Article, Emergency Medicine

Comparison of intranasal ketamine versus IV morphine in reducing pain in patients with renal colic

a b s t r a c t

Background: Various drugs have been used to relieve abdominal pain in patients with renal colic. Ketamine is a popular choice as an analgesic.

Objective: To compare the effectiveness of intranasal (IN) ketamine versus intravenous (IV) morphine in reducing pain in patients with renal colic.

Methods: A randomized double-blind controlled trial was performed in 53 patients with renal colic recruited from the emergency department (ED) in 2015. Finally, 40 patients were enrolled in this study. Patients in the ke- tamine group received IN ketamine 1 mg/kg and IV placebo while patients in the control group received IV mor- phine 0.1 mg/kg and IN placebo. Our goal was to assess Visual analogue scale (VAS) changes between the 2 groups. Patients’ VAS scores were reported before and 5, 15, 30 min after drug injection.

Results: Before drug administration, the mean +- SD VAS score was 7.40 +- 1.18 in the morphine group (group A) and 8.35 +- 1.30 in the ketamine group (group B) (P-value = 0.021). After adjustment by the appropriate anal- ysis, the mean +- SD VAS score in group (A) and (B) at 5 min were (6.07 +- 0.47 vs 6.87 +- 0.47; mean difference

-0.79, 95% confidence interval (CI) -1.48 to -1.04) (P-value = 0.025), at 15 and 30 min, the mean +- SD VAS score in group (A) and (B) were (5.24 +- 0.49 vs 5.60 +- 0.49; mean difference -0.36, 95% CI -1.08 to 0.34) and (4.02 +- 0.59 vs 4.17 +- 0.59; mean difference -0.15, 95% CI -1.02 to 0.71) (P-value = 0.304 and 0.719) respec- tively.

Conclusions: IN ketamine may be effective in decreasing pain in renal colic.

(C) 2016

  1. Introduction

Patients’ pain management in the emergency department (ED) is very important and it is usually provided by intravenous (IV) narcotics [1,2]. Intranasal (IN) access is another option which contrary to IV route, is much less invasive and time consuming. One of the most pop- ular drug used IN, is ketamine. IN ketamine is an effective analgesic with minimal cardiovascular impact [2,3]. Its Analgesic dose is less than its sedative dose. It has different routes of administration (IM, IV, IN, SC) [4].

? Trial was registered in www.irct.ir and trial number is IRCT201412208872N8.

* Corresponding author at: Emergency Medicine Research Center, Emergency Medicine Department, Shariati Hospital, Tehran University of Medical Sciences, North Amirabad Street, Tehran, Iran.

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

Ketamine, structurally similar to Phencyclidine (PCP), non-competi- tively blocks N-methyl-D-aspartate receptors. It is said that the function on these receptors are responsible for the analgesic and behav- ioral effects of ketamine [5,6]. Although its main mechanism of action is antagonism of NMDA receptor, it also interacts with Opioid receptors, monoamine, cholinergic and adrenoreceptor systems as well as having local anesthetic effects. It is believed that ketamine’s immediate analge- sic effects are mediated predominantly by a combination of opioid system sensitization and antinociception [7,8]. Ketamine has a sympa- thomimetic activity, thus it will result in tachycardia, hypertension, high myocardial and cerebral oxygen consumption, elevated cerebral blood flow, emergence phenomenon and increased intracranial and in- traocular pressure [5]. Emergence phenomenon is a visual, auditory, proprioceptive or confusional illusion after ketamine wakeup which occurs in approximately 15% of patients and is mild in almost all [5].

Drugs’ IN route is usually administered via nasal devices like muco- sal atomization device which simplify and fasten drugs administration through mucosal membranes.

http://dx.doi.org/10.1016/j.ajem.2016.11.043

0735-6757/(C) 2016

M.R. Farnia et al. / American Journal of Emergency Medicine 35 (2017) 434437 435

Fig. 1. side effects distribution in the 2 groups.

There are many studies which demonstrate the efficacy of IN ketamine in the treatment of severe acute pain.

The dose of 1.5 mg/kg IN ketamine was studied as an acute pain re- liever and it was showed that it could enhance postoperative analgesia after endoscopic nasal surgery [9].

In another research, it was found that 7.5 mg IN morphine and 30 mg IN ketamine, delivered by nasal spray devices, providED analgesia of about 5 mg IV morphine after molar extraction model with acute moderate-to-severe pain [10].

The analgesic effect of 0.5 mg/kg IN ketamine was evaluated in 44 patients, coming to ED in a trauma center, suffering acute pain (Visual Analogue Scale N 5). Conclusion was that IN ketamine might provide rapid and clinically significant analgesia in ED patients [2].

