Low Dose Ketamine Infusion for Analgesia in the Emergency Department (ED) to Reduce Side Effects: A Double Blind, Double Dummy Randomized Controlled Trial
Phase: PHASE4
Conditions: Pain, Acute, Dissociation
Sponsor: Summa Health System

Ketamine 30 min vs 15 min
Version: 7 
Date: 06.06.2024 
Page 1 of 15 
 
 
 
 
Low Dose Ketamine Infusion for Analgesia in the 
Emergency Department to Reduce Side Effects 
 
Study Protocol and Analysis Plan 
 
NCT05518877 
 
June 6, 2024 
 

Ketamine 30 min vs 15 min
Version: 7 
Date: 06.06.2024 
Page 2 of 15 
 
Study Title: Low Dose Ketamine Infusion for Analgesia in the ED to Reduce Side 
Effects: A Double Blind, Double Dummy Randomized Controlled Trial 
 
 
Principle Investigator: 
PI: Michael J Pallaci, DO 
Sub-Investigator: 
Sub-I: Jay U Patel, MD 
 
Address: 
Summa Health Department of Emergency Medicine 
151 N Forge St 
Akron, OH 44304 
 
1. Purpose of Study 
 
Research has shown low dose ketamine (LDK) Intravenous push (IVP) (0.3mg/kg) to 
have equivalent pain reduction in moderate to severe acute pain in the Emergency 
Department (ED) when compared to standard of care of morphine IVP (0.1mg/kg). 
Ketamine has been shown to produce side effects in these studies, including dizziness, 
feeling of unreality and mood changes. There were no unexpected side effects or adverse 
events during this trial.1 Another study compared IVP with a slower infusion of LDK and 
showed a decrease in side effects while maintaining similar analgesic efficacy. This trial 
found increased feelings of unreality for the IVP group (difference of 37.5%) as well as 
increased rates of sedation.2 
 
In clinical practice, increasing the time/duration of the infusion has resulted in a decrease 
of reported side effects from patients while still maintaining analgesia. There have been 
no studies done to prove that there is a further reduction in side effects with a longer LDK 
infusion. We believe that increasing the infusion time to greater than 15 minutes will 
reduce the frequency and intensity of expected side effects of ketamine felt by recipients 
and allow for further use of ketamine as a non-opiate analgesic in the ED. 
 
Overall aims of project: 
 
 
1. Reduce overall incidence and severity of known side effects of low dose ketamine 
when given over 30 minutes versus 15 minutes. 
2. Maintain adequate pain control, as determined by a Visual Analogue Score (VAS) 
of ≤5 cm (50mm) at 30 minutes after start of ketamine infusion. 

Ketamine 30 min vs 15 min
Version: 7 
Date: 06.06.2024 
Page 3 of 15 
 
 
Hypothesis: Slow infusion of LDK over 30 minutes will provide adequate pain control (as 
defined by VAS score of ≤5 cm (50mm)), and reduce incidence and severity (by at least 
20% or 1 point on Side Effects Rating Scale for Dissociative Anesthetics [SERSDA] scale) 
of known side effects when compared to LDK given over 15 minutes in moderate to severe 
acute pain for patients presenting to the ED. 
 
2. Background and Rationale 
 
Ketamine is a phencyclidine derivative and functions as an antagonist of N-methyl-D- 
aspartate receptor (NMDA).3 Painful stimuli activate nociceptive neurons triggering the 
release of glutamate, which attach to NMDA receptors in the dorsal horn of the spinal 
cord.4 This triggers a cascade responsible for central sensitization and secondary 
hyperalgesia, also known as the “wind-up” phenomenon, making pain relief harder to 
achieve 3,4. NMDA receptors are also known to be involved in the development of opioid 
tolerance.4 
 
Ketamine is FDA approved for anesthesia and procedural sedation but is known to have 
a long history of off label uses such as analgesia and treatment of depression. While the 
medication is not FDA approved for analgesia, it is not restricted for sole use as an 
anesthetic agent. It is generally accepted that off-label use of medications is acceptable 
at the sole discretion of the provider. Off-label use has spurred increase in research and 
has even led to FDA approval in the past, notably for intranasal esketamine for treatment- 
resistant depression in 2019.5 Many of the following articles show that ketamine can be 
used as a safe alternative for analgesia in the hospital setting, notably the Emergency 
Department. 
 
