Pain is one of the most common causes of emergency department (ED) admission, yet it remains inadequately managed despite the availability of a number of analgesics.1,2 Although it is widely recognized that severe pain is very common in EDs, studies have shown that up to 70% of patients do not receive analgesics during their stay in the ED.3,4 Moreover, it has been observed that pain treatment is often delayed in the ED; in general, it is started after the clinical examination or at the end of the diagnostic investigation.4,5 The average waiting time is estimated to range from 70 to 90 minutes before the first administration of analgesia, with a dose often insufficient to relieve patients’ discomfort.4–6 For all these reasons, patients presenting at the ED remain largely dissatisfied.7,8 Over the past 2 decades, medical societies have sought to initiate recommendations to improve the treatment of pain.9 Efforts aiming to improve the quality of pain management resulted in the widespread use of opioid analgesics. In fact, their overall consumption increased 5-fold and their use in EDs increased by >60%.10,11 Moreover, available data suggest a strong correlation between the frequency of opioids prescriptions and deaths from opiate use or abuse.12 Severe adverse events such as hypoxia and hypotension are known to be associated with opioid use in particular when they are administered repeatedly to patients with acute pain. One possible key strategy to decrease the need for rescue opioid prescriptions in the EDs is the early use of opioid-sparing analgesics within the triage process.13,14 With regard to its analgesic effects, ketamine, especially through the intranasal route, can be considered as an appropriate alternative opioid-sparing drug in ED. The aim of this study was to evaluate the impact of early administration of low-dose intranasal ketamine in acute moderate to severe pain, in the ED, on reducing opioids requirement.
PATIENTS AND METHODS
Patients and Study Design
This was a multicenter, randomized and controlled, a double-blind trial carried out in EDs of 3 University Hospitals (Fattouma Bourguiba University Hospital of Monastir, Sahloul University Hospital and Farhat Hached University Hospital of Sousse), over a 2-year period extending from January 2018 to December 2018. The study population consisted of patients who presented to the ED with acute limb trauma pain with a visual analog scale (VAS) ≥50 (the scale ranged from 0 if no pain to 100 for a maximum of pain) having given their informed consent to participation at the triage area. Doctors performed the triage process. Pain is described as moderate when the VAS is between 50 and 60, and as severe pain when the VAS is ≥70.
Excluded from this study were all patients aged under 18 or over 80 years. Hemodynamic instability defined as systolic blood pressure <90 mm Hg or the need for vasoactive drugs, neurological distress (Glasgow Coma Score <15), and respiratory distress (pulse saturation <94%) were exclusion criteria. Weight values <46 kg or >115 kg were also considered as exclusion criteria. Patients with a medical history of acute head or eye injury, seizure, intracranial hypertension, chronic pain, hepatic impairment were excluded. Alcohol or drug abuse, recent (4 h before) analgesic agent use, an inability to assess pain intensity according to the VAS, or a contraindication or an allergy to the treatments used were exclusion criteria. Pregnant or breast-feeding women were excluded from the study. We also excluded from this study all patients whose data were incomplete or inaccurate. Demographic data were recorded prospectively. They included age, sex, medical history, the reason for consultation, and the type of pain. Clinical data recorded at ED admission included VAS, temperature, systolic and diastolic blood pressure, heart rate, and pulse oxygen saturation.
Patients were stratified according to centralized randomization. Patients were randomly assigned (1:1) to the intervention arm or placebo arm by a computerized randomization system run by one of the principal investigators not involved in any other portion of the conduct of the trial. To maintain allocation concealment, assignments were placed in consecutively numbered, sealed opaque study packets in the ED and only opened once a patient is deemed eligible. Blinded study labels in the study packets were affixed to the study drug pump. The randomization assignment was sealed in a separate envelope in the study packet and stored. Randomization tables and all unblinded study documents were maintained by the principal investigators. The preparation of the medication was done by an investigator not involved in the randomization process or in the data record or analysis. The drug and placebo were administered in similar volumes with identical administration procedures. The participants, treating physicians, and nurses remained blinded to the group allocation and to the received medication.
