Uncategorized

Sub dissociative dose of ketamine with haloperidol versus fentanyl on pain reduction in patients with acute pain in the emergency department; a randomized clinical trial

Journal logoUnlabelled imageAmerican Journal of Emergency Medicine 54 (2022) 165-171

Contents lists available at ScienceDirect

American Journal of Emergency Medicine

journal homepage:

Sub dissociative dose of ketamine with haloperidol versus fentanyl on pain reduction in patients with acute pain in the emergency department; a randomized clinical trial

Mohammad Matin Moradi, Mohammad Mobin Moradi, Arash Safaie, Alireza Baratloo, Pooya Payandemehr ?

Prehospital and Hospital emergency research Center, Tehran University of Medical Sciences, Tehran, Iran

a r t i c l e i n f o

Article history:

Received 11 January 2022

Received in revised form 25 January 2022 Accepted 2 February 2022

Keywords:

Emergency department Pain management Ketamine

Haloperidol Fentanyl

a b s t r a c t

Background: Ketamine is known to be an effective factor in reducing pain without significant side effects. Objective: One of the limited side effects of Ketamine is agitation. Due to the reduction of this symptom with Hal- operidol, we decided to design a randomized clinical trial to compare the analgesic effect of Ketamine with Hal- operidol and Fentanyl in reducing acute pain and its complications.

Methods: In this study, 200 adult patients who presented to the emergency department with acute pain are ex- amined. They are randomly divided into two groups. One group received intravenous Ketamine with Haloperidol and the other group received Intravenous fentanyl. Patients are then compared for their pain score before and after administration of the drugs, as well as the side effects they experienced.

Results: There was no significant difference between the mean scores of initial pain in the two groups, but at all intervals of 5, 10, 15 and 30 min after injection, the mean of pain scores of patients in the group receiving Keta- mine and Haloperidol were lower. The need for injection of rescue analgesic was 9% in the Ketamine and Halo- peridol group and 34% in the Fentanyl group. The mean agitation score did not differ between the two groups except in the tenth minute. At tenth minute, the mean agitation score of the Ketamine group was higher.

Conclusion: Ketamine works better than fentanyl in controlling acute pain, and limited side effect of agitation can be controlled if injected with haloperidol. Due to its better function and fewer side effects, it seems that in con- trolling acute pain, Ketamine along with Haloperidol can be a good alternative to opioids.

(C) 2022

  1. Introduction

Pain is one of the most common complaints of patients presenting to emergency departments (ED). Providing effective, safe, and durable an- algesia is a key component in pain management. For a long time, opioids have been considered as the first choice in this regard. But due to their considerable side effects, researchers are trying to find the alternatives, and ketamine, in particular, has attracted a lot of attention. Various trials have evaluated the Analgesic effects of ketamine in acute pain management in specific group of patients. Some studies have shown that ketamine has strong analgesic effects at its sub dissocia- tive doses (usually between 0.1 and 0.6 mg per kilogram and in most cases 0.3 mg per kilogram of patient weight). (1) Previous studies have used it for a specific group of patients, such as renal colic and

Abbreviations: emergency departments, (ED); intravenous, (IV); Numerical Rating Scale, (NRS).

* Corresponding author.

E-mail addresses: [email protected] (A. Safaie), [email protected] (A. Baratloo), [email protected] (P. Payandemehr).

trauma. One study showed sub-dissociative dose of intravenous

(IV) ketamine is as helpful as ketorolac in pain management in renal colic patients. (2) Also another study shows ketamine is a an effective medication in prehospital pain management for trauma pa- tients and can be considered as an alternative to opioids. (3) How- ever, one of the side effects of ketamine is agitation following administration of the drug. This complication is one of the limiting factors for physicians prevent using ketamine in their daily basis and still prefer opioid over ketamine. It should be mentioned that in sub dissociative doses, this side effect is rare and can be treated using benzodiazepines or haloperidol. (4)

Efficacy of sub-dissociative dose of ketamine in terms of pain management has been demonstrated in specific group of patients, but not as a choice in all types of pain in the ED. Therefore, we per- formed this trial to assess the efficacy of IV administration of sub dis- sociative dose of ketamine in combination with IV haloperidol compared with IV fentanyl in acute pain management in our ED. Our hypothesis was that this combination has no less analgesic ef- fects than IV fentanyl in controlling acute pain, and even has fewer side effects than IV fentanyl.

https://doi.org/10.1016/j.ajem.2022.02.012

0735-6757/(C) 2022

  1. Methods
    1. Study design

Z + Z 2 x S2 + S2

n = 2 x

1-?