Ketamine at low (sub-dissociative) doses of 0.1-0.3mg/kg, has been shown to improve 
pain scores as well as reduce perioperative opioid consumption with minimal side effects.4 
At these sub-dissociative doses, it has produced hemodynamically stable anesthesia and 
analgesia with minimal measurable cardiovascular, respiratory, or gastrointestinal side 
effects.3,4 
 
In 2015, a prospective, randomized double blind trial compared low dose ketamine to 
morphine for analgesia and showed promising results. Patients received either 0.3mg/kg 
of ketamine or 0.1mg/kg of morphine for acute moderate to severe pain to study efficacy 
and safety profile. Similar rates of reduction in pain were found in both groups at all time 
points. The ketamine group had more reported side effects including dizziness, 
disorientation, mood changes and nausea at the five-minute mark (73% vs 51%) and at 

Ketamine 30 min vs 15 min
Version: 7 
Date: 06.06.2024 
Page 4 of 15 
 
the fifteen-minute mark (69% vs 31%) but they equalized with the morphine group at the 
thirty-minute mark (36% vs 33%).1 
 
Based on mentioned data, we hypothesized that increasing time for low dose ketamine 
infusion when used in the ED for analgesia will reduce side effects even further than what 
prior studies have shown. There are several research papers that support our hypothesis. 
 
A prospective double-blind trial of 40 patients was conducted for acute musculoskeletal 
trauma pain with treatment groups receiving either intermittent morphine (0.1mg/kg every 
4 hours IV) or continuous infusion of subcutaneous ketamine (0.1mg/kg/hr) after an initial 
bolus (0.25mg/kg). Pain was measured on a 10-point visual analog scale (VAS), along 
with 4-point sedation score and objective vital signs. There was statistically significant 
improvement in pain for the ketamine group starting at fifteen minutes which continued to 
the 24-hour mark. No significant changes in hemodynamics were observed. Two patients 
in the ketamine group, compared to zero in the morphine group, reported dreams as a 
side effect after bolus doses. There were significantly higher rates of nausea and vomiting 
in the morphine group (7 vs 0, p<0.01).6 
 
A prospective study with 38 patients was conducted to describe the analgesic efficacy 
and side effect profile of low dose ketamine for acute severe pain in the emergency 
department (ED). The study trialed a bolus of ketamine (15mg) as intravenous push (IVP) 
followed by slow infusion (20mg) over 60 min. Patients were offered morphine 4mg as 
rescue analgesia at the 20-, 40-, and 60-minute marks. Pain was assessed on a 10-point 
verbal numerical reading scale (NRS), along with vital signs and sedation scores 
frequently over 120 minutes. At the 60-minute mark, side effect rating scale for 
dissociative anesthesia (SERSDA) scale was used to assess side effects. Twenty-two 
patients had clinically significant reduction in pain at 10 minutes. Twenty-five patients had 
clinically significant reduction at the end of the infusion (60 minutes). Twelve patients did 
not require or refused adjunct morphine therapy, as pain was adequately controlled 
throughout the duration of the study. There was a significant proportion of patients that 
experienced side effects (33 patients, 86%) with a large portion grading them as weak or 
modest (20 patients, 53%). Thirteen patients (34%) reported side effects as “very 
bothersome”. The most common side effects were dizziness, fatigue, nausea and feeling 
of unreality. A large portion of patients (32 patients, 84%) reported they would trial 
ketamine again for pain management.7 
 
A case series looked at 14 patients in an urban ED who received low dose ketamine (0.2- 
0.4mg/kg) infusions (10-15min) for analgesia. Thirteen patients had received analgesia 
prior to the ketamine infusion. No patient received rescue analgesia one hour post 

Ketamine 30 min vs 15 min
Version: 7 
Date: 06.06.2024 
Page 5 of 15 
 
infusion. There were no dangerous adverse effects noted. One patient reported tinnitus 
and uneasiness during the infusion while another reported dizziness.8 
 