The study drug was formulated with a ketamine solution of 250 mg/5 mL. It was applied intranasally using a nasal spray opaque pump where each spray delivered ~0.5 mL of solution corresponding to 25 mg of ketamine. In the triage area, each patient having the inclusion criteria receives 1 pulverization (0.5 mL) per nostril of ketamine or normal saline solution according to the predetermined randomization list. Included patients were followed and monitored until their discharge from the ED. All enrolled patients underwent close supervision of study staff to ensure safety. Study investigators record VAS and adverse effects at 15, 30, 60, 90, and 120 minutes and at ED discharge. During ED stay, patients were monitored to evaluate the need for rescue analgesic treatment. Intravenous morphine titration was used as a rescue analgesic if patients report a VAS score of ≥70. It was administered at a dose of 10 mg that was diluted in 10 mL of normal saline solution. The dose of morphine used is 0.1 mg/kg repeated every 3 to 5 minutes until the maximum prescribed dose has been achieved (15 mg) or until a 50% decrease of initial VAS is achieved. Tramadol was also administrated in subcutaneous injection at the dose of 100 mg/2 mL if VAS is between 51 and 69. Patients having a VAS score between 30 and 50 were given paracetamol or a non–steroidal anti-inflammatory analgesic. Paracetamol was administered intravenously at the dose of 1000 mg. As a non–steroidal anti-inflammatory analgesic, Ketoprofen was used intravenously at the dose of 100 mg. Conscious level, blood pressure, heart rate, respiratory rate, and oxygen saturation were monitored every 30 minutes until their ED discharge.
All individual parameters were recorded on the case report form at admission. The study was conducted in accordance with the guidelines of the declaration of Helsinki and the Ethics committee of each participating institution approved the protocol. This trial is registered at clinical trial.gov (NCT03233035). All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
The primary outcome is the need for opioids during ED stay. Secondary outcome included the requirement of nonopioid analgesics agents and the percentage of patients discharged from the ED with VAS<30. A combined outcome score including the 3 outcome items was constructed. Each item was defined by 0 or 1 according to its occurrence or not ranging from 0 to 3.
- Need for opioid (yes=1/no=0).
- Need for nonopioid analgesics (yes=1/no=0).
- VAS at discharge >30 mm (yes=1/ no=0).
Qualitative data were presented as number (%). Comparisons were made among qualitative variables using the Pearson χ2 test.
For quantitative variables, normality was assessed with the Kolmogorov-Smirnov test. Continuous variables were expressed, as appropriate, by mean±SD or by median and interquartile range. All continuous data were sufficiently normally distributed so a comparison between the 2 groups was examined using the T test for independent groups. A P value <0.05 was considered to be statistically significant. If we assume that almost 25% of patients with acute pain should receive morphine in the ED and using an alpha value of 0.05, a sample of 450 patients per study group will have 90% power to detect an absolute10% decrease in the use of these analgesic agents. The sample size was increased by 10% to cover randomized but lost-to-follow patients, that is, 500 patients per study group and a total sample of 1000 patients was needed. Analysis of the results was on the basis of the intention to treat principle. The results obtained in this study were recorded and analyzed by SPSS computer software (English version 21).
A total of 1102 patients were randomized: 550 in the placebo group and 552 in the intranasal ketamine group (Fig. 1). The mean age of our study population was 37.2±12 years with extremes ranging from 18 to 80 years. Our study population comprised 633 men (57.4%). The majority of patients (78.3%) were under 50 years of age and (86.5%) with no previous medical history. Treatment arms were well balanced in terms of age, sex, and baseline admission vital signs between the 2 groups (Table 1).
The mean VAS at triage was 73.9±11.1 for the placebo group and 73.6±11 for the intranasal ketamine group (P=0.63) (Table 1). The mean VAS course from baseline over time in intranasal ketamine and placebo groups is shown in Figure 2. The VAS decrease at 30-minute post-triage and at ED discharge in the 2 groups is shown in Figure 3. The mean VAS decrease was greater and statistically significant in the intranasal ketamine group compared with the placebo group at 30 minutes post-triage (P=0.006) and at discharge (P<0.001) (Fig. 3). Eighty percent of patients in the intranasal ketamine group were discharged with a VAS <30, compared with 68% in the placebo group (P<0.001).
Need for Opioids
The need for opioids was significantly lower in the intranasal ketamine group compared with the placebo group (17.2% vs. 26.5%, P<0.001) (Fig. 4). The requirement for morphine was observed in 20 patients (3.6%) in the intranasal ketamine group compared with 29 patients (5.3%) in the placebo group (P=0.18). The total morphine dose was lower in the intranasal ketamine group (6.9 mg, SD=1.4) compared with placebo (8.1 mg, SD=0.9), P=0.03.
Need for Nonopioid Analgesics
The requirement for nonopioid analgesics was observed in 172 patients (31.1%) in the intranasal ketamine group compared with 218 patients (39.6%) in the placebo group (P=0.003) (Fig. 4).
Combined Outcome Score
The mean combined outcome score was 0.97 in the placebo group and 0.67 in the intranasal ketamine group (P<0.001).
There were significantly more side effects in the intranasal ketamine group (Table 2). Dizziness, nausea, and disorientation were the most reported side effects in 2 groups. Dizziness occurred in 115 patients (20.8%) in the intranasal ketamine group and in 70 patients (12.7%) in the placebo group (P<0.001). Disorientation was more frequent in the intranasal ketamine group (7.8% vs. 0.9; P<0.001) (Table 2).