1-a

1

2

1

(d? 2

1-f

This study was a non-inferiority double-blind randomized clinical trial and was performed on human samples (Fig. 1). The study proposal was approved by ethics committee and also registered in Iranian regis- try of clinical trials.

registration number: (IRCT20200608047684N1), date of first regis- tration: 30 July 2020 The investigators were fully adhered to Helsinki Principles, and informed consent was received from the participants or their legally authorized representative.

    1. Study population

In this study, adult patients who presented to the ED with acute pain were studied. Any adult patient (age > 18 years) admitted with acute mod- erate to severe; pain score above 5 (i.e. 6-10) who neED analgesia were in- cluded. The exclusion criteria were pregnancy and post-partum women, altered mental status, known allergy to ketamine or fentanyl, also unstable vital signs (SBP <= 90 mmHg or >= 180 mmHg; HR >= 150 or <= 50 beats/min; RR <= 10 or >= 30), history of recent eye trauma, history of seizure, chronic pain syndrome, renal or hepatic failure, substance or alcohol abuse, docu- mented psychiatric disorders, and recent use of narcotic analgesics.

    1. Sample size

According to the results of the study by Motov et al. (5) the sample size was calculated based on the amount of pain based on the measure- ment criteria of 0 to 10.

| |)

? = first type error = 5%.

-1? = power = 80%.

S1 = standard deviation IN ketamine group therapy = 2/3. S2 = standard deviation in fentanyl group therapy = 2/3.

d = Maximum tolerable difference that is not clinically significant = 1/5.

? = observed difference between these two methods = 0/2. F = probability of losing samples = 0/05.

N = Minimum sample required in each group = 100

    1. Randomization and blinding

In this study, the patient is blinded. To observe the principle of blind- ness in this study, the researcher and the person recording the pain score are both blinded to the study drug. A person not involved in the study or patient care maintained the randomization list and prepared the medica- tions for the study participants in a blinded manner. A convenience sam- ple of patients was enrolled between July 2020 and October 2020. In our ED a study investigator was available for patient enrollment and a phar- macist was available for medication preparation. Each group received the same number of injections to ensure that the patient was blinded.

    1. Data collection

Pain score obtained according to NRS, patients were initially asked to rate their pain intensity out of ten (i.e. 0-10). Any patient who gave pain

Fig. 1. Flow of study subjects.

more than five points was entered to the study, we excluded individuals according to study exclusion criteria. The initial score of each patient is recorded in the patient information collection form. Each patient’s form is patient-specific and include demographic information, pain intensity, agitation score based on the Richmond Agitation Sedation Scale, vital signs at the time of admission and at scheduled times and, the patient’s need for Rescue analgesia is also recorded.

    1. Interventions

In one group, 2.5 mg of haloperidol (UpToDate) with ketamine at a sub dissociative dose (0.3 mg per kg body weight) administered IV. In the other group IV fentanyl (with a dose of 1 ug per kilogram of patient weight) was injected. (UpToDate).

    1. Outcome measures

After injecting the study medications, the patient is asked about the severity of pain at 5,10,15,30 min intervals after injection, and his/her scoring is recorded. At the same time intervals, the patient’s vital signs and agitation score are taken and recorded. Finally, the data from the study are summarized and analyzed and the analgesic effect, as well as the incidence of side effects of drugs such as changes in respiration and heart rate and the occurrence of agitation (score above zero in the Rich- mond scale) in adult patients complaining of acute pain are compared.

To examine pain, we used a verbal numerical rating scale; upon ar- rival, the patient was asked about the pain, then he was told what score he gives to the pain out of 10 (i.e. 0-10), zero is painless and 10 is the most severe pain he has ever experienced. To evaluate the effec- tiveness of two drugs in reducing pain was zeroing the patient’s pain score. And for patient satisfaction, as in the study of Motov et al. (5), we considered reducing the pain score below 5 (i.e. 0-4) as a measure of the satisfaction of the analgesic effect.

To analyze the incidence of agitation according to the score obtained from the Richmond scale, the mean change of agitation score within each group at 5, 10, 15, and 30 min after injection.