A recent study conducted in 2017 aimed to show reduction in side effects of LDK by giving 
it over 15 minutes compared to standard IVP of less than 5 minutes. A total of 48 patients 
were enrolled and the study showed similar rates of side effects except for overall feeling 
of unreality, which was significantly higher in IVP group (91.7% vs 54.2%, p=0.008). There 
were similar decreases in pain scores for each group (p=0.14) with no significant 
difference in use of rescue analgesia or change in vital signs.2 
 
Another study published in 2018 mimicked the previously mentioned trial comparing LDK 
(0.3mg/kg) IVP (over one minute) and slow infusion (SI) over fifteen minutes, with a 
primary outcome of decreasing side effects. There were 59 participants that completed 
the study with a large reduction in psych perceptual side effects noted in SI group (43.4% 
vs 75.9%). There were also more participants that experienced hallucinations in the IVP 
group (8 vs 2). There was no difference in analgesic efficacy between the groups.9 
 
Trials have shown that ketamine can be used as an adjunct to traditional analgesics with 
significant opioid sparing effects while maintaining, or even improving, analgesia. 
 
A double blind, randomized, placebo trial was conducted with three groups in 2014. The 
three groups were morphine plus placebo (MP), morphine plus 0.15mg/kg ketamine 
(MK15), and morphine plus 0.3mg/kg ketamine (MK3). The purpose of this trial was to 
assess pain control with less opioid requirement. The study found that all groups had 
clinically meaningful decreases in overall pain scores. In both ketamine groups, there was 
a sustained decrease in pain score over two hours. While there were no vital sign 
abnormalities, there was a higher proportion of patients in the ketamine group that 
reported side effects, such as dizziness or lightheadedness.10 
 
A prospective pre-hospital cohort study in 2009 compared morphine 0.2mg/kg (M) to 
morphine 0.1mg/kg plus ketamine 0.2mg/kg (MK) in respect to pain, nausea, sedation, 
and hemodynamics for acute bone fractures. There was a decrease in morphine quantity 
used when combined with ketamine (13.5 ± 3.2mg vs 7.0 ± 1.5mg). The mean ketamine 
dose was 27.9 ± 11.4 mg. Significant changes in pain on numeric rating scale were 
reported in favor of MK (3.1 vs 5.4) along with elevations in BP (167 vs 134). Side 
effects/adverse effects noted include nausea (4 patients vs 1) and vomiting in MK group 
(3 patients vs 0).11 
 
Based on the information from prior studies, ketamine has been proven to be a potent 
analgesic even when compared to standard of care morphine. The downside to ketamine 

Ketamine 30 min vs 15 min
Version: 7 
Date: 06.06.2024 
Page 6 of 15 
 
use seems to be due to the side effect profile that is bothersome to some patients. A 
previous study already showed improvement in side effects, mainly dizziness, when given 
over a longer period of time (15 minutes). We are hypothesizing that further increasing 
the administration duration will produce even less side effects while maintaining analgesic 
properties. 
 
Literature reviews have been done that elaborate on the common side effects of ketamine 
when given for analgesia. One noted most common events to be nausea, altered mood, 
psychomimetic effects and headaches when given intravenously for complex regional 
pain.12 Another article noted that there seemed to be psychomimetic effects along with 
hypertension when given for pain control via intravenous infusion, although appeared to 
improve after infusion was complete.13 Similar side effect profile in terms of 
psychomimetic effects has been seen in other studies and include dizziness, blurred 
vision, vertigo, nausea/vomiting, dysphasia, nystagmus, nightmares or vivid dreams, 
impaired motor function and memory deficit but like other studies, improves rapidly after 
infusion is complete. Cardiovascular effects secondary to the catecholamine release after 
administration have also been documented. The main effects appear to be tachycardia, 
hypertension and increase in cardiac output and recommend use of cardiac monitoring 
but do not seem to be long lasting effects.14 
 
This study has been determined to be exempt from FDA IND requirements based on all 
criteria for exemption being met. 
 