Since there has been no similar study in pain management in renal

colic, this study compares the analgesic effect of IN ketamine versus IV morphine in patients suffering renal stones.

  1. Materials and methods
    1. Participants

The study was approved by the ethics committee of Tehran Univer- sity of medical sciences and it was registered in www.irct.ir with the trial number of IRCT201412208872N8. All patients were required to read informed consent letter and signed it if they accepted to participate in our study. We conducted a prospective, randomized, double-blind and placebo-controlled study (block randomization with block sizes of 4) in patients with renal colic recruited from EDs of Shariati and Imam Khomeini Hospitals, two tertiary referral center, from January 2015 to March 2015. Eligible patients were older than 15 years’ old who pre- sented to the ED because of renal colic pain and they did not need any surgical intervention for their urolithiasis. The diagnosis was confirmed by ultrasound evidence of renal stone and hematuria in Urine analysis. We excluded patients with opioid addiction and prior use of analgesics, pregnancy, history of ketamine or morphine hypersensitivity, nasal oc- clusion, systolic blood pressure (SBP) N 180 or SBP b 90 mm Hg, respira- tory distress, Altered level of consciousness and anyone with no cooperation. The treating emergency physician confirmed diagnosis and contacted the chief investigator. Subjects were randomly divided into two groups of 20 each: a morphine group (A) and a ketamine group (B). Each patient had a code in block randomization, and only the chief investigator and the triage nurse were aware of the assignment and patient’s group. The specified drug and dose were provided by the

triage nurse based on the code and it was injected to the patient by the treating emergency physician who was blinded to the study.

Drug administration

All patients were interviewed and the method of drug administra- tion and VAS (where 10 represented the worst imaginable pain and 0 was pain-free) were discussed to them. During drug administration and follow-up, patients were monitored with Standard monitoring included ECG, pulse oximetry and non-invasive blood pressure cuff. Demographic data including age, sex, past history of renal stone, need for Rescue analgesia and any side effects (e.g., nausea, dizziness, and hypotension or emergence reactions) were collected through a questionnaire by the emergency physician. We chose 1 mg/kg IN ketamine based on its wide range of IN administration mentioned in different studies [2,9]. In group A 0.1 mg/kg diluted IV morphine + IN placebo and in group B 1 mg/kg IN ketamine + IV placebo was administered. Morphine was used as IV bolus.

Primary and secondary endpoints

Patients were requested to express their degree of pain using the VAS score, before, 5, 15 and 30 min after initiation of injection. In case of failure and no decrease in VAS scores in either group after 30 min, fentanyl was administered. The rate of fentanyl infusion was 1-2 ug/kg administered every 5 min and titrated to the effect. Our primary endpoint was changes in VAS score. Adverse reactions and the need for rescue analgesia were our secondary endpoints. The treating emergency physician performed the outcome assessments and monitored the adverse events objectively.

Statistical analysis and sample size calculation

In order to produce 13 mm difference in the mean VAS score, which is considered a Clinically significant change in pain score [2,10], with Power of 80%, CI of 95% and SD of 1.1, a sample size of 20 per treatment group was calculated.

All data were analyzed using SPSS V.22 software. In order to evaluate the normal distribution of quantitative data such as VAS score, we con- ducted a Kolmogorov-Smirnov (KS) test. Analytical statistical tests in- cluded the unpaired, two-tailed t-test for continuous normally distributed data. Because baseline VAS score had significant difference between the two groups before drug administration, we conducted gen- eral linear model (multivariate) ANCOVA analysis (analysis of Covari- ance) on both sample groups in order to adjust the mentioned difference. We used a repeated measures ANCOVA to adjust for both baseline differences and for the repeated measures analysis to adjust for multiple observations within the same individual. All the descriptive data are given as mean +- SD. Variances of the two groups at 5, 15 and 30 min were equal by Levene’s test (P-value = 0.459, 0.860, 0.442 re- spectively). The chi-square and Fisher’s exact tests were used to com- pare proportions of the qualitative variables. Repeated measure ANOVA was used to determine the difference within each group. The level of significance was 0.05. All data had normal distribution between the two groups.

Table 1

Demographic feature of study groups.

Morphine group (N = 20) Ketamine group (N = 20)

Sex

Women

3 (15.0%)

8 (40.0%)

Men

17 (85.0%)

12 (60.0%)

Age, years

34.75 +- 11.71

39.25 +- 10.75

Weight, kg

76.14 +- 10.32

74.10 +- 9.98

History of renal stone

16 (80%)

12 (60%)

436 M.R. Farnia et al. / American Journal of Emergency Medicine 35 (2017) 434437

Table 2

Raw data of the mean value of pain scores in the two groups (before adjustment).