    1. Rescue medicine

If after ten minutes of ketamine with haloperidol or fentanyl injec- tion the patient continues to have a pain score above five; Morphine (0.1 mg per kg body weight) will be given intravenously as rescue anal- gesia.

    1. Statistical analysis

SPSS software version 26 was used for data analysis. Chi-square test was used to compare qualitative variables between the two groups, such as the need for rescue analgesic, and independent t-test was used to compare quantitative variables, such as pain intensity reduction in the two groups. Pair t-test was used to compare changes in vital signs and pain intensity within each group. P-value less than 0.05 was consid- ered statistically significant.

  1. Results
    1. Characteristics of the study subjects

Totally, 200 patients enrolled in this study of whom 139 (69.5%) cases were male. The mean age of the patients was 40.26 +- 14.36 years in a range of 18-90 years. The mean score of initial pain in all pa- tients was 8.63 +- 1.38 points in the range of 6 to 10 points. Baseline characteristics of the patients in the two study groups are presented in Table 1. Based on the findings, in the age, sex, and initial pain score var- iables, there were no significant difference between the two groups (p– value = 0.553, p-value = 0.647, p-value = 0.108). The chi-square test

Table 1

Baseline characteristics of the patients in the two study groups

Variable

Ketamine-Haloperidol

Fentanyl

P-value

Number (%) / mean +- SD

Age

39.65 +- 13.07

40.86 +- 15.59

0.553

Sex

Male

68

71

0.647

Female

Chief complaint

Orthopedic trauma

32

45

29

37

0.945

Abdominal pain

11

13

Renal colic

17

19

Low back pain

10

12

Headache

6

8

Surgical site pain

6

5

Stab wound

Pain score on admission

mean

5

8.79 +- 1.372

6

8.46 +- 1.382

0.108

6

8

10

7

15

17

8

13

26

9

18

11

10

46

36

was used to examine the variable chief complaint (Table 1), which based on the results, the difference in chief complaints between the two groups was not significant (p = 0.945).

    1. Main results
      • Pain

Pain scores of the two groups were normally distributed and inde- pendent t-test was used to compare the mean scores. In the results, at 5, 10, 15, and 30 min after injection, the mean pain score was signifi- cantly different in both groups (p < 0.001) and in these time periods, the mean pain score of the ketamine-haloperidol group was lower than the fentanyl group (Table 2).

The ratio of pain to zero score – painless – between patients in the two groups at 5 and 10 min after injection was evaluated by chi- square test, and at these two times when people received ketamine- haloperidol compared to fentanyl, we found that ketamine is signifi- cantly more analgesia. Tables 3 shows the analgesia ratio in the two groups at 5 and 10 min and the results of the chi-square test.

      • Satisfaction

We used the chi-square test to compare the satisfaction ratio (pain score 0-4 following drug administration) between the two groups at 5, 10, 15, and 30 min after injection. This satisfaction ratio was higher in the ketamine-haloperidol group, based in all periods (p < 0.001). In these 4 time periods, the Satisfactory rate of pain reduction between both groups was significantly different (Fig. 2).

      • Agitation

Agitation scores of the two groups were normally distributed. To an- alyze the incidence of agitation according to the score obtained from the

Table 2

Mean and standard deviation of pain score for all 4 time periods

Time

Ketamine-Haloperidol

Fentanyl

P-value

Mean +- SD

5th min

2.34 +- 3.03

5.55 +- 2.44

<0.001

10th min

1.54 +- 2.62

4.48 +- 2.43

15th min

1.47 +- 2.34

3.79 +- 2.49

30th min

1.60 +- 2.49

3.57 +- 2.52

Table 3

The painless ratio in the 5th and 10th minute after receiving the drug in both groups

Table 4

Mean and standard deviation of agitation score for all 4 time periods

Time

Response

Ketamine-Haloperidol

Fentanyl

P-value

Time

Ketamine-Haloperidol

Fentanyl

K

F

Frequency (%)

Mean +- SD

P-value

5th min

Painless

54

6

< 0.001

5th min

-0.06 +- 0.56533

0.05 +- 0.21904

0.291

0.025

Painful

46

94

10th min

-0.02 +- 0.42593

0.05 +- 0.21904

0.640

0.025

10th min

Painless

67

11

< 0.001

15th min

0.06 +- 0.31205

0.06 +- 0.27780

0.057

0.033

Painful

33

89

30th min

0.06 +- 0.27780

0.06 +- 0.27780

0.033

0.033

Richmond scale, the mean change of agitation score within each group in 5, 10, 15, and 30 min after injection was examined and paired t-test was used. In the fentanyl group, the mean agitation score in all time pe- riods was lower than the mean agitation score at the time of arrival and the difference score was significant (p < 0.05).