3. Study Design 
 
The location of this study will be the Akron City Hospital Emergency Department. The trial 
will enroll approximately 48 evaluable subjects. An evaluable subject is defined as a 
subject who completes the entire infusion (30 minutes) and provides a 30 minute VAS 
and SERSDA score.  
 
This will be an intent to treat prospective, double blind, double-dummy, randomized trial. 
The primary outcome will be a comparison of side effects of sub dissociative dose 
ketamine given by slow IV infusion over 15 minutes vs 30 minutes in treatment of 
moderate to severe acute pain in ED patients. The secondary outcome will be adequate 
pain control (VAS ≤5 cm(50mm)) and need for rescue analgesia between the two groups. 
 
The control group will receive slow IV infusion of ketamine over 15 minutes. The 
experimental group will receive slow IV infusion of ketamine over 30 minutes. 
 
If the patient meets all eligibility criteria, they will be consented by study staff members 
and then randomized to receive ketamine 0.25mg/kg in 100cc normal saline (NS), up to a 

Ketamine 30 min vs 15 min
Version: 7 
Date: 06.06.2024 
Page 7 of 15 
 
maximum of 30mg total dose, as an IV infusion over the specified time, as well as 
“placebo” 100cc NS over the other time slot. 
 
If during the baseline assessment, immediately prior to the start of infusion, the subject 
reports an improved pain score (VAS < 5 cm(50mm)), the subject will be considered no 
longer eligible. The infusion will not be administered, and the subject will be removed from 
the study. 
Since the subject was randomized, the group allocation (control or experimental group) for that 
subject will be reassigned to the randomization block to maintain a total of 48 enrolled (infused) 
subjects. 
 
Pharmacy staff will provide the study medication in a blinded fashion to the nurse who will 
use infusion pumps to deliver both study medication and placebo simultaneously. Nursing 
staff will receive training on administration of the study medication prior to starting the 
study. 
 
We will measure the side effect profile using the Side Effects Rating Scale for Dissociative 
Anesthetics (SERSDA) along with the Visual Analog Scale (VAS) (Appendix A). 
 
Visual Analogue Scale scoring is done by asking the subject to mark the spot on the VAS 
Pain Assessment Tool (0-10cm) to indicate their perception of pain. Following this, the 
investigator scores the intensity of pain according to the 0-100mm corresponding scale 
(one instrument i.e., 5cm= 50mm). The VAS is a validated, subjective measure for acute 
and chronic pain. See below for exact tool that will be used. 
 
Vital signs (heart rate, blood pressure, respiratory rate, and oxygen saturation) will also 
be obtained at 0, 5, 15, 30, 60, and 90 minutes from the start of the ketamine/NS 
placebo infusion. 

Ketamine 30 min vs 15 min
Version: 7 
Date: 06.06.2024 
Page 8 of 15 
 
Rescue Medication 
 
At 30, 60 or 90 minutes post start of the ketamine infusion, if the study subject has a VAS 
score that is between 5-10cm (50-100mm), a single dose of both acetaminophen 
1,000mg (oral) and ketorolac (15-30mg IV) will be given. If alternative medications are 
required, the study investigator will be consulted. 
 
NOTE: EPIC recommends a ketorolac dose of 15mg IV if subject weight is less than 50kg 
or subject age is ≥65 years. 
 
At 30 minutes post start of ketamine infusion, if the study subject has a VAS score that is 
between 8-10cm (80-100mm), fentanyl will be administered at 1mcg/kg up to 100mcg. 
(The dose will be calculated by EPIC to correspond to the nearest 0.05cc). If deemed safe 
and appropriate, the EPIC alert for doses greater than 100mcg may be overridden by the 
treating physician or study investigator to authorize doses greater than 100mcg (per 
institutional policy). 
 
If the VAS score remains 8-10cm (80-100mm)) when assessed at 60 and 90 minutes post 
start of the ketamine infusion, the fentanyl dosing may be repeated. 
 
NOTE: If the VAS score is assessed to be between 8-10cm (80-100mm) at any time point, 
and ketorolac and acetaminophen have not already been administered, ketorolac, 
acetaminophen and fentanyl may be given at the same time point. 
 