The main results of the present study are that intranasal ketamine given in the triage area was followed by greater pain relief and a significant decrease in the use of rescue opioids.
Acute pain is one of the most common causes of ED presentations with up to 78% of visits including pain as a presenting complaint.4 Despite the wide therapeutic choices available for acute pain control in the ED, oligoanalgesia is still common. Morphine and opioid derivatives such as tramadol usually provide rapid and effective analgesia in severe acute pain.15 However, adverse effects sometimes occur and may require discontinuation of treatment before sufficient pain relief is obtained.16 In addition, there are growing concerns about opioid abuse and misuse in the ED.10,11 Many recent recommendations proposed guidelines to decrease opioid use in ED patients17,18 including the combination of nonopioid analgesics to provide a morphine-sparing effect and decrease toxicity. This concept was the basis of multimodal analgesia.19 Ketamine might be one such an opioid-sparing agent with the possibility to use it intranasally. Ketamine is commonly used for dissociative anesthesia and procedural sedation.20,21 In subdissociative doses, it is a potent analgesic20,22 and can be used as adjunctive analgesia with opioids or when opioids are contraindicated.22,23 There is still debate regarding the place of the use of ketamine in the prehospital setting and in the ED. Eight randomized controlled trials, systematic reviews, meta-analysis, and observational studies from 2007 to 2015 analyzed by Motov et al24 support the effectiveness and safety of the use of ketamine in the ED despite its higher rates of minor adverse side effects. More recently, Jonkman et al25 concluded in their review that ketamine can reduce opioid consumption in postoperative pain but its efficacy for acute pain in ED is limited. Although available data are limited concerning the use of intranasal ketamine, this route of ketamine administration could be attractive for pain management because it is rapid, safe, and efficient especially in overcrowded EDs. It was demonstrated that intranasal ketamine is effective and safe for analgesia in burn dressing,26 in postsurgical pain,27 and in pediatric laceration repair.28 Yeaman et al29 found that intranasal ketamine at a dose of 1 mg/kg was moderately effective in providing pain relief as a single agent to adult patients presenting to the ED with severe pain. Andolfatto et al30 found that intranasal ketamine reduced VAS pain scores to a clinically significant degree in 88% of ED patients. In a more recent study conducted by the same authors comparing intranasal ketamine with intranasal placebo added to inhaled nitrous oxide, it was demonstrated that 76% of patients receiving intranasal ketamine patients versus 41% of patients receiving placebo reported a significant reduction of pain at 30 minutes (difference 35%; 95% confidence interval 17% to 51%).31 Our results are consistent with these data as 80% of patients in the intranasal ketamine group were discharged with a VAS <30. Importantly, intranasal ketamine has been compared with opioids and it was demonstrated that it performed equally.32,33
Our study has some limitations. First, the exclusive inclusion of patients with limb trauma. We wonder if the results can be extrapolated to other types of pain. Second, the follow-up was performed during the first 2 hours, whereas the half-life of ketamine is 2 to 3 hours. It is possible that the ketamine effect would be more prolonged and this would underestimate the intensity of ketamine analgesia. Third, our study demonstrated that the ketamine opioid-sparing effect was predominantly related to tramadol use and not to morphine. This result could perhaps be explained by the relatively small doses of ketamine used in this study. In most of the previous studies assessing intranasal ketamine, the usual doses were higher, around 1 mg/kg. Finally, it was stated that intranasal administration is prone to addictive behavior because of the rapid increase in brain concentrations. However, there are very limited data regarding this special issue and although there were more side effects with intranasal ketamine in our study, it was well tolerated.
The main results that emerge from our study are that intranasal ketamine was effective, safe, and reduced opioid requirements in patients with moderate to severe limb trauma pain.
The authors acknowledge all Research Laboratory LR12SP18 University of Monastir members who contributed greatly to this study.
1. Motov SM, Khan AN. Problems and barriers of pain management in the emergency department: are we ever going to get better? J Pain Res. 2008;2:5–11.
2. Rupp T, Delaney KA. Inadequate analgesia in emergency medicine. Ann Emerg Med. 2004;43:494–503.
3. Decosterd I, Hugli O, Tamchès E, et al. Oligoanalgesia in the emergency department: short-term beneficial effects of an education program on acute pain
. Ann Emerg Med. 2007;50:462–471.
4. Todd KH, Ducharme J, Choiniere M, et al. Pain in the emergency department: results of the pain and emergency medicine initiative (PEMI) multicenter study. J Pain. 2007;8:460–466.
5. Cinar O, Jay L, Fosnocht D, et al. Longitudinal trends in the treatment of abdominal pain in an academic emergency department. J Emerg Med. 2013;45:324–331.
6. Vazirani J, Knott JC. Mandatory pain scoring at triage reduces time to analgesia. Ann Emerg Med. 2012;59:134.e2–138.e2.