In the ketamine-haloperidol group, the mean agitation score at the

5th and 10th minute was higher than the mean agitation score at the ar- rival time, but at 15 and 30 min after injection, the mean of these scores had decreased. We used paired t-test to evaluate the significance of the mean differences (Tables 4). The results showed that the difference be- tween the mean agitation score at the arrival time and the agitation score at 5, 10 and, 15 min was not significant, but the decrease in the mean score in the 30th minute compared to the arrival time was signif- icant (p-value = 0.033).

Due to the consideration of “agitation” for a score above zero in the Richmond scale, patients were evaluated with the chi-square test for the incidence ratio of agitation. In the ketamine-haloperidol group, study medication significantly (at p = 0.00 and p = 0.17) caused more agitation at 5 and 10 min after injection. The agitation score had the same distribution in both groups upon arrival.

      • Rescue analgesia

To compare the need for rescue analgesia; Chi-square test was used. Of the 100 samples that received ketamine-haloperidol; 9 people needed morphine injections as rescue analgesics, and of those 100 in the fentanyl group, 24 needed rescue analgesics. In the chi-square test, the difference between the need for rescue analgesia in both groups was significant. (p-value = 0.04, Pearson Chi-Square = 8.165). Fig. 3 shows the ratio of the need for rescue analgesia in both groups.

      • Vital signs

The comparison of the mean arterial pressure at arrival time and in 5, 10, 15 and 30 min after injection. Shows, fentanyl had reduced the mean arterial pressure at all times after injection and this difference was sig- nificant at all time intervals (p-value <0.05). In the ketamine group, the mean arterial pressure at all time intervals increased. But this

mean difference was significant only in 10th minute (p-value = 0.014). Fig. 4 shows the change in mean arterial pressure between both groups at different times.

Respiration rate and heart rate in each group were examined by pair t-test. In the ketamine-haloperidol group, the difference between mean respiratory rate and heart rate at arrival time and intervals of 5, 10, 15, and 30 min was not significant. But in the fentanyl group, the mean heart rate and respiration rate had decreased compared to the arrival time at all intervals, and the difference was significant. (Fig. 5, Fig. 6).

The side effects we observed in patients who entered the study; in ketamine-haloperidol group, we saw five case of vomiting and four case of emergence phenomenon, and in the fentanyl group, we had two case of apnea.

  1. Discussion

Based on the findings of current study, we found that combination of sub-dissociative dose of ketamine plus haloperidol has no fewer analge- sic effects than IV fentanyl in controlling acute pain, and has no life- threatening side effect.

Several studies have assessed the analgesic effects of low-dose (sub dissociative dose) of IV ketamine. For example, Motov et al. (2015) con- ducted a study comparing the analgesic effects of sub dissociative IV ke- tamine versus morphine. They reported that ketamine at 15 and 30 min after the injection has the same effects as morphine; and the proportion of patients who had pain relief in the 15th minute (painless) was more frequent in the ketamine group than in the morphine group. (5) Con- trary to Motov’s study, the pain score reduction was not the same in the two groups we studied, in all time periods the mean pain score in the ketamine-haloperidol group was lower than the fentanyl group and this difference was significant. In other words, the combination of ketamine-haloperidol has been better than fentanyl in reducing pain scores. (Fig. 7).

Also, in our study, the rate of pain relief (zero pain scores) in the ke- tamine group at 5 and 10 min after injection was more frequent than the fentanyl group. In the fifth minute, 54 out of 100 people who re- ceived ketamine-haloperidol scored zero for pain, but in the fentanyl group, 6 patients scored zero for pain. In the 10th minute, 67 people in the ketamine-haloperidol group and 11 people in the fentanyl

100

90

80

70

60

50

40

30

20

10

0

K5 K10 K15 K30 F5 F10 F15 F30

25

15

11

15

72

51

37

33

89

85

85

75

67

63

49

28

100

90

80

70

60

50

40

30

20

10

0

91

Ketamine Fentanyl

76

24

9

Satisfying Unsatisfying

Fig. 2. Satisfactory rate of pain reduction in all time periods.