NOTE: Ketorolac and acetaminophen may only be administered once during the study. 
 
Study Termination 
 
If rescue medication is administered, the patient will continue in the study and all data will 
be collected as outlined in the protocol as ITT (intent to treat). 
 
If the subject experiences side effects which are unable to be managed in order to permit 
the continuation of the ketamine infusion, it will be stopped. All data will continue to be 
collected according to the protocol and the subject will continue to be observed for the 
remainder of the 90-minute study period, unless the subject withdraws their consent to 
participate. 
3.1 Subject Population 
Inclusion and Exclusion Criteria 

Ketamine 30 min vs 15 min
Version: 7 
Date: 06.06.2024 
Page 9 of 15 
 
Inclusion criteria: 
 Patients 18 years of age or older 
 Primary complaint of acute moderate to severe pain on VAS/numeric pain scale (a 
score of ≥5cm which corresponds to 50mm). 
 Pain described as abdominal, flank, back, musculoskeletal, or traumatic chest pain 
 Must be alert and oriented times three 
 Able to provide informed consent. 
 
 
Exclusion criteria: 
 
 Pregnant 
 Breastfeeding 
 Altered mental status 
 Known or reported allergy, hypersensitivity, or intolerance to ketamine 
 Unstable vital signs (systolic blood pressure <80 or >180mmHg, heart rate <50 or 
>150 beats per minute, and respiratory rate <10 or >30 breaths per minute) 
 History of unstable heart disease, such as arrhythmias, congestive heart failure, or 
coronary heart disease. 
 History of untreated or uncontrolled thyroid disease 
 Acute head or eye injury 
 Active or current abuse of alcohol or illicit drugs 
 Known intracranial hypertension 
 Hepatic or renal insufficiency 
 Current active manic phase of bipolar disorder 
 Active delusions, hallucinations, or schizophrenia 
 Patients who have recent fentanyl use within 60 minutes or other analgesic use 
(opiates) within 4 hours of study enrollment (signing of consent) 
 Patients who have enrolled in the study during a previous ED encounter 
 Chronic use of opiates (i.e.: fentanyl patch, SR opiates) 
 
 
It will be at the discretion of the treating ED physician who is taking care of the patient to 
determine whether the patient is appropriate for the study. If it is determined the patient 
requires a more urgent form of pain control intervention, the patient will be excluded. 
 
3.2 Study Intervention 
 
Once consented , participants will be randomized to receive 0.25mg/kg (up to a maximum 

Ketamine 30 min vs 15 min
Version: 7 
Date: 06.06.2024 
Page 10 of 15 
 
of 30mg) intravenous ketamine mixed with 100cc normal saline (NS) either over: (1) 15- 
minute slow infusion (SI) or (2) 30-minute slow infusion. 
 
Each group will receive corresponding placebo of 100cc NS for double dummy design. 
 
The group receiving ketamine over 15-minute SI, will also receive 100cc NS over 30 
minutes and the group receiving ketamine over 30 min SI will also receive 100cc NS over 
15 min. Ketamine/NS placebo infusions will be delivered via infusion pump. The two 
infusions are to be given simultaneously so that time zero (0) is the same for both 
infusions. 
 
Ketamine/NS placebo will be prepared and blinded by pharmacy staff and be 
administered in a blinded fashion by an ED or Research RN. For the purposes of this 
study a subject will be considered enrolled once they have received any portion of the 
investigational product. 
 
Patients may not be enrolled in the study more than one time. They may not be re-enrolled 
if they present to the ED with acute pain a subsequent time. This is to prevent any bias 
from forming in the data analysis secondary to the side effect profile of the drug as well 
as the potential psychotropic effect the drug may have. 
 
3.3 Outcomes/Objectives 
 
The primary objective of this study is to attempt to prove that increasing the length of 
ketamine administration decreases overall incidence and severity of side effects. The side 
effects to be monitored include fatigue, dizziness, headache, feeling of unreality, hearing, 
vision, or mood changes, generalized discomfort, and hallucinations. Our goal is to have 
at least a 20% decrease in overall scores, which equals to a “1” point decrease on the 
SERSDA scale. SERSDA measures severity of nine adverse effects based on a 5-point 
scale from “0” (no adverse effect) to “4” (very bothersome effect). 
 
