pain severity to less than 50% or to 50%. Log rank analysis  revealed significant differences between the two graphs (p<0.0001).

 

Table 2. Hazard ratios of treatment failure according to the studied variables in 100 patients with acute renal colic secondary to urolithiasis receiving morphine (n=50) or Entonox (n=50) as analgesics based on univariate Cox regression.

Variable

Classification

Risk Ratio

Confidence Interval

p-value

Treatment type

Morphine

---

---

---

Entonox

2.33

1.5-3.6

<0.0001

Age

20-29

---

---

---

30-30

1.02

0.62-1.7

0.921

40-50

1.01

0.59-1.7

0.950

Gender

Women

---

---

---

Men

1.2

0.75-1.8

0.456

Smoking

No

---

---

---

Yes

1.06

0.36-1.8

0.228

Location of pain

 

1.13

0.97-1.3

0.114

Size of stone

<4 mm

---

---

---

4-9.9 mm

0.73

0.45-1.2

0.222

≤10 mm

0.5

0.24-1.05

0.071

Hydronephrosis

Mild

---

---

---

Moderate

0.6

0.34-1.02

0.071

Severe

0.86

0.4-1.8

0.686

History of stone

No

---

---

---

Yes

0.56

0.32-0.96

0.037

History of hospitalization

No

---

---

---

Yes

0.61

0.34-1.09

0.098

Presence of multiple stones

No

---

---

---

Yes

0.91

0.56-1.5

0.720

Family history of stone

No

---

---

---

Yes

0.91

0.59-1.4

0.684

 

Table 3. Modeling of risk factors of treatment failure in 100 patients with acute renal colic secondary to urolithiasis receiving morphine (n=50) or Entonox (n=50) as analgesics using multivariate Cox regression analysis.

Variable

Classification

Hazard Ratio

Confidence Interval

p-value

Treatment type

Morphine

---

---

---

 

Entonox

2.1

1.2-3.6

0.006

Location of pain

RLQa

---

---

---

LLQb

1.8

0.89-3.6

0.100

Flank

1.3

0.7-2.5

0.392

LLQ/Flank

0.67

0.08-5.8

0.721

Rt, Lt Flank

1.2

0.13-11.0

0.875

LUQ/Flank

3.4

0.64-18.0

0.149

LLQ/Flank

3.8

0.73-19.4

0.112

Size of stone

<4 mm

---

---

---

4-9.9 mm

1.0

0.54-1.9

0.981

≤10 mm

0.35

0.06-2.0

0.238

Hydronephrosis

Mild

---

---

---

Moderate

0.94

0.47-1.9

0.864

Severe

2.7

0.48-15.0

0.263

History of stone

No

---

---

---

Yes

0.7

0.3-1.8

0.470

History of hospitalization

No

---

---

---

Yes

0.7

0.45-1.3

0.627

aRLQ: Right lower quadrant; bLLQ: Left lower quadrant

 

Discussion

Renal colic is one of the most common and painful medical emergencies affecting almost 10% of the world population [1]. With higher recurrence up to 50% after first episode [3,4]. The first priority in renal colic is providing pain control. Non-steroidal anti- inflammatory drugs (NSAIDs) are first-line agent. Opioids  are also  effective  for  pain  killing  faster than NSAIDs in spite of higher incidence of side effects. The combination of NSAIDS and opiates is an acceptable approach may reduce length of stay in the ED [8]. Entonox provides rapid and effective analgesia with less sedation [16].  Entonox may be associated with adverse effects in few patients such as nausea and vomiting, dizziness, dry mouth, buzzing in the ears ranging from 0 to 30 % [8]. Entonox  like as other anesthetic  agents results in nonspecific suppression of the central nervous system. Nitrous oxide (the effective agent in Entonox) contributed to opioid system of the brain particularly medial thalamic area and spinal cord that have a lot of cells sensitive to morphine [13,17]. Entonox efficacy was proved in relieving pain due to colonoscopy, urologic procedures including transrectal ultrasonography-guided prostate biopsy [18-24], extracorporeal shock wave lithotripsy (ESWL), and labor pain [16,25].Some derivatives of this gas relieve pain in fractures, joint dislocations, musculo-skeletal injuries, ulcers and wounds, ureteral colic, acute abdominal pains, myocardial pain and migraine headaches [17]. Entonox can be effective as much as Fentanyl in pain relievingwith similar rate of side effects [12]. There is limited evidence about Entonox efficacyfor renal colic managementin compare to morphine. Mazdak et al. showed inhaled Entonox, decreases pain severity in patients undergoing treatment with ESWL , significantly[16].
Opiod replacing by a safe and effective drug was tried by Bektas et al. which showed intravenous injection of paracetamol (Apotel) is as effective as intravenous injection of morphine for relieving of renal colic [26]. Serinken et al. used parenteral paracetamol not only is an effective and safe intervention for renal colic [27]. There are omparisons between NSAID and opiods which show lower efficacy of NSAID in compared to morphine[28].
The present study, as the first randomized clinical trial on the subject, showed that Entonox is a more effective drug compared to morphine. Although the pain relief score means  were similar  in the two groups at 30-minute interval, the rate of pain relief by Entonox was more than that by morphine. Since there were no significant differences in re- administration  of the  drugs  and  hospitalization between the two groups it can be concluded that similar to other clinical situations, use of Entonox in renal colic is safer, in addition to higher efficacy compared to morphine.
The present study had some limitations. The patients in the emergency ward were administered drugs for only 30 minutes and if they had been followed for a longer period of time, it was possible that different results would have been achieved. However, what is important in renal colic is rapid pain relief. Therefore, the researchers  in the present study believe that evaluation of patients for 30 minutes is sufficient. Finally,  due to ethical considerations  it was not possible to design a control group. Therefore, the morphine group was in fact considered as the control group and the efficacy of Entonox was compared with that of morphine.
In  conclusion,the   present  study  demonstrated that Entonox, in comparison with morphine, is an effective drug in relieving pain in patients with renal colic. It is a fast-acting drug and is very potent in relieving renal colic. Since Entonox has fewer side effects compared to morphine and leads to no drug dependence, it might be used in relieving pain in patients with renal colic. However, further studies are necessary to substantiate the results of the present study.

Conflict of interest: None declared.

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