Morphine group (N = 20) Ketamine group (N = 20) Mean difference 95% CI of the difference P-value

Lower

Upper

VAS 0 min

7.40 +- 1.18

8.35 +- 1.30

-0.95

-1.75

-0.14

0.02

VAS 5 min

5.60 +- 1.46

7.35 +- 1.72

-1.75

-2.77

-0.72

0.00

VAS 15 min

4.75 +- 1.40

6.10 +- 1.86

-1.35

-2.40

-0.29

0.01

VAS 30 min

3.55 +- 1.79

4.65 +- 1.72

-1.10

-2.22

0.02

0.05

  1. Results

During the study period 53 patients were diagnosed with renal colic and 13 patients were excluded: five patients had respiratory distress, four had SBP below 90 mm Hg, three had morphine hypersensitivity and one had no cooperation. The remaining 40 patients were randomly divided in to two groups of 20 each (Fig. 1). The mean age ranges of group A and B were similar (34.75 +- 11.71 years and 39.25 +- 10.75 years, respectively). The morphine group included 17 men and 3 women and the ketamine group included 12 men and 8 women. The mean weight ranges of group A and B were similar (76.14 +- 10.32 kg and 74.10 +- 9.98 respectively). Eighty percent of patients in group A and 60% of patients in group B had the history of renal stone. There were no significant differences in the baseline participant charac- teristics. Data are shown in Table 1.

At baseline the mean +- SD VAS scores were 7.40 +- 1.18 in group A and 8.35 +- 1.30 in groupB (P-value= 0.021). Comparison of VAS scores before adjustment is shown in Table 2. In order to adjust the significant difference at baseline, we conducted ANCOVA analysis. The results after adjustment are shown in Table 3. These results showed that at 5 min after drug administration there was significant difference in the mean VAS score and morphine was more effective than ketamine. At 15 and 30 min there was no significant difference between the two groups. The VAS score of 7 patients in group A and 5 patients in group B remained the same after 30 min so fentanyl infusion was started (P-value = 0.37). Using repeated measures ANOVA, within subject groups, mean VAS pain score reduction along frequent intervals after both morphine and ketamine administration had significant difference (P-value = 0.000), thus ketamine also caused significant pain reduction along time.

Comparing side effects, hypotension was seen in 8 patients all in group A, and emergence phenomenon in 6 patients all in group B. All pa- tients had at least one side effect (data shown in Fig. 2).

  1. Discussion

Renal stone is one of the most common presentations in EDs and af- fects near 5-15% of the population all around the world [1]. Pain man- agement in these patients is necessary and most drugs used for this purpose are NSAIDs or narcotics with IM, IV or oral administration. Ke- tamine is most commonly used as analgesic in Acute pain control by dif- ferent routes of administration including IN [11]. A pharmacokinetic study in healthy volunteers calculated the bioavailability of IN ketamine 45%, peak plasma level was seen in b 30 min and terminal half-life was around 2 h [11]. Ketamine can induce apnea, laryngospasm, vomiting, Elevated intracranial pressure and emergence phenomenon. In contrast morphine starts its analgesic effect in b 10 min with peak plasma level of

20 min and its Duration of action is near 4 h. Its usual side effects in- clude: hypotension, nausea, vomiting, respiratory depression and al- tered mental status [5]. The use of Opioid analgesia can suppress respiratory system especially when used in non-monitored bed. Respi- ratory depression and deep sedation have been regarded as the main causes of withholding opioid analgesia [2].

Based on the results of previous studies [9,10], we used the dose of 1 mg/kg IN ketamine in group B via mucosal atomization device. Our study shows that IV morphine provides more considerable analgesic state in patients with renal colic at 5 min after drug administration. Com- paring VAS scores at 15 and 30 min, in the two groups, no significant dif- ference was found. Our results concluded that IN ketamine 1 mg/kg could be effective in reducing renal colic pain but with a delay of 10 min.

Huge et al. showed that IN ketamine’s activity in pain reduction would last for about 3 h [12]. Carr et al. showed that IN ketamine would reach a detectable blood level after 2 min, with a maximum con- centration at almost 30 min. Both of these studies showed that IN keta- mine was effective and its adverse effects were minor and transient.

Successful postoperative pain management trial of IN ketamine was observed in a precedent study. This study tested 10-30 mg of IN keta- mine in acute postoperative pain, molar extraction. Patients reported rapid pain relief with no significant side effects. Integrated pain relief over 1 and 3 h after drug administration was significantly better for ketamine than placebo [13].