The primary outcome measure of this study is the reduction of the overall side effects as 
measured by the Side Effect Rating Scale for Dissociative Anesthetics (SERSDA) at 30 
minutes. 
 
The secondary objective is to ensure that adequate pain control (VAS ≤5 cm) is 
maintained when ketamine administration is prolonged. To do this we will be measuring 
pain scores on the 100mm VAS at each protocol specified interval (0, 5, 15, 30, 60 and 
90 minutes from the infusion start time, which is defined as time zero). Studies have 
shown that for clinical significance in pain reduction, there needs to be at least a 13mm 
difference on the 100mm VAS pain scale.15 
 

Ketamine 30 min vs 15 min
Version: 7 
Date: 06.06.2024 
Page 11 of 15 
 
The secondary outcome measure is the severity of self-reported pain on the standard 
100mm VAS pain scale (0-100) at 30 minutes. 
The need to administer rescue analgesic medication will also be assessed, starting at 30 
minutes and again at 60 and 90 minutes post start of the infusion (Time 0). 
We will also be monitoring the need for the administration of other interventions to treat 
ketamine side effects (nausea etc.), as well as vital signs. 
 
The Richmond Agitation Sedation Scale (RASS) (Appendix A) will be used to collect 
additional data. 
 
Study Schedule 
 
 
Time 0 min Time 5 min Time 15 
min 
Time 30 
min 
Time 60 
min 
Time 90 
min 
VITAL 
SIGNS 
X 
X 
X 
X 
X 
X 
SERSDA 
 
X 
X 
X 
X 
X 
VAS 
X 
X 
X 
X 
X 
X 
RASS 
 
X 
 
X 
 
X 
 
 
4. Data Analysis/Plan 
 
The sample size of n=24 in each study arm (n=48 overall) was determined to detect a 
clinically significant median change of one unit in the primary outcome and SERDSA 
scale, for measuring adverse events. This determination assumes the same standard 
deviation of 1.2 units with 80% power assuming a two-sided alpha type I error rate of 5% 
used previously to adequately power the Motov study2 which was based on the estimated 
standard deviation from the Andolfatto16 study. We will enroll stratified by gender 
(male/female) to ensure equality between the two study groups. 
 
Separate sealed envelopes will be provided to the pharmacist containing the 
randomization assignment to allow for more comparability between study arms. Each 
sealed envelope will be identified by gender and patient enrollment number, e.g., ‘Male 
01’, and contain an assignment to either study arm within the envelope. Envelopes for 
randomized subjects will be stored in the investigational pharmacy. A secondary copy of 
the randomization assignments will be managed on a secure research shared drive within 
the Clinical Research Center. Access will be limited to only unblinded study staff. A 

Ketamine 30 min vs 15 min
Version: 7 
Date: 06.06.2024 
Page 12 of 15 
 
maximum enrollment for either gender will be 14 out of the 24 (58.3%) to provide a more 
balanced gender ratio which is more generalizable to the intended population. 
 
Randomized blocks of 2 and 4 units will be employed within each gender strata to allow 
for balance across the enrollment period. 
Study data will be collected via a REDCap instrument. A randomization number will be 
assigned and after baseline data is collected, observation and longitudinal data will be 
captured via a repeated measures survey in REDCap. Time points captured will be 
baseline (0min), 5min, 15min, 30min, 60min and 90min from the start of the study infusion 
which is time zero. 
 
Data from this double-blind, double dummy, randomized comparative study will be 
imported into SPSSv25.0 software (IBM Corp., Armonk, NY) with baseline characteristics 
summarized by treatment arm. A generalized linear model using an underlying gamma 
distribution will be employed for all ordinal data including SERDSA outcomes collected at 
time points before complete resolution to “0”. A mixed model regression will be employed 
for all continuous outcomes across time with missing data assumed to be random. 
Boxplots of outcome will also be provided at each study time point stratified by study arm. 
Additionally, the rates of adverse events will be summarized using frequencies and 
percentages and compared between study arms via Fisher’s exact or Pearson chi-square 
tests depending on cell sample size distribution. 
 