No need for rescue analgesic need for rescue analgesic

Fig. 3. Frequency of rescue analgesic in the fentanyl and the ketamine-haloperidol groups.

101

MEAN ARTERIAL BLOOD PRESSURE

100

99

98

97

96

95

94

93

92

91

UP ON AR R I VAL 5 T H M I NUT E 10T H M I NUT E 15T H M I NUT E 30T H M I NUT E

TIME INTERVALS

Fig. 4. Changes in mean arterial blood pressure.

group claimed to be pain-free. The ratio of pain-free people to people with pain in both groups in these two time periods was assessed by chi-square test and in both stages was significant. Similar results were obtained at 15 and 30 min after injection, but due to receiving the rescue analgesia in some patients, analysis of analgesia was not performed in these two time periods.

In a retrospective study by Motov et al., patients who presented to an ED with a complaint of acute and chronic pain over a 7-year period from 2010 to 2016 and received a sub dissociative dose of ketamine, was ex- amined. In 362 patients, ketamine was recognized as an effective emer- gency analgesic for acute and chronic management. One of the important results of this study was a significant reduction in the need for rescue analgesia in ketamine recipients compared to patients receiv- ing fentanyl. Similar results were obtained in our study. Patients in each group whose pain did not reach the desired level (score below 5) re- ceived IV morphine as rescue analgesia. Only nine in the ketamine- haloperidol group needed rescue analgesia, compared with 24 in the

fentanyl group. These ratios were examined in the chi-square test and were significant. (6)

In a 2014 study by Miller et al., they compared the analgesic effects

of low-dose ketamine (0.3 mg/kg) with morphine (0.1 mg/kg) on acute emergency pain. Fifty-five patients participated in this project, of whom 21 patients received morphine and 24 patients received keta- mine. The time to achieve maximum pain relief was 5 min in the keta- mine group and 100 min in the morphine group. Vital signs, side effects, and satisfaction were similar in both groups. They concluded that low-dose ketamine did not reduce pain intensity more than mor- phine, but its analgesic effect occurred rapidly within 5 min after injec- tion and lasted for an average of up to 2 h. The result of their study was that the pain score in the ketamine group reached its minimum in 5 min while in the morphine group it occurred in 100 min. (7) Also in our study, the ketamine-haloperidol group reached the lowest pain inten- sity earlier, with the lowest mean pain score at 10 min, but the fentanyl group reached the lowest mean pain score at 30 min. We did not

Fentanyl Ketamine

90

88

86

84

PULSE RATE

82

80

78

76

74

72

70

UP O N AR R I V AL 5 TH M I N UTE 1 0 TH MI N UTE 1 5 TH MI N UTE 3 0 TH MI N UTE

TIME INTERVALS

Fig. 5. Changes pulse rate.

17

16.5

16

RESPIRATION RATE

15.5

15

14.5

14

13.5

13

12.5

12

Fentanyl Ketamine

UP O N AR R I V AL 5 TH MI N UTE 1 0 TH MI N UTE 1 5 TH MI N UTE 3 0 TH MI N UTE

TIME INTERVALS

Fig. 6. Changes in respiration rate.

evaluate patients for more than 30 min, but according to the results of Miller’s study, the maximum effect time of morphine is likely to appear after 30 min.

In the study of Majidi Nejad et al., the analgesic effects of ketamine at a dose of 0.5 mg/kg and morphine at a dose of 0.1 mg/kg in long bone fractures were compared. In that study, 100 people were tested, and it was finally concluded that both drugs were successful in reducing pain, and neither of them worked better in reducing patient’s pain, but the incidence of unpleasant side effects such as agitation and hallu- cinations was higher in the ketamine group. (8)

In another study conducted retrospectively by Lester et al., pain re- lief with low-dose ketamine was evaluated in people who presented to the ED with acute pain. One of the important results of this study was the better effectiveness of ketamine in reducing pain scores com- pared to other drugs in addicted people. (9).