7. Guru V, Dubinsky I. The patient vs. caregiver perception of acute pain
in the emergency department. J Emerg Med. 2000;18:7–12.
8. Shill J, Taylor DM, Ngui B, et al. Factors associated with high levels of patient satisfaction with pain management. Acad Emerg Med. 2012;19:1212–1215.
9. Mitchell B. Quality improvement guidelines for the treatment of acute pain
and cancer pain. American Pain Society Quality of Care Committee. JAMA. 1995;274:1874–1880.
10. Manchikanti L, Singh A. Therapeutic opioids: a ten-year perspective on the complexities and complications of the escalating use, abuse, and nonmedical use of opioids. Pain Physician. 2008;11(2 suppl):S63–S88.
11. Pletcher MJ, Kertesz SG, Kohn MA, et al. Trends in opioid
prescribing by race/ethnicity for patients seeking care in US emergency departments. JAMA. 2008;299:70–78.
12. Alexander GC, Kruszewski SP, Webster DW. Rethinking opioid
prescribing to protect patient safety and public health. JAMA. 2012;308:1865–1866.
13. Butti L, Bierti O, Lanfrit R, et al. Evaluation of the effectiveness and efficiency of the triage emergency department nursing protocol for the management of pain. J Pain Res. 2016;10:2479–2488.
14. Fosnocht DE, Swanson ER. Use of a triage pain protocol in the ED. Am J Emerg Med. 2007;25:791–793.
15. Galinski M, Ruscev M, Pommerie F, et al. National survey of emergency management of acute pain
in prehospital setting. Ann Fr Anesth Reanim. 2004;23:1149–1154.
16. Paqueron X, Lumbroso A, Mergoni P, et al. Is morphine-induced sedation synonymous with analgesia during intravenous morphine titration? Br J Anaesth. 2002;89:697–701.
17. Sun BC, Lupulescu-Mann N, Charlesworth CJ, et al. Impact of hospital “best practice” mandates on prescription opioid
dispensing after an emergency department visit. Acad Emerg Med. 2017;24:905–913.
18. Weiner SG, Baker O, Poon SJ, et al. The effect of opioid
prescribing guidelines on prescriptions by emergency physicians in Ohio. Ann Emerg Med. 2017;70:799.e1–808.e1.
19. Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg
20. Craven R. Ketamine. Anaesthesia. 2007;62(suppl 1):48–53.
21. Kost S, Roy A. Procedural sedation and analgesia in the pediatric emergency department: a review of sedative pharmacology. Clin Pediatr Emerg Med. 2010;11:233–243.
22. Quibell R, Prommer EE, Mihalyo M, et al. Ketamine*. J Pain Symptom Manage
23. Richards JR, Rockford RE. Low-dose ketamine analgesia: patient and physician experience in the ED. Am J Emerg Med. 2013;31:390–394.
24. Motov S, Rosenbaum S, Vilke GM, et al. Is there a role for intravenous subdissociative-dose ketamine administered as an adjunct to opioids or as a single agent for acute pain
management in the emergency department? J Emerg Med
25. Jonkman K, Dahan A, van de Donk T, et al. Ketamine for pain. F1000Res. 2017;6:1711.
26. Kulbe J. The use of ketamine nasal spray for short-term analgesia. Home Healthc Nurse. 1998;16:367–370.
27. Christensen K, Rogers E, Green GA, et al. Safety and efficacy of intranasal ketamine
for acute postoperative pain. Acute Pain
28. Tsze DS, Steele DW, Machan JT, et al. Intranasal ketamine
for procedural sedation in pediatric laceration repair: a preliminary report. Pediatr Emerg Care. 2012;28:767–770.
29. Yeaman F, Meek R, Egerton-Warburton D, et al. Sub-dissociative-dose intranasal ketamine
for moderate to severe pain in adult emergency department patients. Emerg Med Australas. 2014;26:237–242.
30. Andolfatto G, Willman E, Joo D, et al. Intranasal ketamine
for analgesia in the emergency department: a prospective observational series. Acad Emerg Med. 2013;20:1050–1054.
31. Andolfatto G, Innes K, Dick W, et al. Prehospital Analgesia With Intranasal Ketamine
(PAIN-K): a randomized double-blind trial in adults. Ann Emerg Med. 2019;74:1–10.
32. Farnia MR, Jalali A, Vahidi E, et al. Comparison of intranasal ketamine
versus IV morphine in reducing pain in patients with renal colic. Am J Emerg Med. 2017;35:434–437.
33. Shimonovich S, Gigi R, Shapira A, et al. Intranasal ketamine
for acute traumatic pain in the emergency department: a prospective, randomized clinical trial of efficacy and safety. BMC Emerg Med. 2016;16:43.