Variables collected during the study include patient demographics (age, sex, pain 
type/location), vital signs on presentation as well as during specified times (heart rate, 
blood pressure, respiratory rate, and oxygen saturation), Visual Analogue Scale (VAS) 
scores, SERSDA scores17, Richmond Agitation-Sedation Scale (RASS) and time to 
rescue analgesia. 
 
If patients withdraw from the study prior to medication administration, they will not be 
included in the final data set. If they decide to withdraw while medication is being 
administered or after the completion of the infusion, but during the follow-up period of 90 
minutes, they will be in the final data set and shown on the diagram as withdrawn. 
 
There may be CITI trained and CRC Credentialed medical students, ED residents and 
faculty members who will help with the enrollment process and data collection. 
Data for this study will be collected in REDCap. REDCap is a HIPAA compliant clinical 
electronic data capture system. All patient records entered into REDCap will have 
identifiers removed and will be given a unique study-specific code. Patient identifiers 
(patient name, DOB, MRN) with codes will be stored separately in an Excel spreadsheet 
located in a secure folder on the Summa G:/ drive, accessible only to authorized study 
personnel. Only authorized study personnel will be given access to the data collection 
sheet in REDCap. Multi-factor authentication (MFA)  security is used to access the 

Ketamine 30 min vs 15 min
Version: 7 
Date: 06.06.2024 
Page 13 of 15 
 
REDCap platform. Full audit trails are kept within REDCap. 
 
All study related data will be kept in the CRC for a minimum of 6 years after study completion, 
unless the study is published. If published, all study data should be kept for 10 years, per 
Summa policy.  
 
5. Data Safety and Monitoring 
 
Study data will be reviewed for safety and interim analysis will be completed at the 
following study subject accrual points: 3 patients, 6 patients, 12 patients, 24 patients and 
40 patients. The review committee will consist of an odd number of physicians, with a 
minimum of one physician who is not associated with the Summa Emergency 
Department. During review, if it is determined the majority of study subjects (75%) did not 
experience a clinically significant reduction in pain (which is an improvement of 13mm on 
the 100mm VAS scale) the study will be stopped. The results of each safety monitoring 
review will be summarized and submitted to the IRB. 
 
CRC staff will be responsible for collecting and communicating AE's, SAE's, UAP's, and 
protocol deviations per institutional policies. 
 
CRC staff will be responsible for data collection and data entry into REDCap. Data will be 
reviewed for accuracy and completion on a regular basis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Ketamine 30 min vs 15 min
Version: 7 
Date: 06.06.2024 
Page 14 of 15 
 
 
References: 
 