In a 2014 study by Beaudoin et al., they compared the analgesic ef- fects of a combination of ketamine and morphine at two different sub dissociative doses with morphine alone. Ketamine was injected at two doses of 0.3 and 0.15 mg/kg body weight and morphine was injected at a dose of 0.1 mg/kg body weight. The results showed a significant

reduction in pain intensity in more than 50% of patients receiving the combination of morphine and ketamine. In addition, they reported de- creased heart rate, decreased mean arterial pressure, and respiratory rate as morphine side effects. These side effects were not seen in pa- tients who received ketamine alone, but agitation and hallucinations were more common in the group who received ketamine alone and Side effects of ketamine at higher doses were evident. (10) In this case, the results of our study were not much different from the results of other researchers. None of the complications and problems with hy- potension on fentanyl injection and hypertension on ketamine injection were problematic for patients.

Regarding the respiration rate and heart rate, as in the results of the study of Motov et al. (6) in our study, it was concluded that injectable ketamine has no effect on the respiration rate and heart rate in any in- tervals. In the fentanyl group, using paired t-test, the mean respiration rate in 5, 10, 15, and 30 min was compared with the mean respiration rate before drug injection. The mean difference was significant in all time periods; fentanyl reduces heart rate and respiration rate. In two of the people who received fentanyl, we had to administer oxygen due to decreased respiration rate and Arterial oxygen saturation.

Image of Fig. 710

9

8

Mean pain score

7

6

5

4

3

2

1

0

Upon arrival 5th minute 10th minute 15th minute 30th minute

intrvals

Fentanyl Ketamine-haloperidol

Fig. 7. Comparative linear graph of the decrease in the mean pain score.

In a 2013 study by Richard and Rockford, 24 patients were evaluated for their response to sub-dissociative ketamine. Overall, patients’ pain scores decreased from 5 to 3.9, although 18 patients (75%) had received opioid analgesics before ketamine. Besides, 55% of patients were satis- fied with the analgesic effects of ketamine at this dose, and 67% of them stated that they would choose ketamine again in the future. We did not ask patients about their choices for the future, and of course, we have no findings in this regard, but in the ketamine group, several patients who had experience with opioids in previous visits were ad- mitted after receiving the drug that they preferred ketamine in similar situations. (11)

Ghate et al. accomplished a systematic review and meta-analysis comparing low-dose ketamine with opioids in patients with acute pain in the ED. A total of 609 patients were included. The main result was the change in patient-reported pain scores 30 min after injection. Both low-dose ketamine and morphine were shown to provide some level of analgesia, but no significant difference was determined between the two groups. The study also announced rates of neuro-psychological adverse events in the ketamine group were 15.4% and in the opioid group were 4.4% (Neuro-psychological events were explained as agita- tion, dysphoria, confusion, and hallucination). (12)

Karlow et al. A meta-analysis that compared sub-dissociative dose of ketamine with a single intravenous dose of opioid. A total of 261 pa- tients in the ED. Because of heterogeneity in pain assessment timing and the methods and other events, adverse events were described as raw data. Ketamine was related to a higher rate of adverse events than morphine in all of the individual studies. But the only acute life- threatening adverse event was decreased oxygen saturation, which was reported ina patient in the opioid groups. (13)

  1. Limitations

We did not evaluate or record the duration of analgesia in this study. And due to the injection of rescue analgesia, the evaluation of pain score and other variables in the recipients of rescue analgesia decreased in ac- curacy and inconsistent data were entered into the study. Also, opioid analgesic effect is highly dependent on tolerance.

The major limitation was obtaining informed consent because peo- ple were in pain when entering the ED and it was difficult to establish a proper relationship to obtain consent.

This study was accomplished between two groups of small samples of patients at a single ED with various conditions requiring emergency management. We believed that it was better to include more patients with a diversity of acute pain conditions. Because of the small sample size, clinical diagnoses were not distributed evenly among both groups. This could cause invalidation if some painful states were more or less sensitive to ketamine or fentanyl.

It was hard to maintain the blind because a person in ketamine with haloperidol group (possibly more awake, possibly with nystagmoid eye movements) would look different than someone who is in fentanyl group (sleepy, miotic pupils, drop in respiratory rate and blood pres- sure).

  1. Conclusion

Ketamine works better than fentanyl in controlling acute pain, and limited side effect of agitation can be controlled if injected with haloper- idol.

