Comparison of Nebulized Ketamine to Nebulized Fentanyl for Treating Acute Painful Conditions in the ED: A Prospective, Randomized, Double-Blind Clinical Trial.
Phase: PHASE4
Conditions: Pain, Acute
Sponsor: Antonios Likourezos

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TITLE: Comparison of Nebulized Ketamine to Nebulized Fentanyl for Treating Acute 
Painful Conditions in the ED: A Prospective, Randomized, Double-Blind Clinical Trial. 
(The KETAFEN Trial) 
 
 
 
 
Unique Protocol ID: 2023-08-14 
 
 
Document Date:  May 5, 2025 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 Introduction 
Ketamine is a non-competitive N-methyl-D-aspartate (NMDA)/glutamate receptor complex 
antagonist. It reduces pain by reducing central sensitization, hyperalgesia, and "wind-up" 
phenomena in the spinal cord (dorsal ganglion) and central nervous system (1). 
Ketamine administration in sub-dissociative doses (SDK) of 0.1–0.3 mg/kg in pre-hospital 
settings and in the Emergency Department (ED) results in effective pain relief in patients with 
acute traumatic and non-traumatic pain, chronic non-cancer and cancer pain, and in patients with 
opioid-tolerant pain. Two commonly utilized routes of SDK administration in the ED include an 
intravenous (IV) route (intravenous push dose or short infusion) and an intranasal (IN) route (2-
11). 
Fentanyl is a synthetic opioid derivative that is a potent agonist at the µ-opioid receptor. (12) It is 
widely used in anesthesia and for acute and chronic pain management (13, 14). Fentanyl has a 
rapid onset and a relatively short duration of action. It is primarily given by the IV route but can 
also be given transdermally, sublingually, intranasally, intrathecally, and by inhalation. 
(15)  Intranasal fentanyl has been studied as a noninvasive method of fentanyl administration for 
quick pain relief; however, the maximum volume of fluid that can be administered via the 
intranasal route limits the dose of fentanyl that can be administered at a time, resulting in the 
need to administer repeated doses of fentanyl to achieve a therapeutic end point. (16) A 
systematic review of seven randomized clinical trials assessing the analgesic efficacy and safety 
of inhaled (nebulized) fentanyl at a dose of 2-4 mcg/kg in ED patients with moderate to severe 
pain demonstrated that nebulized fentanyl is as effective as IV opioids in the treatment of acute 
pain with relatively few adverse effects. (17) 
Background and Significance 
In situations where intravenous access is not readily available or is unobtainable and the 
intranasal route is not feasible, another non-invasive route of ketamine administration, such as 
inhalation via breath-actuated Nebulizer (BAN), is becoming a viable alternative. The BAN 
allows the controlled, patient-initiated delivery of analgesics in a measured and titratable fashion. 
(18) Ketamine has been studied as a nebulized drug in a lot of different settings and for a lot of 
different reasons, such as to treat acute pain after surgery (like a sore throat after being 
intubated), as a pre-medication for general anesthesia, to treat cancer pain, and as a therapy for 
asthmaticus (18, 19).  
Our research team has published two case series of 10 adult patients who were given nebulized 
ketamine (via BAN) for a variety of acute traumatic and non-traumatic painful conditions. The 
patients showed a 60% decrease in pain and a small number of side effects (20, 21). 
Furthermore, our group published a randomized, double-blind trial of 120 adult patients 
evaluating the analgesic efficacy and safety of nebulized ketamine at three different dosing 
regimens for acute pain in the ED (0.75 mg/kg, 1 mg/kg, and 1.5 mg/kg), showing similar 
analgesic efficacy between the three different dosing regimens for short-term (up to 120 minutes) 

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pain relief (22). Lastly, we recently completed a randomized, double-blind, double-dummy 
clinical trial comparing the analgesic efficacy and safety of nebulized ketamine and intravenous 
ketamine in managing acute pain in adult ED patients, with data currently being analyzed. 
Nebulized fentanyl given in the ED to adults with acute traumatic and non-traumatic pain 
syndromes at a dose range of 1.5–4 mcg/kg showed the same or even better pain-relieving effects 
than IV fentanyl and IV morphine alone. (23-25) 
Study Objectives 
To compare the analgesic efficacy and rates of side effects of a 0.75 mg/kg dose of ketamine 
administered via breath-actuated nebulizer (BAN) to a dose of 3 mcg/kg of fentanyl administered 
via breath-actuated nebulizer (BAN) in adult patients presenting to the ED with acute painful 
conditions. 
Hypothesis 
We hypothesized that nebulized fentanyl at 3 mcg/kg per dose would provide better analgesia at 
30 min post-medication administration in comparison to nebulized ketamine administered at 0.75 
mg/kg. The primary outcome of this trial is the comparative reduction in participants’ pain scores 
at 30 minutes post-medication administration. 
Study Design 
Subjects 
Adult patients (18 years and above) presenting to the ED with acute painful conditions such as 
traumatic and non-traumatic abdominal, flank, back, musculoskeletal pain, headache, etc. with 
an initial pain score of 5 or more on a standard 11-point (0 to 10) numeric rating scale (NRS) and 
deemed suitable for nebulized analgesia by the treating attending physician. Study investigators 
and research assistants will perform subjects’ screening and enrollment. All patients will be 
enrolled at various times of the day, when study investigators will be available for patient 
enrollment and an ED pharmacist will be available for medication preparation. 
 