Elia and Tramer in 2005 reviewed different modalities of studies working on varying routes of ketamine administration and dosing regi- mens. They found no clinically significant effect on pain scores (VAS) for 48 h after surgery. This study showed that ketamine could decrease opioid dose with no change in opioid-related adverse effects [14].

  1. Limitations of the study

One limitation of our study was that we were not able to determine the plasma level of ketamine to control its analgesic effect. Our sample size was not sufficient to detect the exact drugs’ effects and adverse events. Further clinical trials with larger sample sizes and longer fol- low-up should therefore be performed to identify adverse events. The other limitation was that we did not choose one-time point as our pri- mary outcome, rather we decided to follow VAS score changes along the study over 30 min. Our patient population was homogenous in the 2 centers, thus there may be issues with external validity.

  1. Conclusion

This study shows that IN ketamine might be effective in alleviating pain in patients with renal colic. Adverse effects were seen in both

Table 3

Mean value of pain scores in the two groups done by ANCOVA analysis.

Morphine group (N = 20) Ketamine group (N = 20) Mean difference 95% CI of the difference P-value

Lower

Upper

VAS 0 min

7.40 +- 1.18

8.35 +- 1.30

-0.95

-1.75

-0.14

0.02

VAS 5 min

6.07 +- 0.47

6.87 +- 0.47

-0.79

-1.48

-0.10

0.02

VAS 15 min

5.24 +- 0.49

5.60 +- 0.49

-0.36

-1.08

0.34

0.30

VAS 30 min

4.02 +- 0.59

4.17 +- 0.59

-0.15

-1.02

0.71

0.71

M.R. Farnia et al. / American Journal of Emergency Medicine 35 (2017) 434437 437

Fig. 2. CONSORT flow diagram.

groups. The need for rescue analgesia in ketamine group was less than in morphine group but this observed difference was not statistically significant.

Funding source

We have no funding source.

Author’s contributions

Farnia M; study design, Jalali R; data gathering and study design, Vahidi E; data analysis, Seyedhosseini J; drafting, Momeni M; data gathering and drafting, Saeedi M; critical revision.

References

  1. Ban KMEJ. Selected urologic problem. In: Marx JA, editor. Rosen’s emergency medicine. ELSEVIER; 2014. p. 1336-42.
  2. Andolfatto G, Willman E, Joo D, Miller P, Wong WB, Koehn M, et al. Intranasal keta- mine for analgesia in the emergency department: a prospective observational series. Acad Emerg Med 2013;20(10):1050-4.
  3. Weinbroum AA. Non-opioid IV adjuvants in the perioperative period: pharmacolog- ical and clinical aspects of ketamine and gabapentinoids. Pharmacol Res 2012;65(4): 411-29.
  4. Kronenberg RH. Ketamine as an analgesic: parenteral, oral, rectal, subcutaneous, transdermal and Intranasal administration. J Pain Palliat Care Pharmacother 2002; 16(3):27-35.
  5. BG K. Anesthetic agents Basic & clinical pharmacology, 1. England: Mc Grawhill; 2010 345-7.
  6. Carr DB, Goudas LC, Denman WT, Brookoff D, Staats PS, Brennen L, et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study. Pain 2004;108(1-2):17-27.
  7. Persson J. Wherefore ketamine? Curr Opin Anaesthesiol 2010;23(4):455-60.
  8. Jamie Sleigha MH, Vossa L, Dennyc B. Ketamine – More mechanisms of action than just NMDA blockade. Trends Anaesth Crit Care 2014;4(2-3):76-81.
  9. Hala SG-A, Salem MA. Safety and Analgesic efficacy of pre-emptive intranasal keta- mine versus Intranasal fentanyl in patients undergoing endoscopic nasal surgery. J Am Sci 2012;8:430-6.
  10. Edward Liao FM, Wright C, et al. Relative Analgesic Potencies of Intranasal Ketamine and Intranasal Morphine Compared to Intravenous morphine. American Academy of pain medicine Orlando. Am Acad Pain Med February 13-16, 2008.
  11. Pamela E, Macintyre DAS, et al. acute pain management. 3 ed. New Zealand: ANZCA;

2010.

  1. Huge VLM, Mageri W, et al. Effects of loe dose intranasal (S)-Ketamine in patients with Neuropathic pain. Eur J Pain 2010;14:387-94.
  2. Dr Daniel B JP, Inc. Safety and Efficacy of Intranasal Ketamine for Acute Pain. Acute

Pain 2007:183-236.

  1. Elia N, Tramer MR. Ketamine and postoperative pain-a quantitative systematic review of randomised trials. Pain 2005;113(1-2):61-70.

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