Due to the absence of fatal complications such as respiratory failure and the lack of need for monitoring, injection of ketamine with haloper- idol can be used as one of the safest and most appropriate sedatives in the ED. By examining and discussing ketamine disadvantages and ad- vantages compared to fentanyl, it may be possible to determine the in- dications for its prescription more accurately, but according to our findings, in situations where the patient’s pain is severe (score 8 and above) and unbearable, it is recommended to use the ketamine- haloperidol combination as emergency analgesic. Ketamine and halo- peridol can also be used in cases where opioids are contraindicated. Ke- tamine can replace opioids in the future due to its speed of effectiveness, greater sedative power, and no dangerous side effects.

CRediT authorship contribution statement

Mohammad Matin Moradi: Conceptualization, Data curation, Pro- ject administration, Writing – original draft, Visualization, Writing – re- view & editing. Mohammad Mobin Moradi: Data curation, Formal analysis, Writing – original draft. Arash Safaie: Investigation, Validation. Alireza Baratloo: Resources, Software, Supervision, Validation, Funding acquisition. Pooya Payandemehr: Conceptualization, Methodology, Re- sources, Supervision, Validation.

References

  1. Drake AB, Milne WK, Carpenter CR. Hot off the press: subdissociative-dose ketamine for acute pain in the emergency department. Acad Emerg Med. 2015;22(7):887-9.
  2. Sotoodehnia M, Farmahini-Farahani M, Safaie A, Rasooli F, Baratloo A. Low-dose in- travenous ketamine versus intravenous ketorolac in pain control in patients with acute renal colic in an emergency setting: a double-blind randomized clinical trial. Korean J Pain. 2019;32(2):97-104.
  3. Yousefifard M, Askarian-Amiri S, Rafiei Alavi SN, Sadeghi M, Saberian P, Baratloo A, et al. The efficacy of ketamine administration in prehospital pain management of trauma patients; a systematic review and meta-analysis. Arch Acad Emerg Med. 2020.;8(1):e1.
  4. Akhlaghi N, Payandemehr P, Yaseri M, Akhlaghi AA, Abdolrazaghnejad A. Premedication with midazolam or haloperidol to prevent recovery agitation in adults undergoing procedural sedation with ketamine: a randomized double-blind clinical trial. Ann Emerg Med. 2019;73(5):462-9.
  5. Motov S, Rockoff B, Cohen V, Pushkar I, Likourezos A, McKay C, et al. Intravenous subdissociative-dose ketamine versus morphine for analgesia in the emergency de- partment: a randomized controlled trial. Ann Emerg Med. 2015.;66(3) 222-9.e1.
  6. Motov S, Drapkin J, Likourezos A, Doros J, Monfort R, Marshall J. Sub-dissociative dose ketamine administration for managing pain in the emergency department. World J Emerg Med. 2018;9(4):249-55.
  7. Miller JP, Schauer SG, Ganem VJ, Bebarta VS. Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial. Am J Emerg Med. 2015;33(3): 402-8.
  8. Majidinejad S, Esmailian M, Emadi M. Comparison of intravenous ketamine with morphine in pain relief of long bones fractures: a double blind randomized clinical trial. Emerg (Tehran). 2014;2(2):77-80.
  9. Lester L, Braude DA, Niles C, Crandall CS. Low-dose ketamine for analgesia in the ED: a retrospective case series. Am J Emerg Med. 2010;28(7):820-7.
  10. Beaudoin FL, Lin C, Guan W, Merchant RC. Low-dose ketamine improves pain relief in patients receiving Intravenous opioids for acute pain in the emergency depart- ment: results of a randomized, double-blind, clinical trial. Acad Emerg Med. 2014; 21(11):1193-202.
  11. Richards JR, Rockford RE. Low-dose ketamine analgesia: patient and physician expe- rience in the ED. Am J Emerg Med. 2013;31(2):390-4.
  12. Ghate G, Clark E, Vaillancourt C. Systematic review of the use of low-dose ketamine for analgesia in the emergency department. Cjem. 2018;20(1):36-45.
  13. Karlow N, Schlaepfer CH, Stoll CRT, Doering M, Carpenter CR, Colditz GA, et al. A sys- tematic review and meta-analysis of ketamine as an alternative to opioids for acute pain in the emergency department. Acad Emerg Med. 2018;25(10):1086-97.