Eligibility Criteria 
Adult patients (18 years and above) presenting to the ED with acute painful conditions such as 
traumatic and non-traumatic abdominal, flank, back, musculoskeletal pain, headache, etc. with a 
pain score of 5 or more on a standard 11-point (0 to 10) numeric rating scale (NRS). Patients will 
have to be awake, alert, and oriented as to person, place, and time and will have to demonstrate 
understanding of the informed consent process and content. Patients will also have to 
demonstrate the ability to verbalize the nature of any adverse effects (AE) they might experience 
as well as express their pain severity by using the NRS. 

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Exclusion Criteria 
Patients  below 18 years; patients with a painful condition warranting emergent/urgent 
intervention in the ED; patients with altered mental status allergy to ketamine or fentanyl, 
pregnant or breastfeeding, weight greater than 100 kg, patients presenting with head injury, 
unstable vital signs (systolic blood pressure <90 mmHg or >180 mmHg, pulse rate <50 beats/min 
or >150 beats/min, and respiration rate <10 breaths/min or >30 breaths/min), inability to provide 
consent, current medical history of alcohol or drug abuse, and administration of opioids or opioid 
antagonist/agonist within 4-6 hours prior to arrival and NSAIDs 6 hours prior to arrival to the 
ED. 
Design 
This is a prospective, randomized, double-blind trial comparing the analgesic efficacy and safety 
of nebulized ketamine administered at 0.75 mg/kg via BAN to nebulized fentanyl administered at 
3 mcg/kg via BAN to adult patients presenting to the ED of Maimonides Medical Center with 
acute painful conditions of moderate to severe intensity. The dosing of nebulized fentanyl at 
three mcg/kg is  based on two randomized, dose-finding clinical trials of acute pain where a one 
mcg/kg dose was compared to a 3 mcg/kg dose with resultant   analgesic superiority of the 3 
mcg/kg dose (26, 27). The dose of nebulized ketamine is based on the results of our own 
randomized clinical trial, which showed that 0.75 mg/kg of nebulized ketamine was as effective 
at relieving short-term pain in the ED as 1 mg/kg and 1.5 mg/kg. Upon meeting the eligibility 
criteria, patients will be randomized into two study groups: Nebulized KetaBAN (Ketamine via 
BAN) and Nebulized FentaBAN (Fentanyl via BAN). 
The on-duty ED pharmacist will prepare either a breath-actuated nebulizer (BAN) with 0.75 
mg/kg of ketamine or a BAN with 3 mcg/kg of fentanyl, depending on the randomization list, 
which will be made in SPSS (version 24; IBM Corp., Armonk, NY) with a block randomization 
of every 10 participants. The medication will be delivered to the treating nurse in a blinded 
fashion. The nebulization of study drugs via BAN will have a minimum time of 5 minutes and a 
maximum time of 15 minutes. If a patient requires further analgesia, a second dose of either 
Ketaban or Fentaban will be offered, or intravenous (IV) fentanyl at 0.75 mcg/kg will be 
administered as a rescue analgesia. 
In addition, study investigators will measure the residual volume of ketamine and fentanyl 
remaining in the breath-actuated nebulizer after each treatment and document the results on a 
waste sheet designed by the pharmacy staff. The pharmacist will receive this sheet and use it to 
determine the actual dose that each study participant received based on their initial 
randomization group. According to the departmental policy on the waste of controlled 
substances, a treating nurse will discard the remaining ketamine and fentanyl in the breath-
actuated nebulizer. 
Data collection procedures  
A study investigator will approach each patient for written informed consent and Health Insurance 
Portability and Accountability Act (HIPAA) authorization after the treating emergency medicine 