1. 
Motov S, Rockoff B, Cohen V, et al. Intravenous Subdissociative-Dose Ketamine 
Versus Morphine for Analgesia in the Emergency Department: A Randomized 
Controlled Trial. Ann Emerg Med. 2015;66(3):222-229.e1. 
doi:10.1016/j.annemergmed.2015.03.004 
2. 
Motov S, Mai M, Pushkar I, et al. A prospective randomized, double-dummy trial 
comparing IV push low dose ketamine to short infusion of low dose ketamine for 
treatment of pain in the ED. Am J Emerg Med. 2017;35(8):1095-1100. 
doi:10.1016/j.ajem.2017.03.004 
3. 
Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: A Review of 
Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain 
Therapy. Clin Pharmacokinet. 2016;55(9):1059-1077. doi:10.1007/s40262-016- 
0383-6 
4. 
Gorlin A, Rosenfeld D, Ramakrishna H. Intravenous sub-anesthetic ketamine for 
perioperative analgesia. J Anaesthesiol Clin Pharmacol. 2016;32(2):160. 
doi:10.4103/0970-9185.182085 
5. 
Kraus C, Wasserman D, Henter ID, Acevedo-Diaz E, Kadriu B, Zarate CA. The 
influence of ketamine on drug discovery in depression. Drug Discov Today. 
2019;24(10):2033-2043. doi:10.1016/j.drudis.2019.07.007 
6. 
Gurnani A, Sharma PK, Rautela RS, Bhattacharya A. Analgesia for Acute 
Musculoskeletal Trauma: Low-Dose Subcutaneous Infusion of Ketamine. Anaesth 
Intensive Care. 1996;24(1):32-36. doi:10.1177/0310057X9602400106 
7. 
Ahern TL, Herring AA, Miller S, Frazee BW. Low-Dose Ketamine Infusion for 
Emergency Department Patients with Severe Pain: Low-Dose Ketamine Infusion in 
Emergency Department. Pain Med. 2015;16(7):1402-1409. 
doi:10.1111/pme.12705 
8. 
Goltser A, Soleyman-Zomalan E, Kresch F, Motov S. Short (low-dose) ketamine 
infusion for managing acute pain in the ED: case-report series. Am J Emerg Med. 
2015;33(4):601.e5-601.e7. doi:10.1016/j.ajem.2014.09.029 
9. 
Clattenburg EJ, Hailozian C, Haro D, et al. Slow Infusion of Low‐dose Ketamine 
Reduces Bothersome Side Effects Compared to Intravenous Push: A Double‐blind, 
Double‐dummy, Randomized Controlled Trial. Miner JR, ed. Acad Emerg Med. 
2018;25(9):1048-1052. doi:10.1111/acem.13428 
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 
Department: Results of a Randomized, Double‐blind, Clinical Trial. Mycyk MB, ed. 
Acad Emerg Med. 2014;21(11):1193-1202. doi:10.1111/acem.12510 

Ketamine 30 min vs 15 min
Version: 7 
Date: 06.06.2024 
Page 15 of 15 
 
11. Johansson P, Kongstad P, Johansson A. The effect of combined treatment with 
morphine sulphate and low-dose ketamine in a prehospital setting. Scand J 
Trauma Resusc Emerg Med. 2009;17(1):61. doi:10.1186/1757-7241-17-61 
12. Allen CA, Ivester JR. Ketamine for Pain Management—Side Effects & Potential 
Adverse Events. Pain Manag Nurs. 2017;18(6):372-377. 
doi:10.1016/j.pmn.2017.05.006 
13. Azari P, Lindsay DR, Briones D, Clarke C, Buchheit T, Pyati S. Efficacy and Safety 
of Ketamine in Patients with Complex Regional Pain Syndrome: A Systematic 
Review. CNS Drugs. 2012;26(3):215-228. doi:10.2165/11595200-000000000- 
00000 
14. Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits: 
Ketamine risks and benefits. Br J Clin Pharmacol. 2014;77(2):357-367. 
doi:10.1111/bcp.12094 
15. Todd KH, Funk KG, Funk JP, Bonacci R. Clinical Significance of Reported 
Changes in Pain Severity☆☆☆★. Ann Emerg Med. 1996;27(4):485-489. 
doi:10.1016/S0196-0644(96)70238-X 
16. Andolfatto G, Willman E, Joo D, et al. Intranasal Ketamine for Analgesia in the 
Emergency Department: A Prospective Observational Series. Miner J, ed. Acad 
Emerg Med. 2013;20(10):1050-1054. doi:10.1111/acem.12229 
17. Eide PK, Stubhaug A, Øye I, Breivik H. Continuous subcutaneous administration of 
the N -methyl-D-aspartic acid (NMDA) receptor antagonist ketamine in the 
treatment of post-herpetic neuralgia. Pain. 1995;61(2):221-228. doi:10.1016/0304- 
3959(94)00182-E 

 
APPENDIX A 
 
Visual Analogue Scale (VAS) 
 
Side Effects Rating Scale for Dissociative Anesthetics (SERSDA) Scale 
 
Side Effects
Severity
Scale
Fatigue
 
0, No Change
Dizziness
 
1, Weak
Headache
 
2, Modest
Feeling of 
Unreality 
 
3, Bothersome
Change in Hearing  
4, Very 
Bothersome 
Change in Vision
 
 
Mood Change
 
 
Generalized 
Discomfort 
 
 
Hallucination
 
 
 
 
The Richmond Agitation Sedation Scale (RASS)