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physician has evaluated them and they meet the study eligibility requirements. Baseline pain score 
will be determined with an 11-point numeric rating scale (0 to 10), described to the patient as "no 
pain" being 0 and "the worst pain imaginable" being 10. A study investigator will record the 
patient’s body weight and baseline vital signs. 
Study investigators will record pain scores, vital signs, and adverse effects at 15, 30, 60, 90, and 
120 minutes. If patients report a pain numeric rating scale score of 5 or greater at any of the 
aforementioned time points and request additional pain relief, intravenous (IV) fentanyl at 0.75 
mcg/kg will be administered as a rescue analgesic. 
The ED pharmacist, research manager, and statistician will be the only ones with knowledge of 
the study arm to which each participant will be randomized. The treating providers, participants, 
and the data collection research team will be blind to the medication received. 
All data will be recorded on data collection sheets, including patients’ sex, demographics, medical 
history, vital signs, adverse events, and need for rescue medication, etc., and entered into SPSS 
(version 24.0; IBM Corp.) by the research manager. The research manager and statistician 
(Michael Silver) will work independently of any data collection to develop the randomization list, 
confirm the acquisition of written consent for all participants, and conduct statistical analyses. The 
randomization will be Bock Randomization every 10 subjects.  
Monitoring and Adverse effects 
Patients will be closely monitored for any change in vital signs and for adverse effects during the 
entire study period (up to 120 minutes) by study investigators. Common adverse effects that are 
associated with sub-dissociative dose ketamine (SDK) are feelings of unreality, dizziness, nausea, 
vomiting, and sedation. Common adverse effects that are associated with fentanyl are nausea, 
vomiting, pruritus, dizziness, somnolence, drowsiness, and respiratory depression. 
Data Analysis 
Data analyses will include frequency distributions, a paired t-test to assess a difference in pain 
scores within each group, and an independent-sample t-test to assess differences in pain scores 
between the two groups at various intervals. Mixed-model linear regression will be used to 
compare changes in the pain numeric rating scale (NRS) across all time points. This will 
compensate for participants lost to follow-up and allow all patients’ data to be analyzed on an 
intention-to-treat principle. 
For categorical outcomes (e.g., complete resolution of pain), a χ2 or Fisher’s exact test will be used 
to compare outcomes at 30 minutes. Percentage differences and 95% confidence intervals between 
the treatment groups will be calculated for all time points with P<.05 to denote statistical 

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significance. Based on the validation of a verbally administered rating scale for acute pain in the 
ED and the comparison of the verbal and visual pain scales, the primary outcome will be a 
difference of at least 1.3 between the two groups at the 30-minute pain assessment time point that 
is clinically meaningful. 28,29 
Sample Size  
Assuming a greater improvement in pain score in the fentanyl group of 1.3 points over the 
ketamine group, with a standard deviation (SD) of 3.0 in both groups, we will need to enroll 67 
patients per group (134 total) to have 80% power at an alpha = 0.0465 for a one-sided z-test. To 
account for possible missing data, the total sample size will be 150 patients (75 per group). A 
pre-planned interim data analysis will occur upon reaching a total of 60 patients (30 patients per 
group), and alpha = 0.0035 will be used to maintain overall power; this will make the overall 
alpha of the study 0.05. 
 Expected Outcomes 
The primary outcome will include a comparative reduction of pain scores on the numeric rating 
pain scale (NRS) between recipients of KetaBAN and FentaBAN at 30 minutes post-analgesic 
administration. 
The secondary outcomes will include a need for rescue analgesia and rates of adverse events 
(AE) in each group up to 120 minutes. With respect to the unique adverse effects of SDK, we 
will use the Side Effect Rating Scale for Dissociative Anesthetics (SERSDA) and the Richmond 
Agitation Sedation Scale (RASS) to assess and record such adverse effects (26, 27). Subjects will 
rate the severity of each side effect on a five-point scale, with "0" denoting the absence of any 
negative effects and "4" denoting a side effect that is extremely bothersome. The SERSDA Scale 
includes fatigue, dizziness, nausea, headaches, feelings of unreality, changes in hearing, mood 
changes, general discomfort, and hallucinations. RASS evaluates the severity of agitation and/or 
sedation in accordance with the nine-point scale, with scores ranging from "−4" (deeply sedated) 
to "0" (alert and calm) to "+4" (combative). 
 
Adverse Events 
Common Side 
Effects related to 
Ketamine: 
Dizziness, nausea, vomiting, agitation, weakness or fatigue, feelings of 
unreality, nightmares, altered mental state, increase in heart rate and blood 
pressure. 
Common Side 
effects related to 
Fentanyl: 
Nausea, vomiting, pruritus, dizziness, somnolence, drowsiness, relaxation, 
euphoria, sedation, confusion, urinary retention, pupillary constriction, and 
respiratory depression. 

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SAE Reporting 
A data and safety monitoring board (DSMB) will be established to review data upon reaching 10 
subjects in each arm and/or if there is an SAE. It will consist of: Sergey Motov, MD; Jefferson 
Drapkin, MPH; Antonios Likourezos, MA MPH; Rukhsana Hossain, MPH; George Fulton, MD. 
Within 24 hours of discovery, the research staff will report any serious adverse event that 
necessitates intervention to the IRB. Less serious adverse events will be reported within a 
week of discovery. There are known expected outcomes and side effects of the medications 
being received, and these are the same risks and side effects as the standard of care; these will be 
reported if they are serious and require intervention.  
 Table 1:   Patient Recruitment and Follow-up Assessment Flow-Chart  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total Patients Recruited 
FentaBAN 
3 mcg/kg 
Baseline Evaluation 
KetaBAN 
     0.75 mg/kg 
Baseline Evaluation 
 
Post-Intervention 
Evaluation at: 
15, 30, 60, 45, 90, and 120 
minutes 
 
 
Post-Intervention 
Evaluation at: 
15, 30, 60, 45, 90, and 120 
minutes 
 
 150 Patients 
 75 Patients 
 75 Patients 
75 Patients 
75 Patients 

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